Chlorogenic Acid Prevents Alcohol-induced Brain Damage in Neonatal Rat

PubMed Central

Guo, Zikang; Li, Jiang

2017-01-01

Abstract The present investigation evaluates the neuroprotective effect of chlorogenic acid (CA) in alcohol-induced brain damage in neonatal rats. Ethanol (12 % v/v, 5 g/kg) was administered orally in the wistar rat pups on postnatal days (PD) 7-9. Chlorogenic acid (100 and 200 mg/kg, p.o.) was administered continuously from PD 6 to 28. Cognitive function was estimated by Morris water maze (MWM) test. However, activity of acetylcholinesterase, inflammatory mediators, parameters of oxidative stress and activity of caspase-3 enzyme was estimated in the tissue homogenate of cerebral cortex and hippocampus of ethanol-exposed pups. It has been observed that treatment with CA attenuates the altered cognitive function in ethanol-exposed pups. There was a significant decrease in the activity of acetylcholinesterase in the CA treated group compared to the negative control group. However, treatment with CA significantly ameliorates the increased oxidative stress and concentration of inflammatory mediators in the brain tissues of ethanol-exposed pups. Activity of caspase-3 enzyme was also found significantly decreased in the CA treated group compared to the negative control group. The present study concludes that CA attenuates the neuronal damage induced in alcohol exposed neonatal rat by decreasing the apoptosis of neuronal cells. PMID:29318034

Animal-assisted activity and emotional status of patients with Alzheimer's disease in day care.

PubMed

Mossello, Enrico; Ridolfi, Alessandro; Mello, Anna Maria; Lorenzini, Giulia; Mugnai, Francesca; Piccini, Carolina; Barone, Domenico; Peruzzi, Anna; Masotti, Giulio; Marchionni, Niccolò

2011-08-01

Preliminary studies suggest beneficial effects of animal-assisted activities (AAA) on behavioral and psychological symptoms of dementia (BPSD), but data are inconsistent. This study aimed to assess the effect of AAA with dogs on cognition, BPSD, emotional status and motor activity in severe Alzheimer's disease (AD). Ten patients attending an Alzheimer Day Care Center (ADCC) participated in a repeated measures study, which included: two weeks' pre-intervention, three weeks' control activity with plush dogs (CA), and three weeks' AAA. Cognitive function (Severe Impairment Battery), mood (Cornell Scale for Depression in Dementia; CSDD), BPSD (Neuropsychiatric Inventory; NPI) and agitation (Cohen-Mansfield Agitation Inventory; CMAI) were assessed at baseline and after each period. Observed Emotion Rating Scale (OERS) for emotional status, Agitated Behavior Mapping Instrument (ABMI) and a checklist for motor activity were completed across the study periods, both during intervention sessions and after three hours. Cognition and NPI were unchanged across the study. Declines in the CMAI and CSDD scores after AAA were not significant, while the NPI anxiety item score decreased in comparison with CA (CA 3.1±2.3, AAA 1.5±2.7, p = 0.04). OERS "sadness" decreased (p = 0.002), while "pleasure" (p = 0.016) and "general alertness" (p = 0.003) increased during AAA compared with CA sessions, and observed sadness remained lower after three hours (p = 0.002). Motor activity increased significantly during AAA. In this sample of severe AD patients in ADCC, AAA was associated with a decrease in anxiety and sadness and an increase in positive emotions and motor activity in comparison with a control activity.

Enhancing Endogenous Nitric Oxide by Whole Body Periodic Acceleration Elicits Neuroprotective Effects in Dystrophic Neurons.

PubMed

Lopez, Jose R; Uryash, A; Kolster, J; Estève, E; Zhang, R; Adams, J A

2018-03-26

We have previously shown that inadequate dystrophin in cortical neurons in mdx mice is associated with age-dependent dyshomeostasis of resting intracellular Ca 2+ ([Ca 2+ ] i ) and Na + ([Na + ] i ), elevated reactive oxygen species (ROS) production, increase in neuronal damage and cognitive deficit. In this study, we assessed the potential therapeutic properties of the whole body periodic acceleration (pGz) to ameliorate the pathology observed in cortical neurons from the mdx mouse. pGz adds small pulses to the circulation, thereby increasing pulsatile shear stress to the vascular endothelium, which in turn increases production of nitric oxide (NO). We found [Ca 2+ ] i and [Na + ] i overload along with reactive oxygen species (ROS) overproduction in mdx neurons and cognitive dysfunction. mdx neurons showed increased activity of superoxide dismutase, glutathione peroxidase, malondialdehyde, and calpain as well as decreased cell viability. mdx neurons were more susceptible to hypoxia-reoxygenation injury than WT. pGz ameliorated the [Ca 2+ ] i , and [Na + ] i elevation and ROS overproduction and further increased the activities of superoxide dismutase, glutathione peroxidase and reduced the malondialdehyde and calpains. pGz diminished cell damage and elevated [Ca 2+ ] i during hypoxia-reoxygenation and improved cognitive function in mdx mice. Moreover, pGz upregulated the expression of utrophin, dystroglycan-β and CAPON, constitutive nitric oxide synthases, prosaposin, brain-derived neurotrophic, and glial cell line-derived neurotrophic factors. The present study demonstrated that pGz is an effective therapeutic approach to improve mdx neurons function, including cognitive functions.

Pretreatment with 5-hydroxymethyl-2-furaldehyde blocks scopolamine-induced learning deficit in contextual and spatial memory in male mice.

PubMed

Lee, Younghwan; Gao, Qingtao; Kim, Eunji; Lee, Younghwa; Park, Se Jin; Lee, Hyung Eun; Jang, Dae Sik; Ryu, Jong Hoon

2015-07-01

5-Hydroxymethyl-2-furaldehyde (5-HMF) is a compound derived from the dehydration of certain sugars. The aim of the present study was to evaluate the effect of 5-HMF on the cognitive impairment induced by scopolamine, a muscarinic receptor antagonist. To measure various cognitive functions, we conducted the step-through passive avoidance task, the Y-maze task and the Morris water maze task. A single administration of 5-HMF (5 or 10mg/kg, p.o.) significantly attenuates scopolamine-induced cognitive impairment in these behavioral tasks without changes in locomotor activity, and the effect of 5-HMF on scopolamine-induced cognitive impairment was significantly reversed by a sub-effective dose of MK-801, an NMDA receptor antagonist. In addition, a single administration of 5-HMF (10mg/kg, p.o.) enhanced the cognitive performance of normal naïve mice in the passive avoidance task. Furthermore, Western blot analysis revealed that the levels of phosphorylated Ca(2+)/calmodulin-dependent protein kinase II-α (CaMKII) and extracellular signal-regulated kinases (ERK) were significantly enhanced by the single administration of 5-HMF in the hippocampal tissues. Taken together, the present study suggests that 5-HMF may block scopolamine-induced learning deficit and enhance cognitive function via the activation of NMDA receptor signaling, including CaMKII and ERK, and would be an effective candidate against cognitive disorders, such as Alzheimer's disease. Copyright © 2015. Published by Elsevier Inc.

Recurrent/moderate hypoglycemia induces hippocampal dendritic injury, microglial activation, and cognitive impairment in diabetic rats

PubMed Central

2012-01-01

Background Recurrent/moderate (R/M) hypoglycemia is common in type 1 diabetes. Although mild or moderate hypoglycemia is not life-threatening, if recurrent, it may cause cognitive impairment. In the present study, we sought to determine whether R/M hypoglycemia leads to neuronal death, dendritic injury, or cognitive impairment. Methods The experiments were conducted in normal and in diabetic rats. Rats were subjected to moderate hypoglycemia by insulin without anesthesia. Oxidative stress was evaluated by 4-Hydroxy-2-nonenal immunostaining and neuronal death was determined by Fluoro-Jade B staining 7 days after R/M hypoglycemia. To test whether oxidative injury caused by NADPH oxidase activation, an NADPH oxidase inhibitor, apocynin, was used. Cognitive function was assessed by Barnes maze and open field tests at 6 weeks after R/M hypoglycemia. Results The present study found that oxidative injury was detected in the dendritic area of the hippocampus after R/M hypoglycemia. Sparse neuronal death was found in the cortex, but no neuronal death was detected in the hippocampus. Significant cognitive impairment and thinning of the CA1 dendritic region was detected 6 weeks after hypoglycemia. Oxidative injury, cognitive impairment, and hippocampal thinning after R/M hypoglycemia were more severe in diabetic rats than in non-diabetic rats. Oxidative damage in the hippocampal CA1 dendritic area and microglial activation were reduced by the NADPH oxidase inhibitor, apocynin. Conclusion The present study suggests that oxidative injury of the hippocampal CA1 dendritic region by R/M hypoglycemia is associated with chronic cognitive impairment in diabetic patients. The present study further suggests that NADPH oxidase inhibition may prevent R/M hypoglycemia-induced hippocampal dendritic injury. PMID:22830525

Erythropoietin Improved Cognitive Function and Decreased Hippocampal Caspase Activity in Rat Pups after Traumatic Brain Injury

PubMed Central

Requena, Daniela F.; Block, Benjamin; Davis, Lizeth J.; Rodesch, Christopher; Casper, T. Charles; Juul, Sandra E.; Kesner, Raymond P.; Lane, Robert H.

2014-01-01

Abstract Traumatic brain injury (TBI) is a leading cause of acquired neurologic disability in children. Erythropoietin (EPO), an anti-apoptotic cytokine, improved cognitive outcome in adult rats after TBI. To our knowledge, EPO has not been studied in a developmental TBI model. Hypothesis: We hypothesized that EPO would improve cognitive outcome and increase neuron fraction in the hippocampus in 17-day-old (P17) rat pups after controlled cortical impact (CCI). Methods: EPO or vehicle was given at 1, 24, and 48 h after CCI and at post injury day (PID) 7. Cognitive outcome at PID14 was assessed using Novel Object Recognition (NOR). Hippocampal EPO levels, caspase activity, and mRNA levels of the apoptosis factors Bcl2, Bax, Bcl-xL, and Bad were measured during the first 14 days after injury. Neuron fraction and caspase activation in CA1, CA3, and DG were studied at PID2. Results: EPO normalized recognition memory after CCI. EPO blunted the increased hippocampal caspase activity induced by CCI at PID1, but not at PID2. EPO increased neuron fraction in CA3 at PID2. Brain levels of exogenous EPO appeared low relative to endogenous. Timing of EPO administration was associated with temporal changes in hippocampal mRNA levels of EPO and pro-apoptotic factors. Conclusion/Speculation: EPO improved recognition memory, increased regional hippocampal neuron fraction, and decreased caspase activity in P17 rats after CCI. We speculate that EPO improved cognitive outcome in rat pups after CCI as a result of improved neuronal survival via inhibition of caspase-dependent apoptosis early after injury. PMID:23972011

A Hippocampal Cognitive Prosthesis: Multi-Input, Multi-Output Nonlinear Modeling and VLSI Implementation

PubMed Central

Berger, Theodore W.; Song, Dong; Chan, Rosa H. M.; Marmarelis, Vasilis Z.; LaCoss, Jeff; Wills, Jack; Hampson, Robert E.; Deadwyler, Sam A.; Granacki, John J.

2012-01-01

This paper describes the development of a cognitive prosthesis designed to restore the ability to form new long-term memories typically lost after damage to the hippocampus. The animal model used is delayed nonmatch-to-sample (DNMS) behavior in the rat, and the “core” of the prosthesis is a biomimetic multi-input/multi-output (MIMO) nonlinear model that provides the capability for predicting spatio-temporal spike train output of hippocampus (CA1) based on spatio-temporal spike train inputs recorded presynaptically to CA1 (e.g., CA3). We demonstrate the capability of the MIMO model for highly accurate predictions of CA1 coded memories that can be made on a single-trial basis and in real-time. When hippocampal CA1 function is blocked and long-term memory formation is lost, successful DNMS behavior also is abolished. However, when MIMO model predictions are used to reinstate CA1 memory-related activity by driving spatio-temporal electrical stimulation of hippocampal output to mimic the patterns of activity observed in control conditions, successful DNMS behavior is restored. We also outline the design in very-large-scale integration for a hardware implementation of a 16-input, 16-output MIMO model, along with spike sorting, amplification, and other functions necessary for a total system, when coupled together with electrode arrays to record extracellularly from populations of hippocampal neurons, that can serve as a cognitive prosthesis in behaving animals. PMID:22438335

Cognitive Screening in Brain Tumors: Short but Sensitive Enough?

PubMed Central

Robinson, Gail A.; Biggs, Vivien; Walker, David G.

2015-01-01

Cognitive deficits in brain tumors are generally thought to be relatively mild and non-specific, although recent evidence challenges this notion. One possibility is that cognitive screening tools are being used to assess cognitive functions but their sensitivity to detect cognitive impairment may be limited. For improved sensitivity to recognize mild and/or focal cognitive deficits in brain tumors, neuropsychological evaluation tailored to detect specific impairments has been thought crucial. This study investigates the sensitivity of a cognitive screening tool, the Montreal Cognitive Assessment (MoCA), compared to a brief but tailored cognitive assessment (CA) for identifying cognitive deficits in an unselected primary brain tumor sample (i.e., low/high-grade gliomas, meningiomas). Performance is compared on broad measures of impairment: (a) number of patients impaired on the global screening measure or in any cognitive domain; and (b) number of cognitive domains impaired and specific analyses of MoCA-Intact and MoCA-Impaired patients on specific cognitive tests. The MoCA-Impaired group obtained lower naming and word fluency scores than the MoCA-Intact group, but otherwise performed comparably on cognitive tests. Overall, based on our results from patients with brain tumor, the MoCA has extremely poor sensitivity for detecting cognitive impairments and a brief but tailored CA is necessary. These findings will be discussed in relation to broader issues for clinical management and planning, as well as specific considerations for neuropsychological assessment of brain tumor patients. PMID:25815273

Acupuncture attenuates cognitive deficits and increases pyramidal neuron number in hippocampal CA1 area of vascular dementia rats.

PubMed

Li, Fang; Yan, Chao-Qun; Lin, Li-Ting; Li, Hui; Zeng, Xiang-Hong; Liu, Yi; Du, Si-Qi; Zhu, Wen; Liu, Cun-Zhi

2015-04-28

Decreased cognition is recognized as one of the most severe and consistent behavioral impairments in dementia. Experimental studies have reported that acupuncture may improve cognitive deficits, relieve vascular dementia (VD) symptoms, and increase cerebral perfusion and electrical activity. Multi-infarction dementia was modeled in rats with 3% microemboli saline suspension. Two weeks after acupuncture at Zusanli (ST36), all rats were subjected to a hidden platform trial to test their 3-day spatial memory using the Morris water maze test. To estimate the numbers of pyramidal neuron, astrocytes, and synaptic boutons in hippocampal CA1 area, we adopted an unbiased stereology method to accurately sample and measure the size of cells. We found that acupuncture at ST36 significantly decreased the escape latency of VD rats. In addition, acupuncture significantly increased the pyramidal neuron number in hippocampal CA1 area (P < 0.05) and tended to decrease the number of astrocytes (P = 0.063). However, there was no significant change in the synaptic bouton number of hippocampal CA1 area in any of the groups (P > 0.05). These findings suggest that acupuncture may improve cognitive deficits and increase pyramidal neuron number of hippocampal CA1 area in VD rats.

Long-term soluble Abeta1-40 activates CaM kinase II in organotypic hippocampal cultures.

PubMed

Tardito, Daniela; Gennarelli, Massimo; Musazzi, Laura; Gesuete, Raffaella; Chiarini, Stefania; Barbiero, Valentina Sara; Rydel, Russell E; Racagni, Giorgio; Popoli, Maurizio

2007-09-01

Recent findings suggested a role for soluble amyloid-beta (Abeta) peptides in Alzheimer's disease associated cognitive decline. We investigated the action of soluble, monomeric Abeta(1-40) on CaM kinase II, a kinase involved in neuroplasticity and cognition. We treated organotypic hippocampal cultures short-term (up to 4h) and long-term (5 days) with Abeta(1-40) (1nM-5microM). Abeta did not induce cell damage, apoptosis or synaptic loss. Short-term treatment down-regulated enzymatic activity of the kinase, by reducing its Thr(286) phosphorylation. In contrast, long-term treatment (1nM-microM) markedly and significantly up-regulated enzymatic activity, with peak stimulation at 10nM (three-fold). Up-regulation of activity was associated with increased expression of the alpha-isoform of CaM kinase II, increased phosphorylation at Thr(286) (activator residue) and decreased phosphorylation at Thr(305-306) (inhibitory residues). We investigated the effect of glutamate on CaM kinase II following exposure to 1 or 10nM Abeta(1-40). As previously reported, glutamate increased CaM kinase II activity. However, the glutamate effect was not altered by pretreatment of slices with Abeta. Short- and long-term Abeta treatment showed opposite effects on CaM kinase II, suggesting that long-term changes are an adaptation to the kinase early down-regulation. The marked effect of Abeta(1-40) on the kinase suggests that semi-physiological and slowly raising peptide concentrations may have a significant impact on synaptic plasticity in the absence of synaptic loss or neuronal cell death.

Dysregulation of neural calcium signaling in Alzheimer disease, bipolar disorder and schizophrenia

PubMed Central

Berridge, Michael J.

2013-01-01

Neurons have highly developed Ca2+ signaling systems responsible for regulating a large number of neural functions such as the control of brain rhythms, information processing and the changes in synaptic plasticity that underpin learning and memory. The tonic excitatory drive, which is activated by the ascending arousal system, is particularly important for processes such as sensory perception, cognition and consciousness. The Ca2+ signaling pathway is a key component of this arousal system that regulates the neuronal excitability responsible for controlling the neural brain rhythms required for information processing and cognition. Dysregulation of the Ca2+ signaling pathway responsible for many of these neuronal processes has been implicated in the development of some of the major neural diseases in man such as Alzheimer disease, bipolar disorder and schizophrenia. Various treatments, which are known to act by reducing the activity of Ca2+ signaling, have proved successful in alleviating the symptoms of some of these neural diseases. PMID:22895098

Time until incident dementia among Medicare beneficiaries using centrally acting or non-centrally acting ACE inhibitors.

PubMed

Hebert, Paul L; McBean, Alexander Marshall; O'Connor, Heidi; Frank, Barbara; Good, Charles; Maciejewski, Matthew L

2013-06-01

Centrally active (CA) angiotensin-converting enzyme inhibitors (ACEIs) are able to cross the blood–brain barrier. Small observational studies and mouse models suggest that use of CA versus non-CA ACEIs is associated with a reduced incidence of Alzheimer's disease and related dementias (ADRD). The aim of this research was to assess the effect of CA versus non-CA ACEI use on incident ADRD. This is a retrospective cohort study with a non-equivalent control group. SETTING AND PATIENTS" This study used a national random sample of Medicare beneficiaries enrolled in Part D with an ACEI prescription. A prevalent ACEI user cohort included beneficiaries (n = 107 179) with an ACEI prescription prior to 30 April 2007; beneficiaries without an ACEI prescription before this date were defined as incident ACEI users (n = 9840). The main outcome was time until first diagnosis of ADRD in Medicare claims. The unadjusted, propensity-matched and instrumental variable analyses of both the prevalent and incident ACEI user cohorts consistently showed similar time until incident ADRD in those taking CA ACEIs compared with those who took non-CA ACEIs. The limitations of this study include the use of observational data, relatively short follow-up time and claims-based measure of cognitive decline. In this analysis of Medicare beneficiaries who were prevalent or incident users of ACEIs in 2007–2009, the use of CA ACEIs was unrelated to cognitive decline within 3 years of index prescription. Continued follow-up of these patients and more sensitive measures of cognitive decline are necessary to determine whether a cognitive benefit of CA ACEIs is realized in the long term.

Physical Frailty Is Associated with Longitudinal Decline in Global Cognitive Function in Non-Demented Older Adults: A Prospective Study.

PubMed

Chen, S; Honda, T; Narazaki, K; Chen, T; Kishimoto, H; Haeuchi, Y; Kumagai, S

2018-01-01

To assess the relationship between physical frailty and subsequent decline in global cognitive function in the non-demented elderly. A prospective population-based study in a west Japanese suburban town, with two-year follow-up. Community-dwellers aged 65 and older without placement in long-term care, and not having a history of dementia, Parkinson's disease and depression at baseline, who participated in the cohort of the Sasaguri Genkimon Study and underwent follow-up assessments two years later (N = 1,045). Global cognitive function was assessed using the Montreal Cognitive Assessment (MoCA). Physical frailty was identified according to the following five components: weight loss, low grip strength, exhaustion, slow gait speed and low physical activities. Linear regression models were used to examine associations between baseline frailty status and the MoCA scores at follow-up. Logistic regression models were used to estimate the risk of cognitive decline (defined as at least two points decrease of MoCA score) according to baseline frailty status. Seven hundred and eight non-demented older adults were included in the final analyses (mean age: 72.6 ± 5.5 years, male 40.3%); 5.8% were frail, and 40.8% were prefrail at baseline. One hundred and fifty nine (22.5%) participants experienced cognitive decline over two years. After adjustment for baseline MoCA scores and all confounders, being frail at baseline was significantly associated with a decline of 1.48 points (95% confidence interval [CI], -2.37 to -0.59) in MoCA scores, as compared with non-frailty. Frail persons were over two times more likely to experience cognitive decline (adjusted odds ratio 2.28; 95% CI, 1.02 to 5.08), compared to non-frail persons. Physical frailty is associated with longitudinal decline in global cognitive function in the non-demented older adults over a period of two years. Physically frail older community-dwellers should be closely monitored for cognitive decline that can be sensitively captured by using the MoCA.

Chronic coffee and caffeine ingestion effects on the cognitive function and antioxidant system of rat brains.

PubMed

Abreu, Renata Viana; Silva-Oliveira, Eliane Moretto; Moraes, Márcio Flávio Dutra; Pereira, Grace Schenatto; Moraes-Santos, Tasso

2011-10-01

Coffee is a popular beverage consumed worldwide and its effect on health protection has been well studied throughout literature. This study investigates the effect of chronic coffee and caffeine ingestion on cognitive behavior and the antioxidant system of rat brains. The paradigms of open field and object recognition were used to assess locomotor and exploratory activities, as well as learning and memory. The antioxidant system was evaluated by determining the activities of glutathione reductase (GR), glutathione peroxidase (GPx) and superoxide dismutase (SOD), as well as the lipid peroxidation and reduced glutathione content. Five groups of male rats were fed for approximately 80 days with different diets: control diet (CD), fed a control diet; 3% coffee diet (3%Co) and 6% coffee diet (6%Co), both fed a diet containing brewed coffee; 0.04% caffeine diet (0.04%Ca) and 0.08% caffeine diet (0.08%Ca), both fed a control diet supplemented with caffeine. The estimated caffeine intake was approximately 20 and 40 mg/kg per day, for the 3%Co-0.04%Ca and 6%Co-0.08%Ca treatments, respectively. At 90 days of life, the animals were subjected to the behavioral tasks and then sacrificed. The results indicated that the intake of coffee, similar to caffeine, improved long-term memory when tested with object recognition; however, this was not accompanied by an increase in locomotor and exploratory activities. In addition, chronic coffee and caffeine ingestion reduced the lipid peroxidation of brain membranes and increased the concentration of reduced-glutathione. The activities of the GR and SOD were similarly increased, but no change in GPx activity could be observed. Thus, besides improving cognitive function, our data show that chronic coffee consumption modulates the endogenous antioxidant system in the brain. Therefore, chronic coffee ingestion, through the protection of the antioxidant system, may play an important role in preventing age-associated decline in the cognitive function. Copyright © 2011 Elsevier Inc. All rights reserved.

The Montreal Cognitive Assessment and the mini-mental state examination as screening instruments for cognitive impairment: item analyses and threshold scores.

PubMed

Damian, Anne M; Jacobson, Sandra A; Hentz, Joseph G; Belden, Christine M; Shill, Holly A; Sabbagh, Marwan N; Caviness, John N; Adler, Charles H

2011-01-01

To perform an item analysis of the Montreal Cognitive Assessment (MoCA) versus the Mini-Mental State Examination (MMSE) in the prediction of cognitive impairment, and to examine the characteristics of different MoCA threshold scores. 135 subjects enrolled in a longitudinal clinicopathologic study were administered the MoCA by a single physician and the MMSE by a trained research assistant. Subjects were classified as cognitively impaired or cognitively normal based on independent neuropsychological testing. 89 subjects were found to be cognitively normal, and 46 cognitively impaired (20 with dementia, 26 with mild cognitive impairment). The MoCA was superior in both sensitivity and specificity to the MMSE, although not all MoCA tasks were of equal predictive value. A MoCA threshold score of 26 had a sensitivity of 98% and a specificity of 52% in this population. In a population with a 20% prevalence of cognitive impairment, a threshold of 24 was optimal (negative predictive value 96%, positive predictive value 47%). This analysis suggests the potential for creating an abbreviated MoCA. For screening in primary care, the MoCA threshold of 26 appears optimal. For testing in a memory disorders clinic, a lower threshold has better predictive value. Copyright © 2011 S. Karger AG, Basel.

Protective effect of a phenolic extract containing indoline amides from Portulaca oleracea against cognitive impairment in senescent mice induced by large dose of D-galactose /NaNO2.

PubMed

Wang, Peipei; Sun, Hongxiang; Liu, Dianyu; Jiao, Zezhao; Yue, Su; He, Xiuquan; Xia, Wen; Ji, Jianbo; Xiang, Lan

2017-05-05

Portulaca oleracea L. is a potherb and also a widely used traditional Chinese medicine. In accordance with its nickname "longevity vegetable", pharmacological study demonstrated that this plant possessed antioxidant, anti-aging, and cognition-improvement function. Active principles pertaining to these functions of P. oleracea need to be elucidated. The present study evaluated the effect of a phenolic extract (PAAs) from P. oleracea which contained specific antioxidant indoline amides on cognitive impairment in senescent mice. PAAs was prepared through AB-8 macroporous resin column chromatography. Total phenol content was determined using colorimetric method, and contents of indoline amides were determined using HPLC-UV method. Senescent Kunming mice with cognitive dysfunction were established by intraperitoneal injection of D-galactose (D-gal, 1250mg/kg/day) and NaNO 2 (90mg/kg/day) for 8 weeks, L-PAAs (360mg/kg/day), H-PAAs (720mg/kg/day), and nootropic drug piracetam (PA, 400mg/kg/day) as the positive control were orally administered. Spatial learning and memory abilities were evaluated by Morris water maze experiment. Activities of AChE, SOD, CAT, and levels of GSH and MDA in the brain or plasma were measured. Hippocampal morphology was observed by HE staining. Chronic treatment of large dose of D-gal/NaNO 2 significantly reduced lifespan, elevated AChE activity, decreased CAT activity, compensatorily up-regulated SOD activity and GSH level, increased MDA level, induced neuronal damage in hippocampal CA1, CA3 and CA4 regions, and impaired cognitive function. Similar to PA, PAAs prolonged the lifespan and improved spatial memory ability. Moreover, PAAs improved learning ability. H-PAAs significantly reversed compensatory increase in SOD activity to the normal level, elevated serum CAT activity, and reduced MDA levels in brain and plasma, more potent than L-PAAs. Besides these, PAAs evidently inhibited hippocampal neuronal damage. However, it had no effect on brain AChE activity. PAAs as the bioactive principles of P. oleracea attenuated oxidative stress, improved survival rate, and enhanced cognitive function in D-gal/NaNO 2 -induced senile mice, similar to piracetam. This phenolic extract provides a promising candidate for prevention of aging and aging-related cognitive dysfunction in clinic. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

Cardiorespiratory Fitness and Cognitive Function are Positively Related Among Participants with Mild and Subjective Cognitive Impairment.

PubMed

Stuckenschneider, Tim; Askew, Christopher David; Rüdiger, Stefanie; Cristina Polidori, Maria; Abeln, Vera; Vogt, Tobias; Krome, Andreas; Olde Rikkert, Marcel; Lawlor, Brian; Schneider, Stefan

2018-01-01

By 2030, about 74 million people will be diagnosed with dementia, and many more will experience subjective (SCI) or mild cognitive impairment (MCI). As physical inactivity has been identified to be a strong modifiable risk factor for dementia, exercise and physical activity (PA) may be important parameters to predict the progression from MCI to dementia, but might also represent disease trajectory modifying strategies for SCI and MCI. A better understanding of the relationship between activity, fitness, and cognitive function across the spectrum of MCI and SCI would provide an insight into the potential utility of PA and fitness as early markers, and treatment targets to prevent cognitive decline. 121 participants were stratified into three groups, late MCI (LMCI), early MCI (EMCI), and SCI based on the Montreal Cognitive Assessment (MoCA). Cognitive function assessments also included the Trail Making Test A+B, and a verbal fluency test. PA levels were evaluated with an interviewer-administered questionnaire (LAPAQ) and an activity monitor. An incremental exercise test was performed to estimate cardiorespiratory fitness and to determine exercise capacity relative to population normative data. ANCOVA revealed that LMCI subjects had the lowest PA levels (LAPAQ, p = 0.018; activity monitor, p = 0.041), and the lowest exercise capacity in relation to normative values (p = 0.041). Moreover, a modest correlation between MoCA and cardiorespiratory fitness (r = 0.25; p < 0.05) was found. These findings suggest that during the earliest stages of cognitive impairment PA and exercise capacity might present a marker for the risk of further cognitive decline. This finding warrants further investigation using longitudinal cohort studies.

Montreal Cognitive Assessment 5-minute protocol is a brief, valid, reliable, and feasible cognitive screen for telephone administration.

PubMed

Wong, Adrian; Nyenhuis, David; Black, Sandra E; Law, Lorraine S N; Lo, Eugene S K; Kwan, Pauline W L; Au, Lisa; Chan, Anne Y Y; Wong, Lawrence K S; Nasreddine, Ziad; Mok, Vincent

2015-04-01

The National Institute of Neurological Disorders and Stroke-Canadian Stroke Network Vascular Cognitive Impairment Harmonization working group proposed a brief cognitive protocol for screening of vascular cognitive impairment. We investigated the validity, reliability, and feasibility of the Montreal Cognitive Assessment 5-minute protocol (MoCA 5-minute protocol) administered over the telephone. Four items examining attention, verbal learning and memory, executive functions/language, and orientation were extracted from the MoCA to form the MoCA 5-minute protocol. One hundred four patients with stroke or transient ischemic attack, including 53 with normal cognition (Clinical Dementia Rating, 0) and 51 with cognitive impairment (Clinical Dementia Rating, 0.5 or 1), were administered the MoCA in clinic and a month later, the MoCA 5-minute protocol over the telephone. Administration of the MoCA 5-minute protocol took 5 minutes over the telephone. Total score of the MoCA 5-minute protocol correlated negatively with age (r=-0.36; P<0.001) and positively with years of education (r=0.41; P<0.001) but not with sex (ρ=0.03; P=0.773). Total scores of the MoCA and MoCA 5-minute protocol were highly correlated (r=0.87; P<0.001). The MoCA 5-minute protocol performed equally well as the MoCA in differentiating patients with cognitive impairment from those without (areas under receiver operating characteristics curve for MoCA 5-minute protocol, 0.78; MoCA=0.74; P>0.05 for difference; Cohen d for group difference, 0.80-1.13). It differentiated cognitively impaired patients with executive domain impairment from those without (areas under receiver operating characteristics curve, 0.89; P<0.001; Cohen d=1.7 for group difference). Thirty-day test-retest reliability was excellent (intraclass correlation coefficient, 0.89). The MoCA 5-minute protocol is a free, valid, and reliable cognitive screen for stroke and transient ischemic attack. It is brief and highly feasible for telephone administration. © 2015 American Heart Association, Inc.

Increased hippocampal activation in ApoE-4 carriers and non-carriers with amnestic mild cognitive impairment.

PubMed

Tran, Tammy T; Speck, Caroline L; Pisupati, Aparna; Gallagher, Michela; Bakker, Arnold

2017-01-01

Increased fMRI activation in the hippocampus is recognized as a signature characteristic of the amnestic mild cognitive impairment (aMCI) stage of Alzheimer's disease (AD). Previous work has localized this increased activation to the dentate gyrus/CA3 subregion of the hippocampus and showed a correlation with memory impairments in those patients. Increased hippocampal activation has also been reported in carriers of the ApoE-4 allelic variation independently of mild cognitive impairment although these findings were not localized to a hippocampal subregion. To assess the ApoE-4 contribution to increased hippocampal fMRI activation, patients with aMCI genotyped for ApoE-4 status and healthy age-matched control participants completed a high-resolution fMRI scan while performing a memory task designed to tax hippocampal subregion specific functions. Consistent with previous reports, patients with aMCI showed increased hippocampal activation in the left dentate gyrus/CA3 region of the hippocampus as well as memory task errors attributable to this subregion. However, this increased fMRI activation in the hippocampus did not differ between ApoE-4 carriers and ApoE-4 non-carriers and the proportion of memory errors attributable to dentate gyrus/CA3 function did not differ between ApoE-4 carriers and ApoE-4 non-carriers. These results indicate that increased fMRI activation of the hippocampus observed in patients with aMCI is independent of ApoE-4 status and that ApoE-4 does not contribute to the dysfunctional hippocampal activation or the memory errors attributable to this subregion in these patients.

CaMKII activity is essential for improvement of memory-related behaviors by chronic rivastigmine treatment.

PubMed

Moriguchi, Shigeki; Tagashira, Hideaki; Sasaki, Yuzuru; Yeh, Jay Z; Sakagami, Hiroyuki; Narahashi, Toshio; Fukunaga, Kohji

2014-03-01

Because the cholinergic system is down-regulated in the brain of Alzheimer's disease patients, cognitive deficits in Alzheimer's disease patients are significantly improved by rivastigmine treatment. To address the mechanism underlying rivastigmine-induced memory improvements, we chronically treated olfactory bulbectomized (OBX) mice with rivastigmine. The chronic rivastigmine treatments for 12-13 days starting at 10 days after OBX operation significantly improved memory-related behaviors assessed by Y-maze task, novel object recognition task, passive avoidance task, and Barnes maze task, whereas the single rivastigmine treatment failed to improve the memory. Consistent with the improved memory-related behaviors, long-term potentiation in the hippocampal CA1 region was markedly restored by rivastigmine treatments. In immunoblotting analyses, the reductions of calcium/calmodulin-dependent protein kinase II (CaMKII) autophosphorylation and calcium/calmodulin-dependent protein kinase IV (CaMKIV) phosphorylation in the CA1 region in OBX mice were significantly restored by rivastigmine treatments. In addition, phosphorylation of AMPAR subunit glutamate receptor 1 (GluA1) (Ser-831) and cAMP-responsive element-binding protein (Ser-133) as downstream targets of CaMKII and CaMKIV, respectively, in the CA1 region was also significantly restored by chronic rivastigmine treatments. Finally, we confirmed that rivastigmine-induced improvements of memory-related behaviors and long-term potentiation were not obtained in CaMKIIα(+/-) mice. On the other hand, CaMKIV(-/-) mice did not exhibit the cognitive impairments. Taken together, the stimulation of CaMKII activity in the hippocampus is essential for rivastigmine-induced memory improvement in OBX mice. © 2013 International Society for Neurochemistry.

Acute Seizures in Old Age Leads to a Greater Loss of CA1 Pyramidal Neurons, an Increased Propensity for Developing Chronic TLE and a Severe Cognitive Dysfunction.

PubMed

Hattiangady, Bharathi; Kuruba, Ramkumar; Shetty, Ashok K

2011-02-01

The aged population displays an enhanced risk for developing acute seizure (AS) activity. However, it is unclear whether AS activity in old age would result in a greater magnitude of hippocampal neurodegeneration and inflammation, and an increased predilection for developing chronic temporal lobe epilepsy (TLE) and cognitive dysfunction. Therefore, we addressed these issues in young-adult (5-months old) and aged (22-months old) F344 rats after three-hours of AS activity, induced through graded intraperitoneal injections of kainic acid (KA), and terminated through a diazepam injection. During the three-hours of AS activity, both young adult and aged groups exhibited similar numbers of stage-V motor seizures but the numbers of stage-IV motor seizures were greater in the aged group. In both age groups, three-hour AS activity induced degeneration of 50-55% of neurons in the dentate hilus, 22-32% of neurons in the granule cell layer and 49-52% neurons in the CA3 pyramidal cell layer without showing any interaction between the age and AS activity. However, degeneration of neurons in the CA1 pyramidal cell layer showed a clear interaction between the age and AS activity (12% in the young adult group and 56% in the aged group), suggesting that an advanced age makes the CA1 pyramidal neurons more susceptible to die with AS activity. The extent of inflammation measured through the numbers of activated microglial cells was similar between the two age groups. Interestingly, the predisposition for developing chronic TLE at 2-3 months after AS activity was 60% for young adult rats but 100% for aged rats. Moreover, both frequency & intensity of spontaneous recurrent seizures in the chronic phase after AS activity were 6-12 folds greater in aged rats than in young adult rats. Furthermore, aged rats lost their ability for spatial learning even in a scrupulous eleven-session water maze learning paradigm after AS activity, in divergence from young adult rats which retained the ability for spatial learning but had memory retrieval dysfunction after AS activity. Thus, AS activity in old age results in a greater loss of hippocampal CA1 pyramidal neurons, an increased propensity for developing robust chronic TLE, and a severe cognitive dysfunction.

Temporal Evolution of Poststroke Cognitive Impairment Using the Montreal Cognitive Assessment.

PubMed

Nijsse, Britta; Visser-Meily, Johanna M A; van Mierlo, Maria L; Post, Marcel W M; de Kort, Paul L M; van Heugten, Caroline M

2017-01-01

The Montreal Cognitive Assessment (MoCA) is nowadays recommended for the screening of poststroke cognitive impairment. However, little is known about the temporal evolution of MoCA-assessed cognition after stroke. The objective of this study was to examine the temporal pattern of overall and domain-specific cognition at 2 and 6 months after stroke using the MoCA and to identify patient groups at risk for cognitive impairment at 6 months after stroke. Prospective cohort study in which 324 patients were administered the MoCA at 2 and 6 months post stroke. Cognitive impairment was defined as MoCA<26. Differences in cognitive impairment rates between 2 and 6 months post stroke were analyzed in different subgroups. Patients with MoCA score <26 at 2 months, who improved by ≥2 points by 6 months, were defined as reverters. Logistic regression analyses were used to identify determinants of (1) cognitive impairment at 6 months post stroke and (2) reverter status. Between 2 and 6 months post stroke, mean MoCA score improved from 23.7 (3.9) to 24.7 (3.5), P<0.001. Prevalence of cognitive impairment at 2 months was 66.4%, compared with 51.9% at 6 months (P<0.001). More comorbidity and presence of cognitive impairment at 2 months were significant independent predictors of cognitive impairment 6 months post stroke. No significant determinants of reverter status were identified. Although cognitive improvement is seen ≤6 months post stroke, long-term cognitive deficits are prevalent. Identifying patients at risk of cognitive impairment is, therefore, important as well as targeting interventions to this group. © 2016 American Heart Association, Inc.

Neuroprotective effects of oleuropein against cognitive dysfunction induced by colchicine in hippocampal CA1 area in rats.

PubMed

Pourkhodadad, Soheila; Alirezaei, Masoud; Moghaddasi, Mehrnoush; Ahmadvand, Hassan; Karami, Manizheh; Delfan, Bahram; Khanipour, Zahra

2016-09-01

Alzheimer's disease is a progressive neurodegenerative disorder with decline in memory. The role of oxidative stress is well known in the pathogenesis of the disease. The purpose of this study was to evaluate pretreatment effects of oleuropein on oxidative status and cognitive dysfunction induced by colchicine in the hippocampal CA1 area. Male Wistar rats were pretreated orally once daily for 10 days with oleuropein at doses of 10, 15 and 20 mg/kg. Thereafter, colchicine (15 μg/rat) was administered into the CA1 area of the hippocampus to induce cognitive dysfunction. The Morris water maze was used to assess learning and memory. Biochemical parameters such as glutathione peroxidase and catalase activities, nitric oxide and malondialdehyde concentrations were measured to evaluate the antioxidant status in the rat hippocampus. Our results indicated that colchicine significantly impaired spatial memory and induced oxidative stress; in contrast, oleuropein pretreatment significantly improved learning and memory retention, and attenuated the oxidative damage. The results clearly indicate that oleuropein has neuroprotective effects against colchicine-induced cognitive dysfunction and oxidative damage in rats.

Calycosin and Formononetin Induce Endothelium-Dependent Vasodilation by the Activation of Large-Conductance Ca2+-Activated K+ Channels (BKCa).

PubMed

Tseng, Hisa Hui Ling; Vong, Chi Teng; Leung, George Pak-Heng; Seto, Sai Wang; Kwan, Yiu Wa; Lee, Simon Ming-Yuen; Hoi, Maggie Pui Man

2016-01-01

Calycosin and formononetin are two structurally similar isoflavonoids that have been shown to induce vasodilation in aorta and conduit arteries, but study of their actions on endothelial functions is lacking. Here, we demonstrated that both isoflavonoids relaxed rat mesenteric resistance arteries in a concentration-dependent manner, which was reduced by endothelial disruption and nitric oxide synthase (NOS) inhibition, indicating the involvement of both endothelium and vascular smooth muscle. In addition, the endothelium-dependent vasodilation, but not the endothelium-independent vasodilation, was blocked by BK Ca inhibitor iberiotoxin (IbTX). Using human umbilical vein endothelial cells (HUVECs) as a model, we showed calycosin and formononetin induced dose-dependent outwardly rectifying K + currents using whole cell patch clamp. These currents were blocked by tetraethylammonium chloride (TEACl), charybdotoxin (ChTX), or IbTX, but not apamin. We further demonstrated that both isoflavonoids significantly increased nitric oxide (NO) production and upregulated the activities and expressions of endothelial NOS (eNOS) and neuronal NOS (nNOS). These results suggested that calycosin and formononetin act as endothelial BK Ca activators for mediating endothelium-dependent vasodilation through enhancing endothelium hyperpolarization and NO production. Since activation of BK Ca plays a role in improving behavioral and cognitive disorders, we suggested that these two isoflavonoids could provide beneficial effects to cognitive disorders through vascular regulation.

Postsynaptic activity reverses the sign of the acetylcholine-induced long-term plasticity of GABAA inhibition

PubMed Central

Domínguez, Soledad; Fernández de Sevilla, David; Buño, Washington

2014-01-01

Acetylcholine (ACh) regulates forms of plasticity that control cognitive functions but the underlying mechanisms remain largely unknown. ACh controls the intrinsic excitability, as well as the synaptic excitation and inhibition of CA1 hippocampal pyramidal cells (PCs), cells known to participate in circuits involved in cognition and spatial navigation. However, how ACh regulates inhibition in function of postsynaptic activity has not been well studied. Here we show that in rat PCs, a brief pulse of ACh or a brief stimulation of cholinergic septal fibers combined with repeated depolarization induces strong long-term enhancement of GABAA inhibition (GABAA-LTP). Indeed, this enhanced inhibition is due to the increased activation of α5βγ2 subunit-containing GABAA receptors by the GABA released. GABAA-LTP requires the activation of M1-muscarinic receptors and an increase in cytosolic Ca2+. In the absence of PC depolarization ACh triggered a presynaptic depolarization-induced suppression of inhibition (DSI), revealing that postsynaptic activity gates the effects of ACh from presynaptic DSI to postsynaptic LTP. These results provide key insights into mechanisms potentially linked with cognitive functions, spatial navigation, and the homeostatic control of abnormal hyperexcitable states. PMID:24938789

Zolpidem Reduces Hippocampal Neuronal Activity in Freely Behaving Mice: A Large Scale Calcium Imaging Study with Miniaturized Fluorescence Microscope

PubMed Central

Berdyyeva, Tamara; Otte, Stephani; Aluisio, Leah; Ziv, Yaniv; Burns, Laurie D.; Dugovic, Christine; Yun, Sujin; Ghosh, Kunal K.; Schnitzer, Mark J.; Lovenberg, Timothy; Bonaventure, Pascal

2014-01-01

Therapeutic drugs for cognitive and psychiatric disorders are often characterized by their molecular mechanism of action. Here we demonstrate a new approach to elucidate drug action on large-scale neuronal activity by tracking somatic calcium dynamics in hundreds of CA1 hippocampal neurons of pharmacologically manipulated behaving mice. We used an adeno-associated viral vector to express the calcium sensor GCaMP3 in CA1 pyramidal cells under control of the CaMKII promoter and a miniaturized microscope to observe cellular dynamics. We visualized these dynamics with and without a systemic administration of Zolpidem, a GABAA agonist that is the most commonly prescribed drug for the treatment of insomnia in the United States. Despite growing concerns about the potential adverse effects of Zolpidem on memory and cognition, it remained unclear whether Zolpidem alters neuronal activity in the hippocampus, a brain area critical for cognition and memory. Zolpidem, when delivered at a dose known to induce and prolong sleep, strongly suppressed CA1 calcium signaling. The rate of calcium transients after Zolpidem administration was significantly lower compared to vehicle treatment. To factor out the contribution of changes in locomotor or physiological conditions following Zolpidem treatment, we compared the cellular activity across comparable epochs matched by locomotor and physiological assessments. This analysis revealed significantly depressive effects of Zolpidem regardless of the animal’s state. Individual hippocampal CA1 pyramidal cells differed in their responses to Zolpidem with the majority (∼65%) significantly decreasing the rate of calcium transients, and a small subset (3%) showing an unexpected and significant increase. By linking molecular mechanisms with the dynamics of neural circuitry and behavioral states, this approach has the potential to contribute substantially to the development of new therapeutics for the treatment of CNS disorders. PMID:25372144

Converting MMSE to MoCA and MoCA 5-minute protocol in an educationally heterogeneous sample with stroke or transient ischemic attack.

PubMed

Wong, Adrian; Black, Sandra E; Yiu, Stanley Y P; Au, Lisa W C; Lau, Alexander Y L; Soo, Yannie O Y; Chan, Anne Y Y; Leung, Thomas W H; Wong, Lawrence K S; Kwok, Timothy C Y; Cheung, Theodore C K; Leung, Kam-Tat; Lam, Bonnie Y K; Kwan, Joseph S K; Mok, Vincent C T

2018-05-01

The Montreal Cognitive Assessment (MoCA) is psychometrically superior over the Mini-mental State Examination (MMSE) for cognitive screening in stroke or transient ischemic attack (TIA). It is free for clinical and research use. The objective of this study is to convert scores from the MMSE to MoCA and MoCA-5-minute protocol (MoCA-5 min) and to examine the ability of the converted scores in detecting cognitive impairment after stroke or TIA. A total of 904 patients were randomly divided into training (n = 623) and validation (n = 281) samples matched for demography and cognition. MMSE scores were converted to MoCA and MoCA-5 min using (1) equipercentile method with log-linear smoothing and (2) Poisson regression adjusting for age and education. Receiver operating characteristics curve analysis was used to examine the ability of the converted scores in differentiating patients with cognitive impairment. The mean education was 5.8 (SD = 4.6; ranged 0-20) years. The entire spectrum of MMSE scores was converted to MoCA and MoCA-5 min using equipercentile method. Relationship between MMSE and MoCA scores was confounded by age and education, and a conversion equation with adjustment for age and education was derived. In the validation sample, the converted scores differentiated cognitively impaired patients with area under receiver operating characteristics curve 0.826 to 0.859. We provided 2 methods to convert scores from the MMSE to MoCA and MoCA-5 min based on a large sample of patients with stroke or TIA having a wide range of education and cognitive levels. The converted scores differentiated patients with cognitive impairment after stroke or TIA with high accuracy. Copyright © 2018 John Wiley & Sons, Ltd.

Associations between modifiable lifestyle factors and multidimensional cognitive health among community-dwelling old adults: stratified by educational level.

PubMed

Yuan, Manqiong; Chen, Jia; Han, Yaofeng; Wei, Xingliang; Ye, Zirong; Zhang, Liangwen; Hong, Y Alicia; Fang, Ya

2018-02-15

Cognition is multidimensional, and each domain plays a unique and crucial part in successful daily life engagement. However, less attention has been paid to multi-domain cognitive health for the elderly, and the role of lifestyle factors in each domain remains unclear. We conducted a cross-sectional study of 3,230 older adults aged 60+ years in Xiamen, China, in 2016. The Montreal Cognitive Assessment (MoCA) was used to measure general cognition and six specific sub-domains. To account for educational effects, we adjusted the MoCA score and divided respondents into three education-specific groups (low, moderate, and high education groups with ≤5, 6~8, and ≥9 years of education, respectively). A series of proportional odds models were used to detect the associations between two categories of lifestyle factors - substance abuse (cigarette and alcohol) and leisure activity (TV watching, reading, smartphone use, social activity, and exercise) - and general cognition and the six sub-domains in those three groups. Among the 3,230 respondents, 2,617 eligible participants were included with a mean age of 69.05 ± 7.07 years. Previous or current smoking/drinking was not associated with MoCA scores in the whole population, but unexpectedly, the ex-smokers in the low education group performed better in general cognition (OR = 2.22) and attention (OR = 2.05) than their never-smoking counterparts. Modest TV watching, reading, and smartphone use also contributed to better cognition among elderly participants in the low education group. For the highly educated elderly, comparatively longer reading (>3.5 hours/week) was inversely associated with general cognition (OR = 0.53), memory (OR = 0.59), and language (OR = 0.54), while adequate exercise (5~7 days/week) was positively related to these factors with OR = 1.48, OR = 1.49, and OR = 1.53, respectively. For the moderately educated elderly, only modest reading was significantly beneficial. Lifestyle factors play different roles in multidimensional cognitive health in different educational groups, indicating that individual intervention strategies should be designed according to specific educational groups and different cognitive sub-domains.

Screening an elderly hearing impaired population for mild cognitive impairment using Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA).

PubMed

Lim, Magdalene Yeok Leng; Loo, Jenny Hooi Yin

2018-07-01

To determine if there is an association between hearing loss and poorer cognitive scores on Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) and to determine if poor hearing acuity affects scoring on the cognitive screening tests of MMSE and MoCA. One hundred fourteen elderly patients (Singapore residents) aged between 55 and 86 years were sampled. Participants completed a brief history questionnaire, pure tone audiometry, and 2 cognitive screening tests-the MMSE and MoCA. Average hearing thresholds of the better ear in the frequencies of 0.5, 1, 2, and 4 kHz were used for data analysis. Hearing loss was significantly associated with poorer cognitive scores in Poisson regression models adjusted for age. Mini-Mental State Examination scores were shown to decrease by 2.8% (P = .029), and MoCA scores by 3.5% (P = .013) for every 10 dB of hearing loss. Analysis of hearing-sensitive components of "Registration" and "Recall" in MMSE and MoCA using chi-square tests showed significantly poorer performance in the hearing loss group as compared to the normal hearing group. Phonetic analysis of target words with high error rates shows that the poor performance was likely contributed by decreased hearing acuity, on top of a possible true deficit in cognition in the hearing impaired. Hearing loss is associated with poorer cognitive scores on MMSE and MoCA, and cognitive scoring is likely confounded by poor hearing ability. This highlights an important, often overlooked aspect of sensory impairment during cognitive screening. Provisions should be made when testing for cognition in the hearing-impaired population to avoid over-referral and subsequent misdiagnoses of cognitive impairment. Copyright © 2018 John Wiley & Sons, Ltd.

The cognition-enhancing activity of E1R, a novel positive allosteric modulator of sigma-1 receptors.

PubMed

Zvejniece, L; Vavers, E; Svalbe, B; Vilskersts, R; Domracheva, I; Vorona, M; Veinberg, G; Misane, I; Stonans, I; Kalvinsh, I; Dambrova, M

2014-02-01

Here, we describe the in vitro and in vivo effects of (4R,5S)-2-(5-methyl-2-oxo-4-phenyl-pyrrolidin-1-yl)-acetamide (E1R), a novel positive allosteric modulator of sigma-1 receptors. E1R was tested for sigma receptor binding activity in a [³H](+)-pentazocine assay, in bradykinin (BK)-induced intracellular Ca²⁺ concentration ([Ca²⁺](i)) assays and in an electrically stimulated rat vas deferens model. E1R's effects on cognitive function were tested using passive avoidance (PA) and Y-maze tests in mice. A selective sigma-1 receptor antagonist (NE-100), was used to study the involvement of the sigma-1 receptor in the effects of E1R. The open-field test was used to detect the effects of E1R on locomotion. Pretreatment with E1R enhanced the selective sigma-1 receptor agonist PRE-084's stimulating effect during a model study employing electrically stimulated rat vasa deferentia and an assay measuring the BK-induced [Ca²⁺](i) increase. Pretreatment with E1R facilitated PA retention in a dose-related manner. Furthermore, E1R alleviated the scopolamine-induced cognitive impairment during the PA and Y-maze tests in mice. The in vivo and in vitro effects of E1R were blocked by treatment with the selective sigma-1 receptor antagonist NE-100. E1R did not affect locomotor activity. E1R is a novel 4,5-disubstituted derivative of piracetam that enhances cognition and demonstrates efficacy against scopolamine-induced cholinergic dysfunction in mice. These effects are attributed to its positive modulatory action on the sigma-1 receptor and this activity may be relevant when developing new drugs for treating cognitive symptoms related to neurodegenerative diseases. © 2013 The British Pharmacological Society.

The cognition-enhancing activity of E1R, a novel positive allosteric modulator of sigma-1 receptors

PubMed Central

Zvejniece, L; Vavers, E; Svalbe, B; Vilskersts, R; Domracheva, I; Vorona, M; Veinberg, G; Misane, I; Stonans, I; Kalvinsh, I; Dambrova, M

2014-01-01

Background and Purpose Here, we describe the in vitro and in vivo effects of (4R,5S)-2-(5-methyl-2-oxo-4-phenyl-pyrrolidin-1-yl)-acetamide (E1R), a novel positive allosteric modulator of sigma-1 receptors. Experimental Approach E1R was tested for sigma receptor binding activity in a [3H](+)-pentazocine assay, in bradykinin (BK)-induced intracellular Ca2+ concentration ([Ca2+]i) assays and in an electrically stimulated rat vas deferens model. E1R's effects on cognitive function were tested using passive avoidance (PA) and Y-maze tests in mice. A selective sigma-1 receptor antagonist (NE-100), was used to study the involvement of the sigma-1 receptor in the effects of E1R. The open-field test was used to detect the effects of E1R on locomotion. Key Results Pretreatment with E1R enhanced the selective sigma-1 receptor agonist PRE-084's stimulating effect during a model study employing electrically stimulated rat vasa deferentia and an assay measuring the BK-induced [Ca2+]i increase. Pretreatment with E1R facilitated PA retention in a dose-related manner. Furthermore, E1R alleviated the scopolamine-induced cognitive impairment during the PA and Y-maze tests in mice. The in vivo and in vitro effects of E1R were blocked by treatment with the selective sigma-1 receptor antagonist NE-100. E1R did not affect locomotor activity. Conclusion and Implications E1R is a novel 4,5-disubstituted derivative of piracetam that enhances cognition and demonstrates efficacy against scopolamine-induced cholinergic dysfunction in mice. These effects are attributed to its positive modulatory action on the sigma-1 receptor and this activity may be relevant when developing new drugs for treating cognitive symptoms related to neurodegenerative diseases. PMID:24490863

Relationship between the Montreal Cognitive Assessment and Mini-mental State Examination for assessment of mild cognitive impairment in older adults.

PubMed

Trzepacz, Paula T; Hochstetler, Helen; Wang, Shufang; Walker, Brett; Saykin, Andrew J

2015-09-07

The Montreal Cognitive Assessment (MoCA) was developed to enable earlier detection of mild cognitive impairment (MCI) relative to familiar multi-domain tests like the Mini-Mental State Exam (MMSE). Clinicians need to better understand the relationship between MoCA and MMSE scores. For this cross-sectional study, we analyzed 219 healthy control (HC), 299 MCI, and 100 Alzheimer's disease (AD) dementia cases from the Alzheimer's Disease Neuroimaging Initiative (ADNI)-GO/2 database to evaluate MMSE and MoCA score distributions and select MoCA values to capture early and late MCI cases. Stepwise variable selection in logistic regression evaluated relative value of four test domains for separating MCI from HC. Functional Activities Questionnaire (FAQ) was evaluated as a strategy to separate dementia from MCI. Equi-percentile equating produced a translation grid for MoCA against MMSE scores. Receiver Operating Characteristic (ROC) analyses evaluated lower cutoff scores for capturing the most MCI cases. Most dementia cases scored abnormally, while MCI and HC score distributions overlapped on each test. Most MCI cases scored ≥ 17 on MoCA (96.3%) and ≥ 24 on MMSE (98.3%). The ceiling effect (28-30 points) for MCI and HC was less using MoCA (18.1%) versus MMSE (71.4%). MoCA and MMSE scores correlated most for dementia (r = 0.86; versus MCI r = 0.60; HC r = 0.43). Equi-percentile equating showed a MoCA score of 18 was equivalent to MMSE of 24. ROC analysis found MoCA ≥ 17 as the cutoff between MCI and dementia that emphasized high sensitivity (92.3%) to capture MCI cases. The core and orientation domains in both tests best distinguished HC from MCI groups, whereas comprehension/executive function and attention/calculation were not helpful. Mean FAQ scores were significantly higher and a greater proportion had abnormal FAQ scores in dementia than MCI and HC. MoCA and MMSE were more similar for dementia cases, but MoCA distributes MCI cases across a broader score range with less ceiling effect. A cutoff of ≥ 17 on the MoCA may help capture early and late MCI cases; depending on the level of sensitivity desired, ≥ 18 or 19 could be used. Functional assessment can help exclude dementia cases. MoCA scores are translatable to the MMSE to facilitate comparison.

Detection and Differentiation of Frontotemporal Dementia and Related Disorders From Alzheimer Disease Using the Montreal Cognitive Assessment.

PubMed

Coleman, Kristy K L; Coleman, Brenda L; MacKinley, Julia D; Pasternak, Stephen H; Finger, Elizabeth C

2016-01-01

The Montreal Cognitive Assessment (MoCA) is a cognitive screening tool used by practitioners worldwide. The efficacy of the MoCA for screening frontotemporal dementia (FTD) and related disorders is unknown. The objectives were: (1) to determine whether the MoCA detects cognitive impairment (CI) in FTD subjects; (2) to determine whether Alzheimer disease (AD) and FTD subtypes and related disorders can be parsed using the MoCA; and (3) describe longitudinal MoCA performance by subtype. We extracted demographic and testing data from a database of patients referred to a cognitive neurology clinic who met criteria for probable AD or FTD (N=192). Logistic regression was used to determine whether dementia subtypes were associated with overall scores, subscores, or combinations of subscores on the MoCA. Initial MoCA results demonstrated CI in the majority of FTD subjects (87%). FTD subjects (N=94) performed better than AD subjects (N=98) on the MoCA (mean scores: 18.1 vs. 16.3; P=0.02). Subscores parsed many, but not all subtypes. FTD subjects had a larger decline on the MoCA within 13 to 36 months than AD subjects (P=0.02). The results indicate that the MoCA is a useful tool to identify and track progression of CI in FTD. Further, the data informs future research on scoring models for the MoCA to enhance cognitive screening and detection of FTD patients.

Usefulness of the Montreal Cognitive Assessment (MoCA) in Huntington's disease.

PubMed

Gluhm, Shea; Goldstein, Jody; Brown, Daniel; Van Liew, Charles; Gilbert, Paul E; Corey-Bloom, Jody

2013-10-01

The Montreal Cognitive Assessment (MoCA) is a brief screening instrument for dementia that is sensitive to executive dysfunction. This study examined its usefulness for assessing cognitive performance in mild, moderate, and severe Huntington's disease (HD), compared with the use of the Mini-Mental State Examination (MMSE). We compared MoCA and MMSE total scores and the number of correct answers in 5 cognitive-specific domains in 104 manifest HD patients and 100 matched controls. For the total HD sample, and for the moderate and severe patients, significant differences between both MoCA and MMSE total scores and almost all cognitive-specific domains emerged. Even mild HD subjects showed significant differences with regard to total score and several cognitive domains on both instruments. We conclude that the MoCA, although not necessarily superior to the MMSE, is a useful instrument for assessing cognitive performance over a broad level of functioning in HD. © 2013 Movement Disorder Society.

Behaviorally activated mRNA expression profiles produce signatures of learning and enhanced inhibition in aged rats with preserved memory.

PubMed

Haberman, Rebecca P; Colantuoni, Carlo; Koh, Ming Teng; Gallagher, Michela

2013-01-01

Aging is often associated with cognitive decline, but many elderly individuals maintain a high level of function throughout life. Here we studied outbred rats, which also exhibit individual differences across a spectrum of outcomes that includes both preserved and impaired spatial memory. Previous work in this model identified the CA3 subfield of the hippocampus as a region critically affected by age and integral to differing cognitive outcomes. Earlier microarray profiling revealed distinct gene expression profiles in the CA3 region, under basal conditions, for aged rats with intact memory and those with impairment. Because prominent age-related deficits within the CA3 occur during neural encoding of new information, here we used microarray analysis to gain a broad perspective of the aged CA3 transcriptome under activated conditions. Behaviorally-induced CA3 expression profiles differentiated aged rats with intact memory from those with impaired memory. In the activated profile, we observed substantial numbers of genes (greater than 1000) exhibiting increased expression in aged unimpaired rats relative to aged impaired, including many involved in synaptic plasticity and memory mechanisms. This unimpaired aged profile also overlapped significantly with a learning induced gene profile previously acquired in young adults. Alongside the increased transcripts common to both young learning and aged rats with preserved memory, many transcripts behaviorally-activated in the current study had previously been identified as repressed in the aged unimpaired phenotype in basal expression. A further distinct feature of the activated profile of aged rats with intact memory is the increased expression of an ensemble of genes involved in inhibitory synapse function, which could control the phenotype of neural hyperexcitability found in the CA3 region of aged impaired rats. These data support the conclusion that aged subjects with preserved memory recruit adaptive mechanisms to retain tight control over excitability under both basal and activated conditions.

The possible consequences for cognitive functions of external electric fields at power line frequency on hippocampal CA1 pyramidal neurons.

PubMed

Migliore, Rosanna; De Simone, Giada; Leinekugel, Xavier; Migliore, Michele

2017-04-01

The possible effects on cognitive processes of external electric fields, such as those generated by power line pillars and household appliances are of increasing public concern. They are difficult to study experimentally, and the relatively scarce and contradictory evidence make it difficult to clearly assess these effects. In this study, we investigate how, why and to what extent external perturbations of the intrinsic neuronal activity, such as those that can be caused by generation, transmission and use of electrical energy can affect neuronal activity during cognitive processes. For this purpose, we used a morphologically and biophysically realistic three-dimensional model of CA1 pyramidal neurons. The simulation findings suggest that an electric field oscillating at power lines frequency, and environmentally measured strength, can significantly alter both the average firing rate and temporal spike distribution properties of a hippocampal CA1 pyramidal neuron. This effect strongly depends on the specific and instantaneous relative spatial location of the neuron with respect to the field, and on the synaptic input properties. The model makes experimentally testable predictions on the possible functional consequences for normal hippocampal functions such as object recognition and spatial navigation. The results suggest that, although EF effects on cognitive processes may be difficult to occur in everyday life, their functional consequences deserve some consideration, especially when they constitute a systematic presence in living environments. © 2016 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

The Cognition and Neuroergonomics (CaN) Collaborative Technology Alliance (CTA): Scientific Vision, Approach, and Translational Paths

DTIC Science & Technology

2012-09-01

The Cognition and Neuroergonomics (CaN) Collaborative Technology Alliance (CTA): Scientific Vision, Approach, and Translational Paths by...The Cognition and Neuroergonomics (CaN) Collaborative Technology Alliance (CTA): Scientific Vision, Approach, and Translational Paths Kelvin S. Oie...REPORT DATE (DD-MM-YYYY) September 2012 2. REPORT TYPE Final 3. DATES COVERED (From - To) 4. TITLE AND SUBTITLE The Cognition and Neuroergonomics

Comparison between mini mental state examination (MMSE) and Montreal cognitive assessment Indonesian version (MoCA-Ina) as an early detection of cognitive impairments in post-stroke patients

NASA Astrophysics Data System (ADS)

Lestari, S.; Mistivani, I.; Rumende, C. M.; Kusumaningsih, W.

2017-08-01

Mild cognitive impairment (MCI) is defined as cognitive impairment that may never develop into dementia. Cognitive impairment is one long-term complication of a stroke. The Mini Mental State Examination (MMSE), which is commonly used as a screening tool for cognitive impairment, has a low sensitivity to detect cognitive impairment, especially MCI. Alternatively, the Montreal Cognitive Assessment Indonesian version (MoCA-Ina) has been reported to have a higher sensitivity than the MMSE. The aim of this study was to compare the proportion of MCI identified between the MMSE and MoCA-Ina in stroke patients. This was a cross-sectional study of stroke outpatients who attended the Polyclinic Neuromuscular Division, Rehabilitation Department, and Polyclinic Stroke, Neurology Department Cipto Mangunkusumo General Hospital, Jakarta. The proportion of MCI identified using the MMSE was 31.03% compared to 72.41% when using the MoCA-Ina. This difference was statistically significant (Fisher’s exact test, p = 0.033). The proportion of MCI in stroke patients was higher when using the MoCA-Ina compared to the MMSE. The MoCA-Ina should be used as an alternative in the early detection of MCI in stroke patients, especially those undergoing rehabilitation.

Validation of Montreal Cognitive Assessment and Discriminant Power of Montreal Cognitive Assessment Subtests in Patients With Mild Cognitive Impairment and Alzheimer Dementia in Turkish Population.

PubMed

Kaya, Yıldız; Aki, Ozlem Erden; Can, Ufuk Anik; Derle, Eda; Kibaroğlu, Seda; Barak, Anil

2014-06-01

Montreal Cognitive Assessment (MoCA) is a new cognitive tool developed for screening mild cognitive impairment (MCI). The authors examined validity of MoCA and discriminating power of subtests in a Turkish population comprising of 474 participants (246 healthy controls, 114 subjects with MCI and 114 subjects with dementia). The ANCOVAs showed that age and education had a main effect on MoCA scores. Cut scores were computed according to different education levels. The overall cut-off values for MCI and dementia were found to be lower compared to western studies. MoCA was found to have good internal consistency. The subtests most useful in discriminating MCI from healthy controls were recall, visuospatial and language, while in discriminating dementia from MCI were visuospatial, orientation and attention subtests. The results demonstrated that MoCA is a valid and reliable instrument in screening MCI, and compared with the MMSE, MoCA was proved to have superior sensitivity and specificity in detecting MCI. © The Author(s) 2014.

Phencyclidine Discoordinates Hippocampal Network Activity But Not Place Fields

PubMed Central

Kao, Hsin-Yi; Kenney, Jana; Kelemen, Eduard

2017-01-01

We used the psychotomimetic phencyclidine (PCP) to investigate the relationships among cognitive behavior, coordinated neural network function, and information processing within the hippocampus place cell system. We report in rats that PCP (5 mg/kg, i.p.) impairs a well learned, hippocampus-dependent place avoidance behavior in rats that requires cognitive control even when PCP is injected directly into dorsal hippocampus. PCP increases 60–100 Hz medium-freguency gamma oscillations in hippocampus CA1 and these increases correlate with the cognitive impairment caused by systemic PCP administration. PCP discoordinates theta-modulated medium-frequency and slow gamma oscillations in CA1 LFPs such that medium-frequency gamma oscillations become more theta-organized than slow gamma oscillations. CA1 place cell firing fields are preserved under PCP, but the drug discoordinates the subsecond temporal organization of discharge among place cells. This discoordination causes place cell ensemble representations of a familiar space to cease resembling pre-PCP representations despite preserved place fields. These findings point to the cognitive impairments caused by PCP arising from neural discoordination. PCP disrupts the timing of discharge with respect to the subsecond timescales of theta and gamma oscillations in the LFP. Because these oscillations arise from local inhibitory synaptic activity, these findings point to excitation–inhibition discoordination as the root of PCP-induced cognitive impairment. SIGNIFICANCE STATEMENT Hippocampal neural discharge is temporally coordinated on timescales of theta and gamma oscillations in the LFP and the discharge of a subset of pyramidal neurons called “place cells” is spatially organized such that discharge is restricted to locations called a cell's “place field.” Because this temporal coordination and spatial discharge organization is thought to represent spatial knowledge, we used the psychotomimetic phencyclidine (PCP) to disrupt cognitive behavior and assess the importance of neural coordination and place fields for spatial cognition. PCP impaired the judicious use of spatial information and discoordinated hippocampal discharge without disrupting firing fields. These findings dissociate place fields from spatial cognitive behavior and suggest that hippocampus discharge coordination is crucial to spatial cognition. PMID:29118102

Montreal Cognitive Assessment (MoCA): validation study for frontotemporal dementia.

PubMed

Freitas, Sandra; Simões, Mário R; Alves, Lara; Duro, Diana; Santana, Isabel

2012-09-01

The Montreal Cognitive Assessment (MoCA) is a brief instrument developed for the screening of milder forms of cognitive impairment, having surpassed the well-known limitations of the Mini-Mental State Examination (MMSE). The aim of the present study was to validate the MoCA as a cognitive screening test for behavioral-variant frontotemporal dementia (bv-FTD) by examining its psychometric properties and diagnostic accuracy. Three matched subgroups of participants were considered: bv-FTD (n = 50), Alzheimer disease (n = 50), and a control group of healthy adults (n = 50). Compared with the MMSE, the MoCA demonstrated consistently superior psychometric properties and discriminant capacity, providing comprehensive information about the patients' cognitive profiles. The diagnostic accuracy of MoCA for bv-FTD was extremely high (area under the curve AUC [MoCA] = 0.934, 95% confidence interval [CI] = 0.866-.974; AUC [MMSE] = 0.772, 95% CI = 0.677-0.850). With a cutoff below 17 points, the MoCA results for sensitivity, specificity, positive predictive value, negative predictive value, and classification accuracy were significantly superior to those of the MMSE. The MoCA is a sensitive and accurate instrument for screening the patients with bv-FTD and represents a better option than the MMSE.

Defining and validating a short form Montreal Cognitive Assessment (s-MoCA) for use in neurodegenerative disease

PubMed Central

Roalf, David R; Moore, Tyler M; Wolk, David A; Arnold, Steven E; Mechanic-Hamilton, Dawn; Rick, Jacqueline; Kabadi, Sushila; Ruparel, Kosha; Chen-Plotkin, Alice S; Chahine, Lama M; Dahodwala, Nabila A; Duda, John E; Weintraub, Daniel A; Moberg, Paul J

2016-01-01

Introduction Screening for cognitive deficits is essential in neurodegenerative disease. Screening tests, such as the Montreal Cognitive Assessment (MoCA), are easily administered, correlate with neuropsychological performance and demonstrate diagnostic utility. Yet, administration time is too long for many clinical settings. Methods Item response theory and computerised adaptive testing simulation were employed to establish an abbreviated MoCA in 1850 well-characterised community-dwelling individuals with and without neurodegenerative disease. Results 8 MoCA items with high item discrimination and appropriate difficulty were identified for use in a short form (s-MoCA). The s-MoCA was highly correlated with the original MoCA, showed robust diagnostic classification and cross-validation procedures substantiated these items. Discussion Early detection of cognitive impairment is an important clinical and public health concern, but administration of screening measures is limited by time constraints in demanding clinical settings. Here, we provide as-MoCA that is valid across neurological disorders and can be administered in approximately 5 min. PMID:27071646

Cognitive performance on the mini-mental state examination and the montreal cognitive assessment across the healthy adult lifespan.

PubMed

Gluhm, Shea; Goldstein, Jody; Loc, Kiet; Colt, Alexandra; Liew, Charles Van; Corey-Bloom, Jody

2013-03-01

We sought to compare age-related performance on the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) across the adult lifespan in an asymptomatic, presumably normal, sample. The MMSE is the most commonly used brief cognitive screening test; however, the MoCA may be better at detecting early cognitive dysfunction. We gave the MMSE and MoCA to 254 community-dwelling participants ranging in age from 20 to 89, stratified by decade, and we compared their scores using the Wilcoxon signed rank test. For the total sample, the MMSE and MoCA differed significantly in total scores as well as in visuospatial, language, and memory domains (for all of these scores, P<0.001). Mean MMSE scores declined only modestly across the decades; mean MoCA scores declined more dramatically. There were no consistent domain differences between the MMSE and MoCA during the third and fourth decades; however, significant differences in memory (P<0.05) and language (P<0.001) emerged in the fifth through ninth decades. We conclude that the MoCA may be a better detector of age-related decrements in cognitive performance than the MMSE, as shown in this community-dwelling adult population.

Factors Influencing Cognitive Function in Subjects With COPD.

PubMed

Dag, Ersel; Bulcun, Emel; Turkel, Yakup; Ekici, Aydanur; Ekici, Mehmet

2016-08-01

The aim of this study was to assess the association between cognitive function and age, pulmonary function, comorbidity index, and the 6-min walk distance in subjects with COPD as well as to compare the Mini Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) in terms of their ability to identify cognitive dysfunction in subjects with COPD. A total of 52 individuals with stable COPD were included in this study. Cognitive function was assessed using MMSE and MoCA. Age, body mass index, the Modified Cumulative Illness Rating Scale, 6-min walk distance, arterial blood gases, and pulmonary function tests were assessed and recorded. The range and SD of scores in subjects with COPD were larger with MoCA than with MMSE. MMSE and MoCA scores are associated with 6-min walk distance and comorbidity index in subjects with COPD. General cognitive function measured by MoCA was negatively correlated with the comorbidity index but was positively associated with 6-min walk distance in subjects with COPD after controlling for possible confounding factors in the multivariate model. However, general cognitive function measured by MMSE was not correlated with the comorbidity index and 6-min walk distance in subjects with COPD, after controlling for possible confounding factors in the multivariate model. MoCA may be a more reliable screening test than MMSE in detecting cognitive impairment in subjects with COPD. The addition of cognitive tests on assessment of subjects with COPD can provide further benefit. Copyright © 2016 by Daedalus Enterprises.

Mild cognitive impairment in symptomatic and asymptomatic cerebrovascular disease.

PubMed

Popović, Irena Martinić; Serić, Vesna; Demarin, Vida

2007-06-15

We tried to evaluate and to compare usefulness of two brief cognitive tests in early detection of cognitive decline in subjects with increased cerebrovascular (CV) risk. As CV risk factors are recognised as important in etiology of dementia, we also aimed to determine the possible associations of specific CV risk factors and cognitive results. Patients (PGs) with first-ever stroke or TIA (N=110) and CV symptoms-free controls (CGs) with CV risk factors present (N=45) matched for age, gender and education level were tested using Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) on admission, at three- and six-month points. In all subjects, detailed CV risk factors profile was assessed. We observed the decrement in cognitive performance during the six-month study period in both groups, more evident if MoCA (p<0.001) than if MMSE was used (p=0.022). Six months after first stroke/TIA 83.6% PGs scored below normal range on MoCA. In PGs, positive associations for cognitive decrement and multiple CV risk factors (>2) were found (p=0.034 for MMSE; p=0.002 for MoCA). In CGs, positive associations were found for cognitive decrement and arterial hypertension with increased IMT values (p<0.001 for MMSE) and for multiple CV risk factors and arterial hypertension (p=0.003 for MoCA). The use of MoCA could aid to early recognition of cognitive deficits in persons with increased CV risk. Individuals with multiple CV risk factors seem to have increased risk of cognitive decline.

Montreal Cognitive Assessment Memory Index Score (MoCA-MIS) as a predictor of conversion from mild cognitive impairment to Alzheimer's disease.

PubMed

Julayanont, Parunyou; Brousseau, Mélanie; Chertkow, Howard; Phillips, Natalie; Nasreddine, Ziad S

2014-04-01

To assess the usefulness of the Montreal Cognitive Assessment (MoCA) total score (MoCA-TS) and Memory Index Score (MoCA-MIS) in predicting conversion to Alzheimer's disease (AD) in individuals with mild cognitive impairment (MCI). Retrospective chart review. Community-based memory clinic. Individuals meeting Petersen's MCI criteria (N = 165). Baseline MoCA scores at MCI diagnosis were collected from charts of eligible individuals with MCI, and MoCA-TS, MoCA-MIS, and a cognitive domain index score were calculated to assess their prognostic value in predicting conversion to AD. One hundred fourteen participants progressed to AD (MCI-AD), and 51 did not (nonconverters; MCI-NC); 90.5% of participants with MCI with a MoCA-TS less than 20/30 and a MoCA-MIS less than 7/15 at baseline converted to AD within the average follow-up period of 18 months, compared with 52.7% of participants with MCI above the cutoffs on both scores. Individuals with multiple-domain amnestic MCI had the highest AD conversion rates (73.9%). Identifying individuals with MCI at high risk of conversion to AD is important clinically and for selecting appropriate subjects for therapeutic trials. Individuals with MCI with a low MoCA-TS and a low newly devised memory index score (MoCA-MIS) are at greater risk of short-term conversion to AD. © 2014, Copyright the Authors Journal compilation © 2014, The American Geriatrics Society.

Brief screening for mild cognitive impairment: validation of the Brazilian version of the Montreal cognitive assessment.

PubMed

Memória, Cláudia M; Yassuda, Mônica S; Nakano, Eduardo Y; Forlenza, Orestes V

2013-01-01

The Montreal Cognitive Assessment (MoCA) is a brief cognitive schedule that has been developed for the screening of patients with Mild Cognitive Impairment (MCI). MCI is recognized as a high-risk state for Alzheimer's disease. The aim of the present study is to examine the reliability and validity of the Brazilian version of the MoCA test (MoCA-BR) in a sample of older individuals with at least 4 years of education. The MoCA-BR was administered to 112 older adults who were classified into three diagnostic groups according to their cognitive state (Alzheimer's disease, n = 28; MCI, n = 43; normal controls, n = 41). This procedure was based on clinical and neuropsychological data. The performance in the MoCA-BR was compared with the Mini-mental state examination (MMSE) and the Cambridge Cognitive Examination. Diagnostic accuracy was examined with the receiver operating characteristic (ROC) curve analyses. Cronbach's alpha for the MoCA-BR was 0.75. Temporal stability (retesting after 3 months) using intraclass correlation coefficient was 0.75 (p < 0.001). The sensitivity and specificity of the MoCA-BR for MCI were 81% and 77%, respectively, with a cut-off score of 25 points. The area under the ROC curve for predicting MCI was 0.82 ± 0.06. The present results indicate that the MoCA-BR maintains its core diagnostic properties rendering it a valid and reliable tool for the screening of MCI among older individuals with at least 4 years of education. Copyright © 2012 John Wiley & Sons, Ltd.

Intellectual and physical activities, but not social activities, are associated with better global cognition: a multi-site evaluation of the cognition and lifestyle activity study for seniors in Asia (CLASSA).

PubMed

Lam, Linda C W; Ong, Paulus Anam; Dikot, Yustiani; Sofiatin, Yulia; Wang, Huali; Zhao, Mei; Li, Wenxiu; Dominguez, Jacqueline; Natividad, Boots; Yusoff, Suraya; Fu, Jong-Ling; Senanarong, Vorapun; Fung, Ada W T; Lai, Ken

2015-09-01

population ageing will lead to a leap in the dementia population in Asia. However, information about potentials for low-cost and low-risk interventions is limited. to study the associations between lifestyle activities and global cognition from the Cognitive and Lifestyle Activity Study for Seniors in Asia (CLASSA). a cross-sectional study. we studied the association between global cognition and lifestyle activity participation in community living older adults (60 years or over) across nine sites in East Asia. A standardised lifestyle activity questionnaire exploring activities from four categories (intellectual, physical, social and recreational) was used to measure the pattern. Global cognition was categorised by locally validated versions of Mini-mental state examination (MMSE) or Montreal Cognitive Assessment (MoCA) (good cognition, GC-scored at the top 25% among participants with no significant cognitive deficit (SCD); normal cognition, NC-middle 50% among participants with no SCD; mild cognitive deficit, MCD-lowest 25% among participants with no SCD; SCD-below local cut-offs for dementia). two thousand four hundred and four (1,009 men; 1,395 women) participants were recruited. The mean age was 71.0 (7.2) years. A higher variety of intellectual and physical activities were associated with GC; more social activities were associated with higher risks of having impaired cognition (multinomial logistic regression). The same association was found in participants with no SCD and had regular activities for over 10 years (n = 574). intellectual activity and physical exercise were associated with better cognitive states in Asian older adults. Community-based intervention may take considerations into specific types of activities to optimise cognition. © The Author 2015. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Mangifera indica Fruit Extract Improves Memory Impairment, Cholinergic Dysfunction, and Oxidative Stress Damage in Animal Model of Mild Cognitive Impairment

PubMed Central

Wattanathorn, Jintanaporn; Muchimapura, Supaporn; Thukham-Mee, Wipawee; Ingkaninan, Kornkanok; Wittaya-Areekul, Sakchai

2014-01-01

To date, the effective preventive paradigm against mild cognitive impairment (MCI) is required. Therefore, we aimed to determine whether Mangifera indica fruit extract, a substance possessing antioxidant and cognitive enhancing effects, could improve memory impairment, cholinergic dysfunction, and oxidative stress damage in animal model of mild cognitive impairment. Male Wistar rats, weighing 180–200 g, were orally given the extract at doses of 12.5, 50, and 200 mg·kg−1 BW for 2 weeks before and 1 week after the bilateral injection of AF64A (icv). At the end of study, spatial memory, cholinergic neurons density, MDA level, and the activities of SOD, CAT, and GSH-Px enzymes in hippocampus were determined. The results showed that all doses of extract could improve memory together with the decreased MDA level and the increased SOD and GSH-Px enzymes activities. The increased cholinergic neurons density in CA1 and CA3 of hippocampus was also observed in rats treated with the extract at doses of 50 and 200 mg·kg−1 BW. Therefore, our results suggested that M. indica, the potential protective agent against MCI, increased cholinergic function and the decreased oxidative stress which in turn enhanced memory. However, further researches are essential to elucidate the possible active ingredients and detail mechanism. PMID:24672632

Mangifera indica fruit extract improves memory impairment, cholinergic dysfunction, and oxidative stress damage in animal model of mild cognitive impairment.

PubMed

Wattanathorn, Jintanaporn; Muchimapura, Supaporn; Thukham-Mee, Wipawee; Ingkaninan, Kornkanok; Wittaya-Areekul, Sakchai

2014-01-01

To date, the effective preventive paradigm against mild cognitive impairment (MCI) is required. Therefore, we aimed to determine whether Mangifera indica fruit extract, a substance possessing antioxidant and cognitive enhancing effects, could improve memory impairment, cholinergic dysfunction, and oxidative stress damage in animal model of mild cognitive impairment. Male Wistar rats, weighing 180-200 g, were orally given the extract at doses of 12.5, 50, and 200 mg · kg(-1) BW for 2 weeks before and 1 week after the bilateral injection of AF64A (icv). At the end of study, spatial memory, cholinergic neurons density, MDA level, and the activities of SOD, CAT, and GSH-Px enzymes in hippocampus were determined. The results showed that all doses of extract could improve memory together with the decreased MDA level and the increased SOD and GSH-Px enzymes activities. The increased cholinergic neurons density in CA1 and CA3 of hippocampus was also observed in rats treated with the extract at doses of 50 and 200 mg · kg(-1) BW. Therefore, our results suggested that M. indica, the potential protective agent against MCI, increased cholinergic function and the decreased oxidative stress which in turn enhanced memory. However, further researches are essential to elucidate the possible active ingredients and detail mechanism.

Comparison of the montreal cognitive assessment and the mini-mental state examination as screening tests in hemodialysis patients without symptoms.

PubMed

Lee, Sun Hwa; Cho, AJin; Min, Yang-Ki; Lee, Young-Ki; Jung, San

2018-11-01

Cognitive impairment in end-stage renal disease patients is associated with an increased risk of mortality. We examined the cognitive function in hemodialysis (HD) patients and compared the Korean versions of the Montreal Cognitive Assessment (K-MoCA) and of the Mini-Mental State Examination (K-MMSE) to identify the better cognitive screening instrument in these patients. Thirty patients undergoing hemodialysis and 30 matched reference group of apparently healthy control were included. All subjects underwent the K-MoCA, K-MMSE and a neuropsychological test battery to measure attention, visuospatial function, language, memory and executive function. All cognitive data were converted to z-scores with appropriate age and education level prior to group comparisons. Cognitive performance 1.0 SD below the mean was defined as modest cognitve impairment while 1.5 below the mean was defined as severe cognitive impairment. Modest cognitive impairment in memory plus other cognitive domains was detected in 27 patients (90%) while severe cognitive impairment in memory plus other cognitive domains was detected in 23 (77%) patients. Total scores in the K-MoCA were significantly lower in HD patients than in the reference group. However, no significant group difference was found in the K-MMSE. The K-MMSE ROC AUC (95% confidence interval) was 0.72 (0.59-0.85) and K-MoCA ROC AUC was 0.77 (0.65-0.89). Cognitive impairment is common but under-diagnosed in this population. The K-MoCA seems to be more sensitive than the K-MMSE in HD patients.

Impaired cognitive discrimination and discoordination of coupled theta-gamma oscillations in Fmr1 knockout mice

PubMed Central

Radwan, Basma; Dvorak, Dino; Fenton, André

2016-01-01

Fragile X syndrome (FXS) patients do not make the fragile X mental retardation protein (FMRP). Absence of FMRP causes dysregulated translation, abnormal synaptic plasticity and the most common form of inherited intellectual disability. But FMRP loss has minimal effects on memory itself, making it difficult to understand why absence of FMRP impairs memory discrimination and increases risk of autistic symptoms in patients, such as exaggerated responses to environmental changes. While Fmr1 knockout (KO) and wild-type (WT) mice perform cognitive discrimination tasks, we find abnormal patterns of coupling between theta and gamma oscillations in perisomatic and dendritic hippocampal CA1 local field potentials of the KO. Perisomatic CA1 theta-gamma phase-amplitude coupling (PAC) decreases with familiarity in both the WT and KO, but activating an invisible shock zone, subsequently changing its location, or turning it off, changes the pattern of oscillatory events in the LFPs recorded along the somato-dendritic axis of CA1. The cognition-dependent changes of this pattern of neural activity are relatively constrained in WT mice compared to KO mice, which exhibit abnormally weak changes during the cognitive challenge caused by changing the location of the shock zone and exaggerated patterns of change when the shock zone is turned off. Such pathophysiology might explain how dysregulated translation leads to intellectual disability in FXS. These findings demonstrate major functional abnormalities after the loss of FMRP in the dynamics of neural oscillations and that these impairments would be difficult to detect by steady-state measurements with the subject at rest or in steady conditions. PMID:26792400

Different Role of CA1 5HT3 Serotonin Receptors on Memory Acquisition Deficit Induced by Total (TSD) and REM Sleep Deprivation (RSD).

PubMed

Eydipour, Zainab; Vaezi, Gholamhassan; Nasehi, Mohammad; Haeri-Rouhani, Seyed-Ali; Zarrindast, Mohammad-Reza

2017-09-01

Serotonin receptors such as 5-HT3 plays critical role in regulation of sleep, wake cycle and cognitive process. Thus, we investigated the role of CA1 5HT3 serotonin receptors in memory acquisition deficit induced by total sleep deprivation (TSD; for 24 hour) and REM sleep deprivation (RSD; for 24 hour). Pain perception and locomotor activity were also assessed as factors that may affect the memory process. Modified water box and multi-platform apparatus were used to induce TSD or RSD, respectively. Passive avoidance, hot plate and open field devices were used for assessment of memory acquisition, pain and locomotor activity, respectively. Totally, 152 male Wistar rats were used in the study. Pre-training, intra-CA1 injection of 5-HT3 receptor agonist Chlorophenylbiguanide (Mchl; 0.01 and 0.001 µg/rat; P < 0.001) and antagonist Y-25130 (0.1 µg/rat; P < 0.001) reduced memory acquisition and did not alter pain response, while higher dose of both drugs increased locomotor activity in normal rats. Both TSD and RSD reduced memory acquisition (P < 0.001) and did not alter locomotor activity, while TSD (P < 0.001) but not RSD induced analgesia effect. The amnesia induced by TSD was restored by subthreshold dose of Y25130 (0.001 µg/rat; P < 0.001) but not Mchl (0.0001 µg/rat), while both drugs reversed TSD-induced analgesia effect (P < 0.01 for Mchl and P < 0.05 for Y25130), and Y25130 increased locomotor activity in TSD rats (P < 0.05). In RSD rats, subthreshold dose of both drugs did not alter memory acquisition deficit and increased locomotor activity (P < 0.001 for Mchl and P < 0.01 for Y25130), while the Y25130 (P < 0.001), but not Mchl induced analgesia in the RSD rats. Based on the above data, CA1 5HT3 receptors seem to play a critical role in cognitive and non-cognitive behaviors induced by TSD and RSD.

The effects of cognitive activity combined with active extremity exercise on balance, walking activity, memory level and quality of life of an older adult sample with dementia.

PubMed

Yoon, Jung Eun; Lee, Suk Min; Lim, Hee Sung; Kim, Tae Hoon; Jeon, Ji Kyeng; Mun, Mee Hyang

2013-12-01

[Purpose] The purpose of this study was to compare the effectiveness of cognitive activity combined with active physical exercise for a sample of older adults with dementia. [Subjects] A convenience sample of 30 patients with dementia (Mini-Mental State Examination score between 16 and 23) was used. Participants were randomly allocated to one of two groups: cognitive activity combined with physical exercise CAE, n=11), and only cognitive activity CA, n=9). [Methods] Both groups participated in a therapeutic exercise program for 30 minutes, three days a week for 12 weeks. The CAE group performed an additional exercise for 30 minutes a day, three days a week for 12 weeks. A Wii Balance Board (WBB, Nintendo, Japan) was used to evaluate postural sway as an assessment of balance. The Berg Balance Scale (BBS) and Modified Falls Efficacy Scale (MFES) were used to assess dynamic balance abilities. The Timed Up-and-Go test (TUG) was used to assess gait, and the Digit Span Test (DST) and 7 Minute Screening Test (7MST) were used to measure memory performance. The Mini-Mental Status Exam-Korean version (MMSE-K), Kenny Self-Care Evaluation (KSCE), and Short Geriatric Depression Scale (GDS) were used to assess quality of life (QOL). [Results] There were significant beneficial effects of the therapeutic program on balance (velocity in EOWB, path length in ECNB, BBS, and MMFE), QOL (MMSE-KC, GDS, KSCE), and memory performance (DSB) in the CAE group compared to CA group, and between pre-test and post-test. [Conclusion] A 12-week CAE program resulted in improvements in balance, memory and QOL. Therefore, some older adults with dementia have the ability to acquire effective skills relevant to daily living.

Traffic-related air pollution impact on mouse brain accelerates myelin and neuritic aging changes with specificity for CA1 neurons

PubMed Central

Woodward, NC; Pakbin, P; Saffari, A; Shirmohammadi, F; Haghani, A; Sioutas, C; Cacciottolo, M; Morgan, TE; Finch, CE

2017-01-01

Traffic-related air pollution (TRAP) is associated with lower cognition and reduced white matter volume in older adults, specifically for particulate matter <2.5 μm diameter (PM2.5). Rodents exposed to TRAP have shown microglial activation and neuronal atrophy. We further investigated age differences of TRAP exposure, with focus on hippocampus for neuritic atrophy, white matter degeneration, and microglial activation. Young and middle-aged mice (3 and 18 month female C57BL/6J) were exposed to nanoscale-PM (nPM, <0.2 μm diameter). Young mice showed selective changes in the hippocampal CA1 region, with neurite atrophy (−25%), decreased MBP (−50%), and increased Iba1 (+50%), with dentate gyrus relatively unaffected. Exposure to nPM of young mice decreased GluA1 protein (−40%) and increased TNFa mRNA (10×). Older controls had age changes approximating nPM effects on young, with no response to nPM, suggesting an age ceiling effect. The CA1 selective vulnerability in young mice parallels CA1 vulnerability in Alzheimer’s disease. We propose that TRAP associated human cognitive and white matter changes involve hippocampal responses to nPM that begin at younger ages. PMID:28212893

[Cognitive impairment, nutritional status and clinical profile in chronic obstructive pulmonary disease].

PubMed

López Torres, Isabel; Torres-Sánchez, Irene; Martín Salvador, Adelina; Ortiz Rubio, Araceli; Rodríguez Alzueta, Elisabeth; Valenza, Marie Carmen

2014-11-01

Chronic obstructive pulmonary disease (COPD) is a progressive disease with a prevalence that increases with the aging of the subject. It presents a high prevalence of comorbidities, such as cognitive decline, which is gaining great clinical relevance in recent years. Factors such as pulmonary function, hypoxemia, hypercapnia or exacerbations contribute to the decline of cognitive functions. The nutritional status has been added to these factors as contributing to cognitive function decline when presenting in COPD. To evidence the relationship between cognitive decline, nutritional status and the clinical profile of patients admitted because of an acute exacerbation of COPD (AECOPD). 110 subjects hospitalized because of COPD, divided in two groups according to their nutritional status and assessment of cognitive decline at admittance, nutritional status and clinical profile. Significant differences between groups concerning nutritional status in anthropometric variables (sex and IMC), functional ability (Barthel index and Daily Life Activities Scale), quality of life (Euroqol- 5D y SGRQ), sleep quality (Pittsburgh), mood (HAD) and cognitive decline (MoCa attention, MoCa abstraction). (p<0.05). Cognitive function is affected in COPD patients with an altered nutritional status when compared to those with a normal nutritional status. The nutritional decline is a factor contributing to the impairment of cognitive functions in this kind of patients, particularly a decline in attention and abstraction ability. Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.

A Recommended Scale for Cognitive Screening in Clinical Trials of Parkinson’s Disease

PubMed Central

Chou, Kelvin L.; Amick, Melissa M.; Brandt, Jason; Camicioli, Richard; Frei, Karen; Gitelman, Darren; Goldman, Jennifer; Growdon, John; Hurtig, Howard I.; Levin, Bonnie; Litvan, Irene; Marsh, Laura; Simuni, Tanya; Tröster, Alexander I.; Uc, Ergun Y.

2010-01-01

Background Cognitive impairment is common in Parkinson’s disease (PD). There is a critical need for a brief, standard cognitive screening measure for use in PD trials whose primary focus is not on cognition. Methods The Parkinson Study Group (PSG) Cognitive/Psychiatric Working Group formed a Task Force to make recommendations for a cognitive scale that could screen for dementia and mild cognitive impairment in clinical trials of PD where cognition is not the primary outcome. This Task Force conducted a systematic literature search for cognitive assessments previously used in a PD population. Scales were then evaluated for their appropriateness to screen for cognitive deficits in clinical trials, including brief administration time (<15 minutes), assessment of the major cognitive domains, and potential to detect subtle cognitive impairment in PD. Results Five scales of global cognition met the predetermined screening criteria and were considered for review. Based on the Task Force’s evaluation criteria the Montreal Cognitive Assessment (MoCA), appeared to be the most suitable measure. Conclusions This Task Force recommends consideration of the MoCA as a minimum cognitive screening measure in clinical trials of PD where cognitive performance is not the primary outcome measure. The MoCA still requires further study of its diagnostic utility in PD populations but appears to be the most appropriate measure among the currently available brief cognitive assessments. Widespread adoption of a single instrument such as the MoCA in clinical trials can improve comparability between research studies on PD. PMID:20878991

Rhynchophylline suppresses soluble Aβ1-42-induced impairment of spatial cognition function via inhibiting excessive activation of extrasynaptic NR2B-containing NMDA receptors.

PubMed

Yang, Yang; Ji, Wei-Gang; Zhu, Zhi-Ru; Wu, Yu-Ling; Zhang, Zhi-Yang; Qu, Shao-Chen

2018-06-01

Rhynchophylline (RIN) is a significant active component isolated from the Chinese herbal medicine Uncaria rhynchophylla. The overproduction of soluble amyloid β protein (Aβ) oligomers in the hippocampus is closely involved in impairments in cognitive function at the early stage of Alzheimer's disease (AD). Growing evidences show that RIN possesses neuroprotective effects against Aβ-induced neurotoxicity. However, whether RIN can prevent soluble Aβ 1-42 -induced impairments in spatial cognitive function and synaptic plasticity is still unclear. Using the combined methods of behavioral tests, immunofluorescence and electrophysiological recordings, we characterized the key neuroprotective properties of RIN and its possible cellular and molecular mechanisms against soluble Aβ 1-42 -related impairments in rats. Our findings are as follows: (1) RIN efficiently rescued the soluble Aβ 1-42 -induced spatial learning and memory deficits in the Morris water maze test and prevented soluble Aβ 1-42 -induced suppression in long term potentiation (LTP) in the entorhinal cortex (EC)-dentate gyrus (DG) circuit. (2) Excessive activation of extrasynaptic GluN2B-NMDAR and subsequent Ca 2+ overload contributed to the soluble Aβ 1-42 -induced impairments in spatial cognitive function and synaptic plasticity. (3) RIN prevented Aβ 1-42 -induced excessive activation of extrasynaptic NMDARs by reducing extrasynaptic NMDARs -mediated excitatory postsynaptic currents and down regulating GluN2B-NMDAR expression in the DG region, which inhibited Aβ 1-42 -induced Ca 2+ overload mediated by extrasynanptic NMDARs. The results suggest that RIN could be an effective therapeutic candidate for cognitive impairment in AD. Copyright © 2018 Elsevier Ltd. All rights reserved.

Gait and Cognition in Parkinson's Disease: Cognitive Impairment Is Inadequately Reflected by Gait Performance during Dual Task.

PubMed

Gaßner, Heiko; Marxreiter, Franz; Steib, Simon; Kohl, Zacharias; Schlachetzki, Johannes C M; Adler, Werner; Eskofier, Bjoern M; Pfeifer, Klaus; Winkler, Jürgen; Klucken, Jochen

2017-01-01

Cognitive and gait deficits are common symptoms in Parkinson's disease (PD). Motor-cognitive dual tasks (DTs) are used to explore the interplay between gait and cognition. However, it is unclear if DT gait performance is indicative for cognitive impairment. Therefore, the aim of this study was to investigate if cognitive deficits are reflected by DT costs of spatiotemporal gait parameters. Cognitive function, single task (ST) and DT gait performance were investigated in 67 PD patients. Cognition was assessed by the Montreal Cognitive Assessment (MoCA) followed by a standardized, sensor-based gait test and the identical gait test while subtracting serial 3's. Cognitive impairment was defined by a MoCA score <26. DT costs in gait parameters [(DT - ST)/ST × 100] were calculated as a measure of DT effect on gait. Correlation analysis was used to evaluate the association between MoCA performance and gait parameters. In a linear regression model, DT gait costs and clinical confounders (age, gender, disease duration, motor impairment, medication, and depression) were correlated to cognitive performance. In a subgroup analysis, we compared matched groups of cognitively impaired and unimpaired PD patients regarding differences in ST, DT, and DT gait costs. Correlation analysis revealed weak correlations between MoCA score and DT costs of gait parameters ( r / r Sp  ≤ 0.3). DT costs of stride length, swing time variability, and maximum toe clearance (| r / r Sp | > 0.2) were included in a regression analysis. The parameters only explain 8% of the cognitive variance. In combination with clinical confounders, regression analysis showed that these gait parameters explained 30% of MoCA performance. Group comparison revealed strong DT effects within both groups (large effect sizes), but significant between-group effects in DT gait costs were not observed. These findings suggest that DT gait performance is not indicative for cognitive impairment in PD. DT effects on gait parameters were substantial in cognitively impaired and unimpaired patients, thereby potentially overlaying the effect of cognitive impairment on DT gait costs. Limits of the MoCA in detecting motor-function specific cognitive performance or variable individual response to the DT as influencing factors cannot be excluded. Therefore, DT gait parameters as marker for cognitive performance should be carefully interpreted in the clinical context.

AWARE-AWAreness during REsuscitation-a prospective study.

PubMed

Parnia, Sam; Spearpoint, Ken; de Vos, Gabriele; Fenwick, Peter; Goldberg, Diana; Yang, Jie; Zhu, Jiawen; Baker, Katie; Killingback, Hayley; McLean, Paula; Wood, Melanie; Zafari, A Maziar; Dickert, Neal; Beisteiner, Roland; Sterz, Fritz; Berger, Michael; Warlow, Celia; Bullock, Siobhan; Lovett, Salli; McPara, Russell Metcalfe Smith; Marti-Navarette, Sandra; Cushing, Pam; Wills, Paul; Harris, Kayla; Sutton, Jenny; Walmsley, Anthony; Deakin, Charles D; Little, Paul; Farber, Mark; Greyson, Bruce; Schoenfeld, Elinor R

2014-12-01

Cardiac arrest (CA) survivors experience cognitive deficits including post-traumatic stress disorder (PTSD). It is unclear whether these are related to cognitive/mental experiences and awareness during CPR. Despite anecdotal reports the broad range of cognitive/mental experiences and awareness associated with CPR has not been systematically studied. The incidence and validity of awareness together with the range, characteristics and themes relating to memories/cognitive processes during CA was investigated through a 4 year multi-center observational study using a three stage quantitative and qualitative interview system. The feasibility of objectively testing the accuracy of claims of visual and auditory awareness was examined using specific tests. The outcome measures were (1) awareness/memories during CA and (2) objective verification of claims of awareness using specific tests. Among 2060 CA events, 140 survivors completed stage 1 interviews, while 101 of 140 patients completed stage 2 interviews. 46% had memories with 7 major cognitive themes: fear; animals/plants; bright light; violence/persecution; deja-vu; family; recalling events post-CA and 9% had NDEs, while 2% described awareness with explicit recall of 'seeing' and 'hearing' actual events related to their resuscitation. One had a verifiable period of conscious awareness during which time cerebral function was not expected. CA survivors commonly experience a broad range of cognitive themes, with 2% exhibiting full awareness. This supports other recent studies that have indicated consciousness may be present despite clinically undetectable consciousness. This together with fearful experiences may contribute to PTSD and other cognitive deficits post CA. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Comparison of the Quick Mild Cognitive Impairment (Qmci) screen to the Montreal Cognitive Assessment (MoCA) in an Australian geriatrics clinic.

PubMed

Clarnette, Roger; O'Caoimh, Rónán; Antony, Deanna N; Svendrovski, Anton; Molloy, D William

2017-06-01

The Montreal Cognitive Assessment (MoCA) accurately differentiates mild cognitive impairment (MCI) from mild dementia and normal controls (NC). While the MoCA is validated in multiple clinical settings, few studies compare it with similar tests also designed to detect MCI. We sought to investigate how the shorter Quick Mild Cognitive Impairment (Qmci) screen compares with the MoCA. Consecutive referrals presenting with cognitive complaints to a teaching hospital geriatric clinic (Fremantle, Western Australia) underwent a comprehensive assessment and were classified as MCI (n = 72) or dementia (n = 109). NC (n = 41) were a sample of convenience. The Qmci and MoCA were scored by trained geriatricians, in random order, blind to the diagnosis. Median Qmci scores for NC, MCI and dementia were 69 (+/-19), 52.5 (+/-12) and 36 (+/-14), respectively, compared with 27 (+/-5), 22 (+/-4) and 15 (+/-7) for the MoCA. The Qmci more accurately identified cognitive impairment (MCI or dementia), area under the curve (AUC) 0.97, than the MoCA (AUC 0.92), p = 0.04. The Qmci was non-significantly more accurate in distinguishing MCI from controls (AUC 0.91 vs 0.84, respectively = 0.16). Both instruments had similar accuracy for differentiating MCI from dementia (AUC of 0.91 vs 0.88, p = 0.35). At the optimal cut-offs, calculated from receiver operating characteristic curves, the Qmci (≤57) had a sensitivity of 91% and specificity of 93% for cognitive impairment, compared with 87% sensitivity and 80% specificity for the MoCA (≤23). While both instruments are accurate in detecting MCI, the Qmci is shorter and arguably easier to complete, suggesting that it is a useful instrument in an Australian geriatric outpatient population. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Validation of a novel Montreal Cognitive Assessment scoring algorithm in non-demented Parkinson's disease patients.

PubMed

Sulzer, Patricia; Becker, Sara; Maetzler, Walter; Kalbe, Elke; van Nueten, Luc; Timmers, Maarten; Machetanz, Gerrit; Streffer, Johannes; Salvadore, Giacomo; Scholz, Erich; Tkaczynska, Zuzanna; Brockmann, Kathrin; Berg, Daniela; Liepelt-Scarfone, Inga

2018-06-23

The early diagnosis of mild cognitive impairment (PD-MCI) in Parkinson's disease (PD) is essential as it increases the future risk for PD dementia (PDD). Recently, a novel weighting algorithm for the Montreal Cognitive Assessment (MoCA) subtests has been reported, to best discriminate between those with and without cognitive impairment in PD. The aim of our study was to validate this scoring algorithm in a large sample of non-demented PD patients, hypothesizing that the weighted MoCA would have a higher diagnostic accuracy for PD-MCI than the original MoCA. In 202 non-demented PD patients, we evaluated cognitive status, clinical and demographic data, as well as the MoCA with a weighted and unweighted score. Receiver operating characteristic (ROC) curve analysis was used to evaluate discriminative ability of the MoCA. Group comparisons and ROC analysis were performed for PD-MCI classifications with a cut-off ≤ 1, 1.5, and 2 standard deviation (SD) below appropriate norms. PD-MCI patients scored lower on the weighted than the original MoCA version (p < 0.001) compared to PD patients with normal cognitive function. Areas under the curve only differed significantly for the 2 SD cut-off, leading to an increased sensitivity of the weighted MoCA score (72.9% vs. 70.5%) and specificity compared to the original version (79.0% vs. 65.4%). Our results indicate better discriminant power for the weighted MoCA compared to the original for more advanced stages of PD-MCI (2 SD cut-off). Future studies are needed to evaluate the predictive value of the weighted MoCA for PDD.

A validation study of the Hong Kong version of Montreal Cognitive Assessment (HK-MoCA) in Chinese older adults in Hong Kong.

PubMed

Yeung, P Y; Wong, L L; Chan, C C; Leung, Jess L M; Yung, C Y

2014-12-01

To validate the Hong Kong version of Montreal Cognitive Assessment (HK-MoCA) in identification of mild cognitive impairment and dementia in Chinese older adults. Cross-sectional study. Cognition clinic and memory clinic of a public hospital in Hong Kong. A total of 272 participants (dementia, n=130; mild cognitive impairment, n=93; normal controls, n=49) aged 60 years or above were assessed using HK-MoCA. The HK-MoCA scores were validated against expert diagnosis according to the Diagnostic and Statistical Manual of Mental Disorders (4th ed) criteria for dementia and Petersen's criteria for mild cognitive impairment. Statistical analysis was performed using receiver operating characteristic curve and regression analyses. Additionally, comparison was made with the Cantonese version of Mini-Mental State Examination and Global Deterioration Scale. The optimal cutoff score for the HK-MoCA to differentiate cognitive impaired persons (mild cognitive impairment and dementia) from normal controls was 21/22 after adjustment of education level, giving a sensitivity of 0.928, specificity of 0.735, and area under the curve of 0.920. Moreover, the cutoff to detect mild cognitive impairment was 21/22 with a sensitivity of 0.828, specificity of 0.735, and area under the curve of 0.847. Score of the Cantonese version of the Mini-Mental State Examination to detect mild cognitive impairment was 26/27 with a sensitivity of 0.785, specificity of 0.816, and area under the curve of 0.857. At the optimal cutoff of 18/19, HK-MoCA identified dementia from controls with a sensitivity of 0.923, specificity of 0.918, and area under the curve of 0.971. The HK-MoCA is a useful cognitive screening instrument for use in Chinese older adults in Hong Kong. A score of less than 22 should prompt further diagnostic assessment. It has comparable sensitivity with the Cantonese version of Mini-Mental State Examination for detection of mild cognitive impairment. It is brief and feasible to conduct in the clinical setting, and can be completed in less than 15 minutes. Thus, HK-MoCA provides an attractive alternative screening instrument to Mini-Mental State Examination which has ceiling effect (ie may fail to detect mild/moderate cognitive impairment in people with high education level or premorbid intelligence) and needs to be purchased due to copyright issues.

Visuomotor adaptability in older adults with mild cognitive decline.

PubMed

Schaffert, Jeffrey; Lee, Chi-Mei; Neill, Rebecca; Bo, Jin

2017-02-01

The current study examined the augmentation of error feedback on visuomotor adaptability in older adults with varying degrees of cognitive decline (assessed by the Montreal Cognitive Assessment; MoCA). Twenty-three participants performed a center-out computerized visuomotor adaptation task when the visual feedback of their hand movement error was presented in a regular (ratio=1:1) or enhanced (ratio=1:2) error feedback schedule. Results showed that older adults with lower scores on the MoCA had less adaptability than those with higher MoCA scores during the regular feedback schedule. However, participants demonstrated similar adaptability during the enhanced feedback schedule, regardless of their cognitive ability. Furthermore, individuals with lower MoCA scores showed larger after-effects in spatial control during the enhanced schedule compared to the regular schedule, whereas individuals with higher MoCA scores displayed the opposite pattern. Additional neuro-cognitive assessments revealed that spatial working memory and processing speed were positively related to motor adaptability during the regular scheduled but negatively related to adaptability during the enhanced schedule. We argue that individuals with mild cognitive decline employed different adaptation strategies when encountering enhanced visual feedback, suggesting older adults with mild cognitive impairment (MCI) may benefit from enhanced visual error feedback during sensorimotor adaptation. Copyright © 2016 Elsevier B.V. All rights reserved.

Cognitive enhancement effects of Bacopa monnieri (Brahmi) on novel object recognition and neuronal density in the prefrontal cortex, striatum and hippocampus in sub-chronic phencyclidine administration rat model of schizophrenia.

PubMed

Wetchateng, Thanitsara; Piyabhan, Pritsana

2015-03-01

Cognitive deficit is a significant problem, which finally occurs in all schizophrenic patients. It can not be attenuated by any antipsychotic drugs. It is well known that changes of neuronal density are correlated with learning and memory deficits. Bacopa monnieri (Brahmi), popularly known as a cognitive enhancer; might be a novel therapeutic agentfor cognitive deficit in schizophrenia by changing cerebral neuronal density. The objective of this study was to determine the effects of Brahmi on attenuation at cognitive deficit and on the neuronal density in the prefrontal cortex, striatum and cornu ammonis subfield 1 (CA1) and 2/3 (CA2/3) of hippocampus in sub-chronic phencyclidine (PCP) rat model of schizophrenia. Rats were assigned to three groups; Group-1: Control, Group-2: PCP administration and Group-3: PCP + Brahmi. Rats were testedfor cognitive ability by using the novel object recognition test. Neuronal density from a serial Nissl stain sections ofthe prefrontal cortex, striatum and hippocampus ofrat model ofschizophrenia were measured by using Image ProPlus software and manual counting. Sub-chronic administration of PCP results in cognitive deficits in novel object recognition task. This occurred alongside significantly increased neuronal density in CA1. The cognitive deficit was recovery to normal in PCP + Brahmi group and it occurred alongside significantly decreased neuronal density in CA1. On the other hand, significantly increased neuronal density was observed in CA2/3 of PCP + Brahmi group compared with PCP alone. Brahmi is a potential cognitive enhancer against schizophrenia. It reduces neuronal density, most likely glutamatergic neuron, which results in neuronal toxicity and cognitive deficit. Therefore, Brahmi has cognitive enhancement effect by reducing glutamatergic neuron in CAI. Moreover, it also has neurogenesis effect in CA2/3, which is needed to be investigated in the further study.

Sex- and dose-dependent effects of calcium ion irradiation on behavioral performance of B6D2F1 mice during contextual fear conditioning training

NASA Astrophysics Data System (ADS)

Raber, Jacob; Weber, Sydney J.; Kronenberg, Amy; Turker, Mitchell S.

2016-06-01

The space radiation environment includes energetic charged particles that may impact behavioral and cognitive performance. The relationship between the dose and the ionization density of the various types of charged particles (expressed as linear energy transfer or LET), and cognitive performance is complex. In our earlier work, whole body exposure to 28Si ions (263 MeV/n, LET = 78keV / μ m ; 1.6 Gy) affected contextual fear memory in C57BL/6J × DBA2/J F1 (B6D2F1) mice three months following irradiation but this was not the case following exposure to 48Ti ions (1 GeV/n, LET = 107keV / μ m ; 0.2 or 0.4 Gy). As an increased understanding of the impact of charged particle exposures is critical for assessment of risk to the CNS of astronauts during and following missions, in this study we used 40Ca ion beams (942 MeV/n, LET = 90keV / μm) to determine the behavioral and cognitive effects for the LET region between that of Si ions and Ti ions. 40Ca ion exposure reduced baseline activity in a novel environment in a dose-dependent manner, which suggests reduced motivation to explore and/or a diminished level of curiosity in a novel environment. In addition, exposure to 40Ca ions had sex-dependent effects on response to shock. 40Ca ion irradiation reduced the response to shock in female, but not male, mice. In contrast, 40Ca ion irradiation did not affect fear learning, memory, or extinction of fear memory for either gender at the doses employed in this study. Thus 40Ca ion irradiation affected behavioral, but not cognitive, performance. The effects of 40Ca ion irradiation on behavioral performance are relevant, as a combination of novelty and aversive environmental stimuli is pertinent to conditions experienced by astronauts during and following space missions.

Sex- and dose-dependent effects of calcium ion irradiation on behavioral performance of B6D2F1 mice during contextual fear conditioning training.

PubMed

Raber, Jacob; Weber, Sydney J; Kronenberg, Amy; Turker, Mitchell S

2016-06-01

The space radiation environment includes energetic charged particles that may impact behavioral and cognitive performance. The relationship between the dose and the ionization density of the various types of charged particles (expressed as linear energy transfer or LET), and cognitive performance is complex. In our earlier work, whole body exposure to (28)Si ions (263 MeV/n, LET=78keV/μm; 1.6 Gy) affected contextual fear memory in C57BL/6J × DBA2/J F1 (B6D2F1) mice three months following irradiation but this was not the case following exposure to (48)Ti ions (1 GeV/n, LET=107keV/μm; 0.2 or 0.4 Gy). As an increased understanding of the impact of charged particle exposures is critical for assessment of risk to the CNS of astronauts during and following missions, in this study we used (40)Ca ion beams (942 MeV/n, LET=90keV/μm) to determine the behavioral and cognitive effects for the LET region between that of Si ions and Ti ions. (40)Ca ion exposure reduced baseline activity in a novel environment in a dose-dependent manner, which suggests reduced motivation to explore and/or a diminished level of curiosity in a novel environment. In addition, exposure to (40)Ca ions had sex-dependent effects on response to shock. (40)Ca ion irradiation reduced the response to shock in female, but not male, mice. In contrast, (40)Ca ion irradiation did not affect fear learning, memory, or extinction of fear memory for either gender at the doses employed in this study. Thus (40)Ca ion irradiation affected behavioral, but not cognitive, performance. The effects of (40)Ca ion irradiation on behavioral performance are relevant, as a combination of novelty and aversive environmental stimuli is pertinent to conditions experienced by astronauts during and following space missions. Copyright © 2016 The Committee on Space Research (COSPAR). Published by Elsevier Ltd. All rights reserved.

Impaired cognitive discrimination and discoordination of coupled theta-gamma oscillations in Fmr1 knockout mice.

PubMed

Radwan, Basma; Dvorak, Dino; Fenton, André A

2016-04-01

Fragile X syndrome (FXS) patients do not make the fragile X mental retardation protein (FMRP). The absence of FMRP causes dysregulated translation, abnormal synaptic plasticity and the most common form of inherited intellectual disability. But FMRP loss has minimal effects on memory itself, making it difficult to understand why the absence of FMRP impairs memory discrimination and increases risk of autistic symptoms in patients, such as exaggerated responses to environmental changes. While Fmr1 knockout (KO) and wild-type (WT) mice perform cognitive discrimination tasks, we find abnormal patterns of coupling between theta and gamma oscillations in perisomatic and dendritic hippocampal CA1 local field potentials of the KO. Perisomatic CA1 theta-gamma phase-amplitude coupling (PAC) decreases with familiarity in both the WT and KO, but activating an invisible shock zone, subsequently changing its location, or turning it off, changes the pattern of oscillatory events in the LFPs recorded along the somato-dendritic axis of CA1. The cognition-dependent changes of this pattern of neural activity are relatively constrained in WT mice compared to KO mice, which exhibit abnormally weak changes during the cognitive challenge caused by changing the location of the shock zone and exaggerated patterns of change when the shock zone is turned off. Such pathophysiology might explain how dysregulated translation leads to intellectual disability in FXS. These findings demonstrate major functional abnormalities after the loss of FMRP in the dynamics of neural oscillations and that these impairments would be difficult to detect by steady-state measurements with the subject at rest or in steady conditions. Copyright © 2016 Elsevier Inc. All rights reserved.

Excessive activation of AhR signaling disrupts neuronal migration in the hippocampal CA1 region in the developing mouse.

PubMed

Kimura, Eiki; Kubo, Ken-Ichiro; Endo, Toshihiro; Nakajima, Kazunori; Kakeyama, Masaki; Tohyama, Chiharu

2017-01-01

The aryl hydrocarbon receptor (AhR) avidly binds dioxin, a ubiquitous environmental contaminant. Disruption of downstream AhR signaling has been reported to alter neuronal development, and rodent offspring exposed to dioxin during gestation and lactation showed abnormalities in learning and memory, emotion, and social behavior. However, the mechanism behind the disrupted AhR signaling and developmental neurotoxicity induced by xenobiotic ligands remains elusive. Therefore, we studied how excessive AhR activation affects neuronal migration in the hippocampal CA1 region of the developing mouse brain. We transfected constitutively active (CA)-AhR, AhR, or control vector plasmids into neurons via in utero electroporation on gestational day 14 and analyzed neuronal positioning in the hippocampal CA1 region of offspring on postnatal day 14. CA-AhR transfection affected neuronal positioning, whereas no change was observed in AhR-transfected or control hippocampus. These results suggest that constitutively activated AhR signaling disrupts neuronal migration during hippocampal development. Further studies are needed to investigate whether such developmental disruption in the hippocampus leads to the abnormal cognition and behavior of rodent offspring upon maternal exposure to AhR xenobiotic ligands.

[Cognitive Function and Calcium. Structures and functions of Ca2+-permeable channels].

PubMed

Kaneko, Shuji

2015-02-01

Calcium is essential for living organisms where the increase in intracellular Ca2+ concentration functions as a second messenger for many cellular processes including synaptic transmission and neural plasticity. The cytosolic concentration of Ca2+ is finely controlled by many Ca2+-permeable ion channels and transporters. The comprehensive view of their expression, function, and regulation will advance our understanding of neural and cognitive functions of Ca2+, which leads to the future drug discovery.

Assessment of cognitive impairment in long-term oxygen therapy-dependent COPD patients.

PubMed

Karamanli, Harun; Ilik, Faik; Kayhan, Fatih; Pazarli, Ahmet Cemal

2015-01-01

A number of studies have shown that COPD, particularly in its later and more severe stages, is associated with various cognitive deficits. Thus, the primary goal of the present study was to elucidate the extent of cognitive impairment in patients with long-term oxygen therapy-dependent (LTOTD) COPD. In addition, this study aimed to determine the effectiveness of two cognitive screening tests, the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA), for COPD patients and the ability of oxygen therapy to mitigate COPD-related deficits in cognitive function. The present study enrolled 45 subjects: 24 nonuser and 21 regular-user LTOTD-COPD patients. All subjects had a similar grade of education, and there were no significant differences regarding age or sex. The MoCA (cutoff: <26 points) and MMSE (cutoff: ≤24 points) scores were compared between these two groups. The nonuser LTOTD-COPD group had a significantly lower MoCA score than that of the regular-user LTOTD-COPD group (19.38±2.99 vs 21.68±2.14, respectively) as well as a significantly lower MMSE score. Moreover, the absence of supplemental oxygen therapy increased the risk of cognitive impairment (MoCA, P=0.007 and MMSE, P=0.014), and the MoCA and MMSE scores significantly correlated with the number of emergency admissions and the number of hospitalizations in the last year. In the present study, the nonuser LTOTD-COPD group exhibited a significant decrease in cognitive status compared with the regular-user LTOTD-COPD group. This suggests that the assessment of cognitive function in nonuser LTOTD-COPD patients and the use of protective strategies, such as continuous supplemental oxygen treatment, should be considered during the management of COPD in this population. In addition, the MoCA score was superior to the MMSE score for the determination of cognitive impairment in the nonuser LTOTD-COPD patients.

Comparison of the MoCA and BEARNI tests for detection of cognitive impairment in in-patients with alcohol use disorders.

PubMed

Pelletier, Stéphanie; Alarcon, Régis; Ewert, Valérie; Forest, Margot; Nalpas, Bertrand; Perney, Pascal

2018-06-01

Screening of cognitive impairment is a major challenge in alcoholics seeking treatment, since cognitive dysfunction may impair the overall efficacy of rehabilitation programs and consequently increase relapse rate. We compared the performance of two screening tools: the MoCA (Montreal Cognitive Assessment), which is widely used in patients with neurological diseases and already used in patients with alcohol use disorder (AUD), and the BEARNI (Brief Evaluation of Alcohol-Related Neuropsychological Impairments), a recent test specifically developed for the alcoholic population. We compared the sensitivity and specificity of the MoCA and the BEARNI in a sample of AUD patients with and without cognitive impairment assessed by a battery of neuropsychological tests. Ninety patients were included. There were 67 men and 23 women aged 48.9 ± 9.6 years. According to the neuropsychological tests, 51.1% of patients had no cognitive impairment, while it was mild or moderate to severe in 31.1 and 17.8%, respectively. The BEARNI sensitivity was extremely high (1.0), since all patients with cognitive impairment were identified, but its specificity was very low (0.04). The MoCA had a lower sensitivity (0.79) than the BEARNI, but its specificity was significantly better (0.65). A detailed analysis of the BEARNI scores showed a discrepancy between the qualitative and quantitative interpretation of the test which could, at least in part, explain its low specificity. Both the MoCA and the BEARNI are screening tools which identified alcoholic patients with cognitive impairment. However, in routine use, the MoCA appeared to be more appropriate given the low specificity of the BEARNI. Copyright © 2018 Elsevier B.V. All rights reserved.

The relationship between sleep and cognitive function in patients with prediabetes and type 2 diabetes.

PubMed

Saetung, Sunee; Nimitphong, Hataikarn; Siwasaranond, Nantaporn; Sumritsopak, Rungtip; Jindahra, Panitha; Krairit, Orapitchaya; Thakkinstian, Ammarin; Anothaisintawee, Thunyarat; Reutrakul, Sirimon

2018-06-06

Diabetes is linked to cognitive impairment. Sleep plays a role in memory consolidation. Sleep disturbances, commonly found in patients with diabetes, were shown to be related to cognitive dysfunction. This study explored the role of sleep in cognitive function of patients with abnormal glucose tolerance. A total of 162 patients (81 type 2 diabetes and 81 prediabetes) participated. Sleep duration and sleep efficiency (an indicator of sleep quality) were obtained using 7-day actigraphy recordings. Obstructive sleep apnea (OSA) was screened using an overnight in-home monitor. Cognitive function was assessed using the Montreal Cognitive Assessment (MoCA). Three sub-scores of MoCA, visuoexecutive function, attention and delayed recall, were also analyzed. Mean age was 54.8 (10.2) years. OSA was diagnosed in 123 participants (76.9%). Mean sleep duration was 6.0 (1.0) h and sleep efficiency was 82.7 (8.1) %. Sleep duration and OSA severity were not related to MoCA scores. Higher sleep efficiency was associated with higher MoCA scores (p = 0.003), and having diabetes (vs. prediabetes) was associated with lower MoCA scores (p = 0.001). After adjusting covariates, both having diabetes (vs. prediabetes) (B = - 1.137, p = 0.002) and sleep efficiency (B = 0.085, p < 0.001) were independently associated with MoCA scores. In addition, diabetes (B = - 0.608, p < 0.001) and sleep efficiency (B = 0.038, p < 0.001) were associated with visuoexecutive function. Sleep parameters were not related to delayed recall or attention scores. Lower sleep efficiency is independently associated with lower cognitive function in patients with abnormal glucose tolerance. Whether sleep optimization may improve cognitive function in these patients should be explored.

Subclinical atherosclerosis and subsequent cognitive function

PubMed Central

Rossetti, Heidi C.; Weiner, Myron; Hynan, Linda S.; Cullum, C. Munro; Khera, Amit; Lacritz, Laura H.

2016-01-01

Objective To examine the relationship between measures of subclinical atherosclerosis and subsequent cognitive function. Method Participants from the Dallas Heart Study (DHS), a population-based multiethnic study of cardiovascular disease pathogenesis, were re-examined 8 years later (DHS-2) with the Montreal Cognitive Assessment (MoCA); N = 1904, mean age = 42.9, range 8–65. Associations of baseline measures of subclinical atherosclerosis (coronary artery calcium, abdominal aortic plaque, and abdominal aortic wall thickness) with MoCA scores measured at follow-up were examined in the group as a whole and in relation to age and ApoE4 status. Results A significant linear trend of successively lower MoCA scores with increasing numbers of atherosclerotic indicators was observed (F(3, 1150) = 5.918, p = .001). CAC was weakly correlated with MoCA scores (p = .047) and MoCA scores were significantly different between participants with and without CAC (M = 22.35 vs 23.69, p = 0.038). With the exception of a small association between abdominal AWT and MoCA in subjects over age 50, abdominal AWT and abdominal aortic plaque did not correlate with MoCA total score (p ≥.052). Cognitive scores and atherosclerosis measures were not impacted by ApoE4 status (p ≥.455). Conclusion In this ethnically diverse population-based sample, subclinical atherosclerosis was minimally associated with later cognitive function in middle-aged adults. PMID:25957568

Validation of the Telephone Interview of Cognitive Status and Telephone Montreal Cognitive Assessment Against Detailed Cognitive Testing and Clinical Diagnosis of Mild Cognitive Impairment After Stroke.

PubMed

Zietemann, Vera; Kopczak, Anna; Müller, Claudia; Wollenweber, Frank Arne; Dichgans, Martin

2017-11-01

Assessment of cognitive status poststroke is recommended by guidelines but follow-up can often not be done in person. The Telephone Interview of Cognitive Status (TICS) and the Telephone Montreal Cognitive Assessment (T-MoCA) are considered useful screening instruments. Yet, evidence to define optimal cut-offs for mild cognitive impairment (MCI) after stroke is limited. We studied 105 patients enrolled in the prospective DEDEMAS study (Determinants of Dementia After Stroke; NCT01334749). Follow-up visits at 6, 12, 36, and 60 months included comprehensive neuropsychological testing and the Clinical Dementia Rating scale, both of which served as reference standards. The original TICS and T-MoCA were obtained in 2 separate telephone interviews each separated from the personal visits by 1 week (1 before and 1 after the visit) with the order of interviews (TICS versus T-MoCA) alternating between subjects. Area under the receiver-operating characteristic curves was determined. Ninety-six patients completed both the face-to-face visits and the 2 interviews. Area under the receiver-operating characteristic curves ranged between 0.76 and 0.83 for TICS and between 0.73 and 0.94 for T-MoCA depending on MCI definition. For multidomain MCI defined by multiple-tests definition derived from comprehensive neuropsychological testing optimal sensitivities and specificities were achieved at cut-offs <36 (TICS) and <18 (T-MoCA). Validity was lower using single-test definition, and cut-offs were higher compared with multiple-test definitions. Using Clinical Dementia Rating as the reference, optimal cut-offs for MCI were <36 (TICS) and approximately 19 (T-MoCA). Both the TICS and T-MoCA are valid screening tools poststroke, particularly for multidomain MCI using multiple-test definition. © 2017 American Heart Association, Inc.

High Ca2+ Influx During Traumatic Brain Injury Leads to Caspase-1-Dependent Neuroinflammation and Cell Death.

PubMed

Abdul-Muneer, P M; Long, Mathew; Conte, Adriano Andrea; Santhakumar, Vijayalakshmi; Pfister, Bryan J

2017-08-01

We investigated the hypothesis that high Ca 2+ influx during traumatic brain injury induces the activation of the caspase-1 enzyme, which triggers neuroinflammation and cell apoptosis in a cell culture model of neuronal stretch injury and an in vivo model of fluid percussion injury (FPI). We first established that stretch injury causes a rapid increase in the intracellular Ca 2+ level, which activates interleukin-converting enzyme caspase-1. The increase in the intracellular Ca 2+ level and subsequent caspase-1 activation culminates into neuroinflammation via the maturation of IL-1β. Further, we analyzed caspase-1-mediated apoptosis by TUNEL staining and PARP western blotting. The voltage-gated sodium channel blocker, tetrodotoxin, mitigated the stretch injury-induced neuroinflammation and subsequent apoptosis by blocking Ca 2+ influx during the injury. The effect of tetrodotoxin was similar to the caspase-1 inhibitor, zYVAD-fmk, in neuronal culture. To validate the in vitro results, we demonstrated an increase in caspase-1 activity, neuroinflammation and neurodegeneration in fluid percussion-injured animals. Our data suggest that neuronal injury/traumatic brain injury (TBI) can induce a high influx of Ca 2+ to the cells that cause neuroinflammation and cell death by activating caspase-1, IL-1β, and intrinsic apoptotic pathways. We conclude that excess IL-1β production and cell death may contribute to neuronal dysfunction and cognitive impairment associated with TBI.

Metabolic syndrome correlates poorly with cognitive performance in stroke-free community-dwelling older adults: a population-based, cross-sectional study in rural Ecuador.

PubMed

Del Brutto, Oscar H; Mera, Robertino M; Zambrano, Mauricio

2016-04-01

Studies investigating a possible correlation between metabolic syndrome and cognitive decline have been inconsistent. To determine whether metabolic syndrome or each of its components correlate with cognitive performance in community-dwelling older adults in rural Ecuador. Stroke-free Atahualpa residents aged ≥60 years were identified during a door-to-door survey. Metabolic syndrome was defined according to the International Diabetes Federation criteria. Cognition was evaluated by the use of the Montreal Cognitive Assessment (MoCA). Multivariate logistic regression models estimated the association between metabolic syndrome and each of its components with cognitive performance. A total of 212 persons (mean age: 69.2 ± 7.2 years, 64 % women) were enrolled. Of these, 120 (57 %) had metabolic syndrome. Mean scores in the MoCA were 18.2 ± 4.6 for persons with and 19 ± 4.7 for those without metabolic syndrome. In fully adjusted logistic models, MoCA scores were not associated with metabolic syndrome (p = 0.101). After testing individual components of metabolic syndrome with the MoCA score, we found that only hypertriglyceridemia was independently associated with the MoCA score (p = 0.009). This population-based study showed a poor correlation of metabolic syndrome with cognitive performance after adjusting for relevant confounders. Of the individual components of metabolic syndrome, only hypertriglyceridemia correlated with worse cognitive performance.

Changes in Cognitive Function in Patients with Primary Insomnia.

PubMed

Guo, Hui; Wei, Meijie; Ding, Wantao

2017-06-25

Neuropsychological evidence is not sufficient concerning whether there is cognitive impairment in patients with primary insomnia. Further study is needed in this regard. To measure the changes in cognitive functioning in patients with primary insomnia. 40 patients with insomnia (insomnia group) and 48 normal sleepers (control group) were tested using the Pittsburgh Sleep Quality Index (PSQI), episodic memory test, and Montreal Cognitive Assessment (MoCA). The insomnia group had significantly lower scores than the control group in the naming ( t =3.17, p= 0.002), immediate memory ( t =3.33, p= 0.001), and delayed recall ( t =6.05, p= 0.001) sections of the MoCA, as well as a lower overall score on the MoCA ( t =3.24, p= 0.002). Participants with different degrees of insomnia also had significantly different scores in naming ( F =7.56, p= 0.001), language ( F =3.22, p= 0.045), total score ( F =6.72, p= 0.002), delayed memory ( F =8.41, p= 0.001), and delayed recall (F=22.67, p= 0.001) sections of the MoCA. The age of primary insomnia patients was correlated to MoCA total score, immediate memory, delayed recall, and delayed recognition function, also with statistical significance. The years of education of primary insomnia patients was also significantly correlated to overall MoCA score, as well as visuospatial and executive function, naming, attention, language, and abstraction sections of the MoCA. Primary insomnia patients have cognitive impairment. The more severe the insomnia is, the wider the range of and the more serious the degree of cognitive impairment is.

Comparison of Alternate and Original Items on the Montreal Cognitive Assessment.

PubMed

Lebedeva, Elena; Huang, Mei; Koski, Lisa

2016-03-01

The Montreal Cognitive Assessment (MoCA) is a screening tool for mild cognitive impairment (MCI) in elderly individuals. We hypothesized that measurement error when using the new alternate MoCA versions to monitor change over time could be related to the use of items that are not of comparable difficulty to their corresponding originals of similar content. The objective of this study was to compare the difficulty of the alternate MoCA items to the original ones. Five selected items from alternate versions of the MoCA were included with items from the original MoCA administered adaptively to geriatric outpatients (N = 78). Rasch analysis was used to estimate the difficulty level of the items. None of the five items from the alternate versions matched the difficulty level of their corresponding original items. This study demonstrates the potential benefits of a Rasch analysis-based approach for selecting items during the process of development of parallel forms. The results suggest that better match of the items from different MoCA forms by their difficulty would result in higher sensitivity to changes in cognitive function over time.

Predictors of cognitive impairment in an early stage Parkinson's disease cohort.

PubMed

Hu, Michele T M; Szewczyk-Królikowski, Konrad; Tomlinson, Paul; Nithi, Kannan; Rolinski, Michal; Murray, Clara; Talbot, Kevin; Ebmeier, Klaus P; Mackay, Clare E; Ben-Shlomo, Yoav

2014-03-01

The impact of Parkinson's disease (PD) dementia is substantial and has major functional and socioeconomic consequences. Early prediction of future cognitive impairment would help target future interventions. The Montreal Cognitive Assessment (MoCA), the Mini-Mental State Examination (MMSE), and fluency tests were administered to 486 patients with PD within 3.5 years of diagnosis, and the results were compared with those from 141 controls correcting for age, sex, and educational years. Eighteen-month longitudinal assessments were performed in 155 patients with PD. The proportion of patients classified with normal cognition, mild cognitive impairment (MCI), and dementia varied considerably, depending on the MoCA and MMSE thresholds used. With the MoCA total score at screening threshold, 47.7%, 40.5%, and 11.7% of patients with PD were classified with normal cognition, MCI, and dementia, respectively; by comparison, 78.7% and 21.3% of controls had normal cognition and MCI, respectively. Cognitive impairment was predicted by lower education, increased age, male sex, and quantitative motor and non-motor (smell, depression, and anxiety) measures. Longitudinal data from 155 patients with PD over 18 months showed significant reductions in MoCA scores, but not in MMSE scores, with 21.3% of patients moving from normal cognition to MCI and 4.5% moving from MCI to dementia, although 13.5% moved from MCI to normal; however, none of the patients with dementia changed their classification. The MoCA may be more sensitive than the MMSE in detecting early baseline and longitudinal cognitive impairment in PD, because it identified 25.8% of those who experienced significant cognitive decline over 18 months. Cognitive decline was associated with worse motor and non-motor features, suggesting that this reflects a faster progressive phenotype. © 2014 The Authors. International Parkinson and Movement Disorder Society published by Wiley Periodicals, Inc.

Evaluating the relationship between education level and cognitive impairment with the Montreal Cognitive Assessment Test.

PubMed

Yancar Demir, Esra; Özcan, Tuba

2015-09-01

Mild cognitive impairment (MCI) is defined as 'a cognitive decline greater than that expected for an individual's age and education level but that does not interfere notably with activities of daily life'. The Montreal Cognitive Assessment (MoCA) is a screening test for MCI. We investigated the performance of the Turkish version of the MoCA in detecting MCI among elderly persons in a rural area, the majority of whom have a low level of education. We evaluated 50 consecutive men referred from an outpatient clinic. Educational level was divided into three categories: group 1, less than primary (<5 years); group 2, primary (5 years); group 3, more than primary (>5 years). We evaluated the effect of education on MoCA scores and compared subjects' test performance among the different categories of education level. A total of 50 male patients with MCI (mean age: 70.74 ± 7.87) met the inclusion criteria. There were no differences in the total scores based on education or in the subscores for visuospatial/executive function, naming, attention, abstraction and delayed recall. Language was the only domain that showed significant differences between the groups. In post-hoc analysis, differences were found between groups 1 and 3 and between groups 1 and 2. Group 1 had significantly lower scores for language. The repeat subscore for language was significantly lower in group 1 than in group 2. In fluency, there were significant differences between groups 2 and 3 and between group 1 and 3. To our knowledge, this is the first study to analyze the applicability of the Turkish version of MoCA in populations with little education. Our results emphasize the need to adapt the language sections of this test, so it can be easily used in populations with low education levels. © 2014 The Authors. Psychogeriatrics © 2014 Japanese Psychogeriatric Society.

Validity of the Montreal Cognitive Assessment Screener in Adolescents and Young Adults With and Without Congenital Heart Disease.

PubMed

Pike, Nancy A; Poulsen, Marie K; Woo, Mary A

Cognitive deficits are common, long-term sequelae in children and adolescents with congenital heart disease (CHD) who have undergone surgical palliation. However, there is a lack of a validated brief cognitive screening tool appropriate for the outpatient setting for adolescents with CHD. One candidate instrument is the Montreal Cognitive Assessment (MoCA) questionnaire. The purpose of the research was to validate scores from the MoCA against the General Memory Index (GMI) of the Wide Range Assessment of Memory and Learning, 2nd Edition (WRAML2), a widely accepted measure of cognition/memory, in adolescents and young adults with CHD. We administered the MoCA and the WRAML2 to 156 adolescents and young adults ages 14-21 (80 youth with CHD and 76 healthy controls who were gender and age matched). Spearman's rank order correlations were used to assess concurrent validity. To assess construct validity, the Mann-Whitney U test was used to compare differences in scores in youth with CHD and the healthy control group. Receiver operating characteristic curves were created and area under the curve, sensitivity, specificity, positive predictive value, and negative predictive value were also calculated. The MoCA median scores in the CHD versus healthy controls were (23, range 15-29 vs. 28, range 22-30; p < .001), respectively. With the screening cutoff scores at <26 points for the MoCA and 85 for GMI (<1 SD, M = 100, SD = 15), the CHD versus healthy control groups showed sensitivity of .96 and specificity of .67 versus sensitivity of .75 and specificity of .90, respectively, in the detection of cognitive deficits. A cutoff score of 26 on the MoCA was optimal in the CHD group; a cutoff of 25 had similar properties except for a lower negative predictive value. The area under the receiver operating characteristic curve (95% CI) for the MoCA was 0.84 (95% CI [0.75, 0.93], p < .001) and 0.84 (95% CI [0.62, 1.00], p = .02) for the CHD and controls, respectively. Scores on the MoCA were valid for screening to detect cognitive deficits in adolescents and young adults aged 14-21 with CHD when a cutoff score of 26 is used to differentiate youth with and without significant cognitive impairment. Future studies are needed in other adolescent disease groups with known cognitive deficits and healthy populations to explore the generalizability of validity of MoCA scores in adolescents and young adults.

Apolipoprotein Eε4: A Biomarker for Executive Dysfunction among Parkinson's Disease Patients with Mild Cognitive Impairment.

PubMed

Samat, Nor A; Abdul Murad, Nor A; Mohamad, Khairiyah; Abdul Razak, Mohd R; Mohamed Ibrahim, Norlinah

2017-01-01

Background: Cognitive impairment is prevalent in Parkinson's disease (PD), affecting 15-20% of patients at diagnosis. α-synuclein expression and genetic polymorphisms of Apolipoprotein E ( ApoE ) have been associated with the presence of cognitive impairment in PD although data have been inconsistent. Objectives: To determine the prevalence of cognitive impairment in patients with PD using Montreal Cognitive Assessment (MoCA), Comprehensive Trail Making Test (CTMT) and Parkinson's disease-cognitive rating scale (PDCRS), and its association with plasma α-synuclein and ApoE genetic polymorphisms. Methods: This was across-sectional study involving 46 PD patients. Patients were evaluated using Montreal cognitive assessment test (MoCA), and detailed neuropsychological tests. The Parkinson's disease cognitive rating scale (PDCRS) was used for cognitive function and comprehensive trail making test (CTMT) for executive function. Blood was drawn for plasma α-synuclein measurements and ApoE genetic analysis. ApoE polymorphism was detected using MutaGEL APoE from ImmunDiagnostik. Plasma α-synuclein was detected using the ELISA Technique (USCN Life Science Inc.) according to the standard protocol. Results: Based on MoCA, 26 (56.5%) patients had mild cognitive impairment (PD-MCI) and 20 (43.5%) had normal cognition (PD-NC). Based on the PDCRS, 18 (39.1%) had normal cognition (PDCRS-NC), 17 (37%) had mild cognitive impairment (PDCRS-MCI), and 11 (23.9%) had dementia (PDCRS-PDD). In the PDCRS-MCI group, 5 (25%) patients were from PD-NC group and all PDCRS-PDD patients were from PD-MCI group. CTMT scores were significantly different between patients with MCI and normal cognition on MoCA ( p = 0.003). Twenty one patients (72.4%) with executive dysfunction were from the PD-MCI group; 17 (77.3%) with severe executive dysfunction and 4 (57.1%) had mild to moderate executive dysfunction. There were no differences in the plasma α-synuclein concentration between the presence or types of cognitive impairment based on MoCA, PDCRS, and CTMT. The ApoEe4 allele carrier frequency was significantly higher in patients with executive dysfunction ( p = 0.014). Conclusion: MCI was prevalent in our PD population. PDCRS appeared to be more discriminatory in detecting MCI and PDD than MoCA. Plasma α-synuclein level was not associated with presence nor type of cognitive impairment, but the ApoEe4 allele carrier status was significantly associated with executive dysfunction in PD.

Normative Values for the German Version of the Montreal Cognitive Assessment (MoCA)

ClinicalTrials.gov

2018-05-30

Cognitive Impairment; Cognitive Decline; Cognition Disorders; Cognitive Symptom; Cognitive Change; Cognitive Deterioration; Cognitive Abnormality; Cognitive Impairment, Mild; Cognition Disorders in Old Age; Dementia; Dementia Alzheimers; Dementia, Alzheimer Type; Dementia, Mild; Dementia of Alzheimer Type

Subclinical atherosclerosis and subsequent cognitive function.

PubMed

Rossetti, Heidi C; Weiner, Myron; Hynan, Linda S; Cullum, C Munro; Khera, Amit; Lacritz, Laura H

2015-07-01

To examine the relationship between measures of subclinical atherosclerosis and subsequent cognitive function. Participants from the Dallas Heart Study (DHS), a population-based multiethnic study of cardiovascular disease pathogenesis, were re-examined 8 years later (DHS-2) with the Montreal Cognitive Assessment (MoCA); N = 1904, mean age = 42.9, range 8-65. Associations of baseline measures of subclinical atherosclerosis (coronary artery calcium, abdominal aortic plaque, and abdominal aortic wall thickness) with MoCA scores measured at follow-up were examined in the group as a whole and in relation to age and ApoE4 status. A significant linear trend of successively lower MoCA scores with increasing numbers of atherosclerotic indicators was observed (F(3, 1150) = 5.918, p = .001). CAC was weakly correlated with MoCA scores (p = .047) and MoCA scores were significantly different between participants with and without CAC (M = 22.35 vs 23.69, p = 0.038). With the exception of a small association between abdominal AWT and MoCA in subjects over age 50, abdominal AWT and abdominal aortic plaque did not correlate with MoCA total score (p ≥ .052). Cognitive scores and atherosclerosis measures were not impacted by ApoE4 status (p ≥ .455). In this ethnically diverse population-based sample, subclinical atherosclerosis was minimally associated with later cognitive function in middle-aged adults. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Cross-cultural difference and validation of the Chinese version of Montreal Cognitive Assessment in older adults residing in Eastern China: preliminary findings.

PubMed

Hu, Jian-bo; Zhou, Wei-hua; Hu, Shao-hua; Huang, Man-li; Wei, Ning; Qi, Hong-li; Huang, Jin-wen; Xu, Yi

2013-01-01

To evaluate the psychometric properties of the Chinese Montreal Cognitive Assessment (MoCA-C) and assess cross-cultural differences in a community-based cohort residing in the Eastern China. The study included 72 patients with Alzheimer's disease (AD), 84 patients with mild cognitive impairment (MCI) and 146 cognitively normal controls. Sensitivities and specificities were calculated using the recommended cut-off scores. Receiver operator characteristic (ROC) curve analyses were performed to determine optimal sensitivity and specificity. Criterion validity, inter-rater, test-retest reliability and internal consistencies of the MoCA-C were examined, and clinical observations made. The influence of age, education level and gender on MoCA score was examined. Using the recommended cut-off score of 26, the area under the ROC (AUC) for predicting MCI groups using the MoCA-C was 0.930 (95%CI: 0.894; 0.965). The MoCA-C demonstrated 92% sensitivity and 85% specificity in screening for MCI. Cultural differences from the original MoCA affected the test response rate. The MoCA-C appears to have utility as a cognitive screen for early detection of AD and for MCI and warrants further investigation regarding its applicability in primary care settings in elderly Chinese people. It will be necessary to revise the contents of the questionnaire to account for by local characteristics. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Continuous infusion of low-dose unfractionated heparin after aneurysmal subarachnoid hemorrhage: a preliminary study of cognitive outcomes.

PubMed

James, Robert F; Khattar, Nicolas K; Aljuboori, Zaid S; Page, Paul S; Shao, Elaine Y; Carter, Lacey M; Meyer, Kimberly S; Daniels, Michael W; Craycroft, John; Gaughen, John R; Chaudry, M Imran; Rai, Shesh N; Everhart, D Erik; Simard, J Marc

2018-05-11

OBJECTIVE Cognitive dysfunction occurs in up to 70% of aneurysmal subarachnoid hemorrhage (aSAH) survivors. Low-dose intravenous heparin (LDIVH) infusion using the Maryland protocol was recently shown to reduce clinical vasospasm and vasospasm-related infarction. In this study, the Montreal Cognitive Assessment (MoCA) was used to evaluate cognitive changes in aSAH patients treated with the Maryland LDIVH protocol compared with controls. METHODS A retrospective analysis of all patients treated for aSAH between July 2009 and April 2014 was conducted. Beginning in 2012, aSAH patients were treated with LDIVH in the postprocedural period. The MoCA was administered to all aSAH survivors prospectively during routine follow-up visits, at least 3 months after aSAH, by trained staff blinded to treatment status. Mean MoCA scores were compared between groups, and regression analyses were performed for relevant factors. RESULTS No significant differences in baseline characteristics were observed between groups. The mean MoCA score for the LDIVH group (n = 25) was 26.4 compared with 22.7 in controls (n = 22) (p = 0.013). Serious cognitive impairment (MoCA ≤ 20) was observed in 32% of controls compared with 0% in the LDIVH group (p = 0.008). Linear regression analysis demonstrated that only LDIVH was associated with a positive influence on MoCA scores (β = 3.68, p =0.019), whereas anterior communicating artery aneurysms and fevers were negatively associated with MoCA scores. Multivariable linear regression analysis resulted in all 3 factors maintaining significance. There were no treatment complications. CONCLUSIONS This preliminary study suggests that the Maryland LDIVH protocol may improve cognitive outcomes in aSAH patients. A randomized controlled trial is needed to determine the safety and potential benefit of unfractionated heparin in aSAH patients.

The effects of educational background on Montreal Cognitive Assessment screening for vascular cognitive impairment, no dementia, caused by ischemic stroke.

PubMed

Wu, Yuanbo; Wang, Muqiu; Ren, Mingshan; Xu, Wenhua

2013-10-01

It is possible that a patient's educational background has an effect on their Montreal Cognitive Assessment (MoCA) score, which is used to evaluate patients for vascular cognitive impairment, no dementia (VCIND) after ischemic stroke. Cognitive impairment was evaluated in patients with no cognitive impairment (NCI) or VCIND using the MoCA. The receiver operating characteristic curve and maximal Youden index were used to determine the optimal cut-off values to distinguish between NCI and VCIND. The sensitivity and specificity of MoCA were calculated for patients with primary, secondary and tertiary educational levels. Patients with NCI (n=111) and VCIND (n=95) were tested. In patients with a primary education, a significant difference was found between the two groups in each of the MoCA factors, except for naming. Likewise, a significant difference was found in all factors, except for naming, attention and calculation, for patients with a secondary education. For the patients with a tertiary education, a significant difference was found only in visuospatial/executive abilities, abstraction and memory (p<0.05). The optimal cut-off value for MoCA in order to identify VCIND was 22-23. MoCA showed an overall sensitivity of 65.26% and specificity of 78.73%. The sensitivity in the primary, secondary and tertiary educated groups was 97.06%, 56.10% and 40%, respectively, with the specificity being 47.22%, 87.80% and 100%, respectively. We suggest that the MoCA score needs to be amended according to the patient's educational levels in order to improve the effectiveness of the screening. Copyright © 2013 Elsevier Ltd. All rights reserved.

The effect of constitutive over-expression of insulin-like growth factor 1 on the cognitive function in aged mice.

PubMed

Hu, Ankang; Yuan, Honghua; Wu, Lianlian; Chen, Renjin; Chen, Quangang; Zhang, Tengye; Wang, Zhenzhen; Liu, Peng; Zhu, Xiaorong

2016-01-15

The neurotrophic factor insulin-like growth factor (IGF)-1 promotes neurogenesis in the mammalian brain and provides protection against brain injury. However, studies regarding the effects of IGF-1 on cognitive function in aged mice remain limited. We investigated the effects of overexpression of IGF-1 specifically in neural stem cells of the hippocampal dentate gyrus on the recognitive function in 18-month-old transgenic mice. Immunohistocytochemistry and Nissl staining revealed the increased population of BrdU-positive cells as well as the upregulated expression of Nestin and neuronal nuclei (NeuN), respective markers for neural progenitors and neurons, in the hippocampus of the aged IGF-1 transgenic mice versus the wild-type, suggesting that IGF-1 overexpression promotes neurogenesis. In addition, the IGF-1 receptor (IGF-1R), the phosphorylation of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) and extracellular signal-regulated kinase (ERK) were enhanced in the transgenic mice than in the wild-type. Transgenic mice also showed superior performance in the Morris water maze and step-down memory tests to their wild-type counterparts. Moreover, the learning and memory abilities of transgenic mice were significantly undermined with the blockage of CaMKII and ERK signaling pathway. Accordingly, our findings indicated that IGF-1 may mitigate the aged-associated cognitive decline via promoting neurogenesis in the hippocampus and activating CaMKII and ERK signaling by binding with IGF-1R. Copyright © 2015 Elsevier B.V. All rights reserved.

Imaging of a glucose analog, calcium and NADH in neurons and astrocytes: dynamic responses to depolarization and sensitivity to pioglitazone

PubMed Central

Pancani, Tristano; Anderson, Katie L.; Porter, Nada M.; Thibault, Olivier

2011-01-01

Neuronal Ca2+ dyshomeostasis associated with cognitive impairment and mediated by changes in several Ca2+ sources has been seen in animal models of both aging and diabetes. In the periphery, dysregulation of intracellular Ca2+ signals may contribute to the development of insulin resistance. In the brain, while it is well-established that type 2 diabetes mellitus is a risk factor for the development of dementia in the elderly, it is not clear whether Ca2+ dysregulation might also affect insulin sensitivity and glucose utilization. Here we present a combination of imaging techniques testing the disappearance of the fluorescent glucose analog 2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose (2-NBDG) as an indication of glycolytic activity in neurons and astrocytes. Our work shows that glucose utilization at rest is greater in neurons compared to astrocytes, and ceases upon activation in neurons with little change in astrocytes. Pretreatment of hippocampal cultures with pioglitazone, a drug used in the treatment of type 2 diabetes, significantly reduced glycolytic activity in neurons and enhanced it in astrocytes. This series of experiments, including FURA-2 and NADH imaging, provides results that are consistent with the idea that Ca2+ levels may rapidly alter glycolytic activity, and that downstream events beyond Ca2+ dysregulation with aging, may alter cellular metabolism in the brain. PMID:21978418

Correcting the MoCA for education: effect on sensitivity.

PubMed

Gagnon, Genevieve; Hansen, Kevin T; Woolmore-Goodwin, Sarah; Gutmanis, Iris; Wells, Jennie; Borrie, Michael; Fogarty, Jennifer

2013-09-01

The goal of this study was to quantify the impact of the suggested education correction on the sensitivity and specificity of the Montreal Cognitive Assessment (MoCA). Twenty-five outpatients with dementia and 39 with amnestic mild cognitive impairment (aMCI) underwent a diagnostic evaluation, which included the MoCA. Thirty-seven healthy controls also completed the MoCA and psychiatric, medical, neurological, functional, and cognitive difficulties were ruled out. For the total MoCA score, unadjusted for education, a cut-off score of 26 yielded the best balance between sensitivity and specificity (80% and 89% respectively) in identifying cognitive impairment (people with either dementia or aMCI, versus controls). When applying the education correction, sensitivity decreased from 80% to 69% for a small specificity increase (89% to 92%). The cut-off score yielding the best balance between sensitivity and specificity for the education adjusted MoCA score fell to 25 (61% and 97%, respectively). Adjusting the MoCA total score for education had a detrimental effect on sensitivity with only a slight increase in specificity. Clinically, this loss in sensitivity can lead to an increased number of false negatives, as education level does not always correlate to premorbid intellectual function. Clinical judgment about premorbid status should guide interpretation. However, as this effect may be cohort specific, age and education corrected norms and cut-offs should be developed to help guide MoCA interpretation.

Development and validation of a new cognitive screening test: The Hong Kong Brief Cognitive Test (HKBC).

PubMed

Chiu, Helen F K; Zhong, Bao-Liang; Leung, Tony; Li, S W; Chow, Paulina; Tsoh, Joshua; Yan, Connie; Xiang, Yu-Tao; Wong, Mike

2018-07-01

To develop and examine the validity of a new brief cognitive test with less educational bias for screening cognitive impairment. A new cognitive test, Hong Kong Brief Cognitive Test (HKBC), was developed based on review of the literature, as well as the views of an expert panel. Three groups of subjects aged 65 or above were recruited after written consent: normal older people recruited in elderly centres, people with mild NCD (neurocognitive disorder), and people with major NCD. The brief cognitive test, Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment Scale (MoCA), were administered to the subjects. The performance of HKBC in differentiating subjects with major NCD, mild NCD, and normal older people were compared with the clinical diagnosis, as well as the MMSE and MoCA scores. In total, 359 subjects were recruited, with 99 normal controls, 132 subjects with major NCD, and 128 with mild NCD. The mean MMSE, MoCA, and HKBC scores showed significant differences among the 3 groups of subjects. In the receiving operating characteristic curve analysis of the HKBC in differentiating normal subjects from those with cognitive impairment (mild NCD + major NCD), the area under the curve was 0.955 with an optimal cut-off score of 21/22. The performances of MMSE and MoCA in differentiating normal from cognitively impaired subjects are slightly inferior to the HKBC. The HKBC is a brief instrument useful for screening cognitive impairment in older adults and is also useful in populations with low educational level. Copyright © 2018 John Wiley & Sons, Ltd.

Comparison of Alternate and Original Items on the Montreal Cognitive Assessment

PubMed Central

Lebedeva, Elena; Huang, Mei; Koski, Lisa

2016-01-01

Background The Montreal Cognitive Assessment (MoCA) is a screening tool for mild cognitive impairment (MCI) in elderly individuals. We hypothesized that measurement error when using the new alternate MoCA versions to monitor change over time could be related to the use of items that are not of comparable difficulty to their corresponding originals of similar content. The objective of this study was to compare the difficulty of the alternate MoCA items to the original ones. Methods Five selected items from alternate versions of the MoCA were included with items from the original MoCA administered adaptively to geriatric outpatients (N = 78). Rasch analysis was used to estimate the difficulty level of the items. Results None of the five items from the alternate versions matched the difficulty level of their corresponding original items. Conclusions This study demonstrates the potential benefits of a Rasch analysis-based approach for selecting items during the process of development of parallel forms. The results suggest that better match of the items from different MoCA forms by their difficulty would result in higher sensitivity to changes in cognitive function over time. PMID:27076861

Enhanced oscillatory activity in the hippocampal-prefrontal network is related to short-term memory function after early-life seizures

PubMed Central

Kleen, Jonathan K.; Wu, Edie X.; Holmes, Gregory L.; Scott, Rod C.; Lenck-Santini, Pierre-Pascal

2011-01-01

Neurological insults during development are associated with later impairments in learning and memory. Although remedial training can help restore cognitive function, the neural mechanisms of this recovery in memory systems are largely unknown. To examine this issue we measured electrophysiological oscillatory activity in the hippocampus (both CA3 and CA1) and prefrontal cortex of adult rats that had experienced repeated seizures in the first weeks of life, while they were remedially trained on a delayed-nonmatch-to-sample memory task. Seizure-exposed rats showed initial difficulties learning the task but performed similar to control rats after extra training. Whole-session analyses illustrated enhanced theta power in all three structures while seizure rats learned response tasks prior to the memory task. Whilst performing the memory task, dynamic oscillation patterns revealed that prefrontal cortex theta power was increased among seizure-exposed rats. This enhancement appeared after the first memory training steps using short delays and plateaued at the most difficult steps which included both short and long delays. Further, seizure rats showed enhanced CA1-prefrontal theta coherence in correct trials compared to incorrect trials when long delays were imposed, suggesting increased hippocampal-prefrontal synchrony for the task in this group when memory demand was high. Seizure-exposed rats also showed heightened gamma power and coherence among all three structures during the trials. Our results demonstrate the first evidence of hippocampal-prefrontal enhancements following seizures in early development. Dynamic compensatory changes in this network and interconnected circuits may underpin cognitive rehabilitation following other neurological insults to higher cognitive systems. PMID:22031886

Blockade of dopamine D2 receptors disrupts intrahippocampal connectivity and enhances pain-related working memory deficits in neuropathic pain rats.

PubMed

Cardoso-Cruz, H; Dourado, M; Monteiro, C; Galhardo, V

2018-05-01

Dopamine (DA) is thought to be important to local hippocampal networks integrity during spatial working memory (sWM) processing. Chronic pain may contribute to deficient dopaminergic signalling, which may in turn affect cognition. However, the neural mechanisms that determine this impairment are poorly understood. Here, we evaluated whether the sWM impairment characteristic of animal models of chronic pain is dependent on DA D2 receptor (D2r) activity. To address this issue, we implanted multichannel arrays of electrodes in the dorsal and ventral hippocampal CA1 field (dvCA1) of rats and recorded the neuronal activity during a classical delayed food-reinforced T-maze sWM task. Within-subject behavioural performance and patterns of dorsoventral neural activity were assessed before and after the onset of persistent neuropathic pain using the spared nerve injury (SNI) model. Our results show that the peripheral nerve lesion caused a disruption in sWM and hippocampus spike activity and that disruption was maximized by the systemic administration of the D2r antagonist raclopride. These deficits are strictly correlated with a selective disruption of hippocampal theta-oscillations. Particularly, we found a significant decrease in intrahippocampal CA1 field connectivity level. Together, these results suggest that disruption of the dopaminergic balance in the intrahippocampal networks may be important for the development of cognitive deficits experienced during painful conditions. This study provides new insights into the role of D2r in the manifestation of pain-related sWM deficits. Our findings support that selective blockade of D2r produces a significant decrease in intrahippocampal connectivity mediated by theta-oscillations, and amplifies pain-related sWM deficits. These results suggest that further characterization of intrahippocampal dopaminergic modulation may be clinically relevant for the understanding of cognitive impairments that accompanies nociceptive stressful conditions. © 2018 European Pain Federation - EFIC®.

Prevalence of Mild Cognitive Impairment and Dementia in Saudi Arabia: A Community-Based Study.

PubMed

Alkhunizan, Muath; Alkhenizan, Abdullah; Basudan, Loay

2018-01-01

The age of the population in Saudi Arabia is shifting toward elderly, which can lead to an increased risk of mild cognitive impairment (MCI) and dementia. The aim of this study is to determine the prevalence of cognitive impairment (MCI and dementia) among elderly patients in a community-based setting in Riyadh, Saudi Arabia. In this cross-sectional study, we included patients aged 60 years and above who were seen in the Family Medicine Clinics affiliated with King Faisal Specialist Hospital and Research Centre. Patients with delirium, active depression, and patients with a history of severe head trauma in the past 3 months were excluded. Patients were interviewed during their regular visit by a trained physician to collect demographic data and to administer the validated Arabic version of the Montreal Cognitive Assessment (MoCA) test. One hundred seventy-one Saudi patients were recruited based on a calculated sample size for the aim of this study. The mean age of included sample was 67 ± 6 years. The prevalence of cognitive impairment was 45%. The prevalence of MCI was 38.6% and the prevalence of dementia was 6.4%. Age, low level of education, hypertension, and cardiovascular disease were risk factors for cognitive impairment. Prevalence of MCI and dementia in Saudi Arabia using MoCA were in the upper range compared to developed and developing countries. The high rate of risk factors for cognitive impairment in Saudi Arabia is contributing to this finding.

MMSE and MoCA in Parkinson’s disease and dementia with Lewy bodies: a multicenter 1-year follow-up study

PubMed Central

Weis, L.; Bostantjopoulou, S.; Stefanova, E.; Falup-Pecurariu, C.; Kramberger, M. G.; Geurtsen, G. J.; Antonini, A.; Weintraub, D.; Aarsland, D.

2016-01-01

The Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) are the most commonly used scales to test cognitive impairment in Lewy body disease (LBD), but there is no consensus on which is best suited to assess cognition in clinical practice and most sensitive to cognitive decline. Retrospective cohort study of 265 LBD patients [Parkinson’s disease (PD) without dementia (PDnD, N = 197), PD with dementia (PDD, N = 40), and dementia with Lewy bodies (DLB, N = 28)] from an international consortium who completed both the MMSE and MoCA at baseline and 1-year follow-up (N = 153). Percentage of relative standard deviation (RSD%) at baseline was the measure of inter-individual variance, and estimation of change (Cohen’s d) over time was calculated. RSD% for the MoCA (21 %) was greater than for the MMSE (13 %) (p = 0.03) in the whole group. This difference was significant only in PDnD (11 vs. 5 %, p < 0.01), but not in PDD (30 vs. 19 %, p = 0.37) or DLB (15 vs. 14 %, p = 0.78). In contrast, the 1-year estimation of change did not differ between the two tests in any of the groups (Cohen’s effect <0.20 in each group). MMSE and MoCA are equal in measuring the rate of cognitive changes over time in LBD. However, in PDnD, the MoCA is a better measure of cognitive status as it lacks both ceiling and floor effects. PMID:26852137

Self-Esteem Trajectories and Their Social Determinants in Adolescents with Different Levels of Cognitive Ability

ERIC Educational Resources Information Center

Morin, Alexandre J. S.; Arens, A. Katrin; Tracey, Danielle; Parker, Philip D.; Ciarrochi, Joseph; Craven, Rhonda G.; Maïano, Christophe

2017-01-01

This study examines the development of self-esteem in a sample of 138 Australian adolescents (90 males; 48 females) with cognitive abilities in the lowest 15% (L-CA) and a matched sample of 556 Australian adolescents (312 males; 244 females) with average to high levels of cognitive abilities (A/H-CA). These participants were measured annually…

Montreal Cognitive Assessment for screening mild cognitive impairment: variations in test performance and scores by education in Singapore.

PubMed

Ng, Tze Pin; Feng, Lei; Lim, Wee Shiong; Chong, Mei Sian; Lee, Tih Shih; Yap, Keng Bee; Tsoi, Tung; Liew, Tau Ming; Gao, Qi; Collinson, Simon; Kandiah, Nagaendran; Yap, Philip

2015-01-01

The Montreal Cognitive Assessment (MoCA) was developed as a screening instrument for mild cognitive impairment (MCI). We evaluated the MoCA's test performance by educational groups among older Singaporean Chinese adults. The MoCA and Mini-Mental State Examination (MMSE) were evaluated in two independent studies (clinic-based sample and community-based sample) of MCI and normal cognition (NC) controls, using receiver operating characteristic curve analyses: area under the curve (AUC), sensitivity (Sn), and specificity (Sp). The MoCA modestly discriminated MCI from NC in both study samples (AUC = 0.63 and 0.65): Sn = 0.64 and Sp = 0.36 at a cut-off of 28/29 in the clinic-based sample, and Sn = 0.65 and Sp = 0.55 at a cut-off of 22/23 in the community-based sample. The MoCA's test performance was least satisfactory in the highest (>6 years) education group: AUC = 0.50 (p = 0.98), Sn = 0.54, and Sp = 0.51 at a cut-off of 27/28. Overall, the MoCA's test performance was not better than that of the MMSE. In multivariate analyses controlling for age and gender, MCI diagnosis was associated with a <1-point decrement in MoCA score (η(2) = 0.010), but lower (1-6 years) and no education was associated with a 3- to 5-point decrement (η(2) = 0.115 and η(2) = 0.162, respectively). The MoCA's ability to discriminate MCI from NC was modest in this Chinese population, because it was far more sensitive to the effect of education than MCI diagnosis. © 2015 S. Karger AG, Basel.

Exercise reduces diet-induced cognitive decline and increases hippocampal brain-derived neurotrophic factor in CA3 neurons

PubMed Central

Noble, Emily E.; Mavanji, Vijayakumar; Little, Morgan R.; Billington, Charles J.; Kotz, Catherine M.; Wang, ChuanFeng

2014-01-01

Background Previous studies have shown that a western diet impairs, whereas physical exercise enhances hippocampus-dependent learning and memory. Both diet and exercise influence expression of hippocampal brain-derived neurotrophic factor (BDNF), which is associated with improved cognition. We hypothesized that exercise reverses diet-induced cognitive decline while increasing hippocampal BDNF. Methods To test the effects of exercise on hippocampal-dependent memory, we compared cognitive scores of Sprague-Dawley rats exercised by voluntary running wheel (RW) access or forced treadmill (TM) to sedentary (Sed) animals. Memory was tested by two-way active avoidance test (TWAA), in which animals are exposed to a brief shock in a specific chamber area. When an animal avoids, escapes or has reduced latency to do either, this is considered a measure of memory. In a second experiment, rats were fed either a high-fat diet or control diet for 16 weeks, then randomly assigned to running wheel access or sedentary condition, and TWAA memory was tested once a week for seven weeks of exercise intervention. Results Both groups of exercised animals had improved memory as indicated by reduced latency to avoid and escape shock, and increased avoid and escape episodes (p<0.05). Exposure to a high-fat diet resulted in poor performance during both the acquisition and retrieval phases of the memory test as compared to controls. Exercise reversed high-fat diet-induced memory impairment, and increased brain-derived neurotrophic factor (BDNF) in neurons of the hippocampal CA3 region. Conclusions These data suggest that exercise improves memory retrieval, particularly with respect to avoiding aversive stimuli, and may be beneficial in protecting against diet induced cognitive decline, likely via elevated BDNF in neurons of the CA3 region. PMID:24755094

Exercise reduces diet-induced cognitive decline and increases hippocampal brain-derived neurotrophic factor in CA3 neurons.

PubMed

Noble, Emily E; Mavanji, Vijayakumar; Little, Morgan R; Billington, Charles J; Kotz, Catherine M; Wang, ChuanFeng

2014-10-01

Previous studies have shown that a western diet impairs, whereas physical exercise enhances hippocampus-dependent learning and memory. Both diet and exercise influence expression of hippocampal brain-derived neurotrophic factor (BDNF), which is associated with improved cognition. We hypothesized that exercise reverses diet-induced cognitive decline while increasing hippocampal BDNF. To test the effects of exercise on hippocampal-dependent memory, we compared cognitive scores of Sprague-Dawley rats exercised by voluntary running wheel (RW) access or forced treadmill (TM) to sedentary (Sed) animals. Memory was tested by two-way active avoidance test (TWAA), in which animals are exposed to a brief shock in a specific chamber area. When an animal avoids, escapes or has reduced latency to do either, this is considered a measure of memory. In a second experiment, rats were fed either a high-fat diet or control diet for 16 weeks, then randomly assigned to running wheel access or sedentary condition, and TWAA memory was tested once a week for 7 weeks of exercise intervention. Both groups of exercised animals had improved memory as indicated by reduced latency to avoid and escape shock, and increased avoid and escape episodes (p<0.05). Exposure to a high-fat diet resulted in poor performance during both the acquisition and retrieval phases of the memory test as compared to controls. Exercise reversed high-fat diet-induced memory impairment, and increased brain-derived neurotrophic factor (BDNF) in neurons of the hippocampal CA3 region. These data suggest that exercise improves memory retrieval, particularly with respect to avoiding aversive stimuli, and may be beneficial in protecting against diet induced cognitive decline, likely via elevated BDNF in neurons of the CA3 region. Published by Elsevier Inc.

Japanese version of the Montreal Cognitive Assessment cut-off score to clarify improvement of mild cognitive impairment after exercise training in community-dwelling older adults.

PubMed

Nara, Marina; Sugie, Masamitsu; Takahashi, Tetsuya; Koyama, Teruyuki; Sengoku, Renpei; Fujiwara, Yoshinori; Obuchi, Shuichi; Harada, Kazumasa; Kyo, Shunei; Ito, Hideki

2018-02-02

Physical exercise improves cognitive function in people with mild cognitive impairment (MCI). However, information about whether the degree of MCI before exercise training affects improvement in cognitive function is lacking. Therefore, we aimed to investigate the cut-off value in a MCI screening tool that predicts reversal to normal cognitive function after exercise training in older adults with MCI. Participants included 112 Japanese community-dwelling older adult outpatients (37 men, 75 women; mean age 76.3 years). We administered the Japanese version of the Montreal Cognitive Assessment (MoCA-J) before and after exercise training. MCI was defined as a MoCA-J score <26. All participants underwent exercise training 2 days per week for 6 months, according to American Heart Association guidelines. The prevalence of MCI was 65.2%. After exercise training, 46.6% of participants with MCI reversed to normal cognitive function. The MoCA-J cut-off score to predict cognitive function potentially reversible to normal was 23, with receiver operating characteristic analysis showing an area under the curve of 0.80, sensitivity of 79.4% and specificity of 69.2%. Multiple logistic regression analysis to predict non-MCI after exercise training showed that MoCA-J score ≥23 (OR 6.9, P < .001), female sex (OR 3.4, P = .04) and age (OR 0.9, P = .04) were independent determinants. The MoCA-J cut-off score of 23 might be useful to predict cognitive function that is potentially reversible to normal among community-dwelling Japanese older adults with MCI. Geriatr Gerontol Int 2018; ••: ••-••. © 2018 The Authors Geriatrics & Gerontology International published by John Wiley & Sons Australia, Ltd on behalf of Japan Geriatrics Society.

Poststroke QEEG informs early prognostication of cognitive impairment.

PubMed

Schleiger, Emma; Wong, Andrew; Read, Stephen; Rowland, Tennille; Finnigan, Simon

2017-02-01

Cognitive impairment is a common consequence of stroke, but remains difficult to predict. We investigate the ability of early QEEG assessment to inform such prediction, using binary logistic regression. Thirty-five patients (12 female, ages 18-87) suffering middle cerebral artery, ischemic stroke were studied. Resting-state EEG was recorded 48-239 h after symptom onset. Relative power for delta, theta, alpha, and beta bands, delta:alpha ratio, and peak alpha frequency were analyzed. Montreal Cognitive Assessment (MoCA) was administered, where possible, on day of EEG and at median 99 days (range 69-138) poststroke. Eight patients could not complete the baseline MoCA, and four the follow-up MoCA, for varying reasons (most commonly, stroke symptoms). Fifteen patients (48%) had cognitive impairment (MoCA score ≤25) at follow-up. One QEEG index was able to correctly predict presence/absence of cognitive impairment in 24/31 patients (77.4%), whereas predischarge MoCA did so in 23 patients. This index, relative theta frequency (4-7.5 Hz) power, was computed from only three posterior electrodes over the stroke-affected hemisphere. Its predictive accuracy (three electrodes) was higher than that of any "global" QEEG measure (averaged over 19 electrodes). These results may signify association between poststroke alpha slowing and cognitive impairment, which may be mediated by attentional (dys)function, which warrants further investigation. Pending further studies, QEEG measure(s)-from a few electrodes-could inform early prognostication of poststroke cognitive outcomes (and clinical decisions), particularly when cognitive function cannot be adequately assessed (due to symptoms, language, or other issues) or when assessment is equivocal. © 2016 Society for Psychophysiological Research.

Association Between Montreal Cognitive Assessment Scores and Measures of Functional Mobility in Lower Extremity Amputees After Inpatient Rehabilitation.

PubMed

Frengopoulos, Courtney; Burley, Joshua; Viana, Ricardo; Payne, Michael W; Hunter, Susan W

2017-03-01

To determine whether scores on a cognitive measure are associated with walking endurance and functional mobility of individuals with transfemoral or transtibial amputations at discharge from inpatient prosthetic rehabilitation. Retrospective cohort study. Rehabilitation hospital. Consecutive admissions (N=176; mean age ± SD, 64.27±13.23y) with transfemoral or transtibial amputation that had data at admission and discharge from an inpatient prosthetic rehabilitation program. Not applicable. Cognitive status was assessed using the Montreal Cognitive Assessment (MoCA). The L Test and the 2-minute walk test (2MWT) were used to estimate functional mobility and walking endurance. The mean ± SD MoCA score was 24.05±4.09 (range, 6-30), and 56.3% of patients had scores <26. MoCA scores had a small positive correlation with the 2MWT (r=.29, P<.01), and a small negative correlation to the L Test (r=-.24, P<.01). In multivariable linear regression, compared with people with the highest MoCA score quartile, there was no difference on the 2MWT, but people in the lowest 2 quartiles took longer to complete the L Test. Cognitive impairment was very prevalent. The association between MoCA and functional mobility was statistically significant. These results highlight the potential for differences on complex motor tasks for individuals with cognitive impairment but does not indicate a need to exclude them from rehabilitation on the basis of cognitive impairment alone. Copyright © 2016 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.

Rescuing prefrontal cAMP-CREB pathway reverses working memory deficits during withdrawal from prolonged alcohol exposure.

PubMed

Dominguez, G; Dagnas, M; Decorte, L; Vandesquille, M; Belzung, C; Béracochéa, D; Mons, N

2016-03-01

Both human and animal studies indicate that alcohol withdrawal following chronic alcohol consumption (CAC) impairs many of the cognitive functions which rely on the prefrontal cortex (PFC). A candidate signaling cascade contributing to memory deficits during alcohol withdrawal is the protein kinase A (PKA)/cAMP-responsive element binding (CREB) cascade, although the role of PKA/CREB cascade in behavioral and molecular changes during sustained withdrawal period remains largely unknown. We demonstrated that 1 week (1W) or 6 weeks (6W) withdrawal after 6-month CAC impairs working memory (WM) in a T-maze spontaneous alternation task and reduces phosphorylated CREB (pCREB) in the PFC but not the dorsal CA1 region (dCA1) of the hippocampus compared with CAC and water conditions. In contrast, both CAC-unimpaired and withdrawn-impaired mice exhibited decreased pCREB in dCA1 as well as reduced histone H4 acetylation in PFC and dCA1, compared with water controls. Next, we showed that enhancing CREB activity through rolipram administration prior to testing improved WM performance in withdrawn mice but impaired WM function in water mice. In addition, WM improvement correlates positively with increased pCREB level selectively in the PFC of withdrawn mice. Results further indicate that direct infusion of the PKA activator (Sp-cAMPS) into the PFC significantly improves or impairs, respectively, WM performance in withdrawn and water animals. In contrast, Sp-cAMPS had no effect on WM when infused into the dCA1. Collectively, these results provide strong support that dysregulation of PKA/CREB-dependent processes in prefrontal neurons is a critical molecular signature underlying cognitive decline during alcohol withdrawal.

Acute neuroinflammation impairs context discrimination memory and disrupts pattern separation processes in hippocampus.

PubMed

Czerniawski, Jennifer; Guzowski, John F

2014-09-10

Although it is known that immune system activation can impair cognition, no study to date has linked cognitive deficits during acute neuroinflammation to dysregulation of task-relevant neuronal ensemble activity. Here, we assessed both neural circuit activity and context discrimination memory retrieval, in a within-subjects design, of male rats given systemic administration of saline or lipopolysaccharide (LPS). Rats were exposed over several days to two similar contexts: one of which was paired with weak foot shock and the other was not. After reaching criteria for discriminative freezing, rats were given systemic LPS or saline injection and tested for retrieval of context discrimination 6 h later. Importantly, LPS administration produced an acute neuroinflammatory response in dorsal hippocampus at this time (as assessed by elevation of proinflammatory cytokine mRNA levels) and abolished retrieval of the previously acquired discrimination. The impact of neuroinflammation on hippocampal CA3 and CA1 neural circuit activity was assessed using the Arc/Homer1a cellular analysis of temporal activity by fluorescence in situ hybridization imaging method. Whereas the saline-treated subjects discriminated and had low overlap of hippocampal ensembles activated in the two contexts, LPS-treated subjects did not discriminate and had greater ensemble overlap (i.e., reduced orthogonalization). Additionally, retrieval of standard contextual fear conditioning, which does not require context discrimination, was not affected by pretesting LPS administration. Together, the behavioral and circuit analyses data provide compelling evidence that LPS administration impairs context discrimination memory by disrupting cellular pattern separation processes within the hippocampus, thus linking acute neuroinflammation to disruption of specific neural circuit functions and cognitive impairment. Copyright © 2014 the authors 0270-6474/14/3412470-11$15.00/0.

Acute Neuroinflammation Impairs Context Discrimination Memory and Disrupts Pattern Separation Processes in Hippocampus

PubMed Central

Czerniawski, Jennifer

2014-01-01

Although it is known that immune system activation can impair cognition, no study to date has linked cognitive deficits during acute neuroinflammation to dysregulation of task-relevant neuronal ensemble activity. Here, we assessed both neural circuit activity and context discrimination memory retrieval, in a within-subjects design, of male rats given systemic administration of saline or lipopolysaccharide (LPS). Rats were exposed over several days to two similar contexts: one of which was paired with weak foot shock and the other was not. After reaching criteria for discriminative freezing, rats were given systemic LPS or saline injection and tested for retrieval of context discrimination 6 h later. Importantly, LPS administration produced an acute neuroinflammatory response in dorsal hippocampus at this time (as assessed by elevation of proinflammatory cytokine mRNA levels) and abolished retrieval of the previously acquired discrimination. The impact of neuroinflammation on hippocampal CA3 and CA1 neural circuit activity was assessed using the Arc/Homer1a cellular analysis of temporal activity by fluorescence in situ hybridization imaging method. Whereas the saline-treated subjects discriminated and had low overlap of hippocampal ensembles activated in the two contexts, LPS-treated subjects did not discriminate and had greater ensemble overlap (i.e., reduced orthogonalization). Additionally, retrieval of standard contextual fear conditioning, which does not require context discrimination, was not affected by pretesting LPS administration. Together, the behavioral and circuit analyses data provide compelling evidence that LPS administration impairs context discrimination memory by disrupting cellular pattern separation processes within the hippocampus, thus linking acute neuroinflammation to disruption of specific neural circuit functions and cognitive impairment. PMID:25209285

Prevalence and correlates of cognitive impairment in kidney transplant recipients.

PubMed

Gupta, Aditi; Mahnken, Jonathan D; Johnson, David K; Thomas, Tashra S; Subramaniam, Dipti; Polshak, Tyler; Gani, Imran; John Chen, G; Burns, Jeffrey M; Sarnak, Mark J

2017-05-12

There is a high prevalence of cognitive impairment in dialysis patients. The prevalence of cognitive impairment after kidney transplantation is unknown. Study Design: Cross-sectional study. Single center study of prevalent kidney transplant recipients from a transplant clinic in a large academic center. Assessment of cognition using the Montreal Cognitive Assessment (MoCA). Demographic and clinical variables associated with cognitive impairment were also examined. Outcomes and Measurements: a) Prevalence of cognitive impairment defined by a MoCA score of <26. b) Multivariable linear and logistic regression to examine the association of demographic and clinical factors with cognitive impairment. Data from 226 patients were analyzed. Mean (SD) age was 54 (13.4) years, 73% were white, 60% were male, 37% had diabetes, 58% had an education level of college or above, and the mean (SD) time since kidney transplant was 3.4 (4.1) years. The prevalence of cognitive impairment was 58.0%. Multivariable linear regression demonstrated that older age, male gender and absence of diabetes were associated with lower MoCA scores (p < 0.01 for all). Estimated glomerular filtration rate (eGFR) was not associated with level of cognition. The logistic regression analysis confirmed the association of older age with cognitive impairment. Cognitive impairment is common in prevalent kidney transplant recipients, at a younger age compared to general population, and is associated with certain demographic variables, but not level of eGFR.

Rasagiline for mild cognitive impairment in Parkinson's disease: A placebo-controlled trial.

PubMed

Weintraub, Daniel; Hauser, Robert A; Elm, Jordan J; Pagan, Fernando; Davis, Matthew D; Choudhry, Azhar

2016-05-01

This study's aims were to determine the efficacy and tolerability of rasagiline, a selective monoamine oxidase inhibitor B, for PD patients with mild cognitive impairment. Patients on stable dopaminergic therapy were randomized to adjunct rasagiline 1 mg/day or placebo in this 24-week, double-blind, placebo-controlled, multisite study. The primary endpoint was mean change from baseline to week 24 on the Scales for Outcomes of Parkinson's Disease-Cognition total score. Key secondary measures included changes in cognition, activities of daily living, motor scores, and Clinical Global Impression of Change, as well as safety and tolerability measures. Of the 170 patients randomized, 151 (88.2%) completed the study. Change in Scales for Outcomes of Parkinson's Disease-Cognition scores were not significantly different in the rasagiline and placebo groups (adjusted mean: 1.6 [standard error {SE} = 0.5] vs. 0.8 [SE = 0.5] points; LS means difference = 0.8; 95% confidence interval: -0.48, 2.05; P = 0.22). There were no between-group differences in change in the MoCA (p=0.84) or Penn Daily Activities Questionnaire (P = 0.48) scores or in the distribution of Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change modified for mild cognitive impairment (P = 0.1). Changes in motor (UPDRS part III; P = 0.02) and activities of daily living (UPDRS part II; P < 0.001) scores favored rasagiline. Rasagiline was well tolerated; the most common adverse events in both groups were falls and dizziness. Rasagiline treatment in PD patients with mild cognitive impairment was not associated with cognitive improvement. Rasagiline did not worsen cognition, improved motor symptoms and activities of daily living, and was well tolerated in elderly cognitively impaired patients. © 2016 International Parkinson and Movement Disorder Society. © 2016 International Parkinson and Movement Disorder Society.

Correlation among personal, social performance and cognitive impairment in male schizophrenic patient

NASA Astrophysics Data System (ADS)

Damanik, R.; Effendy, E.; Camellia, V.

2018-03-01

Schizophrenia is a dramatic mental illness with tragic manifestation. The consequences of the illness are for the individual, affected his or her family and society. Schizophrenia is one of the twenty illness that causes Years Lost due to Disability. Treating only the symptom is insufficient. The aim of treatment must include the quality of life of aschizophrenic person. This study aims to examine the relationship between cognitive impairment and performance of the person with schizophrenia. Cognitive test is scaled with Indonesian version of Montreal Cognitive Assessment (MoCA-Ina), while personal and social performance isscaled with Personal and Social Performance scale. There are many studies that search the relationship between cognitive impairment and social functioning of schizophrenic patients, but this is the first study that uses PSP and MoCA-Ina. Both PSP and MoCA-Ina are easy to use but still have high sensitivity and specificity, and perhaps can build people’s interest to use it in clinical practice. Twenty-five male schizophrenic patients were assessed in Prof. M. Ildrem Mental Hospital of North Sumatera Province of Indonesia. Positive correlations between MoCA-Ina and PSP score were identified. Clinicians should pay attention to cognitive and might give some early intervention to it.

Montreal Cognitive Assessment (MoCA) screening mild cognitive impairment in patients with chronic kidney disease (CKD) pre-dialysis.

PubMed

Paraizo, Marilise de Andrade; Almeida, Ana Laura Maciel; Pires, Leopoldo Antônio; Abrita, Renata Silva Almeida; Crivellari, Mary Hellen Teixeira; Pereira, Beatriz Dos Santos; Fernandes, Natália Maria da Silva; Bastos, Marcus Gomes

2016-03-01

Individuals with chronic kidney disease (CKD) are at higher risk of developing cognitive impairment (CI), initially mild (MCI), potentially identifiable, but still poorly diagnosed and treated. The Montreal Cognitive Assessment (MoCA) has been indicated for MCI screening in CKD. To assess MCI in patients with CKD not yet on dialysis. Study conducted in 72 non-elderly subjects with pre-dialysis CKD. The neuropsychological assessment included: The global cognitive assessment test MoCA; the clock drawing (CD); the digit span forward (DSF) and reverse (DSR); phonemic verbal (VF) fluency (FAS) and semantics (animals); the fist-edge-palm (FEP); and the memory 10 pictures. The average age of the participants was 56.74 ± 7.63 years, with predominance of male sex (55.6%), mainly with ≥ 4 years of education (84.3%), with CKD cathegories 1, 2 and 3a and 3b (67.6%), hypertension (93.1%) and diabetes mellitus (52.1%). MCI (MoCA ≤ 24) was observed in 73.6% of the patients. We did not find association among MCI with demographic and clinical variables, but a tendency to association with age (p = 0.07), educational level (p= 0.06) and diabetes (0.06). The executive function tests CD, DS-reverse and FEP, individually were able to identify CI with good sensibility and negative predictive value compared to MoCA and together, showed the same capability to identify MCI when compared to MoCA. The MCI is common in non-elderly patients with CKD not yet on dialysis. Together, the CD, DSR and FEP showed similar performance in identify MCI in this population when compared to MoCA, suggesting impairment of executive functions.

Distinct cognitive control mechanisms as revealed by modality-specific conflict adaptation effects.

PubMed

Yang, Guochun; Nan, Weizhi; Zheng, Ya; Wu, Haiyan; Li, Qi; Liu, Xun

2017-04-01

Cognitive control is essential to resolve conflict in stimulus-response compatibility (SRC) tasks. The SRC effect in the current trial is reduced after an incongruent trial as compared with a congruent trial, a phenomenon being termed conflict adaptation (CA). The CA effect is found to be domain-specific , such that it occurs when adjacent trials contain the same type of conflict, but disappears when the conflicts are of different types. Similar patterns have been observed when tasks involve different modalities, but the modality-specific effect may have been confounded by task switching. In the current study, we investigated whether or not cognitive control could transfer across auditory and visual conflicts when task-switching was controlled. Participants were asked to respond to a visual or auditory (Experiments 1A/B) stimulus, with conflict coming from either the same or a different modality. CA effects showed modality-specific patterns. To account for potential confounding effects caused by differences in task-irrelevant properties, we specifically examined the influence of task-irrelevant properties on CA effects within the visual modality (Experiments 2A/B). Significant CA effects were observed across different conflicts from distinct task-irrelevant properties, ruling out that the lack of cross-modal CA effects in Experiments 1A/B resulted from differences in task-irrelevant information. Task-irrelevant properties were further matched in Experiments 3A/B to examine the pure effect of modality. Results replicated Experiments 1A/B showing robust modality-specific CA effects. Taken together, we provide supporting evidences that modality affects cognitive control in conflict resolution, which should be taken into account in theories of cognitive control. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

Vagus nerve stimulation enhances perforant path-CA3 synaptic transmission via the activation of β-adrenergic receptors and the locus coeruleus.

PubMed

Shen, Huilian; Fuchino, Yuta; Miyamoto, Daisuke; Nomura, Hiroshi; Matsuki, Norio

2012-05-01

Vagus nerve stimulation (VNS) is an approved treatment for epilepsy and depression and has cognition-enhancing effects in patients with Alzheimer's disease. The hippocampus is widely recognized to be related to epilepsy, depression, and Alzheimer's disease. One possible mechanism of VNS involves its effect on the hippocampus; i.e. it increases the release of noradrenaline in the hippocampus. However, the effect of VNS on synaptic transmission in the hippocampus is unknown. To determine whether VNS modulates neurotransmission in the hippocampus, we examined the effects of VNS on perforant path (PP)-CA3 synaptic transmission electrophysiologically in anaesthetized rats. VNS induces a persistent enhancement of PP-CA3 field excitatory post-synaptic potentials (fEPSPs). Arc, an immediate early gene, was used to identify active brain regions after VNS. The locus coeruleus (LC), which contains the perikarya of noradrenergic projections, harboured more Arc-positive cells, as measured by in-situ hybridization, after 10-min VNS. In addition, electrical lesions of LC neurons or intraventricular administration of the β-adrenergic receptor antagonist timolol prevented the enhancement of PP-CA3 responses by VNS. In conclusion, the protracted increase in PP-CA3 synaptic transmission that is induced by VNS entails activation of the LC and β-adrenergic receptors. Our novel findings suggest that information from the periphery modulates synaptic transmission in the CA3 region of the hippocampus.

Loss of protohaem IX farnesyltransferase in mature dentate granule cells impairs short-term facilitation at mossy fibre to CA3 pyramidal cell synapses.

PubMed

Booker, Sam A; Campbell, Graham R; Mysiak, Karolina S; Brophy, Peter J; Kind, Peter C; Mahad, Don J; Wyllie, David J A

2017-03-15

Neurodegenerative disorders can exhibit dysfunctional mitochondrial respiratory chain complex IV activity. Conditional deletion of cytochrome c oxidase, the terminal enzyme in the respiratory electron transport chain of mitochondria, from hippocampal dentate granule cells in mice does not affect low-frequency dentate to CA3 glutamatergic synaptic transmission. High-frequency dentate to CA3 glutamatergic synaptic transmission and feedforward inhibition are significantly attenuated in cytochrome c oxidase-deficient mice. Intact presynaptic mitochondrial function is critical for the short-term dynamics of mossy fibre to CA3 synaptic function. Neurodegenerative disorders are characterized by peripheral and central symptoms including cognitive impairments which have been associated with reduced mitochondrial function, in particular mitochondrial respiratory chain complex IV or cytochrome c oxidase activity. In the present study we conditionally removed a key component of complex IV, protohaem IX farnesyltransferase encoded by the COX10 gene, in granule cells of the adult dentate gyrus. Utilizing whole-cell patch-clamp recordings from morphologically identified CA3 pyramidal cells from control and complex IV-deficient mice, we found that reduced mitochondrial function did not result in overt deficits in basal glutamatergic synaptic transmission at the mossy-fibre synapse because the amplitude, input-output relationship and 50 ms paired-pulse facilitation were unchanged following COX10 removal from dentate granule cells. However, trains of stimuli given at high frequency (> 20 Hz) resulted in dramatic reductions in short-term facilitation and, at the highest frequencies (> 50 Hz), also reduced paired-pulse facilitation, suggesting a requirement for adequate mitochondrial function to maintain glutamate release during physiologically relevant activity patterns. Interestingly, local inhibition was reduced, suggesting the effect observed was not restricted to synapses with CA3 pyramidal cells via large mossy-fibre boutons, but rather to all synapses formed by dentate granule cells. Therefore, presynaptic mitochondrial function is critical for the short-term dynamics of synapse function, which may contribute to the cognitive deficits observed in pathological mitochondrial dysfunction. © 2017 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.

Fluoxetine ameliorates cognitive impairments induced by chronic cerebral hypoperfusion via down-regulation of HCN2 surface expression in the hippocampal CA1 area in rats.

PubMed

Luo, Pan; Zhang, Xiaoxue; Lu, Yun; Chen, Cheng; Li, Changjun; Zhou, Mei; Lu, Qing; Xu, Xulin; Shen, Guanxin; Guo, Lianjun

2016-01-01

Chronic cerebral hypoperfusion (CCH) causes cognitive impairments and increases the risk of Alzheimer's disease (AD) and vascular dementia (VD) through several biologically plausible pathways, yet the underlying neurobiological mechanisms are still poorly understood. In this study, we investigated whether fluoxetine, a selective serotonin reuptake inhibitor (SSRI), could play a neuroprotective role against chronic cerebral hypoperfusion injury and to clarify underlying mechanisms of its efficacy. Rats were subjected to permanent bilateral occlusion of the common carotid arteries (two-vessel occlusion, 2VO). Two weeks later, rats were treated with 30 mg/kg fluoxetine (intragastric injection, i.g.) for 6 weeks. Cognitive function was evaluated by Morris water maze (MWM) and novel objects recognition (NOR) test. Long-term potentiation (LTP) was used to address the underlying synaptic mechanisms. Western blotting was used to quantify the protein levels. Our results showed that fluoxetine treatment significantly improved the cognitive impairments caused by 2VO, accompanied with a reversion of 2VO-induced inhibitory of LTP. Furthermore, 2VO caused an up-regulation of hyperpolarization-activated cyclic nucleotide-gated channel 2 (HCN2) surface expressions in the hippocampal CA1 area and fluoxetine also effectively recovered the disorder of HCN2 surface expressions, which may be a possible mechanism that fluoxetine treatment ameliorates cognitive impairments in rats with CCH. Copyright © 2015 Elsevier Inc. All rights reserved.

Enriched endogenous omega-3 fatty acids in mice protect against global ischemia injury.

PubMed

Luo, Chuanming; Ren, Huixia; Wan, Jian-Bo; Yao, Xiaoli; Zhang, Xiaojing; He, Chengwei; So, Kwok-Fai; Kang, Jing X; Pei, Zhong; Su, Huanxing

2014-07-01

Transient global cerebral ischemia, one of the consequences of cardiac arrest and cardiovascular surgery, usually leads to delayed death of hippocampal cornu Ammonis1 (CA1) neurons and cognitive deficits. Currently, there are no effective preventions or treatments for this condition. Omega-3 (ω-3) PUFAs have been shown to have therapeutic potential in a variety of neurological disorders. Here, we report that the transgenic mice that express the fat-1 gene encoding for ω-3 fatty acid desaturase, which leads to an increase in endogenous ω-3 PUFAs and a concomitant decrease in ω-6 PUFAs, were protected from global cerebral ischemia injury. The results of the study show that the hippocampal CA1 neuronal loss and cognitive deficits induced by global ischemia insult were significantly less severe in fat-1 mice than in WT mice controls. The protection against global cerebral ischemia injury was closely correlated with increased production of resolvin D1, suppressed nuclear factor-kappa B activation, and reduced generation of pro-inflammatory mediators in the hippocampus of fat-1 mice compared with WT mice controls. Our study demonstrates that fat-1 mice with high endogenous ω-3 PUFAs exhibit protective effects on hippocampal CA1 neurons and cognitive functions in a global ischemia injury model. Copyright © 2014 by the American Society for Biochemistry and Molecular Biology, Inc.

Brain plasticity and cognitive functions after ethanol consumption in C57BL/6J mice.

PubMed

Stragier, E; Martin, V; Davenas, E; Poilbout, C; Mongeau, R; Corradetti, R; Lanfumey, L

2015-12-15

Acute or chronic administrations of high doses of ethanol in mice are known to produce severe cognitive deficits linked to hippocampal damage. However, we recently reported that chronic and moderate ethanol intake in C57BL/6J mice induced chromatin remodeling within the Bdnf promoters, leading to both enhanced brain-derived neurotrophic factor (BDNF) expression and hippocampal neurogenesis under free-choice protocol. We performed here a series of cellular and behavioral studies to analyze the consequences of these modifications. We showed that a 3-week chronic free-choice ethanol consumption in C57BL/6J mice led to a decrease in DNA methylation of the Bdnf gene within the CA1 and CA3 subfields of the hippocampus, and upregulated hippocampal BDNF signaling pathways mediated by ERK, AKT and CREB. However, this activation did not affect long-term potentiation in the CA1. Conversely, ethanol intake impaired learning and memory capacities analyzed in the contextual fear conditioning test and the novel object recognition task. In addition, ethanol increased behavioral perseveration in the Barnes maze test but did not alter the mouse overall spatial capacities. These data suggested that in conditions of chronic and moderate ethanol intake, the chromatin remodeling leading to BDNF signaling upregulation is probably an adaptive process, engaged via epigenetic regulations, to counteract the cognitive deficits induced by ethanol.

Productive and Non-productive Pathways for Synaptotagmin 1 to Support Ca2+-Triggered Fast Exocytosis.

PubMed

Kim, Jaewook; Shin, Yeon-Kyun

2017-01-01

Ca 2+ -triggered SNARE-mediated membrane fusion is essential for neuronal communication. The speed of this process is of particular importance because it sets a time limit to cognitive and physical activities. In this work, we expand the proteoliposome-to-supported bilayer (SBL) fusion assay by successfully incorporating synaptotagmin 1 (Syt1), a major Ca 2+ sensor. We report that Syt1 and Ca 2+ together can elicit more than a 50-fold increase in the number of membrane fusion events when compared with membrane fusion mediated by SNAREs only. What is remarkable is that ~55% of all vesicle fusion events occurs within 20 ms upon vesicle docking. Furthermore, pre-binding of Syt1 to SNAREs prior to Ca 2+ inhibits spontaneous fusion, but intriguingly, this leads to a complete loss of the Ca 2+ responsiveness. Thus, our results suggest that there is a productive and a non-productive pathway for Syt1, depending on whether there is a premature interaction between Syt1 and SNAREs. Our results show that Ca 2+ binding to Syt1 prior to Syt1's binding to SNAREs may be a prerequisite for the productive pathway. The successful reconstitution of Syt1 activities in the physiological time scale provides new opportunities to test the current mechanistic models for Ca 2+ -triggered exocytosis.

REACH: study protocol of a randomised trial of rehabilitation very early in congenital hemiplegia

PubMed Central

Boyd, Roslyn N; Ziviani, Jenny; Sakzewski, Leanne; Novak, Iona; Badawi, Nadia; Pannek, Kerstin; Elliott, Catherine; Greaves, Susan; Guzzetta, Andrea; Whittingham, Koa; Valentine, Jane; Morgan, Cathy; Wallen, Margaret; Eliasson, Ann-Christin; Findlay, Lisa; Ware, Robert; Fiori, Simona; Rose, Stephen

2017-01-01

Objectives Congenital hemiplegia is the most common form of cerebral palsy (CP). Children with unilateral CP show signs of upper limb asymmetry by 8 months corrected age (ca) but are frequently not referred to therapy until after 12 months ca. This study compares the efficacy of infant-friendly modified constraint-induced movement therapy (Baby mCIMT) to infant friendly bimanual therapy (Baby BIM) on upper limb, cognitive and neuroplasticity outcomes in a multisite randomised comparison trial. Methods and analysis 150 infants (75 in each group), aged between 3 and 6 months ca, with asymmetric brain injury and clinical signs of upper extremity asymmetry will be recruited. Children will be randomised centrally to receive equal doses of either Baby mCIMT or Baby BIM. Baby mCIMT comprises restraint of the unimpaired hand using a simple restraint (eg, glove, sock), combined with intensive parent implemented practice focusing on active use of the impaired hand in a play-based context. In contrast, Baby BIM promotes active play requiring both hands in a play-based context. Both interventions will be delivered by parents at home with monthly home visits and interim telecommunication support by study therapists. Assessments will be conducted at study entry; at 6, 12 months ca immediately postintervention (primary outcome) and 24 months ca (retention). The primary outcome will be the Mini-Assisting Hand Assessment. Secondary outcomes include the Bayley Scale for Infant and Toddler Development (cognitive and motor domains) and the Hand Assessment of Infants. A subset of children will undertake MRI scans at 24 months ca to evaluate brain lesion severity and brain (re)organisation after intervention. Ethics and dissemination Full ethical approvals for this study have been obtained from the relevant sites. The findings will be disseminated in peer-reviewed publications. Trial registration number Australian and New Zealand Clinical Trials Registry: ACTRN12615000180516, Pre results. PMID:28928195

Association between Metabolic Syndrome and Cognitive Impairment after Acute Ischemic Stroke: A Cross-Sectional Study in a Chinese Population.

PubMed

Li, Pan; Quan, Wei; Lu, Da; Wang, Yan; Zhang, Hui-Hong; Liu, Shuai; Jiang, Rong-Cai; Zhou, Yu-Ying

2016-01-01

Metabolic syndrome (MetS), a risk factor for many vascular conditions, is associated with vascular cognitive disorders. The objective of the present study was to explore the associations of MetS and its individual components with the risks of cognitive impairment and neurological dysfunction in patients after acute stroke. This cross-sectional study enrolled 840 patients ranging in age from 53 to 89 years from the Tianjin area of North China. Cognitive function was evaluated using the Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination. Neuropsychiatric behavior was assessed using the Neuropsychiatric Inventory Questionnaire. Emotional state was examined according to the Hamilton Depression Rating Scale, and neuromotor function was evaluated using the National Institutes of Health Stroke Scale, Barthel index, and the Activity of Daily Living test. After overnight fasting, blood samples were obtained to measure biochemistry indicators. MetS and its individual components were closely correlated with MoCA score. MetS patients had high levels of inflammation and a 3.542-fold increased odds ratio (OR) for cognitive impairment [95% confidence interval (CI): 1.972-6.361]. Of the individual MetS components, central obesity (OR 3.039; 95% CI: 1.839-5.023), high fasting plasma glucose (OR 1.915; 95% CI: 1.016-3.607), and type 2 diabetes (OR 2.241; 95% CI: 1.630-3.081) were associated with an increased incidence of cognitive impairment. Consistent and significant worsening in different neurological domains was observed with greater numbers of MetS components. MetS was associated with worse cognitive function, neuromotor dysfunction, and neuropsychological symptoms among Chinese acute stroke patients.

Self-Esteem Trajectories and Their Social Determinants in Adolescents With Different Levels of Cognitive Ability.

PubMed

Morin, Alexandre J S; Arens, A Katrin; Tracey, Danielle; Parker, Philip D; Ciarrochi, Joseph; Craven, Rhonda G; Maïano, Christophe

2017-11-01

This study examines the development of self-esteem in a sample of 138 Australian adolescents (90 males; 48 females) with cognitive abilities in the lowest 15% (L-CA) and a matched sample of 556 Australian adolescents (312 males; 244 females) with average to high levels of cognitive abilities (A/H-CA). These participants were measured annually (Grade 7 to 12). The findings showed that adolescents with L-CA and A/H-CA experience similar high and stable self-esteem trajectories that present similar relations with key predictors (sex, school usefulness and dislike, parenting, and peer integration). Both groups revealed substantial gender differences showing higher levels of self-esteem for adolescent males remaining relatively stable over time, compared to lower levels among adolescent females which decreased until midadolescence before increasing back.

Selective decline of neurotrophin and neurotrophin receptor genes within CA1 pyramidal neurons and hippocampus proper: Correlation with cognitive performance and neuropathology in mild cognitive impairment and Alzheimer's disease.

PubMed

Ginsberg, Stephen D; Malek-Ahmadi, Michael H; Alldred, Melissa J; Che, Shaoli; Elarova, Irina; Chen, Yinghua; Jeanneteau, Freddy; Kranz, Thorsten M; Chao, Moses V; Counts, Scott E; Mufson, Elliott J

2017-09-09

Hippocampal CA1 pyramidal neurons, a major component of the medial temporal lobe memory circuit, are selectively vulnerable during the progression of Alzheimer's disease (AD). The cellular mechanism(s) underlying degeneration of these neurons and the relationship to cognitive performance remains largely undefined. Here, we profiled neurotrophin and neurotrophin receptor gene expression within microdissected CA1 neurons along with regional hippocampal dissections from subjects who died with a clinical diagnosis of no cognitive impairment (NCI), mild cognitive impairment (MCI), or AD using laser capture microdissection (LCM), custom-designed microarray analysis, and qPCR of CA1 subregional dissections. Gene expression levels were correlated with cognitive test scores and AD neuropathology criteria. We found a significant downregulation of several neurotrophin genes (e.g., Gdnf, Ngfb, and Ntf4) in CA1 pyramidal neurons in MCI compared to NCI and AD subjects. In addition, the neurotrophin receptor transcripts TrkB and TrkC were decreased in MCI and AD compared to NCI. Regional hippocampal dissections also revealed select neurotrophic gene dysfunction providing evidence for vulnerability within the hippocampus proper during the progression of dementia. Downregulation of several neurotrophins of the NGF family and cognate neurotrophin receptor (TrkA, TrkB, and TrkC) genes correlated with antemortem cognitive measures including the Mini-Mental State Exam (MMSE), a composite global cognitive score (GCS), and Episodic, Semantic, and Working Memory, Perceptual Speed, and Visuospatial domains. Significant correlations were found between select neurotrophic expression downregulation and neuritic plaques (NPs) and neurofibrillary tangles (NFTs), but not diffuse plaques (DPs). These data suggest that dysfunction of neurotrophin signaling complexes have profound negative sequelae within vulnerable hippocampal cell types, which play a role in mnemonic and executive dysfunction during the progression of AD. © 2017 Wiley Periodicals, Inc.

BDNF (brain-derived neurotrophic factor) serum levels in schizophrenic patients with cognitive deficits

NASA Astrophysics Data System (ADS)

Utami, N.; Effendy, E.; Amin, M. M.

2018-03-01

Schizophrenia is a complex neurodevelopmental disorder with cognitive impairment as the main part. BDNF regulates aspects of developmental plasticity in the brain and is involved in cognitive function. Cognitive functions include capabilities such as attention, executive functioning, assessing, monitoring and evaluating. The aim of the study was to know the BDNF levels in schizophrenic patients with cognitive deficits. The study was held in October 2016 - March 2017, and was the first in Indonesia, especially in North Sumatra. The study was approved by the medical ethics committee of the University of North Sumatera. The study is descriptive based on a retrospective method with cross-sectional approach. The subject is 40 male schizophrenia. Cognitive deficits were assessed by MoCA-Ina. BDNF serum levels were analyzed using the quantitative sandwich enzyme immunoassay. The average MoCA-Ina score is 21.03±5.21. This suggests that there is a cognitive function deficit in schizophrenic patients. The mean serum BDNF level was 26629±6762. MoCA-Ina scores in schizophrenic patients <26 who experienced a deficit of 77.5% and serum BDNF levels with normal values ranging from 6.186 to 42.580pg/ml.

Altered thalamocortical rhythmicity and connectivity in mice lacking CaV3.1 T-type Ca2+ channels in unconsciousness

PubMed Central

Choi, Soonwook; Yu, Eunah; Lee, Seongwon; Llinás, Rodolfo R.

2015-01-01

In unconscious status (e.g., deep sleep and anesthetic unconsciousness) where cognitive functions are not generated there is still a significant level of brain activity present. Indeed, the electrophysiology of the unconscious brain is characterized by well-defined thalamocortical rhythmicity. Here we address the ionic basis for such thalamocortical rhythms during unconsciousness. In particular, we address the role of CaV3.1 T-type Ca2+ channels, which are richly expressed in thalamic neurons. Toward this aim, we examined the electrophysiological and behavioral phenotypes of mice lacking CaV3.1 channels (CaV3.1 knockout) during unconsciousness induced by ketamine or ethanol administration. Our findings indicate that CaV3.1 KO mice displayed attenuated low-frequency oscillations in thalamocortical loops, especially in the 1- to 4-Hz delta band, compared with control mice (CaV3.1 WT). Intriguingly, we also found that CaV3.1 KO mice exhibited augmented high-frequency oscillations during unconsciousness. In a behavioral measure of unconsciousness dynamics, CaV3.1 KO mice took longer to fall into the unconscious state than controls. In addition, such unconscious events had a shorter duration than those of control mice. The thalamocortical interaction level between mediodorsal thalamus and frontal cortex in CaV3.1 KO mice was significantly lower, especially for delta band oscillations, compared with that of CaV3.1 WT mice, during unconsciousness. These results suggest that the CaV3.1 channel is required for the generation of a given set of thalamocortical rhythms during unconsciousness. Further, that thalamocortical resonant neuronal activity supported by this channel is important for the control of vigilance states. PMID:26056284

Altered thalamocortical rhythmicity and connectivity in mice lacking CaV3.1 T-type Ca2+ channels in unconsciousness.

PubMed

Choi, Soonwook; Yu, Eunah; Lee, Seongwon; Llinás, Rodolfo R

2015-06-23

In unconscious status (e.g., deep sleep and anesthetic unconsciousness) where cognitive functions are not generated there is still a significant level of brain activity present. Indeed, the electrophysiology of the unconscious brain is characterized by well-defined thalamocortical rhythmicity. Here we address the ionic basis for such thalamocortical rhythms during unconsciousness. In particular, we address the role of CaV3.1 T-type Ca(2+) channels, which are richly expressed in thalamic neurons. Toward this aim, we examined the electrophysiological and behavioral phenotypes of mice lacking CaV3.1 channels (CaV3.1 knockout) during unconsciousness induced by ketamine or ethanol administration. Our findings indicate that CaV3.1 KO mice displayed attenuated low-frequency oscillations in thalamocortical loops, especially in the 1- to 4-Hz delta band, compared with control mice (CaV3.1 WT). Intriguingly, we also found that CaV3.1 KO mice exhibited augmented high-frequency oscillations during unconsciousness. In a behavioral measure of unconsciousness dynamics, CaV3.1 KO mice took longer to fall into the unconscious state than controls. In addition, such unconscious events had a shorter duration than those of control mice. The thalamocortical interaction level between mediodorsal thalamus and frontal cortex in CaV3.1 KO mice was significantly lower, especially for delta band oscillations, compared with that of CaV3.1 WT mice, during unconsciousness. These results suggest that the CaV3.1 channel is required for the generation of a given set of thalamocortical rhythms during unconsciousness. Further, that thalamocortical resonant neuronal activity supported by this channel is important for the control of vigilance states.

Strong Association between Plasma Dipeptidyl Peptidase-4 Activity and Impaired Cognitive Function in Elderly Population with Normal Glucose Tolerance.

PubMed

Chen, Bo; Zheng, Tianpeng; Qin, Linyuan; Hu, Xueping; Zhang, Xiaoxi; Liu, Yihong; Liu, Hongbo; Qin, Shenghua; Li, Gang; Li, Qinghua

2017-01-01

Objective: Inflammation, oxidative stress, and decreased glucagon-like peptide-1 (GLP-1) are risk factors for cognitive impairment. Dipeptidyl peptidase-4 (DPP4) was identified as a novel adipokine capable of enhancing these risk factors. Hence, we investigated the relationship between plasma DPP4 activity and impaired cognitive function in elderly Chinese population with normal glucose tolerance (NGT). Methods: We performed a cross-sectional study using data from 1229 elderly participants (60 years or older) in Guilin. Plasma DPP4 activity, oxidative stress parameters, fasting active GLP-1, and inflammatory markers were measured in all participants. Impaired cognitive function was diagnosed according to the National Institute on Aging-Alzheimer's Association workgroups criteria. Results: Participants in the upper quartile of plasma DPP4 activity had higher C-reactive protein (CRP), interleukin-6 (IL-6), 8-iso-PGF2a, nitrotyrosine, and lower GLP-1 and Montreal Cognitive Assessment (MoCA) scores compared with those in the lowest quartile ( P < 0.001). The odds ratios (ORs) for increased CRP, IL-6, 8-iso-PGF2a, nitrotyrosine, and decreased active GLP-1 were higher with increasing DPP4 quartiles after adjustment for confounders (all P < 0.001). In the highest DPP4 quartile, impaired cognitive function risk was higher (OR, 2.26; 95% confidence interval, 1.36-3.76) than in the lowest quartile after adjustment for potential confounders. The risk for impaired cognitive function increased more with higher levels of DPP4 activity, nitrotyrosine and 8-iso-PGF2a ( P < 0.05), but not with higher IL-6, CRP or lower GLP-1. Conclusion: Plasma DPP4 activity is significantly and independently associated with impaired cognitive function, mainly executive, in elderly Chinese population with NGT. The underlying mechanisms for this association may be partly attributed to the effect of DPP4 on oxidative stress. Plasma DPP4 activity might serve as a risk biomarker or therapeutic target for the prevention and treatment of impaired cognitive function.

Response of extracellular zinc in the ventral hippocampus against novelty stress.

PubMed

Takeda, Atsushi; Sakurada, Naomi; Kanno, Shingo; Minami, Akira; Oku, Naoto

2006-10-01

An extensive neuronal activity takes place in the hippocampus during exploratory behavior. However, the role of hippocampal zinc in exploratory behavior is poorly understood. To analyze the response of extracellular zinc in the hippocampus against novelty stress, rats were placed for 50 min in a novel environment once a day for 8 days. Extracellular glutamate in the hippocampus was increased during exploratory behavior on day 1, whereas extracellular zinc was decreased. The same phenomenon was observed during exploratory behavior on day 2 and extracellular zinc had returned to the basal level during exploratory behavior on day 8. To examine the significance of the decrease in extracellular zinc in exploratory activity, exploratory behavior was observed during perfusion with 1 mm CaEDTA, a membrane-impermeable zinc chelator. Locomotor activity in the novel environment was decreased by perfusion with CaEDTA. The decrease in extracellular zinc and the increase in extracellular glutamate in exploratory period were abolished by perfusion with CaEDTA. These results suggest that zinc uptake by hippocampal cells is linked to exploratory activity and is required for the activation of the glutamatergic neurotransmitter system. The zinc uptake may be involved in the response to painless psychological stress or in the cognitive processes.

[Application of Chinese version of ACE-Ⅲ in type 2 diabetes mellitus patients with mild cognitive impairment].

PubMed

Xin, J W; Xiao, X L; Chen, X C; Pan, X D

2017-11-28

Objective: To investigate the application and best cut-off value of Chinese version of Addenbrooke's cognitive examination-Ⅲ(ACE-Ⅲ) in type 2 diabetes mellitus (T2DM) patients with mild cognitive impairment. Methods: A total of 18 T2DM patients with normal cognitive function (NCI group) and 40 T2DM patients with mild cognitive impairment (MCI group) treated in outpatient clinic or ward of Department of Neurology and Endocrinology in Fujian Medical University Union Hospital between January 2015 and February 2016 were enrolled. Mini Mental State Scale (MMSE), Montreal cognitive assessment scale (MoCA), Activity of Daily Living Scale (ADL) and the Chinese version of ACE-Ⅲ were used to assess cognitive function of subjects and to assess the value of ACE-Ⅲ in the diagnosis of T2DM patients with mild cognitive impairment. Results: The Cronbach's alpha of the Chinese version of ACE-Ⅲ is 0.768. ACE-Ⅲ and MoCA were correlative ( r =0.768, P <0.001). The area under the receiver operating characteristic (ROC) curve for ACE-Ⅲ was 0.906 (95% CI : 0.827-0.985). When the cut-off value for diagnosis was 87.5, the maximum Youden index was 0.769, with a sensitivity of 0.825 and a specificity of 0.944. Patients in MCI group got a lower score in the sub-items of attention/orientation, memory, verbal fluency, language and visual space of ACE-Ⅲ compared to those in NCI group, and the differences were statistically significant ( t =5.336, P <0.001; t =5.530, P <0.001; t =4.556, P <0.001; t =5.301, P <0.001; t =2.821, P =0.008). Conclusion: The Chinese version of ACE-Ⅲ had good internal consistency reliability, and it could effectively detect impairment of general cognitive function and single cognitive domains in T2DM patients.

Activation of Muscarinic M1 Acetylcholine Receptors Induces Long-Term Potentiation in the Hippocampus

PubMed Central

Dennis, Siobhan H.; Pasqui, Francesca; Colvin, Ellen M.; Sanger, Helen; Mogg, Adrian J.; Felder, Christian C.; Broad, Lisa M.; Fitzjohn, Steve M.; Isaac, John T.R.; Mellor, Jack R.

2016-01-01

Muscarinic M1 acetylcholine receptors (M1Rs) are highly expressed in the hippocampus, and their inhibition or ablation disrupts the encoding of spatial memory. It has been hypothesized that the principal mechanism by which M1Rs influence spatial memory is by the regulation of hippocampal synaptic plasticity. Here, we use a combination of recently developed, well characterized, selective M1R agonists and M1R knock-out mice to define the roles of M1Rs in the regulation of hippocampal neuronal and synaptic function. We confirm that M1R activation increases input resistance and depolarizes hippocampal CA1 pyramidal neurons and show that this profoundly increases excitatory postsynaptic potential-spike coupling. Consistent with a critical role for M1Rs in synaptic plasticity, we now show that M1R activation produces a robust potentiation of glutamatergic synaptic transmission onto CA1 pyramidal neurons that has all the hallmarks of long-term potentiation (LTP): The potentiation requires NMDA receptor activity and bi-directionally occludes with synaptically induced LTP. Thus, we describe synergistic mechanisms by which acetylcholine acting through M1Rs excites CA1 pyramidal neurons and induces LTP, to profoundly increase activation of CA1 pyramidal neurons. These features are predicted to make a major contribution to the pro-cognitive effects of cholinergic transmission in rodents and humans. PMID:26472558

Measurement Error, Reliability, and Minimum Detectable Change in the Mini-Mental State Examination, Montreal Cognitive Assessment, and Color Trails Test among Community Living Middle-Aged and Older Adults.

PubMed

Feeney, Joanne; Savva, George M; O'Regan, Claire; King-Kallimanis, Bellinda; Cronin, Hilary; Kenny, Rose Anne

2016-05-31

Knowing the reliability of cognitive tests, particularly those commonly used in clinical practice, is important in order to interpret the clinical significance of a change in performance or a low score on a single test. To report the intra-class correlation (ICC), standard error of measurement (SEM) and minimum detectable change (MDC) for the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Color Trails Test (CTT) among community dwelling older adults. 130 participants aged 55 and older without severe cognitive impairment underwent two cognitive assessments between two and four months apart. Half the group changed rater between assessments and half changed time of day. Mean (standard deviation) MMSE was 28.1 (2.1) at baseline and 28.4 (2.1) at repeat. Mean (SD) MoCA increased from 24.8 (3.6) to 25.2 (3.6). There was a rater effect on CTT, but not on the MMSE or MoCA. The SEM of the MMSE was 1.0, leading to an MDC (based on a 95% confidence interval) of 3 points. The SEM of the MoCA was 1.5, implying an MDC95 of 4 points. MoCA (ICC = 0.81) was more reliable than MMSE (ICC = 0.75), but all tests examined showed substantial within-patient variation. An individual's score would have to change by greater than or equal to 3 points on the MMSE and 4 points on the MoCA for the rater to be confident that the change was not due to measurement error. This has important implications for epidemiologists and clinicians in dementia screening and diagnosis.

Comparison of two commonly used clinical cognitive screening tests to diagnose mild cognitive impairment in heart failure with the golden standard European Consortium Criteria.

PubMed

Alagiakrishnan, Kannayiram; Mah, Darren; Dyck, Jason R B; Senthilselvan, Ambikaipakan; Ezekowitz, Justin

2017-02-01

This study on mild cognitive impairment (MCI) in heart failure (HF) compares the utility of Montreal Cognitive Assessment (MoCA) to the Mini-Mental Status Exam (MMSE) for diagnosing MCI in a HF population when compared to the golden standard European Consortium Criteria (ECC). Participants were recruited from the Alberta HEART study at the Mazankowski Alberta Heart Institute in Edmonton and St. Mary's hospital in Camrose. This study enrolled 53 community adults aged>50years: 33 HF and 20 controls. Participants were assessed using both the MMSE and MoCA for MCI. MCI was diagnosed using the golden standard, European Consortium Criteria. Sensitivity and specificity analysis, positive and negative predictive values, likelihood ratios and kappa statistic were calculated. The mean age was 72.8years (SD 8.4), 60.4% were females and 34% had underlying ischemic heart disease. Overall, two thirds of patients (22/33, 66%) with HF had MCI. In comparison to European Consortium Criteria, the sensitivity and specificity of MoCA were 82% and 91% in identifying individuals with MCI, and MMSE were 9% and 91%, respectively. The positive and negative predictive values for MoCA were 95% and 71%, and for MMSE were 67% and 33%, respectively. Kappa statistics showed good agreement between MoCA and consortium criteria (kappa=0.68) and a low agreement between MMSE and consortium criteria (kappa=0.07). Cognitive dysfunction is common in patients with HF. Overall, the MoCA seems to be a better screening tool than MMSE for MCI in HF patients. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Neuroprotective effects of Bacopa monnieri (Brahmi) on novel object recognition and NMDAR1 immunodensity in the prefrontal cortex, striatum and hippocampus of sub-chronic phencyclidine rat model of schizophrenia.

PubMed

Piyabhan, Pritsana; Wetchateng, Thanitsara

2014-08-01

Cognitive impairment is a major problem, which eventually develops in schizophrenia. It contributes to the patients 'functional disability and cannot be attenuated by antipsychotic drugs. Bacopa monnieri (Brahmi), a neuroprotective herbal medicine in the elderly, might be a novel neuroprotective agent for prevention of cognitive deficit in schizophrenia. To study neuroprotective effects ofBrahmi on novel object recognition task and cerebral glutamate/N-methyl-D- aspartate receptor subtype 1 (NMDAR1) immunodensity in sub-chronic phencyclidine (PCP) rat model ofschizophrenia. Rats were assigned to three groups; Group-A: Control, Group-B: PCP administration and Group- C: Brahmi + PCP. Discrimination ratio (DR) representing cognitive ability was obtainedfrom novel object recognition task. NMDAR1 immunodensity was measured in prefrontal cortex, striatum, cornu ammonis fields I (CA 1) and 2/3 (CA2/3) and dentate gyrus (DG) using immunohistochemistry. DR was significantly reduced in PCP group compared with control. This occurred alongside NMDAR1 up-regulation in CA2/3 and DG but not in prefrontal cortex, striatum or CA1. Brahmi + PCP group showed an increased DR score up to normal which occurred alongside a significantly decreased NMDARI immunodensity in CA2/3 and DG compared with PCP group. Cognitive deficit observed in rats receiving PCP was mediated by NMDAR1 up-regulation in CA2/3 and DG Interestingly, receiving Brahmi before PCP administration can restore this cognitive deficit by decreasingNMDAR1 in these brain areas. Therefore, Brahmi could be a novel neuroprotective agentfor the prevention ofcognitive deficit in schizophrenia.

The Montreal Cognitive Assessment-Basic (MoCA-B) is not a reliable screening tool for cognitive decline in HIV patients receiving combination antiretroviral therapy in rural South Africa.

PubMed

Hakkers, C S; Beunders, A J M; Ensing, M H M; Barth, R E; Boelema, S; Devillé, W L J; Tempelman, H A; Coutinho, R A; Hoepelman, A I M; Arends, J E; van Zandvoort, M J E

2018-02-01

HIV-associated neurocognitive disorders (HAND) are frequently occurring comorbidities in HIV-positive patients, diagnosed by means of a neuropsychological assessment (NPA). Due to the magnitude of the HIV-positive population in Sub-Saharan Africa, easy-to-use cognitive screening tools are essential. This was a cross-sectional clinical trial involving 44 HIV-positive patients (on stable cART) and 73 HIV-negative controls completing an NPA, the International HIV Dementia Scale (IHDS), and a culturally appropriate cognitive screening tool, the Montreal Cognitive Assessment-Basic (MoCA-B). HAND were diagnosed by calculating Z-scores using internationally published normative data on NPA, as well as by using data from the HIV-negative group to validate the MoCA-B. One hundred and seventeen patients were included (25% male, median age 35 years, median 11 years of education). A moderate correlation was found between the MoCA-B and NPA total Z-score (Pearson's r=0.36, p=0.02). Area under the curve (AUC) values for MoCA-B and IHDS were 0.59 and 0.70, respectively. The prevalence of HAND in HIV-positive patients was 66% when calculating Z-scores using published normative data versus 48% when using the data from the present HIV-negative cohort. The MoCA-B appeared not to be a valid screening tool for HAND in this setting. The prevalence of HAND in this setting is high, but appeared overestimated when using published norms. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Slower EEG alpha generation, synchronization and "flow"-possible biomarkers of cognitive impairment and neuropathology of minor stroke.

PubMed

Petrovic, Jelena; Milosevic, Vuk; Zivkovic, Miroslava; Stojanov, Dragan; Milojkovic, Olga; Kalauzi, Aleksandar; Saponjic, Jasna

2017-01-01

We investigated EEG rhythms, particularly alpha activity, and their relationship to post-stroke neuropathology and cognitive functions in the subacute and chronic stages of minor strokes. We included 10 patients with right middle cerebral artery (MCA) ischemic strokes and 11 healthy controls. All the assessments of stroke patients were done both in the subacute and chronic stages. Neurological impairment was measured using the National Institute of Health Stroke Scale (NIHSS), whereas cognitive functions were assessed using the Montreal Cognitive Assessment (MoCA) and MoCA memory index (MoCA-MIS). The EEG was recorded using a 19 channel EEG system with standard EEG electrode placement. In particular, we analyzed the EEGs derived from the four lateral frontal (F3, F7, F4, F8), and corresponding lateral posterior (P3, P4, T5, T6) electrodes. Quantitative EEG analysis included: the group FFT spectra, the weighted average of alpha frequency (αAVG), the group probability density distributions of all conventional EEG frequency band relative amplitudes (EEG microstructure), the inter- and intra-hemispheric coherences, and the topographic distribution of alpha carrier frequency phase potentials (PPs). Statistical analysis was done using a Kruskal-Wallis ANOVA with a post-hoc Mann-Whitney U two-tailed test, and Spearman's correlation. We demonstrated transient cognitive impairment alongside a slower alpha frequency ( α AVG) in the subacute right MCA stroke patients vs. the controls. This slower alpha frequency showed no amplitude change, but was highly synchronized intra-hemispherically, overlying the ipsi-lesional hemisphere, and inter-hemispherically, overlying the frontal cortex. In addition, the disturbances in EEG alpha activity in subacute stroke patients were expressed as a decrease in alpha PPs over the frontal cortex and an altered "alpha flow", indicating the sustained augmentation of inter-hemispheric interactions. Although the stroke induced slower alpha was a transient phenomenon, the increased alpha intra-hemispheric synchronization, overlying the ipsi-lesional hemisphere, the increased alpha F3-F4 inter-hemispheric synchronization, the delayed alpha waves, and the newly established inter-hemispheric "alpha flow" within the frontal cortex, remained as a permanent consequence of the minor stroke. This newly established frontal inter-hemispheric "alpha flow" represented a permanent consequence of the "hidden" stroke neuropathology, despite the fact that cognitive impairment has been returned to the control values. All the detected permanent changes at the EEG level with no cognitive impairment after a minor stroke could be a way for the brain to compensate for the lesion and restore the lost function. Our study indicates slower EEG alpha generation, synchronization and "flow" as potential biomarkers of cognitive impairment onset and/or compensatory post-stroke re-organizational processes.

TRPM2 Channel Aggravates CNS Inflammation and Cognitive Impairment via Activation of Microglia in Chronic Cerebral Hypoperfusion.

PubMed

Miyanohara, Jun; Kakae, Masashi; Nagayasu, Kazuki; Nakagawa, Takayuki; Mori, Yasuo; Arai, Ken; Shirakawa, Hisashi; Kaneko, Shuji

2018-04-04

Chronic cerebral hypoperfusion is a characteristic seen in widespread CNS diseases, including neurodegenerative and mental disorders, and is commonly accompanied by cognitive impairment. Recently, several studies demonstrated that chronic cerebral hypoperfusion can induce the excessive inflammatory responses that precede neuronal dysfunction; however, the precise mechanism of cognitive impairment due to chronic cerebral hypoperfusion remains unknown. Transient receptor potential melastatin 2 (TRPM2) is a Ca 2+ -permeable channel that is abundantly expressed in immune cells and is involved in aggravation of inflammatory responses. Therefore, we investigated the pathophysiological role of TRPM2 in a mouse chronic cerebral hypoperfusion model with bilateral common carotid artery stenosis (BCAS). When male mice were subjected to BCAS, cognitive dysfunction and white matter injury at day 28 were significantly improved in TRPM2 knock-out (TRPM2-KO) mice compared with wild-type (WT) mice, whereas hippocampal damage was not observed. There were no differences in blood-brain barrier breakdown and H 2 O 2 production between the two genotypes at 14 and 28 d after BCAS. Cytokine production was significantly suppressed in BCAS-operated TRPM2-KO mice compared with WT mice at day 28. In addition, the number of Iba1-positive cells gradually decreased from day 14. Moreover, daily treatment with minocycline significantly improved cognitive perturbation. Surgical techniques using bone marrow chimeric mice revealed that activated Iba1-positive cells in white matter could be brain-resident microglia, not peripheral macrophages. Together, these findings suggest that microglia contribute to the aggravation of cognitive impairment by chronic cerebral hypoperfusion, and that TRPM2 may be a potential target for chronic cerebral hypoperfusion-related disorders. SIGNIFICANCE STATEMENT Chronic cerebral hypoperfusion is manifested in a wide variety of CNS diseases, including neurodegenerative and mental disorders that are accompanied by cognitive impairment; however, the underlying mechanisms require clarification. Here, we used a chronic cerebral hypoperfusion mouse model to investigate whether TRPM2, a Ca 2+ -permeable cation channel highly expressed in immune cells, plays a destructive role in the development of chronic cerebral hypoperfusion-induced cognitive impairment, and propose a new hypothesis in which TRPM2-mediated activation of microglia, not macrophages, specifically contributes to the pathology through the aggravation of inflammatory responses. These findings shed light on the understanding of the mechanisms of chronic cerebral hypoperfusion-related inflammation, and are expected to provide a novel therapeutic molecule for cognitive impairment in CNS diseases. Copyright © 2018 the authors 0270-6474/18/383521-14$15.00/0.

[Effects of temporal lobe epilepsy and idiopathic epilepsy on cognitive function and emotion in children].

PubMed

Yang, Xiao-Yan; Long, Li-Li; Xiao, Bo

2016-07-01

To investigate the effects of temporal lobe epilepsy and idiopathic epilepsy on cognitive function and emotion in children and the risk factors for cognitive impairment. A retrospective analysis was performed for the clinical data of 38 children with temporal lobe epilepsy and 40 children with idiopathic epilepsy. The controls were 42 healthy children. All subjects received the following neuropsychological tests: Montreal Cognitive Assessment (MoCA) scale, verbal fluency test, digit span test, block design test, Social Anxiety Scale for Children (SASC), and Depression Self-rating Scale for Children (DSRSC). Compared with the control group, the temporal lobe epilepsy and idiopathic epilepsy groups showed significantly lower scores of MoCA, verbal fluency, digit span, and block design (P<0.05) and significantly higher scores on SASC and DSRSC (P<0.05). Compared with the idiopathic epilepsy group, the temporal lobe epilepsy group showed significantly lower scores of MoCA, verbal fluency, digit span, and block design (P<0.05) and significantly higher scores on SASC and DSRSC (P<0.05). In the temporal lobe epilepsy group, MoCA score was negatively correlated with SASC score, DSRSC score, and seizure frequency (r=-0.571, -0.529, and -0.545 respectively; P<0.01). In the idiopathic epilepsy group, MoCA score was also negatively correlated with SASC score, DSRSC score, and seizure frequency (r=-0.542, -0.487, and -0.555 respectively; P<0.01). Children with temporal lobe epilepsy and idiopathic epilepsy show impaired whole cognition, verbal fluency, memory, and executive function and have anxiety and depression, which are more significant in children with temporal lobe epilepsy. High levels of anxiety, depression, and seizure frequency are risk factors for impaired cognitive function.

Occlusal force is correlated with cognitive function directly as well as indirectly via food intake in community-dwelling older Japanese: From the SONIC study.

PubMed

Ikebe, Kazunori; Gondo, Yasuyuki; Kamide, Kei; Masui, Yukie; Ishizaki, Taturo; Arai, Yasumichi; Inagaki, Hiroki; Nakagawa, Takeshi; Kabayama, Mai; Ryuno, Hirochika; Okubo, Hitomi; Takeshita, Hajime; Inomata, Chisato; Kurushima, Yuko; Mihara, Yusuke; Hatta, Kohdai; Fukutake, Motoyoshi; Enoki, Kaori; Ogawa, Taiji; Matsuda, Ken-Ichi; Sugimoto, Ken; Oguro, Ryosuke; Takami, Yoichi; Itoh, Norihisa; Takeya, Yasushi; Yamamoto, Koichi; Rakugi, Hiromi; Murakami, Shinya; Kitamura, Masahiro; Maeda, Yoshinobu

2018-01-01

Growing evidence suggests that oral health may be an important factor associated with cognitive function in aged populations. However, many previous studies on this topic used insensitive oral indicators or did not include certain essential covariates. Thus, we examined the association between occlusal force and cognitive function in a large sample of older adults, controlling for dietary intake, vascular risk factors, inflammatory biomarkers, depression, and genetic factors. In this cross-sectional study of older community-dwelling Japanese adults, we examined data collected from 994 persons aged 70 years and 968 persons aged 80 years. Cognitive function was measured using the Japanese version of the Montreal Cognitive Assessment (MoCA-J). Oral status and function were evaluated according to the number of remaining teeth, periodontal pocket depth, and maximal occlusal force. Associations between MoCA-J scores and occlusal force were investigated via bivariate and multivariate analyses. Education level, financial status, depression score, and intake of green and yellow vegetables, as well as number of teeth and occlusal force, were significantly correlated with MoCA-J scores in both age groups. Among individuals aged 80 years, CRP and periodontal status were weakly but significantly associated with MoCA-J score. After controlling for all significant variables via bivariate analyses, the correlation between maximal occlusal force and cognitive function persisted. A path analysis confirmed the hypothesis that cognitive function is associated with occlusal force directly as well as indirectly via food intake. After controlling for possible factors, maximal occlusal force was positively associated with cognitive function directly as well as indirectly through dietary intake.

Longitudinal association of hypertension and diabetes mellitus with cognitive functioning in a general 70-year-old population: the SONIC study.

PubMed

Ryuno, Hirochika; Kamide, Kei; Gondo, Yasuyuki; Kabayama, Mai; Oguro, Ryosuke; Nakama, Chikako; Yokoyama, Serina; Nagasawa, Motonori; Maeda-Hirao, Satomi; Imaizumi, Yuki; Takeya, Miyuki; Yamamoto, Hiroko; Takeda, Masao; Takami, Yoichi; Itoh, Norihisa; Takeya, Yasushi; Yamamoto, Koichi; Sugimoto, Ken; Nakagawa, Takeshi; Yasumoto, Saori; Ikebe, Kazunori; Inagaki, Hiroki; Masui, Yukie; Takayama, Michiyo; Arai, Yasumichi; Ishizaki, Tatsuro; Takahashi, Ryutaro; Rakugi, Hiromi

2017-07-01

Both hypertension and diabetes in middle-aged individuals have been suggested to be predictive indicators of cognitive decline. However, the association of hypertension, diabetes and their combination with cognitive functioning is still controversial in older people. The purpose of this study was to investigate the association between cognitive decline and hypertension, diabetes, and their combination in 70-year-old people based on a 3-year longitudinal analysis. Four hundred and fifty-four people aged 70 (±1) years who participated in the Japanese longitudinal cohort study of Septuagenarians, Octogenarians and Nonagenarians Investigation with Centenarians (SONIC) were recruited randomly from a general population and were monitored for 3 years. The data, including most of the demographics, cognitive functioning measured by the Montreal Cognitive Assessment Japanese version (MoCA-J), blood pressure, blood chemistry and other medical histories, were collected at baseline and during the follow-up. The prevalence of hypertension noted in the follow-up survey was significantly higher than than noted at baseline. The mean MoCA-J score at follow-up was not significantly different from the score obtained at baseline. However, the participants with diabetes, especially combined with hypertension at baseline, had significantly lower MoCA-J scores than those without lifestyle-related diseases. The combination of hypertension and diabetes was still a significant risk factor for cognitive decline, considering the MoCA-J scores obtained during the follow-up after adjustments at baseline, relative to sex, body mass index, dyslipidemia, smoking, excessive alcohol intake, antihypertensive treatment and education level (β=-0.14; P<0.01). Our findings indicate that diabetes and the combination of hypertension and diabetes are clear risk factors for future cognitive decline in elderly individuals who are 70 years of age.

The relationship between dual-task and cognitive performance among elderly participants who exercise regularly

PubMed Central

Lima, Luciana C. A.; Ansai, Juliana H.; Andrade, Larissa P.; Takahashi, Anielle C. M.

2015-01-01

BACKGROUND: The dual-task performance is associated with the functionality of the elderly and it becomes more complex with age. OBJECTIVE: To investigate the relationship between the Timed Up and Go dual task (TUG-DT) and cognitive tests among elderly participants who exercise regularly. METHOD: This study examined 98 non-institutionalized people over 60 years old who exercised regularly. Participants were assessed using the TUG-DT (i.e. doing the TUG while listing the days of the week in reverse order), the Montreal Cognitive Assessment (MoCA), the Clock Drawing Test (CDT), and the Mini Mental State Examination (MMSE). The motor (i.e. time and number of steps) and cognitive (i.e. number of correct words) data were collected from TUG-DT . We used a significance level of α=0.05 and SPSS 17.0 for all data analyses. RESULTS: This current elderly sample featured a predominance of women (69.4%) who were highly educated (median=10 years of education) compared to Brazilian population and mostly non-fallers (86.7%). The volunteers showed a good performance on the TUG-DT and the other cognitive tests, except the MoCA, with scores below the cutoff of 26 points. Significant and weak correlations were observed between the TUG-DT (time) and the visuo-spatial/executive domain of the MoCA and the MMSE. The cognitive component of the TUG-DT showed strong correlations between the total MoCA performance score and its visuo-spatial/executive domain. CONCLUSIONS: The use of the TUG-DT to assess cognition is promising; however, the use of more challenging cognitive tasks should be considered when the study population has a high level of education. PMID:25993629

Use of the MoCA in Detecting Early Alzheimer's Disease in a Spanish-Speaking Population with Varied Levels of Education

PubMed Central

Zhou, Yan; Ortiz, Freddy; Nuñez, Christopher; Elashoff, David; Woo, Ellen; Apostolova, Liana G.; Wolf, Sheldon; Casado, Maria; Caceres, Nenette; Panchal, Hemali; Ringman, John M.

2015-01-01

Background/Aims Performance on the Montreal Cognitive Assessment (MoCA) has been demonstrated to be dependent on the educational level. The purpose of this study was to identify how to best adjust MoCA scores and to identify MoCA items most sensitive to cognitive decline in incipient Alzheimer's disease (AD) in a Spanish-speaking population with varied levels of education. Methods We analyzed data from 50 Spanish-speaking participants. We examined the pattern of diagnosis-adjusted MoCA residuals in relation to education and compared four alternative score adjustments using bootstrap sampling. Sensitivity and specificity analyses were performed for the raw and each adjusted score. The interval reliability of the MoCA as well as item discrimination and item validity were examined. Results We found that with progressive compensation added for those with lower education, unexplained residuals decreased and education-residual association moved to zero, suggesting that more compensation was necessary to better adjust MoCA scores in those with a lower educational level. Cube copying, sentence repetition, delayed recall, and orientation were most sensitive to cognitive impairment due to AD. Conclusion A compensation of 3-4 points was needed for <6 years of education. Overall, the Spanish version of the MoCA maintained adequate psychometric properties in this population. PMID:25873930

Age-related Changes in Lateral Entorhinal and CA3 Neuron Allocation Predict Poor Performance on Object Discrimination

PubMed Central

Maurer, Andrew P.; Johnson, Sarah A.; Hernandez, Abbi R.; Reasor, Jordan; Cossio, Daniela M.; Fertal, Kaeli E.; Mizell, Jack M.; Lubke, Katelyn N.; Clark, Benjamin J.; Burke, Sara N.

2017-01-01

Age-related memory deficits correlate with dysfunction in the CA3 subregion of the hippocampus, which includes both hyperactivity and overly rigid activity patterns. While changes in intrinsic membrane currents and interneuron alterations are involved in this process, it is not known whether alterations in afferent input to CA3 also contribute. Neurons in layer II of the lateral entorhinal cortex (LEC) project directly to CA3 through the perforant path, but no data are available regarding the effects of advanced age on LEC activity and whether these activity patterns update in response to environmental change. Furthermore, it is not known the extent to which age-related deficits in sensory discrimination relate to the inability of aged CA3 neurons to update in response to new environments. Young and aged rats were pre-characterized on a LEGO© object discrimination task, comparable to behavioral tests in humans in which CA3 hyperactivity has been linked to impairments. The cellular compartment analysis of temporal activity with fluorescence in situ hybridization for the immediate-early gene Arc was then used to identify the principal cell populations that were active during two distinct epochs of random foraging in different environments. This approach enabled the extent to which rats could discriminate two similar objects to be related to the ability of CA3 neurons to update across different environments. In both young and aged rats, there were animals that performed poorly on the LEGO object discrimination task. In the aged rats only, however, the poor performers had a higher percent of CA3 neurons that were active during random foraging in a novel environment, but this is not related to the ability of CA3 neurons to remap when the environment changed. Afferent neurons to CA3 in LEC, as identified with the retrograde tracer choleratoxin B (CTB), also showed a higher percentage of cells that were positive for Arc mRNA in aged poor performing rats. This suggests that LEC contributes to the hyperactivity seen in CA3 of aged animals with object discrimination deficits and age-related cognitive decline may be the consequence of dysfunction endemic to the larger network. PMID:28713251

Applicability of the MoCA-S test in populations with little education in Colombia.

PubMed

Gómez, F; Zunzunegui, Mv; Lord, C; Alvarado, B; García, A

2013-08-01

The objectives of this study were to report on the use of the Spanish version of the Montreal Cognitive Assessment (MoCA-S) as cognitive screening tool in a population aged 65 to 74 years in the Andes Mountains of Colombia, assessing the influence of education, and to examine its test-retest reliability. We performed a cross-sectional study of 150 subjects aged 65 to 74 years recruited from older community social centers in Manizales, Colombia. The Leganes Cognitive Test (LCT), a cognitive screening test for populations with low education, was used to exclude those who were likely to have dementia. The associations between the MoCA total score and cognitive domains and education were examined in the total sample and in those likely free of dementia. MoCA-S test-retest reliability was estimated by the intraclass correlation coefficient (ICC) between two measurements taken 7 days apart. Participants had low levels of formal education (mean years of schooling, 4.8). According to the LCT, the proportion of people screening positive for dementia was 16% (n = 24). The mean MoCA-S scores were 16.1/30 among illiterate subjects, 18.2/30 among those with incomplete primary school, and 20.3/30 among those with complete primary school (p < 0.001). Errors were frequent in the cube and clock drawing, attention-serial subtraction, verbal fluency, and abstraction. Test-retest reliability was high, ICC = 0.86, 95% CI (0.76-0.93). The MoCA-S has high reliability in low-educated older Colombians, but scores were strongly dependent on years of education. Social and cultural factors must be considered when interpreting MoCA-S given the high error rates on items that depend on the ability to read and write and on culture. Copyright © 2012 John Wiley & Sons, Ltd.

Combined Memantine and Donepezil Treatment Improves Behavioral and Psychological Symptoms of Dementia-Like Behaviors in Olfactory Bulbectomized Mice.

PubMed

Yabuki, Yasushi; Matsuo, Kazuya; Hirano, Koga; Shinoda, Yasuharu; Moriguchi, Shigeki; Fukunaga, Kohji

2017-01-01

Memantine, an uncompetitive N-methyl-D-aspartate receptor antagonist, and the cholinesterase inhibitor, donepezil, are approved in most countries for treating moderate-to-severe Alzheimer's disease (AD). These drugs have different molecular targets; thus, it is expected that the effects of combined treatment would be synergistic. Some reports do show memantine/donepezil synergy in ameliorating cognition in AD model animals, but their combined effects on behavioral and psychological symptoms of dementia (BPSD)-like behaviors have not been addressed. Here, we investigate combined memantine/donepezil effects on cognitive impairment and BPSD-like behaviors in olfactory bulbectomized (OBX) mice. Interestingly, combined administration synergistically improved both depressive-like behaviors and impaired social interaction in OBX mice, whereas only weak synergistic effects on cognitive performance were seen. To address mechanisms underlying these effects, we used in vivo microdialysis study and observed impaired nicotine-induced serotonin (5-HT) release in OBX mouse hippocampus. Combined memantine/donepezil administration, but not single administration of either, significantly antagonized the decrease in nicotine-induced 5-HT release seen in OBX mouse hippocampus. Furthermore, decreased autophosphorylation of calcium/calmodulin dependent protein kinase II (CaMKII) was rescued in hippocampal CA1 and dentate gyrus of OBX mice by combined memantine/donepezil administration. These results suggest that improvement of BPSD-like behaviors by the co-administration of both drugs is in part mediated by enhanced 5-HT release and CaMKII activity in OBX mouse hippocampus. © 2016 S. Karger AG, Basel.

Sensitivity and Specificity of a Five-Minute Cognitive Screening Test in Patients With Heart Failure.

PubMed

Cameron, Janette D; Gallagher, Robyn; Pressler, Susan J; McLennan, Skye N; Ski, Chantal F; Tofler, Geoffrey; Thompson, David R

2016-02-01

Cognitive impairment occurs in up to 80% of patients with heart failure (HF). The National Institute for Neurological Disorders and Stroke (NINDS) and the Canadian Stroke Network (CSN) recommend a 5-minute cognitive screening protocol that has yet to be psychometrically evaluated in HF populations. The aim of this study was to conduct a secondary analysis of the sensitivity and specificity of the NINDS-CSN brief cognitive screening protocol in HF patients. The Montreal Cognitive Assessment (MoCA) was administered to 221 HF patients. The NINDS-CSN screen comprises 3 MoCA items, with lower scores indicating poorer cognitive function. Receiver operator characteristic (ROC) curves were constructed, determining the sensitivity, specificity and appropriate cutoff scores of the NINDS-CSN screen. In an HF population aged 76 ± 12 years, 136 (62%) were characterized with cognitive impairment (MoCA <26). Scores on the NINDS-CSN screen ranged from 3-11. The area under the receiver operating characteristic curve indicated good accuracy in screening for cognitive impairment (0.88; P < .01; 95% CI 0.83-0.92). A cutoff score of ≤9 provided 89% sensitivity and 71% specificity. The NINDS-CSN protocol offers clinicians a feasible telephone method to screen for cognitive impairment in patients with HF. Future studies should include a neuropsychologic battery to more comprehensively examine the diagnostic accuracy of brief cognitive screening protocols. Copyright © 2016 Elsevier Inc. All rights reserved.

Stroke Location Is an Independent Predictor of Cognitive Outcome.

PubMed

Munsch, Fanny; Sagnier, Sharmila; Asselineau, Julien; Bigourdan, Antoine; Guttmann, Charles R; Debruxelles, Sabrina; Poli, Mathilde; Renou, Pauline; Perez, Paul; Dousset, Vincent; Sibon, Igor; Tourdias, Thomas

2016-01-01

On top of functional outcome, accurate prediction of cognitive outcome for stroke patients is an unmet need with major implications for clinical management. We investigated whether stroke location may contribute independent prognostic value to multifactorial predictive models of functional and cognitive outcomes. Four hundred twenty-eight consecutive patients with ischemic stroke were prospectively assessed with magnetic resonance imaging at 24 to 72 hours and at 3 months for functional outcome using the modified Rankin Scale and cognitive outcome using the Montreal Cognitive Assessment (MoCA). Statistical maps of functional and cognitive eloquent regions were derived from the first 215 patients (development sample) using voxel-based lesion-symptom mapping. We used multivariate logistic regression models to study the influence of stroke location (number of eloquent voxels from voxel-based lesion-symptom mapping maps), age, initial National Institutes of Health Stroke Scale and stroke volume on modified Rankin Scale and MoCA. The second part of our cohort was used as an independent replication sample. In univariate analyses, stroke location, age, initial National Institutes of Health Stroke Scale, and stroke volume were all predictive of poor modified Rankin Scale and MoCA. In multivariable analyses, stroke location remained the strongest independent predictor of MoCA and significantly improved the prediction compared with using only age, initial National Institutes of Health Stroke Scale, and stroke volume (area under the curve increased from 0.697-0.771; difference=0.073; 95% confidence interval, 0.008-0.155). In contrast, stroke location did not persist as independent predictor of modified Rankin Scale that was mainly driven by initial National Institutes of Health Stroke Scale (area under the curve going from 0.840 to 0.835). Similar results were obtained in the replication sample. Stroke location is an independent predictor of cognitive outcome (MoCA) at 3 months post stroke. © 2015 American Heart Association, Inc.

Neocortical 40 Hz oscillations during carbachol-induced rapid eye movement sleep and cataplexy.

PubMed

Torterolo, Pablo; Castro-Zaballa, Santiago; Cavelli, Matías; Chase, Michael H; Falconi, Atilio

2016-02-01

Higher cognitive functions require the integration and coordination of large populations of neurons in cortical and subcortical regions. Oscillations in the gamma band (30-45 Hz) of the electroencephalogram (EEG) have been involved in these cognitive functions. In previous studies, we analysed the extent of functional connectivity between cortical areas employing the 'mean squared coherence' analysis of the EEG gamma band. We demonstrated that gamma coherence is maximal during alert wakefulness and is almost absent during rapid eye movement (REM) sleep. The nucleus pontis oralis (NPO) is critical for REM sleep generation. The NPO is considered to exert executive control over the initiation and maintenance of REM sleep. In the cat, depending on the previous state of the animal, a single microinjection of carbachol (a cholinergic agonist) into the NPO can produce either REM sleep [REM sleep induced by carbachol (REMc)] or a waking state with muscle atonia, i.e. cataplexy [cataplexy induced by carbachol (CA)]. In the present study, in cats that were implanted with electrodes in different cortical areas to record polysomnographic activity, we compared the degree of gamma (30-45 Hz) coherence during REMc, CA and naturally-occurring behavioural states. Gamma coherence was maximal during CA and alert wakefulness. In contrast, gamma coherence was almost absent during REMc as in naturally-occurring REM sleep. We conclude that, in spite of the presence of somatic muscle paralysis, there are remarkable differences in cortical activity between REMc and CA, which confirm that EEG gamma (≈40 Hz) coherence is a trait that differentiates wakefulness from REM sleep. © 2015 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Bacopa monnieri (Brahmi) Enhanced Cognitive Function and Prevented Cognitive Impairment by Increasing VGLUT2 Immunodensity in Prefrontal Cortex of Sub-Chronic Phencyclidine Rat Model of Schizophrenia.

PubMed

Piyabhan, Pritsana; Wetchateng, Thanitsara

2015-04-01

Glutamatergic hypofunction is affected in schizophrenia. The decrement ofpresynaptic glutamatergic marker remarkably vesicular glutamate transporter type 1 (VGLUT1) indicates the deficit ofglutamatergic and cognitive function in schizophrenic brain. However there have been afew studies in VGLUT2. Brahmi, a traditional herbal medicine, might be a new frontier of cognitive deficit treatment and prevention in schizophrenia by changing cerebral VGLUT2 density. To study cognitive enhancement- and neuroprotective-effects of Brahmi on novel object recognition task and cerebral VGLUT2 immunodensity in sub-chronic phencyclidine (PCP) rat model of schizophrenia. Cognitive enhancement effect study; rats were assigned to three groups; Group-1: Control, Group-2: PCP administration and Group-3: PCP + Brahmi. Neuroprotective effect study; rats were assigned to three groups; Group-1: Control, Group-2: PCP administration and Group-3: Brahmi + PCP Discrimination ratio (DR) representing cognitive ability was obtained from novel object recognition task. VGLUT2 immunodensity was measured in prefrontal cortex, striatum, cornu ammonis fields 1 (CA1) and 2/3 (CA2/3) of hippocampus using immunohistochemistry. DR was significantly reduced in PCP group compared with control. This occurred alongside VGLUT2 reduction in prefrontal cortex, but not in striatum, CA1 or CA2/3. Both PCP + Brahmi and Brahmi + PCP groups showed an increased DR score up to normal, which occurred alongside a significantly increased VGLUT2 immunodensity in the prefrontal cortex, compared with PCP group. The decrement of VGLUT2 density in prefrontal cortex resulted in cognitive deficit in rats receiving PCP. Interestingly, receiving Brahmi after PCP administration can restore this cognitive deficit by increasing VGLUT2 density in prefrontal cortex. This investigation is defined as Brahmi's cognitive enhancement effect. Additionally, receiving Brahmi before PCP administration can also prevent cognitive impairment by elevating VGLUT2 density in prefrontal cortex. This observation indicates neuroprotective effect of Brahmi. Therefore, Brahmi could be a new frontier of restoration and prevention of cognitive deficit in schizophrenia.

Cognitive function and advanced kidney disease: longitudinal trends and impact on decision-making.

PubMed

Iyasere, Osasuyi; Okai, David; Brown, Edwina

2017-02-01

Background: Cognitive impairment commonly affects renal patients. But little is known about the influence of dialysis modality on cognitive trends or the influence of cognitive impairment on decision-making in renal patients. This study evaluated cognitive trends amongst chronic kidney disease (CKD), haemodialysis (HD) and peritoneal dialysis (PD) patients. The relationship between cognitive impairment and decision-making capacity (DMC) was also assessed. Methods: Patients were recruited from three outpatient clinics. Cognitive function was assessed 4-monthly for up to 2 years, using the Montreal Cognitive Assessment (MoCA) tool. Cognitive trends were assessed using mixed model analysis. DMC was assessed using the Macarthur Competency Assessment tool (MacCAT-T). MacCAT-T scores were compared between patients with cognitive impairment (MoCA <26) and those without. Results: In total, 102 (41 HD, 25 PD and 36 CKD) patients were recruited into the prospective study. After multivariate analysis, the total MoCA scores declined faster in dialysis compared with CKD patients [coefficient = -0.03, 95% confidence interval (95% CI) = -0.056 to - 0.004; P = 0.025]. The MoCA executive scores declined faster in the HD compared with PD patients (coefficient = -0.12, 95% CI = -0.233 to - 0.007; P = 0.037). DMC was assessed in 10 patients. Those with cognitive impairment had lower MacCAT-T compared with those without [median (interquartile range) 19 (17.9-19.6) versus 17.4 (16.3-18.4); P = 0.049]. Conclusions: Cognition declines faster in dialysis patients compared with CKD patients and in HD patients compared with PD patients. Cognitive impairment affects DMC in patients with advanced kidney disease.

Voluntary Running Depreciates the Requirement of Ca[superscript 2+]-Stimulated cAMP Signaling in Synaptic Potentiation and Memory Formation

ERIC Educational Resources Information Center

Zheng, Fei; Zhang, Ming; Ding, Qi; Sethna, Ferzin; Yan, Lily; Moon, Changjong; Yang, Miyoung; Wang, Hongbing

2016-01-01

Mental health and cognitive functions are influenced by both genetic and environmental factors. Although having active lifestyle with physical exercise improves learning and memory, how it interacts with the specific key molecular regulators of synaptic plasticity is largely unknown. Here, we examined the effects of voluntary running on long-term…

Influence of depression, anxiety and stress on cognitive performance in community-dwelling older adults living in rural Ecuador: results of the Atahualpa Project.

PubMed

Del Brutto, Oscar H; Mera, Robertino M; Del Brutto, Victor J; Maestre, Gladys E; Gardener, Hannah; Zambrano, Mauricio; Wright, Clinton B

2015-04-01

To assess the relationship between cognitive status and self-reported symptoms of depression, anxiety and stress of older adults living in an underserved rural South American population. Community-dwelling Atahualpa residents aged ≥60 years were identified during a door-to-door census, and evaluated with the Depression Anxiety Stress Scale-21 (DASS-21) and the Montreal Cognitive Assessment (MoCA). We explored whether positivity in each of the DASS-21 axes was related to total and domain-specific MoCA performance after adjustment for age, sex and education. A total of 280 persons (59% women; mean age, mean age 70 ± 8 years) were included. Based on established cut-offs for the DASS-21, 12% persons had depression, 15% had anxiety and 5% had stress. Mean total MoCA scores were significantly lower for depressed than for not depressed individuals (15.9 ± 5.5 vs 18.9 ± 4.4, P < 0.0001). Depressed participants had significantly lower total and domain-specific MoCA scores for abstraction, short-term memory and orientation. Anxiety was related to significantly lower total MoCA scores (17 ± 4.7 vs 18.8 ± 4.5, P = 0.02), but not to differences in domain-specific MoCA scores. Stress was not associated with significant differences in MoCA scores. The present study suggests that depression and anxiety are associated with poorer cognitive performance in elderly residents living in rural areas of developing countries. © 2014 Japan Geriatrics Society.

The Montreal Cognitive Assessment is superior to National Institute of Neurological Disease and Stroke-Canadian Stroke Network 5-minute protocol in predicting vascular cognitive impairment at 1 year.

PubMed

Dong, YanHong; Xu, Jing; Chan, Bernard Poon-Lap; Seet, Raymond Chee Seong; Venketasubramanian, Narayanaswamy; Teoh, Hock Luen; Sharma, Vijay Kumar; Chen, Christopher Li-Hsian

2016-04-12

The predictive ability of National Institute of Neurological Disease and Stroke-Canadian Stroke Network (NINDS-CSN) 5-minute protocol and Montreal Cognitive Assessment (MoCA) administered sub-acutely and at the convalescent phase after stroke for significant vascular cognitive impairment (VCI) at 1 year is unknown. We compared prognostic values of these tests. Patients with ischemic stroke and transient ischemic attack (TIA) received MoCA sub-acutely (within 2 weeks) and 3-6 months after stroke followed by a formal neuropsychological evaluation at 1 year. The total score of NINDS-CSN 5-minutes protocol was derived from MoCA. Moderate-severe VCI was defined as neuropsychological impairment in ≥ 3 domains. Area under the receiver operating characteristic curve (AUC) analyses were conducted to establish the optimal cutoff points and discriminatory properties of the MoCA and NINDS-CSN 5-minute protocol in detecting moderate-severe VCI. Four hundre patients were recruited at baseline. Of these, 291 received a formal neuropsychological assessment 1 year after stroke. 19% patients had moderate-severe VCI. The MoCA was superior to the NINDS-CSN 5-minute protocol [sub-acute AUCs: 0.89 vs 0.80, p < 0.01; 3-6 months AUCs: 0.90 vs 0.83, p < 0.01] in predicting for moderate-severe VCI at 1 year. At respective cutoff points, MoCA had significantly higher sensitivity than the NINDS-CSN 5-minute protocol at baseline (p = 0.01) and 3-6 months (p = 0.04). MoCA administered sub-acutely and 3-6 months after stroke is superior to the NINDS-CSN 5-minute protocol in predicting moderate-severe VCI at 1 year.

Huperzine A attenuates cognitive deficits and hippocampal neuronal damage after transient global ischemia in gerbils.

PubMed

Zhou, J; Zhang, H Y; Tang, X C

2001-11-09

The protective effects of huperzine A on transient global ischemia in gerbils were investigated. Five min of global ischemia in gerbils results in working memory impairments shown by increased escape latency in a water maze and reduced time spent in the target quadrant. These signs of dysfunction are accompanied by delayed degeneration of pyramidal hippocampal CA1 neurons and by decrease in acetylcholinesterase activity in the hippocampus. Subchronic oral administration of huperzine A (0.1 mg/kg, twice per day for 14 days) after ischemia significantly reduced the memory impairment, reduced neuronal degeneration in the CA1 region, and partially restored hippocampal choline acetyltransferase activity. The ability of huperzine A to attenuate memory deficits and neuronal damage after ischemia might be beneficial in cerebrovascular type dementia.

Cognitive impairment in the first year after breast cancer diagnosis: A prospective cohort study.

PubMed

Ramalho, Mariana; Fontes, Filipa; Ruano, Luís; Pereira, Susana; Lunet, Nuno

2017-04-01

The objective of this study was to assess the relation between cancer treatments and incident cognitive impairment in breast cancer patients, taking into account the levels of anxiety before treatment. We conducted a prospective cohort study with 418 newly diagnosed breast cancer patients with no cognitive impairment, defined as values at least 1.5 standard deviations below age- and education-adjusted cut-offs in the Montreal Cognitive Assessment (MoCA), at baseline. The Hospital Anxiety and Depression Scale and MoCA were used for evaluations before treatment and at 1-year after diagnosis. We used Poisson regressions to compute adjusted relative risks (RR) and corresponding 95% confidence intervals (95%CI) to identify predictors of cognitive impairment. The median (Percentile 25, Percentile 75) MoCA score before treatment was 24 (21, 26). A total of 8.1% (95%CI: 5.8, 11.2) of the patients presented incident cognitive impairment during the follow-up. There was a statistically significant interaction between anxiety at baseline and the effect of chemotherapy on the incidence of cognitive impairment (P for interaction = 0.028). There was a significantly increased risk of incident cognitive impairment among patients with no anxiety prior to treatment with schemes including doxorubicin and cyclophosphamide (adjusted RR = 4.22, 95%CI: 1.22, 14.65). There was a statistically significant association between chemotherapy and cognitive impairment, but only among women with no anxiety at baseline. Copyright © 2017 Elsevier Ltd. All rights reserved.

A possible mechanism for improvement by a cognition-enhancer nefiracetam of spatial memory function and cAMP-mediated signal transduction system in sustained cerebral ischaemia in rats

PubMed Central

Takeo, Satoshi; Niimura, Makiko; Miyake-Takagi, Keiko; Nagakura, Akira; Fukatsu, Tomoko; Ando, Tsuyoshi; Takagi, Norio; Tanonaka, Kouichi; Hara, Junko

2003-01-01

Accumulated evidence indicates that the adenylyl cyclase (AC)/cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)/cAMP-responsive element binding protein (CREB) signal transduction system may be linked to learning and memory function. The effects of nefiracetam, which has been developed as a cognition enhancer, on spatial memory function and the AC/cAMP/PKA/CREB signal transduction system in rats with sustained cerebral ischaemia were examined. Microsphere embolism (ME)-induced sustained cerebral ischaemia was produced by injection of 700 microspheres (48 μm in diameter) into the right hemisphere of rats. Daily oral administration of nefiracetam (10 mg kg−1 day−1) was started from 15 h after the operation. The delayed treatment with nefiracetam attenuated the ME-induced prolongation of the escape latency in the water maze task that was examined on day 7 to 9 after ME, but it did not reduce the infarct size. ME decreased Ca2+/calmodulin (CaM)-stimulated AC (AC-I) activity, cAMP content, cytosolic PKA Cβ level, nuclear PKA Cα and Cβ levels, and reduced the phosphorylation and DNA-binding activity of CREB in the nucleus in the right parietal cortex and hippocampus on day 3 after ME. The ME-induced changes in these variables did not occur by the delayed treatment with nefiracetam. These results suggest that nefiracetam preserved cognitive function, or prevented cognitive dysfunction, after sustained cerebral ischaemia and that the effect is, in part, attributable to the prevention of the ischaemia-induced impairment of the AC/cAMP/PKA/CREB signal transduction pathway. PMID:12598418

5-Hydroxytryptamine1A receptor-activation hyperpolarizes pyramidal cells and suppresses hippocampal gamma oscillations via Kir3 channel activation

PubMed Central

Johnston, April; McBain, Chris J; Fisahn, André

2014-01-01

Rhythmic cortical neuronal oscillations in the gamma frequency band (30–80 Hz, gamma oscillations) have been associated with cognitive processes such as sensory perception and integration, attention, learning, and memory. Gamma oscillations are disrupted in disorders for which cognitive deficits are hallmark symptoms such as schizophrenia and Alzheimer's disease. In vitro, various neurotransmitters have been found to modulate gamma oscillations. Serotonin (5-HT) has long been known to be important for both behavioural and cognitive functions such as learning and memory. Multiple 5-HT receptor subtypes are expressed in the CA3 region of the hippocampus and high doses of 5-HT reduce the power of induced gamma oscillations. Hypothesizing that 5-HT may have cell- and receptor subtype-specific modulatory effects, we investigated the receptor subtypes, cell types and cellular mechanisms engaged by 5-HT in the modulation of gamma oscillations in mice and rats. We found that 5-HT decreases the power of kainate-induced hippocampal gamma oscillations in both species via the 5-HT1A receptor subtype. Whole-cell patch clamp recordings demonstrated that this decrease was caused by a hyperpolarization of CA3 pyramidal cells and a reduction of their firing frequency, but not by alteration of inhibitory neurotransmission. Finally, our results show that the effect on pyramidal cells is mediated via the G protein-coupled receptor inwardly rectifying potassium channel Kir3. Our findings suggest this novel cellular mechanism as a potential target for therapies that are aimed at alleviating cognitive decline by helping the brain to maintain or re-establish normal gamma oscillation levels in neuropsychiatric and neurodegenerative disorders. PMID:25107925

The impact of falls on motor and cognitive recovery after discharge from in-patient stroke rehabilitation

PubMed Central

Wong, Jennifer S.; Brooks, Dina; Inness, Elizabeth L.; Mansfield, Avril

2016-01-01

Background Falls are common among community-dwelling stroke survivors. The aim of this study was to (1) compare motor and cognitive outcomes between individuals who fell in the six months post-discharge from in-patient stroke rehabilitation and those who did not fall, and (2) explore potential mechanisms underlying the relationship between falls and recovery of motor and cognitive function. Methods Secondary analysis of a prospective cohort study of individuals discharged home from in-patient rehabilitation was conducted. Participants were recruited at discharge and completed a six-month falls monitoring period using postcards with follow-up. Non-fallers and fallers were compared at the six-month follow-up assessment on the Berg Balance Scale (BBS), Chedoke-McMaster Stroke Assessment (CMSA), gait speed, and Montreal Cognitive Assessment (MoCA). Measures of balance confidence and physical activity were also assessed. Results 23 fallers were matched to 23 non-fallers on age and functional balance scores at discharge. A total of 43 falls were reported during the study period (8 participants fell more than once). At follow-up, BBS scores (p=0.0066) and CMSA foot scores (p=0.0033) were significantly lower for fallers than non-fallers. The two groups did not differ on CMSA leg scores (p=0.049), gait speed (p=0.47) or MoCA (p=0.23). There was no significant association between change in balance confidence scores and change in physical activity levels among all participants from the first and third questionnaire (r=0.27, p=0.08). Conclusions Performance in balance and motor recovery of the foot were compromised in fallers when compared to non-fallers at six months post-discharge from in-patient stroke rehabilitation. PMID:27062418

Cognitive impairment in Parkinson's disease: Association between patient-reported and clinically measured outcomes.

PubMed

Mills, Kelly A; Mari, Zoltan; Pontone, Gregory M; Pantelyat, Alexander; Zhang, Angela; Yoritomo, Nadine; Powers, Emma; Brandt, Jason; Dawson, Ted M; Rosenthal, Liana S

2016-12-01

In Parkinson's disease, the association between objective and patient-reported measures of cognitive dysfunction is unknown and highly relevant to research and clinical care. To determine which cognitive domain-specific Montreal Cognitive Assessment (MoCA) subscores are most strongly associated with patient-reported cognitive impairment on question 1 (Q1) of the Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS). We analyzed data from 759 PD participants and 481 persons without PD with in a retrospective, cross sectional analysis using data from the NINDS Parkinson's Disease Biomarkers Program (PDBP), a longitudinal, multicenter biomarker study. The relationship between a patient-reported cognitive rating (MDS-UPDRS q1.1) and objective cognitive assessments (MoCA) was assessed using multinomial logistic regression modeling and the outcomes reported as conditional odds ratios (cOR's) representing the relative odds of a participant reporting cognitive impairment that is "slight" versus "normal" on MDS-UPDRSq1.1 for a one unit increase in a MoCA sub-score, adjusted for age and education. In PD participants, changes in visuospatial-executive performance and memory had the most significant impact on subjective cognitive impairment. A 1-point increase in visuospatial-executive function decreased the chance of reporting a MDS-UPDRS Q1 score of "slight" versus "normal" by a factor of 0.686 (p < 0.001) and each 1 point improvement in delayed recall decreased the odds of reporting "slight" cognitive impairment by a factor of 0.836 (p < 0.001). Conversion from a PD patient's report of "normal" to "slight" cognitive impairment may be associated with changes in visuospatial-executive dysfunction and memory more than other cognitive domains. Copyright © 2016 Elsevier Ltd. All rights reserved.

Correlation between Lymphocyte CD4 Count, Treatment Duration, Opportunistic Infection and Cognitive Function in Human Immunodeficiency Virus-Acquired Immunodeficiency Syndrome (HIV-AIDS) Patients.

PubMed

Fitri, Fasihah Irfani; Rambe, Aldy Safruddin; Fitri, Aida

2018-04-15

Human immunodeficiency virus (HIV) infection is an epidemic worldwide, despite the marked benefits of antiretroviral therapy (ARV) in reducing severe HIV-associated dementia. A milder form of neurocognitive disorders are still prevalent and remain a challenge. This study aimed to determine the correlation between plasma cluster of differentiation 4 (CD4) lymphocyte, duration of ARV treatment, opportunistic infections, and cognitive function in HIV-AIDS patients. A cross-sectional study involving 85 HIV-AIDS patients was conducted at Adam Malik General Hospital Medan, Indonesia. All subjects were subjected to physical, neurologic examination and Montreal Cognitive Assessment-Indonesian Version (MoCA-INA) to assess cognitive function and measurement of lymphocyte CD4 counts. Out of the 85 subjects evaluated, the proportion concerning sexes include 52 males (61.2 %) and 33 females (38.8%). The mean age was 38.53 ± 9.77 years old. There was a significant correlation between CD4 lymphocyte counts and MoCA-INA score (r = 0.271, p = 0.012), but there was no significant correlation between duration of ARV treatment and MoCA-INA score. There was also no difference in MoCA-INA score based on the presence of opportunistic infection. Lymphocyte CD4 count was independently correlated with cognitive function in HIV-AIDS patients.

Ethanol Inhibition of Recombinant NMDA Receptors Is Not Altered by Co-Expression of CaMKII-α or CaMKII-β

PubMed Central

Xu, Minfu; Chandler, L. Judson; Woodward, John J.

2008-01-01

Previous studies have shown that the N-methyl-D-aspartate (NMDA) receptor is an important target for the actions of ethanol in the brain. NMDA receptors are glutamate-activated ion channels that are highly expressed in neurons. They are activated during periods of significant glutamatergic synaptic activity and are an important source of the signaling molecule calcium in the post-synaptic spine. Alterations in the function of NMDA receptors by drugs or disease are associated with deficits in motor, sensory and cognitive processes of the brain. Acutely, ethanol inhibits ion flow through NMDA receptors while sustained exposure to ethanol can induce compensatory changes in the density and localization of the receptor. Defining factors that govern the acute ethanol sensitivity of NMDA receptors is an important step in how an individual responds to ethanol. In the present study, we investigated the effect of calcium-calmodulin dependent protein kinase II (CaMKII) on the ethanol sensitivity of recombinant NMDA receptors. CaMKII is a major constituent of the post-synaptic density and is critically involved in various forms of learning and memory. NMDA receptor subunits were transiently expressed in human embryonic kidney 293 cells (HEK 293) along with CaMKII-α or CaMKII-β tagged with the green fluorescent protein (GFP). Whole cell currents were elicited by brief exposures to glutamate and were measured using patchclamp electrophysiology. Neither CaMKII-α or CaMKII-β had any significant effect on the ethanol inhibition of NR1/2A or NR1/2B receptors. Ethanol inhibition was also unaltered by deletion of CaMKII binding domains in NR1 or NR2 subunits or by phospho-site mutants that mimic or occlude CaMKII phosphorylation. Chronic treatment of cortical neurons with ethanol had no significant effect on the expression of CaMKII-α or CaMKII-β. The results of this study suggest that CaMKII is not involved in regulating the acute ethanol sensitivity of NMDA receptors. PMID:18562151

An Interactive Activation Model of the Effect of Context in Perception. Part 2

DTIC Science & Technology

1980-07-15

nonword strings are often seen with letters transposed if the transposition will produce legal strings (Estes, 1975a; c.f. experiment by Stevens reported...Activation Model Rumelhart & McClelland Part II 90 References Anderson, J. A. Neural models with cognitive implications. In D. LaBerge & S. J. Samuels...Washington, DC 20372 Coe391 Dr. Gory PoockNavy Personnel R&D Center Operations Research Department LT Steven D. Harris. MSC, USN San Diego, CA 92152 Code

A Putative Mechanism of Age-Related Synaptic Dysfunction Based on the Impact of IGF-1 Receptor Signaling on Synaptic CaMKIIα Phosphorylation.

PubMed

Ogundele, Olalekan M; Pardo, Joaquin; Francis, Joseph; Goya, Rodolfo G; Lee, Charles C

2018-01-01

Insulin-like growth factor 1 receptor (IGF-1R) signaling regulates the activity and phosphorylation of downstream kinases linked to inflammation, neurodevelopment, aging and synaptic function. In addition to the control of Ca 2+ currents, IGF-1R signaling modulates the activity of calcium-calmodulin-dependent kinase 2 alpha (CaMKIIα) and mitogen activated protein kinase (MAPK/ErK) through multiple signaling pathways. These proteins (CaMKIIα and MAPK) regulate Ca 2+ movement and long-term potentiation (LTP). Since IGF-1R controls the synaptic activity of Ca 2+ , CaMKIIα and MAPK signaling, the possible mechanism through which an age-dependent change in IGF-1R can alter the synaptic expression and phosphorylation of these proteins in aging needs to be investigated. In this study, we evaluated the relationship between an age-dependent change in brain IGF-1R and phosphorylation of CaMKIIα/MAPK. Furthermore, we elucidated possible mechanisms through which dysregulated CaMKIIα/MAPK interaction may be linked to a change in neurotransmitter processing and synaptic function. Male C57BL/6 VGAT-Venus mice at postnatal days 80 (P80), 365 and 730 were used to study age-related neural changes in two brain regions associated with cognitive function: hippocampus and prefrontal cortex (PFC). By means of high throughput confocal imaging and quantitative immunoblotting, we evaluated the distribution and expression of IGF-1, IGF-1R, CaMKIIα, p-CaMKIIα, MAPK and p-MAPK in whole brain lysate, hippocampus and cortex. Furthermore, we compared protein expression patterns and regional changes at P80, P365 and P730. Ultimately, we determined the relative phosphorylation pattern of CaMKIIα and MAPK through quantification of neural p-CaMKIIα and p-MAPK/ErK, and IGF-1R expression for P80, P365 and P730 brain samples. In addition to a change in synaptic function, our results show a decrease in neural IGF-1/IGF-1R expression in whole brain, hippocampus and cortex of aged mice. This was associated with a significant upregulation of phosphorylated neural MAPK (p-MAPK) and decrease in total brain CaMKIIα (i.e., CaMKIIα and p-CaMKIIα) in the aged brain. Taken together, we showed that brain aging is associated with a change in neural IGF-1/IGF-1R expression and may be linked to a change in phosphorylation of synaptic kinases (CaMKIIα and MAPK) that are involved in the modulation of LTP.

The MoCA-Memory Index Score: An Efficient Alternative to Paragraph Recall for the Detection of Amnestic Mild Cognitive Impairment.

PubMed

Kaur, Antarpreet; Edland, Steven D; Peavy, Guerry M

2018-01-01

To compare ability of 2 measures of delayed memory (word list, story paragraph) to discriminate Normal Control (NC) subjects from those with amnestic mild cognitive impairment (aMCI). Demographic, neuropsychological, and diagnostic data contributed by 34 Alzheimer's Disease Centers to the National Alzheimer's Coordinating Center characterized 2717 individuals with a diagnosis of either NC (n=2205) or aMCI (n=512). The Montreal Cognitive Assessment-Memory Index Score (MoCA-MIS) assessed delayed word recall, and the Craft Story 21, delayed story recall. Logistic regression and receiver operator characteristic curves controlling for age, sex, and education assessed the ability of each test to differentiate NCs from subjects with aMCI. The MoCA-MIS had significantly better sensitivity and specificity (area under the receiver operator characteristic curve 0.83 vs. 0.80, P=0.004). At sensitivity 80%, the specificity of the MoCA-MIS was 69.1%, compared with 62.8% for the Craft Story. These data suggest that the MoCA-MIS, a recall score from items within the MoCA, is better at discriminating NCs from subjects with aMCI than the Craft Story. Word recall may be an efficient alternative to paragraph recall for diagnostic screening within clinical practice and research settings.

Pyridoindole antioxidant-induced preservation of rat hippocampal pyramidal cell number linked with reduction of oxidative stress yet without influence on cognitive deterioration in Alzheimer-like neurodegeneration.

PubMed

Gasparova, Zdenka; Stara, Veronika; Janega, Pavol; Navarova, Jana; Sedlackova, Natalia; Mach, Mojmir; Ujhazy, Eduard

2014-01-01

The idea of antioxidant therapy attenuating Alzheimer disease (AD) neuropathology starts to be attractive. Animal models are often used in these studies. An AD-like model of trimethyltin (TMT)-induced neurodegeneration, targeting the hippocampus, involves neuronal cell death and cognitive impairment. Effect of the pyridoindole SMe1EC2 (3×50 mg/kg) and vitamin C (3×50mg/kg) was analyzed in the model of TMT-induced (8 mg/kg) neurodegeneration. The study was focused on the effect of the antioxidants tested on learning performance in the Morris water maze (MWM) on days 21-25 after TMT administration, on biochemical variables - malondyaldehyde (MDA) and lysosomal enzyme NAGA in brain cortex and blood serum, and on pyramidal cell number in the CA1 area of the hippocampus on day 31 after TMT administration in adult male Wistar rats (n=32). Critical deterioration of learning performance was observed due to the TMT administration in the MWM. Further, apparent reduction of pyramidal cell number to 21% in the CA1 area of the hippocampus, increased MDA and NAGA activity in serum and increased NAGA activity in the cortex were determined contrary to controls. In serum, an increase of MDA level was prevented by both antioxidants tested without any effect on NAGA activity. SMe1EC2 apparently preserved pyramidal cell viability in the CA1 area. Both substances tested failed to ameliorate the detrimental effect of TMT on spatial memory. The biochemical and morphometrical findings suggest that reduction of oxidative stress may play a role in AD-like neurodegeneration. Different doses and timing of SMe1EC2 administration might bring improvement in next learning performance.

Dim nighttime light impairs cognition and provokes depressive-like responses in a diurnal rodent.

PubMed

Fonken, Laura K; Kitsmiller, Emily; Smale, Laura; Nelson, Randy J

2012-08-01

Circadian disruption is a common by-product of modern life. Although jet lag and shift work are well-documented challenges to circadian organization, many more subtle environmental changes cause circadian disruption. For example, frequent fluctuations in the timing of the sleep/wake schedule, as well as exposure to nighttime lighting, likely affect the circadian system. Most studies of these effects have focused on nocturnal rodents, which are very different from diurnal species with respect to their patterns of light exposure and the effects that light can have on their activity. Thus, the authors investigated the effect of nighttime light on behavior and the brain of a diurnal rodent, the Nile grass rat. Following 3 weeks of exposure to standard light/dark (LD; 14:10 light [~150 lux] /dark [0 lux]) or dim light at night (dLAN; 14:10 light [~150 lux] /dim [5 lux]), rats underwent behavioral testing, and hippocampal neurons within CA1, CA3, and the dentate gyrus (DG) were examined. Three behavioral effects of dLAN were observed: (1) decreased preference for a sucrose solution, (2) increased latency to float in a forced swim test, and (3) impaired learning and memory in the Barnes maze. Light at night also reduced dendritic length in DG and basilar CA1 dendrites. Dendritic length in the DG positively correlated with sucrose consumption in the sucrose anhedonia task. Nighttime light exposure did not disrupt the pattern of circadian locomotor activity, and all grass rats maintained a diurnal activity pattern. Together, these data suggest that exposure to dLAN can alter affective responses and impair cognition in a diurnal animal.

Altered Whole-Brain Structural Covariance of the Hippocampal Subfields in Subcortical Vascular Mild Cognitive Impairment and Amnestic Mild Cognitive Impairment Patients.

PubMed

Wang, Xuetong; Yu, Yang; Zhao, Weina; Li, Qiongling; Li, Xinwei; Li, Shuyu; Yin, Changhao; Han, Ying

2018-01-01

The hippocampus plays important roles in memory processing. However, the hippocampus is not a homogeneous structure, which consists of several subfields. The hippocampal subfields are differently affected by many neurodegenerative diseases, especially mild cognitive impairment (MCI). Amnestic mild cognitive impairment (aMCI) and subcortical vascular mild cognitive impairment (svMCI) are the two subtypes of MCI. aMCI is characterized by episodic memory loss, and svMCI is characterized by extensive white matter hyperintensities and multiple lacunar infarctions on magnetic resonance imaging. The primary cognitive impairment in svMCI is executive function, attention, and semantic memory. Some variations or disconnections within specific large-scale brain networks have been observed in aMCI and svMCI patients. The aim of this study was to investigate abnormalities in structural covariance networks (SCNs) between hippocampal subfields and the whole cerebral cortex in aMCI and svMCI patients, and whether these abnormalities are different between the two groups. Automated segmentation of hippocampal subfields was performed with FreeSurfer 5.3, and we selected five hippocampal subfields as the seeds of SCN analysis: CA1, CA2/3, CA4/dentate gyrus (DG), subiculum, and presubiculum. SCNs were constructed based on these hippocampal subfield seeds for each group. Significant correlations between hippocampal subfields, fusiform gyrus (FFG), and entorhinal cortex (ERC) in gray matter volume were found in each group. We also compared the differences in the strength of structural covariance between any two groups. In the aMCI group, compared to the normal controls (NC) group, we observed an increased association between the left CA1/CA4/DG/subiculum and the left temporal pole. Additionally, the hippocampal subfields (bilateral CA1, left CA2/3) significantly covaried with the orbitofrontal cortex in the svMCI group compared to the NC group. In the aMCI group compared to the svMCI group, we observed decreased association between hippocampal subfields and the right FFG, while we also observed an increased association between the bilateral subiculum/presubiculum and bilateral ERC. These findings provide new evidence that there is altered whole-brain structural covariance of the hippocampal subfields in svMCI and aMCI patients and provide insights to the pathological mechanisms of different MCI subtypes.

Entorhinal theta-frequency input to the dentate gyrus trisynaptically evokes hippocampal CA1 LTP

PubMed Central

Stepan, Jens; Dine, Julien; Fenzl, Thomas; Polta, Stephanie A.; von Wolff, Gregor; Wotjak, Carsten T.; Eder, Matthias

2012-01-01

There exists substantial evidence that some forms of explicit learning in mammals require long-term potentiation (LTP) at hippocampal CA3-CA1 synapses. While CA1 LTP has been well characterized at the monosynaptic level, it still remains unclear how the afferent systems to the hippocampus can initiate formation of this neuroplastic phenomenon. Using voltage-sensitive dye imaging (VSDI) in a mouse brain slice preparation, we show that evoked entorhinal cortical (EC) theta-frequency input to the dentate gyrus highly effectively generates waves of neuronal activity which propagate through the entire trisynaptic circuit of the hippocampus (“HTC-Waves”). This flow of activity, which we also demonstrate in vivo, critically depends on frequency facilitation of mossy fiber to CA3 synaptic transmission. The HTC-Waves are rapidly boosted by the cognitive enhancer caffeine (5 μM) and the stress hormone corticosterone (100 nM). They precisely follow the rhythm of the EC input, involve high-frequency firing (>100 Hz) of CA3 pyramidal neurons, and induce NMDA receptor-dependent CA1 LTP within a few seconds. Our study provides the first experimental evidence that synchronous theta-rhythmical spiking of EC stellate cells, as occurring during EC theta oscillations, has the capacity to drive induction of CA1 LTP via the hippocampal trisynaptic pathway. Moreover, we present data pointing to a basic filter mechanism of the hippocampus regarding EC inputs and describe a methodology to reveal alterations in the “input–output relationship” of the hippocampal trisynaptic circuit. PMID:22988432

Moringa oleifera mitigates memory impairment and neurodegeneration in animal model of age-related dementia.

PubMed

Sutalangka, Chatchada; Wattanathorn, Jintanaporn; Muchimapura, Supaporn; Thukham-mee, Wipawee

2013-01-01

To date, the preventive strategy against dementia is still essential due to the rapid growth of its prevalence and the limited therapeutic efficacy. Based on the crucial role of oxidative stress in age-related dementia and the antioxidant and nootropic activities of Moringa oleifera, the enhancement of spatial memory and neuroprotection of M. oleifera leaves extract in animal model of age-related dementia was determined. The possible underlying mechanism was also investigated. Male Wistar rats, weighing 180-220 g, were orally given M. oleifera leaves extract at doses of 100, 200, and 400 mg/kg at a period of 7 days before and 7 days after the intracerebroventricular administration of AF64A bilaterally. Then, they were assessed memory, neuron density, MDA level, and the activities of SOD, CAT, GSH-Px, and AChE in hippocampus. The results showed that the extract improved spatial memory and neurodegeneration in CA1, CA2, CA3, and dentate gyrus of hippocampus together with the decreased MDA level and AChE activity but increased SOD and CAT activities. Therefore, our data suggest that M. oleifera leaves extract is the potential cognitive enhancer and neuroprotectant. The possible mechanism might occur partly via the decreased oxidative stress and the enhanced cholinergic function. However, further explorations concerning active ingredient(s) are still required.

Activation of G-protein coupled estrogen receptor 1 improves early-onset cognitive impairment via PI3K/Akt pathway in rats with traumatic brain injury.

PubMed

Wang, Ze-Fen; Pan, Zhi-Yong; Xu, Cheng-Shi; Li, Zhi-Qiang

2017-01-22

Previous studies experimentally reveal that G-protein coupled estrogen receptor 1(GPER) has neuroprotection against ischemic injury. However, its effect on traumatic brain injury (TBI) is less well-established. Cognitive impairment following human TBI is a common clinical observation, and TBI is considered as a risk factor for Alzheimer's disease (AD). This study aimed to observe the possible protective effect of GPER on early-onset cognitive impairment after a single TBI and investigate the cellular mechanism underlying its actions. We found that selective GPER agonist G-1 significantly reduced hippocampal CA1 neuronal loss and improved cognitive impairment in TBI rats. Although previous studies have shown that AD-like tau pathology occurs many years after both repetitive and single TBI, accumulation of hyperphosphorylated tau was not observed within days (detected at 24 h and 7d) after TBI. Furthermore, tau phosphorylation was not altered by G-1 treatment. It was found that G-1 administration caused an increase in p-Akt level. However, the neuroprotective effects of G-1 on spatial cognition and neuronal death were attenuated by PI3K/Akt inhibitor LY294002. These findings indicate that GPER agonist G-1 had protection on cognitive function via activation of PI3K/Akt signaling. Early-onset cognitive impairment following a single TBI was closely associated with acute hippocampal neuronal loss rather than tau pathology. This study suggests that early activation of GPER might be a promising therapeutic strategy for improvement of TBI-induced cognitive outcomes. Copyright © 2016 Elsevier Inc. All rights reserved.

Cognitive function in middle-aged and older adults participating in synchronized swimming-exercise.

PubMed

Maeshima, Etsuko; Okumura, Yuka; Tatsumi, Juri; Tomokane, Sayaka; Ikeshima, Akiko

2017-01-01

[Purpose] The purpose of the present study was to examine cognitive function in middle-aged and older adults regularly engaging in synchronized swimming-exercise. [Subjects and Methods] Twenty-three female synchronized swimmers ranging in age from 49 to 85 years were recruited for the present study. The duration of synchronized swimming experience ranged from 1 to 39 years. The control group consisted of 36 age- and gender-matched community-dwelling middle-aged and older adults (age range: 49 to 77 years). Cognitive function was evaluated using the Japanese version of the Montreal Cognitive Assessment (MoCA-J) and compared between the synchronized swimmers and control participants. [Results] No significant differences in mean total MoCA-J scores were observed between the synchronized swimmers and control participants (23.2 ± 3.1 and 22.2 ± 3.6, respectively). Twenty-nine subjects in the control group and 17 in the synchronized swimming group scored below 26 on the MoCA-J, indicative of mild cognitive impairment. Significant differences in delayed recall-but not in visuospatial/executive function, naming, attention, language, abstraction, or orientation-were also observed between the two groups. [Conclusion] The results of the present study suggest that synchronized swimming has beneficial effects on cognitive function, particularly with regard to recent memory.

Dysregulation of synaptic plasticity precedes appearance of morphological defects in a Pten conditional knockout mouse model of autism.

PubMed

Takeuchi, Koichi; Gertner, Michael J; Zhou, Jing; Parada, Luis F; Bennett, Michael V L; Zukin, R Suzanne

2013-03-19

The phosphoinositide signaling system is a crucial regulator of neural development, cell survival, and plasticity. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) negatively regulates phosphatidylinositol 3-kinase signaling and downstream targets. Nse-Cre Pten conditional knockout mice, in which Pten is ablated in granule cells of the dentate gyrus and pyramidal neurons of the hippocampal CA3, but not CA1, recapitulate many of the symptoms of humans with inactivating PTEN mutations, including progressive hypertrophy of the dentate gyrus and deficits in hippocampus-based social and cognitive behaviors. However, the impact of Pten loss on activity-dependent synaptic plasticity in this clinically relevant mouse model of Pten inactivation remains unclear. Here, we show that two phosphatidylinositol 3-kinase- and protein synthesis-dependent forms of synaptic plasticity, theta burst-induced long-term potentiation and metabotropic glutamate receptor (mGluR)-dependent long-term depression, are dysregulated at medial perforant path-to-dentate gyrus synapses of young Nse-Cre Pten conditional knockout mice before the onset of visible morphological abnormalities. In contrast, long-term potentiation and mGluR-dependent long-term depression are normal at CA3-CA1 pyramidal cell synapses at this age. Our results reveal that deletion of Pten in dentate granule cells dysregulates synaptic plasticity, a defect that may underlie abnormal social and cognitive behaviors observed in humans with Pten inactivating mutations and potentially other autism spectrum disorders.

Enhanced Cognition and Hypoglutamatergic Signaling in a Growth Hormone Receptor Knockout Mouse Model of Successful Aging.

PubMed

Hascup, Kevin N; Lynn, Mary K; Fitzgerald, Patrick J; Randall, Shari; Kopchick, John J; Boger, Heather A; Bartke, Andrzej; Hascup, Erin R

2017-03-01

Growth hormone receptor knockout (GHR-KO) mice are long lived with improved health span, making this an excellent model system for understanding biochemical mechanisms important to cognitive reserve. The purpose of the present study was to elucidate differences in cognition and glutamatergic dynamics between aged (20- to 24-month-old) GHR-KO and littermate controls. Glutamate plays a critical role in hippocampal learning and memory and is implicated in several neurodegenerative disorders, including Alzheimer's disease. Spatial learning and memory were assessed using the Morris water maze (MWM), whereas independent dentate gyrus (DG), CA3, and CA1 basal glutamate, release, and uptake measurements were conducted in isoflurane anesthetized mice utilizing an enzyme-based microelectrode array (MEA) coupled with constant potential amperometry. These MEAs have high temporal and low spatial resolution while causing minimal damage to the surrounding parenchyma. Littermate controls performed worse on the memory portion of the MWM behavioral task and had elevated DG, CA3, and CA1 basal glutamate and stimulus-evoked release compared with age-matched GHR-KO mice. CA3 basal glutamate negatively correlated with MWM performance. These results support glutamatergic regulation in learning and memory and may have implications for therapeutic targets to delay the onset of, or reduce cognitive decline, in Alzheimer's disease. © The Author 2016. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Correlation between hypertension and cognitive function in elderly

NASA Astrophysics Data System (ADS)

Fitri, F. I.; Rambe, A. S.

2018-03-01

Hypertension and cognitive impairment are common disorders among elderly adults, and their prevalences tend to rise as the population ages. This study aimed to determine the correlation between hypertension and cognitive function in elderly. It was a cross-sectional study involving 62 elderly subjects. All subjects underwent physical and neurologic examination and Montreal Cognitive Assessment-Indonesian Version (MoCA-INA) to assess cognitive function. This study included 62 subjects consisted of 26 males (41.9%) and 36 females (58.1%). There were 24 subjects (38.2%) with hypertension and 38 (61.3%) normal elderly subjects. The mean age was 65.71±4.49 years old. There were no significant differences in demographic characteristics, total MoCA-INA scores, and scores based on cognitive domains between two groups, except for visuospatial and executive function (p=0.026). There was a significant correlation between hypertension and visuospatial and executive function (r=0.301, p=0.017). Hypertension is correlated with cognitive impairment mainly on visuospatial and executive function in elderly.

Plasma cytokine IL-6 levels and subjective cognitive decline: preliminary findings.

PubMed

Keegan, Andrew P; Paris, Daniel; Luis, Cheryl A; Abdullah, Laila; Ait-Ghezala, Ghania; Beaulieu-Abdelahad, David; Pryor, Makenzie; Chaykin, Jillian; Crynen, Gogce; Crawford, Fiona; Mullan, Michael

2018-02-01

Detection of Alzheimer's disease (AD) prior to clinical inception will be paramount for introducing disease modifying treatments. We have begun collecting baseline characteristics of a community cohort for longitudinal assessment and testing of antecedent blood-based biomarkers. We describe the baseline visit from the first 131 subjects in relationship to a commonly described cytokine, interleukin 6 (IL-6). Subjects from the community presented for a free memory screening with varying degrees of memory concern. We quantified the baseline plasma levels of the cytokine IL-6 and assessed cognition (Montreal Cognitive Assessment, MoCA) and mood (Geriatric Depression Scale, GDS) in relationship to their memory concern. Baseline MoCA scores were inversely related to age, and this association was influenced by an AD risk factor, Apolipoprotein E (APOE4) carrier status. The degree of subjective cognitive decline correlated with GDS and was inversely related to MoCA scores. Interleukin 6 levels were related to age, body mass index, and years of education. It will be important to assess how these baseline IL-6 levels and forthcoming novel biomarkers relate to future cognitive decline. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

Association between Sedentary Behaviour and Physical, Cognitive, and Psychosocial Status among Older Adults in Assisted Living.

PubMed

Leung, Pet-Ming; Ejupi, Andreas; van Schooten, Kimberley S; Aziz, Omar; Feldman, Fabio; Mackey, Dawn C; Ashe, Maureen C; Robinovitch, Stephen N

2017-01-01

Identification of the factors that influence sedentary behaviour in older adults is important for the design of appropriate intervention strategies. In this study, we determined the prevalence of sedentary behaviour and its association with physical, cognitive, and psychosocial status among older adults residing in Assisted Living (AL). Participants ( n = 114, mean age = 86.7) from AL sites in British Columbia wore waist-mounted activity monitors for 7 consecutive days, after being assessed with the Timed Up and Go (TUG), Montreal Cognitive Assessment (MoCA), Short Geriatric Depression Scale (GDS), and Modified Fall Efficacy Scale (MFES). On average, participants spent 87% of their waking hours in sedentary behaviour, which accumulated in 52 bouts per day with each bout lasting an average of 13 minutes. Increased sedentary behaviour associated significantly with scores on the TUG ( r = 0.373, p < 0.001) and MFES ( r = -0.261, p = 0.005), but not with the MoCA or GDS. Sedentary behaviour also associated with male gender, use of mobility aid, and multiple regression with increased age. We found that sedentary behaviour among older adults in AL associated with TUG scores and falls-related self-efficacy, which are modifiable targets for interventions to decrease sedentary behaviour in this population.

Subchronic phencyclidine treatment in adult mice increases GABAergic transmission and LTP threshold in the hippocampus

PubMed Central

Nomura, Toshihiro; Oyamada, Yoshihiro; Fernandes, Herman B.; Remmers, Christine; Xu, Jian; Meltzer, Herbert; Contractor, Anis

2015-01-01

Repeated administration of non-competitive N-methyl-d-aspartate (NMDA) receptor antagonists such as phencyclidine (PCP) to rodents causes long-lasting deficits in cognition and memory, and has effects on behaviors that have been suggested to be models of the cognitive impairment associated with schizophrenia (CIAS). Despite this being a widely studied animal model, little is known about the long lasting changes in synapses and circuits that underlie the altered behaviors. Here we examined synaptic transmission ex-vivo in the hippocampus of mice after a subchronic PCP (scPCP) administration regime. We found that after at least one week of drug free washout period when mice have impaired cognitive function, the threshold for long term potentiation (LTP) of CA1 excitatory synapses was elevated. This elevated LTP threshold was directly related to increased inhibitory input to CA1 pyramidal cells through increased activity of GABAergic neurons. These results suggest repeated PCP administration causes a long-lasting metaplastic change in the inhibitory circuits in the hippocampus that results in impaired LTP, and could contribute to the deficits in hippocampal-dependent memory in PCP-treated mice. Changes in GABA signaling have been described in patients with schizophrenia, therefore our results support using scPCP as a model of CIAS. PMID:25937215

The Neuroprotective Effect of Dark Chocolate in Monosodium Glutamate-Induced Nontransgenic Alzheimer Disease Model Rats: Biochemical, Behavioral, and Histological Studies.

PubMed

Madhavadas, Sowmya; Kapgal, Vijaya Kumar; Kutty, Bindu M; Subramanian, Sarada

2016-01-01

The vulnerability to oxidative stress and cognitive decline continue to increase during both normal and pathological aging. Dietary changes and sedentary life style resulting in mid-life obesity and type 2 diabetes, if left uncorrected, further add to the risk of cognitive decline and Alzheimer disease (AD) in the later stages of life. Certain antioxidant agents such as dietary polyphenols, taken in adequate quantities, have been suggested to improve the cognitive processes. In this study, we examined the effect of oral administration of dark chocolate (DC) containing 70% cocoa solids and 4% total polyphenol content for three months at a dose of 500 mg/Kg body weight per day to 17-month-old monosodium glutamate treated obese Sprague-Dawley rats, earlier characterized as a nontransgenic AD (NTAD) rat model after reversal of obesity, diabetes, and consequent cognitive impairments. The results demonstrated that DC reduced the hyperglycemia, inhibited the cholinesterase activity in the hippocampal tissue homogenates, and improved the cognitive performance in spatial memory related Barnes maze task. Histological studies revealed an increase in cell volume in the DC treated rats in the CA3 region of the hippocampus. These findings demonstrated the benefits of DC in enhancing cognitive function and cholinergic activity in the hippocampus of the aged NTAD rats while correcting their metabolic disturbances.

Activation of PPARγ Ameliorates Spatial Cognitive Deficits through Restoring Expression of AMPA Receptors in Seipin Knock-Out Mice.

PubMed

Zhou, Libin; Chen, Tingting; Li, Guoxi; Wu, Chaoming; Wang, Conghui; Li, Lin; Sha, Sha; Chen, Lei; Liu, George; Chen, Ling

2016-01-27

A characteristic phenotype of congenital generalized lipodystrophy 2 (CGL2) that is caused by loss-of-function of seipin gene is mental retardation. Here, we show that seipin deficiency in hippocampal CA1 pyramidal cells caused the reduction of peroxisome proliferator-activated receptor gamma (PPARγ). Twelve-week-old systemic seipin knock-out mice and neuronal seipin knock-out (seipin-nKO) mice, but not adipose seipin knock-out mice, exhibited spatial cognitive deficits as assessed by the Morris water maze and Y-maze, which were ameliorated by the treatment with the PPARγ agonist rosiglitazone (rosi). In addition, seipin-nKO mice showed the synaptic dysfunction and the impairment of NMDA receptor-dependent LTP in hippocampal CA1 regions. The density of AMPA-induced current (IAMPA) in CA1 pyramidal cells and GluR1/GluR2 expression were significantly reduced in seipin-nKO mice, whereas the NMDA-induced current (INMDA) and NR1/NR2 expression were not altered. Rosi treatment in seipin-nKO mice could correct the decrease in expression and activity of AMPA receptor (AMPAR) and was accompanied by recovered synaptic function and LTP induction. Furthermore, hippocampal ERK2 and CREB phosphorylation in seipin-nKO mice were reduced and this could be rescued by rosi treatment. Rosi treatment in seipin-nKO mice elevated BDNF concentration. The MEK inhibitor U0126 blocked rosi-restored AMPAR expression and LTP induction in seipin-nKO mice, but the Trk family inhibitor K252a did not. These findings indicate that the neuronal seipin deficiency selectively suppresses AMPAR expression through reducing ERK-CREB activities, leading to the impairment of LTP and spatial memory, which can be rescued by PPARγ activation. Congenital generalized lipodystrophy 2 (CGL2), caused by loss-of-function mutation of seipin gene, is characterized by mental retardation. By the generation of systemic or neuronal seipin knock-out mice, the present study provides in vivo evidence that neuronal seipin deficiency causes deficits in spatial memory and hippocampal LTP induction. Neuronal seipin deficiency selectively suppresses AMPA receptor expression, ERK-CREB phosphorylation with the decline of PPARγ. The PPARγ agonist rosiglitazone can ameliorate spatial cognitive deficits and rescue the LTP induction in seipin knock-out mice by restoring AMPA receptor expression and ERK-CREB activities. Copyright © 2016 the authors 0270-6474/16/361242-12$15.00/0.

Role of activity-dependent BDNF expression in hippocampal–prefrontal cortical regulation of behavioral perseverance

PubMed Central

Sakata, Kazuko; Martinowich, Keri; Woo, Newton H.; Schloesser, Robert J.; Jimenez, Dennisse V.; Ji, Yuanyuan; Shen, Liya; Lu, Bai

2013-01-01

Activity-dependent gene transcription, including that of the brain-derived neurotrophic factor (Bdnf) gene, has been implicated in various cognitive functions. We previously demonstrated that mutant mice with selective disruption of activity-dependent BDNF expression (BDNF-KIV mice) exhibit deficits in GABA-mediated inhibition in the prefrontal cortex (PFC). Here, we show that disruption of activity-dependent BDNF expression impairs BDNF-dependent late-phase long-term potentiation (L-LTP) in CA1, a site of hippocampal output to the PFC. Interestingly, early-phase LTP and conventional L-LTP induced by strong tetanic stimulation were completely normal in BDNF-KIV mice. In parallel, attenuation of activity-dependent BDNF expression significantly impairs spatial memory reversal and contextual memory extinction, two executive functions that require intact hippocampal–PFC circuitry. In contrast, spatial and contextual memory per se were not affected. Thus, activity-dependent BDNF expression in the hippocampus and PFC may contribute to cognitive and behavioral flexibility. These results suggest distinct roles for different forms of L-LTP and provide a link between activity-dependent BDNF expression and behavioral perseverance, a hallmark of several psychiatric disorders. PMID:23980178

Can We Understand Why Cognitive Function Predicts Mortality? Results from the Caerphilly Prospective Study (CaPS)

ERIC Educational Resources Information Center

Gallacher, John; Bayer, Anthony; Dunstan, Frank; Yarnell, John; Elwood, Peter; Ben-Shlomo, Yoav

2009-01-01

The association between cognitive function and mortality is of increasing interest. We followed 1870 men aged 55-69 years at cognitive assessment for 16 years to establish associations with all case and cause specific mortality. Cognitive assessment included AH4, 4 choice reaction time (used as estimates of mid-life cognition) and the National…

Cross-Cultural Applicability of the Montreal Cognitive Assessment (MoCA): A Systematic Review.

PubMed

O'Driscoll, Ciarán; Shaikh, Madiha

2017-01-01

The Montreal Cognitive Assessment (MoCA) is widely used to screen for mild cognitive impairment (MCI). While there are many available versions, the cross-cultural validity of the assessment has not been explored sufficiently. We aimed to interrogate the validity of the MoCA in a cross-cultural context: in differentiating MCI from normal controls (NC); and identifying cut-offs and adjustments for age and education where possible. This review sourced a wide range of studies including case-control studies. In addition, we report findings for differentiating dementias from NC and MCI from dementias, however, these were not considered to be an appropriate use of the MoCA. The subject of the review assumes heterogeneity and therefore meta-analyses was not conducted. Quality ratings, forest plots of validated studies (sensitivity and specificity) with covariates (suggested cut-offs, age, education and country), and summary receiver operating characteristic curve are presented. The results showed a wide range in suggested cutoffs for MCI cross-culturally, with variability in levels of sensitivity and specificity ranging from low to high. Poor methodological rigor appears to have affected reported accuracy and validity of the MoCA. The review highlights the necessity for cross-cultural considerations when using the MoCA, and recognizing it as a screen and not a diagnostic tool. Appropriate cutoffs and point adjustments for education are suggested.

Frailty and Short-Term Outcomes in Patients With Hip Fracture

PubMed Central

Nicholas, Joseph A.; Kates, Stephen L.; Friedman, Susan M.

2015-01-01

Objectives: To assess the prevalence of frailty and its ability to predict short-term outcomes in older patients with hip fracture. Design: Prospective cohort study. Setting: University-affiliated community hospital. Participants: Thirty-five patients aged ≥65 treated with hip fracture. Measurements: Frailty was assessed using the 5 criteria of the Fried Frailty Index, modified for a post-fracture population. Cognitive impairment was assessed with the Montreal Cognitive Assessment (MoCA). The primary outcome was overall hospital complication rate. Secondary outcomes were length of stay (LOS) and specific complications. Differences between the frail and the non-frail were identified using chi-square analysis and analysis of variance (ANOVA) for categorical and continuous variables, respectively. Results: Eighteen (51%) participants were frail. Seventeen (49%) had ≥1 hospital complication. Twelve (67%) frail patients versus 5 (29%) non-frail patients had a complication (P = .028). Mean LOS was longer in patients with frailty (7.3 ± 5.9 vs 4.1 ± 1.2 days, P = .038). Most were frail for the weakness criterion (94%), and few were frail for the physical activity criterion (9%). Excluding these criteria, we developed a 3-criteria frailty index (shrinking, exhaustion, and slowness) that identified an increased risk of complications (64.7% vs 33.3%, P = .061) and LOS (7.4 ± 6.1 vs 4.2 ± 1.3 days, P = .040) in participants with frailty. Among non-frail participants with a high MoCA score of ≥20 (n = 12), 2 (17%) had complications compared to 10 (71%) frail participants with a low MoCA score (n = 14). Conclusion: Frailty is common in older patients with hip fracture and associated with increased LOS and postoperative complications. A low MoCA score, a hypothesized marker of more advanced cognitive frailty, may further increase risk. Frailty assessment has a role in prognostic discussion and care planning. The 3-criteria frailty index is an easily used tool with potential application in clinical practice. PMID:26328238

Cognitive impairment and PD patients' capacity to consent to research

PubMed Central

Cary, Mark; Moelter, Stephen T.; Siderowf, Andrew; Sullo, Elizabeth; Xie, Sharon; Weintraub, Daniel

2013-01-01

Objective: To examine how cognitive impairment affects Parkinson disease (PD) patients' research consent capacity. Methods: A cross-sectional study of 90 patients with PD, divided using Mattis Dementia Rating Scale–2 scores into 3 groups of 30 (normal, borderline, and impaired), and 30 neurologically normal older adults completed 2 capacity interviews (an early-phase randomized and controlled drug trial and a sham-controlled surgical implantation of genetic tissue) using the MacArthur Competence Assessment Tool for Clinical Research. Expert clinicians used the interviews to classify the patients as either capable or not capable of providing their own informed consent. These judgments were compared with performance on the Montreal Cognitive Assessment (MoCA) and the Mini-Mental State Examination (MMSE). Results: Cognitively normal PD patients typically scored well on the capacity measures. In contrast, patients with impaired cognition were not capable of providing their own informed consent: 17% (5/30) on the drug trial and 3% (1/30) on the surgery trial were judged capable. Patients with borderline impairment showed adequate performance on measures of appreciation and reasoning, but impaired performance on understanding the drug trial compared with normal controls and normal PD patients, and on understanding the surgery trial compared with normal controls. Sixty-seven percent (20/30) on the drug trial and 57% (17/30) on the surgery trial were judged capable of consent. Receiver operating characteristic analyses showed that the MMSE and MoCA could detect the likelihood of impaired capacity, with the MoCA demonstrating greater sensitivity. Conclusions: PD patients with borderline cognitive impairment have impairments in their decisional capacity. The MoCA may be useful to identify the patients at risk of impaired capacity. PMID:23892706

Intelligent and Adaptive Interface (IAI) for Cognitive Cockpit (CC)

DTIC Science & Technology

2004-03-31

goals3 and plans and generating system plans would be incorporated as task knowledge. The Dialogue Model, which is currently undeveloped in LOCATE...pieces of software. Modularity can also serve to improve the organisational effectiveness of software, whereby a suitable division of labour among...a sophisticated tool in support of future combat aircraft acquisition. While CA can monitor similar activities in countries like the UK and USA we

Duration and frequency of migraines affect cognitive function: evidence from neuropsychological tests and event-related potentials.

PubMed

Huang, Lifang; Juan Dong, Hong; Wang, Xi; Wang, Yan; Xiao, Zheman

2017-12-01

The aim of this study was to evaluate the changes in the cognitive performance of migraine patients using a comprehensive series of cognitive/behavioral and electrophysiological tests. A randomized, cross-sectional, within subject approach was used to compare neuropsychological and electrophysiological evaluations from migrane-affected and healthy subjects. Thirty-four patients with migraine (6 males, 28 females, average 36 years old) were included. Migraineurs performed worse in the majority of the Montreal Cognitive Assessment (MoCA) (p = 0.007) compared to the healthy subjects, significantly in language (p = 0.005), memory (p = 0.006), executive functions (p = 0.042), calculation (p = 0.018) and orientation (p = 0.012). Migraineurs had a lower score on the memory trial of the Rey-Osterrieth complex figure test (ROCF) (p = 0.012). The P3 latency in Fz, Cz, Pz was prolonged in migraineurs compared with the normal control group (P < 0.001). In addition, we analyzed significant correlations between MoCA score and the duration of migraine. We also observed that a decrease in the MoCA-executive functions and calculation score and in the ROCF-recall score were both correlated to the frequency of migraine. Migraineurs were more anxious than healthy subjects (p = 0.001), which is independent of cognitive testing. Differences were unrelated to age, gender and literacy. Cognitive performance decreases during migraine, and cognitive dysfunction can be related to the duration and frequency of a migraine attack.

Neonatal Stress Has a Long-Lasting Sex-Dependent Effect on Anxiety-Like Behavior and Neuronal Morphology in the Prefrontal Cortex and Hippocampus.

PubMed

de Melo, Silvana Regina; de David Antoniazzi, Caren Tatiane; Hossain, Shakhawat; Kolb, Bryan

2018-01-01

The long-lasting effects of early stress on brain development have been well studied. Recent evidence indicates that males and females respond differently to the same stressor. We examined the chronic effects of daily maternal separation (MS) on behavior and cerebral morphology in both male and female rats. Cognitive and anxiety-like behaviors were evaluated, and neuroplastic changes in 2 subregions of the prefrontal cortex (dorsal agranular insular cortex [AID] and cingulate cortex [Cg3]) and hippocampus (CA1 and dentate gyrus) were measured in adult male and female rats. The animals were subjected to MS on postnatal day (P) 3-14 for 3 h per day. Cognitive and emotional behaviors were assessed in the object/context mismatch task, elevated plus maze, and locomotor activity test in early adulthood (P87-P95). Anatomical assessments were performed in the prefrontal cortex (i.e., cortical thickness and spine density) and hippocampus (i.e., spine density). Sex-dependent effects were observed. MS increased anxiety-related behavior only in males, whereas locomotor activity was higher in females, with no effects on cognition. MS decreased spine density in the AID and increased spine density in the CA1 area in males. Females exhibited an increase in spine density in the Cg3. Our findings confirm previous work that found that MS causes long-term behavioral and anatomical effects, and these effects were dependent on sex and the duration of MS stress. © 2018 S. Karger AG, Basel.

Amyloid-beta oligomers impair fear conditioned memory in a calcineurin-dependent fashion in mice.

PubMed

Dineley, Kelly T; Kayed, Rakez; Neugebauer, Volker; Fu, Yu; Zhang, Wenru; Reese, Lindsay C; Taglialatela, Giulio

2010-10-01

Soluble oligomeric aggregates of the amyloid-beta (A beta) peptide are believed to be the most neurotoxic A beta species affecting the brain in Alzheimer disease (AD), a terminal neurodegenerative disorder involving severe cognitive decline underscored by initial synaptic dysfunction and later extensive neuronal death in the CNS. Recent evidence indicates that A beta oligomers are recruited at the synapse, oppose expression of long-term potentiation (LTP), perturb intracellular calcium balance, disrupt dendritic spines, and induce memory deficits. However, the molecular mechanisms behind these outcomes are only partially understood; achieving such insight is necessary for the comprehension of A beta-mediated neuronal dysfunction. We have investigated the role of the phosphatase calcineurin (CaN) in these pathological processes of AD. CaN is especially abundant in the CNS, where it is involved in synaptic activity, LTP, and memory function. Here, we describe how oligomeric A beta treatment causes memory deficits and depresses LTP expression in a CaN-dependent fashion. Mice given a single intracerebroventricular injection of A beta oligomers exhibited increased CaN activity and decreased pCREB, a transcription factor involved in proper synaptic function, accompanied by decreased memory in a fear conditioning task. These effects were reversed by treatment with the CaN inhibitor FK506. We further found that expression of hippocampal LTP in acutely cultured rodent brain slices was opposed by A beta oligomers and that this effect was also reversed by FK506. Collectively, these results indicate that CaN activation may play a central role in mediating synaptic and memory disruption induced by acute oligomeric A beta treatment in mice. (c) 2010 Wiley-Liss, Inc.

Control of recollection by slow gamma dominating mid-frequency gamma in hippocampus CA1

PubMed Central

Dvorak, Dino; Radwan, Basma; Sparks, Fraser T.; Talbot, Zoe Nicole

2018-01-01

Behavior is used to assess memory and cognitive deficits in animals like Fmr1-null mice that model Fragile X Syndrome, but behavior is a proxy for unknown neural events that define cognitive variables like recollection. We identified an electrophysiological signature of recollection in mouse dorsal Cornu Ammonis 1 (CA1) hippocampus. During a shocked-place avoidance task, slow gamma (SG) (30–50 Hz) dominates mid-frequency gamma (MG) (70–90 Hz) oscillations 2–3 s before successful avoidance, but not failures. Wild-type (WT) but not Fmr1-null mice rapidly adapt to relocating the shock; concurrently, SG/MG maxima (SGdom) decrease in WT but not in cognitively inflexible Fmr1-null mice. During SGdom, putative pyramidal cell ensembles represent distant locations; during place avoidance, these are avoided places. During shock relocation, WT ensembles represent distant locations near the currently correct shock zone, but Fmr1-null ensembles represent the formerly correct zone. These findings indicate that recollection occurs when CA1 SG dominates MG and that accurate recollection of inappropriate memories explains Fmr1-null cognitive inflexibility. PMID:29346381

Effectiveness of Gotu Kola Extract 750 mg and 1000 mg Compared with Folic Acid 3 mg in Improving Vascular Cognitive Impairment after Stroke

PubMed Central

Wibowo, Samekto

2016-01-01

This study aimed to determine the effectiveness of gotu kola (Centella asiatica) in improving cognitive function in patients with vascular cognitive impairment (VCI). This study uses a quasi-experimental design. Subjects in this study were patients with poststroke cognitive impairment who were treated at two hospitals in Yogyakarta, Indonesia. The number of subjects was 48: 17 subjects were treated with 1000 mg/day of gotu kola extract, 17 subjects treated with 750 mg/day of gotu kola extract, and 14 subjects treated with 3 mg/day of folic acid for 6 weeks. A Montreal Cognitive Assessment-Indonesian version (MoCA-Ina) was conducted at the beginning of treatment and after 6 weeks of therapy. It was found that all trials effectively improved poststroke VCI based on MoCA-Ina scores over the course of the study. There is no significant difference in ΔMoCA-Ina (score at the 6th week of treatment − score at the beginning) mean score among the three groups, indicating that gotu kola is as effective as folic acid in improving poststroke VCI. Gotu kola was shown to be more effective than folic acid in improving memory domain. This study suggested that gotu kola extract is effective in improving cognitive function after stroke. PMID:27340413

Effectiveness of Gotu Kola Extract 750 mg and 1000 mg Compared with Folic Acid 3 mg in Improving Vascular Cognitive Impairment after Stroke.

PubMed

Farhana, Kun Marisa; Malueka, Rusdy Ghazali; Wibowo, Samekto; Gofir, Abdul

2016-01-01

This study aimed to determine the effectiveness of gotu kola (Centella asiatica) in improving cognitive function in patients with vascular cognitive impairment (VCI). This study uses a quasi-experimental design. Subjects in this study were patients with poststroke cognitive impairment who were treated at two hospitals in Yogyakarta, Indonesia. The number of subjects was 48: 17 subjects were treated with 1000 mg/day of gotu kola extract, 17 subjects treated with 750 mg/day of gotu kola extract, and 14 subjects treated with 3 mg/day of folic acid for 6 weeks. A Montreal Cognitive Assessment-Indonesian version (MoCA-Ina) was conducted at the beginning of treatment and after 6 weeks of therapy. It was found that all trials effectively improved poststroke VCI based on MoCA-Ina scores over the course of the study. There is no significant difference in ΔMoCA-Ina (score at the 6th week of treatment - score at the beginning) mean score among the three groups, indicating that gotu kola is as effective as folic acid in improving poststroke VCI. Gotu kola was shown to be more effective than folic acid in improving memory domain. This study suggested that gotu kola extract is effective in improving cognitive function after stroke.

Maternal Education Level Predicts Cognitive, Language, and Motor Outcome in Preterm Infants in the Second Year of Life.

PubMed

Patra, Kousiki; Greene, Michelle M; Patel, Aloka L; Meier, Paula

2016-07-01

Objective To evaluate the relative impact of maternal education level (MEL) on cognitive, language, and motor outcomes at 20 months' corrected age (CA) in preterm infants. Study Design A total of 177 preterm infants born between 2008 and 2010 were tested at 20 months' CA using the Bayley Scales of Infant and Toddler Development-III. Multiple regression analyses were done to determine the relative impact of MEL on cognitive, language, and motor scores. Results Infants born to mothers with high school MEL were 3.74 times more likely to have a subnormal motor index, while those born to mothers with some college and graduate school MEL had reduced odds (0.36 and 0.12, respectively) of having subnormal language index at 20 months. In linear regression, MEL was the strongest predictor of cognitive, language, and motor scores, and graduate school MEL was associated with increases in cognitive, motor, and language scores of 8.49, 8.23, and 15.74 points, respectively. Conclusions MEL is the most significant predictor of cognitive, language, and motor outcome at 20 months' CA in preterm infants. Further research is needed to evaluate if targeted interventions that focus on early childhood learning and parenting practices can ameliorate the impact of low MEL. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Mild cognitive impairment and asymptomatic Alzheimer disease subjects: equivalent β-amyloid and tau loads with divergent cognitive outcomes.

PubMed

Iacono, Diego; Resnick, Susan M; O'Brien, Richard; Zonderman, Alan B; An, Yang; Pletnikova, Olga; Rudow, Gay; Crain, Barbara; Troncoso, Juan C

2014-04-01

Older adults with intact cognition before death and substantial Alzheimer disease (AD) lesions at autopsy have been termed "asymptomatic AD subjects" (ASYMAD). We previously reported hypertrophy of neuronal cell bodies, nuclei, and nucleoli in the CA1 of the hippocampus (CA1), anterior cingulate gyrus, posterior cingulate gyrus, and primary visual cortex of ASYMAD versus age-matched Control and mild cognitive impairment (MCI) subjects. However, it was unclear whether the neuronal hypertrophy could be attributed to differences in the severity of AD pathology. Here, we performed quantitative analyses of the severity of β-amyloid (Aβ) and phosphorylated tau (tau) loads in the brains of ASYMAD, Control, MCI, and AD subjects (n = 15 per group) from the Baltimore Longitudinal Study of Aging. Tissue sections from CA1, anterior cingulate gyrus, posterior cingulate gyrus, and primary visual cortex were immunostained for Aβ and tau; the respective loads were assessed using unbiased stereology by measuring the fractional areas of immunoreactivity for each protein in each region. The ASYMAD and MCI groups did not differ in Aβ and tau loads. These data confirm that ASYMAD and MCI subjects have comparable loads of insoluble Aβ and tau in regions vulnerable to AD pathology despite divergent cognitive outcomes. These findings imply that cognitive impairment in AD may be caused or modulated by factors other than insoluble forms of Aβ and tau.

Possible cause for altered spatial cognition of prepubescent rats exposed to chronic radiofrequency electromagnetic radiation.

PubMed

Narayanan, Sareesh Naduvil; Kumar, Raju Suresh; Karun, Kalesh M; Nayak, Satheesha B; Bhat, P Gopalakrishna

2015-10-01

The effects of chronic and repeated radiofrequency electromagnetic radiation (RFEMR) exposure on spatial cognition and hippocampal architecture were investigated in prepubescent rats. Four weeks old male Wistar rats were exposed to RF-EMR (900 MHz; SAR-1.15 W/kg with peak power density of 146.60 μW/cm(2)) for 1 h/day, for 28 days. Followed by this, spatial cognition was evaluated by Morris water maze test. To evaluate the hippocampal morphology; H&E staining, cresyl violet staining, and Golgi-Cox staining were performed on hippocampal sections. CA3 pyramidal neuron morphology and surviving neuron count (in CA3 region) were studied using H&E and cresyl violet stained sections. Dendritic arborization pattern of CA3 pyramidal neuron was investigated by concentric circle method. Progressive learning abilities were found to be decreased in RF-EMR exposed rats. Memory retention test performed 24 h after the last training revealed minor spatial memory deficit in RF-EMR exposed group. However, RF-EMR exposed rats exhibited poor spatial memory retention when tested 48 h after the final trial. Hirano bodies and Granulovacuolar bodies were absent in the CA3 pyramidal neurons of different groups studied. Nevertheless, RF-EMR exposure affected the viable cell count in dorsal hippocampal CA3 region. RF-EMR exposure influenced dendritic arborization pattern of both apical and basal dendritic trees in RF-EMR exposed rats. Structural changes found in the hippocampus of RF-EMR exposed rats could be one of the possible reasons for altered cognition.

BDNF pathway is involved in the protective effects of SS-31 on isoflurane-induced cognitive deficits in aging mice.

PubMed

Wu, Jing; Zhang, Mingqiang; Li, Huihui; Sun, Xiaoru; Hao, Shuangying; Ji, Muhuo; Yang, Jianjun; Li, Kuanyu

2016-05-15

Mitochondrial dysfunction has been linked to the earliest pathogenesis of isoflurane-induced cognitive impairments in developing or aging mammalian brain. However, its molecular mechanism is poorly understood and a pharmacologic treatment to rapidly reverse mitochondrial dysfunction is lacking. Fifteen-month-old male C57BL/6 mice were exposed to isoflurane for two hours following intraperitoneal administration of mitochondrion-targeted peptide SS-31 or vehicle with 30min interval. The hippocampus was immediately removed for biochemical assays and mitochondria isolation after inhalation. Behavioral tests were evaluated by the open field test and fear conditioning test 24h after the experiment. We showed that cognitive deficits induced by exposure of the aging mice to isoflurane were accompanied by mitochondrial dysfunction in hippocampus due to loss of the enzymatic activity of complex I. This loss resulted in the increase of reactive oxygen species production, decrease of ATP production and mitochondrial membrane potential, and opening of mitochondrial permeability transition pore. Further, we provided evidence that the BDNF signaling pathway was involved in this process to regulate synaptic plasticity-related proteins, for instance, downregulation of synapsin 1, PSD-95 and p-CREB, and upregulation of NR2A, NR2B, CaMKIIα and CaMKIIβ. Of note, the isoflurane-induced cognitive deficits were rescued by SS-31 through reversal of mitochondrial dysfunction, which facilitated the regulation of BDNF signaling including the expression reversal of aforementioned important synaptic-signaling proteins in aging mice. Our data demonstrate that reversing mitochondrial dysfunction by SS-31 enhances BDNF signaling pathway and synaptic plasticity, and provides protective effects on cognitive function, thereby support the notion that SS-31 may have therapeutic benefits for elderly humans undertaking anesthesia. Copyright © 2016 Elsevier B.V. All rights reserved.

Parvalbumin and neuropeptide Y expressing hippocampal GABA-ergic inhibitory interneuron numbers decline in a model of Gulf War illness.

PubMed

Megahed, Tarick; Hattiangady, Bharathi; Shuai, Bing; Shetty, Ashok K

2014-01-01

Cognitive dysfunction is amongst the most conspicuous symptoms in Gulf War illness (GWI). Combined exposure to the nerve gas antidote pyridostigmine bromide (PB), pesticides and stress during the Persian Gulf War-1 (PGW-1) are presumed to be among the major causes of GWI. Indeed, our recent studies in rat models have shown that exposure to GWI-related (GWIR) chemicals and mild stress for 4 weeks engenders cognitive impairments accompanied with several detrimental changes in the hippocampus. In this study, we tested whether reduced numbers of hippocampal gamma-amino butyric acid (GABA)-ergic interneurons are among the pathological changes induced by GWIR-chemicals and stress. Animals were exposed to low doses of GWIR-chemicals and mild stress for 4 weeks. Three months after this exposure, subpopulations of GABA-ergic interneurons expressing the calcium binding protein parvalbumin (PV), the neuropeptide Y (NPY) and somatostatin (SS) in the hippocampus were stereologically quantified. Animals exposed to GWIR-chemicals and stress for 4 weeks displayed reduced numbers of PV-expressing GABA-ergic interneurons in the dentate gyrus and NPY-expressing interneurons in the CA1 and CA3 subfields. However, no changes in SS+ interneuron population were observed in the hippocampus. Furthermore, GABA-ergic interneuron deficiency in these animals was associated with greatly diminished hippocampus neurogenesis. Because PV+ and NPY+ interneurons play roles in maintaining normal cognitive function and neurogenesis, and controlling the activity of excitatory neurons in the hippocampus, reduced numbers of these interneurons may be one of the major causes of cognitive dysfunction and reduced neurogenesis observed in GWI. Hence, strategies that improve inhibitory neurotransmission in the hippocampus may prove beneficial for reversing cognitive dysfunction in GWI.

Modulation of Kalirin-7 Expression by Hippocampal CA1 5-HT1B Receptors in Spatial Memory Consolidation.

PubMed

Zhou, Meng-He; Sun, Fang-Fang; Xu, Chang; Chen, Hui-Bin; Qiao, Hui; Cai, Xiang; Ma, Xin-Ming; An, Shu-Cheng

2018-06-24

Serotonin 5-HT1B receptors (5-HT1BRs) are distributed in hippocampal CA1 and play a pivotal role in cognitive function. Activation of 5-HT1BRs regulates synaptic plasticity at the excitatory synapses in the hippocampus. However, the role and its underlying mechanism of 5-HT1BR activation-mediated glutamatergic synaptic plasticity in spatial memory are not fully understood. In this study, spatial memory of Sprague-Dawley (SD) rats was assessed in a Morris water maze after bilateral dorsal hippocampal CA1 infusion of the 5-HT1BR antagonist GR55562 (25 μg/μL) or agonist CP93129 (25 μg/μL). GR55562 did not affect the spatial memory acquisition but significantly increased the target quadrant preference during the memory consolidation probe performed 14 d after the training session, while CP93129 impaired the memory consolidation process. Moreover, GR55562 significantly increased, while CP93129 significantly decreased, the density of dendritic spines on the distal apical dendrites of CA1 pyramidal neurons. Furthermore, western blot experiments indicated that GR55562 significantly increased, but CP93129 significantly reduced, the expression of Kalirin-7 (Kal-7), PSD95, and GluA2/3 subunits of AMPA receptors. Our results suggest that Kal-7 and Kal-7-mediatedalteration of AMPA receptor subtype expression may play crucial roles in the impact of hippocampal CA1 5-HT1BR activation on spatial memory consolidation. Copyright © 2018. Published by Elsevier B.V.

Central role for NMDA receptors in redox mediated impairment of synaptic function during aging and Alzheimer's disease.

PubMed

Foster, T C; Kyritsopoulos, C; Kumar, A

2017-03-30

Increased human longevity has magnified the negative impact that aging can have on cognitive integrity of older individuals experiencing some decline in cognitive function. Approximately 30% of the elderly will have cognitive problems that influence their independence. Impaired executive function and memory performance are observed in normal aging and yet can be an early sign of a progressive cognitive impairment of Alzheimer's disease (AD), the most common form of dementia. Brain regions that are vulnerable to aging exhibit the earliest pathology of AD. Senescent synaptic function is observed as a shift in Ca 2+ -dependent synaptic plasticity and similar mechanisms are thought to contribute to the early cognitive deficits associated with AD. In the case of aging, intracellular redox state mediates a shift in Ca 2+ regulation including N-methyl-d-aspartate (NMDA) receptor hypofunction and increased Ca 2+ release from intracellular stores to alter synaptic plasticity. AD can interact with these aging processes such that molecules linked to AD, β-amyloid (Aβ) and mutated presenilin 1 (PS1), can also degrade NMDA receptor function, promote Ca 2+ release from intracellular stores, and may increase oxidative stress. Thus, age is one of the most important predictors of AD and brain aging likely contributes to the onset of AD. The focus of this review article is to provide an update on mechanisms that contribute to the senescent synapse and possible interactions with AD-related molecules, with special emphasis on regulation of NMDA receptors. Copyright © 2016 Elsevier B.V. All rights reserved.

Moringa oleifera Mitigates Memory Impairment and Neurodegeneration in Animal Model of Age-Related Dementia

PubMed Central

Sutalangka, Chatchada; Wattanathorn, Jintanaporn; Muchimapura, Supaporn; Thukham-mee, Wipawee

2013-01-01

To date, the preventive strategy against dementia is still essential due to the rapid growth of its prevalence and the limited therapeutic efficacy. Based on the crucial role of oxidative stress in age-related dementia and the antioxidant and nootropic activities of Moringa oleifera, the enhancement of spatial memory and neuroprotection of M. oleifera leaves extract in animal model of age-related dementia was determined. The possible underlying mechanism was also investigated. Male Wistar rats, weighing 180–220 g, were orally given M. oleifera leaves extract at doses of 100, 200, and 400 mg/kg at a period of 7 days before and 7 days after the intracerebroventricular administration of AF64A bilaterally. Then, they were assessed memory, neuron density, MDA level, and the activities of SOD, CAT, GSH-Px, and AChE in hippocampus. The results showed that the extract improved spatial memory and neurodegeneration in CA1, CA2, CA3, and dentate gyrus of hippocampus together with the decreased MDA level and AChE activity but increased SOD and CAT activities. Therefore, our data suggest that M. oleifera leaves extract is the potential cognitive enhancer and neuroprotectant. The possible mechanism might occur partly via the decreased oxidative stress and the enhanced cholinergic function. However, further explorations concerning active ingredient(s) are still required. PMID:24454988

Computerized Cognitive Screen (CoCoSc): A Self-Administered Computerized Test for Screening for Cognitive Impairment in Community Social Centers.

PubMed

Wong, Adrian; Fong, Ching-Hang; Mok, Vincent Chung-Tong; Leung, Kam-Tat; Tong, Raymond Kai-Yu

2017-01-01

Computerized cognitive tests may serve as a preliminary, low-cost method to identify individuals with suspected cognitive impairment in the community. To develop a self-administered computerized test, namely the "Computerized Cognitive Screen (CoCoSc), Hong Kong version", for screening of individuals with cognitive impairment (CI) in community settings. The CoCoSc is a 15-min computerized cognitive screen covering memory, executive functions, orientation, attention and working memory, and prospective memory administered on a touchscreen computer. Individuals with CI and cognitively normal controls were administered the CoCoSc and the Montreal Cognitive Assessment (MoCA). Validity of the CoCoSc was assessed based on the relationship with the MoCA using Pearson correlation. Receiver operating characteristic curve (ROC) was used to examine the ability of the CoCoSc to differentiate CI from controls. Fifty-nine individuals with CI and 101 controls were recruited. Seventy-five (46.9%) participants had ≤6 years of education. Performance on the CoCoSc differed between normal and CI groups in both low and high education subgroups. Total scores of the CoCoSc and MoCA were significantly correlated (r = 0.71, p < 0.001). The area under ROC was 0.78, p < 0.001 for the CoCoSc total score in differentiating the CI group from the cognitively normal group. A cut-off of ≤30 on the CoCoSc was associated with a sensitivity of 0.78 and specificity of 0.69. The CoCoSc was well accepted by attendees of community social centers. The CoCoSc is a promising computerized cognitive screen for self-administration in community social centers. It is feasible for testing individuals with high or low education levels.

Striatal cell signaling in chronically food-restricted rats under basal conditions and in response to brief handling.

PubMed

Pan, Yan; Siregar, Ermanda; Carr, Kenneth D

2006-01-30

Chronic food restriction increases exploratory behavior, cognitive function, and the rewarding effects of abused drugs. Recently, striatal neuroadaptations that may be involved in these effects were observed. Specifically, D-1 dopamine (DA) receptor agonist challenge produced stronger activation of extracellular signal-regulated kinase (ERK), calcium-calmodulin-dependent kinase II (CaMKII), and the nuclear transcription factor cAMP response element binding protein (CREB) in nucleus accumbens (NAc) of food-restricted (FR) relative to ad libitum fed (AL) rats. Further, when FR rats were injected intracerebroventricularly (i.c.v.) with vehicle (saline) they displayed stronger activation of c-Jun N-terminal protein kinase (JNK), ERK and CaMKII than did AL rats. It is not known to what extent the latter effects represent the basal state of FR rats or an amplified response to the brief handling involved in the i.c.v. injection procedure. Using Western blotting it was found that basal phospho-JNK is higher in caudate-putamen (CPu) and NAc of FR relative to AL rats. Interestingly, brief handling decreased phospho-JNK levels in FR subjects. Basal phospho-ERK1/2 also tended to be elevated in CPu and NAc of FR rats but the elevation was not significant. However, phospho-MEK--the activated kinase upstream of ERK1/2--was significantly elevated in NAc of FR rats. Neither ERK1/2 nor MEK were activated by brief handling. CaMKII was selectively activated by handling in NAc of FR rats, suggesting a state-dependent response to a salient event. Given the established involvement of mitogen-activated protein kinase (MAPK) and CaMKII in synaptic plasticity, learning and memory, the increase in basal phospho-MEK and hyperresponsiveness of CaMKII in NAc may represent adaptive cellular responses to persistent negative energy balance that facilitate associative learning in connection with food-seeking.

Ammon's Horn 2 (CA2) of the Hippocampus: A Long-Known Region with a New Potential Role in Neurodegeneration.

PubMed

Pang, Cindy Chi-Ching; Kiecker, Clemens; O'Brien, John T; Noble, Wendy; Chang, Raymond Chuen-Chung

2018-06-01

The hippocampus has a critical role in cognition and human memory and is one of the most studied structures in the brain. Despite more than 400 years of research, little is known about the Ammon's horn region cornu ammonis 2 (CA2) subfield in comparison to other subfield regions (CA1, CA3, and CA4). Recent findings have shown that CA2 plays a bigger role than previously thought. Here, we review understanding of hippocampus and CA2 ontogenesis, together with basic and clinical findings about the potential role of this region in neurodegenerative disease. The CA2 has widespread anatomical connectivity, unique signaling molecules, and intrinsic electrophysiological properties. Experimental studies using in vivo models found that the CA2 region has a role in cognition, especially in social memory and object recognition. In models of epilepsy and hypoxia, the CA2 exhibits higher resilience to cell death and hypoxia in comparison with neighboring regions, and while hippocampal atrophy remains poorly understood in Parkinson's disease (PD) and dementia with Lewy bodies (DLB), findings from postmortem PD brain demonstrates clear accumulation of α-synuclein pathology in CA2, and the CA2-CA3 region shows relatively more atrophy compared with other hippocampal subfields. Taken together, there is a growing body of evidence suggesting that the CA2 can be an ideal hallmark with which to differentiate different neurodegenerative stages of PD. Here, we summarize these recent data and provide new perspectives/ideas for future investigations to unravel the contribution of the CA2 to neurodegenerative diseases.

Investigating Mental Workload Changes in a Long Duration Supervisory Control Task

DTIC Science & Technology

2015-05-06

attention to local and global target features. Brain Cogn ., 81, 370–375. Derosière, G., Mandrick, K., Dray, G., Ward, T.E. and Perrey, S. (2013) NIRS...measured prefrontal cortex activity in neuroer- gonomics: strengths and weaknesses. Front. Hum. Neurosci ., 7, 583. Durantin, G., Gagnon, J.-F., Tremblay...Foundations of Augmented Cognition. Neuroergonomics and Operational Neuroscience , San Diego, CA. Interacting with Computers, Vol. 27 No. 5, 2015 by

Pulse wave velocity is associated with cognitive impairment in hemodialysis patients.

PubMed

Angermann, Susanne; Baumann, Marcus; Wassertheurer, Siegfried; Mayer, Christopher Clemens; Steubl, Dominik; Hauser, Christine; Suttmann, Yana; Reichelt, Anna-Lena; Satanovskij, Robin; Lorenz, Georg; Lukas, Moritz; Haller, Bernhard; Heemann, Uwe; Grimmer, Timo; Schmaderer, Christoph

2017-07-01

Cognitive impairment in hemodialysis patients is common and associated with adverse outcomes. So far, the underlying pathogenesis remains unclear. Therefore, we examined the potential relationship between cognitive impairment and three different categories of risk factors with particular focus on arterial stiffness measured by pulse wave velocity (PWV). A total of 201 chronic hemodialysis patients underwent cognitive testing under standardized conditions using the Montreal Cognitive Assessment (MoCA). Demographic data including cardiovascular risk factors, dialysis-associated factors as well as factors related to chronic kidney disease (CKD) were analyzed. To account for arterial stiffness, PWV was measured by ambulatory blood pressure monitoried with an oscillometric device that records brachial blood pressure along with pulse waves. In our cohort, 60.2% of patients showed pathological MoCA test results indicating cognitive impairment. PWV was significantly associated with cognitive impairment apart from age, educational level, diabetes, and hypercholesterolemia. High prevalence of cognitive impairment in hemodialysis patients was confirmed. For the first time, an association between cognitive impairment and arterial stiffness was detected in a larger cohort of hemodialysis patients. Concerning the underlying pathogenesis of cognitive impairment, current results revealed a potential involvement of arterial stiffness, which has to be further evaluated in future studies. © 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

Memory and Executive Screening for the Detection of Cognitive Impairment in Obstructive Sleep Apnea.

PubMed

Mu, Li; Peng, Liping; Zhang, Zhengjiao; Jie, Jing; Jia, Siqi; Yuan, Haibo

2017-10-01

Obstructive sleep apnea (OSA) is commonly associated with cognitive dysfunction, which is more apparent in severe OSA and impairs quality of life. However, the clinical screening methods for these impairments in OSA are still limited. In this study, we evaluated the feasibility of using the Memory and Executive Screening (MES) for assessing cognitive performance in OSA. Twenty-four patients with nonsevere OSA and 36 patients with severe OSA participated in this study. All participants underwent comprehensive, laboratory-based polysomnography and completed assessments of cognitive function, which included both the MES and the Beijing version of the Montreal Cognitive Assessment (MoCA-BJ). Both the total MES scores and 5 recall scores of the MES (MES-5R) were significantly lower in the severe OSA group than those in the nonsevere OSA group. The patients with severe OSA performed worse on the memory subtests of the MES-5R, especially on immediate recall. The sensitivity and specificity of the MES for identifying cognitive impairment in patients with OSA were 63.89% and 66.67%, respectively, for a cutoff value of <92 out of 100 points. An optimal cutoff between nonsevere and severe OSA was also set at 45 points (MES-5R) and at 0.94 points (MES ratio). Compared with the MES, the MoCA-BJ had similar sensitivity (61.11%) and specificity (66.67%). The MES is an acceptable tool for detecting cognitive dysfunction in patients with OSA. The sensitivity and specificity of the MES were similar to those of the MoCA-BJ. The MES-5R and total MES scores can assess the presence and severity of cognitive impairment in patients with severe OSA. Copyright © 2017 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.

Effect of Carotid Artery Stenting on Cognitive Function in Patients with Internal Carotid Artery Stenosis and Cerebral Lacunar Infarction: A 3-Year Follow-Up Study in China

PubMed Central

Xia, Zhang Yong; Sun, Qin Jian; Yang, Hua; Zhang, Ming Xia; Ban, Ru; Xu, Ge Lin; Wu, Ya Ping; Wang, Le Xin; Du, Yi Feng

2015-01-01

Background and Objectives Carotid artery stenting (CAS) is an important therapeutic strategy for patients with carotid artery stenosis. However, the potential influence of CAS on cognitive function in patients with carotid artery stenosis and cerebral lacunar infarction has not been determined. This study investigated changes in cognitive function associated with CAS and the factors related to these changes. Methods This prospective cohort study comprised 579 Chinese patients with cerebral lacunar infarction and carotid artery stenosis for whom CAS was indicated, and a matched control group of 552 healthy individuals. Cognitive function before CAS and at scheduled intervals from 6 months to 3 years was assessed with instruments that included the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) scale. Potential factors that might affect cognitive function were analyzed via logistic regression. Results The MMSE and MoCA scores of the patients before CAS were significantly lower than that of the control subjects. These scores were significantly higher 6 months after CAS and sustained or increased throughout the 3-year follow-up. Also significantly improved after CAS from baseline were scores for an alternating trail test, cube copying, clock-drawing, attention, and delayed recall in an auditory-verbal learning test. Logistic regression analyses showed that age greater than 65 y, little education, diabetes, and hypertension were independent risk factors for deteriorated MoCA scores 3 years after CAS. Conclusion CAS was associated with significantly improved cognitive function in cerebral lacunar infarction patients with severe stenosis. PMID:26067432

Mild cognitive impairment in older adults with pre-dialysis patients with chronic kidney disease: Prevalence and association with physical function.

PubMed

Otobe, Yuhei; Hiraki, Koji; Hotta, Chiharu; Nishizawa, Hajime; Izawa, Kazuhiro P; Taki, Yasuhiro; Imai, Naohiko; Sakurada, Tsutomu; Shibagaki, Yugo

2017-09-26

Chronic kidney disease (CKD) is a risk factor for declining cognitive and physical function. However, the prevalence of mild cognitive impairment (MCI) and its relationship with physical function is not clear. Therefore, our aim was to evaluate the prevalence of MCI and the relationship between MCI and physical function among older adults with pre-dialysis CKD. We conducted a cross-sectional study of 120 patients, aged ≥ 65 years (mean age, 77.3 years), with pre-dialysis CKD but without probable dementia (Mini Mental State Examination < 24). MCI was evaluated using the Japanese version of the Montreal Cognitive Assessment (MoCA-J). For analysis, patients were classified into two cognitive function groups: normal (MoCA-J ≥26) and MCI (MoCA-J <26). Physical, clinical, and biochemical parameters were compared between the groups. Logistic and linear regression analyses were used to evaluate the specific association between cognitive and physical function. Seventy-five patients (62.5%) patients belonged to the MCI group. Significant differences between the two groups were identified for gait speed, balance, age, and haemoglobin concentration. After adjustment for covariates, only gait speed was significantly associated with MCI (odds ratio, 0.06; 95% confidence interval, 0.009-0,411). The prevalence of MCI among older adults with pre-dialysis CKD was as high as 62.5%. The association between MCI and reduced gait speed supports the possible interaction between physical and cognitive functions and the need for early screening. This article is protected by copyright. All rights reserved.

Bacopa monnieri (Brahmi) improved novel object recognition task and increased cerebral vesicular glutamate transporter type 3 in sub-chronic phencyclidine rat model of schizophrenia.

PubMed

Piyabhan, Pritsana; Wannasiri, Supaporn; Naowaboot, Jarinyaporn

2016-12-01

Reduced vesicular glutamate transporter 1 (VGLUT1) and 2 (VGLUT2) indicate glutamatergic hypofunction leading to cognitive impairment in schizophrenia. However, VGLUT3 involvement in cognitive dysfunction has not been reported in schizophrenia. Brahmi (Bacopa monnieri) might be a new treatment and prevention for cognitive deficits in schizophrenia by acting on cerebral VGLUT3 density. We aimed to study cognitive enhancement- and neuroprotective-effects of Brahmi on novel object recognition and cerebral VGLUT3 immunodensity in sub-chronic (2 mg/kg, Bid, ip) phencyclidine (PCP) rat model of schizophrenia. Rats were assigned to three groups for cognitive enhancement effect study: Group 1, Control; Group 2, PCP administration; Group 3, PCP+Brahmi. A neuroprotective-effect study was also carried out. Rats were again assigned to three groups: Group 1, Control; Group 2, PCP administration; Group 3, Brahmi+PCP. Discrimination ratio (DR) representing cognitive ability was obtained from a novel object recognition task. VGLUT3 immunodensity was measured in the prefrontal cortex, striatum and cornu ammonis fields 1-3 (CA1-3) using immunohistochemistry. We found reduced DR in the PCP group, which occurred alongside VGLUT3 reduction in all brain areas. PCP+Brahmi showed higher DR score with increased VGLUT3 immunodensity in the prefrontal cortex and striatum. Brahmi+PCP group showed a higher DR score with increased VGLUT3 immunodensity in the prefrontal cortex, striatum and CA1-3. We concluded that reduced cerebral VGLUT3 was involved in cognitive deficit in PCP-administrated rats. Receiving Brahmi after PCP restored cognitive deficit by increasing VGLUT3 in the prefrontal cortex and striatum. Receiving Brahmi before PCP prevented cognitive impairment by elevating VGLUT3 in prefrontal cortex, striatum and CA1-3. Therefore, Brahmi could be a new frontier of restoration and prevention of cognitive deficit in schizophrenia. © 2016 John Wiley & Sons Australia, Ltd.

The Association between Montreal Cognitive Assessment Memory Scores and Hippocampal Volume in a Neurodegenerative Disease Sample

PubMed Central

Ritter, Aaron; Hawley, Nanako; Banks, Sarah J.; Miller, Justin B.

2017-01-01

Despite widespread use, there have been few investigations into the neuroanatomical correlates of the Montreal Cognitive Assessment (MoCA). In a sample of 138 consecutive patients presenting with cognitive complaints, we report significant correlations between lower MoCA memory scores and smaller hippocampal volumes (r = 0.36–0.41, p < 0.001). We also report that the newly devised memory index score, designed to better capture encoding deficits than the standard delayed recall score, was not significantly better for predicting hippocampal volume. These initial results suggest that poor performance on the MoCA’s memory section should prompt further evaluation for hippocampal atrophy. PMID:28453481

Astrocytic calcium activation in a mouse model of tDCS—Extended discussion

PubMed Central

Monai, Hiromu; Hirase, Hajime

2016-01-01

ABSTRACT Transcranial direct current stimulation (tDCS) has been reported to be effective for alleviation of neuropsychiatric and neurological conditions as well as enhancement of memory and cognition. Despite the positive effects of tDCS in humans, its mechanism of action remains poorly understood. Recently, we reported that astrocytes, a major glial cell type in the brain, show an increase in intracellular Ca2+ levels during tDCS in the cerebral cortex of the awake mouse. This tDCS-induced elevation in astrocytic Ca2+ has subsequently been demonstrated to be important for cortical plasticity. In this commentary article, we discuss possible interpretations and implications of our findings from the viewpoint of neuron-glia interactions. PMID:27830161

Distributed encoding of spatial and object categories in primate hippocampal microcircuits

PubMed Central

Opris, Ioan; Santos, Lucas M.; Gerhardt, Greg A.; Song, Dong; Berger, Theodore W.; Hampson, Robert E.; Deadwyler, Sam A.

2015-01-01

The primate hippocampus plays critical roles in the encoding, representation, categorization and retrieval of cognitive information. Such cognitive abilities may use the transformational input-output properties of hippocampal laminar microcircuitry to generate spatial representations and to categorize features of objects, images, and their numeric characteristics. Four nonhuman primates were trained in a delayed-match-to-sample (DMS) task while multi-neuron activity was simultaneously recorded from the CA1 and CA3 hippocampal cell fields. The results show differential encoding of spatial location and categorization of images presented as relevant stimuli in the task. Individual hippocampal cells encoded visual stimuli only on specific types of trials in which retention of either, the Sample image, or the spatial position of the Sample image indicated at the beginning of the trial, was required. Consistent with such encoding, it was shown that patterned microstimulation applied during Sample image presentation facilitated selection of either Sample image spatial locations or types of images, during the Match phase of the task. These findings support the existence of specific codes for spatial and numeric object representations in primate hippocampus which can be applied on differentially signaled trials. Moreover, the transformational properties of hippocampal microcircuitry, together with the patterned microstimulation are supporting the practical importance of this approach for cognitive enhancement and rehabilitation, needed for memory neuroprosthetics. PMID:26500473

Subchronic phencyclidine treatment in adult mice increases GABAergic transmission and LTP threshold in the hippocampus.

PubMed

Nomura, Toshihiro; Oyamada, Yoshihiro; Fernandes, Herman B; Remmers, Christine L; Xu, Jian; Meltzer, Herbert Y; Contractor, Anis

2016-01-01

Repeated administration of non-competitive N-methyl-d-aspartate (NMDA) receptor antagonists such as phencyclidine (PCP) to rodents causes long-lasting deficits in cognition and memory, and has effects on behaviors that have been suggested to be models of the cognitive impairment associated with schizophrenia (CIAS). Despite this being a widely studied animal model, little is known about the long lasting changes in synapses and circuits that underlie the altered behaviors. Here we examined synaptic transmission ex-vivo in the hippocampus of mice after a subchronic PCP (scPCP) administration regime. We found that after at least one week of drug free washout period when mice have impaired cognitive function, the threshold for long-term potentiation (LTP) of CA1 excitatory synapses was elevated. This elevated LTP threshold was directly related to increased inhibitory input to CA1 pyramidal cells through increased activity of GABAergic neurons. These results suggest repeated PCP administration causes a long-lasting metaplastic change in the inhibitory circuits in the hippocampus that results in impaired LTP, and could contribute to the deficits in hippocampal-dependent memory in PCP-treated mice. Changes in GABA signaling have been described in patients with schizophrenia, therefore our results support using scPCP as a model of CIAS. This article is part of the Special Issue entitled 'Synaptopathy--from Biology to Therapy'. Copyright © 2015 Elsevier Ltd. All rights reserved.

Over-expression of TSPO in the hippocampal CA1 area alleviates cognitive dysfunction caused by lipopolysaccharide in mice.

PubMed

Zhang, Hui; Ma, Li; Yin, Yan-Ling; Dong, Lian-Qiang; Cheng, Gang-Ge; Ma, Ya-Qun; Li, Yun-Feng; Xu, Bai-Nan

2016-09-01

The translocator protein 18kDa (TSPO) is closely related to regulation of immune/inflammatory response. However, the putative role and signaling mechanisms of TSPO in regulation of neuroinflammation remain unclear. GV287 lentiviral vectors mediating TSPO over-expression were injected into bilateral hippocampal CA1 areas to test whether TSPO over-expression was neuroprotective in lipopolysaccharide (LPS)-induced mice model. Finasteride, a blocker of allopregnanolone production, was used to test whether the protective effects were related to steroideogenesis. The results demonstrated that TSPO over-expression increased progesterone and allopregnanolone synthesis. TSPO over-expression in CA1 area improved LPS-induced cognitive deficiency in mice and this cognitive improvement was reversed by finasteride administration. These data suggest that up-regulation of TSPO level during neuroinflammation may be an adaptive response mechanism, a way to provide more neurosteroids. We confer that TSPO could be an attractive drug target for controlling neuroinflammation in the future. Copyright © 2016 Elsevier B.V. All rights reserved.

Dim light at night interacts with intermittent hypoxia to alter cognitive and affective responses.

PubMed

Aubrecht, Taryn G; Weil, Zachary M; Magalang, Ulysses J; Nelson, Randy J

2013-07-01

Obstructive sleep apnea (OSA) and dim light at night (dLAN) have both been independently associated with alterations in mood and cognition. We aimed to determine whether dLAN would interact with intermittent hypoxia (IH), a condition characteristic of OSA, to alter the behavioral, cognitive, and affective responses. Adult male mice were housed in either standard lighting conditions (14:10-h light-dark cycle; 150 lux:0 lux) or dLAN (150 lux:5 lux). Mice were then exposed to IH (15 cycles/h, 8 h/day, FiO2 nadir of 5%) for 3 wk, then tested in assays of affective and cognitive responses; brains were collected for dendritic morphology and PCR analysis. Exposure to dLAN and IH increased anxiety-like behaviors, as assessed in the open field, elevated plus maze, and the light/dark box. dLAN and IH increased depressive-like behaviors in the forced swim test. IH impaired learning and memory performance in the passive avoidance task; however, no differences were observed in spatial working memory, as assessed by y-maze or object recognition. IH combined with dLAN decreased cell body area in the CA1 and CA3 regions of the hippocampus. Overall, IH decreased apical spine density in the CA3, whereas dLAN decreased spine density in the CA1 of the hippocampus. TNF-α gene expression was not altered by IH or lighting condition, whereas VEGF expression was increased by dLAN. The combination of IH and dLAN provokes negative effects on hippocampal dendritic morphology, affect, and cognition, suggesting that limiting nighttime exposure to light in combination with other established treatments may be of benefit to patients with OSA.

Dim light at night interacts with intermittent hypoxia to alter cognitive and affective responses

PubMed Central

Weil, Zachary M.; Magalang, Ulysses J.; Nelson, Randy J.

2013-01-01

Obstructive sleep apnea (OSA) and dim light at night (dLAN) have both been independently associated with alterations in mood and cognition. We aimed to determine whether dLAN would interact with intermittent hypoxia (IH), a condition characteristic of OSA, to alter the behavioral, cognitive, and affective responses. Adult male mice were housed in either standard lighting conditions (14:10-h light-dark cycle; 150 lux:0 lux) or dLAN (150 lux:5 lux). Mice were then exposed to IH (15 cycles/h, 8 h/day, FiO2 nadir of 5%) for 3 wk, then tested in assays of affective and cognitive responses; brains were collected for dendritic morphology and PCR analysis. Exposure to dLAN and IH increased anxiety-like behaviors, as assessed in the open field, elevated plus maze, and the light/dark box. dLAN and IH increased depressive-like behaviors in the forced swim test. IH impaired learning and memory performance in the passive avoidance task; however, no differences were observed in spatial working memory, as assessed by y-maze or object recognition. IH combined with dLAN decreased cell body area in the CA1 and CA3 regions of the hippocampus. Overall, IH decreased apical spine density in the CA3, whereas dLAN decreased spine density in the CA1 of the hippocampus. TNF-α gene expression was not altered by IH or lighting condition, whereas VEGF expression was increased by dLAN. The combination of IH and dLAN provokes negative effects on hippocampal dendritic morphology, affect, and cognition, suggesting that limiting nighttime exposure to light in combination with other established treatments may be of benefit to patients with OSA. PMID:23657638

Individual differences in associative memory among older adults explained by hippocampal subfield structure and function.

PubMed

Carr, Valerie A; Bernstein, Jeffrey D; Favila, Serra E; Rutt, Brian K; Kerchner, Geoffrey A; Wagner, Anthony D

2017-11-07

Older adults experience impairments in episodic memory, ranging from mild to clinically significant. Given the critical role of the medial temporal lobe (MTL) in episodic memory, age-related changes in MTL structure and function may partially account for individual differences in memory. Using ultra-high-field 7T structural MRI and high-resolution 3T functional MRI (hr-fMRI), we evaluated MTL subfield thickness and function in older adults representing a spectrum of cognitive health. Participants performed an associative memory task during hr-fMRI in which they encoded and later retrieved face-name pairs. Motivated by prior research, we hypothesized that differences in performance would be explained by the following: ( i ) entorhinal cortex (ERC) and CA1 apical neuropil layer [CA1-stratum radiatum lacunosum moleculare (SRLM)] thickness, and ( ii ) activity in ERC and the dentate gyrus (DG)/CA3 region. Regression analyses revealed that this combination of factors significantly accounted for variability in memory performance. Among these metrics, CA1-SRLM thickness was positively associated with memory, whereas DG/CA3 retrieval activity was negatively associated with memory. Furthermore, including structural and functional metrics in the same model better accounted for performance than did single-modality models. These results advance the understanding of how independent but converging influences of both MTL subfield structure and function contribute to age-related memory impairment, complementing findings in the rodent and human postmortem literatures.

Systemic lipopolysaccharide administration impairs retrieval of context-object discrimination, but not spatial, memory: Evidence for selective disruption of specific hippocampus-dependent memory functions during acute neuroinflammation

PubMed Central

Czerniawski, Jennifer; Miyashita, Teiko; Lewandowski, Gail; Guzowski, John F.

2014-01-01

Neuroinflammation is implicated in impairments in neuronal function and cognition that arise with aging, trauma, and/or disease. Therefore, understanding the underlying basis of the effect of immune system activation on neural function could lead to therapies for treating cognitive decline. Although neuroinflammation is widely thought to preferentially impair hippocampus-dependent memory, data on the effects of cytokines on cognition are mixed. One possible explanation for these inconsistent results is that cytokines may disrupt specific neural processes underlying some forms of memory but not others. In an earlier study, we tested the effect of systemic administration of bacterial lipopolysaccharide (LPS) on retrieval of hippocampus-dependent context memory and neural circuit function in CA3 and CA1 (Czerniawski and Guzowski, 2014). Paralleling impairment in context discrimination memory, we observed changes in neural circuit function consistent with disrupted pattern separation function. In the current study we tested the hypothesis that acute neuroinflammation selectively disrupts memory retrieval in tasks requiring hippocampal pattern separation processes. Male Sprague-Dawley rats given LPS systemically prior to testing exhibited intact performance in tasks that do not require hippocampal pattern separation processes: novel object recognition and spatial memory in the water maze. By contrast, memory retrieval in a task thought to require hippocampal pattern separation, context-object discrimination, was strongly impaired in LPS-treated rats in the absence of any gross effects on exploratory activity or motivation. These data show that LPS administration does not impair memory retrieval in all hippocampus-dependent tasks, and support the hypothesis that acute neuroinflammation impairs context discrimination memory via disruption of pattern separation processes in hippocampus. PMID:25451612

Systemic lipopolysaccharide administration impairs retrieval of context-object discrimination, but not spatial, memory: Evidence for selective disruption of specific hippocampus-dependent memory functions during acute neuroinflammation.

PubMed

Czerniawski, Jennifer; Miyashita, Teiko; Lewandowski, Gail; Guzowski, John F

2015-02-01

Neuroinflammation is implicated in impairments in neuronal function and cognition that arise with aging, trauma, and/or disease. Therefore, understanding the underlying basis of the effect of immune system activation on neural function could lead to therapies for treating cognitive decline. Although neuroinflammation is widely thought to preferentially impair hippocampus-dependent memory, data on the effects of cytokines on cognition are mixed. One possible explanation for these inconsistent results is that cytokines may disrupt specific neural processes underlying some forms of memory but not others. In an earlier study, we tested the effect of systemic administration of bacterial lipopolysaccharide (LPS) on retrieval of hippocampus-dependent context memory and neural circuit function in CA3 and CA1 (Czerniawski and Guzowski, 2014). Paralleling impairment in context discrimination memory, we observed changes in neural circuit function consistent with disrupted pattern separation function. In the current study we tested the hypothesis that acute neuroinflammation selectively disrupts memory retrieval in tasks requiring hippocampal pattern separation processes. Male Sprague-Dawley rats given LPS systemically prior to testing exhibited intact performance in tasks that do not require hippocampal pattern separation processes: novel object recognition and spatial memory in the water maze. By contrast, memory retrieval in a task thought to require hippocampal pattern separation, context-object discrimination, was strongly impaired in LPS-treated rats in the absence of any gross effects on exploratory activity or motivation. These data show that LPS administration does not impair memory retrieval in all hippocampus-dependent tasks, and support the hypothesis that acute neuroinflammation impairs context discrimination memory via disruption of pattern separation processes in hippocampus. Copyright © 2014 Elsevier Inc. All rights reserved.

Excitotoxicity Induced by Realgar in the Rat Hippocampus: the Involvement of Learning Memory Injury, Dysfunction of Glutamate Metabolism and NMDA Receptors.

PubMed

Huo, Tao-guang; Li, Wei-kai; Zhang, Ying-hua; Yuan, Jie; Gao, Lan-yue; Yuan, Yuan; Yang, Hui-lei; Jiang, Hong; Sun, Gui-fan

2015-01-01

Realgar is a type of mineral drug containing arsenic. The nervous system toxicity of realgar has received extensive attention. However, the underlying mechanisms of realgar-induced neurotoxicity have not been clearly elucidated. To explore the mechanisms that contribute to realgar-induced neurotoxicity, weanling rats were exposed to realgar (0, 0.3, 0.9, 2.7 g/kg) for 6 weeks, and cognitive ability was tested using the Morris water maze (MWM) test and object recognition task (ORT). The levels of arsenic in the blood and hippocampus were monitored. The ultrastructures of hippocampal neurons were observed. The levels of glutamate (Glu) and glutamine (Gln) in the hippocampus and hippocampal CA1 region; the activities of glutamine synthetase (GS) and phosphate-activated glutaminase (PAG); the mRNA and protein expression of glutamate transporter 1 (GLT-1), glutamate/aspartate transporter (GLAST), and N-methyl-D-aspartate (NMDA) receptors; and the level of intracellular Ca(2+) were also investigated. The results indicate that the rats developed deficiencies in cognitive ability after a 6-week exposure to realgar. The arsenic contained in realgar and the arsenic metabolites passed through the blood-brain barrier (BBB) and accumulated in the hippocampus, which resulted in the excessive accumulation of Glu in the extracellular space. The excessive accumulation of Glu in the extracellular space induced excitotoxicity, which was shown by enhanced GS and PAG activities, inhibition of GLT-1 mRNA and protein expression, alterations in NMDA receptor mRNA and protein expression, disturbance of intracellular Ca(2+) homeostasis, and ultrastructural changes in hippocampal neurons. In conclusion, the findings from our study indicate that exposure to realgar induces excitotoxicity and that the mechanism by which this occurs may be associated with disturbances in Glu metabolism and transportation and alterations in NMDA receptor expression.

Neuroprotective role of Ginkgo biloba against cognitive deficits associated with Bisphenol A exposure: An animal model study.

PubMed

El Tabaa, Manar Mohammed; Sokkar, Samia Salem; Ramadan, Ehab Sayed; Abd El Salam, Inas Zakria; Zaid, Anis

2017-09-01

Our study aimed to elucidate to what extent Ginkgo biloba (Gb) can protect rats from cognitive deficits induced by exposure to Bisphenol A (BPA) at high dose. Therefore, sixty male Wistar rats were randomly divided into four groups of 15 animals in each group: Vehicle group, Gb-control group, BPA-exposed group and Gb pre-treated group. All administrations were given daily by an oral gavage once a day for eight weeks. Cognitive function was assessed using Morris water maze; Y-maze and Novel object recognition tasks. Additionally, hippocampal levels of DA, NE and 5-HT were measured. BPA-induced oxidative stress was evaluated by determining SOD activity, NO and MDA levels in rat hippocampus as well as level of circulating adiponectin. Moreover, histopathological changes in CA3 region of rat hippocampus and immunohistochemical expression of NF-κB and Caspase-3 were investigated. We found that Gb pretreatment significantly improved cognitive performance; may be via increasing hippocampal levels of estrogen-dependent biogenic amines. At the same time, Gb could strictly control BPA-induced oxidative stress by improving SOD activity and adiponectin level with decrease in NO and MDA levels. Lastly, Gb alleviated the histopathological injuries induced by BPA and inhibited NF-κB and caspase-3 activation. In conclusion, our results suggested that Gb has potential to ameliorate BPA-induced hippocampal neuronal damage and subsequent cognitive deficits through mechanisms involving its ability to enhance the release of biogenic amines as well as its antioxidant and adiponectin pro-secretory effects. Copyright © 2017 Elsevier Ltd. All rights reserved.

An Exploration of Students' Science Learning Interest Related to Their Cognitive Anxiety, Cognitive Load, Self-Confidence and Learning Progress Using Inquiry-Based Learning With an iPad

NASA Astrophysics Data System (ADS)

Hong, Jon-Chao; Hwang, Ming-Yueh; Tai, Kai-Hsin; Tsai, Chi-Ruei

2017-12-01

Based on the cognitive-affective theory, the present study designed a science inquiry learning model, predict-observe-explain (POE), and implemented it in an app called "WhyWhy" to examine the effectiveness of students' science inquiry learning practice. To understand how POE can affect the cognitive-affective learning process, as well as the learning progress, a pretest and a posttest were given to 152 grade 5 elementary school students. The students practiced WhyWhy during six sessions over 6 weeks, and data related to interest in learning science (ILS), cognitive anxiety (CA), and extraneous cognitive load (ECL) were collected and analyzed through confirmatory factor analysis with structure equation modeling. The results showed that students with high ILS have low CA and ECL. In addition, the results also indicated that students with a high level of self-confidence enhancement showed significant improvement in the posttest. The implications of this study suggest that by using technology-enhanced science learning, the POE model is a practical approach to motivate students to learn.

Higher plasma CD4 lymphocyte count correlates with better cognitive function in human immunodeficiency virus-acquired immunodeficiency syndrome (HIV-AIDS) patients

NASA Astrophysics Data System (ADS)

Fitri, F. I.; Rambe, A. S.; Fitri, A.

2018-03-01

Neurocognitive disorders in HIV-AIDS are still prevalent despite the use of antiretroviral therapy and seem to be under-recognized. Plasma lymphocyte CD4 count is a marker for general immunology status, but its association with cognitive function remains unclear. The aim of this study was to determine the correlation between plasma CD4 lymphocyte and cognitive function in HIV-AIDS patients.This was a cross-sectional study involving 48 HIV-AIDS patients. All subjects underwent physical, neurologic examination and Montreal Cognitive Assessment-Indonesian Version (MoCA-INA) to assess cognitive function and measurement of lymphocyte CD4 counts.This study included 48 subjects consisted of 29 males (60.4%) and 19 females (39.6%). The mean age was 39.17±11.21 years old. There was a significant correlation between CD4 lymphocyte counts and MoCA-INA score (r=0.347, p=0.016).Higher plasma CD4 lymphocyte count is correlated with better cognitive function in HIV-AIDS patients.

The Art Gallery Test: A Preliminary Comparison between Traditional Neuropsychological and Ecological VR-Based Tests.

PubMed

Gamito, Pedro; Oliveira, Jorge; Alghazzawi, Daniyal; Fardoun, Habib; Rosa, Pedro; Sousa, Tatiana; Maia, Ines; Morais, Diogo; Lopes, Paulo; Brito, Rodrigo

2017-01-01

Ecological validity should be the cornerstone of any assessment of cognitive functioning. For this purpose, we have developed a preliminary study to test the Art Gallery Test (AGT) as an alternative to traditional neuropsychological testing. The AGT involves three visual search subtests displayed in a virtual reality (VR) art gallery, designed to assess visual attention within an ecologically valid setting. To evaluate the relation between AGT and standard neuropsychological assessment scales, data were collected on a normative sample of healthy adults ( n = 30). The measures consisted of concurrent paper-and-pencil neuropsychological measures [Montreal Cognitive Assessment (MoCA), Frontal Assessment Battery (FAB), and Color Trails Test (CTT)] along with the outcomes from the three subtests of the AGT. The results showed significant correlations between the AGT subtests describing different visual search exercises strategies with global and specific cognitive measures. Comparative visual search was associated with attention and cognitive flexibility (CTT); whereas visual searches involving pictograms correlated with global cognitive function (MoCA).

An Interactive Activation Model of the Effect of Context in Perception. Part I.

DTIC Science & Technology

1980-05-15

interested in word perception (Adams, 1979; Estes, 1975; LaBerge & Samuels, 1974; Johnston & McClelland, in press; McClelland, 1976). Our model differs from... LaBerge , D., & Samuels, S. Toward a theory of automatic information process- ing in -eading. Cognitive Psychology, 1974, 6, 293-323. Levin, J. A...Frederick Hayes-Roth I DR. ALBERT STEVENS Stanford University The lad Corporation BOLT BRINEX 4 NEWMAN, INC. Stanford, CA 94305 1700 Main Street 50

Interactive pediatric emergency checklists to the palm of your hand - How the Pedi Crisis App traveled around the world.

PubMed

Gálvez, Jorge A; Lockman, Justin L; Schleelein, Laura E; Simpao, Allan F; Ahumada, Luis M; Wolf, Bryan A; Shah, Maully J; Heitmiller, Eugenie; Rehman, Mohamed

2017-08-01

Cognitive aids help clinicians manage critical events and have been shown to improve outcomes by providing critical information at the point of care. Critical event guidelines, such as the Society of Pediatric Anesthesia's Critical Events Checklists described in this article, can be distributed globally via interactive smartphone apps. From October 1, 2013 to January 1, 2014, we performed an observational study to determine the global distribution and utilization patterns of the Pedi Crisis cognitive aid app that the Society for Pediatric Anesthesia developed. We analyzed distribution and utilization metrics of individuals using Pedi Crisis on iOS (Apple Inc., Cupertino, CA) devices worldwide. We used Google Analytics software (Google Inc., Mountain View, CA) to monitor users' app activity (eg, screen views, user sessions). The primary outcome measurement was the number of user-sessions and geographic locations of Pedi Crisis user sessions. Each user was defined by the use of a unique Apple ID on an iOS device. Google Analytics correlates session activity with geographic location based on local Internet service provider logs. Pedi Crisis had 1 252 active users (both new and returning) and 4 140 sessions across 108 countries during the 3-month study period. Returning users used the app longer and viewed significantly more screens that new users (mean screen views: new users 1.3 [standard deviation +/-1.09, 95% confidence interval 1.22-1.55]; returning users 7.6 [standard deviation +/-4.19, 95% confidence interval 6.73-8.39]P<.01) CONCLUSIONS: Pedi Crisis was used worldwide within days of its release and sustained utilization beyond initial publication. The proliferation of handheld electronic devices provides a unique opportunity for professional societies to improve the worldwide dissemination of guidelines and evidence-based cognitive aids. © 2017 John Wiley & Sons Ltd.

Influx of extracellular Zn(2+) into the hippocampal CA1 neurons is required for cognitive performance via long-term potentiation.

PubMed

Takeda, A; Suzuki, M; Tempaku, M; Ohashi, K; Tamano, H

2015-09-24

Physiological significance of synaptic Zn(2+) signaling was examined in the CA1 of young rats. In vivo CA1 long-term potentiation (LTP) was induced using a recording electrode attached to a microdialysis probe and the recording region was locally perfused with artificial cerebrospinal fluid (ACSF) via the microdialysis probe. In vivo CA1 LTP was inhibited under perfusion with CaEDTA and ZnAF-2DA, extracellular and intracellular Zn(2+) chelators, respectively, suggesting that the influx of extracellular Zn(2+) is required for in vivo CA1 LTP induction. The increase in intracellular Zn(2+) was chelated with intracellular ZnAF-2 in the CA1 1h after local injection of ZnAF-2DA into the CA1, suggesting that intracellular Zn(2+) signaling induced during learning is blocked with intracellular ZnAF-2 when the learning was performed 1h after ZnAF-2DA injection. Object recognition was affected when training of object recognition test was performed 1h after ZnAF-2DA injection. These data suggest that intracellular Zn(2+) signaling in the CA1 is required for object recognition memory via LTP. Surprisingly, in vivo CA1 LTP was affected under perfusion with 0.1-1μM ZnCl2, unlike the previous data that in vitro CA1 LTP was enhanced in the presence of 1-5μM ZnCl2. The influx of extracellular Zn(2+) into CA1 pyramidal cells has bidirectional action in CA1 LTP. The present study indicates that the degree of extracellular Zn(2+) influx into CA1 neurons is critical for LTP and cognitive performance. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

The effects of holistic health group interventions on improving the cognitive ability of persons with mild cognitive impairment: a randomized controlled trial.

PubMed

Young, Kim-Wan; Ng, Petrus; Kwok, Timothy; Cheng, Daphne

2017-01-01

Persons with mild cognitive impairment (PwMCI) are at a higher risk of developing dementia than those without cognitive impairment. This research study aims to evaluate the effectiveness of a holistic health group intervention, which is based on the holistic brain health approach as well as an Eastern approach to health care, on improving the cognitive ability of Chinese PwMCI. In a randomized controlled trial (RCT), 38 Chinese PwMCI were randomly assigned to either a 10-session holistic health intervention group or the control group. The holistic health treatment group attempted to promote the acceptance of their illness, enhance memory and coping skills, develop a positive lifestyle, maintain positive emotions, and facilitate emotional support among participants. The 10-session holistic health group intervention was structured, with each session conducted once per week and ~90 minutes in length. Control group patients and their family caregivers received standardized basic educational materials that provided basic information on cognitive decline for them to read at home. The Montreal Cognitive Assessment (MoCA) test was used to assess the cognitive ability of PwMCI in the pre- and posttreatment periods by a research assistant who was blind to the group assignment of the participants. The paired-samples t -test indicated that the treatment group (n=18) showed significant improvement in the MoCA score, whereas the control group (n=20) did not. Moreover, 2×2 (group × time) repeated-measures analysis of covariance (ANCOVA) demonstrated that the holistic health group treatment was significantly more effective than the control intervention in improving the MoCA score, with a moderate effect size, and improving the delayed recall (ie, short-term memory), with a strong effect size, after controlling for age, sex, education, and marital status. This present RCT provides evidence to support the feasibility and effectiveness of the holistic health group intervention in improving the cognitive and short-term memory abilities of PwMCI.

Propofol ameliorates electroconvulsive shock-induced learning and memory impairment by regulation of synaptic metaplasticity via autophosphorylation of CaMKIIa at Thr 305 in stressed rats.

PubMed

Ren, Li; Zhang, Fan; Min, Su; Hao, Xuechao; Qin, Peipei; Zhu, Xianlin

2016-06-30

Electroconvulsive therapy (ECT) is an effective treatment for depression, but it can induce learning and memory impairment. Our previous study found propofol (γ-aminobutyric acid (GABA) receptor agonist) could ameliorate electroconvulsive shock (ECS, an analog of ECT to animals)-induced cognitive impairment, however, the underlying molecular mechanisms remain unclear. This study aimed to investigate the effects of propofol on metaplasticity and autophosphorylation of CaMKIIa in stressed rats receiving ECS. Depressive-like behavior and learning and memory function were assessed by sucrose preference test and Morris water test respectively. LTP were tested by electrophysiological experiment, the expression of CaMKIIa, p-T305-CaMKII in hippocampus and CaMKIIα in hippocampal PSD fraction were evaluated by western blot. Results suggested ECS raised the baseline fEPSP and impaired the subsequent LTP, increased the expression of p-T305-CaMKII and decreased the expression of CaMKIIα in hippocampal PSD fraction, leading to cognitive dysfunction in stressed rats. Propofol could down-regulate the baseline fEPSP and reversed the impairment of LTP partly, decreased the expression of p-T305-CaMKII and increased the expression of CaMKIIα in hippocampal PSD fraction and alleviated ECS-induced learning and memory impairment. In conclusion, propofol ameliorates ECS-induced learning and memory impairment, possibly by regulation of synaptic metaplasticity via p-T305-CaMKII. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

A study on the relationships between age, work experience, cognition, and work ability in older employees working in heavy industry.

PubMed

Chung, Jaeyeop; Park, Juhyung; Cho, Milim; Park, Yunhee; Kim, DeokJu; Yang, Dongju; Yang, Yeongae

2015-01-01

[Purpose] The purpose of this study was to examine the correlation of age, work experience, cognition, and work ability in older employees working in heavy industry. [Subjects and Methods] The study was conducted using 100 subjects who were over 55 years old and worked in heavy industry. To obtain data, we first had the subjects complete the MoCA-K test and Work Ability Index (WAI). The data were then analyzed by frequency and correlation using statistical software (SPSS 21.0). [Results] Through this study, we discovered a significant positive correlation between WAI and MoCA-K, age, and work experience. [Conclusion] This study revealed that work ability in older employees increases not with the number of years worked but with the enhancement of cognitive ability. Special management that focuses on cognition is therefore required for senior employees working in the field of heavy industry.

The Montreal Cognitive Assessment as a preliminary assessment tool in general psychiatry: Validity of MoCA in psychiatric patients.

PubMed

Gierus, J; Mosiołek, A; Koweszko, T; Wnukiewicz, P; Kozyra, O; Szulc, A

2015-01-01

The aim of the presented research was to obtain the initial data regarding the validity of Montreal Cognitive Assessment (MoCA) in diagnosing cognitive impairment in psychiatrically hospitalized patients. The results in MoCA obtained from 221 patients were analyzed in terms of proportional participation of patients with particular diagnosis in three result ranges. In 67 patients, additional version of the scale was also used. Comparative analysis of average results in particular diagnostic groups (organically based disorders, disorders due to psychoactive substance use, psychotic disorders, neurotic disorders and personality disorders) was also carried out, as well as an analysis of the scale's accuracy as a diagnostic test in detecting organic disorders. The reliability of the test measured with between tests correlation coefficient rho=0.92 (P=.000). Significant differences between particular diagnoses groups were detected (J-T=13736; P=.000). The cutoff points of 23 turned out to have a satisfactory sensitivity and specificity (0.82 and 0.70, respectively) in diagnosing organically based disorders. The area below the receiver operating characteristic curve (AUC=0.854; P=.000) suggests that MoCA has a satisfactory value as a classifier. The initial data suggest MoCA's high value in prediction of future diagnosis of organically based disorders. The initial results obtained in particular group of diagnoses support construct validity of the method. Copyright © 2015 Elsevier Inc. All rights reserved.

Acetylcholinesterase inhibition in cognition-relevant brain areas of mice treated with a nootropic Amazonian herbal (Marapuama).

PubMed

Figueiró, M; Ilha, J; Pochmann, D; Porciúncula, L O; Xavier, L L; Achaval, M; Nunes, D S; Elisabetsky, E

2010-10-01

The goal of acetylcholinesterase inhibitors (AChEIs) used to treat Alzheimer's patients is an improvement in cholinergic transmission. While currently available AChEIs have limited success, a huge impediment to the development of newer ones is access to the relevant brain areas. Promnesic, anti-amnesic and AChEI properties were identified in a standardized ethanol extract from Ptychopetalum olacoides (POEE), a medicinal plant favored by the elderly in Amazon communities. The purpose of this study was to provide conclusive evidence that orally given POEE induces AChE inhibition in brain areas relevant to cognition. Histochemistry experiments confirmed that the anticholinesterase compound(s) present in POEE are orally bioavailable, inducing meaningful AChE inhibition in the hippocampus CA1 (∼33%) and CA3 (∼20%), and striatum (∼17%). Ellman's colorimetric analysis revealed that G1 and G4 AChE isoforms activities were markedly inhibited (66 and 72%, respectively) in hippocampus and frontal cortex (50 and 63%, respectively), while G4 appeared to be selectively inhibited (72%) in the striatum. Western blotting showed that POEE did not induce significant changes in the AChE immunocontent suggesting that its synthesis is not extensively modified. This study provides definitive proof of meaningful anticholinesterase activity compatible with the observed promnesic and anti-amnesic effects of POEE in mice, reaffirming the potential of this extract for treating neurodegenerative conditions where a hypofunctioning cholinergic neurotransmission is prominent. Adequate assessment of the safety and efficacy of this extract and/or its isolated active compound(s) are warranted. 2010 Elsevier GmbH. All rights reserved.

FK506-binding protein 1b/12.6: a key to aging-related hippocampal Ca2+ dysregulation?

PubMed Central

Gant, JC; Blalock, EM; K-C, Chen; Kadish, I; Porter, NM; Norris, CM; Thibault, O; Landfield, PW

2014-01-01

It has been recognized for some time that the Ca2+-dependent slow afterhyperpolarization (sAHP) is larger in hippocampal neurons of aged compared with young animals. In addition, extensive studies since have shown that other Ca2+-mediated electrophysiological responses are increased in hippocampus with aging, including Ca2+ transients, L-type voltage-gated Ca2+ channel activity, Ca2+ spike duration and action potential accommodation. Elevated Ca2+-induced Ca2+ release from ryanodine receptors (RyRs) appears to drive amplification of the Ca2+ responses. Components of this Ca2+ dysregulation phenotype correlate with deficits in cognitive function and plasticity, indicating they may play critical roles in aging-related impairment of brain function. However, the molecular mechanisms underlying aging-related Ca2+ dysregulation are not well understood. FK506-binding proteins 1a and 1b (FKBP1a/1b, also known as FKBP12/12.6) are immunophilin proteins that bind the immunosuppressant drugs FK506 and rapamycin. In muscle cells, FKBP1a/1b also bind RyRs and inhibits Ca2+-induced Ca2+ release, but it is not clear whether FKBPs act similarly in brain cells. Recently, we found that selectively disrupting hippocampal FKBP1b function in young rats, either by microinjecting adeno-associated viral vectors containing siRNA, or by treatment with rapamycin, increases the sAHP and recapitulates much of the hippocampal Ca2+ dysregulation phenotype. Moreover, in microarray studies, we found FKBP1b gene expression was downregulated in hippocampus of aging rats and early-stage Alzheimer’s disease subjects. These results suggest the novel hypothesis that declining FKBP function is a key factor in aging-related Ca2+ dysregulation in the brain and point to potential new therapeutic targets for counteracting unhealthy brain aging. PMID:24291098

A new clinical tool for assessing numerical abilities in neurological diseases: numerical activities of daily living

PubMed Central

Semenza, Carlo; Meneghello, Francesca; Arcara, Giorgio; Burgio, Francesca; Gnoato, Francesca; Facchini, Silvia; Benavides-Varela, Silvia; Clementi, Maurizio; Butterworth, Brian

2014-01-01

The aim of this study was to build an instrument, the numerical activities of daily living (NADL), designed to identify the specific impairments in numerical functions that may cause problems in everyday life. These impairments go beyond what can be inferred from the available scales evaluating activities of daily living in general, and are not adequately captured by measures of the general deterioration of cognitive functions as assessed by standard clinical instruments like the MMSE and MoCA. We assessed a control group (n = 148) and a patient group affected by a wide variety of neurological conditions (n = 175), with NADL along with IADL, MMSE, and MoCA. The NADL battery was found to have satisfactory construct validity and reliability, across a wide age range. This enabled us to calculate appropriate criteria for impairment that took into account age and education. It was found that neurological patients tended to overestimate their abilities as compared to the judgment made by their caregivers, assessed with objective tests of numerical abilities. PMID:25126077

Impact of β-hydroxy β-methylbutyrate (HMB) on age-related functional deficits in mice.

PubMed

Munroe, Michael; Pincu, Yair; Merritt, Jennifer; Cobert, Adam; Brander, Ryan; Jensen, Tor; Rhodes, Justin; Boppart, Marni D

2017-01-01

β-Hydroxy β-methylbutyrate (HMB) is a metabolite of the essential amino acid leucine. Recent studies demonstrate a decline in plasma HMB concentrations in humans across the lifespan, and HMB supplementation may be able to preserve muscle mass and strength in older adults. However, the impact of HMB supplementation on hippocampal neurogenesis and cognition remains largely unexplored. The purpose of this study was to simultaneously evaluate the impact of HMB on muscle strength, neurogenesis and cognition in young and aged mice. In addition, we evaluated the influence of HMB on muscle-resident mesenchymal stem/stromal cell (Sca-1 + CD45 - ; mMSC) function to address these cells potential to regulate physiological outcomes. Three month-old (n=20) and 24 month-old (n=18) female C57BL/6 mice were provided with either Ca-HMB or Ca-Lactate in a sucrose solution twice per day for 5.5weeks at a dose of 450mg/kg body weight. Significant decreases in relative peak and mean force, balance, and neurogenesis were observed in aged mice compared to young (age main effects, p≤0.05). Short-term HMB supplementation did not alter activity, balance, neurogenesis, or cognitive function in young or aged mice, yet HMB preserved relative peak force in aged mice. mMSC gene expression was significantly reduced with age, but HMB supplementation was able to recover expression of select growth factors known to stimulate muscle repair (HGF, LIF). Overall, our findings demonstrate that while short-term HMB supplementation does not appear to affect neurogenesis or cognitive function in young or aged mice, HMB may maintain muscle strength in aged mice in a manner dependent on mMSC function. Copyright © 2016 Elsevier Inc. All rights reserved.

Gastrodin Attenuates Bilateral Common Carotid Artery Occlusion-Induced Cognitive Deficits via Regulating Aβ-Related Proteins and Reducing Autophagy and Apoptosis in Rats

PubMed Central

Liu, Bo; Gao, Jian-Mei; Li, Fei; Gong, Qi-Hai; Shi, Jing-Shan

2018-01-01

Gastrodin (GAS), an active constituent extracted from Gastrodia elata Blume, is used to treat ischemic stroke, epilepsy, dizziness, and dementia for centuries in China. This study examined its effects on vascular dementia (VD) and the underlying molecular mechanisms. VD was established by ligation of bilateral common carotid artery occlusion (BCCAO). A total of 7 days after BCCAO surgery, GAS (15, 30, and 60 mg/kg) was orally administered for 28 consecutive days to evaluate therapeutic effects. Cognitive function was tested by the Morris water maze. The neuronal morphological changes were examined via Hematoxylin–Eosin staining. Flow cytometry was used for evaluating apoptosis in the hippocampi. The target protein expression was examined by Western blot. The results showed that BCCAO induced cognitive impairment, hippocampus CA1 and CA3 pyramidal neuron damage, beta-amyloid (Aβ) deposition, excessive autophagy, and apoptosis. GAS treatment significantly improved BCCAO-induced cognitive deficits and hippocampus neuron damage. Molecular analysis revealed that GAS exerted the protective effect via reducing the levels of Aβ1–40/42, APP, and β-site APP-cleaving enzyme 1 expression, and increasing Aβ-related protein, a disintegrin and metalloprotease 10, and insulin degrading enzyme expression. Meanwhile, GAS inhibited excessive autophagy via decreasing Beclin-1, LC3-II, and p62 levels. Furthermore, GAS inhibited apoptosis through the downregulation of Bax and upregulation of Bcl-2. Moreover, P38 MAPK signaling pathway was involved in the process. Our findings demonstrate that GAS was effective in the treatment of BCCAO-induced VD via targeting Aβ-related protein formation and inhibiting autophagy and apoptosis of hippocampus neurons. PMID:29755351

Cerebral glucose metabolism and cognition in newly diagnosed Parkinson's disease: ICICLE-PD study.

PubMed

Firbank, M J; Yarnall, A J; Lawson, R A; Duncan, G W; Khoo, T K; Petrides, G S; O'Brien, J T; Barker, R A; Maxwell, R J; Brooks, D J; Burn, D J

2017-04-01

To assess reductions of cerebral glucose metabolism in Parkinson's disease (PD) with 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET), and their associations with cognitive decline. FDG-PET was performed on a cohort of 79 patients with newly diagnosed PD (mean disease duration 8 months) and 20 unrelated controls. PD participants were scanned while on their usual dopaminergic medication. Cognitive testing was performed at baseline, and after 18 months using the Cognitive Drug Research (CDR) and Cambridge Neuropsychological Test Automated Battery (CANTAB) computerised batteries, the Mini-Mental State Examination (MMSE), and the Montreal Cognitive Assessment (MoCA). We used statistical parametric mapping (SPM V.12) software to compare groups and investigate voxelwise correlations between FDG metabolism and cognitive score at baseline. Linear regression was used to evaluate how levels of cortical FDG metabolism were predictive of subsequent cognitive decline rated with the MMSE and MoCA. PD participants showed reduced glucose metabolism in the occipital and inferior parietal lobes relative to controls. Low performance on memory-based tasks was associated with reduced FDG metabolism in posterior parietal and temporal regions, while attentional performance was associated with more frontal deficits. Baseline parietal to cerebellum FDG metabolism ratios predicted MMSE (β=0.38, p=0.001) and MoCA (β=0.3, p=0.002) at 18 months controlling for baseline score. Reductions in cortical FDG metabolism were present in newly diagnosed PD, and correlated with performance on neuropsychological tests. A reduced baseline parietal metabolism is associated with risk of cognitive decline and may represent a potential biomarker for this state and the development of PD dementia. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Impairment in long-term memory formation and learning-dependent synaptic plasticity in mice lacking glycogen synthase in the brain

PubMed Central

Duran, Jordi; Saez, Isabel; Gruart, Agnès; Guinovart, Joan J; Delgado-García, José M

2013-01-01

Glycogen is the only carbohydrate reserve of the brain, but its overall contribution to brain functions remains unclear. Although it has traditionally been considered as an emergency energetic reservoir, increasing evidence points to a role of glycogen in the normal activity of the brain. To address this long-standing question, we generated a brain-specific Glycogen Synthase knockout (GYS1Nestin-KO) mouse and studied the functional consequences of the lack of glycogen in the brain under alert behaving conditions. These animals showed a significant deficiency in the acquisition of an associative learning task and in the concomitant activity-dependent changes in hippocampal synaptic strength. Long-term potentiation (LTP) evoked in the hippocampal CA3-CA1 synapse was also decreased in behaving GYS1Nestin-KO mice. These results unequivocally show a key role of brain glycogen in the proper acquisition of new motor and cognitive abilities and in the underlying changes in synaptic strength. PMID:23281428

Neurogranin restores amyloid β-mediated synaptic transmission and long-term potentiation deficits.

PubMed

Kaleka, Kanwardeep Singh; Gerges, Nashaat Z

2016-03-01

Amyloid β (Aβ) is widely considered one of the early causes of cognitive deficits observed in Alzheimer's disease. Many of the deficits caused by Aβ are attributed to its disruption of synaptic function represented by its blockade of long-term potentiation (LTP) and its induction of synaptic depression. Identifying pathways that reverse these synaptic deficits may open the door to new therapeutic targets. In this study, we explored the possibility that Neurogranin (Ng)-a postsynaptic calmodulin (CaM) targeting protein that enhances synaptic function-may rescue Aβ-mediated deficits in synaptic function. Our results show that Ng is able to reverse synaptic depression and LTP deficits induced by Aβ. Furthermore, Ng's restoration of synaptic transmission is through the insertion of GluA1-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate receptors (AMPARs). These restorative effects of Ng are dependent on the interaction of Ng and CaM and CaM-dependent activation of CaMKII. Overall, this study identifies a novel mechanism to rescue synaptic deficits induced by Aβ oligomers. It also suggests Ng and CaM signaling as potential therapeutic targets for Alzheimer's disease as well as important tools to further explore the pathophysiology underlying the disease. Copyright © 2015 Elsevier Inc. All rights reserved.

Evaluating Recall and Recognition Memory Using the Montreal Cognitive Assessment: Applicability for Alzheimer's and Huntington's Diseases.

PubMed

Van Liew, Charles; Santoro, Maya S; Goldstein, Jody; Gluhm, Shea; Gilbert, Paul E; Corey-Bloom, Jody

2016-12-01

We sought to investigate whether the Montreal Cognitive Assessment (MoCA) could provide a brief assessment of recall and recognition using Huntington disease (HD) and Alzheimer disease (AD) as disorders characterized by different memory deficits. This study included 80 participants with HD, 64 participants with AD, and 183 community-dwelling control participants. Random-effects hierarchical logistic regressions were performed to assess the relative performance of the normal control (NC), participants with HD, and participants with AD on verbal free recall, cued recall, and multiple-choice recognition on the MoCA. The NC participants performed significantly better than participants with AD at all the 3 levels of assessment. No difference existed between participants with HD and NC for cued recall, but NC participants performed significantly better than participants with HD on free recall and recognition. The participants with HD performed significantly better than participants with AD at all the 3 levels of assessment. The MoCA appears to be a valuable, brief cognitive assessment capable of identifying specific memory deficits consistent with known differences in memory profiles. © The Author(s) 2016.

Impact of hypertension severity on arterial stiffness, cerebral vasoreactivity, and cognitive performance.

PubMed

Muela, Henrique Cotchi Simbo; Costa-Hong, Valeria A; Yassuda, Monica Sanches; Machado, Michel Ferreira; Nogueira, Ricardo de Carvalho; Moraes, Natalia C; Memória, Claudia Maia; Macedo, Thiago A; Bor-Seng-Shu, Edson; Massaro, Ayrton Roberto; Nitrini, Ricardo; Bortolotto, Luiz A

2017-01-01

Aging, hypertension (HTN), and other cardiovascular risk factors contribute to structural and functional changes of the arterial wall. To evaluate whether arterial stiffness (AS) is related to cerebral blood flow changes and its association with cognitive function in patients with hypertension. 211 patients (69 normotensive and 142 hypertensive) were included. Patients with hypertension were divided into 2 stages: HTN stage-1 and HTN stage-2. The mini-mental state examination (MMSE), Montreal Cognitive Assessment (MoCA) and a battery of neuropsychological (NPE) tests were used to determine cognitive function. Pulse wave velocity was measured using the Complior ® . Carotid properties were assessed by radiofrequency ultrasound. Central arterial pressure and augmentation index were obtained using applanation tonometry. Middle cerebral artery flow velocity was measured by transcranial Doppler ultrasonography. Both arterial stiffness parameters and cerebral vasoreactivity worsened in line with HTN severity. There was a negative correlation between breath holding index (BHI) and arterial stiffness parameters. Cognitive performance worsened in line with HTN severity, with statistical difference occurring mainly between the HTN-2 and normotension groups on both the MMSE and MoCA. The same tendency was observed on the NPE tests. Hypertension severity was associated with higher AS, worse BHI, and lower cognitive performance.

Potential contribution of the neurodegenerative disorders risk loci to cognitive performance in an elderly male gout population.

PubMed

Han, Lin; Jia, Zhaotong; Cao, Chunwei; Liu, Zhen; Liu, Fuqiang; Wang, Lin; Ren, Wei; Sun, Mingxia; Wang, Baoping; Li, Changgui; Chen, Li

2017-09-01

Cognitive impairment has been described in elderly subjects with high normal concentrations of serum uric acid. However, it remains unclear if gout confers an increased poorer cognition than those in individuals with asymptomatic hyperuricemia. The present study aimed at evaluating cognitive function in patients suffering from gout in an elderly male population, and further investigating the genetic contributions to the risk of cognitive function.This study examined the cognitive function as assessed by Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) in 205 male gout patients and 204 controls. The genetic basis of these cognitive measures was evaluated by genome-wide association study (GWAS) data in 102 male gout patients. Furthermore, 7 loci associated with cognition in GWAS were studied for correlation with gout in 1179 male gout patients and 1848 healthy male controls.Compared with controls, gout patients had significantly lower MoCA scores [22.78 ± 3.01 vs 23.42 ± 2.95, P = .023, adjusted by age, body mass index (BMI), education, and emotional disorder]. GWAS revealed 7 single-nucleotide polymorphisms (SNPs) associations with MoCA test at a level of conventional genome-wide significance (P < 9.6 × 10). The most significant association was observed between rs12895072 and rs12434554 within the KTN1 gene (Padjusted = 4.2 × 10, Padjusted = 4.7 × 10) at 14q22. The next best signal was in RELN gene (rs155333, Padjusted = 1.3 × 10) at 7q22, while the other variants at rs17458357 (Padjusted = 3.98 × 10), rs2572683 (Padjusted = 8.9 × 10), rs12555895 (Padjusted = 2.6 × 10), and rs3764030 (Padjusted = 9.4 × 10) were also statistically significant. The 7 SNPs were not associated with gout in further analysis (all P > .05).Elderly male subjects with gout exhibit accelerated decline in cognition performance. Several neurodegenerative disorders risk loci were identified for genetic contributors to cognitive performance in our Chinese elderly male gout population. Larger prospective studies of the cognitive performance and genetic analysis in gout subjects are recommended.

The Hong Kong version of the Oxford Cognitive Screen (HK-OCS): validation study for Cantonese-speaking chronic stroke survivors.

PubMed

Kong, Anthony Pak-Hin; Lam, Pinky Hiu-Ping; Ho, Diana Wai-Lam; Lau, Johnny King; Humphreys, Glyn W; Riddoch, Jane; Weekes, Brendan

2016-09-01

This study reports the validation of the Hong Kong version of Oxford Cognitive Screen (HK-OCS). Seventy Cantonese-speaking healthy individuals participated to establish normative data and 46 chronic stroke survivors were assessed using the HK-OCS, Albert's Test of Visual Neglect, short test of gestural production, and Hong Kong version of the following assessments: Western Aphasia Battery, MMSE, MoCA, Modified Barthel Index, and Lawton Instrumental Activities of Daily Living scale. The validity of the HK-OCS was appraised by the difference between the two participant groups. Neurologically unimpaired individuals performed significantly better than stroke survivors on the HK-OCS. Positive and significant correlations found between cognitive subtests in the HK-OCS and related assessments indicated good concurrent validity. Excellent intra-rater and inter-rater reliabilities, fair test-retest reliability, and acceptable internal consistency suggested that the HK-OCS had good reliability. Specific HK-OCS subtests including semantics, episodic memory, number writing, and orientation were the best predictors of functional outcomes.

Electroencephalographic findings related with mild cognitive impairment in idiopathic rapid eye movement sleep behavior disorder.

PubMed

Sasai, Taeko; Matsuura, Masato; Inoue, Yuichi

2013-12-01

Mild cognitive impairment (MCI) and electroencephalographic (EEG) slowing have been reported as common findings of idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD) and α-synucleinopathies. The objective of this study is to clarify the relation between MCI and physiological markers in iRBD. Cross-sectional study. Yoyogi Sleep Disorder Center. Thirty-one patients with iRBD including 17 younger patients with iRBD (younger than 70 y) and 17 control patients for the younger patients with iRBD. N/A. Montreal Cognitive Assessment (MoCA) and n-polysomnogram (PSG) were conducted of all participants. In patients with iRBD, the factors associated with MCI were explored among parameters of REM sleep without atonia (RWA), score of Sniffin' Sticks Test (threshold-discrimination-identification [TDI] score), RBD morbidity, and RBD severity evaluated with the Japanese version of the RBD questionnaire (RBDQ-JP). The younger iRBD group showed significantly lower alpha power during wake and lower MoCA score than the age-matched control group. MCI was detected in 13 of 17 patients (76.5%) on MoCA in this group. Among patients wtih iRBD, the MoCA score negatively correlated with age, proportion of slow wave sleep, TDI score, and EEG spectral power. Multiple regression analysis provided the following equation: MoCA score = 50.871-0.116*age -5.307*log (δ power during REM sleep) + 0.086*TDI score (R² = 0.598, P < 0.01). The standardized partial regression coefficients were -0.558 for age, -0.491 for log (δ power during REM sleep), and 0.357 for TDI score (F = 9.900, P < 0.001). Electroencephalographic slowing, especially during rapid eye movement sleep and olfactory dysfunction, was revealed to be associated with cognitive decline in idiopathic rapid eye movement sleep behavior disorder.

The effect of sugammadex on postoperative cognitive function and recovery.

PubMed

Pişkin, Özcan; Küçükosman, Gamze; Altun, Deniz Utku; Çimencan, Murat; Özen, Banu; Aydın, Bengü Gülhan; Okyay, Rahşan Dilek; Ayoğlu, Hilal; Turan, Işıl Özkoçak

2016-01-01

Sugammadex is the first selective relaxant binding agent. When compared with neostigmine, following sugammadex administration patients wake earlier and have shorter recovery times. In this study, we hypothesized that fast and clear awakening in patients undergoing general anesthesia has positive effects on cognitive functions in the early period after operation. Approved by the local ethical committee, 128 patients were enrolled in this randomized, prospective, controlled, double-blind study. Patients were allocated to either Sugammadex group (Group S) or the Neostigmine group (Group N). The primary outcome of the study was early postoperative cognitive recovery as measured by the Montreal Cognitive Assessment (MoCA) and Mini Mental State Examination (MMSE). After baseline assessment 12-24h before the operation. After the operation, when the Modified Aldrete Recovery Score was ≥9 the MMSE and 1h later the MoCA tests were repeated. Although there was a reduction in MoCA and MMSE scores in both Group S and Group N between preoperative and postoperative scores, there was no statistically significant difference in the slopes (p>0.05). The time to reach TOF 0.9 was 2.19min in Group S and 6.47min in Group N (p<0.0001). Recovery time was 8.26min in Group S and 16.93min in Group N (p<0.0001). We showed that the surgical procedure and/or accompanying anesthetic procedure may cause a temporary or permanent regression in cognitive function in the early postoperative period. However, better cognitive performance could not be proved in the Sugammadex compared to the Neostigmine. Copyright © 2015 Sociedade Brasileira de Anestesiologia. Published by Elsevier Editora Ltda. All rights reserved.

Mid-life environmental enrichment increases synaptic density in CA1 in a mouse model of Aβ-associated pathology and positively influences synaptic and cognitive health in healthy ageing.

PubMed

Stuart, Kimberley E; King, Anna E; Fernandez-Martos, Carmen M; Dittmann, Justin; Summers, Mathew J; Vickers, James C

2017-06-01

Early-life cognitive enrichment may reduce the risk of experiencing cognitive deterioration and dementia in later-life. However, an intervention to prevent or delay dementia is likely to be taken up in mid to later-life. Hence, we investigated the effects of environmental enrichment in wildtype mice and in a mouse model of Aβ neuropathology (APP SWE /PS1 dE9 ) from 6 months of age. After 6 months of housing in standard laboratory cages, APP SWE /PS1 dE9 (n = 27) and healthy wildtype (n = 21) mice were randomly assigned to either enriched or standard housing. At 12 months of age, wildtype mice showed altered synaptic protein levels and relatively superior cognitive performance afforded by environmental enrichment. Environmental enrichment was not associated with alterations to Aβ plaque pathology in the neocortex or hippocampus of APP SWE /PS1 dE9 mice. However, a significant increase in synaptophysin immunolabeled puncta in the hippocampal subregion, CA1, in APP SWE /PS1 dE9 mice was detected, with no significant synaptic density changes observed in CA3, or the Fr2 region of the prefrontal cortex. Moreover, a significant increase in hippocampal BDNF was detected in APP SWE /PS1 dE9 mice exposed to EE, however, no changes were detected in neocortex or between Wt animals. These results demonstrate that mid to later-life cognitive enrichment has the potential to promote synaptic and cognitive health in ageing, and to enhance compensatory capacity for synaptic connectivity in pathological ageing associated with Aβ deposition. © 2017 Wiley Periodicals, Inc.

TRPM2 channel deficiency prevents delayed cytosolic Zn2+ accumulation and CA1 pyramidal neuronal death after transient global ischemia

PubMed Central

Ye, M; Yang, W; Ainscough, J F; Hu, X-P; Li, X; Sedo, A; Zhang, X-H; Zhang, X; Chen, Z; Li, X-M; Beech, D J; Sivaprasadarao, A; Luo, J-H; Jiang, L-H

2014-01-01

Transient ischemia is a leading cause of cognitive dysfunction. Postischemic ROS generation and an increase in the cytosolic Zn2+ level ([Zn2+]c) are critical in delayed CA1 pyramidal neuronal death, but the underlying mechanisms are not fully understood. Here we investigated the role of ROS-sensitive TRPM2 (transient receptor potential melastatin-related 2) channel. Using in vivo and in vitro models of ischemia–reperfusion, we showed that genetic knockout of TRPM2 strongly prohibited the delayed increase in the [Zn2+]c, ROS generation, CA1 pyramidal neuronal death and postischemic memory impairment. Time-lapse imaging revealed that TRPM2 deficiency had no effect on the ischemia-induced increase in the [Zn2+]c but abolished the cytosolic Zn2+ accumulation during reperfusion as well as ROS-elicited increases in the [Zn2+]c. These results provide the first evidence to show a critical role for TRPM2 channel activation during reperfusion in the delayed increase in the [Zn2+]c and CA1 pyramidal neuronal death and identify TRPM2 as a key molecule signaling ROS generation to postischemic brain injury. PMID:25429618

Voluntary running depreciates the requirement of Ca2+-stimulated cAMP signaling in synaptic potentiation and memory formation

PubMed Central

Zheng, Fei; Zhang, Ming; Ding, Qi; Sethna, Ferzin; Yan, Lily; Moon, Changjong; Yang, Miyoung

2016-01-01

Mental health and cognitive functions are influenced by both genetic and environmental factors. Although having active lifestyle with physical exercise improves learning and memory, how it interacts with the specific key molecular regulators of synaptic plasticity is largely unknown. Here, we examined the effects of voluntary running on long-term potentiation (LTP) and memory formation in mice lacking type 1 adenylyl cyclase (AC1), a neurospecific synaptic enzyme that contributes to Ca2+-stimulated cAMP production. Following 1 mo of voluntary running-wheel exercise, the impaired LTP and object recognition memory in AC1 knockout (KO) mice were significantly attenuated. Running up-regulated exon II mRNA level of BDNF (brain-derived neurotrophic factor), though it failed to increase exon I and IV mRNAs in the hippocampus of AC1 KO mice. Intrahippocampal infusion of recombinant BDNF was sufficient to rescue LTP and object recognition memory defects in AC1 KO mice. Therefore, voluntary running and exogenous BDNF application overcome the defective Ca2+-stimulated cAMP signaling. Our results also demonstrate that alteration in Ca2+-stimulated cAMP can affect the molecular outcome of physical exercise. PMID:27421897

Sex differences in obesity and cognitive function in a cognitively normal aging Chinese Han population.

PubMed

Li, Wei; Qiu, Qi; Sun, Lin; Yue, Ling; Wang, Tao; Li, Xia; Xiao, Shifu

2017-01-01

Sex differences in Alzheimer's disease and mild cognitive impairment have been well recognized. However, sex differences in cognitive function and obesity in cognitively normal aging Chinese Han population have not attracted much attention. The aim of this study was to investigate the relationship between sex, obesity, and cognitive function in an elderly Chinese population with normal cognitive function. A total of 228 cognitively normal aging participants (males/females =93/135) entered this study. Their general demographic information (sex, age, and education) was collected by standardized questionnaire. Apolipoprotein E (APOE) genotype and serum lipid levels were measured. The Montreal Cognitive Assessment (MoCA) was used to assess participants' cognitive function. The prevalence of obesity in elderly women (18/133, 13.5%) was significantly higher than that in men (5/92, 5.4%, P =0.009). Regression analyses showed that obesity was associated with drinking alcohol (OR =13.695, P =0.045) and triglyceride (OR =1.436, P =0.048) in women and limited to low-density lipoprotein (OR =11.829, P =0.023) in men. Women performed worse on the naming score for MoCA than men ( P <0.01). Stepwise linear regression analysis showed that education ( t =3.689, P <0.001) and smoking ( t =2.031, P =0.045) were related to the score of naming in female, while high-density lipoprotein ( t =-2.077, P =0.041) was related to the score of naming in male; however, no correlation was found between body mass index and cognitive function in both male and female ( P >0.05). Our finding suggests that there are significant sex differences in obesity and specific cognitive domains in aging Chinese Han population with normal cognitive function.

Hippocampal substructural vulnerability to sleep disturbance and cognitive impairment in patients with chronic primary insomnia: magnetic resonance imaging morphometry.

PubMed

Joo, Eun Yeon; Kim, Hosung; Suh, Sooyeon; Hong, Seung Bong

2014-07-01

Despite compelling evidence from animal studies indicating hippocampal subfield-specific vulnerability to poor sleep quality and related cognitive impairment, there have been no human magnetic resonance imaging (MRI) studies investigating the relationship between hippocampal subfield volume and sleep disturbance. Our aim was to investigate the pattern of volume changes across hippocampal subfields in patients with primary insomnia relative to controls. Pointwise morphometry allowed for volume measurements of hippocampal regions on T1-weighted MRI. University hospital. Twenty-seven unmedicated patients (age: 51.2 ± 9.6 y) and 30 good sleepers as controls (50.4 ± 7.1 y). N/A. We compared hippocampal subfield volumes between patients and controls and correlated volume with clinical and neuropsychological features in patients. Patients exhibited bilateral atrophy across all hippocampal subfields (P < 0.05 corrected). Cornu ammonis (CA) 1 subfield atrophy was associated with worse sleep quality (higher Pittsburgh Sleep Quality Index and higher arousal index of polysomnography) (r < -0.45, P < 0.005). The volume of the combined region, including the dentate gyrus (DG) and CA3-4, negatively correlated with verbal memory, verbal information processing, and verbal fluency in patients (|r| > 0.45, P < 0.05). Hemispheric volume asymmetry of this region (left smaller than right) was associated with impaired verbal domain functions (r = 0.50, P < 0.005). Hippocampal subfield atrophy in chronic insomnia suggests reduced neurogenesis in the dentate gyrus (DG) and neuronal loss in the cornu ammonis (CA) subfields in conditions of sleep fragmentation and related chronic stress condition. Atrophy in the CA3-4-DG region was associated with impaired cognitive functions in patients. These observations may provide insight into pathophysiological mechanisms that make patients with chronic sleep disturbance vulnerable to cognitive impairment. Joo EY, Kim H, Suh S, Hong SB. Hippocampal substructural vulnerability to sleep disturbance and cognitive impairment in patients with chronic primary insomnia: magnetic resonance imaging morphometry.

Prevalence of Cognitive Impairment Among Peritoneal Dialysis Patients, Impact on Peritonitis and Role of Assisted Dialysis.

PubMed

Shea, Yat Fung; Lam, Man Fai; Lee, Mi Suen Connie; Mok, Ming Yee Maggie; Lui, Sing-Leung; Yip, Terence P S; Lo, Wai Kei; Chu, Leung Wing; Chan, Tak-Mao

2016-01-01

♦ Chronic renal failure and aging are suggested as risk factors for cognitive impairment (CI). We studied the prevalence of CI among peritoneal dialysis (PD) patients using Montreal Cognitive Assessment (MoCA), its impact on PD-related peritonitis in the first year, and the potential role of assisted PD. ♦ One hundred fourteen patients were newly started on PD between February 2011 and July 2013. Montreal Cognitive Assessment was performed in the absence of acute illness. Data on patient characteristics including demographics, comorbidities, blood parameters, dialysis adequacy, presence of helpers, medications, and the number PD-related infections were collected. ♦ The age of studied patients was 59±15.0 years, and 47% were female. The prevalence of CI was 28.9%. Patients older than 65 years old (odds ratio [OR] 4.88, confidence interval [CI] 1.79 - 13.28 p = 0.002) and with an education of primary level or below (OR 4.08, CI 1.30 - 12.81, p = 0.016) were independent risk factors for CI in multivariate analysis. Patients with PD-related peritonitis were significantly older (p < 0.001) and more likely to have CI as defined by MoCA (p = 0.035). After adjustment for age, however, CI was not a significant independent risk factor for PD-related peritonitis among self-care PD patients (OR 2.20, CI 0.65 - 7.44, p = 0.20). When we compared patients with MoCA-defined CI receiving self-care and assisted PD, there were no statistically significant differences between the 2 groups in terms of age, MoCA scores, or comorbidities. There were also no statistically significant differences in 1-year outcome of PD-related peritonitis rates or exit-site infections. ♦ Cognitive impairment is common among local PD patients. Even with CI, peritonitis rate in self-care PD with adequate training is similar to CI patients on assisted PD. Copyright © 2016 International Society for Peritoneal Dialysis.

The effect of student-centered and teacher-centered instruction with and without conceptual advocacy on biology students' misconceptions, achievement, attitudes toward science, and cognitive retention

NASA Astrophysics Data System (ADS)

Gallop, Roger Graham

The purpose of this study was to investigate the effect of student-centered and teacher-centered instructional strategies with and without conceptual advocacy (CA) on ninth-grade biology students' misconceptions (MIS), biology achievement (ACH), attitudes toward science (ATT), and cognitive retention of scientific method and measurement, spontaneous generation, and characteristics of living things. Students were purposively selected using intact classes and assigned to one of four treatment groups (i.e., student-centered instruction without CA, student-centered instruction with CA, teacher-centered instruction with CA, and teacher-centered instruction without CA). A modified quasi-experimental design was used in which students were not matched in the conventional sense but instead, groups were shown to be equivalent on the dependent measure via a pretest. A 5-day treatment implementation period addressed science conceptions under investigation. The treatment period was based on the number of class periods teachers at the target school actually spend teaching the biological concepts under investigation using traditional instruction. At the end of the treatment period, students were posttested using the Concepts in Biology instrument and Science Questionnaire. Eight weeks after the posttest, these instruments were administered again as a delayed posttest to determine cognitive retention of the correct biological conceptions and attitudes toward science. MANCOVA and follow-up univariate ANCOVA results indicated that student-centered instruction without CA (i.e., Group 1) did not have a significant effect on students' MIS, ACH, and ATT (F = .029, p = .8658; F = .002, p =.9688, F = .292, p = .5897, respectively). On the other hand, student-centered instruction with CA (i.e., Group 2) had a significant effect on students' MIS and ACH (F =10.33, p = .0016 and F = 10.17, p = .0017, respectively), but did not on ATT (F = .433, p = .5117). Teacher-centered instruction with CA (i.e., Group 3) had a significant effect on students' MIS in favor of Group 4 (i.e., control group) (F = 4.11, p = .0444), and did not have a significant effect on ACH and ATT (F = 1.83, p = .1777 and F = 1.89, p = .1709, respectively). Student gender and teacher gender did not have a significant effect on students' MIS, ACH, and ATT. In the cognitive retention model, there was no significant difference among the research factors relative to the 3 dependent measures.

The effects of holistic health group interventions on improving the cognitive ability of persons with mild cognitive impairment: a randomized controlled trial

PubMed Central

Young, Kim-wan; Ng, Petrus; Kwok, Timothy; Cheng, Daphne

2017-01-01

Purpose Persons with mild cognitive impairment (PwMCI) are at a higher risk of developing dementia than those without cognitive impairment. This research study aims to evaluate the effectiveness of a holistic health group intervention, which is based on the holistic brain health approach as well as an Eastern approach to health care, on improving the cognitive ability of Chinese PwMCI. Research methods In a randomized controlled trial (RCT), 38 Chinese PwMCI were randomly assigned to either a 10-session holistic health intervention group or the control group. The holistic health treatment group attempted to promote the acceptance of their illness, enhance memory and coping skills, develop a positive lifestyle, maintain positive emotions, and facilitate emotional support among participants. The 10-session holistic health group intervention was structured, with each session conducted once per week and ~90 minutes in length. Control group patients and their family caregivers received standardized basic educational materials that provided basic information on cognitive decline for them to read at home. The Montreal Cognitive Assessment (MoCA) test was used to assess the cognitive ability of PwMCI in the pre- and posttreatment periods by a research assistant who was blind to the group assignment of the participants. Results The paired-samples t-test indicated that the treatment group (n=18) showed significant improvement in the MoCA score, whereas the control group (n=20) did not. Moreover, 2×2 (group × time) repeated-measures analysis of covariance (ANCOVA) demonstrated that the holistic health group treatment was significantly more effective than the control intervention in improving the MoCA score, with a moderate effect size, and improving the delayed recall (ie, short-term memory), with a strong effect size, after controlling for age, sex, education, and marital status. Conclusion This present RCT provides evidence to support the feasibility and effectiveness of the holistic health group intervention in improving the cognitive and short-term memory abilities of PwMCI. PMID:29026292

Radiation-induced functional connectivity alterations in nasopharyngeal carcinoma patients with radiotherapy.

PubMed

Ma, Qiongmin; Wu, Donglin; Zeng, Ling-Li; Shen, Hui; Hu, Dewen; Qiu, Shijun

2016-07-01

The study aims to investigate the radiation-induced brain functional alterations in nasopharyngeal carcinoma (NPC) patients who received radiotherapy (RT) using functional magnetic resonance imaging (fMRI) and statistic scale.The fMRI data of 35 NPC patients with RT and 24 demographically matched untreated NPC patients were acquired. Montreal Cognitive Assessment (MoCA) was also measured to evaluate their global cognition performance. Multivariate pattern analysis was performed to find the significantly altered functional connections between these 2 groups, while the linear correlation level was detected between the altered functional connections and the MoCA scores.Forty-five notably altered functional connections were found, which were mainly located between 3 brain networks, the cerebellum, sensorimotor, and cingulo-opercular. With strictly false discovery rate correction, 5 altered functional connections were shown to have significant linear correlations with the MoCA scores, that is, the connections between the vermis and hippocampus, cerebellum lobule VI and dorsolateral prefrontal cortex, precuneus and dorsal frontal cortex, cuneus and middle occipital lobe, and insula and cuneus. Besides, the connectivity between the vermis and hippocampus was also significantly correlated with the attention score, 1 of the 7 subscores of the MoCA.The present study provides new insights into the radiation-induced functional connectivity impairments in NPC patients. The results showed that the RT may induce the cognitive impairments, especially the attention alterations. The 45 altered functional connections, especially the 5 altered functional connections that were significantly correlated to the MoCA scores, may serve as the potential biomarkers of the RT-induced brain functional impairments and provide valuable targets for further functional recovery treatment.

Curcuma treatment prevents cognitive deficit and alteration of neuronal morphology in the limbic system of aging rats.

PubMed

Vidal, Blanca; Vázquez-Roque, Rubén A; Gnecco, Dino; Enríquez, Raúl G; Floran, Benjamin; Díaz, Alfonso; Flores, Gonzalo

2017-03-01

Curcuma is a natural compound that has shown neuroprotective properties, and has been reported to prevent aging and improve memory. While the mechanism(s) underlying these effects are unclear, they may be related to increases in neural plasticity. Morphological changes have been reported in neuronal dendrites in the limbic system in animals and elderly humans with cognitive impairment. In this regard, there is a need to use alternative therapies that delay the onset of morphologies and behavioral characteristics of aging. Therefore, the objective of this study was to evaluate the effect of curcuma on cognitive processes and dendritic morphology of neurons in the prefrontal cortex (PFC), the CA1 and CA3 regions of the dorsal hippocampus, the dentate gyrus, and the basolateral amygdala (BLA) of aged rats. 18-month-old rats were administered curcuma (100 mg/kg) daily for 60 days. After treatment, recognition memory was assessed using the novel object recognition test. Curcuma-treated rats showed a significant increase in the exploration quotient. Dendritic morphology was assessed by Golgi-Cox staining and followed by Sholl analysis. Curcuma-treated rats showed a significant increase in dendritic spine density and dendritic length in pyramidal neurons of the PFC, the CA1 and CA3, and the BLA. The preservation of dendritic morphology was positively correlated with cognitive improvements. Our results suggest that curcuma induces modification of dendritic morphology in the aforementioned regions. These changes may explain how curcuma slows the aging process that has already begun in these animals, preventing deterioration in neuronal morphology of the limbic system and recognition memory. © 2016 Wiley Periodicals, Inc.

Music exposure improves spatial cognition by enhancing the BDNF level of dorsal hippocampal subregions in the developing rats.

PubMed

Xing, Yingshou; Chen, Wenxi; Wang, Yanran; Jing, Wei; Gao, Shan; Guo, Daqing; Xia, Yang; Yao, Dezhong

2016-03-01

Previous research has shown that dorsal hippocampus plays an important role in spatial memory process. Music exposure can enhance brain-derived neurotrophic factor (BDNF) expression level in dorsal hippocampus (DH) and thus enhance spatial cognition ability. But whether music experience may affect different subregions of DH in the same degree remains unclear. Here, we studied the effects of exposure to Mozart K.448 on learning behavior in developing rats using the classical Morris water maze task. The results showed that early music exposure could enhance significantly learning performance of the rats in the water maze test. Meanwhile, the BDNF/TrkB level of dorsal hippocampus CA3 (dCA3) and dentate gyrus (dDG) was significantly enhanced in rats exposed to Mozart music as compared to those without music exposure. In contrast, the BDNF/TrkB level of dorsal hippocampus CA1 (dCA1) was not affected. The results suggest that the spatial memory improvement by music exposure in rats may be associated with the enhanced BDNF/TrkB level of dCA3 and dDG. Copyright © 2016 Elsevier Inc. All rights reserved.

Chinese-Language Montreal Cognitive Assessment for Cantonese or Mandarin Speakers: Age, Education, and Gender Effects

PubMed Central

Zheng, Ling; Teng, Evelyn L.; Varma, Rohit; Mack, Wendy J.; Mungas, Dan; Lu, Po H.; Chui, Helena C.

2012-01-01

The Montreal Cognitive Assessment Chinese-Language Los Angeles version (MoCA-ChLA) was developed and administered during an in-home interview to 1,192 participants (mean age 62.5 years, mean education 11.6 years) in a population-based Chinese American Eye Study (CHES) in Los Angeles. The MoCA-ChLA score (mean ± SD) was 23.8 ± 4.2 with little ceiling and no floor effects. The score increased with higher education, decreased with advancing age, and was not related to gender. Compared to the education 1–6 years group, the mean MoCA-ChLA score was 2.6 and 4.6 higher in the education 7–11 and 12–20 years groups, respectively. The Mandarin- (n = 612) and Cantonese- (n = 612) speaking subgroups performed comparably; Cronbach's alpha of the MoCA-ChLA score was 0.78 and 0.79 for these two groups, respectively. Item response theory analysis showed good discriminating power for executive function and memory. These properties support the MoCA-ChLA as a useful screening tool for aging and dementia studies for Mandarin or Cantonese speakers. PMID:22830073

Smartkuber: A Serious Game for Cognitive Health Screening of Elderly Players.

PubMed

Boletsis, Costas; McCallum, Simon

2016-08-01

The goal of this study was to design and develop a serious game for cognitive health screening of the elderly, namely Smartkuber, and evaluate its construct, criteria (concurrent and predictive), and content validity, assessing its relationship with the Montreal Cognitive Assessment (MoCA) test. Furthermore, the study aims to evaluate the elderly players' game experience with Smartkuber. Thirteen older adults were enrolled in the study. The game was designed and developed by a multidisciplinary team. The study follows a mixed methodological approach, utilizing the In-Game Experience Questionnaire to assess the players' game experience and a correlational study, to examine the relationship between the Smartkuber and MoCA scores. The learning effect is also examined by comparing the mean game scores of the first and last game sessions of each player (Delta scores). All 13 participants (mean age: 68.69, SD: 7.24) successfully completed the study. Smartkuber demonstrated high concurrent validity with the MoCA test (r = 0.81, P = 0.001) and satisfying levels of predictive and content validity. The Delta scores showed no statistically significant differences in scoring, thus indicating no learning effects during the Smartkuber game sessions. The study shows that Smartkuber is a promising tool for cognitive health screening, providing an entertaining and motivating gaming experience to elderly players. Limitations of the study and future directions are discussed.

Increase of glucocorticoid receptor expression after environmental enrichment: relations to spatial memory, exploration and anxiety-related behaviors.

PubMed

Sampedro-Piquero, P; Begega, A; Arias, J L

2014-04-22

Environmental enrichment (EE) produces a remarkable degree of structural and functional plasticity in the hippocampus and possible mediators of these changes, such as glucocorticoid receptors (GRs), are of considerable interest. GRs are richly expressed in the hippocampus and they are involved in the adaptation to stressors and facilitate active coping in anxious situations. In this study, we assessed the effect of an EE protocol (24h/day during 69days) in adult Wistar rats on the activity in the elevated-zero maze (EZM), performance in the holeboard task (HB) and we also examined the changes in the glucocorticoid receptors (GRs) expression in the dorsal hippocampus (CA1, CA3 and DG). Our EE protocol reduced anxious behaviors in the EZM, so the animals spent more time and made more entries into the open sections. In the HB task, the enriched group showed more explorative behavior, a reduction of anxiety-related behaviors and a better cognitive performance compared to non-enriched animals. With regard to the GR expression, the EE condition produced an increase in the number of immunopositive cells for GRs in CA1, CA3 and DG. These results suggest that the better performance of enriched animals could be mediated in part by the increase of GRs in the dorsal hippocampus, which may alter the hippocampal neuronal function and accordingly, the anxiety levels, the spatial memory performance and the exploration levels in these animals. Copyright © 2014 Elsevier Inc. All rights reserved.

Montreal Cognitive Assessment: One Cutoff Never Fits All.

PubMed

Wong, Adrian; Law, Lorraine S N; Liu, Wenyan; Wang, Zhaolu; Lo, Eugene S K; Lau, Alexander; Wong, Lawrence K S; Mok, Vincent C T

2015-12-01

The objective of this study is to examine the discrepancy between single versus age and education corrected cutoff scores in classifying performance on the Montreal Cognitive Assessment (MoCA) in patients with stroke or transient ischemic attack. MoCA norms were collected from 794 functionally independent and stroke- and dementia-free persons aged ≥65 years. magnetic resonance imaging was used to exclude healthy controls with significant brain pathology and medial temporal lobe atrophy. Cutoff scores at 16th, 7th, and 2nd percentiles by age and education were derived for the MoCA and MoCA 5-minute Protocol. MoCA performance in 919 patients with stroke or transient ischemic attack was classified using the single and norm-derived cutoff scores. The norms for the Hong Kong version of the MoCA total and domain scores and the total score of the MoCA 5-minute protocol are described. Only 65.1% and 25.7% healthy controls and 45.2% and 19.0% patients scored above the conventional cutoff scores of 21/22 and 25/26 on the MoCA. Using classification with norm-derived cutoff scores as reference, locally derived cutoff score of 21/22 yielded a classification discrepancy of ≤42.4%. Discrepancy increased with higher age and lower education level, with the majority being false positives by single cutoffs. With the 25/26 cutoff of the original MoCA, discrepancy further increased to ≤74.3%. Conventional single cutoff scores are associated with substantially high rates of misclassification especially in older and less-educated patients with stroke. These results caution against the use of one-size-fits-all cutoffs on the MoCA. © 2015 American Heart Association, Inc.

The effects of an extensive exercise programme on the progression of Mild Cognitive Impairment (MCI): study protocol for a randomised controlled trial.

PubMed

Devenney, Kate E; Sanders, Marit L; Lawlor, Brian; Olde Rikkert, Marcel G M; Schneider, Stefan

2017-03-22

Exercise interventions to prevent dementia and delay cognitive decline have gained considerable attention in recent years. Human and animal studies have demonstrated that regular physical activity targets brain function by increasing cognitive reserve. There is also evidence of structural changes caused by exercise in preventing or delaying the genesis of neurodegeneration. Although initial studies indicate enhanced cognitive performance in patients with mild cognitive impairment (MCI) following an exercise intervention, little is known about the effect of an extensive, controlled and regular exercise regimen on the neuropathology of patients with MCI. This study aims to determine the effects of an extensive exercise programme on the progression of MCI. This randomised controlled clinical intervention study will take place across three European sites. Seventy-five previously sedentary patients with a clinical diagnosis of MCI will be recruited at each site. Participants will be randomised to one of three groups. One group will receive a standardised 1-year extensive aerobic exercise intervention (3 units of 45 min/week). The second group will complete stretching and toning (non-aerobic) exercise (3 units of 45 min/week) and the third group will act as the control group. Change in all outcomes will be measured at baseline (T0), after six months (T1) and after 12 months (T2). The primary outcome, cognitive performance, will be determined by a neuropsychological test battery (CogState battery, Trail Making Test and Verbal fluency). Secondary outcomes include Montreal Cognitive Assessment (MoCA), cardiovascular fitness, physical activity, structural changes of the brain, quality of life measures and measures of frailty. Furthermore, outcome variables will be related to genetic variations on genes related to neurogenesis and epigenetic changes in these genes caused by the exercise intervention programme. The results will add new insights into the prevailing notion that exercise may slow the rate of cognitive decline in MCI. ClinicalTrials.gov NCT02913053.

Validity of a novel computerized screening test system for mild cognitive impairment.

PubMed

Park, Jin-Hyuck; Jung, Minye; Kim, Jongbae; Park, Hae Yean; Kim, Jung-Ran; Park, Ji-Hyuk

2018-06-20

ABSTRACTBackground:The mobile screening test system for screening mild cognitive impairment (mSTS-MCI) was developed for clinical use. However, the clinical usefulness of mSTS-MCI to detect elderly with MCI from those who are cognitively healthy has yet to be validated. Moreover, the comparability between this system and traditional screening tests for MCI has not been evaluated. The purpose of this study was to examine the validity and reliability of the mSTS-MCI and confirm the cut-off scores to detect MCI. The data were collected from 107 healthy elderly people and 74 elderly people with MCI. Concurrent validity was examined using the Korean version of Montreal Cognitive Assessment (MoCA-K) as a gold standard test, and test-retest reliability was investigated using 30 of the study participants at four-week intervals. The sensitivity, specificity, positive predictive value, and negative predictive value (NPV) were confirmed through Receiver Operating Characteristic (ROC) analysis, and the cut-off scores for elderly people with MCI were identified. Concurrent validity showed statistically significant correlations between the mSTS-MCI and MoCA-K and test-rests reliability indicated high correlation. As a result of screening predictability, the mSTS-MCI had a higher NPV than the MoCA-K. The mSTS-MCI was identified as a system with a high degree of validity and reliability. In addition, the mSTS-MCI showed high screening predictability, indicating it can be used in the clinical field as a screening test system for mild cognitive impairment.

Dysregulation of mTOR signaling in fragile X syndrome.

PubMed

Sharma, Ali; Hoeffer, Charles A; Takayasu, Yukihiro; Miyawaki, Takahiro; McBride, Sean M; Klann, Eric; Zukin, R Suzanne

2010-01-13

Fragile X syndrome, the most common form of inherited mental retardation and leading genetic cause of autism, is caused by transcriptional silencing of the Fmr1 gene. The fragile X mental retardation protein (FMRP), the gene product of Fmr1, is an RNA binding protein that negatively regulates translation in neurons. The Fmr1 knock-out mouse, a model of fragile X syndrome, exhibits cognitive deficits and exaggerated metabotropic glutamate receptor (mGluR)-dependent long-term depression at CA1 synapses. However, the molecular mechanisms that link loss of function of FMRP to aberrant synaptic plasticity remain unclear. The mammalian target of rapamycin (mTOR) signaling cascade controls initiation of cap-dependent translation and is under control of mGluRs. Here we show that mTOR phosphorylation and activity are elevated in hippocampus of juvenile Fmr1 knock-out mice by four functional readouts: (1) association of mTOR with regulatory associated protein of mTOR; (2) mTOR kinase activity; (3) phosphorylation of mTOR downstream targets S6 kinase and 4E-binding protein; and (4) formation of eukaryotic initiation factor complex 4F, a critical first step in cap-dependent translation. Consistent with this, mGluR long-term depression at CA1 synapses of FMRP-deficient mice is exaggerated and rapamycin insensitive. We further show that the p110 subunit of the upstream kinase phosphatidylinositol 3-kinase (PI3K) and its upstream activator PI3K enhancer PIKE, predicted targets of FMRP, are upregulated in knock-out mice. Elevated mTOR signaling may provide a functional link between overactivation of group I mGluRs and aberrant synaptic plasticity in the fragile X mouse, mechanisms relevant to impaired cognition in fragile X syndrome.

Xuefu zhuyu decoction improves cognitive impairment in experimental traumatic brain injury via synaptic regulation

PubMed Central

Zhou, Jing; Liu, Tao; Cui, Hanjin; Fan, Rong; Zhang, Chunhu; Peng, Weijun; Yang, Ali; Zhu, Lin; Wang, Yang; Tang, Tao

2017-01-01

An overarching consequence of traumatic brain injury (TBI) is the cognitive impairment. It may hinder individual performance of daily tasks and determine people's subjective well-being. The damage to synaptic plasticity, one of the key mechanisms of cognitive dysfunction, becomes the potential therapeutic strategy of TBI. In this study, we aimed to investigate whether Xuefu Zhuyu Decoction (XFZYD), a traditional Chinese medicine, provided a synaptic regulation to improve cognitive disorder following TBI. Morris water maze and modified neurological severity scores were performed to assess the neurological and cognitive abilities. The PubChem Compound IDs of the major compounds of XFZYD were submitted into BATMAN-TCM, an online bioinformatics analysis tool, to predict the druggable targets related to synaptic function. Furthermore, we validated the prediction through immunohistochemical, RT-PCR and western blot analyses. We found that XFZYD enhanced neuroprotection, simultaneously improved learning and memory performances in controlled cortical impact rats. Bioinformatics analysis revealed that the improvements of XFZYD implied the Long-term potentiation relative proteins including NMDAR1, CaMKII and GAP-43. The further confirmation of molecular biological studies confirmed that XFZYD upregulated the mRNA and protein levels of NMDAR1, CaMKII and GAP-43. Pharmacological synaptic regulation of XFZYD could provide a novel therapeutic strategy for cognitive impairment following TBI. PMID:29069769

Impact of hypertension severity on arterial stiffness, cerebral vasoreactivity, and cognitive performance

PubMed Central

Muela, Henrique Cotchi Simbo; Costa-Hong, Valeria A.; Yassuda, Monica Sanches; Machado, Michel Ferreira; Nogueira, Ricardo de Carvalho; Moraes, Natalia C.; Memória, Claudia Maia; Macedo, Thiago A.; Bor-Seng-Shu, Edson; Massaro, Ayrton Roberto; Nitrini, Ricardo; Bortolotto, Luiz A.

2017-01-01

ABSTRACT. Aging, hypertension (HTN), and other cardiovascular risk factors contribute to structural and functional changes of the arterial wall. Objective: To evaluate whether arterial stiffness (AS) is related to cerebral blood flow changes and its association with cognitive function in patients with hypertension. Methods: 211 patients (69 normotensive and 142 hypertensive) were included. Patients with hypertension were divided into 2 stages: HTN stage-1 and HTN stage-2. The mini-mental state examination (MMSE), Montreal Cognitive Assessment (MoCA) and a battery of neuropsychological (NPE) tests were used to determine cognitive function. Pulse wave velocity was measured using the Complior®. Carotid properties were assessed by radiofrequency ultrasound. Central arterial pressure and augmentation index were obtained using applanation tonometry. Middle cerebral artery flow velocity was measured by transcranial Doppler ultrasonography. Results: Both arterial stiffness parameters and cerebral vasoreactivity worsened in line with HTN severity. There was a negative correlation between breath holding index (BHI) and arterial stiffness parameters. Cognitive performance worsened in line with HTN severity, with statistical difference occurring mainly between the HTN-2 and normotension groups on both the MMSE and MoCA. The same tendency was observed on the NPE tests. Conclusion: Hypertension severity was associated with higher AS, worse BHI, and lower cognitive performance. PMID:29354219

An eye-tracking controlled neuropsychological battery for cognitive assessment in neurological diseases.

PubMed

Poletti, Barbara; Carelli, Laura; Solca, Federica; Lafronza, Annalisa; Pedroli, Elisa; Faini, Andrea; Zago, Stefano; Ticozzi, Nicola; Ciammola, Andrea; Morelli, Claudia; Meriggi, Paolo; Cipresso, Pietro; Lulé, Dorothée; Ludolph, Albert C; Riva, Giuseppe; Silani, Vincenzo

2017-04-01

Traditional cognitive assessment in neurological conditions involving physical disability is often prevented by the presence of verbal-motor impairment; to date, an extensive motor-verbal-free neuropsychological battery is not available for such purposes. We adapted a set of neuropsychological tests, assessing language, attentional abilities, executive functions and social cognition, for eye-tracking (ET) control, and explored its feasibility in a sample of healthy participants. Thirty healthy subjects performed a neuropsychological assessment, using an ET-based neuropsychological battery, together with standard "paper and pencil" cognitive measures for frontal (Frontal Assessment Battery-FAB) and working memory abilities (Digit Sequencing Task) and for global cognitive efficiency (Montreal Cognitive Assessment-MoCA). Psychological measures of anxiety (State-Trait Anxiety Inventory-Y-STAI-Y) and depression (Beck Depression Inventory-BDI) were also collected, and a usability questionnaire was administered. Significant correlations were observed between the "paper and pencil" screening of working memory abilities and the ET-based neuropsychological measures. The ET-based battery also correlated with the MoCA, while poor correlations were observed with the FAB. Usability aspects were found to be influenced by both working memory abilities and psychological components. The ET-based neuropsychological battery developed could provide an extensive assessment of cognitive functions, allowing participants to perform tasks independently from the integrity of motor or verbal channels. Further studies will be aimed at investigating validity and usability components in neurological populations with motor-verbal impairments.

Feasibility of a Preventive Parenting Intervention for Very Preterm Children at 18 Months Corrected Age: A Randomized Pilot Trial.

PubMed

Flierman, Monique; Koldewijn, Karen; Meijssen, Dominique; van Wassenaer-Leemhuis, Aleid; Aarnoudse-Moens, Cornelieke; van Schie, Petra; Jeukens-Visser, Martine

2016-09-01

To evaluate the feasibility and potential efficacy of an age-appropriate additional parenting intervention for very preterm born toddlers. In a randomized controlled pilot study, 60 of 94 eligible very preterm born children who had received a responsive parenting intervention in their first year were randomized to usual care or the additional intervention, consisting of 4-6 home visits between 18 and 22 months' corrected gestational age (CA). Parents were supported to responsively interact during increasingly complex daily activities and play. Parental satisfaction with the intervention was evaluated with a questionnaire. At baseline and 24 months CA, parents completed the Infant Toddler Social and Emotional Assessment, the Ages and Stages Questionnaire, and the Dutch Schlichting Lexilist for receptive language. At 24 months CA, motor, and cognitive development was measured by the Bayley Scales of Infant and Toddler Development, Third Edition Dutch version, and parent-child interaction was evaluated by the Emotional Availability Scales. Parental compliance and satisfaction with the intervention was high. Effect sizes (after correction for baseline variables) were small for internalizing and competence behavior, receptive language, and problem solving; medium for cognitive development and parent-child interaction; and large for externalizing and dysregulation behavior and motor development. After a postdischarge intervention during the first year, an additional responsive parenting support at toddler-age is feasible and associated with positive outcomes in a broad array of parental and child outcome measures. www.toetsingonline.nl: NL40208.018.12. Copyright © 2016 Elsevier Inc. All rights reserved.

Effects of Sleep Deprivation on the Cognitive Performance of Nurses Working in Shift.

PubMed

Kaliyaperumal, Deepalakshmi; Elango, Yaal; Alagesan, Murali; Santhanakrishanan, Iswarya

2017-08-01

Sleep deprivation and altered circadian rhythm affects the cognitive performance of an individual. Quality of sleep is compromised in those who are frequently involved in extended working hours and shift work which is found to be more common among nurses. Cognitive impairment leads to fatigability, decline in attention and efficiency in their workplace which puts their health and patients' health at risk. To find out the prevalence of sleep deprivation and its impact on cognition among shift working nurses. Sleep deprivation among 97 female and three male healthy nurses of age 20-50 years was assessed by Epworth sleepiness scale (ESS). Cognition was assessed by Montreal Cognitive Assessment (MoCA) questionnaire. Mobile applications were used to test their vigilance, reaction time, photographic memory and numerical cognition. The above said parameters were assessed during end of day shift and 3-4 days after start of night shift. Poor sleep quality was observed among 69% of shift working nurses according to ESS scores. The cognitive performance was analysed using Wilcoxon signed rank test. The MoCA score was found to be lesser among 66% of nurses during night (25.72) than day (26.81). During the night, 32% made more mathematical errors. It was also found that, 71%, 83% and 68% of the nurses scored lesser during night in the Stroop's colour test, vigilance test and memory tests respectively. Thus, impairment in cognitive performance was statistically significant (p<0.001) among shift working nurses. Cognitive performance was found to be impaired among shift working nurses, due to poor sleep quality and decreased alertness during wake state. Thus, shift work poses significant cognitive risks in work performance of nurses.

Leptin-induced spine formation requires TrpC channels and the CaM kinase cascade in the hippocampus.

PubMed

Dhar, Matasha; Wayman, Gary A; Zhu, Mingyan; Lambert, Talley J; Davare, Monika A; Appleyard, Suzanne M

2014-07-23

Leptin is a critical neurotrophic factor for the development of neuronal pathways and synaptogenesis in the hypothalamus. Leptin receptors are also found in other brain regions, including the hippocampus, and a postnatal surge in leptin correlates with a time of rapid growth of dendritic spines and synapses in the hippocampus. Leptin is critical for normal hippocampal dendritic spine formation as db/db mice, which lack normal leptin receptor signaling, have a reduced number of dendritic spines in vivo. Leptin also positively influences hippocampal behaviors, such as cognition, anxiety, and depression, which are critically dependent on dendritic spine number. What is not known are the signaling mechanisms by which leptin initiates spine formation. Here we show leptin induces the formation of dendritic protrusions (thin headless, stubby and mushroom shaped spines), through trafficking and activation of TrpC channels in cultured hippocampal neurons. Leptin-activation of the TrpC current is dose dependent and blocked by targeted knockdown of the leptin receptor. The nonselective TrpC channel inhibitors SKF96365 and 2-APB or targeted knockdown of TrpC1 or 3, but not TrpC5, channels also eliminate the leptin-induced current. Leptin stimulates the phosphorylation of CaMKIγ and β-Pix within 5 min and their activation is required for leptin-induced trafficking of TrpC1 subunits to the membrane. Furthermore, we show that CaMKIγ, CaMKK, β-Pix, Rac1, and TrpC1/3 channels are all required for both the leptin-sensitive current and leptin-induced spine formation. These results elucidate a critical pathway underlying leptin's induction of dendritic morphological changes that initiate spine and excitatory synapse formation. Copyright © 2014 the authors 0270-6474/14/3410022-12$15.00/0.

Novel nootropic drug sunifiram enhances hippocampal synaptic efficacy via glycine-binding site of N-methyl-D-aspartate receptor.

PubMed

Moriguchi, Shigeki; Tanaka, Tomoya; Narahashi, Toshio; Fukunaga, Kohji

2013-10-01

Sunifiram is a novel pyrrolidone nootropic drug structurally related to piracetam, which was developed for neurodegenerative disorder like Alzheimer's disease. Sunifiram is known to enhance cognitive function in some behavioral experiments such as Morris water maze task. To address question whether sunifiram affects N-methyl-D-aspartate receptor (NMDAR)-dependent synaptic function in the hippocampal CA1 region, we assessed the effects of sunifiram on NMDAR-dependent long-term potentiation (LTP) by electrophysiology and on phosphorylation of synaptic proteins by immunoblotting analysis. In mouse hippocampal slices, sunifiram at 10-100 nM significantly enhanced LTP in a bell-shaped dose-response relationship which peaked at 10 nM. The enhancement of LTP by sunifiram treatment was inhibited by 7-chloro-kynurenic acid (7-ClKN), an antagonist for glycine-binding site of NMDAR, but not by ifenprodil, an inhibitor for polyamine site of NMDAR. The enhancement of LTP by sunifilam was associated with an increase in phosphorylation of α-amino-3-hydroxy-5-methylisozazole-4-propionate receptor (AMPAR) through activation of calcium/calmodulin-dependent protein kinase II (CaMKII) and an increase in phosphorylation of NMDAR through activation of protein kinase Cα (PKCα). Sunifiram treatments at 1-1000 nM increased the slope of field excitatory postsynaptic potentials (fEPSPs) in a dose-dependent manner. The enhancement was associated with an increase in phosphorylation of AMPAR receptor through activation of CaMKII. Interestingly, under the basal condition, sunifiram treatments increased PKCα (Ser-657) and Src family (Tyr-416) activities with the same bell-shaped dose-response curve as that of LTP peaking at 10 nM. The increase in phosphorylation of PKCα (Ser-657) and Src (Tyr-416) induced by sunifiram was inhibited by 7-ClKN treatment. The LTP enhancement by sunifiram was significantly inhibited by PP2, a Src family inhibitor. Finally, when pretreated with a high concentration of glycine (300 μM), sunifiram treatments failed to potentiate LTP in the CA1 region. Taken together, sunifiram stimulates the glycine-binding site of NMDAR with concomitant PKCα activation through Src kinase. Enhancement of PKCα activity triggers to potentiate hippocampal LTP through CaMKII activation. Copyright © 2013 Wiley Periodicals, Inc.

Chronic Fluoxetine Induces Activity Changes in Recovery From Poststroke Anxiety, Depression, and Cognitive Impairment.

PubMed

Vahid-Ansari, Faranak; Albert, Paul R

2018-01-01

Poststroke depression (PSD) is a common outcome of stroke that limits recovery and is only partially responsive to chronic antidepressant treatment. In order to elucidate changes in the cortical-limbic circuitry associated with PSD and its treatment, we examined a novel mouse model of persistent PSD. Focal endothelin-1-induced ischemia of the left medial prefrontal cortex (mPFC) in male C57BL6 mice resulted in a chronic anxiety and depression phenotype. Here, we show severe cognitive impairment in spatial learning and memory in the stroke mice. The behavioral and cognitive phenotypes were reversed by chronic (4-week) treatment with fluoxetine, alone or with voluntary exercise (free-running wheel), but not by exercise alone. To assess chronic cellular activation, FosB + cells were co-labeled for markers of glutamate/pyramidal (VGluT1-3/CaMKIIα), γ-aminobutyric acid (GAD67), and serotonin (TPH). At 6 weeks poststroke versus sham (or 4 days poststroke), left mPFC stroke induced widespread FosB activation, more on the right (contralesional) than on the left side. Stroke activated glutamate cells of the mPFC, nucleus accumbens, amygdala, hippocampus, and raphe serotonin neurons. Chronic fluoxetine balanced bilateral neuronal activity, reducing total FosB and FosB/CamKII + cells (mPFC, nucleus accumbens), and unlike exercise, increasing FosB/GAD67 + cells (septum, amygdala) or both (hippocampus, raphe). In summary, chronic antidepressant but not exercise mediates recovery in this unilateral ischemic PSD model that is associated with region-specific reversal of stroke-induced pyramidal cell hyperactivity and increase in γ-aminobutyric acidergic activity. Targeted brain stimulation to restore brain activity could provide a rational approach for treating clinical PSD.

Hippocampal Ghrelin-positive neurons directly project to arcuate hypothalamic and medial amygdaloid nuclei. Could they modulate food-intake?

PubMed

Russo, Cristina; Russo, Antonella; Pellitteri, Rosalia; Stanzani, Stefania

2017-07-13

Feeding is a process controlled by a complex of associations between external and internal stimuli. The processes that involve learning and memory seem to exert a strong control over appetite and food intake, which is modulated by a gastrointestinal hormone, Ghrelin (Ghre). Recent studies claim that Ghre is involved in cognitive and neurobiological mechanisms that underlie the conditioning of eating behaviors. The expression of Ghre increases in anticipation of food intake based on learned behaviors. The hippocampal Ghre-containing neurons neurologically influence the orexigenic hypothalamus and consequently the learned feeding behavior. The CA1 field of Ammon's horn of the hippocampus (H-CA1) constitutes the most important neural substrate to control both appetitive and ingestive behavior. It also innervates amygdala regions that in turn innervate the hypothalamus. A recent study also implies that Ghre effects on cue-potentiated feeding behavior occur, at the least, via indirect action on the amygdala. In the present study, we investigate the neural substrates through which endogenous Ghre communicates conditioned appetite and feeding behavior within the CNS. We show the existence of a neural Ghre dependent pathway whereby peripherally-derived Ghre activates H-CA1 neurons, which in turn activate Ghre-expressing hypothalamic and amygdaloid neurons to stimulate appetite and feeding behavior. To highlight this pathway, we use two fluorescent retrograde tracers (Fluoro Gold and Dil) and immunohistochemical detection of Ghre expression in the hippocampus. Triple fluorescent-labeling has determined the presence of H-CA1 Ghre-containing collateralized neurons that project to the hypothalamus and amygdala monosynaptically. We hypothesize that H-Ghre-containing neurons in H-CA1 modulate food-intake behavior through direct pathways to the arcuate hypothalamic nucleus and medial amygdaloid nucleus. Copyright © 2017 Elsevier B.V. All rights reserved.

Dentate granule cell recruitment of feedforward inhibition governs engram maintenance and remote memory generalization.

PubMed

Guo, Nannan; Soden, Marta E; Herber, Charlotte; Kim, Michael TaeWoo; Besnard, Antoine; Lin, Paoyan; Ma, Xiang; Cepko, Constance L; Zweifel, Larry S; Sahay, Amar

2018-05-01

Memories become less precise and generalized over time as memory traces reorganize in hippocampal-cortical networks. Increased time-dependent loss of memory precision is characterized by an overgeneralization of fear in individuals with post-traumatic stress disorder (PTSD) or age-related cognitive impairments. In the hippocampal dentate gyrus (DG), memories are thought to be encoded by so-called 'engram-bearing' dentate granule cells (eDGCs). Here we show, using rodents, that contextual fear conditioning increases connectivity between eDGCs and inhibitory interneurons (INs) in the downstream hippocampal CA3 region. We identify actin-binding LIM protein 3 (ABLIM3) as a mossy-fiber-terminal-localized cytoskeletal factor whose levels decrease after learning. Downregulation of ABLIM3 expression in DGCs was sufficient to increase connectivity with CA3 stratum lucidum INs (SLINs), promote parvalbumin (PV)-expressing SLIN activation, enhance feedforward inhibition onto CA3 and maintain a fear memory engram in the DG over time. Furthermore, downregulation of ABLIM3 expression in DGCs conferred conditioned context-specific reactivation of memory traces in hippocampal-cortical and amygdalar networks and decreased fear memory generalization at remote (i.e., distal) time points. Consistent with the observation of age-related hyperactivity of CA3, learning failed to increase DGC-SLIN connectivity in 17-month-old mice, whereas downregulation of ABLIM3 expression was sufficient to restore DGC-SLIN connectivity, increase PV+ SLIN activation and improve the precision of remote memories. These studies exemplify a connectivity-based strategy that targets a molecular brake of feedforward inhibition in DG-CA3 and may be harnessed to decrease time-dependent memory generalization in individuals with PTSD and improve memory precision in aging individuals.

Atherosclerosis in epilepsy: its causes and implications.

PubMed

Hamed, Sherifa A

2014-12-01

Evidence from epidemiological, longitudinal, prospective, double-blinded clinical trials as well as case reports documents age-accelerated atherosclerosis with increased carotid artery intima media thickness (CA-IMT) in patients with epilepsy. These findings raise concern regarding their implications for age-accelerated cognitive and behavioral changes in midlife and risk of later age-related cognitive disorders including neurodegenerative processes such as Alzheimer's disease (AD). Chronic epilepsy, cerebral atherosclerosis, and age-related cognitive disorders including AD share many clinical manifestations (e.g. characteristic cognitive deficits), risk factors, and structural and pathological brain abnormalities. These shared risk factors include increased CA-IMT, hyperhomocysteinemia (HHcy), lipid abnormalities, weight gain and obesity, insulin resistance (IR), and high levels of inflammatory and oxidative stresses. The resulting brain structural and pathological abnormalities include decreased volume of the hippocampus, increased cortical thinning of the frontal lobe, ventricular expansion and increased white matter ischemic disease, total brain atrophy, and β-amyloid protein deposition in the brain. The knowledge that age-accelerated atherosclerosis may contribute to age-accelerated cognitive and behavioral abnormalities and structural brain pathologies in patients with chronic epilepsy represents an important research path to pursue future clinical and management considerations. Copyright © 2014 Elsevier Inc. All rights reserved.

Donepezil attenuates hippocampal neuronal damage and cognitive deficits after global cerebral ischemia in gerbils.

PubMed

Min, Dongyu; Mao, Xiaoyuan; Wu, Kuncan; Cao, Yonggang; Guo, Feng; Zhu, Shu; Xie, Ni; Wang, Lei; Chen, Tianbao; Shaw, Chris; Cai, Jiqun

2012-02-21

Decreased cerebral blood flow causes cognitive impairments and neuronal injury in vascular dementia. In the present study, we reported that donepezil, a cholinesterase inhibitor, improved transient global cerebral ischemia-induced spatial memory impairment in gerbils. Treatment with 5mg/kg of donepezil for 21 consecutive days following a 10-min period of ischemia significantly inhibited delayed neuronal death in the hippocampal CA1 region. In Morris water maze test, memory impairment was significantly improved by donepezil treatment. Western blot analysis showed that donepezil treatment prevented reductions in p-CaMKII and p-CREB protein levels in the hippocampus. These results suggest that donepezil attenuates the memory deficit induced by transient global cerebral ischemia and this neuroprotection may be associated with the phosphorylation of CaMKII and CERB in the hippocampus. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Loss of Functional A-Type Potassium Channels in the Dendrites of CA1 Pyramidal Neurons from a Mouse Model of Fragile X Syndrome

PubMed Central

Routh, Brandy N.; Johnston, Daniel

2013-01-01

Despite the critical importance of voltage-gated ion channels in neurons, very little is known about their functional properties in Fragile X syndrome: the most common form of inherited cognitive impairment. Using three complementary approaches, we investigated the physiological role of A-type K+ currents (IKA) in hippocampal CA1 pyramidal neurons from fmr1-/y mice. Direct measurement of IKA using cell-attached patch-clamp recordings revealed that there was significantly less IKA in the dendrites of CA1 neurons from fmr1-/y mice. Interestingly, the midpoint of activation for A-type K+ channels was hyperpolarized for fmr1-/y neurons compared with wild-type, which might partially compensate for the lower current density. Because of the rapid time course for recovery from steady-state inactivation, the dendritic A-type K+ current in CA1 neurons from both wild-type and fmr1-/y mice is likely mediated by KV4 containing channels. The net effect of the differences in IKA was that back-propagating action potentials had larger amplitudes producing greater calcium influx in the distal dendrites of fmr1-/y neurons. Furthermore, CA1 pyramidal neurons from fmr1-/y mice had a lower threshold for LTP induction. These data suggest that loss of IKA in hippocampal neurons may contribute to dendritic pathophysiology in Fragile X syndrome. PMID:24336711

[Use of cholinomimetics in the treatment of endogenous autism in children].

PubMed

Krasnoperova, M G; Simashkova, N V; Bashina, V M

2004-01-01

Twenty children with endogenous autism of mild and moderate severity (30-44.5 scores according to the CARS), aged 3-8 years, were treated with choline alfoscerate (CA), 400 mg/day, during 8 weeks in the presence of maintenance therapy with neuroleptics (17 cases). Positive therapeutic effect was observed in 89% of the patients: significant improvement--in 61% and minimal efficacy--in 28%. Statistically significant positive changes in the patient's state were observed in the general improvement of behavior (p<0.001), development of social and communicative skills, as well as self-service, reduction of marked speech disturbances (p<0.001) and motor sphere (p<0.001), enhancement of learning activity and productivity (p<0.05). Good tolerability to the therapy, without patient's state worsening was registered. Some patients exhibited strengthening of affective lability in the first weeks of the treatment which attenuated to the 4th week as the CA dosages decreased to 400 mg every other day. CA may be recommended for combined therapy with neuroleptics as an effective and safe medicine for the treatment of cognitive and behavioral disorders in patients with children's autism.

Potential contribution of the neurodegenerative disorders risk loci to cognitive performance in an elderly male gout population

PubMed Central

Han, Lin; Jia, Zhaotong; Cao, Chunwei; Liu, Zhen; Liu, Fuqiang; Wang, Lin; Ren, Wei; Sun, Mingxia; Wang, Baoping; Li, Changgui; Chen, Li

2017-01-01

Abstract Cognitive impairment has been described in elderly subjects with high normal concentrations of serum uric acid. However, it remains unclear if gout confers an increased poorer cognition than those in individuals with asymptomatic hyperuricemia. The present study aimed at evaluating cognitive function in patients suffering from gout in an elderly male population, and further investigating the genetic contributions to the risk of cognitive function. This study examined the cognitive function as assessed by Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) in 205 male gout patients and 204 controls. The genetic basis of these cognitive measures was evaluated by genome-wide association study (GWAS) data in 102 male gout patients. Furthermore, 7 loci associated with cognition in GWAS were studied for correlation with gout in 1179 male gout patients and 1848 healthy male controls. Compared with controls, gout patients had significantly lower MoCA scores [22.78 ± 3.01 vs 23.42 ± 2.95, P = .023, adjusted by age, body mass index (BMI), education, and emotional disorder]. GWAS revealed 7 single-nucleotide polymorphisms (SNPs) associations with MoCA test at a level of conventional genome-wide significance (P < 9.6 × 10–8). The most significant association was observed between rs12895072 and rs12434554 within the KTN1 gene (Padjusted = 4.2 × 10−9, Padjusted = 4.7 × 10–9) at 14q22. The next best signal was in RELN gene (rs155333, Padjusted = 1.3 × 10–8) at 7q22, while the other variants at rs17458357 (Padjusted = 3.98 × 10–8), rs2572683 (Padjusted = 8.9 × 10–8), rs12555895 (Padjusted = 2.6 × 10–8), and rs3764030 (Padjusted = 9.4 × 10–8) were also statistically significant. The 7 SNPs were not associated with gout in further analysis (all P > .05). Elderly male subjects with gout exhibit accelerated decline in cognition performance. Several neurodegenerative disorders risk loci were identified for genetic contributors to cognitive performance in our Chinese elderly male gout population. Larger prospective studies of the cognitive performance and genetic analysis in gout subjects are recommended. PMID:28953682

Association between dietary patterns and cognitive function among 70-year-old Japanese elderly: a cross-sectional analysis of the SONIC study.

PubMed

Okubo, Hitomi; Inagaki, Hiroki; Gondo, Yasuyuki; Kamide, Kei; Ikebe, Kazunori; Masui, Yukie; Arai, Yasumichi; Ishizaki, Tatsuro; Sasaki, Satoshi; Nakagawa, Takeshi; Kabayama, Mai; Sugimoto, Ken; Rakugi, Hiromi; Maeda, Yoshinobu

2017-09-11

An increasing number of studies in Western countries have shown that healthy dietary patterns may have a protective effect against cognitive decline and dementia. However, information on this relationship among non-Western populations with different cultural settings is extremely limited. We aim to examine the relationship between dietary patterns and cognitive function among older Japanese people. This cross-sectional study included 635 community-dwelling people aged 69-71 years who participated in the prospective cohort study titled Septuagenarians, Octogenarians, Nonagenarians Investigation with Centenarians (SONIC). Diet was assessed over a one-month period with a validated, brief-type, self-administered diet history questionnaire. Dietary patterns from thirty-three predefined food groups [energy-adjusted food (g/d)] were extracted by factor analysis. Cognitive function was assessed using the Japanese version of the Montreal Cognitive Assessment (MoCA-J). Multivariate regression analysis was performed to examine the relationship between dietary patterns and cognitive function. Three dietary patterns were identified: the 'Plant foods and fish', 'Rice and miso soup', and 'Animal food' patterns. The 'Plant foods and fish' pattern, characterized by high intakes of green and other vegetables, soy products, seaweeds, mushrooms, potatoes, fruit, fish, and green tea, was significantly associated with a higher MoCA-J score [MoCA-J score per one-quartile increase in dietary pattern: β = 0.56 (95% CI: 0.33, 0.79), P for trend <0.001]. This association was still evident after adjustment for potential confounding factors [β = 0.41 (95% CI: 0.17, 0.65), P for trend <0.001]. In contrast, neither the 'Rice and miso soup' nor the 'Animal food' pattern was related to cognitive function. To confirm the possibility of reverse causation we also conducted a sensitivity analysis excluding 186 subjects who reported substantial changes in their diet for any reason, but the results did not change materially. This preliminary cross-sectional study suggests that a diet with high intakes of vegetables, soy products, fruit, and fish may have a beneficial effect on cognitive function in older Japanese people. Further prospective studies are needed to confirm this finding.

Intranasal post-cardiac arrest treatment with orexin-A facilitates arousal from coma and ameliorates neuroinflammation.

PubMed

Modi, Hiren R; Wang, Qihong; Gd, Sahithi; Sherman, David; Greenwald, Elliot; Savonenko, Alena V; Geocadin, Romergryko G; Thakor, Nitish V

2017-01-01

Cardiac arrest (CA) entails significant risks of coma resulting in poor neurological and behavioral outcomes after resuscitation. Significant subsequent morbidity and mortality in post-CA patients are largely due to the cerebral and cardiac dysfunction that accompanies prolonged whole-body ischemia post-CA syndrome (PCAS). PCAS results in strong inflammatory responses including neuroinflammation response leading to poor outcome. Currently, there are no proven neuroprotective therapies to improve post-CA outcomes apart from therapeutic hypothermia. Furthermore, there are no acceptable approaches to promote cortical or cognitive arousal following successful return of spontaneous circulation (ROSC). Hypothalamic orexinergic pathway is responsible for arousal and it is negatively affected by neuroinflammation. However, whether activation of the orexinergic pathway can curtail neuroinflammation is unknown. We hypothesize that targeting the orexinergic pathway via intranasal orexin-A (ORXA) treatment will enhance arousal from coma and decrease the production of proinflammatory cytokines resulting in improved functional outcome after resuscitation. We used a highly validated CA rat model to determine the effects of intranasal ORXA treatment 30-minute post resuscitation. At 4hrs post-CA, the mRNA levels of proinflammatory markers (IL1β, iNOS, TNF-α, GFAP, CD11b) and orexin receptors (ORX1R and ORX2R) were examined in different brain regions. CA dramatically increased proinflammatory markers in all brain regions particularly in the prefrontal cortex, hippocampus and hypothalamus. Post-CA intranasal ORXA treatment significantly ameliorated the CA-induced neuroinflammatory markers in the hypothalamus. ORXA administration increased production of orexin receptors (ORX1R and ORX2R) particularly in hypothalamus. In addition, ORXA also resulted in early arousal as measured by quantitative electroencephalogram (EEG) markers, and recovery of the associated behavioral neurologic deficit scale score (NDS). Our results indicate that intranasal delivery of ORXA post-CA has an anti-inflammatory effect and accelerates cortical EEG and behavioral recovery. Beneficial outcomes from intranasal ORXA treatment lay the groundwork for therapeutic clinical approach to treating post-CA coma.

Radiation-induced functional connectivity alterations in nasopharyngeal carcinoma patients with radiotherapy

PubMed Central

Ma, Qiongmin; Wu, Donglin; Zeng, Ling-Li; Shen, Hui; Hu, Dewen; Qiu, Shijun

2016-01-01

Abstract The study aims to investigate the radiation-induced brain functional alterations in nasopharyngeal carcinoma (NPC) patients who received radiotherapy (RT) using functional magnetic resonance imaging (fMRI) and statistic scale. The fMRI data of 35 NPC patients with RT and 24 demographically matched untreated NPC patients were acquired. Montreal Cognitive Assessment (MoCA) was also measured to evaluate their global cognition performance. Multivariate pattern analysis was performed to find the significantly altered functional connections between these 2 groups, while the linear correlation level was detected between the altered functional connections and the MoCA scores. Forty-five notably altered functional connections were found, which were mainly located between 3 brain networks, the cerebellum, sensorimotor, and cingulo-opercular. With strictly false discovery rate correction, 5 altered functional connections were shown to have significant linear correlations with the MoCA scores, that is, the connections between the vermis and hippocampus, cerebellum lobule VI and dorsolateral prefrontal cortex, precuneus and dorsal frontal cortex, cuneus and middle occipital lobe, and insula and cuneus. Besides, the connectivity between the vermis and hippocampus was also significantly correlated with the attention score, 1 of the 7 subscores of the MoCA. The present study provides new insights into the radiation-induced functional connectivity impairments in NPC patients. The results showed that the RT may induce the cognitive impairments, especially the attention alterations. The 45 altered functional connections, especially the 5 altered functional connections that were significantly correlated to the MoCA scores, may serve as the potential biomarkers of the RT-induced brain functional impairments and provide valuable targets for further functional recovery treatment. PMID:27442663

The Complex Interplay Between Depression/Anxiety and Executive Functioning: Insights From the ECAS in a Large ALS Population

PubMed Central

Solca, Federica; Faini, Andrea; Madotto, Fabiana; Lafronza, Annalisa; Monti, Alessia; Zago, Stefano; Doretti, Alberto; Ciammola, Andrea; Ticozzi, Nicola; Silani, Vincenzo; Poletti, Barbara

2018-01-01

Introduction: The observed association between depressive symptoms and cognitive performances has not been previously clarified in patients with amyotrophic lateral sclerosis (pALS). In fact, the use of cognitive measures often not accommodating for motor disability has led to heterogeneous and not conclusive findings about this issue. The aim of the present study was to evaluate the relationship between cognitive and depressive/anxiety symptoms by means of the recently developed Edinburgh Cognitive and Behavioral ALS Screen (ECAS), a brief assessment specifically designed for pALS. Methods: Sample included 168 pALS (114 males, 54 females); they were administered two standard cognitive screening tools (FAB; MoCA) and the ECAS, assessing different cognitive domains, including ALS-specific (executive functions, verbal fluency, and language tests) and ALS non-specific subtests (memory and visuospatial tests). Two psychological questionnaires for depression and anxiety (BDI; STAI/Y) were also administered to patients. Pearson’s correlation coefficient was used to assess the degree of association between cognitive and psychological measures. Results: Depression assessment negatively correlated with the ECAS, more significantly with regard to the executive functions subdomain. In particular, Sentence Completion and Social Cognition subscores were negatively associated with depression levels measured by BDI total score and Somatic-Performance symptoms subscore. Conversely, no significant correlations were observed between depression level and cognitive functions as measured by traditional screening tools for frontal abilities (FAB) and global cognition (MoCA) assessment. Finally, no significant correlations were observed between state/trait anxiety and the ECAS. Discussion and conclusion: This represents the first study focusing on the relationship between cognitive and psychological components in pALS by means of the ECAS, the current gold standard for ALS cognitive-behavioral assessment. If confirmed by further investigations, the observed association between depression and executive functions suggests the need for a careful screening and treatment of depression, to avoid overestimation of cognitive involvement and possibly improve cognitive performances in ALS. PMID:29674987

Sleep deprivation causes memory deficits by negatively impacting neuronal connectivity in hippocampal area CA1

PubMed Central

Havekes, Robbert; Park, Alan J; Tudor, Jennifer C; Luczak, Vincent G; Hansen, Rolf T; Ferri, Sarah L; Bruinenberg, Vibeke M; Poplawski, Shane G; Day, Jonathan P; Aton, Sara J; Radwańska, Kasia; Meerlo, Peter; Houslay, Miles D; Baillie, George S; Abel, Ted

2016-01-01

Brief periods of sleep loss have long-lasting consequences such as impaired memory consolidation. Structural changes in synaptic connectivity have been proposed as a substrate of memory storage. Here, we examine the impact of brief periods of sleep deprivation on dendritic structure. In mice, we find that five hours of sleep deprivation decreases dendritic spine numbers selectively in hippocampal area CA1 and increased activity of the filamentous actin severing protein cofilin. Recovery sleep normalizes these structural alterations. Suppression of cofilin function prevents spine loss, deficits in hippocampal synaptic plasticity, and impairments in long-term memory caused by sleep deprivation. The elevated cofilin activity is caused by cAMP-degrading phosphodiesterase-4A5 (PDE4A5), which hampers cAMP-PKA-LIMK signaling. Attenuating PDE4A5 function prevents changes in cAMP-PKA-LIMK-cofilin signaling and cognitive deficits associated with sleep deprivation. Our work demonstrates the necessity of an intact cAMP-PDE4-PKA-LIMK-cofilin activation-signaling pathway for sleep deprivation-induced memory disruption and reduction in hippocampal spine density. DOI: http://dx.doi.org/10.7554/eLife.13424.001 PMID:27549340

Ethnicity and cognitive performance among older African Americans, Japanese Americans, and Caucasians: the role of education.

PubMed

Shadlen, M F; Larson, E B; Gibbons, L E; Rice, M M; McCormick, W C; Bowen, J; McCurry, S M; Graves, A B

2001-10-01

This cross-sectional analysis evaluated the association between ethnicity and cognitive performance and determined whether education modifies this association for nondemented older people (103 African Americans, 1,388 Japanese Americans, 2,306 Caucasians) in a study of dementia incidence. African Americans scored lower (median 89 out of 100) than Japanese Americans (93) and Caucasians (94) on the Cognitive Abilities Screening Instrument (CASI). Education affected CA

Mode of Information Delivery Does Not Effect Anesthesia Trainee Performance During Simulated Perioperative Pediatric Critical Events: A Trial of Paper Versus Electronic Cognitive Aids.

PubMed

Watkins, Scott C; Anders, Shilo; Clebone, Anna; Hughes, Elisabeth; Patel, Vikram; Zeigler, Laura; Shi, Yaping; Shotwell, Matthew S; McEvoy, Matthew D; Weinger, Matthew B

2016-12-01

Cognitive aids (CAs), including emergency manuals and checklists, have been recommended as a means to address the failure of healthcare providers to adhere to evidence-based standards of treatment during crisis situations. Unfortunately, users of CAs still commit errors, omit critical steps, fail to achieve perfect adherence to guidelines, and frequently choose to not use CA during both simulated and real crisis events. We sought to evaluate whether the mode in which a CA presents information (ie, paper vs. electronic) affects clinician performance during simulated critical events. In a prospective, randomized, controlled trial, anesthesia trainees managed simulated events under 1 of the following 3 conditions: (1) from memory alone (control), (2) with a paper CA, or (3) with an electronic version of the same CA. Management of the events was assessed using scenario-specific checklists. Mixed-effect regression models were used for analysis of overall checklist score and for elapsed time. One hundred thirty-nine simulated events were observed and rated. Approximately, 1 of 3 trainees assigned to use a CA (electronic 29%, paper 36%) chose not to use it during the scenario. Compared with the control group (52%), the overall score was 6% higher in the paper CA group and 8% higher (95% confidence interval, 0.914.5; P = 0.03) in the electronic CA group. The difference between paper and electronic CA was not significant. There was a wide range in time to first use of the CA, but the time to task completion was not affected by CA use, nor did the time to CA use impact CA effectiveness as measured by performance. The format (paper or electronic) of the CA did not affect the impact of the CA on clinician performance in this study. Clinician compliance with the use of the CA was unaffected by format, suggesting that other factors may determine whether clinicians choose to use a CA or not. Time to use of the CA did not affect clinical performance, suggesting that it may not be when CAs are used but how they are used that determines their impact. The current study highlights the importance of not just familiarizing clinicians with the content of CA but also training clinicians in when and how to use an emergency CA.

Validation of the Conversion between the Mini-Mental State Examination and Montreal Cognitive assessment in Korean Patients with Parkinson’s Disease

PubMed Central

Kim, Ryul; Kim, Han-Joon; Kim, Aryun; Jang, Mi-Hee; Kim, Hyun Jeong; Jeon, Beomseok

2018-01-01

Objective Two conversion tables between the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) have recently been established for Parkinson’s disease (PD). This study aimed to validate them in Korean patients with PD and to evaluate whether they could be influenced by educational level. Methods A total of 391 patients with PD who undertook both the Korean MMSE and the Korean MoCA during the same session were retrospectively assessed. The mean, median, and root mean squared error (RMSE) of the difference between the true and converted MMSE scores and the intraclass correlation coefficient (ICC) were calculated according to educational level (6 or fewer years, 7–12 years, or 13 or more years). Results Both conversions had a median value of 0, with a small mean and RMSE of differences, and a high correlation between the true and converted MMSE scores. In the classification according to educational level, all groups had roughly similar values of the median, mean, RMSE, and ICC both within and between the conversions. Conclusion Our findings suggest that both MMSE-MoCA conversion tables are useful instruments for transforming MoCA scores into converted MMSE scores in Korean patients with PD, regardless of educational level. These will greatly enhance the utility of the existing cognitive data from the Korean PD population in clinical and research settings. PMID:29316782

Social and novel contexts modify hippocampal CA2 representations of space

PubMed Central

Alexander, Georgia M.; Farris, Shannon; Pirone, Jason R.; Zheng, Chenguang; Colgin, Laura L.; Dudek, Serena M.

2016-01-01

The hippocampus supports a cognitive map of space and is critical for encoding declarative memory (who, what, when and where). Recent studies have implicated hippocampal subfield CA2 in social and contextual memory but how it does so remains unknown. Here we find that in adult male rats, presentation of a social stimulus (novel or familiar rat) or a novel object induces global remapping of place fields in CA2 with no effect on neuronal firing rate or immediate early gene expression. This remapping did not occur in CA1, suggesting this effect is specific for CA2. Thus, modification of existing spatial representations might be a potential mechanism by which CA2 encodes social and novel contextual information. PMID:26806606

A novel approach to rapidly prevent age-related cognitive decline

PubMed Central

Adlard, Paul A; Sedjahtera, Amelia; Gunawan, Lydia; Bray, Lisa; Hare, Dominic; Lear, Jessica; Doble, Philip; Bush, Ashley I; Finkelstein, David I; Cherny, Robert A

2014-01-01

The loss of cognitive function is a pervasive and often debilitating feature of the aging process for which there are no effective therapeutics. We hypothesized that a novel metal chaperone (PBT2; Prana Biotechnology, Parkville, Victoria, Australia) would enhance cognition in aged rodents. We show here that PBT2 rapidly improves the performance of aged C57Bl/6 mice in the Morris water maze, concomitant with increases in dendritic spine density, hippocampal neuron number and markers of neurogenesis. There were also increased levels of specific glutamate receptors (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and N-methyl-d-aspartate), the glutamate transporter (VGLUT1) and glutamate itself. Markers of synaptic plasticity [calmodulin-dependent protein kinase II (CaMKII) and phosphorylated CaMKII, CREB, synaptophysin] were also increased following PBT2 treatment. We also demonstrate that PBT2 treatment results in a subregion-specific increase in hippocampal zinc, which is increasingly recognized as a potent neuromodulator. These data demonstrate that metal chaperones are a novel approach to the treatment of age-related cognitive decline. PMID:24305557

The Nun study: clinically silent AD, neuronal hypertrophy, and linguistic skills in early life.

PubMed

Iacono, D; Markesbery, W R; Gross, M; Pletnikova, O; Rudow, G; Zandi, P; Troncoso, J C

2009-09-01

It is common to find substantial Alzheimer disease (AD) lesions, i.e., neuritic beta-amyloid plaques and neurofibrillary tangles, in the autopsied brains of elderly subjects with normal cognition assessed shortly before death. We have termed this status asymptomatic AD (ASYMAD). We assessed the morphologic substrate of ASYMAD compared to mild cognitive impairment (MCI) in subjects from the Nun Study. In addition, possible correlations between linguistic abilities in early life and the presence of AD pathology with and without clinical manifestations in late life were considered. Design-based stereology was used to measure the volumes of neuronal cell bodies, nuclei, and nucleoli in the CA1 region of hippocampus (CA1). Four groups of subjects were compared: ASYMAD (n = 10), MCI (n = 5), AD (n = 10), and age-matched controls (n = 13). Linguistic ability assessed in early life was compared among all groups. A significant hypertrophy of the cell bodies (+44.9%), nuclei (+59.7%), and nucleoli (+80.2%) in the CA1 neurons was found in ASYMAD compared with MCI. Similar differences were observed with controls. Furthermore, significant higher idea density scores in early life were observed in controls and ASYMAD group compared to MCI and AD groups. 1) Neuronal hypertrophy may constitute an early cellular response to Alzheimer disease (AD) pathology or reflect compensatory mechanisms that prevent cognitive impairment despite substantial AD lesions; 2) higher idea density scores in early life are associated with intact cognition in late life despite the presence of AD lesions.

Roles for Arc in metabotropic glutamate receptor-dependent LTD and synapse elimination: Implications in health and disease.

PubMed

Wilkerson, Julia R; Albanesi, Joseph P; Huber, Kimberly M

2018-05-01

The Arc gene is robustly transcribed in specific neural ensembles in response to experience-driven activity. Upon induction, Arc mRNA is transported to dendrites, where it can be rapidly and locally translated by activation of metabotropic glutamate receptors (mGluR1/5). mGluR-induced dendritic synthesis of Arc is implicated in weakening or elimination of excitatory synapses by triggering endocytosis of postsynaptic AMPARs in both hippocampal CA1 and cerebellar Purkinje neurons. Importantly, CA1 neurons with experience-induced Arc mRNA are susceptible, or primed for mGluR-induced long-term synaptic depression (mGluR-LTD). Here we review mechanisms and function of Arc in mGluR-LTD and synapse elimination and propose roles for these forms of plasticity in Arc-dependent formation of sparse neural representations of learned experience. We also discuss accumulating evidence linking dysregulation of Arc and mGluR-LTD in human cognitive disorders such as intellectual disability, autism and Alzheimer's disease. Copyright © 2017 Elsevier Ltd. All rights reserved.

Focus group discussion in mathematical physics learning

NASA Astrophysics Data System (ADS)

Ellianawati; Rudiana, D.; Sabandar, J.; Subali, B.

2018-03-01

The Focus Group Discussion (FGD) activity in Mathematical Physics learning has helped students perform the stages of problem solving reflectively. The FGD implementation was conducted to explore the problems and find the right strategy to improve the students' ability to solve the problem accurately which is one of reflective thinking component that has been difficult to improve. The research method used is descriptive qualitative by using single subject response in Physics student. During the FGD process, one student was observed of her reflective thinking development in solving the physics problem. The strategy chosen in the discussion activity was the Cognitive Apprenticeship-Instruction (CA-I) syntax. Based on the results of this study, it is obtained the information that after going through a series of stages of discussion, the students' reflective thinking skills is increased significantly. The scaffolding stage in the CA-I model plays an important role in the process of solving physics problems accurately. Students are able to recognize and formulate problems by describing problem sketches, identifying the variables involved, applying mathematical equations that accord to physics concepts, executing accurately, and applying evaluation by explaining the solution to various contexts.

Critical role of CA1 muscarinic receptors on memory acquisition deficit induced by total (TSD) and REM sleep deprivation (RSD).

PubMed

Javad-Moosavi, Bibi-Zahra; Vaezi, Gholamhassan; Nasehi, Mohammad; Haeri-Rouhani, Seyed-Ali; Zarrindast, Mohammad-Reza

2017-10-03

Despite different theories regarding sleep physiological function, an overall census indicates that sleep is useful for neural plasticity which eventually strengthens cognition and brain performance. Different studies show that sleep deprivation (SD) leads to impaired learning and hippocampus dependent memory. According to some studies, cholinergic system plays an important role in sleep (particularly REM sleep), learning, memory, and its retrieval. So this study has been designed to investigate the effect of CA1 Cholinergic Muscarinic Receptors on memory acquisition deficit induced by total sleep deprivation (TSD) and REM sleep deprivation (RSD). A modified water box (locomotor activity may be provide a limiting factor in this method of SD) or multiple platforms were used for induction of TSD or RSD, respectively. Inhibitory passive avoidance apparatus has been used to determine the effects of SD and its changes by physostigmine (as cholinesterase inhibitor) or scopolamine (muscarinic receptor antagonist) on memory formation. Because locomotor activity and pain perception induce critical roles in passive avoidance memory formation, we also measured these factors by open field and hot-plate instruments, respectively. The results showed that TSD and RSD for 24 hours impaired memory formation but they did not alter locomotor activity. TSD also induced analgesia effect, but RSD did not alter it. Intra-CA1 injection of physostigmine (0.0001μg/rat) and scopolamine (0.01μg/rat) did not alter memory acquisition in the sham-TSD or sham-RSD, by themselves. Moreover, intra-CA1 injection of sub-threshold dose of physostigmine (0.0001μg/rat) and scopolamine (0.01μg/rat) could restore the memory acquisition deficit induced by RSD, while scopolamine could restore TSD-induced amnesia. Both drugs reversed analgesia induced by TSD. None of previous interventions altered locomotor activity. According to this study, CA1 cholinergic muscarinic receptors play an important role in amnesia induced by both TSD and RSD. However further studies are needed for showing cellular and molecular mechanisms of surprising result of similar pharmacological effects using compounds with opposite profiles. Copyright © 2016. Published by Elsevier Inc.

Osthole, a natural coumarin improves cognitive impairments and BBB dysfunction after transient global brain ischemia in C57 BL/6J mice: involvement of Nrf2 pathway.

PubMed

Chen, ZiWei; Mao, XueXuan; Liu, AnMin; Gao, XiaoYun; Chen, XiaoHong; Ye, MinZhong; Ye, JianTao; Liu, PeiQing; Xu, SuoWen; Liu, JianXin; He, Wei; Lian, QiShen; Pi, RongBiao

2015-01-01

Oxidative stress and blood-brain barrier (BBB) disruption play important roles in cerebral ischemic pathogenesis and may represent targets for treatment. Earlier studies have shown that osthole, a main active constituent isolated from Cnidium monnieri (L.) Cusson, could be considered as an attractive therapeutic agent in the treatment of ischemic stroke. However, the mechanism underlying the protective effect remains vague. In this study we aimed to investigate the effect of osthole on transient cerebral ischemia as well as its mechanism(s) in C57 BL/6 J mice. Mice were subjected to transient global cerebral ischemia induced by bilateral common carotid artery occlusion for 25 min. Behavioral test was performed at 4 days after ischemia, followed by assessment of neuronal loss in hippocampal CA1 region. Osthole significantly improved the cognitive ability and enhanced the survival of pyramidal neurons in the CA1 region of mice after lesion. Further studies showed that osthole attenuated the permeation of BBB, which may contribute to antioxidative effect by increasing the superoxide dismutase activity and decreasing the malondialdehyde level in model mice. Further studies revealed that osthole obviously up-regulated the protein levels of nuclear factor erythroid 2-related factor 2/heme oxygenase 1 in HT22 cells. In conclusion, our findings indicated that osthole exerts neuroprotective effects against global cerebral ischemia injury by reducing oxidative stress injury and reserving the disruption of BBB, which may be attributed to elevating the protein levels of Nrf2 and HO-1.

Cognitive status is a determinant of health resource utilization among individuals with a history of falls: a 12-month prospective cohort study.

PubMed

Davis, J C; Dian, L; Khan, K M; Bryan, S; Marra, C A; Hsu, C L; Jacova, P; Chiu, B K; Liu-Ambrose, T

2016-03-01

Falls are a costly public health problem worldwide. The literature is devoid of prospective data that identifies factors among fallers that significantly drive health care resource utilization. We found that cognitive function--specifically, executive functions--and cognitive status are significant determinants of health resource utilization among older fallers. Although falls are costly, there are no prospective data examining factors among fallers that drive health care resource utilization. We identified key determinants of health resource utilization (HRU) at 6 and 12 months among older adults with a history of falls. Specifically, with the increasing recognition that cognitive impairment is associated with increased falls risk, we investigated cognition as a potential driver of health resource utilization. This 12-month prospective cohort study at the Vancouver Falls Prevention Clinic (n = 319) included participants with a history of at least one fall in the previous 12 months. Based on their cognitive status, participants were divided into two groups: (1) no mild cognitive impairment (MCI) and (2) MCI. We constructed two linear regression models with HRU at 6 and 12 months as the dependent variables for each model, respectively. Predictors relating to mobility, global cognition, executive functions, and cognitive status (MCI versus no MCI) were examined. Age, sex, comorbidities, depression status, and activities of daily living were included regardless of statistical significance. Global cognition, comorbidities, working memory, and cognitive status (MCI versus no MCI ascertained using the Montreal Cognitive Assessment (MoCA)) were significant determinants of total HRU at 6 months. The number of medical comorbidities and global cognition were significant determinants of total HRU at 12 months. MCI status was a determinant of HRU at 6 months among older adults with a history of falls. As such, efforts to minimize health care resource use related to falls, it is important to tailor future interventions to be effective for people with MCI who fall. ClinicalTrials.gov Identifier: NCT01022866.

Recall Tests Are Effective to Detect Mild Cognitive Impairment: A Systematic Review and Meta-analysis of 108 Diagnostic Studies.

PubMed

Tsoi, Kelvin K F; Chan, Joyce Y C; Hirai, Hoyee W; Wong, Adrian; Mok, Vincent C T; Lam, Linda C W; Kwok, Timothy C Y; Wong, Samuel Y S

2017-09-01

Mild cognitive impairment (MCI) is a prevalent symptom associated with the increased risk of dementia. There are many cognitive tests available for detection of MCI, and investigation of the diagnostic performance of the tests is deemed necessary. This study aims to evaluate the diagnostic performance of different cognitive tests used for MCI detection. A list of cognitive tests was identified in previous reviews and from online search engines. Literature searches were performed on each of the cognitive tests in MEDLINE, Embase, and PsycINFO from the earliest available dates of individual databases to December 31, 2016. Google Scholar was used as a supplementary search tool. Studies that were used to assess the diagnostic performance of the cognitive tests were extracted with inclusion and exclusion criteria. Each test's performance was compared with the standard diagnostic criteria. Bivariate random effects models were used to summarize the test performance as a point estimate for sensitivity and specificity, and presented in a summary receiver operating characteristic curve. Reporting quality and risk of bias were evaluated. A total of 108 studies with 23,546 participants were selected to evaluate 9 cognitive tests for MCI detection. Most of the studies used the Mini-Mental State Examination (MMSE) (n = 58) and the Montreal Cognitive Assessment (MoCA) (n = 35). The combined diagnostic performance of the MMSE in MCI detection was 0.71 sensitivity [95% confidence interval (CI): 0.66-0.75] and 0.74 specificity (95% CI: 0.70-0.78), and of the MoCA in MCI detection was 0.83 sensitivity (95% CI: 0.80-0.86) and 0.75 specificity (95% CI: 0.69-0.80). Among the 9 cognitive tests, recall tests showed the best diagnostic performance with 0.89 sensitivity (95% CI: 0.86-0.92) and 0.84 specificity (95% CI, 0.79-0.89). In subgroup analyses, long- or short-delay recall tests have shown better performance than immediate recall tests. Recall tests were shown to be the most effective test in MCI detection, especially for the population with symptoms of memory deterioration. They can be potentially used as the triage screening test for MCI in primary care setting. But when a patient shows cognitive impairments beyond memory deterioration, a more comprehensive test such as the MoCA should be used. Copyright © 2017 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.

AMP-activated protein kinase-mediated feedback phosphorylation controls the Ca2+/calmodulin (CaM) dependence of Ca2+/CaM-dependent protein kinase kinase β.

PubMed

Nakanishi, Akihiro; Hatano, Naoya; Fujiwara, Yuya; Sha'ri, Arian; Takabatake, Shota; Akano, Hiroki; Kanayama, Naoki; Magari, Masaki; Nozaki, Naohito; Tokumitsu, Hiroshi

2017-12-01

The Ca 2+ /calmodulin-dependent protein kinase kinase β (CaMKKβ)/5'-AMP-activated protein kinase (AMPK) phosphorylation cascade affects various Ca 2+ -dependent metabolic pathways and cancer growth. Unlike recombinant CaMKKβ that exhibits higher basal activity (autonomous activity), activation of the CaMKKβ/AMPK signaling pathway requires increased intracellular Ca 2+ concentrations. Moreover, the Ca 2+ /CaM dependence of CaMKKβ appears to arise from multiple phosphorylation events, including autophosphorylation and activities furnished by other protein kinases. However, the effects of proximal downstream kinases on CaMKKβ activity have not yet been evaluated. Here, we demonstrate feedback phosphorylation of CaMKKβ at multiple residues by CaMKKβ-activated AMPK in addition to autophosphorylation in vitro , leading to reduced autonomous, but not Ca 2+ /CaM-activated, CaMKKβ activity. MS analysis and site-directed mutagenesis of AMPK phosphorylation sites in CaMKKβ indicated that Thr 144 phosphorylation by activated AMPK converts CaMKKβ into a Ca 2+ /CaM-dependent enzyme as shown by completely Ca 2+ /CaM-dependent CaMKK activity of a phosphomimetic T144E CaMKKβ mutant. CaMKKβ mutant analysis indicated that the C-terminal domain (residues 471-587), including the autoinhibitory region, plays an important role in stabilizing an inactive conformation in a Thr 144 phosphorylation-dependent manner. Furthermore, immunoblot analysis with anti-phospho-Thr 144 antibody revealed phosphorylation of Thr 144 in CaMKKβ in transfected COS-7 cells that was further enhanced by exogenous expression of AMPKα. These results indicate that AMPK-mediated feedback phosphorylation of CaMKKβ regulates the CaMKKβ/AMPK signaling cascade and may be physiologically important for intracellular maintenance of Ca 2+ -dependent AMPK activation by CaMKKβ. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Hippocampal Substructural Vulnerability to Sleep Disturbance and Cognitive Impairment in Patients with Chronic Primary Insomnia: Magnetic Resonance Imaging Morphometry

PubMed Central

Joo, Eun Yeon; Kim, Hosung; Suh, Sooyeon; Hong, Seung Bong

2014-01-01

Study Objectives: Despite compelling evidence from animal studies indicating hippocampal subfield-specific vulnerability to poor sleep quality and related cognitive impairment, there have been no human magnetic resonance imaging (MRI) studies investigating the relationship between hippocampal subfield volume and sleep disturbance. Our aim was to investigate the pattern of volume changes across hippocampal subfields in patients with primary insomnia relative to controls. Design: Pointwise morphometry allowed for volume measurements of hippocampal regions on T1-weighted MRI. Setting: University hospital. Patients: Twenty-seven unmedicated patients (age: 51.2 ± 9.6 y) and 30 good sleepers as controls (50.4 ± 7.1 y). Interventions: N/A. Measurements: We compared hippocampal subfield volumes between patients and controls and correlated volume with clinical and neuropsychological features in patients. Results: Patients exhibited bilateral atrophy across all hippocampal subfields (P < 0.05 corrected). Cornu ammonis (CA) 1 subfield atrophy was associated with worse sleep quality (higher Pittsburgh Sleep Quality Index and higher arousal index of polysomnography) (r < -0.45, P < 0.005). The volume of the combined region, including the dentate gyrus (DG) and CA3-4, negatively correlated with verbal memory, verbal information processing, and verbal fluency in patients (|r| > 0.45, P < 0.05). Hemispheric volume asymmetry of this region (left smaller than right) was associated with impaired verbal domain functions (r = 0.50, P < 0.005). Conclusion: Hippocampal subfield atrophy in chronic insomnia suggests reduced neurogenesis in the dentate gyrus (DG) and neuronal loss in the cornu ammonis (CA) subfields in conditions of sleep fragmentation and related chronic stress condition. Atrophy in the CA3-4-DG region was associated with impaired cognitive functions in patients. These observations may provide insight into pathophysiological mechanisms that make patients with chronic sleep disturbance vulnerable to cognitive impairment. Citation: Joo EY, Kim H, Suh S, Hong SB. Hippocampal substructural vulnerability to sleep disturbance and cognitive impairment in patients with chronic primary insomnia: magnetic resonance imaging morphometry. SLEEP 2014;37(7):1189-1198. PMID:25061247

Loss of Female Sex Hormones Exacerbates Cerebrovascular and Cognitive Dysfunction in Aortic Banded Miniswine Through a Neuropeptide Y-Ca2+-Activated Potassium Channel-Nitric Oxide Mediated Mechanism.

PubMed

Olver, T Dylan; Hiemstra, Jessica A; Edwards, Jenna C; Schachtman, Todd R; Heesch, Cheryl M; Fadel, Paul J; Laughlin, M Harold; Emter, Craig A

2017-10-31

Postmenopausal women represent the largest cohort of patients with heart failure with preserved ejection fraction, and vascular dementia represents the most common form of dementia in patients with heart failure with preserved ejection fraction. Therefore, we tested the hypotheses that the combination of cardiac pressure overload (aortic banding [AB]) and the loss of female sex hormones (ovariectomy [OVX]) impairs cerebrovascular control and spatial memory. Female Yucatan miniswine were separated into 4 groups (n=7 per group): (1) control, (2) AB, (3) OVX, and (4) AB-OVX. Pigs underwent OVX and AB at 7 and 8 months of age, respectively. At 14 months, cerebral blood flow velocity and spatial memory (spatial hole-board task) were lower in the OVX groups ( P <0.05), with significant impairments in the AB-OVX group ( P <0.05). Resting carotid artery β stiffness and vascular resistance during central hypovolemia were increased in the AB-OVX group ( P <0.05), and blood flow recovery after central hypovolemia was reduced in both OVX groups ( P <0.05). Isolated pial artery (pressure myography) vasoconstriction to neuropeptide Y was greatest in the AB-OVX group ( P <0.05), and vasodilation to the Ca 2+ -activated potassium channel α-subunit agonist NS-1619 was impaired in both AB groups ( P <0.05). The ratio of phosphorylated endothelial nitric oxide synthase:total endothelial nitric oxide synthase was depressed and Ca 2+ -activated potassium channel α-subunit protein was increased in AB groups ( P <0.05). Mechanistically, impaired cerebral blood flow control in experimental heart failure may be the result of heightened neuropeptide Y-induced vasoconstriction along with reduced vasodilation associated with decreased Ca 2+ -activated potassium channel function and impaired nitric oxide signaling, the effects of which are exacerbated in the absence of female sex hormones. © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

Non-conventional apoptotic response to ionising radiation mediated by N-methyl D-aspartate receptors in immature neuronal cells

PubMed Central

SAMARI, NADA; DE SAINT-GEORGES, LOUIS; PANI, GIUSEPPE; BAATOUT, SARAH; LEYNS, LUC; BENOTMANE, MOHAMMED ABDERRAFI

2013-01-01

During cortical development, N-methyl D-aspartate (NMDA) receptors are highly involved in neuronal maturation and synapse establishment. Their implication in the phenomenon of excitotoxicity has been extensively described in several neurodegenerative diseases due to the permissive entry of Ca2+ ions and massive accumulation in the intracellular compartment, which is highly toxic to cells. Ionising radiation is also a source of stress to the cells, particularly immature neurons. Their capacity to induce cell death has been described for various cell types either by directly damaging the DNA or indirectly through the generation of reactive oxygen species responsible for the activation of a battery of stress response effectors leading in certain cases, to cell death. In this study, in order to determine whether a link exists between NMDA receptors-mediated excitotoxicity and radiation-induced cell death, we evaluated radiation-induced cell death in vitro and in vivo in maturing neurons during the fetal period. Cell death induction was assessed by TUNEL, caspase-3 activity and DNA ladder assays, with or without the administration of dizocilpine (MK-801), a non-competitive NMDA receptor antagonist which blocks neuronal Ca2+ influx. To further investigate the possible involvement of Ca2+-dependent enzyme activation, known to occur at high Ca2+ concentrations, we examined the protective effect of a calpain inhibitor on cell death induced by radiation. Doses ranging from 0.2 to 0.6 Gy of X-rays elicited a clear apoptotic response that was prevented by the injection of dizocilpine (MK-801) or calpain inhibitor. These data demonstrate the involvement of NMDA receptors in radiation-induced neuronal death by the activation of downstream effectors, including calpain-related pathways. An increased apoptotic process elicited by radiation, occurring independently of the normal developmental scheme, may eliminate post-mitotic but immature neuronal cells and deeply impair the establishment of the neuronal network, which in the case of cortical development is critical for cognitive capacities. PMID:23338045

Regulation of GABAergic Inputs to CA1 Pyramidal Neurons by Nicotinic Receptors and Kynurenic Acid

PubMed Central

Banerjee, Jyotirmoy; Alkondon, Manickavasagom; Pereira, Edna F. R.

2012-01-01

Impaired α7 nicotinic acetylcholine receptor (nAChR) function and GABAergic transmission in the hippocampus and elevated brain levels of kynurenic acid (KYNA), an astrocyte-derived metabolite of the kynurenine pathway, are key features of schizophrenia. KYNA acts as a noncompetitive antagonist with respect to agonists at both α7 nAChRs and N-methyl-d-aspartate receptors. Here, we tested the hypothesis that in hippocampal slices tonically active α7 nAChRs control GABAergic transmission to CA1 pyramidal neurons and are sensitive to inhibition by rising levels of KYNA. The α7 nAChR-selective antagonist α-bungarotoxin (α-BGT; 100 nM) and methyllycaconitine (MLA; 10 nM), an antagonist at α7 and other nAChRs, reduced by 51.3 ± 1.3 and 65.2 ± 1.5%, respectively, the frequency of GABAergic postsynaptic currents (PSCs) recorded from CA1 pyramidal neurons. MLA had no effect on miniature GABAergic PSCs. Thus, GABAergic synaptic activity in CA1 pyramidal neurons is maintained, in part, by tonically active α7 nAChRs located on the preterminal region of axons and/or the somatodendritic region of interneurons that synapse onto the neurons under study. l-Kynurenine (20 or 200 μM) or KYNA (20–200 μM) suppressed concentration-dependently the frequency of GABAergic PSCs; the inhibitory effect of 20 μM l-kynurenine had an onset time of approximately 35 min and could not be detected in the presence of 100 nM α-BGT. These results suggest that KYNA levels generated from 20 μM kynurenine inhibit tonically active α7 nAChR-dependent GABAergic transmission to the pyramidal neurons. Disruption of nAChR-dependent GABAergic transmission by mildly elevated levels of KYNA can be an important determinant of the cognitive deficits presented by patients with schizophrenia. PMID:22344459

Are we comparing frontotemporal dementia and Alzheimer disease patients with the right measures?

PubMed

Deutsch, Mariel B; Liang, Li-Jung; Jimenez, Elvira E; Mather, Michelle J; Mendez, Mario F

2016-09-01

Clinical research studies of behavioral variant frontotemporal dementia (bvFTD) often use Alzheimer disease (AD) as a comparison group for control of dementia variables, using tests of cognitive function to match the groups. These two dementia syndromes, however, are very different in clinical manifestations, and the comparable severity of these dementias may not be reflected by commonly used cognitive scales such as the Mini-Mental State Examination (MMSE). We evaluated different measures of dementia severity and symptoms among 20 people with bvFTD compared to 24 with early-onset AD. Despite similar ages, disease-duration, education, and cognitive performance on two tests of cognitive function, the MMSE and the Montreal Cognitive Assessment (MoCA), the bvFTD participants, compared to the AD participants, were significantly more impaired on other measures of disease severity, including function (Functional Assessment Questionnaire (FAQ)), neuropsychiatric symptoms (Neuropsychiatric Inventory (NPI)), and global dementia stage (Clinical Dementia Rating Scales (CDRs)). However, when we adjusted for the frontotemporal lobar degeneration-CDR (FTLD-CDR) in the analyses, the two dementia groups were comparable across all measures despite significant differences on the cognitive scales. We found tests of cognitive functions (MMSE and MoCA) to be insufficient measures for ensuring comparability between bvFTD and AD groups. In clinical studies, the FTLD-CDR, which includes additional language and behavior items, may be a better overall way to match bvFTD and AD groups on dementia severity.

Effects of an Exercise Protocol for Improving Handgrip Strength and Walking Speed on Cognitive Function in Patients with Chronic Stroke.

PubMed

Kim, Jaeeun; Yim, Jongeun

2017-11-13

BACKGROUND Handgrip strength and walking speed predict and influence cognitive function. We aimed to investigate an exercise protocol for improving handgrip strength and walking speed, applied to patients with chronic stroke who had cognitive function disorder. MATERIAL AND METHODS Twenty-nine patients with cognitive function disorder participated in this study, and were randomly divided into one of two groups: exercise group (n=14) and control group (n=15). Both groups underwent conventional physical therapy for 60 minutes per day. Additionally, the exercise group followed an exercise protocol for handgrip using the hand exerciser, power web exerciser, Digi-Flex (15 minutes); and treadmill-based weight loading training on their less-affected leg (15 minutes) using a sandbag for 30 minutes, three times per day, for six weeks. Outcomes, including cognitive function and gait ability, were measured before and after the training. RESULTS The Korean version of Montreal Cognitive Assessment (K-MoCA), Stroop test (both simple and interference), Trail Making-B, Timed Up and Go, and 10-Meter Walk tests (p<0.05) yielded improved results for the exercise group compared with the control group. Importantly, the K-MoCA, Timed Up and Go, and 10-Meter Walk test results were significantly different between the two groups (p<0.05). CONCLUSIONS The exercise protocol for improving handgrip strength and walking speed had positive effects on cognitive function in patients with chronic stroke.

Are we comparing frontotemporal dementia and Alzheimer disease patients with the right measures?

PubMed Central

Deutsch, Mariel B.; Liang, Li-Jung; Jimenez, Elvira E.; Mather, Michelle J.; Mendez, Mario F.

2016-01-01

Background Clinical research studies of behavioral variant frontotemporal dementia (bvFTD) often use Alzheimer disease (AD) as a comparison group for control of dementia variables, using tests of cognitive function to match the groups. These two dementia syndromes, however, are very different in clinical manifestations, and the comparable severity of these dementias may not be reflected by commonly used cognitive scales such as the Mini-Mental State Examination (MMSE). Methods We evaluated different measures of dementia severity and symptoms among 20 people with bvFTD compared to 24 with early-onset AD. Results Despite similar ages, disease-duration, education, and cognitive performance on two tests of cognitive function, the MMSE and the Montreal Cognitive Assessment (MoCA), the bvFTD participants, compared to the AD participants, were significantly more impaired on other measures of disease severity, including function (Functional Assessment Questionnaire (FAQ)), neuropsychiatric symptoms (Neuropsychiatric Inventory (NPI)), and global dementia stage (Clinical Dementia Rating Scales (CDRs)). However, when we adjusted for the frontotemporal lobar degeneration-CDR (FTLD-CDR) in the analyses, the two dementia groups were comparable across all measures despite significant differences on the cognitive scales. Conclusion We found tests of cognitive functions (MMSE and MoCA) to be insufficient measures for ensuring comparability between bvFTD and AD groups. In clinical studies, the FTLD-CDR, which includes additional language and behavior items, may be a better overall way to match bvFTD and AD groups on dementia severity. PMID:27079571

Free and nanoencapsulated curcumin prevents cigarette smoke-induced cognitive impairment and redox imbalance.

PubMed

Jaques, Jeandre Augusto dos Santos; Doleski, Pedro Henrique; Castilhos, Lívia Gelain; da Rosa, Michelle Melgarejo; Souza, Viviane do Carmo Gonçalves; Carvalho, Fabiano Barbosa; Marisco, Patrícia; Thorstenberg, Maria Luiza Prates; Rezer, João Felipe Peres; Ruchel, Jader Betch; Coradini, Karine; Beck, Ruy Carlos Ruver; Rubin, Maribel Antonello; Schetinger, Maria Rosa Chitolina; Leal, Daniela Bitencourt Rosa

2013-02-01

Cigarette smoke-exposure promotes neurobiological changes associated with neurocognitive abnormalities. Curcumin, a natural polyphenol, have shown to be able to prevent cigarette smoke-induced cognitive impairment. Here, we investigated possible mechanisms involved in curcumin protection against cigarette smoke-induced cognitive impairment and, due to its poor bioavailability, we investigated the potential of using curcumin-loaded lipid-core nanocapsules (C-LNC) suspension. Rats were treated with curcumin and cigarette smoke, once a day, 5 days each week, for 30 days. Animals were divided into ten groups: I, control (vehicle/corn oil); II, curcumin 12.5mg/kg; III, curcumin 25mg/kg; IV, curcumin 50mg/kg; V, C-LNC 4 mg/kg; VI, tobacco exposed; VII, curcumin 12.5mg/kg along with tobacco exposure; VIII, curcumin 25mg/kg along with tobacco exposure; IX, curcumin 50mg/kg along with tobacco exposure; X, C-LNC 4 mg/kg along with tobacco exposure. Cigarette smoke-exposure impaired object recognition memory (P<0.001), indicated by the low recognition index, increased biomarkers of oxidative/nitrosative stress such as TBARS (P<0.05) and NOx (P<0.01), decreased antioxidant defenses such as NPSH content (P<0.01) and SOD activity (P<0.01) and inhibited the activities of enzymes involved in ion homeostasis such as Na(+),K(+)-ATPase and Ca(2+)-ATPase. Both curcumin formulations (free and nanoencapsulated) prevented the memory impairment, the redox imbalance and the alterations observed in the ATPases activities. Maintenance of ion homeostasis and redox balance is involved in the protective mechanism of curcumin against tobacco-induced cognitive impairment. Our results suggest that curcumin is a potential therapeutic agent for neurocognition and that C-LNC may be an alternative to its poor bioavailability. Copyright © 2012 Elsevier Inc. All rights reserved.

The Impact of Captivity and Posttraumatic Stress Disorder on Cognitive Performance Among Former Prisoners of War: A Longitudinal Study.

PubMed

Aloni, Roy; Crompton, Laura; Levin, Yafit; Solomon, Zahava

2018-04-24

War captivity is a potent pathogen for various aspects of mental health, including cognitive impairments. However, little is known about the long-term impact of war captivity and posttraumatic stress disorder (PTSD) on cognitive functioning among former prisoners of war (ex-POWs). This study assesses the effect of captivity, PTSD trajectories, and the accumulating differential effect in the prediction of cognitive performance. This longitudinal research includes 4 assessments (1991 [T1], 2003 [T2], 2008 [T3], 2015 [T4]) of Israeli ex-POWs and comparable combatants from the 1973 Yom Kippur War. Accordingly, 95 ex-POWs and 26 comparable combatants were included in this study. PTSD was assessed according to the DSM-IV, and cognitive performance was assessed using the Montreal Cognitive Assessment (MoCA). Ex-POWs reported higher levels of PTSD symptoms compared to controls (P = 0.007). No difference was found between the groups regarding MoCA total score. Ex-POWs with chronic PTSD were found to have more difficulty in overall cognitive functioning, compared to ex-POWs with delayed, recovery, and resilient trajectories (P = 0.03). Finally, physical and psychological suffering in captivity and intrusion symptoms predicted cognitive performance (P < .001, R² = 37.9%). These findings support the potent pathogenic effects of war captivity on cognitive abilities, more than 4 decades after the end of the traumatic event. Our results showed captivity to be a unique and powerful traumatic experience, leading to PTSD and long-lasting and enduring neuropsychological implications. These findings highlight the importance of viewing ex-POWs, in particular those suffering from chronic PTSD, especially as they age, as a high-risk population for cognitive disorders. This requires the appropriate diagnosis and cognitive therapy as a way to preserve cognitive abilities among this population. © Copyright 2018 Physicians Postgraduate Press, Inc.

Cognitive assessment tools in Asia: a systematic review.

PubMed

Rosli, Roshaslina; Tan, Maw Pin; Gray, William Keith; Subramanian, Pathmawathi; Chin, Ai-Vyrn

2016-02-01

The prevalence of dementia is increasing in Asia than in any other continent. However, the applicability of the existing cognitive assessment tools is limited by differences in educational and cultural factors in this setting. We conducted a systematic review of published studies on cognitive assessments tools in Asia. We aimed to rationalize the results of available studies which evaluated the validity of cognitive tools for the detection of cognitive impairment and to identify the issues surrounding the available cognitive impairment screening tools in Asia. Five electronic databases (CINAHL, MEDLINE, Embase, Cochrane Library, and Science Direct) were searched using the keywords dementia Or Alzheimer Or cognitive impairment And screen Or measure Or test Or tool Or instrument Or assessment, and 2,381 articles were obtained. Thirty-eight articles, evaluating 28 tools in seven Asian languages, were included. Twenty-nine (76%) of the studies had been conducted in East Asia with only four studies conducted in South Asia and no study from northern, western, or central Asia or Indochina. Local language translations of the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) were assessed in 15 and six studies respectively. Only three tools (the Korean Dementia Screening Questionnaire, the Picture-based Memory Intelligence Scale, and the revised Hasegawa Dementia Screen) were derived de novo from Asian populations. These tools were assessed in five studies. Highly variable cut-offs were reported for the MMSE (17-29/30) and MoCA (21-26/30), with 13/19 (68%) of studies reporting educational bias. Few cognitive assessment tools have been validated in Asia, with no published validation studies for many Asian nations and languages. In addition, many available tools display educational bias. Future research should include concerted efforts to develop culturally appropriate tools with minimal educational bias.

Cognitive dysfunction in patients with Systemic Lupus Erythematosus.

PubMed

Butt, Bilal Azeem; Farman, Sumaira; Khan, Saira Elaine Anwer; Saeed, Muhammad Ahmed; Ahmad, Nighat Mir

2017-01-01

To determine the frequency of cognitive dysfunction in patients with Systemic Lupus Erythematosus in a Pakistani population, presenting at a tertiary care Rheumatology setting. This cross-sectional study was conducted at the Division of Rheumatology, Fatima Memorial Hospital, Lahore, from March to June 2016. A total of 43 consecutive patients, who fulfilled the 2012 SLICC (Systemic Lupus International Collaborating Clinics) classification criteria for Systemic Lupus Erythematosus (SLE), were enrolled. Cognitive function was assessed using Montréal Cognitive Assessment (MoCA) questionnaire. Demographic data and disease dynamics were collected in a proforma. Cognitive dysfunction was defined as score < 26/30, adjusted for duration of formal education. SPSS version 16.0 for windows was used to analyse data and to calculate frequency of cognitive dysfunction. Out of 43 enrolled patients, 95.3% were females and 4.7% were males, with mean age of 28.72 ± 9.25 years and mean formal education duration of 10.98 ± 3.29 years. The mean disease duration was 24.21 ± 30.46 months. Anti-nuclear antibodies (ANA) were present in all patients and anti-ds DNA in 93% patients. Cognitive dysfunction according to MoCA score was found in 65.1% (n=28) patients. For patients with disease duration more than two years, cognitive dysfunction was found in 60% patients [p>0.05] and for duration of formal education less than 12 years in 74.1% patients [p>0.05]. In this study, two third of SLE patients had Cognitive dysfunction. Hence, there is an increasing need to recognise and initiate early therapy for this overlooked aspect of SLE with an aim to achieve better quality of life.

Prevention of Hippocampal Neuronal Damage and Cognitive Function Deficits in Vascular Dementia by Dextromethorphan.

PubMed

Xu, Xiaofeng; Zhang, Bin; Lu, Kaili; Deng, Jiangshan; Zhao, Fei; Zhao, Bing-Qiao; Zhao, Yuwu

2016-07-01

Dextromethorphan (DM) is a non-competitive antagonist of NMDA receptors and a widely used component of cough medicine. Recently, its indication has been extended experimentally to a wide range of disorders including inflammation-mediated central nervous system disorders such as Parkinson disease (PD) and multiple sclerosis (MS). In this study, we investigate whether DM treatment has protective effects on the hippocampal neuron damage induced by bilateral occlusion of the common carotid arteries (two-vessel occlusion [2VO]), an animal model of vascular dementia (VaD). Sprague-Dawley (SD) (10 weeks of age) rats were subjected to the 2VO, and DM was injected intraperitoneally once per day for 37 days. Neuron death, glial activation, and cognitive function were assessed at 37 days after 2VO (0.2 mg/kg, i.p., "DM-0.2" and 2 mg/kg, i.p., "DM-2"). DM-2 treatment provided protection against neuronal death and glial activation in the hippocampal CA1 subfield and reduced cognitive impairment induced by 2VO in rats. The study also demonstrates that activation of the Nrf2-HO-1 pathway and upregulation of superoxide dismutase (SOD) play important roles in these effects. These results suggest that DM is effective in treating VaD and protecting against oxidative stress, which is strongly implicated in the pathogenesis of VaD. Therefore, the present study suggests that DM treatment may represent a new and promising protective strategy for treating VaD.

MK-801 Impairs Cognitive Coordination on a Rotating Arena (Carousel) and Contextual Specificity of Hippocampal Immediate-Early Gene Expression in a Rat Model of Psychosis

PubMed Central

Kubík, Štěpán; Buchtová, Helena; Valeš, Karel; Stuchlík, Aleš

2014-01-01

Flexible behavior in dynamic, real-world environments requires more than static spatial learning and memory. Discordant and unstable cues must be organized in coherent subsets to give rise to meaningful spatial representations. We model this form of cognitive coordination on a rotating arena – Carousel where arena- and room-bound spatial cues are dissociated. Hippocampal neuronal ensemble activity can repeatedly switch between multiple representations of such an environment. Injection of tetrodotoxin into one hippocampus prevents cognitive coordination during avoidance of a stationary room-defined place on the Carousel and increases coactivity of previously unrelated neurons in the uninjected hippocampus. Place avoidance on the Carousel is impaired after systemic administration of non-competitive NMDAr blockers (MK-801) used to model schizophrenia in animals and people. We tested if this effect is due to cognitive disorganization or other effect of NMDAr antagonism such as hyperlocomotion, spatial memory impairment, or general learning deficit. We also examined if the same dose of MK-801 alters patterns of immediate-early gene (IEG) expression in the hippocampus. IEG expression is triggered in neuronal nuclei in a context-specific manner after behavioral exploration and it is used to map activity in neuronal populations. IEG expression is critical for maintenance of synaptic plasticity and memory consolidation. We show that the same dose of MK-801 that impairs spatial coordination of rats on the Carousel also eliminates contextual specificity of IEG expression in hippocampal CA1 ensembles. This effect is due to increased similarity between ensembles activated in different environments, consistent with the idea that it is caused by increased coactivity between neurons, which did not previously fire together. Our data support the proposition of the Hypersynchrony theory that cognitive disorganization in psychosis is due to increased coactivity between unrelated neurons. PMID:24659959

Cardiovascular risk profile: cross-sectional analysis of motivational determinants, physical fitness and physical activity.

PubMed

Sassen, Barbara; Kok, Gerjo; Schaalma, Herman; Kiers, Henri; Vanhees, Luc

2010-10-07

Cardiovascular risk factors are associated with physical fitness and, to a lesser extent, physical activity. Lifestyle interventions directed at enhancing physical fitness in order to decrease the risk of cardiovascular diseases should be extended. To enable the development of effective lifestyle interventions for people with cardiovascular risk factors, we investigated motivational, social-cognitive determinants derived from the Theory of Planned Behavior (TPB) and other relevant social psychological theories, next to physical activity and physical fitness. In the cross-sectional Utrecht Police Lifestyle Intervention Fitness and Training (UP-LIFT) study, 1298 employees (aged 18 to 62) were asked to complete online questionnaires regarding social-cognitive variables and physical activity. Cardiovascular risk factors and physical fitness (peak VO2) were measured. For people with one or more cardiovascular risk factors (78.7% of the total population), social-cognitive variables accounted for 39% (p < .001) of the variance in the intention to engage in physical activity for 60 minutes every day. Important correlates of intention to engage in physical activity were attitude (beta = .225, p < .001), self-efficacy (beta = .271, p < .001), descriptive norm (beta = .172, p < .001) and barriers (beta = -.169, p < .01). Social-cognitive variables accounted for 52% (p < .001) of the variance in physical active behaviour (being physical active for 60 minutes every day). The intention to engage in physical activity (beta = .469, p < .001) and self-efficacy (beta = .243, p < .001) were, in turn, important correlates of physical active behavior.In addition to the prediction of intention to engage in physical activity and physical active behavior, we explored the impact of the intensity of physical activity. The intensity of physical activity was only significantly related to physical active behavior (beta = .253, p < .01, R2 = .06, p < .001). An important goal of our study was to investigate the relationship between physical fitness, the intensity of physical activity and social-cognitive variables. Physical fitness (R2 = .23, p < .001) was positively associated with physical active behavior (beta = .180, p < .01), self-efficacy (beta = .180, p < .01) and the intensity of physical activity (beta = .238, p < .01).For people with one or more cardiovascular risk factors, 39.9% had positive intentions to engage in physical activity and were also physically active, and 10.5% had a low intentions but were physically active. 37.7% had low intentions and were physically inactive, and about 11.9% had high intentions but were physically inactive. This study contributes to our ability to optimize cardiovascular risk profiles by demonstrating an important association between physical fitness and social-cognitive variables. Physical fitness can be predicted by physical active behavior as well as by self-efficacy and the intensity of physical activity, and the latter by physical active behavior.Physical active behavior can be predicted by intention, self-efficacy, descriptive norms and barriers. Intention to engage in physical activity by attitude, self-efficacy, descriptive norms and barriers. An important input for lifestyle changes for people with one or more cardiovascular risk factors was that for ca. 40% of the population the intention to engage in physical activity was in line with their actual physical active behavior.

Mesenchymal stem cells can modulate longitudinal changes in cortical thickness and its related cognitive decline in patients with multiple system atrophy

PubMed Central

Sunwoo, Mun Kyung; Yun, Hyuk Jin; Song, Sook K.; Ham, Ji Hyun; Hong, Jin Yong; Lee, Ji E.; Lee, Hye S.; Sohn, Young H.; Lee, Jong-Min; Lee, Phil Hyu

2014-01-01

Multiple system atrophy (MSA) is an adult-onset, sporadic neurodegenerative disease. Because the prognosis of MSA is fatal, neuroprotective or regenerative strategies may be invaluable in MSA treatment. Previously, we obtained clinical and imaging evidence that mesenchymal stem cell (MSC) treatment could have a neuroprotective role in MSA patients. In the present study, we evaluated the effects of MSC therapy on longitudinal changes in subcortical deep gray matter volumes and cortical thickness and their association with cognitive performance. Clinical and imaging data were obtained from our previous randomized trial of autologous MSC in MSA patients. During 1-year follow-up, we assessed longitudinal differences in automatic segmentation-based subcortical deep gray matter volumes and vertex-wise cortical thickness between placebo (n = 15) and MSC groups (n = 11). Next, we performed correlation analysis between the changes in cortical thickness and changes in the Korean version of the Montreal Cognitive Assessment (MoCA) scores and cognitive performance of each cognitive subdomain using a multiple, comparison correction. There were no significant differences in age at baseline, age at disease onset, gender ratio, disease duration, clinical severity, MoCA score, or education level between the groups. The automated subcortical volumetric analysis revealed that the changes in subcortical deep gray matter volumes of the caudate, putamen, and thalamus did not differ significantly between the groups. The areas of cortical thinning over time in the placebo group were more extensive, including the frontal, temporal, and parietal areas, whereas these areas in the MSC group were less extensive. Correlation analysis indicated that declines in MoCA scores and phonemic fluency during the follow-up period were significantly correlated with cortical thinning of the frontal and posterior temporal areas and anterior temporal areas in MSA patients, respectively. In contrast, no significant correlations were observed in the MSC group. These results suggest that MSC treatment in patients with MSA may modulate cortical thinning over time and related cognitive performance, inferring a future therapeutic candidate for cognitive disorders. PMID:24982631

Astrocytic Activation Generates De Novo Neuronal Potentiation and Memory Enhancement.

PubMed

Adamsky, Adar; Kol, Adi; Kreisel, Tirzah; Doron, Adi; Ozeri-Engelhard, Nofar; Melcer, Talia; Refaeli, Ron; Horn, Henrike; Regev, Limor; Groysman, Maya; London, Michael; Goshen, Inbal

2018-05-18

Astrocytes respond to neuronal activity and were shown to be necessary for plasticity and memory. To test whether astrocytic activity is also sufficient to generate synaptic potentiation and enhance memory, we expressed the Gq-coupled receptor hM3Dq in CA1 astrocytes, allowing their activation by a designer drug. We discovered that astrocytic activation is not only necessary for synaptic plasticity, but also sufficient to induce NMDA-dependent de novo long-term potentiation in the hippocampus that persisted after astrocytic activation ceased. In vivo, astrocytic activation enhanced memory allocation; i.e., it increased neuronal activity in a task-specific way only when coupled with learning, but not in home-caged mice. Furthermore, astrocytic activation using either a chemogenetic or an optogenetic tool during acquisition resulted in memory recall enhancement on the following day. Conversely, directly increasing neuronal activity resulted in dramatic memory impairment. Our findings that astrocytes induce plasticity and enhance memory may have important clinical implications for cognitive augmentation treatments. Copyright © 2018 Elsevier Inc. All rights reserved.

School-Based Prevention of Depression and Anxiety Symptoms in Early Adolescence: A Pilot of a Parent Intervention Component

ERIC Educational Resources Information Center

Gillham, Jane E.; Reivich, Karen J.; Freres, Derek R.; Lascher, Marisa; Litzinger, Samantha; Shatte, Andrew; Seligman, Martin E. P.

2006-01-01

Previous studies suggest that school-based cognitive-behavioral interventions can reduce and prevent depressive symptoms in youth. This pilot study investigated the effectiveness of a cognitive-behavioral depression prevention program, the Penn Resiliency Program for Children and Adolescents (the PRP-CA), when combined with a parent intervention…

Neurodevelopmental Role for VGLUT2 in Pyramidal Neuron Plasticity, Dendritic Refinement, and in Spatial Learning

PubMed Central

He, Hongbo; Mahnke, Amanda H.; Doyle, Sukhjeevan; Fan, Ni; Wang, Chih-Chieh; Hall, Benjamin J.; Tang, Ya-Ping; Inglis, Fiona M.; Chen, Chu; Erickson, Jeffrey D.

2012-01-01

The level and integrity of glutamate transmission during critical periods of postnatal development plays an important role in the refinement of pyramidal neuron dendritic arbor, synaptic plasticity, and cognition. Presently, it is not clear how excitatory transmission via the two predominant isoforms of the vesicular glutamate transporter (VGLUT1 and VGLUT2) participate in this process. To assess a neurodevelopmental role for VGLUT2 in pyramidal neuron maturation we have generated recombinant VGLUT2 knockout mice and inactivated VGLUT2 throughout development using Emx1-Cre+/+ knockin mice. We show that VGLUT2-deficiency in cortico-limbic circuits results in reduced evoked glutamate transmission, release probability, and LTD at hippocampal CA3-CA1 synapses during a formative developmental period (postnatal days 11–14). In adults, we find a marked reduction in the amount of dendritic arbor across the span of the dendritic tree of CA1 pyramidal neurons, reduced LTP and levels of synaptic markers spinophilin and VGLUT1. Loss of dendritic arbor is accompanied by corresponding reductions in the number of dendritic spines, suggesting widespread alterations in synaptic connectivity. Conditional VGLUT2 knockout mice exhibit increased open-field exploratory activity, yet impaired spatial learning and memory; endophenotypes similar to NMDA receptor knockdown mice. Remarkably, the impairment in learning can be partially restored selectively increasing NMDA-receptor mediated glutamate transmission in adult mice by prolonged treatment with D-serine and a D-amino acid oxidase inhibitor. Our data indicate that VGLUT2 expression is pivotal to the proper development of mature pyramidal neuronal architecture and plasticity, and that such glutamatergic deficiency leads to cognitive malfunction as observed in several neurodevelopmental psychiatric disorders. PMID:23136427

Neurodevelopmental role for VGLUT2 in pyramidal neuron plasticity, dendritic refinement, and in spatial learning.

PubMed

He, Hongbo; Mahnke, Amanda H; Doyle, Sukhjeevan; Fan, Ni; Wang, Chih-Chieh; Hall, Benjamin J; Tang, Ya-Ping; Inglis, Fiona M; Chen, Chu; Erickson, Jeffrey D

2012-11-07

The level and integrity of glutamate transmission during critical periods of postnatal development plays an important role in the refinement of pyramidal neuron dendritic arbor, synaptic plasticity, and cognition. Presently, it is not clear how excitatory transmission via the two predominant isoforms of the vesicular glutamate transporter (VGLUT1 and VGLUT2) participate in this process. To assess a neurodevelopmental role for VGLUT2 in pyramidal neuron maturation, we generated recombinant VGLUT2 knock-out mice and inactivated VGLUT2 throughout development using Emx1-Cre(+/+) knock-in mice. We show that VGLUT2 deficiency in corticolimbic circuits results in reduced evoked glutamate transmission, release probability, and LTD at hippocampal CA3-CA1 synapses during a formative developmental period (postnatal days 11-14). In adults, we find a marked reduction in the amount of dendritic arbor across the span of the dendritic tree of CA1 pyramidal neurons and reduced long-term potentiation and levels of synaptic markers spinophilin and VGLUT1. Loss of dendritic arbor is accompanied by corresponding reductions in the number of dendritic spines, suggesting widespread alterations in synaptic connectivity. Conditional VGLUT2 knock-out mice exhibit increased open-field exploratory activity yet impaired spatial learning and memory, endophenotypes similar to those of NMDA receptor knock-down mice. Remarkably, the impairment in learning can be partially restored by selectively increasing NMDA receptor-mediated glutamate transmission in adult mice by prolonged treatment with d-serine and a d-amino acid oxidase inhibitor. Our data indicate that VGLUT2 expression is pivotal to the proper development of mature pyramidal neuronal architecture and plasticity, and that such glutamatergic deficiency leads to cognitive malfunction as observed in several neurodevelopmental psychiatric disorders.

The vanadium (IV) compound rescues septo-hippocampal cholinergic neurons from neurodegeneration in olfactory bulbectomized mice.

PubMed

Han, F; Shioda, N; Moriguchi, S; Qin, Z-H; Fukunaga, K

2008-02-06

The bilateral olfactory bulbectomy (OBX) mouse exhibits neurodegeneration of cholinergic neurons in the medial septum with concomitant cognitive deficits. Consistent with our previous observations, choline acetyltransferase (ChAT) protein levels in the medial septum decreased by 43.5% 2 weeks after OBX without changes in glutamic acid decarboxylase-65 (GAD65) levels. Interestingly, levels of the vesicular acetylcholine transporter (VAChT), which is localized at cholinergic neuron terminals, decreased both in hippocampal CA1 and CA3 regions following OBX. Confocal microscopy showed that VAChT expression was more severely reduced in CA3 14 days after OBX compared with CA1. Intriguingly, chronic treatment with a vanadium (IV) compound, VO(OPT) [bis(1-N-oxide-pyridine-2-thiolato)oxovanadium(IV)] (0.5-1 mg as vanadium (V)/kg/day, i.p.), significantly rescued cholinergic neurons in the medial septum in a dose-dependent manner. VO(OPT) treatment also prevented decreased VAChT immunoreactivity both in CA1 and CA3 regions in the hippocampus. Consistent with these findings, an impaired hippocampal long-term potentiation (LTP) and memory deficits seen in OBX mice were significantly prevented by VO(OPT) treatment. Taken together, OBX induces neurodegeneration of septo-hippocampal cholinergic neurons and impairment of memory-related behaviors. The neuroprotective effect of VO(OPT) could lead to novel therapeutic strategies to ameliorate cognitive deficits associated with cholinergic neuron degeneration in Alzheimer's disease and other neurodegenerative disorders.

Differential protection among fractionated blueberry polyphenolic families against DA-, ABeta 42 and LPS-induced decrements in Ca2+ buffering in primary hippocampal cells

USDA-ARS?s Scientific Manuscript database

It has been postulated that at least part of the loss of cognitive function in aging may be the result of deficits in Ca2+ recovery (CAR) and increased oxidative/inflammatory (OX/INF) stress signaling. However, previous research showed that aged animals supplemented with blueberry (BB) extract, show...

Towards an Integration of the Non-Invasive Methodologies of Cognitive Neuroscience: The Eleventh Carmel Workshop

DTIC Science & Technology

1990-09-18

10:00 David LaBerge , University of California, Irvine "Why Should Cognitive Science Bother with the Brain?" This lecture will focus on those aspects...PA 19104 Bronx, N Y 10461 Earle Heffley David LaBerge University of Illinois University of California Department of Psychology Department of Cognitive...Science 603 East Daniel St. Irvine, CA 92717 Champaign, IL 61820 Paul C. Lauterbur Steven A. Hillyard University of Illinois U. of California, San

The effect of ovariectomy on learning and memory and relationship to changes in brain volume and neuronal density.

PubMed

Su, Jian; Sripanidkulchai, Kittisak; Hu, Ying; Wyss, J Michael; Sripanidkulchai, Bungorn

2012-10-01

The loss of sex hormones in postmenopausal women has been suggested to be involved in cognitive degenerative diseases, such as Alzheimer's disease. In the present study, ovariectomized (OVX) and control rats were tested for 4 months in a Morris water maze (MWM) task to track their memory status. Thereafter, postmortem frozen brain sections were analyzed to determine if changes in brain area volumes and neuronal density were related to changes in cognitive ability. A modified artificial-land-mark-based method was used to assure the fidelity of the three dimensions (3D) reconstructed structures. Volumetric areas of the hippocampus, cortex, caudate putamen (cpu), and cerebellum were estimated from the reconstructions, and neuron densities of CA1 and CA3 subregions of the hippocampus were measured in an adjacent second series of Nissl-stained sections. Compared to the control rats, OVX rats displayed memory impairments, beginning in the second month after the ovariectomy (p < .05). Assessments at the end of the study demonstrated that OVX (compared to control) rats displayed reduced brain volume in the hippocampus and neocortex and in the brain as a whole. In contrast, when compared to controls, the volumes of cpu and cerebellum of OVX rats increased slightly. CA3 neuron density of OVX (compared to controls) rats was significantly lower, but the CA1 neuron density was significantly higher. In conclusion, ovariectomy impaired spatial memory and led to morphological changes in cognitive centers of rat brain. The results demonstrate that the 3D reconstructed method is useful for the study of brain morphological abnormality in rats.

Blocking leukotriene synthesis attenuates the pathophysiology of traumatic brain injury and associated cognitive deficits

PubMed Central

Corser-Jensen, Chelsea E.; Goodell, Dayton J.; Freund, Ronald K.; Serbedzija, Predrag; Murphy, Robert C.; Farias, Santiago E.; Dell'Acqua, Mark L.; Frey, Lauren C.; Serkova, Natalie; Heidenreich, Kim A.

2014-01-01

Neuroinflammation is a component of secondary injury following traumatic brain injury (TBI) that can persist beyond the acute phase. Leukotrienes are potent, pro-inflammatory lipid mediators generated from membrane phospholipids. In the absence of injury, leukotrienes are undetectable in brain, but after trauma they are rapidly synthesized by a transcellular event involving infiltrating neutrophils and endogenous brain cells. Here, we investigate the efficacy of MK-886, an inhibitor of 5-lipoxygenase activating protein (FLAP), in blocking leukotriene synthesis, secondary brain damage, synaptic dysfunction, and cognitive impairments after TBI. Male Sprague Dawley rats (9-11 weeks) received either MK-886 or vehicle after they were subjected to unilateral moderate fluid percussion injury (FPI) to assess the potential clinical use of FLAP inhibitors for TBI. MK-886 was also administered before FPI to determine the preventative potential of FLAP inhibitors. MK-886 given before or after injury significantly blocked the production of leukotrienes, measured by reverse-phase liquid chromatography coupled to tandem mass spectrometry (RP LC-MS/MS), and brain edema, measured by T2-weighted magnetic resonance imaging (MRI). MK-886 significantly attenuated blood-brain barrier disruption in the CA1 hippocampal region and deficits in long-term potentiation (LTP) at CA1 hippocampal synapses. The prevention of FPI-induced synaptic dysfunction by MK-886 was accompanied by fewer deficits in post-injury spatial learning and memory performance in the radial arms water maze (RAWM). These results indicate that leukotrienes contribute significantly to secondary brain injury and subsequent cognitive deficits. FLAP inhibitors represent a novel anti-inflammatory approach for treating human TBI that is feasible for both intervention and prevention of brain injury and neurologic deficits. PMID:24681156

Impact of Rivastigmine on Cognitive Dysfunction and Falling in Parkinson's Disease Patients.

PubMed

Li, Zhenguang; Yu, Zhancai; Zhang, Jinbiao; Wang, Jing; Sun, Chao; Wang, Pengfei; Zhang, Jiangshan

2015-01-01

The purpose of this study was to observe the incidence of falls in Parkinson's disease (PD) patients with different cognitive levels and to investigate the effect of the cholinesterase inhibitor Rivastigmine on cognitive dysfunction and falling in PD patients. Data from 176 PD patients participating in the collaborative PD study between June 2010 and June 2014 were collected; the Chinese edition of the Montreal Cognitive Assessment (MoCA) score was used to evaluate the cognitive function of patients, and falls were recorded. PD patients with cognitive dysfunction were randomly administered either a placebo or Rivastigmine. The cognitive function changes and difference in fall incidence were compared between the 2 groups. The average number of falls per person in PD patients without cognitive impairment dysfunction was significantly lower than that in patients in the PD mild cognitive impairment (PD-MCI) group and that in the PD dementia (PDD) group (p < 0.01, p < 0.001, respectively), and the incidence of falls was significantly lower than that in patients in the PD-MCI and PDD groups (p < 0.01, p < 0.01, respectively). Compared to the PD-MCI group, the incidence of falls of patients in the PDD group (OR 2.45, 95% CI 0.97-6.20, p < 0.01) and the number of falls per person were significantly increased (p < 0.01). After taking the placebo or Rivastigmine for 12 months, the MoCA scores of patients in the Rivastigmine treatment group were significantly higher than those of the control group (p = 0.002). The number of falls per person and the incidence of falls of patients in Rivastigmine treatment group were significantly lower than those in the placebo group (p < 0.01). This study suggests that the degree of cognitive impairment is closely associated with the incidence of falls, and the cholinesterase inhibitor Rivastigmine can delay the deterioration of cognitive function and lower the incidence of falls in PD patients. © 2015 S. Karger AG, Basel.

Early deficits in spatial memory and theta rhythm in experimental temporal lobe epilepsy.

PubMed

Chauvière, Laetitia; Rafrafi, Nadia; Thinus-Blanc, Catherine; Bartolomei, Fabrice; Esclapez, Monique; Bernard, Christophe

2009-04-29

Patients with temporal lobe epilepsy (TLE), the most common form of epilepsy in adults, often display cognitive deficits. The time course and underlying mechanisms of cognitive decline remain unknown during epileptogenesis (the process leading to epilepsy). Using the rat pilocarpine model of TLE, we performed a longitudinal study to assess spatial and nonspatial cognitive performance during epileptogenesis. In parallel, we monitored interictal-like activity (ILA) in the hippocampal CA1 region, as well as theta oscillations, a brain rhythm central to numerous cognitive processes. Here, we report that spatial memory was altered soon after pilocarpine-induced status epilepticus, i.e., already during the seizure-free, latent period. Spatial deficits correlated with a decrease in the power of theta oscillations but not with the frequency of ILA. Spatial deficits persisted when animals had spontaneous seizures (chronic stage) without further modification. In contrast, nonspatial memory performances remained unaffected throughout. We conclude that the reorganization of hippocampal circuitry that immediately follows the initial insult can affect theta oscillation mechanisms, in turn, resulting in deficits in hippocampus-dependent memory tasks. These deficits may be dissociated from the process that leads to epilepsy itself but could instead constitute, as ILA, early markers in at-risk patients and/or provide beneficial therapeutic targets.

Psychostimulants, antidepressants and neurokinin-1 receptor antagonists ('motor disinhibitors') have overlapping, but distinct, effects on monoamine transmission: the involvement of L-type Ca2+ channels and implications for the treatment of ADHD.

PubMed

Stanford, S Clare

2014-12-01

Both psychostimulants and antidepressants target monoamine transporters and, as a consequence, augment monoamine transmission. These two groups of drugs also increase motor activity in preclinical behavioural screens for antidepressants. Substance P-preferring receptor (NK1R) antagonists similarly increase both motor activity in these tests and monoamine transmission in the brain. In this article, the neurochemical and behavioural responses to these three groups of drugs are compared. It becomes evident that NK1R antagonists represent a distinct class of compounds ('motor disinhibitors') that differ substantially from both psychostimulants and antidepressants, especially during states of heightened arousal or stress. Also, all three groups of drugs influence the activation of voltage-gated Ca(v)1.2 and Ca(v)1.3 L-type channels (LTCCs) in the brain, albeit in different ways. This article discusses evidence that points to disruption of these functional interactions between NK1R and LTCCs as a contributing factor in the cognitive and behavioural abnormalities that are prominent features of Attention Deficit Hyperactivity Disorder (ADHD). Arising from this is the interesting possibility that the hyperactivity and impulsivity (as in ADHD) and psychomotor retardation (as in depression) reflect opposite poles of a behavioural continuum. A better understanding of this pharmacological network could help explain why psychostimulants augment motor behaviour during stress (e.g., in preclinical screens for antidepressants) and yet reduce locomotor activity and impulsivity in ADHD. This article is part of the Special Issue entitled 'CNS Stimulants'. Copyright © 2014 The Author. Published by Elsevier Ltd.. All rights reserved.

Upper-Extremity Dual-Task Function: An Innovative Method to Assess Cognitive Impairment in Older Adults.

PubMed

Toosizadeh, Nima; Najafi, Bijan; Reiman, Eric M; Mager, Reine M; Veldhuizen, Jaimeson K; O'Connor, Kathy; Zamrini, Edward; Mohler, Jane

2016-01-01

Difficulties in orchestrating simultaneous tasks (i.e., dual-tasking) have been associated with cognitive impairments in older adults. Gait tests have been commonly used as the motor task component for dual-task assessments; however, many older adults have mobility impairments or there is a lack of space in busy clinical settings. We assessed an upper-extremity function (UEF) test as an alternative motor task to study the dual-task motor performance in older adults. Older adults (≥65 years) were recruited, and cognitive ability was measured using the Montreal cognitive assessment (MoCA). Participants performed repetitive elbow flexion with their maximum pace, once single-task, and once while counting backward by one (dual-task). Single- and dual-task gait tests were also performed with normal speed. Three-dimensional kinematics was measured both from upper-extremity and lower-extremity using wearable sensors to determine UEF and gait parameters. Parameters were compared between the cognitively impaired and healthy groups using analysis of variance tests, while controlling for age, gender, and body mass index (BMI). Correlations between UEF and gait parameters for dual-task and dual-task cost were assessed using linear regression models. Sixty-seven older adults were recruited (age = 83 ± 10 years). Based on MoCA, 10 (15%) were cognitively impaired. While no significant differences were observed in the single-task condition, within the dual-task condition, the cognitively impaired group showed significantly less arm flexion speed (62%, d = 1.51, p = 0.02) and range of motion (27%, d = 0.93, p = 0.04), and higher speed variability (88%, d = 1.82, p < 0.0001) compared to the cognitively intact group, when adjusted with age, gender, and BMI. Significant correlations were observed between UEF speed parameters and gait stride velocity for dual-task condition (r = 0.55, p < 0.0001) and dual-task cost (r = 0.28, p = 0.03). We introduced a novel test for assessing dual-task performance in older adults that lasts 20 s and is based on upper-extremity function. Our results confirm significant associations between upper-extremity speed, range of motion, and speed variability with both the MoCA score and the gait performance within the dual-task condition.

Upper-Extremity Dual-Task Function: An Innovative Method to Assess Cognitive Impairment in Older Adults

PubMed Central

Toosizadeh, Nima; Najafi, Bijan; Reiman, Eric M.; Mager, Reine M.; Veldhuizen, Jaimeson K.; O’Connor, Kathy; Zamrini, Edward; Mohler, Jane

2016-01-01

Background: Difficulties in orchestrating simultaneous tasks (i.e., dual-tasking) have been associated with cognitive impairments in older adults. Gait tests have been commonly used as the motor task component for dual-task assessments; however, many older adults have mobility impairments or there is a lack of space in busy clinical settings. We assessed an upper-extremity function (UEF) test as an alternative motor task to study the dual-task motor performance in older adults. Methods: Older adults (≥65 years) were recruited, and cognitive ability was measured using the Montreal cognitive assessment (MoCA). Participants performed repetitive elbow flexion with their maximum pace, once single-task, and once while counting backward by one (dual-task). Single- and dual-task gait tests were also performed with normal speed. Three-dimensional kinematics was measured both from upper-extremity and lower-extremity using wearable sensors to determine UEF and gait parameters. Parameters were compared between the cognitively impaired and healthy groups using analysis of variance tests, while controlling for age, gender, and body mass index (BMI). Correlations between UEF and gait parameters for dual-task and dual-task cost were assessed using linear regression models. Results: Sixty-seven older adults were recruited (age = 83 ± 10 years). Based on MoCA, 10 (15%) were cognitively impaired. While no significant differences were observed in the single-task condition, within the dual-task condition, the cognitively impaired group showed significantly less arm flexion speed (62%, d = 1.51, p = 0.02) and range of motion (27%, d = 0.93, p = 0.04), and higher speed variability (88%, d = 1.82, p < 0.0001) compared to the cognitively intact group, when adjusted with age, gender, and BMI. Significant correlations were observed between UEF speed parameters and gait stride velocity for dual-task condition (r = 0.55, p < 0.0001) and dual-task cost (r = 0.28, p = 0.03). Conclusion: We introduced a novel test for assessing dual-task performance in older adults that lasts 20 s and is based on upper-extremity function. Our results confirm significant associations between upper-extremity speed, range of motion, and speed variability with both the MoCA score and the gait performance within the dual-task condition. PMID:27458374

Calycosin and Formononetin Induce Endothelium-Dependent Vasodilation by the Activation of Large-Conductance Ca2+-Activated K+ Channels (BKCa)

PubMed Central

Tseng, Hisa Hui Ling; Vong, Chi Teng; Leung, George Pak-Heng; Seto, Sai Wang; Lee, Simon Ming-Yuen

2016-01-01

Calycosin and formononetin are two structurally similar isoflavonoids that have been shown to induce vasodilation in aorta and conduit arteries, but study of their actions on endothelial functions is lacking. Here, we demonstrated that both isoflavonoids relaxed rat mesenteric resistance arteries in a concentration-dependent manner, which was reduced by endothelial disruption and nitric oxide synthase (NOS) inhibition, indicating the involvement of both endothelium and vascular smooth muscle. In addition, the endothelium-dependent vasodilation, but not the endothelium-independent vasodilation, was blocked by BKCa inhibitor iberiotoxin (IbTX). Using human umbilical vein endothelial cells (HUVECs) as a model, we showed calycosin and formononetin induced dose-dependent outwardly rectifying K+ currents using whole cell patch clamp. These currents were blocked by tetraethylammonium chloride (TEACl), charybdotoxin (ChTX), or IbTX, but not apamin. We further demonstrated that both isoflavonoids significantly increased nitric oxide (NO) production and upregulated the activities and expressions of endothelial NOS (eNOS) and neuronal NOS (nNOS). These results suggested that calycosin and formononetin act as endothelial BKCa activators for mediating endothelium-dependent vasodilation through enhancing endothelium hyperpolarization and NO production. Since activation of BKCa plays a role in improving behavioral and cognitive disorders, we suggested that these two isoflavonoids could provide beneficial effects to cognitive disorders through vascular regulation. PMID:27994632

Combined Treatment With Environmental Enrichment and (-)-Epigallocatechin-3-Gallate Ameliorates Learning Deficits and Hippocampal Alterations in a Mouse Model of Down Syndrome.

PubMed

Catuara-Solarz, Silvina; Espinosa-Carrasco, Jose; Erb, Ionas; Langohr, Klaus; Gonzalez, Juan Ramon; Notredame, Cedric; Dierssen, Mara

2016-01-01

Intellectual disability in Down syndrome (DS) is accompanied by altered neuro-architecture, deficient synaptic plasticity, and excitation-inhibition imbalance in critical brain regions for learning and memory. Recently, we have demonstrated beneficial effects of a combined treatment with green tea extract containing (-)-epigallocatechin-3-gallate (EGCG) and cognitive stimulation in young adult DS individuals. Although we could reproduce the cognitive-enhancing effects in mouse models, the underlying mechanisms of these beneficial effects are unknown. Here, we explored the effects of a combined therapy with environmental enrichment (EE) and EGCG in the Ts65Dn mouse model of DS at young age. Our results show that combined EE-EGCG treatment improved corticohippocampal-dependent learning and memory. Cognitive improvements were accompanied by a rescue of cornu ammonis 1 (CA1) dendritic spine density and a normalization of the proportion of excitatory and inhibitory synaptic markers in CA1 and dentate gyrus.

Combined Treatment With Environmental Enrichment and (-)-Epigallocatechin-3-Gallate Ameliorates Learning Deficits and Hippocampal Alterations in a Mouse Model of Down Syndrome

PubMed Central

Gonzalez, Juan Ramon; Notredame, Cedric

2016-01-01

Intellectual disability in Down syndrome (DS) is accompanied by altered neuro-architecture, deficient synaptic plasticity, and excitation-inhibition imbalance in critical brain regions for learning and memory. Recently, we have demonstrated beneficial effects of a combined treatment with green tea extract containing (-)-epigallocatechin-3-gallate (EGCG) and cognitive stimulation in young adult DS individuals. Although we could reproduce the cognitive-enhancing effects in mouse models, the underlying mechanisms of these beneficial effects are unknown. Here, we explored the effects of a combined therapy with environmental enrichment (EE) and EGCG in the Ts65Dn mouse model of DS at young age. Our results show that combined EE-EGCG treatment improved corticohippocampal-dependent learning and memory. Cognitive improvements were accompanied by a rescue of cornu ammonis 1 (CA1) dendritic spine density and a normalization of the proportion of excitatory and inhibitory synaptic markers in CA1 and dentate gyrus. PMID:27844057

Cholesteryl Ester Transfer Protein Intimately Involved in Dyslipidemia-Related Susceptibility to Cognitive Deficits in Type 2 Diabetic Patients.

PubMed

Sun, Jie; Cai, Rongrong; Huang, Rong; Wang, Pin; Tian, Sai; Sun, Haixia; Xia, Wenqing; Wang, Shaohua

2016-08-01

Cholesteryl ester transfer protein (CETP) is involved in diabetic dyslipidemia. We aim to test the hypothesis that CETP might be of importance in mediating dyslipidemia-related susceptibility to cognitive deficits in diabetic patients. We recruited 190 type 2 diabetic patients and divided them into two groups according to the Montreal Cognitive Assessment (MoCA) score. The association between CETP and cognitive decline was analyzed with logistic regression and stratification. There were 110 diabetic patients with mild cognition impairment (MCI) and 80 healthy cognition subjects as controls. Dyslipidemia is more common among diabetic patients with MCI; they had a significant increase of serum CETP concentrations, which was negatively correlated with MoCA (r = -0.638; p < 0.001). Negative correlations were also found between the serum CETP concentration with the Auditory Verbal Learning Test (r = -0.266; p = 0.008), indicating memory deficit. Logistic regression analysis revealed that CETP concentration was an independent factor of diabetic MCI (p < 0.001). Further stratification study showed that high serum levels of CETP was an independent risk factor of MCI in diabetic patients with a low density lipoproteins level ≥2.59 mmol/L, or high density lipoproteins level ≤1.0 mmol/L for men and ≤1.3 mmol/L for women, or TG level ≥1.7 mmol/L, after adjusting for age, sex, education, and glucose control (all ps < 0.05). CETP was intimately involved in dyslipidemia-related susceptibility to cognitive decline, especially memory function in type 2 diabetic patients.

The association between orthostatic hypotension and cognitive state among adults 65 years and older who underwent a comprehensive geriatric assessment

PubMed Central

Punchick, Boris; Freud, Tamar; Press, Yan

2016-01-01

Abstract The prevalence of cognitive impairment and orthostatic hypotension (OH) increases with age, but the results of studies that assessed possible associations between them are inconsistent. The aim of this study is to assess possible associations between cognitive impairment and OH in patients ≥65 years of age who underwent a comprehensive geriatric assessment. A retrospective analysis was conducted of the computerized medical records of the study population from 2005 to 2013. Data collected included blood pressure measurements that enabled the calculation of OH, results of the mini-mental state examination (MMSE), results of the Montreal cognitive assessment (MoCA) test, and cognitive diagnoses that were determined over the course of the assessment. The rate of OH in the study population of 571 adults was 32.1%. The mean MMSE score was 22.5 ± 5.2 among participants with OH and 21.6 ± 5.8 among those without OH (P = 0.09). The absence of a significant association between OH and MMSE remained after adjusting the MMSE score for age and education level. The mean MoCA score was 16.4 ± 5.0 among participants with OH and 16.4 ± 4.8 among those without (P = 0.33). The prevalence of OH was 39% among participants without cognitive impairment, 28.9% among those with mild cognitive impairment (MCI), and 30.6% among those with dementia (P = 0.13). There was no association between OH and cognitive impairment in adults who underwent a comprehensive geriatric assessment. PMID:27442658

Correlation between cognitive impairment during the acute phase of first cerebral infarction and development of long-term pseudobulbar affect

PubMed Central

Wang, Yuan; Wang, Yuliang; Ma, Wenbin; Lu, Shujun; Chen, Jinbo; Cao, Lili

2018-01-01

Purpose The relationship between cognitive impairment during the acute phase of first cerebral infarction and the development of long-term pseudobulbar affect (PBA) has not been elucidated. Therefore, in this study, we aimed to determine if cognitive impairment during the acute phase of cerebral infarction will increase the risk of long-term post-infarction PBA. Patients and methods This was a nested case–control study using a prospective approach. A consecutive multicenter matched 1:1 case–control study of cognitive impairment cases following acute cerebral infarction (N=26) with 26 sex-, education years-, and age-matched controls. Univariate and multivariate conditional logistic regression analyses were performed to study the clinical features and changes in cognitive domain as well as the risk factors for PBA. Results Long-term PBA was independently predicted by low Montreal cognitive assessment (MoCA) scores at baseline. Multivariable regression models showed that post-infarction low MoCA scores remained independent predictors of long-term PBA (odds ratio [OR]=0.72; 95% confidence interval [CI]=0.54–0.95; P=0.018). Among all cognitive disorders, digit span test (DST) scores (OR=0.39; 95% CI=0.16–0.91, P=0.030), StroopC time (OR=1.15; 95% CI=1.01–1.31; P=0.037), and clock-drawing task (CDT) scores (OR=0.62; 95% CI=0.42–0.90; P=0.013) were found to be the independent risk factors for PBA. Conclusion Cognitive impairment during the acute phase of cerebral infarction increased the risk of cerebral infarction-induced long-term PBA. Development of PBA was closely associated with executive function, attention, and visuospatial disorder. PMID:29636612

Correlation between cognitive impairment during the acute phase of first cerebral infarction and development of long-term pseudobulbar affect.

PubMed

Wang, Yuan; Wang, Yuliang; Ma, Wenbin; Lu, Shujun; Chen, Jinbo; Cao, Lili

2018-01-01

The relationship between cognitive impairment during the acute phase of first cerebral infarction and the development of long-term pseudobulbar affect (PBA) has not been elucidated. Therefore, in this study, we aimed to determine if cognitive impairment during the acute phase of cerebral infarction will increase the risk of long-term post-infarction PBA. This was a nested case-control study using a prospective approach. A consecutive multicenter matched 1:1 case-control study of cognitive impairment cases following acute cerebral infarction (N=26) with 26 sex-, education years-, and age-matched controls. Univariate and multivariate conditional logistic regression analyses were performed to study the clinical features and changes in cognitive domain as well as the risk factors for PBA. Long-term PBA was independently predicted by low Montreal cognitive assessment (MoCA) scores at baseline. Multivariable regression models showed that post-infarction low MoCA scores remained independent predictors of long-term PBA (odds ratio [OR]=0.72; 95% confidence interval [CI]=0.54-0.95; P =0.018). Among all cognitive disorders, digit span test (DST) scores (OR=0.39; 95% CI=0.16-0.91, P =0.030), StroopC time (OR=1.15; 95% CI=1.01-1.31; P =0.037), and clock-drawing task (CDT) scores (OR=0.62; 95% CI=0.42-0.90; P =0.013) were found to be the independent risk factors for PBA. Cognitive impairment during the acute phase of cerebral infarction increased the risk of cerebral infarction-induced long-term PBA. Development of PBA was closely associated with executive function, attention, and visuospatial disorder.

The Utility of the Montreal Cognitive Assessment as a Mental Capacity Assessment Tool for Patients with a Learning Disability

ERIC Educational Resources Information Center

Edge, Daniel; Oyefeso, Adenekan; Evans, Carys; Evans, Amber

2016-01-01

Objective: To determine the psychometric properties of the Montreal Cognitive Assessment (MoCA) in patients with a learning disability and examine it's utility for conducting mental capacity assessment. Method: This study was a cross-sectional, instrument validation study in an inpatient hospital setting, located in the East of England. The sample…

Application of Cognitive Apprenticeship Model to a Graduate Course in Performance Systems Analysis: A Case Study

ERIC Educational Resources Information Center

Darabi, A. Aubteen

2005-01-01

This article reports a case study describing how the principles of a cognitive apprenticeship (CA) model developed by Collins, Brown, and Holum (1991) were applied to a graduate course on performance systems analysis (PSA), and the differences this application made in student performance and evaluation of the course compared to the previous…

[Acupuncture at Baihui(GV 20) and Shenting(GV 24) combined with basic treatment and regular rehabilitation for post-stroke cognitive impairment:a randomized controlled trial].

PubMed

Zhan, Jie; Pan, Ruihuan; Guo, Youhua; Zhan, Lechang; He, Mingfeng; Wang, Qiuchun; Chen, Hongxia

2016-08-12

To observe the clinical effect of acupuncture at Baihui(GV 20) and Shenting(GV 24) combined with rehabilitation for post-stroke cognitive impairment(PSCI). Fifty patients with PSCI were randomly assigned to an observation group and a control group,25 cases in each one. In the control group,basic treatment and regular rehabilitation were applied. In the observation group,acupuncture at Baihui(GV 20) and Shenting(GV 24) and the same therapies as the control group were used for continuous four weeks,once a day and five times a week. Mini-mental state examination(MMSE) and Montreal cognitive assessment(MoCA) were observed before and after treatment in the two groups. After treatment,the scores of MMSE and MoCA were improved apparently(both P <0.05),with better results in the observation group(both P <0.05). Acupuncture at Baihui(GV 20) and Shenting(GV 24) combined with basic treatment and regular rehabilitation can obviously improve the cognitive function of PSCI,and the effect is superior to that of basic treatment and regular rehabilitation.

Pharmacotherapy with Fluoxetine Restores Functional Connectivity from the Dentate Gyrus to Field CA3 in the Ts65Dn Mouse Model of Down Syndrome

PubMed Central

Guidi, Sandra; Ciani, Elisabetta; Mangano, Chiara; Calzà, Laura; Bartesaghi, Renata

2013-01-01

Down syndrome (DS) is a high-incidence genetic pathology characterized by severe impairment of cognitive functions, including declarative memory. Impairment of hippocampus-dependent long-term memory in DS appears to be related to anatomo-functional alterations of the hippocampal trisynaptic circuit formed by the dentate gyrus (DG) granule cells - CA3 pyramidal neurons - CA1 pyramidal neurons. No therapies exist to improve cognitive disability in individuals with DS. In previous studies we demonstrated that pharmacotherapy with fluoxetine restores neurogenesis, granule cell number and dendritic morphology in the DG of the Ts65Dn mouse model of DS. The goal of the current study was to establish whether treatment rescues the impairment of synaptic connectivity between the DG and CA3 that characterizes the trisomic condition. Euploid and Ts65Dn mice were treated with fluoxetine during the first two postnatal weeks and examined 45–60 days after treatment cessation. Untreated Ts65Dn mice had a hypotrophyc mossy fiber bundle, fewer synaptic contacts, fewer glutamatergic contacts, and fewer dendritic spines in the stratum lucidum of CA3, the terminal field of the granule cell projections. Electrophysiological recordings from CA3 pyramidal neurons showed that in Ts65Dn mice the frequency of both mEPSCs and mIPSCs was reduced, indicating an overall impairment of excitatory and inhibitory inputs to CA3 pyramidal neurons. In treated Ts65Dn mice all these aberrant features were fully normalized, indicating that fluoxetine can rescue functional connectivity between the DG and CA3. The positive effects of fluoxetine on the DG-CA3 system suggest that early treatment with this drug could be a suitable therapy, possibly usable in humans, to restore the physiology of the hippocampal networks and, hence, memory functions. PMID:23620781

Wnt5a is essential for hippocampal dendritic maintenance and spatial learning and memory in adult mice

PubMed Central

Chen, Chih-Ming; Orefice, Lauren L.; Chiu, Shu-Ling; LeGates, Tara A.; Huganir, Richard L.; Zhao, Haiqing; Xu, Baoji; Kuruvilla, Rejji

2017-01-01

Stability of neuronal connectivity is critical for brain functions, and morphological perturbations are associated with neurodegenerative disorders. However, how neuronal morphology is maintained in the adult brain remains poorly understood. Here, we identify Wnt5a, a member of the Wnt family of secreted morphogens, as an essential factor in maintaining dendritic architecture in the adult hippocampus and for related cognitive functions in mice. Wnt5a expression in hippocampal neurons begins postnatally, and its deletion attenuated CaMKII and Rac1 activity, reduced GluN1 glutamate receptor expression, and impaired synaptic plasticity and spatial learning and memory in 3-mo-old mice. With increased age, Wnt5a loss caused progressive attrition of dendrite arbors and spines in Cornu Ammonis (CA)1 pyramidal neurons and exacerbated behavioral defects. Wnt5a functions cell-autonomously to maintain CA1 dendrites, and exogenous Wnt5a expression corrected structural anomalies even at late-adult stages. These findings reveal a maintenance factor in the adult brain, and highlight a trophic pathway that can be targeted to ameliorate dendrite loss in pathological conditions. PMID:28069946

APOE ε4 status in healthy older African Americans is associated with deficits in pattern separation and hippocampal hyperactivation.

PubMed

Sinha, Neha; Berg, Chelsie N; Tustison, Nicholas J; Shaw, Ashlee; Hill, Diane; Yassa, Michael A; Gluck, Mark A

2018-05-26

African Americans are 1.4 times more likely than European Americans to carry the apolipoprotein E (APOE) ε4 allele, a risk factor for Alzheimer's disease (AD). However, little is known about the neural correlates of cognitive function in older African Americans and how they relate to genetic risk for AD. In particular, no past study on African Americans has examined the effect of APOE ε4 status on pattern separation-mnemonic discrimination performance and its corresponding neural computations in the hippocampus. Previous work using the mnemonic discrimination paradigm has localized increased activation in the DG/CA3 hippocampal subregions as being correlated with discrimination deficits. In a case-control high-resolution functional magnetic resonance imaging study of 30 healthy African Americans, aged 60 years and older, we observed APOE ε4-related impairments in mnemonic discrimination, coincident with dysfunctional hyperactivation in the DG/CA3, and CA1 regions, despite no evidence of structural differences in the hippocampus between carriers and noncarriers. Our results add to the growing body of evidence that deficits in pattern separation may be an early marker for AD-related neuronal dysfunction. Copyright © 2018 Elsevier Inc. All rights reserved.

Dorsal hippocampal NMDA receptors mediate the interactive effects of arachidonylcyclopropylamide and MDMA/ecstasy on memory retrieval in rats.

PubMed

Ghaderi, Marzieh; Rezayof, Ameneh; Vousooghi, Nasim; Zarrindast, Mohammad-Reza

2016-04-03

A combination of cannabis and ecstasy may change the cognitive functions more than either drug alone. The present study was designed to investigate the possible involvement of dorsal hippocampal NMDA receptors in the interactive effects of arachidonylcyclopropylamide (ACPA) and ecstasy/MDMA on memory retrieval. Adult male Wistar rats were cannulated into the CA1 regions of the dorsal hippocampus (intra-CA1) and memory retrieval was examined using the step-through type of passive avoidance task. Intra-CA1 microinjection of a selective CB1 receptor agonist, ACPA (0.5-4ng/rat) immediately before the testing phase (pre-test), but not after the training phase (post-training), impaired memory retrieval. In addition, pre-test intra-CA1 microinjection of MDMA (0.5-1μg/rat) dose-dependently decreased step-through latency, indicating an amnesic effect of the drug by itself. Interestingly, pre-test microinjection of a higher dose of MDMA into the CA1 regions significantly improved ACPA-induced memory impairment. Moreover, pre-test intra-CA1 microinjection of a selective NMDA receptor antagonist, D-AP5 (1 and 2μg/rat) inhibited the reversal effect of MDMA on the impairment of memory retrieval induced by ACPA. Pre-test intra-CA1 microinjection of the same doses of D-AP5 had no effect on memory retrieval alone. These findings suggest that ACPA or MDMA consumption can induce memory retrieval impairment, while their co-administration improves this amnesic effect through interacting with hippocampal glutamatergic-NMDA receptor mechanism. Thus, it seems that the tendency to abuse cannabis with ecstasy may be for avoiding cognitive dysfunction. Copyright © 2015. Published by Elsevier Inc.

Pharmacological Intervention of Hippocampal CA3 NMDA Receptors Impairs Acquisition and Long-Term Memory Retrieval of Spatial Pattern Completion Task

ERIC Educational Resources Information Center

Fellini, Laetitia; Florian, Cedrick; Courtey, Julie; Roullet, Pascal

2009-01-01

Pattern completion is the ability to retrieve complete information on the basis of incomplete retrieval cues. Although it has been demonstrated that this cognitive capacity depends on the NMDA receptors (NMDA-Rs) of the hippocampal CA3 region, the role played by these glutamatergic receptors in the pattern completion process has not yet been…

The neuropeptide-12 improves recognition memory and neuronal plasticity of the limbic system in old rats.

PubMed

Hernández-Hernández, Elizabeth Monserrat; Caporal Hernandez, Karen; Vázquez-Roque, Rubén Antonio; Díaz, Alfonso; de la Cruz, Fidel; Florán, Benjamin; Flores, Gonzalo

2018-08-01

Aging is a stage of life where cognitive and motor functions are impaired. This is because oxidative and inflammatory processes exacerbate neurodegeneration, which affects dendritic morphology and neuronal communication of limbic regions with memory loss. Recently, the use of trophic substances has been proposed to prevent neuronal deterioration. The neuropeptide-12 (N-PEP-12) has been evaluated in elderly patients with dementia, showing improvements in cognitive tasks due to acts as a neurotrophic factor. In the present work, we evaluated the effect of N-PEP-12 on motor activity and recognition memory, as well as its effects on dendritic morphology and the immunoreactivity of GFAP, Synaptophysin (SYP), and BDNF in neurons of the prefrontal cortex (PFC), dorsal hippocampus (DH) and nucleus accumbens (NAcc) of aged rats. The results show that N-PEP-12 improved the recognition memory, but the motor activity was not modified compared to the control animals. N-PEP-12 increases the density of dendritic spines and the total dendritic length in neurons of the PFC (layers 3 and 5) and in DH (CA1 and CA3). Interestingly NAcc neurons showed a reduction in the number of dendritic spines. In the N-PEP-12 animals, when evaluating the immunoreactivity for SYP and BDNF, there was an increase in the three brain regions, while the mark for GFAP decreased significantly. Our results suggest that N-PEP-12 promotes neuronal plasticity in the limbic system of aged animals, which contributes to improving recognition memory. In this sense, N-PEP-12 can be considered as a pharmacological alternative to prevent or delay brain aging and control senile dementias. © 2018 Wiley Periodicals, Inc.

Rhynchophylline Protects Against the Amyloid β-Induced Increase of Spontaneous Discharges in the Hippocampal CA1 Region of Rats.

PubMed

Shao, Hui; Mi, Ze; Ji, Wei-gang; Zhang, Cheng-huan; Zhang, Teng; Ren, Shuan-cheng; Zhu, Zhi-ru

2015-11-01

Accumulated soluble amyloid β (Aβ)-induced aberrant neuronal network activity has been recognized as a key causative factor leading to cognitive deficits which are the most outstanding characteristic of Alzheimer's disease (AD). As an important structure associated with learning and memory, the hippocampus is one of the brain regions that are impaired very early in AD, and the hippocampal CA1 region is selectively vulnerable to soluble Aβ oligomers. Our recent study showed that soluble Aβ1-42 oligomers induced hyperactivity and perturbed the firing patterns in hippocampal neurons. Rhynchophylline (RIN) is an important active tetracyclic oxindole alkaloid isolated from Uncaria rhynchophylla which is a traditional Chinese medicine and often used to treat central nervous system illnesses such as hypertension, convulsions, tremor, stroke etc. Previous evidence showed that RIN possessed neuroprotective effects of improving the cognitive function of mice with Alzheimer-like symptoms. In the present study, we aimed to investigate the protective effect of RIN against soluble Aβ1-42 oligomers-induced hippocampal hyperactivity. The results showed that (1) the mean frequency of spontaneous discharge was increased by the local application of 3 μM soluble Aβ1-42 oligomers; (2) 30 μM RIN did not exert any obvious effects on basal physiological discharges; and (3) treatment with RIN effectively inhibited the soluble Aβ1-42 oligomers-induced enhancement of spontaneous discharge, in a concentration-dependent manner with an IC50 = 9.0 μM. These in vivo electrophysiological results indicate that RIN can remold the spontaneous discharges disturbed by Aβ and counteract the deleterious effect of Aβ1-42 on neural circuit. The experimental findings provide further evidence to affirm the potential of RIN as a worthy candidate for further development into a therapeutic agent for AD.

Microglial response to Alzheimer's disease is differentially modulated by voluntary wheel running and enriched environments.

PubMed

Rodríguez, J J; Noristani, H N; Verkhratsky, A

2015-03-01

Alzheimer's disease (AD) is an untreatable neurodegenerative disease that deteriorates memory. Increased physical/cognitive activity reduces dementia risk by promoting neuronal and glial response. Although few studies have investigated microglial response in wild-type rodents following exposure to physical/cognitive stimulation, environmental-induced changes of microglia response to AD have been neglected. We investigated effects of running (RUN) and enriched (ENR) environments on numerical density (N v, #/mm(3)) and morphology of microglia in a triple transgenic (3×Tg-AD) mouse model of AD that closely mimics AD pathology in humans. We used immunohistochemical approach to characterise microglial domain by measuring their overall cell surface, volume and somata volume. 3×Tg-AD mice housed in standard control (STD) environment showed significant increase in microglial N v (11.7 %) in CA1 stratum lacunosum moleculare (S.Mol) of the hippocampus at 12 months compared to non-transgenic (non-Tg) animals. Exposure to combined RUN and ENR environments prevented an increase in microglial N v in 3×Tg-AD and reduced microglial numbers to non-Tg control levels. Interestingly, 3×Tg-AD mice housed solely in ENR environment displayed significant decrease in microglial N v in CA1 subfield (9.3 % decrease), stratum oriens (11.5 % decrease) and S.Mol (7.6 % decrease) of the hippocampus compared to 3×Tg-AD mice housed in STD environment. Morphological analysis revealed microglial hypertrophy due to pronounced increase in microglia surface, volume and somata volume (61, 78 and 41 %) in 3×Tg-AD mice housed in RUN (but not in ENR) compared to STD environment. These results indicate that exposure to RUN and ENR environments have differential effects on microglial density and activation-associated changes in microglial morphology.

Community-based parent-delivered early detection and intervention programme for infants at high risk of cerebral palsy in a low-resource country (Learning through Everyday Activities with Parents (LEAP-CP): protocol for a randomised controlled trial.

PubMed

Benfer, Katherine A; Novak, Iona; Morgan, Catherine; Whittingham, Koa; Khan, Naila Zaman; Ware, Robert S; Bell, Kristie L; Bandaranayake, Sasaka; Salt, Alison; Ghosh, Asis Kumar; Bhattacharya, Anjan; Samanta, Sandip; Moula, Golam; Bose, Dilip; Tripathi, Santanu; Boyd, Roslyn N

2018-06-22

Cerebral palsy (CP) is the most common childhood physical disability, with 80% estimated to be in low-middle-income countries. This study aims to (1) determine the accuracy of General Movements (GMs)/Hammersmith Infant Neurological Examination (HINE) for detecting CP at 18 months corrected age (CA); (2) determine the effectiveness of a community-based parent-delivered early intervention for infants at high risk of CP in West Bengal, India (Learning through Everyday Activities with Parents for infants with CP; LEAP-CP). This study comprises two substudies: (1) a study of the predictive validity of the GMs and HINE for detecting CP; (2) randomised, double-blinded controlled trial of a novel intervention delivered through peer trainers (Community Disability Workers, CDW) compared with health advice (15 fortnightly visits). 142 infants at high risk of CP ('absent fidgety' GMs; 'high risk score' on HINE) aged 12-40 weeks CA will be recruited to the intervention substudy, with infants randomised based on a computer-generated sequence. Researchers will be masked to group allocation, and caregivers and CDWs naïve to intervention status. Visits will include therapeutic modules (goal-directed active motor/cognitive strategies and LEAP-CP games) and parent education. Health advice is based on the Integrated Management of Childhood Illness, WHO. Infants will be evaluated at baseline, post intervention and 18 months CA. The primary hypothesis is that infants receiving LEAP-CP will have greater scaled scores on the Pediatric Evaluation of Disability Inventory-Computer Adaptive Test (mobility domain) at 18 months compared with health advice. Secondary outcomes include infant functional motor, cognitive, visual and communication development; infant growth; maternal mental health. This study is approved through appropriate Australian and Indian ethics committees (see in text) with families providing written informed consent. Findings from this trial will be disseminated through peer-reviewed journal publications and conference presentations. 12616000653460p; Pre-results. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Signers and co-speech gesturers adopt similar strategies for portraying viewpoint in narratives.

PubMed

Quinto-Pozos, David; Parrill, Fey

2015-01-01

Gestural viewpoint research suggests that several dimensions determine which perspective a narrator takes, including properties of the event described. Events can evoke gestures from the point of view of a character (CVPT), an observer (OVPT), or both perspectives. CVPT and OVPT gestures have been compared to constructed action (CA) and classifiers (CL) in signed languages. We ask how CA and CL, as represented in ASL productions, compare to previous results for CVPT and OVPT from English-speaking co-speech gesturers. Ten ASL signers described cartoon stimuli from Parrill (2010). Events shown by Parrill to elicit a particular gestural strategy (CVPT, OVPT, both) were coded for signers' instances of CA and CL. CA was divided into three categories: CA-torso, CA-affect, and CA-handling. Signers used CA-handling the most when gesturers used CVPT exclusively. Additionally, signers used CL the most when gesturers used OVPT exclusively and CL the least when gesturers used CVPT exclusively. Copyright © 2014 Cognitive Science Society, Inc.

Excess influx of Zn(2+) into dentate granule cells affects object recognition memory via attenuated LTP.

PubMed

Suzuki, Miki; Fujise, Yuki; Tsuchiya, Yuka; Tamano, Haruna; Takeda, Atsushi

2015-08-01

The influx of extracellular Zn(2+) into dentate granule cells is nonessential for dentate gyrus long-term potentiation (LTP) and the physiological significance of extracellular Zn(2+) dynamics is unknown in the dentate gyrus. Excess increase in extracellular Zn(2+) in the hippocampal CA1, which is induced with excitation of zincergic neurons, induces memory deficit via excess influx of Zn(2+) into CA1 pyramidal cells. In the present study, it was examined whether extracellular Zn(2+) induces object recognition memory deficit via excess influx of Zn(2+) into dentate granule cells. KCl (100 mM, 2 µl) was locally injected into the dentate gyrus. The increase in intracellular Zn(2+) in dentate granule cells induced with high K(+) was blocked by co-injection of CaEDTA and CNQX, an extracellular Zn(2+) chelator and an AMPA receptor antagonist, respectively, suggesting that high K(+) increases the influx of Zn(2+) into dentate granule cells via AMPA receptor activation. Dentate gyrus LTP induction was attenuated 1 h after KCl injection into the dentate gyrus and also attenuated when KCl was injected 5 min after the induction. Memory deficit was induced when training of object recognition test was performed 1 h after KCl injection into the dentate gyrus and also induced when KCl was injected 5 min after the training. High K(+)-induced impairments of LTP and memory were rescued by co-injection of CaEDTA. These results indicate that excess influx of Zn(2+) into dentate granule cells via AMPA receptor activation affects object recognition memory via attenuated LTP induction. Even in the dentate gyrus where is scarcely innervated by zincergic neurons, it is likely that extracellular Zn(2+) homeostasis is strictly regulated for cognition. Copyright © 2015 Elsevier Ltd. All rights reserved.

Brain Structure and Function Associated with Younger Adults in Growth Hormone Receptor-Deficient Humans

PubMed Central

Nashiro, Kaoru; Braskie, Meredith N.; Velasco, Rico; Balasubramanian, Priya; Wei, Min; Thompson, Paul M.; Nelson, Marvin D.; Guevara, Alexandra

2017-01-01

Growth hormone receptor deficiency (GHRD) results in short stature, enhanced insulin sensitivity, and low circulating levels of insulin and insulin-like growth factor 1 (IGF-1). Previous studies in mice and humans suggested that GHRD has protective effects against age-related diseases, including cancer and diabetes. Whereas GHRD mice show improved age-dependent cognitive performance, the effect of GHRD on human cognition remains unknown. Using MRI, we compared brain structure, function, and connectivity between 13 people with GHRD and 12 unaffected relatives. We assessed differences in white matter microstructural integrity, hippocampal volume, subregional volumes, and cortical thickness and surface area of selected regions. We also evaluated brain activity at rest and during a hippocampal-dependent pattern separation task. The GHRD group had larger surface areas in several frontal and cingulate regions and showed trends toward larger dentate gyrus and CA1 regions of the hippocampus. They had lower mean diffusivity in the genu of the corpus callosum and the anterior thalamic tracts. The GHRD group showed enhanced cognitive performance and greater task-related activation in frontal, parietal, and hippocampal regions compared with controls. Furthermore, they had greater functional synchronicity of activity between the precuneus and the rest of the default mode network at rest. The results suggest that, compared with controls, GHRD subjects have brain structure and function that are more consistent with those observed in younger adults reported in previous studies. Further investigation may lead to improved understanding of underlying mechanisms and could contribute to the identification of treatments for age-related cognitive deficits. SIGNIFICANCE STATEMENT People and mice with growth hormone receptor deficiency (GHRD or Laron syndrome) are protected against age-related diseases including cancer and diabetes. However, in humans, it is unknown whether cognitive function and brain structure are affected by GHRD. Using MRI, we examined cognition in an Ecuadorian population with GHRD and their unaffected relatives. The GHRD group showed better memory performance than their relatives. The differences in brain structure and function that we saw between the two groups were not consistent with variations typically associated with brain deficits. This study contributes to our understanding of the connection between growth genes and brain aging in humans and provides data indicating that GHR inhibition has the potential to protect against age-dependent cognitive decline. PMID:28073935

The cognitive nuances of surprising events: exposure to unexpected stimuli elicits firing variations in neurons of the dorsal CA1 hippocampus.

PubMed

Valenti, Ornella; Mikus, Nace; Klausberger, Thomas

2018-05-22

The ability to recognize novel situations is among the most fascinating and vital of the brain functions. A hypothesis posits that encoding of novelty is prompted by failures in expectancy, according to computation matching incoming information with stored events. Thus, unexpected changes in context are detected within the hippocampus and transferred to downstream structures, eliciting the arousal of the dopamine system. Nevertheless, the precise locus of detection is a matter of debate. The dorsal CA1 hippocampus (dCA1) appears as an ideal candidate for operating a mismatch computation and discriminating the occurrence of diverse stimuli within the same environment. In this study, we sought to determine dCA1 neuronal firing during the experience of novel stimuli embedded in familiar contexts. We performed population recordings while head-fixed mice navigated virtual environments. Three stimuli were employed, namely a novel pattern of visual cues, an odor, and a reward with enhanced valence. The encounter of unexpected events elicited profound variations in dCA1 that were assessed both as opposite rate directions and altered network connectivity. When experienced in sequence, novel stimuli elicited specific responses that often exhibited cross-sensitization. Short-latency, event-triggered responses were in accordance with the detection of novelty being computed within dCA1. We postulate that firing variations trigger neuronal disinhibition, and constitute a fundamental mechanism in the processing of unexpected events and in learning. Elucidating the mechanisms underlying detection and computation of novelty might help in understanding hippocampal-dependent cognitive dysfunctions associated with neuropathologies and psychiatric conditions.

Correlation or Limits of Agreement? Applying the Bland-Altman Approach to the Comparison of Cognitive Screening Instruments.

PubMed

Larner, A J

2016-01-01

Calculation of correlation coefficients is often undertaken as a way of comparing different cognitive screening instruments (CSIs). However, test scores may correlate but not agree, and high correlation may mask lack of agreement between scores. The aim of this study was to use the methodology of Bland and Altman to calculate limits of agreement between the scores of selected CSIs and contrast the findings with Pearson's product moment correlation coefficients between the test scores of the same instruments. Datasets from three pragmatic diagnostic accuracy studies which examined the Mini-Mental State Examination (MMSE) vs. the Montreal Cognitive Assessment (MoCA), the MMSE vs. the Mini-Addenbrooke's Cognitive Examination (M-ACE), and the M-ACE vs. the MoCA were analysed to calculate correlation coefficients and limits of agreement between test scores. Although test scores were highly correlated (all >0.8), calculated limits of agreement were broad (all >10 points), and in one case, MMSE vs. M-ACE, was >15 points. Correlation is not agreement. Highly correlated test scores may conceal broad limits of agreement, consistent with the different emphases of different tests with respect to the cognitive domains examined. Routine incorporation of limits of agreement into diagnostic accuracy studies which compare different tests merits consideration, to enable clinicians to judge whether or not their agreement is close. © 2016 S. Karger AG, Basel.

The Addenbrooke's Cognitive Examination Revised (ACE-R) and its sub-scores: normative values in an Italian population sample.

PubMed

Siciliano, Mattia; Raimo, Simona; Tufano, Dario; Basile, Giuseppe; Grossi, Dario; Santangelo, Franco; Trojano, Luigi; Santangelo, Gabriella

2016-03-01

The Addenbrooke's Cognitive Examination Revised (ACE-R) is a rapid screening battery, including five sub-scales to explore different cognitive domains: attention/orientation, memory, fluency, language and visuospatial. ACE-R is considered useful in discriminating cognitively normal subjects from patients with mild dementia. The aim of present study was to provide normative values for ACE-R total score and sub-scale scores in a large sample of Italian healthy subjects. Five hundred twenty-six Italian healthy subjects (282 women and 246 men) of different ages (age range 20-93 years) and educational level (from primary school to university) underwent ACE-R and Montreal Cognitive Assessment (MoCA). Multiple linear regression analysis revealed that age and education significantly influenced performance on ACE-R total score and sub-scale scores. A significant effect of gender was found only in sub-scale attention/orientation. From the derived linear equation, a correction grid for raw scores was built. Inferential cut-offs score were estimated using a non-parametric technique and equivalent scores (ES) were computed. Correlation analysis showed a good significant correlation between ACE-R adjusted scores with MoCA adjusted scores (r = 0.612, p < 0.001). The present study provided normative data for the ACE-R in an Italian population useful for both clinical and research purposes.

The effect of resveratrol on beta amyloid-induced memory impairment involves inhibition of phosphodiesterase-4 related signaling

PubMed Central

Wang, Gang; Chen, Ling; Pan, Xiaoyu; Chen, Jiechun; Wang, Liqun; Wang, Weijie; Cheng, Ruochuan; Wu, Fan; Feng, Xiaoqing; Yu, Yingcong; Zhang, Han-Ting; O'Donnell, James M.; Xu, Ying

2016-01-01

Resveratrol, a natural polyphenol found in red wine, has wide spectrum of pharmacological properties including antioxidative and antiaging activities. Beta amyloid peptides (Aβ) are known to involve cognitive impairment, neuroinflammatory and apoptotic processes in Alzheimer's disease (AD). Activation of cAMP and/or cGMP activities can improve memory performance and decrease the neuroinflammation and apoptosis. However, it remains unknown whether the memory enhancing effect of resveratrol on AD associated cognitive disorders is related to the inhibition of phosphodiesterase 4 (PDE4) subtypes and subsequent increases in intracellular cAMP and/or cGMP activities. This study investigated the effect of resveratrol on Aβ1-42-induced cognitive impairment and the participation of PDE4 subtypes related cAMP or cGMP signaling. Mice microinfused with Aβ1-42 into bilateral CA1 subregions displayed learning and memory impairment, as evidenced by reduced memory acquisition and retrieval in the water maze and retention in the passive avoidance tasks; it was also significant that neuroinflammatory and pro-apoptotic factors were increased in Aβ1-42-treated mice. Aβ1-42-treated mice also increased in PDE4A, 4B and 4D expression, and decreased in PKA level. However, PKA inhibitor H89, but not PKG inhibitor KT5823, prevented resveratrol's effects on these parameters. Resveratrol also reversed Aβ1-42-induced decreases in phosphorylated cAMP response-element binding protein (pCREB), brain derived neurotrophic factor (BDNF) and anti-apoptotic factor BCl-2 expression, which were reversed by H89. These findings suggest that resveratrol reversing Aβ-induced learning and memory disorder may involve the regulation of neuronal inflammation and apoptosis via PDE4 subtypes related cAMP-CREB-BDNF signaling. PMID:26980711

Cognitive Ameliorating Effect of Acanthopanax koreanum Against Scopolamine-Induced Memory Impairment in Mice.

PubMed

Lee, Sunhee; Park, Ho Jae; Jeon, Se Jin; Kim, Eunji; Lee, Hyung Eun; Kim, Haneul; Kwon, Yubeen; Zhang, Jiabao; Jung, In Ho; Ryu, Jong Hoon

2017-03-01

Acanthopanax koreanum Nakai (Araliaceae) is one of the most widely cultivated medicinal plants in Jeju Island, Korea, and the roots and stem bark of A. koreanum have been traditionally used as a tonic agent for general weakness. However, the use of A. koreanum for general weakness observed in the elderly, including those with declined cognitive function, has not been intensively investigated. This study was performed to investigate the effect of the ethanol extract of A. koreanum (EEAK) on cholinergic blockade-induced memory impairment in mice. To evaluate the ameliorating effects of EEAK against scopolamine-induced memory impairment, mice were orally administered EEAK (25, 50, 100, or 200 mg/kg), and several behavioral tasks, including a passive avoidance task, the Y-maze, and a novel object recognition task, were employed. Besides, western blot analysis was conducted to examine whether EEAK affected memory-associated signaling molecules, such as protein kinase B (Akt), Ca 2+ /calmodulin-dependent protein kinase II (CaMKII), and cAMP response element-binding protein (CREB). The administration of EEAK (100 or 200 mg/kg, p.o.) significantly ameliorated the scopolamine-induced cognitive impairment in the passive avoidance task, the Y-maze, and the novel object recognition task. The phosphorylation levels of both Akt and CaMKII were significantly increased by approximately two-fold compared with the control group because of the administration of EEAK (100 or 200 mg/kg) (p < 0.05). Moreover, the phosphorylation level of CREB was also significantly increased compared with the control group by the administration of EEAK (200 mg/kg) (p < 0.05). The present study suggests that EEAK ameliorates the cognitive dysfunction induced by the cholinergic blockade, in part, via several memory-associated signaling molecules and may hold therapeutic potential against cognitive dysfunction, such as that presented in neurodegenerative diseases, for example, Alzheimer's disease. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

Long-Term Enrichment Enhances the Cognitive Behavior of the Aging Neurogranin Null Mice without Affecting Their Hippocampal LTP

ERIC Educational Resources Information Center

Huang, Freesia L.; Huang, Kuo-Ping; Boucheron, Catherine

2007-01-01

Neurogranin (Ng), a PKC substrate, is abundantly expressed in brain regions important for cognitive functions. Deletion of Ng caused severe deficits in spatial learning and LTP in the hippocampal CA1 region of mice. These Ng-/- mice also exhibit deficits in the amplification of their hippocampal signaling pathways critical for learning and memory.…

A daily single dose of a novel modafinil analogue CE-123 improves memory acquisition and memory retrieval.

PubMed

Kristofova, Martina; Aher, Yogesh D; Ilic, Marija; Radoman, Bojana; Kalaba, Predrag; Dragacevic, Vladimir; Aher, Nilima Y; Leban, Johann; Korz, Volker; Zanon, Lisa; Neuhaus, Winfried; Wieder, Marcus; Langer, Thierry; Urban, Ernst; Sitte, Harald H; Hoeger, Harald; Lubec, Gert; Aradska, Jana

2018-05-02

Dopamine reuptake inhibitors have been shown to improve cognitive parameters in various tasks and animal models. We recently reported a series of modafinil analogues, of which the most promising, 5-((benzhydrylsulfinyl)methyl) thiazole (CE-123), was selected for further development. The present study aims to characterize pharmacological properties of CE-123 and to investigate the potential to enhance memory performance in a rat model. In vitro transporter assays were performed in cells expressing human transporters. CE-123 blocked uptake of [3H] dopamine (IC50 = 4.606 μM) while effects on serotonin (SERT) and the norepinephrine transporter (NET) were negligible. Blood-brain barrier and pharmacokinetic studies showed that the compound reached the brain and lower elimination than R-modafinil. The Pro-cognitive effect was evaluated in a spatial hole-board task in male Sprague-Dawley rats and CE-123 enhances memory acquisition and memory retrieval, represented by significantly increased reference memory indices and shortened latency. Since DAT blockers can be considered as indirect dopamine receptor agonists, western blotting was used to quantify protein levels of dopamine receptors D1R, D2R and D5R and DAT in the synaptosomal fraction of hippocampal subregions CA1, CA3 and dentate gyrus (DG). CE-123 administration in rats increased total DAT levels and D1R protein levels were significantly increased in CA1 and CA3 in treated/trained groups. The increase of D5R was observed in DG only. Dopamine receptors, particularly D1R, seem to play a role in mediating CE-123-induced memory enhancement. Dopamine reuptake inhibition by CE-123 may represent a novel and improved stimulant therapeutic for impairments of cognitive functions. Copyright © 2018 Elsevier B.V. All rights reserved.

Increased work and social engagement is associated with increased stroke specific quality of life in stroke survivors at 3 months and 12 months post-stroke: a longitudinal study of an Australian stroke cohort.

PubMed

Tse, Tamara; Binte Yusoff, Siti Zubaidah; Churilov, Leonid; Ma, Henry; Davis, Stephen; Donnan, Geoffrey Alan; Carey, Leeanne M

2017-09-01

There is a relative lack of longitudinal studies investigating stroke-specific outcomes and quality of life (QOL). This study aimed to identify which factors (level of disability, cognitive functioning, depressive symptoms, physical activity, and work and social engagement) were independently associated with each stroke-specific domain of QOL, adjusting for age and gender, at 3 months and 12 months post-stroke in an Australian cohort. Survivors of ischemic stroke were recruited from 18 sites of the STroke imAging pRevention and Treatment (START) longitudinal cohort study. Survivors were assessed at 3 months (n = 185) and 12 months (n = 170) post-stroke using the Stroke Impact Scale (SIS), modified Rankin Scale (mRS), Montreal Cognitive Assessment (MoCA), Montgomery-Asberg Depression Rating Scale, Rapid Assessment of Physical Activity, and Work and Social Adjustment Scale (WSAS). WSAS was independently associated with the SIS domains of: Physical Composite function; Participation; and Perceived Recovery at 3 months and 12 months and SIS domain of Emotion at 12 months post-stroke. The presence of depressive symptoms was independently associated with the SIS domains of: Memory and Thinking; and Emotion at 3 months. At 12 months post-stroke, mRS was independently associated with SIS domain of Physical Composite function and MoCA with SIS domain of Communication. Engaging in work and social activities is an important factor associated with stroke-specific domains of QOL over time. It is recommended that services focus on improving work and social engagement given their importance related to QOL in the first year of recovery post-stroke. Identifying and treating those with depressive symptoms may enhance QOL in the early months post-stroke. START-PrePARE Australian New Zealand Clinical Trials, www.anzctr.org.au , Registry number: ACTRN12610000987066. EXTEND ClinicalTrial.gov identifier: NCT00887328.

DL-3-n-butylphthalide alleviates vascular cognitive impairment induced by chronic cerebral hypoperfusion by activating the Akt/Nrf2 signaling pathway in the hippocampus of rats.

PubMed

Qi, Qianqian; Xu, Jing; Lv, Peiyuan; Dong, Yanhong; Liu, Zhijuan; Hu, Ming; Xiao, Yining; Jia, Yanqiu; Jin, Wei; Fan, Mingyue; Zhang, Dandan; Meng, Nan

2018-04-13

Oxidative stress induced by chronic cerebral hypoperfusion (CCH) plays an important role in the pathogenesis of vascular cognitive impairment (VCI). The Akt/Nrf2 signaling pathway is one of the most important antioxidative stress pathways. To explore whether NBP (DL-3-n-butylphthalide) could alleviate VCI induced by CCH via activating the Akt/Nrf2 signaling pathway and modifying the levels of apoptosis-related proteins, adult male Sprague-Dawley rats were subjected to permanent occlusion of bilateral common carotid arteries (BCCAO) and treated either with vehicle or NBP (applied in two doses, 40 mg/kg and 80 mg/kg) while sham operated animals were treated with vehicle. Treatments were administered daily for 28 days. The obtained results indicate that both administrated doses of NBP significantly ameliorated the spatial learning and memory impairments as indicated by the Morris water maze test while Hematoxylin-Eosin staining revealed that morphological defects in the CA1 area of hippocampus were improved. Moreover, NBP reversed the BCCAO-induced downregulation of investigated oxidative stress-related proteins (p-Akt, t-Nrf2, n-Nrf2 and HO-1) along with the upregulation of pro-apoptotic molecule, Bax and reduction of the expression of anti-apoptotic protein, Bcl-2. According to presented results, NBP may have a protective effect against cognitive and morphological impairments induced by CCH via activation of Akt/Nrf2 signaling pathway and inhibition of apoptotic cascade. Copyright © 2017. Published by Elsevier B.V.

Houttuynia cordata Improves Cognitive Deficits in Cholinergic Dysfunction Alzheimer's Disease-Like Models.

PubMed

Huh, Eugene; Kim, Hyo Geun; Park, Hanbyeol; Kang, Min Seo; Lee, Bongyong; Oh, Myung Sook

2014-05-01

Cognitive impairment is a result of dementia of diverse causes, such as cholinergic dysfunction and Alzheimer's disease (AD). Houttuynia cordata Thunb. (Saururaceae) has long been used as a traditional herbal medicine. It has biological activities including protective effects against amyloid beta (Aβ) toxicity, via regulation of calcium homeostasis, in rat hippocampal cells. To extend previous reports, we investigated the effects of water extracts of H. cordata herb (HCW) on tauopathies, also involving calcium influx. We then confirmed the effects of HCW in improving memory impairment and neuronal damage in mice with Aβ-induced neurotoxicity. We also investigated the effects of HCW against scopolamine-induced cholinergic dysfunction in mice. In primary neuronal cells, HCW inhibited the phosphorylation of tau by regulating p25/p35 expression in Aβ-induced neurotoxicity. In mice with Aβ-induced neurotoxicity, HCW improved cognitive impairment, as assessed with behavioral tasks, such as novel object recognition, Y-maze, and passive avoidance tasks. HCW also inhibited the degeneration of neurons in the CA3 region of the hippocampus in Aβ-induced neurotoxicity. Moreover, HCW, which had an IC50 value of 79.7 μg/ml for acetylcholinesterase inhibition, ameliorated scopolamine-induced cognitive impairment significantly in Y-maze and passive avoidance tasks. These results indicate that HCW improved cognitive impairment, due to cholinergic dysfunction, with inhibitory effects against tauopathies and cholinergic antagonists, suggesting that HCW may be an interesting candidate to investigate for the treatment of AD.

Houttuynia cordata Improves Cognitive Deficits in Cholinergic Dysfunction Alzheimer’s Disease-Like Models

PubMed Central

Huh, Eugene; Kim, Hyo Geun; Park, Hanbyeol; Kang, Min Seo; Lee, Bongyong; Oh, Myung Sook

2014-01-01

Cognitive impairment is a result of dementia of diverse causes, such as cholinergic dysfunction and Alzheimer’s disease (AD). Houttuynia cordata Thunb. (Saururaceae) has long been used as a traditional herbal medicine. It has biological activities including protective effects against amyloid beta (Aβ) toxicity, via regulation of calcium homeostasis, in rat hippocampal cells. To extend previous reports, we investigated the effects of water extracts of H. cordata herb (HCW) on tauopathies, also involving calcium influx. We then confirmed the effects of HCW in improving memory impairment and neuronal damage in mice with Aβ-induced neurotoxicity. We also investigated the effects of HCW against scopolamine-induced cholinergic dysfunction in mice. In primary neuronal cells, HCW inhibited the phosphorylation of tau by regulating p25/p35 expression in Aβ-induced neurotoxicity. In mice with Aβ-induced neurotoxicity, HCW improved cognitive impairment, as assessed with behavioral tasks, such as novel object recognition, Y-maze, and passive avoidance tasks. HCW also inhibited the degeneration of neurons in the CA3 region of the hippocampus in Aβ-induced neurotoxicity. Moreover, HCW, which had an IC50 value of 79.7 μg/ml for acetylcholinesterase inhibition, ameliorated scopolamine-induced cognitive impairment significantly in Y-maze and passive avoidance tasks. These results indicate that HCW improved cognitive impairment, due to cholinergic dysfunction, with inhibitory effects against tauopathies and cholinergic antagonists, suggesting that HCW may be an interesting candidate to investigate for the treatment of AD. PMID:25009697

Disruption of hippocampal CA3 network: effects on episodic-like memory processing in C57BL/6J mice.

PubMed

Daumas, Stéphanie; Halley, Hélène; Lassalle, Jean-Michel

2004-07-01

Lesion studies have demonstrated the prominent role of the hippocampus in spatial and contextual learning. To better understand how contextual information is processed in the CA3 region during learning, we focused on the CA3 autoassociative network hypothesis. We took advantage of a particularity of the mossy fibre (MF) synapses, i.e. their high zinc concentration, to reversibly disrupt the afferent MF pathway by microinfusions of an intracellular (DEDTC) or an extracellular (CaEDTA) zinc chelator into the CA3 area of the dorsal hippocampus of mice. Disruption of the CA3 network significantly impaired the acquisition and the consolidation of contextual fear conditioning, whereas contextual retrieval was unaffected. These results also suggest a heterogeneity between the cognitive processes underlying spatial and contextual memory that might be linked to the specific involvement of free zinc in contextual information processing.

PERK Regulates Working Memory and Protein Synthesis-Dependent Memory Flexibility

PubMed Central

Zhu, Siying; Henninger, Keely; McGrath, Barbara C.; Cavener, Douglas R.

2016-01-01

PERK (EIF2AK3) is an ER-resident eIF2α kinase required for memory flexibility and metabotropic glutamate receptor-dependent long-term depression, processes known to be dependent on new protein synthesis. Here we investigated PERK’s role in working memory, a cognitive ability that is independent of new protein synthesis, but instead is dependent on cellular Ca2+ dynamics. We found that working memory is impaired in forebrain-specific Perk knockout and pharmacologically PERK-inhibited mice. Moreover, inhibition of PERK in wild-type mice mimics the fear extinction impairment observed in forebrain-specific Perk knockout mice. Our findings reveal a novel role of PERK in cognitive functions and suggest that PERK regulates both Ca2+ -dependent working memory and protein synthesis-dependent memory flexibility. PMID:27627766

G protein-gated K+ channel ablation in forebrain pyramidal neurons selectively impairs fear learning

PubMed Central

Victoria, Nicole C.; de Velasco, Ezequiel Marron Fernandez; Ostrovskaya, Olga; Metzger, Stefania; Xia, Zhilian; Kotecki, Lydia; Benneyworth, Michael A.; Zink, Anastasia N.; Martemyanov, Kirill A.; Wickman, Kevin

2015-01-01

Background Cognitive dysfunction occurs in many debilitating conditions including Alzheimer’s disease, Down syndrome, schizophrenia, and mood disorders. The dorsal hippocampus is a critical locus of cognitive processes linked to spatial and contextual learning. G protein-gated inwardly rectifying K+ (GIRK/Kir3) channels, which mediate the postsynaptic inhibitory effect of many neurotransmitters, have been implicated in hippocampal-dependent cognition. Available evidence, however, derives primarily from constitutive gain-of-function models that lack cellular specificity. Methods We used constitutive and neuron-specific gene ablation models targeting an integral subunit of neuronal GIRK channels (GIRK2) to probe the impact of GIRK channels on associative learning and memory. Results Constitutive Girk2−/− mice exhibited a striking deficit in hippocampal-dependent (contextual) and hippocampal-independent (cue) fear conditioning. Mice lacking GIRK2 in GABA neurons (GAD-Cre:Girk2flox/flox mice) exhibited a clear deficit in GIRK-dependent signaling in dorsal hippocampal GABA neurons, but no evident behavioral phenotype. Mice lacking GIRK2 in forebrain pyramidal neurons (CaMKII-Cre(+):Girk2flox/flox mice) exhibited diminished GIRK-dependent signaling in dorsal, but not ventral, hippocampal pyramidal neurons. CaMKII-Cre(+):Girk2flox/flox mice also displayed a selective impairment in contextual fear conditioning, as both cue-fear and spatial learning were intact in these mice. Finally, loss of GIRK2 in forebrain pyramidal neurons correlated with enhanced long-term depression and blunted depotentiation of long-term potentiation at the Schaffer collateral/CA1 synapse in the dorsal hippocampus. Conclusions Our data suggest that GIRK channels in dorsal hippocampal pyramidal neurons are necessary for normal learning involving aversive stimuli, and support the contention that dysregulation of GIRK-dependent signaling may underlie cognitive dysfunction in some disorders. PMID:26612516

Novel Therapeutic Approaches for the Treatment of Depression and CognitiveDeficits in a Rodent Model of Gulf War Veterans’ Illness

DTIC Science & Technology

2016-10-01

elevated hippocampal neuronal [Ca2+]i following DFP exposures We have demonstrated that Status Epilepticus leads to development of sustained neuronal Ca2...Pharmacological blockade of the calcium plateau provides neuroprotection following organophosphate paraoxon induced status epilepticus in rats...2010) Development of a prolonged calcium plateau in hippocampal neurons in rats surviving status epilepticus induced by the organophosphate

Modulation of anxiety and fear via distinct intrahippocampal circuits.

PubMed

Engin, Elif; Smith, Kiersten S; Gao, Yudong; Nagy, David; Foster, Rachel A; Tsvetkov, Evgeny; Keist, Ruth; Crestani, Florence; Fritschy, Jean-Marc; Bolshakov, Vadim Y; Hajos, Mihaly; Heldt, Scott A; Rudolph, Uwe

2016-03-14

Recent findings indicate a high level of specialization at the level of microcircuits and cell populations within brain structures with regards to the control of fear and anxiety. The hippocampus, however, has been treated as a unitary structure in anxiety and fear research despite mounting evidence that different hippocampal subregions have specialized roles in other cognitive domains. Using novel cell-type- and region-specific conditional knockouts of the GABAA receptor α2 subunit, we demonstrate that inhibition of the principal neurons of the dentate gyrus or CA3 via α2-containing GABAA receptors (α2GABAARs) is required to suppress anxiety, while the inhibition of CA1 pyramidal neurons is required to suppress fear responses. We further show that the diazepam-modulation of hippocampal theta activity shows certain parallels with our behavioral findings, suggesting a possible mechanism for the observed behavioral effects. Thus, our findings demonstrate a double dissociation in the regulation of anxiety versus fear by hippocampal microcircuitry.

Modulation of anxiety and fear via distinct intrahippocampal circuits

PubMed Central

Engin, Elif; Smith, Kiersten S; Gao, Yudong; Nagy, David; Foster, Rachel A; Tsvetkov, Evgeny; Keist, Ruth; Crestani, Florence; Fritschy, Jean-Marc; Bolshakov, Vadim Y; Hajos, Mihaly; Heldt, Scott A; Rudolph, Uwe

2016-01-01

Recent findings indicate a high level of specialization at the level of microcircuits and cell populations within brain structures with regards to the control of fear and anxiety. The hippocampus, however, has been treated as a unitary structure in anxiety and fear research despite mounting evidence that different hippocampal subregions have specialized roles in other cognitive domains. Using novel cell-type- and region-specific conditional knockouts of the GABAA receptor α2 subunit, we demonstrate that inhibition of the principal neurons of the dentate gyrus and CA3 via α2-containing GABAA receptors (α2GABAARs) is required to suppress anxiety, while the inhibition of CA1 pyramidal neurons is required to suppress fear responses. We further show that the diazepam-modulation of hippocampal theta activity shows certain parallels with our behavioral findings, suggesting a possible mechanism for the observed behavioral effects. Thus, our findings demonstrate a double dissociation in the regulation of anxiety versus fear by hippocampal microcircuitry. DOI: http://dx.doi.org/10.7554/eLife.14120.001 PMID:26971710

Glutamatergic drive along the septo-temporal axis of hippocampus boosts prelimbic oscillations in the neonatal mouse

PubMed Central

Ahlbeck, Joachim; Song, Lingzhen; Chini, Mattia; Bitzenhofer, Sebastian H

2018-01-01

The long-range coupling within prefrontal-hippocampal networks that account for cognitive performance emerges early in life. The discontinuous hippocampal theta bursts have been proposed to drive the generation of neonatal prefrontal oscillations, yet the cellular substrate of these early interactions is still unresolved. Here, we selectively target optogenetic manipulation of glutamatergic projection neurons in the CA1 area of either dorsal or intermediate/ventral hippocampus at neonatal age to elucidate their contribution to the emergence of prefrontal oscillatory entrainment. We show that despite stronger theta and ripples power in dorsal hippocampus, the prefrontal cortex is mainly coupled with intermediate/ventral hippocampus by phase-locking of neuronal firing via dense direct axonal projections. Theta band-confined activation by light of pyramidal neurons in intermediate/ventral but not dorsal CA1 that were transfected by in utero electroporation with high-efficiency channelrhodopsin boosts prefrontal oscillations. Our data causally elucidate the cellular origin of the long-range coupling in the developing brain. PMID:29631696

Activation of the Ano1 (TMEM16A) chloride channel by calcium is not mediated by calmodulin

PubMed Central

Zhu, Jinqiu; Qu, Zhiqiang; Cui, Yuan-Yuan; Hartzell, H. Criss

2014-01-01

The Ca2+-activated Cl channel anoctamin-1 (Ano1; Tmem16A) plays a variety of physiological roles, including epithelial fluid secretion. Ano1 is activated by increases in intracellular Ca2+, but there is uncertainty whether Ca2+ binds directly to Ano1 or whether phosphorylation or additional Ca2+-binding subunits like calmodulin (CaM) are required. Here we show that CaM is not necessary for activation of Ano1 by Ca2+ for the following reasons. (a) Exogenous CaM has no effect on Ano1 currents in inside-out excised patches. (b) Overexpression of Ca2+-insensitive mutants of CaM have no effect on Ano1 currents, whereas they eliminate the current mediated by the small-conductance Ca2+-activated K+ (SK2) channel. (c) Ano1 does not coimmunoprecipitate with CaM, whereas SK2 does. Furthermore, Ano1 binds very weakly to CaM in pull-down assays. (d) Ano1 is activated in excised patches by low concentrations of Ba2+, which does not activate CaM. In addition, we conclude that reversible phosphorylation/dephosphorylation is not required for current activation by Ca2+ because the current can be repeatedly activated in excised patches in the absence of ATP or other high-energy compounds. Although Ano1 is blocked by the CaM inhibitor trifluoperazine (TFP), we propose that TFP inhibits the channel in a CaM-independent manner because TFP does not inhibit Ano1 when applied to the cytoplasmic side of excised patches. These experiments lead us to conclude that CaM is not required for activation of Ano1 by Ca2+. Although CaM is not required for channel opening by Ca2+, work of other investigators suggests that CaM may have effects in modulating the biophysical properties of the channel. PMID:24420770

Constitutive activation of CaMKKα signaling is sufficient but not necessary for mTORC1 activation and growth in mouse skeletal muscle.

PubMed

Ferey, Jeremie L A; Brault, Jeffrey J; Smith, Cheryl A S; Witczak, Carol A

2014-10-15

Skeletal muscle loading/overload stimulates the Ca²⁺-activated, serine/threonine kinase Ca²⁺/calmodulin-dependent protein kinase kinase-α (CaMKKα); yet to date, no studies have examined whether CaMKKα regulates muscle growth. The purpose of this study was to determine if constitutive activation of CaMKKα signaling could stimulate muscle growth and if so whether CaMKKα is essential for this process. CaMKKα signaling was selectively activated in mouse muscle via expression of a constitutively active form of CaMKKα using in vivo electroporation. After 2 wk, constitutively active CaMKKα expression increased muscle weight (~10%) and protein content (~10%), demonstrating that activation of CaMKKα signaling can stimulate muscle growth. To determine if active CaMKKα expression stimulated muscle growth via increased mammalian target of rapamycin complex 1 (mTORC1) signaling and protein synthesis, [³H]phenylalanine incorporation into proteins was assessed with or without the mTORC1 inhibitor rapamycin. Constitutively active CaMKKα increased protein synthesis ~60%, and this increase was prevented by rapamycin, demonstrating a critical role for mTORC1 in this process. To determine if CaMKKα is essential for growth, muscles from CaMKKα knockout mice were stimulated to hypertrophy via unilateral ablation of synergist muscles (overload). Surprisingly, compared with wild-type mice, muscles from CaMKKα knockout mice exhibited greater growth (~15%) and phosphorylation of the mTORC1 substrate 70-kDa ribosomal protein S6 kinase (Thr³⁸⁹; ~50%), demonstrating that CaMKKα is not essential for overload-induced mTORC1 activation or muscle growth. Collectively, these results demonstrate that activation of CaMKKα signaling is sufficient but not necessary for activation of mTORC1 signaling and growth in mouse skeletal muscle. Copyright © 2014 the American Physiological Society.

Constitutive activation of CaMKKα signaling is sufficient but not necessary for mTORC1 activation and growth in mouse skeletal muscle

PubMed Central

Ferey, Jeremie L. A.; Brault, Jeffrey J.; Smith, Cheryl A. S.

2014-01-01

Skeletal muscle loading/overload stimulates the Ca2+-activated, serine/threonine kinase Ca2+/calmodulin-dependent protein kinase kinase-α (CaMKKα); yet to date, no studies have examined whether CaMKKα regulates muscle growth. The purpose of this study was to determine if constitutive activation of CaMKKα signaling could stimulate muscle growth and if so whether CaMKKα is essential for this process. CaMKKα signaling was selectively activated in mouse muscle via expression of a constitutively active form of CaMKKα using in vivo electroporation. After 2 wk, constitutively active CaMKKα expression increased muscle weight (∼10%) and protein content (∼10%), demonstrating that activation of CaMKKα signaling can stimulate muscle growth. To determine if active CaMKKα expression stimulated muscle growth via increased mammalian target of rapamycin complex 1 (mTORC1) signaling and protein synthesis, [3H]phenylalanine incorporation into proteins was assessed with or without the mTORC1 inhibitor rapamycin. Constitutively active CaMKKα increased protein synthesis ∼60%, and this increase was prevented by rapamycin, demonstrating a critical role for mTORC1 in this process. To determine if CaMKKα is essential for growth, muscles from CaMKKα knockout mice were stimulated to hypertrophy via unilateral ablation of synergist muscles (overload). Surprisingly, compared with wild-type mice, muscles from CaMKKα knockout mice exhibited greater growth (∼15%) and phosphorylation of the mTORC1 substrate 70-kDa ribosomal protein S6 kinase (Thr389; ∼50%), demonstrating that CaMKKα is not essential for overload-induced mTORC1 activation or muscle growth. Collectively, these results demonstrate that activation of CaMKKα signaling is sufficient but not necessary for activation of mTORC1 signaling and growth in mouse skeletal muscle. PMID:25159322

HIV and Cognitive Impairment in Clinical Practice: The Evaluation of a Stepwise Screening Protocol in Relation to Clinical Outcomes and Management.

PubMed

Hakkers, Charlotte S; Kraaijenhof, Jordan M; van Oers-Hazelzet, Esther B; Visser-Meily, Anne J M A; Hoepelman, Andy I M; Arends, Joop E; Barth, Roos E

2017-09-01

Neurocognitive impairment (NCI) is an increasingly important comorbidity in an ageing HIV+ population. Despite the lack of available treatment modalities, screening for NCI is recommended. In the UMC Utrecht, yearly NCI screening is done using the Montreal Cognitive Assessment (MoCA) tool and the HIV Dementia Scale (HDS). The aim of this study was to evaluate this screening protocol in relation to clinical outcomes and management. A retrospective cohort study was performed in suppressed adult HIV+ patients. Apart from the MoCa and the HDS, the Utrecht Scale for Evaluation of Rehabilitation-Participation (USER-P) and the Hospital Anxiety and Depression Scale (HADS) were performed. Patients scoring below average on cognitive screening tests or with subjective cognitive complaints were further evaluated using a standardized protocol, including optimizing cART and checking for somatic disorders. In patients with cognitive complaints and participation restrictions, cognitive rehabilitation was proposed. Two hundred eighty-six patients were screened. The vast majority were MSM with an average age of 49 years. One hundred forty-four out of 286 patients (50%) had an abnormal test score and/or had subjective cognitive complaints. Restrictions in participation were present in 23% of patients. Six patients on Efavirenz switched their regimes, as this drug is known for its potential central nervous system (CNS) side effects. A depressive component was present in 58 patients (40%). Five patients had a clinical relevant laboratory abnormality. Moreover, six patients were referred for cognitive rehabilitation, which resulted in a 100% success rate in set goals in the five evaluable patients. Although the protocol was not fully adhered to in all patients, it did result in detectable underlying causes of NCI in 59% of patients, and 21% was referred for further treatment. Moreover, cognitive rehabilitation appears to be a very successful intervention for patients with NCI who experience subjective complaints and participation restrictions.

Cognitive-behavioral longitudinal assessment in ALS: the Italian Edinburgh Cognitive and Behavioral ALS screen (ECAS).

PubMed

Poletti, Barbara; Solca, Federica; Carelli, Laura; Faini, Andrea; Madotto, Fabiana; Lafronza, Annalisa; Monti, Alessia; Zago, Stefano; Ciammola, Andrea; Ratti, Antonia; Ticozzi, Nicola; Abrahams, Sharon; Silani, Vincenzo

2018-08-01

The study presents data on the longitudinal administration of the Italian Edinburgh Cognitive and Behavioral ALS Screen (ECAS). We investigated cognitive-behavioral performance in a group of ALS patients over time and the feasibility of repeating the ECAS longitudinally compared with standard neuropsychological tests. Finally, correlations between clinical/genetic and cognitive/behavioral data were considered. One hundred and sixty-eight ALS patients were tested at baseline (T 0 ). Among these, 48 patients performed the ECAS after 6 months (T 1 ), 18 patients performed it at T 2 (12 months), and five patients were assessed after 24 months (T 3 ). Participants were also administered two cognitive test (FAB; MoCA) and psychological questionnaires (BDI; STAI/Y). The FBI was carried out with caregivers. No cognitive deterioration was found across follow-ups. In contrast, although scores did not change between T 0 and T 1 , scores improved significantly for ECAS Total/ALS Non-specific and Memory domains when the ECAS was repeated on three occasions (T 0 , T 1 , T 2 ). Apathy/Inertia was the most common behavioral symptom, but no worsening of behavioral scores was detected over time. After 12-24 months, patients were still able to perform the ECAS in total, in contrast to FAB and MoCA, which were only partially administrable. The significant improvement of some ECAS scores over time supports the presence of possible practice effects, particularly in the memory domain, highlighting the need to accommodate for these in longitudinal assessments, through healthy controls groups or alternate versions. This work represents the first Italian ECAS follow-up study and confirms ECAS feasibility in patients with increasing physical disability.

Cognitive Effects of Androgen Deprivation Therapy in Men With Advanced Prostate Cancer.

PubMed

Gunlusoy, Bulent; Ceylan, Yasin; Koskderelioglu, Aslı; Gedizlioglu, Muhtesem; Degirmenci, Tansu; Ortan, Pınar; Kozacioglu, Zafer

2017-05-01

To evaluate the prostate cancer effects of androgen deprivation therapy (ADT) by using a systematic set of methods to calculate specific cognitive functions in men with locally advanced or metastatic prostate cancer. From April 2014 to February 2016, a prospective, comparative study was done to evaluate the cognitive effects of hormone therapy. Group 1 consisted of 78 patients with locally advanced or metastatic prostate cancer who received complete ADT treatment continuously for 12 months and group 2 (control group) consisted of 78 patients who underwent radical prostatectomy without any additional treatment. The Montreal Cognitive Assessment (MoCA) test and the Frontal Assessment Battery (FAB) test with Turkish language version were used to evaluate multiple domains of cognitive function. Post-treatment results of both tests revealed that patients in group 1 achieved lower mean total scores than group 2. In MoCA test, the deficits were especially prominent in the areas of language ability and short-term memory capacity (P < .05 and P < .05). No significant differences could be identified between groups in respect to attention, executive functions, visuospatial abilities, abstract thinking, calculating abilities, and orientation. In FAB test, the deficits were especially prominent in the areas of mental flexibility and inhibitory control (P < .05 and P < .05). No significant differences could be identified between groups in conceptualization, motor series, conflicting instructions, and environmental autonomy. ADT affects cognitive functions such as language ability, short-term memory capacity, mental flexibility, and inhibitory control. Urologists should keep in mind these side effects and inform the patients and their families for the early symptoms of cognitive dysfunction. Copyright © 2017 Elsevier Inc. All rights reserved.

A Serious Game for Clinical Assessment of Cognitive Status: Validation Study.

PubMed

Tong, Tiffany; Chignell, Mark; Tierney, Mary C; Lee, Jacques

2016-05-27

We propose the use of serious games to screen for abnormal cognitive status in situations where it may be too costly or impractical to use standard cognitive assessments (eg, emergency departments). If validated, serious games in health care could enable broader availability of efficient and engaging cognitive screening. The objective of this work is to demonstrate the feasibility of a game-based cognitive assessment delivered on tablet technology to a clinical sample and to conduct preliminary validation against standard mental status tools commonly used in elderly populations. We carried out a feasibility study in a hospital emergency department to evaluate the use of a serious game by elderly adults (N=146; age: mean 80.59, SD 6.00, range 70-94 years). We correlated game performance against a number of standard assessments, including the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and the Confusion Assessment Method (CAM). After a series of modifications, the game could be used by a wide range of elderly patients in the emergency department demonstrating its feasibility for use with these users. Of 146 patients, 141 (96.6%) consented to participate and played our serious game. Refusals to play the game were typically due to concerns of family members rather than unwillingness of the patient to play the game. Performance on the serious game correlated significantly with the MoCA (r=-.339, P <.001) and MMSE (r=-.558, P <.001), and correlated (point-biserial correlation) with the CAM (r=.565, P <.001) and with other cognitive assessments. This research demonstrates the feasibility of using serious games in a clinical setting. Further research is required to demonstrate the validity and reliability of game-based assessments for clinical decision making.

A Serious Game for Clinical Assessment of Cognitive Status: Validation Study

PubMed Central

Chignell, Mark; Tierney, Mary C.; Lee, Jacques

2016-01-01

Background We propose the use of serious games to screen for abnormal cognitive status in situations where it may be too costly or impractical to use standard cognitive assessments (eg, emergency departments). If validated, serious games in health care could enable broader availability of efficient and engaging cognitive screening. Objective The objective of this work is to demonstrate the feasibility of a game-based cognitive assessment delivered on tablet technology to a clinical sample and to conduct preliminary validation against standard mental status tools commonly used in elderly populations. Methods We carried out a feasibility study in a hospital emergency department to evaluate the use of a serious game by elderly adults (N=146; age: mean 80.59, SD 6.00, range 70-94 years). We correlated game performance against a number of standard assessments, including the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and the Confusion Assessment Method (CAM). Results After a series of modifications, the game could be used by a wide range of elderly patients in the emergency department demonstrating its feasibility for use with these users. Of 146 patients, 141 (96.6%) consented to participate and played our serious game. Refusals to play the game were typically due to concerns of family members rather than unwillingness of the patient to play the game. Performance on the serious game correlated significantly with the MoCA (r=–.339, P <.001) and MMSE (r=–.558, P <.001), and correlated (point-biserial correlation) with the CAM (r=.565, P <.001) and with other cognitive assessments. Conclusions This research demonstrates the feasibility of using serious games in a clinical setting. Further research is required to demonstrate the validity and reliability of game-based assessments for clinical decision making. PMID:27234145

A Six-Month Cognitive-Motor and Aerobic Exercise Program Improves Executive Function in Persons with an Objective Cognitive Impairment: A Pilot Investigation Using the Antisaccade Task.

PubMed

Heath, Matthew; Weiler, Jeffrey; Gregory, Michael A; Gill, Dawn P; Petrella, Robert J

2016-10-04

Persons with an objective cognitive impairment (OCI) are at increased risk for progression to Alzheimer's disease and related dementias. The present pilot project sought to examine whether participation in a long-term exercise program involving cognitive-motor (CM) dual-task gait training and aerobic exercise training improves executive function in persons with an OCI. To accomplish our objective, individuals with an OCI (n = 12) as determined by a Montreal Cognitive Assessment (MoCA) score of less than 26 and older adults (n = 11) deemed to be cognitively healthy (i.e., control group: MoCA score ≥26) completed a six-month moderate-to-high intensity (65-85% maximum heart rate) treadmill-based CM and aerobic exercise training program wherein pre- and post-intervention executive control was examined via the antisaccade task. Notably, antisaccades require a goal-directed eye-movement mirror-symmetrical to a target and represent an ideal tool for the study of executive deficits because of its hands- and language-free nature. As well, the cortical networks mediating antisaccades represent regions associated with neuropathology in cognitive decline and dementia (e.g., dorsolateral prefrontal cortex). Results showed that antisaccade reaction times for the OCI group reliably decreased by 30 ms from pre- to post-intervention, whereas the control group did not produce a reliable pre- to post-intervention change in reaction time (i.e., 6 ms). Thus, we propose that in persons with OCI long-term CM and aerobic training improves the efficiency and effectiveness of the executive mechanisms mediating high-level oculomotor control.

A randomized controlled trial of mindfulness-based stress reduction for women with early-stage breast cancer receiving radiotherapy.

PubMed

Henderson, Virginia P; Massion, Ann O; Clemow, Lynn; Hurley, Thomas G; Druker, Susan; Hébert, James R

2013-09-01

To testthe relative effectiveness of a mindfulness-based stress reduction program (MBSR) compared with a nutrition education intervention (NEP) and usual care (UC) in women with newly diagnosed early-stage breast cancer (BrCA)undergoing radiotherapy. Datawere available from a randomized controlled trialof 172 women, 20 to 65 years old, with stage I or II BrCA. Data from women completing the 8-week MBSR program plus 3 additional sessions focuses on special needs associated with BrCA were compared to women receiving attention control NEP and UC. Follow-up was performed at 3 post-intervention points: 4 months, and 1 and 2 years. Standardized, validated self-administered questionnaires were used to assess psychosocial variables. Descriptive analyses compared women by randomization assignment. Regression analyses, incorporating both intention-to-treat and post hoc multivariable approaches, were used to control for potential confounding variables. A subset of 120 women underwent radiotherapy; 77 completed treatment prior to the study, and 40 had radiotherapy during the MBSR intervention. Women who actively received radiotherapy (art) while participating in the MBSR intervention (MBSR-art) experienced a significant (P < .05) improvement in 16 psychosocial variables compared with the NEP-art, UC-art, or both at 4 months. These included health-related, BrCA-specific quality of life and psychosocial coping, which were the primary outcomes, and secondary measures, including meaningfulness, helplessness, cognitive avoidance, depression, paranoid ideation, hostility, anxiety, global severity, anxious preoccupation, and emotional control. MBSR appears to facilitate psychosocial adjustment in BrCA patients receiving radiotherapy, suggesting applicability for MBSR as adjunctive therapy in oncological practice.

Corruption of the dentate gyrus by "dominant" granule cells: Implications for dentate gyrus function in health and disease.

PubMed

Scharfman, Helen E; Myers, Catherine E

2016-03-01

The dentate gyrus (DG) and area CA3 of the hippocampus are highly organized lamellar structures which have been implicated in specific cognitive functions such as pattern separation and pattern completion. Here we describe how the anatomical organization and physiology of the DG and CA3 are consistent with structures that perform pattern separation and completion. We then raise a new idea related to the complex circuitry of the DG and CA3 where CA3 pyramidal cell 'backprojections' play a potentially important role in the sparse firing of granule cells (GCs), considered important in pattern separation. We also propose that GC axons, the mossy fibers, already known for their highly specialized structure, have a dynamic function that imparts variance--'mossy fiber variance'--which is important to pattern separation and completion. Computational modeling is used to show that when a subset of GCs become 'dominant,' one consequence is loss of variance in the activity of mossy fiber axons and a reduction in pattern separation and completion in the model. Empirical data are then provided using an example of 'dominant' GCs--subsets of GCs that develop abnormally and have increased excitability. Notably, these abnormal GCs have been identified in animal models of disease where DG-dependent behaviors are impaired. Together these data provide insight into pattern separation and completion, and suggest that behavioral impairment could arise from dominance of a subset of GCs in the DG-CA3 network. Copyright © 2015 Elsevier Inc. All rights reserved.

Calcium/calmodulin‐dependent kinase 2 mediates Epac‐induced spontaneous transient outward currents in rat vascular smooth muscle

PubMed Central

Humphries, Edward S. A.; Kamishima, Tomoko; Quayle, John M.

2017-01-01

Key points The Ca2+ and redox‐sensing enzyme Ca2+/calmodulin‐dependent kinase 2 (CaMKII) is a crucial and well‐established signalling molecule in the heart and brain.In vascular smooth muscle, which controls blood flow by contracting and relaxing in response to complex Ca2+ signals and oxidative stress, surprisingly little is known about the role of CaMKII.The vasodilator‐induced second messenger cAMP can relax vascular smooth muscle via its effector, exchange protein directly activated by cAMP (Epac), by activating spontaneous transient outward currents (STOCs) that hyperpolarize the cell membrane and reduce voltage‐dependent Ca2+ influx. How Epac activates STOCs is unknown.In the present study, we map the pathway by which Epac increases STOC activity in contractile vascular smooth muscle and show that a critical step is the activation of CaMKII.To our knowledge, this is the first report of CaMKII activation triggering cellular activity known to induce vasorelaxation. Abstract Activation of the major cAMP effector, exchange protein directly activated by cAMP (Epac), induces vascular smooth muscle relaxation by increasing the activity of ryanodine (RyR)‐sensitive release channels on the peripheral sarcoplasmic reticulum. Resultant Ca2+ sparks activate plasma membrane Ca2+‐activated K+ (BKCa) channels, evoking spontaneous transient outward currents (STOCs) that hyperpolarize the cell and reduce voltage‐dependent Ca2+ entry. In the present study, we investigate the mechanism by which Epac increases STOC activity. We show that the selective Epac activator 8‐(4‐chloro‐phenylthio)‐2′‐O‐methyladenosine‐3′, 5‐cyclic monophosphate‐AM (8‐pCPT‐AM) induces autophosphorylation (activation) of calcium/calmodulin‐dependent kinase 2 (CaMKII) and also that inhibition of CaMKII abolishes 8‐pCPT‐AM‐induced increases in STOC activity. Epac‐induced CaMKII activation is probably initiated by inositol 1,4,5‐trisphosphate (IP3)‐mobilized Ca2+: 8‐pCPT‐AM fails to induce CaMKII activation following intracellular Ca2+ store depletion and inhibition of IP3 receptors blocks both 8‐pCPT‐AM‐mediated CaMKII phosphorylation and STOC activity. 8‐pCPT‐AM does not directly activate BKCa channels, but STOCs cannot be generated by 8‐pCPT‐AM in the presence of ryanodine. Furthermore, exposure to 8‐pCPT‐AM significantly slows the initial rate of [Ca2+]i rise induced by the RyR activator caffeine without significantly affecting the caffeine‐induced Ca2+ transient amplitude, a measure of Ca2+ store content. We conclude that Epac‐mediated STOC activity (i) occurs via activation of CaMKII and (ii) is driven by changes in the underlying behaviour of RyR channels. To our knowledge, this is the first report of CaMKII initiating cellular activity linked to vasorelaxation and suggests novel roles for this Ca2+ and redox‐sensing enzyme in the regulation of vascular tone and blood flow. PMID:28731505

A randomised controlled trial of aerobic exercise after transient ischaemic attack or minor stroke to prevent cognitive decline: the MoveIT study protocol.

PubMed

Boss, H M; Van Schaik, S M; Deijle, I A; de Melker, E C; van den Berg, B T J; Scherder, E J A; Bosboom, W M J; Weinstein, H C; Van den Berg-Vos, R M

2014-12-31

Patients with transient ischaemic attack (TIA) or stroke are at risk for cognitive impairment and dementia. Currently, there is no known effective strategy to prevent this cognitive decline. Increasing evidence exists that physical exercise is beneficial for cognitive function. However, in patients with TIA or stroke who are at risk of cognitive impairment and dementia, only a few trials have been conducted. In this study, we aim to investigate whether a physical exercise programme (MoveIT) can prevent cognitive decline in patients in the acute phase after a TIA or minor ischaemic stroke. A single-blinded randomised controlled trial will be conducted to investigate the effect of an aerobic exercise programme on cognition compared with usual care. 120 adult patients with a TIA or minor ischaemic stroke less than 1 month ago will be randomly allocated to an exercise programme consisting of a 12-week aerobic exercise programme and regular follow-up visits to a specialised physiotherapist during the period of 1 year or to usual care. Outcome measures will be assessed at the baseline, and at the 1-year and 2-year follow-up. The primary outcome is cognitive functioning measured with the Montreal Cognitive Assessment (MoCA) test and with additional neuropsychological tests. Secondary outcomes include maximal exercise capacity, self-reported physical activity and measures of secondary prevention. The study received ethical approval from the VU University Amsterdam Ethics committee (2011/383). The results of this study will be published in peer-reviewed journals and presented at international conferences. We will also disseminate the main results to our participants in a letter. The Nederlands Trial Register NTR3884. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

C-A1-01: Changes in Physical Activity and Nutrition in a Behavioral Intervention Pilot Study - Passport to Brain Wellness

PubMed Central

Hanson, Leah R; Martinson, Brian C; Sherwood, Nancy E; Crain, A Lauren; Hayes, Marcia G; O’Connor, Patrick J; Matthews, Rachel B; Cooner, Jacob M

2010-01-01

Background/Aims: Increasing concerns about cognitive decline and dementia in the aging populations of most westernized countries suggests the need for interventions that can preserve cognitive function, are cost-effective, and feasibly implemented on a large scale. Empirical evidence is accumulating that points to the potential beneficial effects of cardiovascular fitness, healthy diet, social integration and participation in cognitively stimulating activities in the maintenance of cognitive function. We have developed and pilot tested “Passport,” a multi-component, cognitive-behavioral, phone and mail based intervention to promote such lifestyle changes in older adults. Methods: Cognitively intact (TICS ≥ 31), sedentary (<90 min physical activity[PA] per week) adults aged 61–80 years were recruited from among HealthPartners’ members. Baseline assessments included cognitive function, biomarkers, lifestyle factors, and physical traits. In the first phase, 21 participants were recruited and all assigned (non-randomized) to receive a course book, pedometer, tool kit and 7 bi-weekly phone coaching calls. In the second phase, 42 participants were recruited and randomized to either the Guided Intervention (n=22) or a Self-Directed (n=20) group, who received the study materials but no coaching. We completed 6 month follow-up measures with 58 (92%) subjects, and report here on their PA and nutritional outcomes. Results: The 63 enrolled subjects were female (60%), 70 years old, highly educated (73% college or more), predominantly retired (81%), non-Hispanic White (71%;) and married (65%). On average, they were overweight, BMI M=29.8, normotensive, systolic BP M=122.8, and normocholesterolemic, total serum cholesterol M=189.3. Mixed-model analyses indicated a time*treatment group effect on objectively monitored MVPA (p<.05), with a significant increase in the guided group (7.3 to 16.5mins/day, p<.05). We observed a significant effect of time on saturated fat intake (p<.05), with a significant pre-post reduction among Guided participants (26.1 to 23.4 grams, p<.05). Similar patterns of effects were observed for intake of fruits, vegetables and dietary fiber. Finally, we observed a time effect on intake of fish high in omega-3 fatty acids, driven by an increase in the non-randomized group (p<.05). Conclusions: Passport shows promise for improving aspects of lifestyle behaviors hypothesized to be important for the primary prevention of cognitive decline in older adults.

[Quantitative evaluation of inhibitory effects of epileptic spikes on theta rhythms in the network of hippocampal CA3 and entorhinal cortex in patients with temporal lobe epilepsy].

PubMed

Ge, Man-Ling; Guo, Jun-Dan; Chen, Sheng-Hua; Zhang, Ji-Chang; Fu, Xiao-Xuan; Chen, Yu-Min

2017-02-25

Epileptic spike is an indicator of hyper-excitability and hyper-synchrony in the neural networks. The inhibitory effects of spikes on theta rhythms (4-8 Hz) might be helpful to understand the mechanism of epileptic damage on the cognitive functions. To quantitatively evaluate the inhibitory effects of spikes on theta rhythms, intracerebral electroencephalogram (EEG) recordings with both sporadic spikes (SSs) and spike-free transient period between adjacent spikes were selected in 4 patients in the status of rapid eyes movement (REM) sleep with temporal lobe epilepsy (TLE) under the pre-surgical monitoring. The electrodes of hippocampal CA3 and entorhinal cortex (EC) were employed, since CA3 and EC built up one of key loops to investigate cognition and epilepsy. These SSs occurred only in CA3, only in EC, or in both CA3 and EC synchronously. Theta power was respectively estimated around SSs and during the spike-free transient period by Gabor wavelet transform and Hilbert transform. The intermittent extent was then estimated to represent for the loss of theta rhythms during the spike-free transient period. The following findings were obtained: (1) The prominent rhythms were in theta frequency band; (2) The spikes could transiently reduce theta power, and the inhibitory effect was severer around SSs in both CA3 and EC synchronously than that around either SSs only in EC or SSs only in CA3; (3) During the spike-free transient period, theta rhythms were interrupted with the intermittent theta rhythms left and theta power level continued dropping, implying the inhibitory effect was sustained. Additionally, the intermittent extent of theta rhythms was converged to the inhibitory extent around SSs; (4) The average theta power level during the spike-free transient period might not be in line with the inhibitory extent of theta rhythms around SSs. It was concluded that the SSs had negative effects on theta rhythms transiently and directly, the inhibitory effects aroused by SSs sustained during the spike-free transient period and were directly related to the intermittent extent. It was indicated that the loss of theta rhythms might qualify exactly the sustained inhibitory effects on theta rhythms aroused by spikes in EEG. The work provided an argumentation about the relationship between the transient negative impact of interictal spike and the loss of theta rhythms during spike-free activity for the first time, offered an intuitive methodology to estimate the inhibitory effect of spikes by EEG, and might be helpful to the analysis of EEG rhythms based on local field potentials (LFPs) in deep brain.

Electrolytic lesions of dorsal CA3 impair episodic-like memory in rats.

PubMed

Li, Jay-Shake; Chao, Yuen-Shin

2008-02-01

Episodic memory is the ability to recollect one's past experiences occurring in an unique spatial and temporal context. In non-human animals, it is expressed in the ability to combine "what", "where" and "when" factors to form an integrated memory system. During the search for its neural substrates, the hippocampus has attracted a lot of attentions. Yet, it is not yet possible to induce a pure episodic-like memory deficit in animal studies without being confounded by impairments in the spatial cognition. Here, we present a lesion study evidencing direct links between the hippocampus CA3 region and the episodic-like memory in rats. In a spontaneous object exploration task, lesioned rats showed no interaction between the temporal and spatial elements in their memory associated with the objects. In separate tests carried out subsequently, the same animals still expressed abilities to process spatial, temporal, and object recognition memory. In conclusions, our results support the idea that the hippocampus CA3 has a particular status in the neural mechanism of the episodic-like memory system. It is responsible for combining information from different modules of cognitive processes.

Retigabine ameliorates acute stress-induced impairment of spatial memory retrieval through regulating USP2 signaling pathways in hippocampal CA1 area.

PubMed

Li, Cai; Zhang, Ji; Xu, Haiwei; Chang, Mujun; Lv, Chuntao; Xue, Wenhua; Song, Zhizhen; Zhang, Lizhen; Zhang, Xiaojian; Tian, Xin

2018-06-01

Acute stress could trigger maladaptive changes associated with stress-related cognitive and emotional deficits. Dysfunction of ion channel or receptor in the hippocampal area has been linked to the cognitive deficits induced by stress. It is known that Kv7 channel openers, including FDA-approved drug retigabine, show cognitive protective efficacy. However, the underlying molecular mechanisms remain elusive. Here we showed that exposing adult male rats to acute stress significantly impaired the spatial memory, a cognitive process controlled by the hippocampus. Concomitantly, significantly reduced AMPA receptor expression was found in hippocampal CA1 area from acute stressed rats. This effect relied on the down-regulation of deubiquitinating enzyme USP2 and its upstream regulators (PGC-1α and β-catenin), and the subsequent enhancement of mTOR-related autophagy which is regulated by USP2. These findings suggested that acute stress dampened AMPA receptor expression by controlling USP2-related signaling, which caused the detrimental effect on hippocampus-dependent cognitive processes. We also found that retigabine alleviated acute stress-induced spatial memory retrieval impairment through adjusting the aberrance of USP2, its upstream regulators (PGC-1α, E4BP4 and β-catenin) and its downstream targets (mTOR, autophagy and GluA1). Our results have identified USP2 as a key molecule that mediates stress-induced spatial memory retrieval impairment, which provides a framework for new druggable targets to conceptually treat stress-associated cognitive deficits. Copyright © 2018 Elsevier Ltd. All rights reserved.

The relationship between cognitive function and arterial partial pressure O2 in patients with COPD: A meta-analysis.

PubMed

Wen, Xia-Hong; Li, Yan; Han, Dong; Sun, Li; Ren, Ping-Xiao; Ren, Dan

2018-01-01

The high incidence of cognition disorders in chronic obstructive pulmonary disease (COPD) patients represents a main focus in public health field recently. Thus, we tried to explore relationship between cognitive function and arterial partial pressure O2 (PaO2) in patients with COPD as assessed by Mini-mental State Examination (MMSE) and/or Montreal Cognitive Assessment (MoCA). Medical and scientific literature databases, such as Web of Science, PubMed, Cochrane Library, China National Knowledge Infrastructure, and Wanfang Database, were searched independently by 2 reviewers until February 2016. Correlation coefficient (r or rs) values were obtained from each study, and 95% confidence intervals (CIs) were calculated using STATA12.0 software. A total of 2049 studies were produced, and 9 of which were analyzed (714 participants) in the meta-analysis. The pooled r observed medium relationship for all selected studies (r = 0.405, 95% CI 0.31-0.55), and notable heterogeneity was also tested between studies (χ = 17.72, P = .023; I = 54.9%). After the sensitivity and subgroup analysis, the heterogeneity significantly decreased. Subgroup analysis showed that MMSE score was stronger correlation between PaO2 and cognitive function than MoCA score in the COPD patients. Begg test did not indicate potential risk of publication bias. There was a negative correlation between cognitive function and anoxia in patients with COPD, so it may be extremely essential to predict and improve the status of hypoxia in COPD patients.

Synthesis and biological evaluation of histamine Schiff bases as carbonic anhydrase I, II, IV, VII, and IX activators.

PubMed

Akocak, Suleyman; Lolak, Nabih; Vullo, Daniela; Durgun, Mustafa; Supuran, Claudiu T

2017-12-01

A series of 20 histamine Schiff base was synthesised by reaction of histamine, a well known carbonic anhydrase (CA, E.C 4.2.2.1.) activator pharmacophore, with substituted aldehydes. The obtained histamine Schiff bases were assayed as activators of five selected human (h) CA isozymes, the cytosolic hCA I, hCA II, and hCA VII, the membrane-anchored hCA IV and transmembrane hCA IX. Some of these compounds showed efficient activity (in the nanomolar range) against the cytosolic isoform hCA VII, which is a key CA enzyme involved in brain metabolism. Moderate activity was observed against hCA I and hCA IV (in the nanomolar to low micromolar range). The structure-activity relationship for activation of these isoforms with the new histamine Schiff bases is discussed in detail based on the nature of the aliphatic, aromatic, or heterocyclic moiety present in the aldehyde fragment of the molecule, which may participate in diverse interactions with amino acid residues at the entrance of the active site, where activators bind, and which is the most variable part among the different CA isoforms.

Skeletal muscle Ca(2+)-independent kinase activity increases during either hypertrophy or running

NASA Technical Reports Server (NTRS)

Fluck, M.; Waxham, M. N.; Hamilton, M. T.; Booth, F. W.

2000-01-01

Spikes in free Ca(2+) initiate contractions in skeletal muscle cells, but whether and how they might signal to transcription factors in skeletal muscles of living animals is unknown. Since previous studies in non-muscle cells have shown that serum response factor (SRF) protein, a transcription factor, is phosphorylated rapidly by Ca(2+)/calmodulin (CaM)-dependent protein kinase after rises in intracellular Ca(2+), we measured enzymatic activity that phosphorylates SRF (designated SRF kinase activity). Homogenates from 7-day-hypertrophied anterior latissimus dorsi muscles of roosters had more Ca(2+)-independent SRF kinase activity than their respective control muscles. However, no differences were noted in Ca(2+)/CaM-dependent SRF kinase activity between control and trained muscles. To determine whether the Ca(2+)-independent and Ca(2+)/CaM-dependent forms of Ca(2+)/CaM-dependent protein kinase II (CaMKII) might contribute to some of the SRF kinase activity, autocamtide-3, a synthetic substrate that is specific for CaMKII, was employed. While the Ca(2+)-independent form of CaMKII was increased, like the Ca(2+)-independent form of SRF kinase, no alteration in CaMKII occurred at 7 days of stretch overload. These observations suggest that some of SRF phosphorylation by skeletal muscle extracts could be due to CaMKII. To determine whether this adaptation was specific to the exercise type (i.e., hypertrophy), similar measurements were made in the white vastus lateralis muscle of rats that had completed 2 wk of voluntary running. Although Ca(2+)-independent SRF kinase was increased, no alteration occurred in Ca(2+)/CaM-dependent SRF kinase activity. Thus any role of Ca(2+)-independent SRF kinase signaling has downstream modulators specific to the exercise phenotype.

Nrf2 Deficiency Exacerbates Obesity-Induced Oxidative Stress, Neurovascular Dysfunction, Blood-Brain Barrier Disruption, Neuroinflammation, Amyloidogenic Gene Expression, and Cognitive Decline in Mice, Mimicking the Aging Phenotype.

PubMed

Tarantini, Stefano; Valcarcel-Ares, M Noa; Yabluchanskiy, Andriy; Tucsek, Zsuzsanna; Hertelendy, Peter; Kiss, Tamas; Gautam, Tripti; Zhang, Xin A; Sonntag, William E; de Cabo, Rafael; Farkas, Eszter; Elliott, Michael H; Kinter, Michael T; Deak, Ferenc; Ungvari, Zoltan; Csiszar, Anna

2018-06-14

Obesity has deleterious effects on cognitive function in the elderly adults. In mice, aging exacerbates obesity-induced oxidative stress, microvascular dysfunction, blood-brain barrier (BBB) disruption, and neuroinflammation, which compromise cognitive health. However, the specific mechanisms through which aging and obesity interact to remain elusive. Previously, we have shown that Nrf2 signaling plays a critical role in microvascular resilience to obesity and that aging is associated with progressive Nrf2 dysfunction, promoting microvascular impairment. To test the hypothesis that Nrf2 deficiency exacerbates cerebromicrovascular dysfunction induced by obesity Nrf2+/+ and Nrf2-/-, mice were fed an adipogenic high-fat diet (HFD). Nrf2 deficiency significantly exacerbated HFD-induced oxidative stress and cellular senescence, impairment of neurovascular coupling responses, BBB disruption, and microglia activation, mimicking the aging phenotype. Obesity in Nrf2-/- mice elicited complex alterations in the amyloidogenic gene expression profile, including upregulation of amyloid precursor protein. Nrf2 deficiency and obesity additively reduced long-term potentiation in the CA1 area of the hippocampus. Collectively, Nrf2 dysfunction exacerbates the deleterious effects of obesity, compromising cerebromicrovascular and brain health by impairing neurovascular coupling mechanisms, BBB integrity and synaptic function and promoting neuroinflammation. These results support a possible role for age-related Nrf2 dysfunction in the pathogenesis of vascular cognitive impairment and Alzheimer's disease.

p-Coumaric acid enhances long-term potentiation and recovers scopolamine-induced learning and memory impairments.

PubMed

Kim, Hyun-Bum; Lee, Seok; Hwang, Eun-Sang; Maeng, Sungho; Park, Ji-Ho

2017-10-21

Due to the improvement of medical level, life expectancy increased. But the increased incidence of cognitive disorders is an emerging social problem. Current drugs for dementia treatment can only delay the progress rather than cure. p-Coumaric acid is a phenylpropanoic acid derived from aromatic amino acids and known as a precursor for flavonoids such as resveratrol and naringenin. It was shown to reduce oxidative stress, inhibit genotoxicity and exert neuroprotection. Based on these findings, we evaluated whether p-coumaric acid can protect scopolamine induced learning and memory impairment by measuring LTP in organotypic hippocampal slice and cognitive behaviors in rats. p-Coumaric acid dose-dependently increased the total activity of fEPSP after high frequency stimulation and attenuated scopolamine-induced blockade of fEPSP in the hippocampal CA1 area. In addition, while scopolamine shortened the step-through latency in the passive avoidance test and prolonged the latency as well as reduced the latency in the target quadrant in the Morris water maze test, co-treatment of p-coumaric acid improved avoidance memory and long-term retention of spatial memory in behavioral tests. Since p-coumaric acid improved electrophysiological and cognitive functional deterioration by scopolamine, it may have regulatory effects on central cholinergic synapses and is expected to improve cognitive problems caused by abnormality of the cholinergic nervous system. Copyright © 2017 Elsevier Inc. All rights reserved.

Abnormalities in Dynamic Brain Activity Caused by Mild Traumatic Brain Injury Are Partially Rescued by the Cannabinoid Type-2 Receptor Inverse Agonist SMM-189

PubMed Central

McAfee, Samuel S.; Guley, Natalie M.; Del Mar, Nobel; Bu, Wei; Heldt, Scott A.; Honig, Marcia G.; Moore, Bob M.

2017-01-01

Abstract Mild traumatic brain injury (mTBI) can cause severe long-term cognitive and emotional deficits, including impaired memory, depression, and persevering fear, but the neuropathological basis of these deficits is uncertain. As medial prefrontal cortex (mPFC) and hippocampus play important roles in memory and emotion, we used multi-site, multi-electrode recordings of oscillatory neuronal activity in local field potentials (LFPs) in awake, head-fixed mice to determine if the functioning of these regions was abnormal after mTBI, using a closed-skull focal cranial blast model. We evaluated mPFC, hippocampus CA1, and primary somatosensory/visual cortical areas (S1/V1). Although mTBI did not alter the power of oscillations, it did cause increased coherence of θ (4-10 Hz) and β (10-30 Hz) oscillations within mPFC and S1/V1, reduced CA1 sharp-wave ripple (SWR)-evoked LFP activity in mPFC, downshifted SWR frequencies in CA1, and enhanced θ-γ phase-amplitude coupling (PAC) within mPFC. These abnormalities might be linked to the impaired memory, depression, and persevering fear seen after mTBI. Treatment with the cannabinoid type-2 (CB2) receptor inverse agonist SMM-189 has been shown to mitigate functional deficits and neuronal injury after mTBI in mice. We found that SMM-189 also reversed most of the observed neurophysiological abnormalities. This neurophysiological rescue is likely to stem from the previously reported reduction in neuron loss and/or the preservation of neuronal function and connectivity resulting from SMM-189 treatment, which appears to stem from the biasing of microglia from the proinflammatory M1 state to the prohealing M2 state by SMM-189. PMID:28828401

Abnormalities in Dynamic Brain Activity Caused by Mild Traumatic Brain Injury Are Partially Rescued by the Cannabinoid Type-2 Receptor Inverse Agonist SMM-189.

PubMed

Liu, Yu; McAfee, Samuel S; Guley, Natalie M; Del Mar, Nobel; Bu, Wei; Heldt, Scott A; Honig, Marcia G; Moore, Bob M; Reiner, Anton; Heck, Detlef H

2017-01-01

Mild traumatic brain injury (mTBI) can cause severe long-term cognitive and emotional deficits, including impaired memory, depression, and persevering fear, but the neuropathological basis of these deficits is uncertain. As medial prefrontal cortex (mPFC) and hippocampus play important roles in memory and emotion, we used multi-site, multi-electrode recordings of oscillatory neuronal activity in local field potentials (LFPs) in awake, head-fixed mice to determine if the functioning of these regions was abnormal after mTBI, using a closed-skull focal cranial blast model. We evaluated mPFC, hippocampus CA1, and primary somatosensory/visual cortical areas (S1/V1). Although mTBI did not alter the power of oscillations, it did cause increased coherence of θ (4-10 Hz) and β (10-30 Hz) oscillations within mPFC and S1/V1, reduced CA1 sharp-wave ripple (SWR)-evoked LFP activity in mPFC, downshifted SWR frequencies in CA1, and enhanced θ-γ phase-amplitude coupling (PAC) within mPFC. These abnormalities might be linked to the impaired memory, depression, and persevering fear seen after mTBI. Treatment with the cannabinoid type-2 (CB2) receptor inverse agonist SMM-189 has been shown to mitigate functional deficits and neuronal injury after mTBI in mice. We found that SMM-189 also reversed most of the observed neurophysiological abnormalities. This neurophysiological rescue is likely to stem from the previously reported reduction in neuron loss and/or the preservation of neuronal function and connectivity resulting from SMM-189 treatment, which appears to stem from the biasing of microglia from the proinflammatory M1 state to the prohealing M2 state by SMM-189.

Angiotensin IV possibly acts through PKMzeta in the hippocampus to regulate cognitive memory in rats.

PubMed

Chow, Lok-Hi; Tao, Pao-Luh; Chen, Yuan-Hao; Lin, Yu-Hui; Huang, Eagle Yi-Kung

2015-10-01

Ang IV is an endogenous peptide generated from the degradation of angiotensin II. Ang IV was found to enhance learning and memory in CNS. PKMzeta was identified to be a fragment of PKCzeta (protein kinase Czeta). Its continuous activation was demonstrated to be correlated with the formation of memory in the hippocampus. Therefore, we investigated whether PKMzeta participates in the effects of Ang IV on memory. We first examined the effect of Ang IV on non-spatial memory/cognition in modified object recognition test in rats. Our data showed that Ang IV could increase the exploration time on novel object. The co-administration of ZIP (PKMzeta inhibitor) with Ang IV significantly blocked the effect by Ang IV. The effects of Ang IV on hippocampal LTP at the CA1 region were also evaluated. Ang IV significantly increased the amplitude and slope of the EPSPs, which was consistent with other reports. Surprisingly, instead of potentiating LTP, Ang IV caused a failed maintenance of LTP. Moreover, there was no quantitative change in PKMzeta induced by Ang IV and/or ZIP after behavioral experiments. Taken together, our data re-confirmed the finding of the positive effect of Ang IV to enhance memory/cognition. The increased strength of EPSPs with Ang IV could also have certain functional relevance. Since the behavioral results suggested the involvement of PKMzeta, we hypothesized that the enhancement of memory/cognition by Ang IV may rely on an increase in PKMzeta activity. Overall, the present study provided important advances in our understanding of the action of Ang IV in the hippocampus. Copyright © 2015 Elsevier Ltd. All rights reserved.

Multiple Past Concussions Are Associated with Ongoing Post-Concussive Symptoms but Not Cognitive Impairment in Active-Duty Army Soldiers.

PubMed

Dretsch, Michael N; Silverberg, Noah D; Iverson, Grant L

2015-09-01

The extent to which multiple past concussions are associated with lingering symptoms or mental health problems in military service members is not well understood. The purpose of this study was to examine the association between lifetime concussion history, cognitive functioning, general health, and psychological health in a large sample of fit-for-duty U.S. Army soldiers preparing for deployment. Data on 458 active-duty soldiers were collected and analyzed. A computerized cognitive screening battery (CNS-Vital Signs(®)) was used to assess complex attention (CA), reaction time (RT), processing speed (PS), cognitive flexibility (CF), and memory. Health questionnaires included the Neurobehavioral Symptom Inventory (NSI), PTSD Checklist-Military Version (PCL-M), Zung Depression and Anxiety Scales (ZDS; ZAS), Perceived Stress Scale (PSS), Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS), and the Alcohol Use and Dependency Identification Test (AUDIT). Soldiers with a history of multiple concussions (i.e., three or more concussions) had significantly greater post-concussive symptom scores compared with those with zero (d=1.83, large effect), one (d=0.64, medium effect), and two (d=0.64, medium effect) prior concussions. Although the group with three or more concussions also reported more traumatic stress symptoms, the results revealed that traumatic stress was a mediator between concussions and post-concussive symptom severity. There were no significant differences on neurocognitive testing between the number of concussions. These results add to the accumulating evidence suggesting that most individuals recover from one or two prior concussions, but there is a greater risk for ongoing symptoms if one exceeds this number of injuries.

Inhibitory actions of synthesised polyamine spider toxins and their analogues on Ca2+-activated Cl- currents recorded from cultured DRG neurones from neonatal rats.

PubMed

Sutton, K G; Stapleton, S R; Scott, R H

1998-07-24

The whole cell variant of the patch clamp technique was used to investigate the actions of polyamine spider toxins and their analogues on high voltage-activated Ca2+ currents and Ca2+-activated Cl- currents (I(Cl(Ca))). The actions of synthesised FTX (putative natural toxin from the American funnel web spider), sFTX-3.3, Orn-FTX-3.3, Lys-FTX-3.3, and argiotoxin-636 on cultured dorsal root ganglion neurones from neonatal rats were investigated. Synthesised FTX (1 microM) inhibited I(Cl(Ca)) but did not inhibit high voltage-activated Ca2+ currents. In contrast, sFTX-3.3 (10 microM) inhibited both high voltage-activated Ca2+ currents and the associated I(Cl(Ca)) in near equal proportions. Argiotoxin-636 (1-10 microM) inhibited I(Cl(Ca)) evoked by Ca2+ entry through voltage-activated channels and by intracellular photorelease of Ca2+ from a caged precursor DM-nitrophen. This data indicates that synthesised FTX and argiotoxin-636 directly inhibit Ca2+-activated Cl- channels. In conclusion, the potency of polyamines as non-selective inhibitors of Ca2+ channels and Ca2+-activated Cl- channels is in part determined by the presence of a terminal arginine and this may involve an interaction between terminal guanidino groups and Ca2+ binding sites.

Brain-specific Foxp1 deletion impairs neuronal development and causes autistic-like behaviour.

PubMed

Bacon, C; Schneider, M; Le Magueresse, C; Froehlich, H; Sticht, C; Gluch, C; Monyer, H; Rappold, G A

2015-05-01

Neurodevelopmental disorders are multi-faceted and can lead to intellectual disability, autism spectrum disorder and language impairment. Mutations in the Forkhead box FOXP1 gene have been linked to all these disorders, suggesting that it may play a central role in various cognitive and social processes. To understand the role of Foxp1 in the context of neurodevelopment leading to alterations in cognition and behaviour, we generated mice with a brain-specific Foxp1 deletion (Nestin-Cre(Foxp1-/-)mice). The mutant mice were viable and allowed for the first time the analysis of pre- and postnatal neurodevelopmental phenotypes, which included a pronounced disruption of the developing striatum and more subtle alterations in the hippocampus. More detailed analysis in the CA1 region revealed abnormal neuronal morphogenesis that was associated with reduced excitability and an imbalance of excitatory to inhibitory input in CA1 hippocampal neurons in Nestin-Cre(Foxp1-/-) mice. Foxp1 ablation was also associated with various cognitive and social deficits, providing new insights into its behavioural importance.

Impaired hippocampal place cell dynamics in a mouse model of the 22q11.2 deletion

PubMed Central

Zaremba, Jeffrey D; Diamantopoulou, Anastasia; Danielson, Nathan B; Grosmark, Andres D; Kaifosh, Patrick W; Bowler, John C; Liao, Zhenrui; Sparks, Fraser T; Gogos, Joseph A; Losonczy, Attila

2018-01-01

Hippocampal place cells represent the cellular substrate of episodic memory. Place cell ensembles reorganize to support learning but must also maintain stable representations to facilitate memory recall. Despite extensive research, the learning-related role of place cell dynamics in health and disease remains elusive. Using chronic two-photon Ca2+ imaging in hippocampal area CA1 of wild-type and Df(16)A+/− mice, an animal model of 22q11.2 deletion syndrome, one of the most common genetic risk factors for cognitive dysfunction and schizophrenia, we found that goal-oriented learning in wild-type mice was supported by stable spatial maps and robust remapping of place fields toward the goal location. Df(16)A+/− mice showed a significant learning deficit accompanied by reduced spatial map stability and the absence of goal-directed place cell reorganization. These results expand our understanding of the hippocampal ensemble dynamics supporting cognitive flexibility and demonstrate their importance in a model of 22q11.2-associated cognitive dysfunction. PMID:28869582

Fluoxetine attenuates the impairment of spatial learning ability and prevents neuron loss in middle-aged APPswe/PSEN1dE9 double transgenic Alzheimer's disease mice.

PubMed

Ma, Jing; Gao, Yuan; Jiang, Lin; Chao, Feng-Lei; Huang, Wei; Zhou, Chun-Ni; Tang, Wei; Zhang, Lei; Huang, Chun-Xia; Zhang, Yi; Luo, Yan-Min; Xiao, Qian; Yu, Hua-Rong; Jiang, Rong; Tang, Yong

2017-04-25

Selective serotonin reuptake inhibitors (SSRIs) have been reported to increase cognitive performance in some clinical studies of Alzheimer's disease (AD). However, there is a lack of evidence supporting the efficacy of SSRIs as cognition enhancers in AD, and the role of SSRIs as a treatment for AD remains largely unclear. Here, we characterized the impact of fluoxetine (FLX), a well-known SSRI, on neurons in the dentate gyrus (DG) and in CA1 and CA3 of the hippocampus of middle-aged (16 to 17 months old) APPswe/PSEN1dE9 (APP/PS1) transgenic AD model mice. We found that intraperitoneal (i.p.) injection of FLX (10 mg/kg/day) for 5 weeks effectively alleviated the impairment of spatial learning ability in middle-aged APP/PS1 mice as evaluated using the Morris water maze. More importantly, the number of neurons in the hippocampal DG was significantly increased by FLX. Additionally, FLX reduced the deposition of beta amyloid, inhibited GSK-3β activity and increased the level of β-catenin in middle-aged APP/PS1 mice. Collectively, the results of this study indicate that FLX delayed the progression of neuronal loss in the hippocampal DG in middle-aged AD mice, and this effect may underlie the FLX-induced improvement in learning ability. FLX may therefore serve as a promising therapeutic drug for AD.

Fluoxetine attenuates the impairment of spatial learning ability and prevents neuron loss in middle-aged APPswe/PSEN1dE9 double transgenic Alzheimer's disease mice

PubMed Central

Ma, Jing; Gao, Yuan; Jiang, Lin; Chao, Feng-lei; Huang, Wei; Zhou, Chun-ni; Tang, Wei; Zhang, Lei; Huang, Chun-xia; Zhang, Yi; Luo, Yan-min; Xiao, Qian; Yu, Hua-rong; Jiang, Rong; Tang, Yong

2017-01-01

Selective serotonin reuptake inhibitors (SSRIs) have been reported to increase cognitive performance in some clinical studies of Alzheimer’s disease (AD). However, there is a lack of evidence supporting the efficacy of SSRIs as cognition enhancers in AD, and the role of SSRIs as a treatment for AD remains largely unclear. Here, we characterized the impact of fluoxetine (FLX), a well-known SSRI, on neurons in the dentate gyrus (DG) and in CA1 and CA3 of the hippocampus of middle-aged (16 to 17 months old) APPswe/PSEN1dE9 (APP/PS1) transgenic AD model mice. We found that intraperitoneal (i.p.) injection of FLX (10 mg/kg/day) for 5 weeks effectively alleviated the impairment of spatial learning ability in middle-aged APP/PS1 mice as evaluated using the Morris water maze. More importantly, the number of neurons in the hippocampal DG was significantly increased by FLX. Additionally, FLX reduced the deposition of beta amyloid, inhibited GSK-3β activity and increased the level of β-catenin in middle-aged APP/PS1 mice. Collectively, the results of this study indicate that FLX delayed the progression of neuronal loss in the hippocampal DG in middle-aged AD mice, and this effect may underlie the FLX-induced improvement in learning ability. FLX may therefore serve as a promising therapeutic drug for AD. PMID:28430602

Rapamycin Reverses Status Epilepticus-Induced Memory Deficits and Dendritic Damage

PubMed Central

Brewster, Amy L.; Lugo, Joaquin N.; Patil, Vinit V.; Lee, Wai L.; Qian, Yan; Vanegas, Fabiola; Anderson, Anne E.

2013-01-01

Cognitive impairments are prominent sequelae of prolonged continuous seizures (status epilepticus; SE) in humans and animal models. While often associated with dendritic injury, the underlying mechanisms remain elusive. The mammalian target of rapamycin complex 1 (mTORC1) pathway is hyperactivated following SE. This pathway modulates learning and memory and is associated with regulation of neuronal, dendritic, and glial properties. Thus, in the present study we tested the hypothesis that SE-induced mTORC1 hyperactivation is a candidate mechanism underlying cognitive deficits and dendritic pathology seen following SE. We examined the effects of rapamycin, an mTORC1 inhibitor, on the early hippocampal-dependent spatial learning and memory deficits associated with an episode of pilocarpine-induced SE. Rapamycin-treated SE rats performed significantly better than the vehicle-treated rats in two spatial memory tasks, the Morris water maze and the novel object recognition test. At the molecular level, we found that the SE-induced increase in mTORC1 signaling was localized in neurons and microglia. Rapamycin decreased the SE-induced mTOR activation and attenuated microgliosis which was mostly localized within the CA1 area. These findings paralleled a reversal of the SE-induced decreases in dendritic Map2 and ion channels levels as well as improved dendritic branching and spine density in area CA1 following rapamycin treatment. Taken together, these findings suggest that mTORC1 hyperactivity contributes to early hippocampal-dependent spatial learning and memory deficits and dendritic dysregulation associated with SE. PMID:23536771

The Cholinergic Signaling Responsible for the Expression of a Memory-Related Protein in Primary Rat Cortical Neurons.

PubMed

Chen, Tsan-Ju; Chen, Shun-Sheng; Wang, Dean-Chuan; Hung, Hui-Shan

2016-11-01

Cholinergic dysfunction in the brain is closely related to cognitive impairment including memory loss. In addition to the degeneration of basal forebrain cholinergic neurons, deficits in the cholinergic receptor signaling may also play an important role. In the present study, to examine the cholinergic signaling pathways responsible for the induction of a memory-related postsynaptic protein, a cholinergic agonist carbachol was used to induce the expression of activity-regulated cytoskeleton associated protein (Arc) in primary rat cortical neurons. After pretreating neurons with various antagonists or inhibitors, the levels of carbachol-induced Arc protein expression were detected by Western blot analysis. The results show that carbachol induces Arc protein expression mainly through activating M1 acetylcholine receptors and the downstream phospholipase C pathway, which may lead to the activation of the MAPK/ERK signaling pathway. Importantly, carbachol-mediated M2 receptor activation exerts negative effects on Arc protein expression and thus counteracts the enhanced effects of M1 activation. Furthermore, it is suggested for the first time that M1-mediated enhancement of N-methyl-D-aspartate receptor (NMDAR) responses, leading to Ca(2+) entry through NMDARs, contributes to carbachol-induced Arc protein expression. These findings reveal a more complete cholinergic signaling that is responsible for carbachol-induced Arc protein expression, and thus provide more information for developing treatments that can modulate cholinergic signaling and consequently alleviate cognitive impairment. J. Cell. Physiol. 231: 2428-2438, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Targeting Epigenetic Mechanisms in Pain due to Trauma and TBI

DTIC Science & Technology

2017-10-01

pain by Anacardic acid. Karen Amanda Irvine, Peyman Sahbaie, De-Yong Liang, J. David Clark. Journal of Neurotrauma (Submitted). 4. Sex differences in...CA on Nov. 15, 2016. 17  2. Sex differences in nociceptive alterations and cognitive impairments in a preclinical model of polytrauma. Presented at...TBI Research Forum annual meeting at VA Palo Alto Health Care System, CA on March 31, 2017. 3. Sex differences in nociceptive alterations and

More than Just IQ: A Longitudinal Examination of Self-Perceived Abilities as Predictors of Academic Performance in a Large Sample of UK Twins

ERIC Educational Resources Information Center

Chamorro-Premuzic, Tomas; Harlaar, Nicole; Greven, Corina U.; Plomin, Robert

2010-01-01

This paper examines the longitudinal causal relationship between self-perceived abilities (SPA) and academic achievement (Ach) while controlling for cognitive ability (CA). In all, 5957 UK school children were assessed on SPA, Ach and CA at ages 9 and 12. Results indicated that SPA and Ach at age 9 independently affected both SPA and Ach at age…

The Relative Efficacy of Intuitive and Analytical Cognition: A Second Direct Comparison

DTIC Science & Technology

1984-06-01

Review, 90(4), 293-315. Wallsten, T. S., & Budescu, D. V. (1981). Addivity and nonaddivity in judging MMPI profiles. Journal of Experimental Psychology...San Diego, CA 92152 "CDR Thomas Berghage Vaval Health Research Center San Diego, CA 92152 7 Department of the Navy Department of the Navy Mr. Paul...Research Lab Pensacola, FL 32508 Dr. S. Schiflett Human Factors Section Commanding Officer Systems Engineering Test Naval Health Research Center

Telemedicine for Improved Delivery of Psychosocial Treatments for Post Traumatic Stress Disorder

DTIC Science & Technology

2014-05-01

therapy approach. International Journal of Geriatric Psychiatry, 22, 131-143. PMID: 17096462 10. Wetherell, J. L., Kim, D. S., Lindamer, L. A., Thorp, S...Behavioral Therapy with Older Adults. Paper presented at the West Coast Geriatric Psychiatry Conference, San Diego, CA. 29. Aupperle, R. L., Allard, C. B...Cognitive Behavioral Therapy with Older Adults. Paper presented at the West Coast Geriatric Psychiatry Conference, San Diego, CA. 49. Zuest, D., Agha, Z

Four Ca2+ Ions Activate TRPM2 Channels by Binding in Deep Crevices near the Pore but Intracellularly of the Gate

PubMed Central

Törőcsik, Beáta

2009-01-01

TRPM2 is a tetrameric Ca2+-permeable channel involved in immunocyte respiratory burst and in postischaemic neuronal death. In whole cells, TRPM2 activity requires intracellular ADP ribose (ADPR) and intra- or extracellular Ca2+, but the mechanism and the binding sites for Ca2+ activation remain unknown. Here we study TRPM2 gating in inside-out patches while directly controlling intracellular ligand concentrations. Concentration jump experiments at various voltages and Ca2+ dependence of steady-state single-channel gating kinetics provide unprecedented insight into the molecular mechanism of Ca2+ activation. In patches excised from Xenopus laevis oocytes expressing human TRPM2, coapplication of intracellular ADPR and Ca2+ activated ∼50-pS nonselective cation channels; K1/2 for ADPR was ∼1 µM at saturating Ca2+. Intracellular Ca2+ dependence of TRPM2 steady-state opening and closing rates (at saturating [ADPR] and low extracellular Ca2+) reveals that Ca2+ activation is a consequence of tighter binding of Ca2+ in the open rather than in the closed channel conformation. Four Ca2+ ions activate TRPM2 with a Monod-Wymann-Changeux mechanism: each binding event increases the open-closed equilibrium constant ∼33-fold, producing altogether 106-fold activation. Experiments in the presence of 1 mM of free Ca2+ on the extracellular side clearly show that closed channels do not sense extracellular Ca2+, but once channels have opened Ca2+ entering passively through the pore slows channel closure by keeping the “activating sites” saturated, despite rapid continuous Ca2+-free wash of the intracellular channel surface. This effect of extracellular Ca2+ on gating is gradually lost at progressively depolarized membrane potentials, where the driving force for Ca2+ influx is diminished. Thus, the activating sites lie intracellularly from the gate, but in a shielded crevice near the pore entrance. Our results suggest that in intact cells that contain micromolar ADPR a single brief puff of Ca2+ likely triggers prolonged, self-sustained TRPM2 activity. PMID:19171771

Mitochondrial Ca2+ overload underlies Abeta oligomers neurotoxicity providing an unexpected mechanism of neuroprotection by NSAIDs.

PubMed

Sanz-Blasco, Sara; Valero, Ruth A; Rodríguez-Crespo, Ignacio; Villalobos, Carlos; Núñez, Lucía

2008-07-23

Dysregulation of intracellular Ca(2+) homeostasis may underlie amyloid beta peptide (Abeta) toxicity in Alzheimer's Disease (AD) but the mechanism is unknown. In search for this mechanism we found that Abeta(1-42) oligomers, the assembly state correlating best with cognitive decline in AD, but not Abeta fibrils, induce a massive entry of Ca(2+) in neurons and promote mitochondrial Ca(2+) overload as shown by bioluminescence imaging of targeted aequorin in individual neurons. Abeta oligomers induce also mitochondrial permeability transition, cytochrome c release, apoptosis and cell death. Mitochondrial depolarization prevents mitochondrial Ca(2+) overload, cytochrome c release and cell death. In addition, we found that a series of non-steroidal anti-inflammatory drugs (NSAIDs) including salicylate, sulindac sulfide, indomethacin, ibuprofen and R-flurbiprofen depolarize mitochondria and inhibit mitochondrial Ca(2+) overload, cytochrome c release and cell death induced by Abeta oligomers. Our results indicate that i) mitochondrial Ca(2+) overload underlies the neurotoxicity induced by Abeta oligomers and ii) inhibition of mitochondrial Ca(2+) overload provides a novel mechanism of neuroprotection by NSAIDs against Abeta oligomers and AD.

CaMKII and CaMKIV mediate distinct prosurvival signaling pathways in response to depolarization in neurons

PubMed Central

Bok, Jinwoong; Wang, Qiong; Huang, Jie; Green, Steven H.

2007-01-01

By fusing the CaMKII inhibitory peptide AIP to GFP, we constructed a specific and effective CaMKII inhibitor, GFP-AIP. Expression of GFP-AIP and/or dominant-inhibitory CaMKIV in cultured neonatal rat spiral ganglion neurons (SGNs) shows that CaMKII and CaMKIV act additively and in parallel, to mediate the prosurvival effect of depolarization. Depolarization or expression of constitutively-active CaMKII functionally inactivates Bad, indicating that this is one means by which CaMKII promotes neuronal survival. CaMKIV, but not CaMKII, requires CREB to promote SGN survival, consistent with the exclusively nuclear localization of CaMKIV and indicating that the principal prosurvival function of CaMKIV is activation of CREB. Consistent with this, a constitutively-active CREB construct that provides a high level of CREB activity promotes SGN survival, although low levels of CREB activity did not do so. Also, in apoptotic SGNs, activation of CREB by depolarization is disabled, presumably as part of a cellular commitment to apoptosis. PMID:17651987

TRPC1 is involved in Ca²⁺ influx and cytotoxicity following Pb²⁺ exposure in human embryonic kidney cells.

PubMed

Zhang, Hongmei; Li, Wenjun; Xue, Yong; Zou, Fei

2014-08-17

Lead (Pb(2+)) is a divalent heavy metal ion which causes severe damage to almost all life forms and is therefore considered a notorious toxicant. Exposure to Pb(2+) is associated with poor cognitive development in children at relatively low levels that previously were thought to be safe. The mechanism through which Pb(2+) enters cells, however, is unclear. Previous studies have showed that Ca(2+) release-activated Ca(2+) protein 1 (Orai1), a component of store-operated Ca(2+) channels (SOCs), contributes to Pb(2+) cellular entry. Canonical transient receptor potential (TRPC1) channel 1 is a transient receptor potential (TRP) channel which is sometimes referred to as a SOC. The present study was designed to investigate the role of TRPC1 in Pb(2+) entry and toxicity in human embryonic kidney cells (HEK293). Additionally, changes in intracellular Ca(2+) concentration were determined through Fluo-4 and Mag-fluo-4 fluorescent Ca(2+) imaging. Following Pb(2+) exposure, there was a dose-dependent decrease in cell viability. Overexpression of TRPC1 increased Pb(2+)-induced cell death, while knockdown of this channel attenuated cell death. There was increased entry of Pb(2+), as measured by inductively coupled plasma mass spectrometry (ICP-MS), following overexpression of TRPC1. Conversely, knockdown of TRPC1 led to a decrease in Pb(2+) influx. Down-regulation of STIM1 by RNA interference attenuated the Pb(2+) influx, and transfection with a mutant STIM1, which could not gate TRPC1, had a similar effect. Co-transfection of mutant STIM1 and mutant TRPC1, which restore the electrostatic interaction between STIM1 and TRPC1, resumed Pb(2+) entry in HEK293 cells. Down-regulation of TRPC1 by RNA interference decreased Ca(2+) influx whilst its overexpression increased Ca(2+) entry in HEK293 cells. These results suggest that TRPC1 is involved in the cytotoxicity and entry of Pb(2+) through molecular interactions with STIM1 and subsequent Ca(2+) influx in HEK293 cells. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Identification and in vitro pharmacological characterization of a novel and selective α7 nicotinic acetylcholine receptor agonist, Br-IQ17B.

PubMed

Tang, Jing-shu; Xie, Bing-xue; Bian, Xi-ling; Xue, Yu; Wei, Ning-ning; Zhou, Jing-heng; Hao, Yu-chen; Li, Gang; Zhang, Liang-ren; Wang, Ke-wei

2015-07-01

Alpha7-nicotinic acetylcholine receptor (α7 nAChR) is a ligand-gated Ca(2+)-permeable ion channel implicated in cognition and neuropsychiatric disorders. Activation of α7 nAChR improves learning, memory, and sensory gating in animal models. To identify novel α7 nAChR agonists, we synthesized a series of small molecules and characterized a representative compound, Br-IQ17B, N-[(3R)-1-azabicyclo[2,2,2]oct-3-yl]-5-bromoindolizine-2-carboxamide, which specifically activates α7 nAChR. Two-electrode voltage clamp (TEVC) recordings were primarily used for screening in Xenopus oocytes expressing human α7 nAChR. Assays, including radioisotope ligand binding, Western blots, whole-cell recordings of hippocampal culture neurons, and spontaneous IPSC recordings of brain slices, were also utilized to evaluate and confirm the specific activation of α7 nAChR by Br-IQ17B. Br-IQ17B potently activates α7 nAChR with an EC50 of 1.8±0.2 μmol/L. Br-IQ17B is selective over other subtypes such as α4β2 and α3β4, but it blocks 5-HT3A receptors. Br-IQ17B displaced binding of the α7 blocker [(3)H]-MLA to hippocampal crude membranes with a Ki of 14.9±3.2 nmol/L. In hippocampal neurons, Br-IQ17B evoked α7-like currents that were inhibited by MLA and enhanced in the presence of the α7 PAM PNU-120596. In brain slice recordings, Br-IQ17B enhanced GABAergic synaptic transmission in CA1 neurons. Mechanistically, Br-IQ17B increased ERK1/2 phosphorylation that was MLA-sensitive. We identified the novel, potent, and selective α7 agonist Br-IQ17B, which enhances synaptic transmission. Br-IQ17B may be a helpful tool to understand new aspects of α7 nAChR function, and it also has potential for being developed as therapy for schizophrenia and cognitive deficits.

Identification and in vitro pharmacological characterization of a novel and selective α7 nicotinic acetylcholine receptor agonist, Br-IQ17B

PubMed Central

Tang, Jing-shu; Xie, Bing-xue; Bian, Xi-ling; Xue, Yu; Wei, Ning-ning; Zhou, Jing-heng; Hao, Yu-chen; Li, Gang; Zhang, Liang-ren; Wang, Ke-wei

2015-01-01

Aim: Alpha7-nicotinic acetylcholine receptor (α7 nAChR) is a ligand-gated Ca2+-permeable ion channel implicated in cognition and neuropsychiatric disorders. Activation of α7 nAChR improves learning, memory, and sensory gating in animal models. To identify novel α7 nAChR agonists, we synthesized a series of small molecules and characterized a representative compound, Br-IQ17B, N-[(3R)-1-azabicyclo[2,2,2]oct-3-yl]-5-bromoindolizine-2-carboxamide, which specifically activates α7 nAChR. Methods: Two-electrode voltage clamp (TEVC) recordings were primarily used for screening in Xenopus oocytes expressing human α7 nAChR. Assays, including radioisotope ligand binding, Western blots, whole-cell recordings of hippocampal culture neurons, and spontaneous IPSC recordings of brain slices, were also utilized to evaluate and confirm the specific activation of α7 nAChR by Br-IQ17B. Results: Br-IQ17B potently activates α7 nAChR with an EC50 of 1.8±0.2 μmol/L. Br-IQ17B is selective over other subtypes such as α4β2 and α3β4, but it blocks 5-HT3A receptors. Br-IQ17B displaced binding of the α7 blocker [3H]-MLA to hippocampal crude membranes with a Ki of 14.9±3.2 nmol/L. In hippocampal neurons, Br-IQ17B evoked α7-like currents that were inhibited by MLA and enhanced in the presence of the α7 PAM PNU-120596. In brain slice recordings, Br-IQ17B enhanced GABAergic synaptic transmission in CA1 neurons. Mechanistically, Br-IQ17B increased ERK1/2 phosphorylation that was MLA-sensitive. Conclusion: We identified the novel, potent, and selective α7 agonist Br-IQ17B, which enhances synaptic transmission. Br-IQ17B may be a helpful tool to understand new aspects of α7 nAChR function, and it also has potential for being developed as therapy for schizophrenia and cognitive deficits. PMID:25948478

Acute stress causes rapid synaptic insertion of Ca2+-permeable AMPA receptors to facilitate long-term potentiation in the hippocampus

PubMed Central

Jo, Jihoon; Hogg, Ellen L.; Piers, Thomas; Kim, Dong-Hyun; Seaton, Gillian; Seok, Heon; Bru-Mercier, Gilles; Son, Gi Hoon; Regan, Philip; Hildebrandt, Lars; Waite, Eleanor; Kim, Byeong-Chae; Kerrigan, Talitha L.; Kim, Kyungjin; Whitcomb, Daniel J.; Lightman, Stafford L.

2013-01-01

The neuroendocrine response to episodes of acute stress is crucial for survival whereas the prolonged response to chronic stress can be detrimental. Learning and memory are particularly susceptible to stress with cognitive deficits being well characterized consequences of chronic stress. Although there is good evidence that acute stress can enhance cognitive performance, the mechanism(s) for this are unclear. We find that hippocampal slices, either prepared from rats following 30 min restraint stress or directly exposed to glucocorticoids, exhibit an N-methyl-d-aspartic acid receptor-independent form of long-term potentiation. We demonstrate that the mechanism involves an NMDA receptor and PKA-dependent insertion of Ca2+-permeable AMPA receptors into synapses. These then trigger the additional NMDA receptor-independent form of LTP during high frequency stimulation. PMID:24271563

Association of Anxiety and Depression With Microtubule-Associated Protein 2– and Synaptopodin-Immunolabeled Dendrite and Spine Densities in Hippocampal CA3 of Older Humans

PubMed Central

Soetanto, Ainie; Wilson, Robert S.; Talbot, Konrad; Un, Ashley; Schneider, Julie A.; Sobiesk, Mark; Kelly, Jeremiah; Leurgans, Sue; Bennett, David A.; Arnold, Steven E.

2010-01-01

Context Chronic psychological distress has deleterious effects on many of the body’s physiological systems. In experimental animal models, chronic stress leads to neuroanatomic changes in the hippocampus, in particular a decrease in the length and branching of dendrites as well as a decrease in the number of dendritic spines. Objectives To examine whether analogous distress-related neuroanatomic changes occur in humans and whether such changes might also be related to cognitive dysfunction observed in older people who report greater psychological distress. Design Postmortem study of brain tissues from participants of the Religious Orders Study, an ongoing population-based clinicopathological study of aging and cognition. Setting The Rush University Religious Orders Study and the University of Pennsylvania Cellular and Molecular Neuropathology Program. Participants Seventy-two deceased participants of the Religious Orders Study. Main Outcome Measures Densities of microtubule-associated protein 2–immunolabeled dendrites and synaptopodin-immunolabeled dendritic spines in the CA3 subfield of the hippocampus, quantified using semiautomated image acquisition and analysis. Results Higher levels of trait anxiety and longitudinal depression scores were associated with decreased densities of dendrites and spines in CA3. Dendrite and spine densities did not correlate with an index of global cognition or with densities of common age-related pathological changes. Conclusions Regressive neuronal changes occur in humans who experience greater psychological distress. These changes are analogous to neuronal changes in animal models of chronic stress. PMID:20439826

Hippocampal extracellular matrix alterations contribute to cognitive impairment associated with a chronic depressive-like state in rats.

PubMed

Riga, Danai; Kramvis, Ioannis; Koskinen, Maija K; van Bokhoven, Pieter; van der Harst, Johanneke E; Heistek, Tim S; Jaap Timmerman, A; van Nierop, Pim; van der Schors, Roel C; Pieneman, Anton W; de Weger, Anouk; van Mourik, Yvar; Schoffelmeer, Anton N M; Mansvelder, Huib D; Meredith, Rhiannon M; Hoogendijk, Witte J G; Smit, August B; Spijker, Sabine

2017-12-20

Patients with depression often suffer from cognitive impairments that contribute to disease burden. We used social defeat-induced persistent stress (SDPS) to induce a depressive-like state in rats and then studied long-lasting memory deficits in the absence of acute stressors in these animals. The SDPS rat model showed reduced short-term object location memory and maintenance of long-term potentiation (LTP) in CA1 pyramidal neurons of the dorsal hippocampus. SDPS animals displayed increased expression of synaptic chondroitin sulfate proteoglycans in the dorsal hippocampus. These effects were abrogated by a 3-week treatment with the antidepressant imipramine starting 8 weeks after the last defeat encounter. Next, we observed an increase in the number of perineuronal nets (PNNs) surrounding parvalbumin-expressing interneurons and a decrease in the frequency of inhibitory postsynaptic currents (IPSCs) in the hippocampal CA1 region in SDPS animals. In vivo breakdown of the hippocampus CA1 extracellular matrix by the enzyme chondroitinase ABC administered intracranially restored the number of PNNs, LTP maintenance, hippocampal inhibitory tone, and memory performance on the object place recognition test. Our data reveal a causal link between increased hippocampal extracellular matrix and the cognitive deficits associated with a chronic depressive-like state in rats exposed to SDPS. Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Extracellular calcium-sensing-receptor (CaR)-mediated opening of an outward K(+) channel in murine MC3T3-E1 osteoblastic cells: evidence for expression of a functional CaR

NASA Technical Reports Server (NTRS)

Ye, C. P.; Yamaguchi, T.; Chattopadhyay, N.; Sanders, J. L.; Vassilev, P. M.; Brown, E. M.; O'Malley, B. W. (Principal Investigator)

2000-01-01

The existence in osteoblasts of the G-protein-coupled extracellular calcium (Ca(o)(2+))-sensing receptor (CaR) that was originally cloned from parathyroid and kidney remains controversial. In our recent studies, we utilized multiple detection methods to demonstrate the expression of CaR transcripts and protein in several osteoblastic cell lines, including murine MC3T3-E1 cells. Although we and others have shown that high Ca(o)(2+) and other polycationic CaR agonists modulate the function of MC3T3-E1 cells, none of these actions has been unequivocally shown to be mediated by the CaR. Previous investigations using neurons and lens epithelial cells have shown that activation of the CaR stimulates Ca(2+)-activated K(+) channels. Because osteoblastic cells express a similar type of channel, we have examined the effects of specific "calcimimetic" CaR activators on the activity of a Ca(2+)-activated K(+) channel in MC3T3-E1 cells as a way of showing that the CaR is not only expressed in those cells but is functionally active. Patch-clamp analysis in the cell-attached mode showed that raising Ca(o)(2+) from 0.75 to 2.75 mmol/L elicited about a fourfold increase in the open state probability (P(o)) of an outward K(+) channel with a conductance of approximately 92 pS. The selective calcimimetic CaR activator, NPS R-467 (0.5 micromol/L), evoked a similar activation of the channel, while its less active stereoisomer, NPSS-467 (0.5 micromol/L), did not. Thus, the CaR is not only expressed in MC3T3-E1 cells, but is also functionally coupled to the activity of a Ca(2+)-activated K(+) channel. This receptor, therefore, could transduce local or systemic changes in Ca(o)(2+) into changes in the activity of this ion channel and related physiological processes in these and perhaps other osteoblastic cells.

Mutation/SNP analysis in EF-hand calcium binding domain of mitochondrial Ca[Formula: see text] uptake 1 gene in bipolar disorder patients.

PubMed

Safari, Roghaiyeh; Salimi, Reza; Tunca, Zeliha; Ozerdem, Aysegul; Ceylan, Deniz; Sakizli, Meral

2016-06-01

Calcium signaling is important for synaptic plasticity, generation of brain rhythms, regulating neuronal excitability, data processing and cognition. Impairment in calcium homeostasis contributed to the development of psychiatric disorders such as bipolar disorder (BP). MCU is the most important calcium transporter in mitochondria inner membrane responsible for influx of Ca[Formula: see text]. MICU1 is linked with MCU and has two canonical EF hands that are vital for its activity and regulates MCU-mediated Ca[Formula: see text] influx. In the current study, we aimed to investigate the role of genetic alteration of EF hand calcium binding motifs of MICU1 on the development of BP. We examined patients with BP, first degree relatives of these patients and healthy volunteers for mutations and polymorphisms in EF hand calcium binding motifs of MICU1. The result showed no SNP/mutation in BP patients, in healthy subjects and in first degree relatives. Additionally, alignment of the EF hand calcium binding regions among species (Gallus-gallus, Canis-lupus-familiaris, Bos-taurus, Mus-musculus, Rattus-norvegicus, Pan-troglodytes, Homosapiens and Danio-rerio) showed exactly the same amino acids (DLNGDGEVDMEE and DCDGNGELSNKE) except in one of the calcium binding domain of Danio-rerio that there was only one difference; leucine instead of Methionine. Our results showed that the SNP on EF-hand Ca[Formula: see text] binding domains of MICU1 gene had no effect in phenotypic characters of BP patients.

Enduring medial perforant path short-term synaptic depression at high pressure.

PubMed

Talpalar, Adolfo E; Giugliano, Michele; Grossman, Yoram

2010-01-01

The high pressure neurological syndrome develops during deep-diving (>1.1 MPa) involving impairment of cognitive functions, alteration of synaptic transmission and increased excitability in cortico-hippocampal areas. The medial perforant path (MPP), connecting entorhinal cortex with the hippocampal formation, displays synaptic frequency-dependent-depression (FDD) under normal conditions. Synaptic FDD is essential for specific functions of various neuronal networks. We used rat cortico-hippocampal slices and computer simulations for studying the effects of pressure and its interaction with extracellular Ca(2+) ([Ca(2+)](o)) on FDD at the MPP synapses. At atmospheric pressure, high [Ca(2+)](o) (4-6 mM) saturated single MPP field EPSP (fEPSP) and increased FDD in response to short trains at 50 Hz. High pressure (HP; 10.1 MPa) depressed single fEPSPs by 50%. Increasing [Ca(2+)](o) to 4 mM at HP saturated synaptic response at a subnormal level (only 20% recovery of single fEPSPs), but generated a FDD similar to atmospheric pressure. Mathematical model analysis of the fractions of synaptic resources used by each fEPSP during trains (normalized to their maximum) and the total fraction utilized within a train indicate that HP depresses synaptic activity also by reducing synaptic resources. This data suggest that MPP synapses may be modulated, in addition to depression of single events, by reduction of synaptic resources and then may have the ability to conserve their dynamic properties under different conditions.

Enduring Medial Perforant Path Short-Term Synaptic Depression at High Pressure

PubMed Central

Talpalar, Adolfo E.; Giugliano, Michele; Grossman, Yoram

2010-01-01

The high pressure neurological syndrome develops during deep-diving (>1.1 MPa) involving impairment of cognitive functions, alteration of synaptic transmission and increased excitability in cortico-hippocampal areas. The medial perforant path (MPP), connecting entorhinal cortex with the hippocampal formation, displays synaptic frequency-dependent-depression (FDD) under normal conditions. Synaptic FDD is essential for specific functions of various neuronal networks. We used rat cortico-hippocampal slices and computer simulations for studying the effects of pressure and its interaction with extracellular Ca2+ ([Ca2+]o) on FDD at the MPP synapses. At atmospheric pressure, high [Ca2+]o (4–6 mM) saturated single MPP field EPSP (fEPSP) and increased FDD in response to short trains at 50 Hz. High pressure (HP; 10.1 MPa) depressed single fEPSPs by 50%. Increasing [Ca2+]o to 4 mM at HP saturated synaptic response at a subnormal level (only 20% recovery of single fEPSPs), but generated a FDD similar to atmospheric pressure. Mathematical model analysis of the fractions of synaptic resources used by each fEPSP during trains (normalized to their maximum) and the total fraction utilized within a train indicate that HP depresses synaptic activity also by reducing synaptic resources. This data suggest that MPP synapses may be modulated, in addition to depression of single events, by reduction of synaptic resources and then may have the ability to conserve their dynamic properties under different conditions. PMID:21048901

Cognitive intervention through a training program for picture book reading in community-dwelling older adults: a randomized controlled trial.

PubMed

Suzuki, Hiroyuki; Kuraoka, Masataka; Yasunaga, Masashi; Nonaka, Kumiko; Sakurai, Ryota; Takeuchi, Rumi; Murayama, Yoh; Ohba, Hiromi; Fujiwara, Yoshinori

2014-11-21

Non-pharmacological interventions are expected to be important strategies for reducing the age-adjusted prevalence of senile dementia, considering that complete medical treatment for cognitive decline has not yet been developed. From the viewpoint of long-term continuity of activity, it is necessary to develop various cognitive stimulating programs. The aim of this study is to examine the effectiveness of a cognitive intervention through a training program for picture book reading for community-dwelling older adults. Fifty-eight Japanese older participants were divided into the intervention and control groups using simple randomization (n =29 vs 29). In the intervention group, participants took part in a program aimed at learning and mastering methods of picture book reading as a form of cognitive training intervention. The control group listened to lectures about elderly health maintenance. Cognitive tests were conducted individually before and after the programs. The rate of memory retention, computed by dividing Logical Memory delayed recall by immediate recall, showed a significant interaction (p < .05) in analysis of covariance. Simple main effects showed that the rate of memory retention of the intervention group improved after the program completion (p < .05). In the participants with mild cognitive impairment (MCI) examined by Japanese version of the Montreal Cognitive Assessment (MoCA-J) (n =14 vs 15), significant interactions were seen in Trail Making Test-A (p < .01), Trail Making Test-B (p < .05), Kana pick-out test (p < .05) and the Mini-Mental State Examination (p < .05). The intervention effect was found in delayed verbal memory. This program is also effective for improving attention and executive function in those with MCI. The short-term interventional findings suggest that this program might contribute to preventing a decline in memory and executive function. UMIN000014712 (Date of ICMJE and WHO compliant trial information disclosure: 30 July 2014).

P/Q-type calcium channels activate neighboring calcium-dependent potassium channels in mouse motor nerve terminals.

PubMed

Protti, D A; Uchitel, O D

1997-08-01

The identity of the voltage-dependent calcium channels (VDCC), which trigger the Ca2+-gated K+ currents (IK(Ca)) in mammalian motor nerve terminals, was investigated by means of perineurial recordings. The effects of Ca2+ chelators with different binding kinetics on the activation of IK(Ca) were also examined. The calcium channel blockers of the P/Q family, omega-agatoxin IVA (omega-Aga-IVA) and funnel-web spider toxin (FTX), have been shown to exert a strong blocking effect on IK(Ca). In contrast, nitrendipine and omega-conotoxin GVIA (omega-CgTx) did not affect the Ca2+-activated K+ currents. The intracellular action of the fast Ca2+ buffers BAPTA and DM-BAPTA prevented the activation of the IK(Ca), while the slow Ca2+ buffer EGTA was ineffective at blocking it. These data indicate that P/Q-type VDCC mediate the Ca2+ influx which activates IK(Ca). The spatial association between Ca2+ and Ca2+-gated K+ channels is discussed, on the basis of the differential effects of the fast and slow Ca2+ chelators.

[Effects of different application rates of calcium cyanamide on soil microbial biomass and enzyme activity in cucumber continuous cropping].

PubMed

Zhang, Xue-peng; Ning, Tang-yuan; Yang, Yan; Sun, Tao; Zhang, Shu-min; Wang, Bin

2015-10-01

A 2-year field experiment was conducted to study the effects of CaCN2 combined with cucumber straw retention on soil microbial biomass carbon (SMBC) , soil microbial biomass nitrogen (SMBN) and soil enzyme activities under cucumber continuous cropping system. Four treatments were used in this study as follows: CK (null CaCN2), CaCN2-90 (1350 kg CaCN2 . hm-2) CaCN2-60 (900 kg CaCN2 . hm-2), CaCN2-30 (450 kg CaCN2 . hm-2). The results indicated that, compared with the other treatments, CaCN2-90 treatment significantly decreased SMBC in 0-10 cm soil layer at seedling stage, but increased SMBC in 0-20 cm soil layer after early-fruit stage. Compared with CK, CaCN2 increased SMBC in 0-20 cm soil layer at late-fruit stage, and increased SMBN in 0-10 cm soil layer at mid- and late-fruit stages, however there was no significant trend among CaCN2 treatments in the first year (2012), while in the second year (2013) SMBN increased with the increasing CaCN2 amount after mid-fruit stage. CaCN2 increased straw decaying and nutrients releasing, and also increased soil organic matter. Furthermore, the CaCN2-90 could accelerate straw decomposition. Compared with CK, CaCN2 effectively increased soil urease, catalase and polyphenol oxidase activity. The soil urease activity increased while the polyphenol oxidase activity decreased with the increase of CaCN2, and CaCN2-60 could significantly improve catalase activity. Soil organic matter, urease activity and catalase activity had significant positive correlations with SMBC and SMBN. However, polyphenol oxidase activity was negatively correlated to SMBC and SMBN. Our findings indicated that CaCN2 application at 900 kg . hm-2 combined with cucumber straw retention could effectively improve soil environment, alleviating the soil obstacles under the cucumber continuous cropping system.

Regulation of AMP-activated protein kinase by LKB1 and CaMKK in adipocytes.

PubMed

Gormand, Amélie; Henriksson, Emma; Ström, Kristoffer; Jensen, Thomas Elbenhardt; Sakamoto, Kei; Göransson, Olga

2011-05-01

AMP-activated protein kinase (AMPK) is a serine/threonine kinase that regulates cellular and whole body energy homeostasis. In adipose tissue, activation of AMPK has been demonstrated in response to a variety of extracellular stimuli. However, the upstream kinase that activates AMPK in adipocytes remains elusive. Previous studies have identified LKB1 as a major AMPK kinase in muscle, liver, and other tissues. In certain cell types, Ca(2+) /calmodulin-dependent protein kinase kinase β (CaMKKβ) has been shown to activate AMPK in response to increases of intracellular Ca(2+) levels. Our aim was to investigate if LKB1 and/or CaMKK function as AMPK kinases in adipocytes. We used adipose tissue and isolated adipocytes from mice in which the expression of LKB1 was reduced to 10-20% of that of wild-type (LKB1 hypomorphic mice). We show that adipocytes from LKB1 hypomorphic mice display a 40% decrease in basal AMPK activity and a decrease of AMPK activity in the presence of the AMPK activator phenformin. We also demonstrate that stimulation of 3T3L1 adipocytes with intracellular [Ca(2+) ]-raising agents results in an activation of the AMPK pathway. The inhibition of CaMKK isoforms, particularly CaMKKβ, by the inhibitor STO-609 or by siRNAs, blocked Ca(2+) -, but not phenformin-, AICAR-, or forskolin-induced activation of AMPK, indicating that CaMKK activated AMPK in response to Ca(2+) . Collectively, we show that LKB1 is required to maintain normal AMPK-signaling in non-stimulated adipocytes and in the presence of phenformin. In addition, we demonstrate the existence of a Ca(2+) /CaMKK signaling pathway that can also regulate the activity of AMPK in adipocytes. Copyright © 2011 Wiley-Liss, Inc.

Conference on the Neurobiology of Learning and Memory (2nd).

DTIC Science & Technology

1986-05-30

Illinois The Rockefeller University 603 E. Daniel 1230 York Ave. Champaign, IL 61820 New York, NY 10021 Mr. Steven M. Guich Dr. Franz Hock Social Sciences...Psychology Edmonton, Alberta T6H 2B9 John Hopkins University Canada Baltimore, MD 21218 Mr. Steven Hampson Ms. Carol A. Hunt Information and Computer...Irvine, CA 92717 University of California Irvine, CA 92717 Dr. David LaBerge Cognitive Sciences Mr. Richard S. Lewis University of California Department

Presynaptic kainate receptor-mediated facilitation of glutamate release involves Ca2+ -calmodulin at mossy fiber-CA3 synapses.

PubMed

Andrade-Talavera, Yuniesky; Duque-Feria, Paloma; Negrete-Díaz, José Vicente; Sihra, Talvinder S; Flores, Gonzalo; Rodríguez-Moreno, Antonio

2012-09-01

Presynaptic kainate receptors (KARs) modulate the release of glutamate at synapses established between mossy fibers (MF) and CA3 pyramidal cells in the hippocampus. The activation of KAR by low, nanomolar, kainate concentrations facilitates glutamate release. KAR-mediated facilitation of glutamate release involves the activation of an adenylate cyclase/cyclic adenosine monophosphate/protein kinase A cascade at MF-CA3 synapses. Here, we studied the mechanisms by which KAR activation produces this facilitation of glutamate release in slices and synaptosomes. We find that the facilitation of glutamate release mediated by KAR activation requires an increase in Ca(2+) levels in the cytosol and the formation of a Ca(2+) -calmodulin complex to activate adenylate cyclase. The increase in cytosolic Ca(2+) underpinning this modulation is achieved, both, by Ca(2+) entering via Ca(2+) -permeable KARs and, by the mobilization of intraterminal Ca(2+) stores. Finally, we find that, congruent with the Ca(2+) -calmodulin support of KAR-mediated facilitation of glutamate release, induction of long-term potentiation at MF-CA3 synapses has an obligate requirement for Ca(2+) -calmodulin activity. © 2012 The Authors. Journal of Neurochemistry © 2012 International Society for Neurochemistry.

Executive dysfunction, obsessive-compulsive symptoms, and attention deficit and hyperactivity disorder in Systemic Lupus Erythematosus: Evidence for basal ganglia dysfunction?

PubMed

Maciel, Ricardo Oliveira Horta; Ferreira, Gilda Aparecida; Akemy, Bárbara; Cardoso, Francisco

2016-01-15

Chorea is well described in a group of patients with Systemic Lupus Erythematosus (SLE). There is less information, however, on other movement disorders as well as non-motor neuropsychiatric features such as obsessive-compulsive symptoms (OCS), executive dysfunction and attention deficit and hyperactivity disorder (ADHD) in subjects with SLE. Fifty-four subjects with SLE underwent a battery of neuropsychiatric tests that included the Mini Mental State Examination, the Montreal Cognitive Assessment, the Frontal Assessment Battery (FAB), the FAS verbal and the categorical (animals) semantic fluency tests, the Obsessive and Compulsive Inventory - Revised, the Yale-Brown Obsessive and Compulsive Scale and Beck's Anxiety and Depression Scales. ADHD was diagnosed according to DSM-IV criteria. SLE disease activity and cumulative damage were evaluated according to the modified SLE Disease Activity Index 2000 (mSLEDAI-2K) and the SLICC/ACR, respectively. Six (11.1%) and 33 (61.1%) patients had cognitive impairment according to the MMSE and MoCA, respectively. Eleven (20.4%) had abnormal FAB scores, and 5 (9.3%) had lower semantic fluency scores than expected. The overall frequency of cognitive dysfunction was 72.2% (39 patients) and of neuropsychiatric SLE was 77.8% (42 patients). Two patients (3.7%) had movement disorders. Fifteen (27.8%) had OCS and 17 (31.5%) met diagnostic criteria for ADHD. ADHD and OCS correlated with higher disease activity, p=0.003 and 0.006, respectively. Higher cumulative damage correlated with lower FAB scores (p 0.026). Executive dysfunction, ADHD, OCS, and movement disorders are common in SLE. Our finding suggests that there is frequent basal ganglia dysfunction in SLE. Copyright © 2015 Elsevier B.V. All rights reserved.

Aniracetam reversed learning and memory deficits following prenatal ethanol exposure by modulating functions of synaptic AMPA receptors.

PubMed

Vaglenova, Julia; Pandiella, Noemi; Wijayawardhane, Nayana; Vaithianathan, Tiru; Birru, Sandjay; Breese, Charles; Suppiramaniam, Vishnu; Randal, Clark

2008-04-01

Specific pharmacological treatments are currently not available to address problems resulting from fetal ethanol exposure, described as Fetal Alcohol Syndrome or Fetal Alcohol Spectrum Disorders (FASD). The present study evaluated the therapeutic effects of aniracetam against cognitive deficits in a well-characterized and sensitive FASD Sprague-Dawley rat model. Ethanol, administered orally at a moderate dose (4 g/kg/24 h; 38% v/v) during the entire course of pregnancy, caused severe cognitive deficits in offspring. Furthermore, both progeny genders were affected by a spectrum of behavioral abnormalities, such as a delay in the development of the righting reflex, poor novelty seeking behavior, and high anxiety levels in female rats. Cognitive disabilities, monitored in adult rats by a two-way active avoidance task, correlated well with a significant reduction of AMPA (alpha-amino-3 hydro-5 methyl-isoxazole propionic acid) receptor-mediated miniature excitatory postsynaptic responses (mEPSCs) in the hippocampus. Administration of aniracetam for 10 days (post-natal days (PND) 18-27), at a dose of 50 mg/kg reversed cognitive deficits in both rat genders, indicated by a significant increase in the number of avoidances and the number of 'good learners'. After the termination of the nootropic treatment, a significant increase in both amplitude and frequency of AMPA receptor-mediated mEPSCs in hippocampal CA-1 pyramidal cells was observed. Significant anxiolytic effects on PND 40 also preceded acquisition improvements in the avoidance task. This study provides evidence for the therapeutic potential of aniracetam in reversing cognitive deficits associated with FASD through positive post-natal modulation of AMPA receptors.

Would Confucius benefit from psychotherapy? The compatibility of cognitive behaviour therapy and Chinese values.

PubMed

Hodges, Julie; Oei, Tian P S

2007-05-01

The purpose of the present paper is to explore the conceptual compatibility between cognitive behaviour therapy (CBT) and the common values of Chinese Culture. In order to address such a question, the distinctive processes attributed to CBT (e.g., teaching of skills, emphasis on homework, cognitive processes, present/future focus), as summarized in the meta-analysis by Blagys and Hilsenroth [(2002). Distinctive activities of cognitive-behavioral therapy: A review of the comparative psychotherapy process literature. Clinical Psychology Review, 22, 671-706], and the core values of Chinese Culture, determined through an integration of The Hofstede Project, [Hofstede, G.H. (1980). Culture's consequences: International differences in work related values. Beverly Hills: Sage]. The Chinese Value Survey [Chinese Culture Connection (1987). Chinese values and the search for culture-free dimensions of culture. Journal of Cross-Cultural Psychology, 18, 143-164]. The Schwartz Value Survey [Schwartz, S.H. (1994). Cultural dimensions of values: Towards an understanding of national differences. In Kim, U., Trandis, H.C., Katiticibasi, C., Choi, S.C., & Yoon, G. (eds.), Individualism and collectivism: Theory, method and application (pp. 85-119). Thousand Oaks, CA: Sage] were used. A strong degree of compatibility between the two was found and it is argued that rather than developing new indigenized therapies, with some structural changes to the processes of CBT, this therapy can be effective for Chinese clients. It is further proposed that Chinese clients may benefit from challenging their irrational cognitions that are bound up in their strict adherence to social norms. Future recommendations for increasing the compatibility of CBT to Chinese culture are discussed.

Measuring discrimination- and reversal learning in mouse models within 4 days and without prior food deprivation

PubMed Central

Smit, August B.; Verhage, Matthijs

2016-01-01

Many neurological and psychiatric disorders are characterized by deficits in cognitive flexibility. Modeling cognitive flexibility in mice enables the investigation of mechanisms underlying these deficits. The majority of currently available behavioral tests targeting this cognitive domain are reversal learning tasks that require scheduled food restriction, extended training periods and labor-intensive, and stress-inducing animal handling. Here, we describe a novel 4-day (4-d) continuously running task measuring discrimination- and reversal learning in an automated home cage (CognitionWall DL/RL task) that largely eliminates these limitations. In this task, mice can earn unlimited number of food rewards by passing through the correct hole of the three-holed CognitionWall. To assess the validity and sensitivity of this novel task, the performance of C57BL/6J mice, amyloid precursor protein/presenilin1 transgenic (APP/PS1) mice, α-calmodulin kinase-II (αCaMKII) T305D knock-in mice, and mice with an orbitofrontal cortex lesion were examined. We found that C57BL/6J mice reach stable performance levels within the 4 d of the task, while experiencing only slight reductions in weight and no major effects on circadian rhythm. The task detected learning deficits in APP/PS1 transgenic and αCaMKII T305D mutant mice. Additionally, we established that the orbitofrontal cortex underlies reversal learning performance in our task. Because of its short duration and the absence of food deprivation and concurrent weight loss, this novel automated home-cage task substantially improves comprehensive preclinical assessment of cognitive functions in mouse models of psychiatric and neurological disorders and also enables analysis during specific developmental stages. PMID:27918287

Fish oil promotes survival and protects against cognitive decline in severely undernourished mice by normalizing satiety signals

PubMed Central

Avraham, Yosefa; Saidian, Mayer; Burston, James J.; Mevorach, Raphael; Vorobiev, Lia; Magen, Iddo; Kunkes, Eithan; Borges, Beatriz; Lichtman, Aron H.; Berry, Elliot M.

2010-01-01

Severe malnutrition resulting from anorexia nervosa or involuntary starvation leads to low weight, cognitive deficits, and increased mortality rates. In the present study, we examined whether fish oil supplementation, compared with canola oil, would ameliorate the morbidity and mortality associated with these conditions by normalizing endocannabinoid and monoaminergeric systems as well as other systems involved in satiety and cognitive function within the hypothalamus and hippocampus. Female Sabra mice restricted to 40% of their daily food intake exhibited decreased body weight, were sickly in appearance, displayed cognitive deficits, and had increased mortality rates. Strikingly, fish oil supplementation that contains high omega-3 fatty acids levels decreased mortality and morbidity, and normalized the expression of genes and neurotransmitters in the hippocampus and hypothalamus. Fish oil supplementation, but not canola oil, increased survival rates, improved general appearance, and prevented cognitive decline, despite the facts that both diets contained an equivalent number of calories and that there were no differences in weight between mice maintained on the two diets in 100% but decrease in the 40%. In the hypothalamus, the beneficial effects of fish oil supplementation were related to normalization of the endocannabinoid 2-arachidonylglycerol (2-AG), serotonin (5-HT) (p<0.056), dopamine (DA), neuropeptide Y (NPY), and Ca2+/calmodulin (CaM)-dependent protein kinase (Camkk2). In the hippocampus, fish oil supplementation normalized 5-HT, Camkk2, silent mating type information regulation 1 (SIRT-1), and brain-derived neurotrophic factor (BDNF). In conclusion, dietary supplements of fish oil, as source of omega-3 fatty acids, may alleviate cognitive impairments associated with severe diet restriction and prolong survival independently of weight gain by normalizing neurochemical systems. PMID:21109417

Serum 25-hydroxyvitamin D is associated with reduced verbal episodic memory in healthy, middle-aged and older adults.

PubMed

Lam, Virginie; Albrecht, Matthew A; Takechi, Ryusuke; Prasopsang, Prachya; Lee, Ya Ping; Foster, Jonathan K; Mamo, John C L

2016-06-01

There is increasing evidence supporting an association of higher serum vitamin D concentration with better cognitive performance in older individuals. However, to date, consideration of the putative association between vitamin D and cognition has been based principally on studies investigating clinical participant samples manifesting vitamin D deficiency, particularly in older people. Moreover, relationships between vitamin D and cognition are typically not considered in the context of counter-regulatory calcium-modulating hormones or calcium homeostasis. Serum vitamin D/bioactive (ionised) calcium/parathyroid hormone homeostasis was considered in the context of cognitive performance in healthy, middle-aged and older individuals. A cross-sectional sample of 179 participants between the ages of 47-84 years was recruited for this study (114 females, 65 males). Participants provided fasting blood samples for analysis of serum 25-hydroxyvitamin D levels, ionised calcium (iCa) and parathyroid hormone (PTH) and completed cognitive measures of verbal episodic learning and memory. Serum 25-hydroxyvitamin D concentrations were negatively associated (with and without covariates of age, gender, depression and NART scores, iCa, and PTH) with measures of verbal episodic learning and memory, in particular with trial 5 of the Rey Auditory Verbal Learning Test (RAVLT) and long-delay free recall on the RAVLT. Overall, the findings from this study suggest an association between higher vitamin D status and poorer performance on verbal episodic memory in middle-aged and older individuals with normal vitamin D-calcium-PTH homeostasis. Despite requiring replication in other participant samples, this is a potentially important finding as it indicates that it may not be beneficial from a cognitive perspective to provide vitamin D supplements in individuals with already adequate vitamin D status.

Changes in hippocampal synaptic functions and protein expression in monosodium glutamate-treated obese mice during development of glucose intolerance.

PubMed

Sasaki-Hamada, Sachie; Hojo, Yuki; Koyama, Hajime; Otsuka, Hayuma; Oka, Jun-Ichiro

2015-05-01

Glucose is the sole neural fuel for the brain and is essential for cognitive function. Abnormalities in glucose tolerance may be associated with impairments in cognitive function. Experimental obese model mice can be generated by an intraperitoneal injection of monosodium glutamate (MSG; 2 mg/g) once a day for 5 days from 1 day after birth. MSG-treated mice have been shown to develop glucose intolerance and exhibit chronic neuroendocrine dysfunction associated with marked cognitive malfunctions at 28-29  weeks old. Although hippocampal synaptic plasticity is impaired in MSG-treated mice, changes in synaptic transmission remain unknown. Here, we investigated whether glucose intolerance influenced cognitive function, synaptic properties and protein expression in the hippocampus. We demonstrated that MSG-treated mice developed glucose intolerance due to an impairment in the effectiveness of insulin actions, and showed cognitive impairments in the Y-maze test. Moreover, long-term potentiation (LTP) at Schaffer collateral-CA1 pyramidal synapses in hippocampal slices was impaired, and the relationship between the slope of extracellular field excitatory postsynaptic potential and stimulus intensity of synaptic transmission was weaker in MSG-treated mice. The protein levels of vesicular glutamate transporter 1 and GluA1 glutamate receptor subunits decreased in the CA1 region of MSG-treated mice. These results suggest that deficits in glutamatergic presynapses as well as postsynapses lead to impaired synaptic plasticity in MSG-treated mice during the development of glucose intolerance, though it remains unknown whether impaired LTP is due to altered inhibitory transmission. It may be important to examine changes in glucose tolerance in order to prevent cognitive malfunctions associated with diabetes. © 2015 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Computed tomography perfusion imaging may predict cognitive impairment in patients with first-time anterior circulation transient ischemic attack.

PubMed

Wang, Jun; Li, Yunming; Zheng, Bo; Wang, Jian; Wang, Zhiqiang; Duan, Dan; Li, Yuxia; Wang, Qingsong

2016-04-01

To determine whether computed tomography perfusion imaging (CTPI)-derived parameters are associated with vascular cognitive impairment (VCI) in patients with transient ischemic attack (TIA). Patients with first-time anterior circulation TIA (diagnosed within 24 h of onset) and normal cognition, treated between August 2009 and August 2014 at the Department of Neurology of Chengdu Military General Hospital, China, were analyzed retrospectively. Patients underwent whole-brain CTPI within 1 week of TIA to detect cerebral blood volume (CBV), cerebral blood flow (CBF), mean transit time (MTT) and time to peak (TTP) in the ischemic region. Based on cognitive function assessment 4 weeks after TIA, using the Montreal cognitive assessment (MoCA) and mini mental state examination, the patients were divided into control and VCI groups. CTPI parameters and other clinical data were compared between groups, and Spearman's correlation analysis used to identify associations between cognitive scores and CTPI parameters in the VCI group. 50 patients (25 per group; aged 55-72 years) were included. Patient age, gender, smoking status, alcohol consumption, educational level, time from TIA onset to admission, time from TIA onset to CTPI, and prevalence of hypertension, diabetes mellitus, hyperlipidemia, atrial fibrillation and hyperhomocysteinemia did not differ between groups. Both groups showed TTP and MTT prolongation, CBF reduction, but no change in CBV in the ischemic region; these changes were significantly larger in the VCI group (P < 0.05). MTT correlated negatively with MoCA score (r = -0.51, P = 0.009). CTPI could facilitate early diagnosis of VCI in patients with anterior circulation TIA.

Measuring discrimination- and reversal learning in mouse models within 4 days and without prior food deprivation.

PubMed

Remmelink, Esther; Smit, August B; Verhage, Matthijs; Loos, Maarten

2016-11-01

Many neurological and psychiatric disorders are characterized by deficits in cognitive flexibility. Modeling cognitive flexibility in mice enables the investigation of mechanisms underlying these deficits. The majority of currently available behavioral tests targeting this cognitive domain are reversal learning tasks that require scheduled food restriction, extended training periods and labor-intensive, and stress-inducing animal handling. Here, we describe a novel 4-day (4-d) continuously running task measuring discrimination- and reversal learning in an automated home cage (CognitionWall DL/RL task) that largely eliminates these limitations. In this task, mice can earn unlimited number of food rewards by passing through the correct hole of the three-holed CognitionWall. To assess the validity and sensitivity of this novel task, the performance of C57BL/6J mice, amyloid precursor protein/presenilin1 transgenic (APP/PS1) mice, α-calmodulin kinase-II (αCaMKII) T305D knock-in mice, and mice with an orbitofrontal cortex lesion were examined. We found that C57BL/6J mice reach stable performance levels within the 4 d of the task, while experiencing only slight reductions in weight and no major effects on circadian rhythm. The task detected learning deficits in APP/PS1 transgenic and αCaMKII T305D mutant mice. Additionally, we established that the orbitofrontal cortex underlies reversal learning performance in our task. Because of its short duration and the absence of food deprivation and concurrent weight loss, this novel automated home-cage task substantially improves comprehensive preclinical assessment of cognitive functions in mouse models of psychiatric and neurological disorders and also enables analysis during specific developmental stages. © 2016 Remmelink et al.; Published by Cold Spring Harbor Laboratory Press.

Using Commercial Activity Monitors to Measure Gait in Patients with Suspected iNPH: Implications for Ambulatory Monitoring

PubMed Central

Gaglani, Shiv; Haynes, M Ryan; Hoffberger, Jamie B; Rigamonti, Daniele

2015-01-01

Objectives: This study seeks to validate the use of activity monitors to detect and record gait abnormalities, potentially identifying patients with idiopathic normal pressure hydrocephalus (iNPH) prior to the onset of cognitive or urinary symptoms. Methods: This study compared the step counts of four common activity monitors (Omron Step Counter HJ-113, New Lifestyles 2000, Nike Fuelband, and Fitbit Ultra) to an observed step count in 17 patients with confirmed iNPH. Results: Of the four devices, the Fitbit Ultra (Fitbit, Inc., San Francisco, CA) provided the most accurate step count. The correlation with the observed step count was significantly higher (p<0.009) for the Fitbit Ultra than for any of the other three devices. Conclusions: These preliminary findings suggest that existing activity monitors have variable efficacy in the iNPH patient population and that the MEMS tri-axial accelerometer and algorithm of the Fitbit Ultra provides the most accurate gait measurements of the four devices tested. PMID:26719825

Using Commercial Activity Monitors to Measure Gait in Patients with Suspected iNPH: Implications for Ambulatory Monitoring.

PubMed

Gaglani, Shiv; Moore, Jessica; Haynes, M Ryan; Hoffberger, Jamie B; Rigamonti, Daniele

2015-11-17

This study seeks to validate the use of activity monitors to detect and record gait abnormalities, potentially identifying patients with idiopathic normal pressure hydrocephalus (iNPH) prior to the onset of cognitive or urinary symptoms. This study compared the step counts of four common activity monitors (Omron Step Counter HJ-113, New Lifestyles 2000, Nike Fuelband, and Fitbit Ultra) to an observed step count in 17 patients with confirmed iNPH. Of the four devices, the Fitbit Ultra (Fitbit, Inc., San Francisco, CA) provided the most accurate step count. The correlation with the observed step count was significantly higher (p<0.009) for the Fitbit Ultra than for any of the other three devices. These preliminary findings suggest that existing activity monitors have variable efficacy in the iNPH patient population and that the MEMS tri-axial accelerometer and algorithm of the Fitbit Ultra provides the most accurate gait measurements of the four devices tested.

Dual Ca2+ requirement for optimal lipid peroxidation of low density lipoprotein by activated human monocytes.

PubMed

Li, Q; Tallant, A; Cathcart, M K

1993-04-01

The oxidative modification of LDL seems a key event in atherogenesis and may participate in inflammatory tissue injury. Our previous studies suggested that the process of LDL oxidation by activated human monocytes/macrophages required O2- and activity of intracellular lipoxygenase. Herein, we studied the mechanisms involved in this oxidative modification of LDL. In this study, we used the human monocytoid cell line U937 to examine the role of Ca2+ in U937 cell-mediated lipid peroxidation of LDL. U937 cells were activated by opsonized zymosan. Removal of Ca2+ from cell culture medium by EGTA inhibited U937 cell-mediated peroxidation of LDL lipids. Therefore, Ca2+ influx and mobilization were examined for their influence on U937 cell-mediated LDL lipid peroxidation. Ca2+ channel blockers nifedipine and verapamil blocked both Ca2+ influx and LDL lipid peroxidation by activated U937 cells. The inhibitory effects of nifedipine and verapamil were dose dependent. TMB-8 and ryanodine, agents known to prevent Ca2+ release from intracellular stores, also caused a dose-dependent inhibition of LDL lipid peroxidation by activated U937 cells while exhibiting no effect on Ca2+ influx. Thus, both Ca2+ influx through functional calcium channels and Ca2+ mobilization from intracellular stores participate in the oxidative modification of LDL by activated U937 cells. 45Ca2+ uptake experiments revealed profound Ca2+ influx during the early stages of U937 cell activation, however, the Ca2+ ionophore 4-bromo A23187 was unable to induce activation of U937 cells and peroxidation of LDL lipids. Release of intracellular Ca2+ by thapsigargin only caused a suboptimal peroxidation of LDL lipids. Our results indicate that although increases in intracellular Ca2+ levels provided by both influx and intracellular Ca2+ mobilization are required, other intracellular signals may be involved for optimal peroxidation of LDL lipids by activated human monocytes.

Calcium feedback mechanisms regulate oscillatory activity of a TRP-like Ca2+ conductance in C. elegans intestinal cells

PubMed Central

Estevez, Ana Y; Strange, Kevin

2005-01-01

Inositol-1,4,5-trisphosphate (IP3)-dependent Ca2+ oscillations in Caenorhabditis elegans intestinal epithelial cells regulate the nematode defecation cycle. The role of plasma membrane ion channels in intestinal cell oscillatory Ca2+ signalling is unknown. We have shown previously that cultured intestinal cells express a Ca2+-selective conductance, IORCa, that is biophysically similar to TRPM7 currents. IORCa activates slowly and stabilizes when cells are patch clamped with pipette solutions containing 10 mm BAPTA and free Ca2+ concentrations of ∼17 nm. However, when BAPTA concentration is lowered to 1 mm, IORCa oscillates. Oscillations in channel activity induced simultaneous oscillations in cytoplasmic Ca2+ levels. Removal of extracellular Ca2+ inhibited IORCa oscillations, whereas readdition of Ca2+ to the bath caused a rapid and transient reactivation of the current. Experimental manoeuvres that elevated intracellular Ca2+ blocked current oscillations. Elevation of intracellular Ca2+ in the presence of 10 mm BAPTA to block IORCa oscillations led to a dose-dependent increase in the rate of current activation. At intracellular Ca2+ concentrations of 250 nm, current activation was transient. Patch pipette solutions buffered with 1–4 mm of either BAPTA or EGTA gave rise to similar patterns of IORCa oscillations. We conclude that changes in Ca2+ concentration close to the intracellular opening of the channel pore regulate channel activity. Low concentrations of Ca2+ activate the channel. As Ca2+ enters and accumulates near the pore mouth, channel activity is inhibited. Oscillating plasma membrane Ca2+ entry may play a role in generating intracellular Ca2+ oscillations that regulate the C. elegans defecation rhythm. PMID:15961418

Competitive tuning: Competition's role in setting the frequency-dependence of Ca2+-dependent proteins

PubMed Central

Patel, Neal M.; Kinzer-Ursem, Tamara L.

2017-01-01

A number of neurological disorders arise from perturbations in biochemical signaling and protein complex formation within neurons. Normally, proteins form networks that when activated produce persistent changes in a synapse’s molecular composition. In hippocampal neurons, calcium ion (Ca2+) flux through N-methyl-D-aspartate (NMDA) receptors activates Ca2+/calmodulin signal transduction networks that either increase or decrease the strength of the neuronal synapse, phenomena known as long-term potentiation (LTP) or long-term depression (LTD), respectively. The calcium-sensor calmodulin (CaM) acts as a common activator of the networks responsible for both LTP and LTD. This is possible, in part, because CaM binding proteins are “tuned” to different Ca2+ flux signals by their unique binding and activation dynamics. Computational modeling is used to describe the binding and activation dynamics of Ca2+/CaM signal transduction and can be used to guide focused experimental studies. Although CaM binds over 100 proteins, practical limitations cause many models to include only one or two CaM-activated proteins. In this work, we view Ca2+/CaM as a limiting resource in the signal transduction pathway owing to its low abundance relative to its binding partners. With this view, we investigate the effect of competitive binding on the dynamics of CaM binding partner activation. Using an explicit model of Ca2+, CaM, and seven highly-expressed hippocampal CaM binding proteins, we find that competition for CaM binding serves as a tuning mechanism: the presence of competitors shifts and sharpens the Ca2+ frequency-dependence of CaM binding proteins. Notably, we find that simulated competition may be sufficient to recreate the in vivo frequency dependence of the CaM-dependent phosphatase calcineurin. Additionally, competition alone (without feedback mechanisms or spatial parameters) could replicate counter-intuitive experimental observations of decreased activation of Ca2+/CaM-dependent protein kinase II in knockout models of neurogranin. We conclude that competitive tuning could be an important dynamic process underlying synaptic plasticity. PMID:29107982

Localization and quantification of carbonic anhydrase activity in the symbiotic Scyphozoan Cassiopea xamachana.

PubMed

Estes, Anne M; Kempf, Stephen C; Henry, Raymond P

2003-06-01

The relationship between density and location of zooxanthellae and levels of carbonic anhydrase (CA) activity was examined in Cassiopea xamachana. In freshly collected symbiotic animals, high densities of zooxanthellae corresponded with high levels of CA activity in host bell and oral arm tissues. Bleaching resulted in a significant loss of zooxanthellae and CA activity. Recolonization resulted in full restoration of zooxanthellar densities but only partial restoration of CA activity. High levels of CA activity were also seen in structures with inherently higher zooxanthellar densities, such as oral arm tissues. Similarly, the oral epidermal layer of bell tissue had significantly higher zooxanthellar densities and levels of CA activity than did aboral bell tissues. Fluorescent labeling, using 5-dimethylaminonapthalene-1-sulfonamide (DNSA) also reflected this tight-knit relationship between the presence and density of zooxanthellae, as DNSA-CA fluorescence intensity was greatest in host oral epithelial cells directly overlying zooxanthellae. However, the presence and density of zooxanthellae did not always correspond with enzyme activity levels. A transect of bell tissue from the margin to the manubrium revealed a gradient of CA activity, with the highest values at the bell margin and the lowest at the manubrium, despite an even distribution of zooxanthellae. Thus, abiotic factors may also influence the distribution of CA and the levels of CA activity.

Mechanisms of CaMKII Activation in the Heart.

PubMed

Erickson, Jeffrey R

2014-01-01

Calcium/calmodulin (Ca(2+)/CaM) dependent protein kinase II (CaMKII) has emerged as a key nodal protein in the regulation of cardiac physiology and pathology. Due to the particularly elegant relationship between the structure and function of the kinase, CaMKII is able to translate a diverse set of signaling events into downstream physiological effects. While CaMKII is typically autoinhibited at basal conditions, prolonged rapid Ca(2+) cycling can activate the kinase and allow post-translational modifications that depend critically on the biochemical environment of the heart. These modifications result in sustained, autonomous CaMKII activation and have been associated with pathological cardiac signaling. Indeed, improved understanding of CaMKII activation mechanisms could potentially lead to new clinical therapies for the treatment or prevention of cardiovascular disease. Here we review the known mechanisms of CaMKII activation and discuss some of the pathological signaling pathways in which they play a role.

Manganese-dependent carboanhydrase activity of photosystem II proteins.

PubMed

Shitov, A V; Pobeguts, O V; Smolova, T N; Allakhverdiev, S I; Klimov, V V

2009-05-01

Four sources of carbonic anhydrase (CA) activity in submembrane preparations of photosystem II (PS II) isolated from pea leaves were examined. Three of them belong to the hydrophilic proteins of the oxygen-evolving complex of PS II with molecular mass 33 kDa (protein PsbO), 24 kDa (protein PsbP), and 18 kDa (protein PsbQ). The fourth source of CA activity is associated with a pigment-protein complex of PS II after removing three hydrophilic proteins by salt treatment. Except for protein PsbQ, the CA activity of all these proteins depends on the presence of Mn2+: the purified protein PsbO did not show CA activity before adding Mn2+ into the medium (concentration of Mn2+ required for 50% effect, EC(50), was 670 microM); CA activity of protein mixture composed of PsbP and PsbQ increased more than 5-fold upon adding Mn2+ (EC(50) was 45 microM). CA activity of purified protein PsbP increased 2-fold in the presence of 200 microM Mn2+. As indicated for the mixture of two proteins (PsbP and PsbQ), Mg2+, Ca2+, and Zn2+, in contrast to Mn2+, suppressed CA activity (both initial and Mn2+-induced activity). Since the found sources of CA activity demonstrated properties different from ones of typical CA (need for Mn2+, insensitivity or low sensitivity to acetazolamide or ethoxyzolamide) and such CA activity was found only among PS II proteins, we cannot exclude that they belong to the type of Mn-dependent CA associated with PS II.

Increased Sparsity of Hippocampal CA1 Neuronal Ensembles in a Mouse Model of Down Syndrome Assayed by Arc Expression

PubMed Central

Smith-Hicks, Constance L.; Cai, Peiling; Savonenko, Alena V.; Reeves, Roger H.; Worley, Paul F.

2017-01-01

Down syndrome (DS) is the leading chromosomal cause of intellectual disability, yet the neural substrates of learning and memory deficits remain poorly understood. Here, we interrogate neural networks linked to learning and memory in a well-characterized model of DS, the Ts65Dn mouse. We report that Ts65Dn mice exhibit exploratory behavior that is not different from littermate wild-type (WT) controls yet behavioral activation of Arc mRNA transcription in pyramidal neurons of the CA1 region of the hippocampus is altered in Ts65Dn mice. In WT mice, a 5 min period of exploration of a novel environment resulted in Arc mRNA transcription in 39% of CA1 neurons. By contrast, the same period of exploration resulted in only ~20% of CA1 neurons transcribing Arc mRNA in Ts65Dn mice indicating increased sparsity of the behaviorally induced ensemble. Like WT mice the CA1 pyramidal neurons of Ts65Dn mice reactivated Arc transcription during a second exposure to the same environment 20 min after the first experience, but the size of the reactivated ensemble was only ~60% of that in WT mice. After repeated daily exposures there was a further decline in the size of the reactivated ensemble in Ts65Dn and a disruption of reactivation. Together these data demonstrate reduction in the size of the behaviorally induced network that expresses Arc in Ts65Dn mice and disruption of the long-term stability of the ensemble. We propose that these deficits in network formation and stability contribute to cognitive symptoms in DS. PMID:28217086

Cognitive Activity Mediates the Association between Social Activity and Cognitive Performance: A Longitudinal Study

PubMed Central

Brown, Cassandra L.; Robitaille, Annie; Zelinski, Elizabeth M.; Dixon, Roger A.; Hofer, Scott M.; Piccinin, Andrea M.

2016-01-01

Social activity is one aspect of an active lifestyle and some evidence indicates it is related to preserved cognitive function in older adulthood. However, the potential mechanisms underlying this association remain unclear. We investigate four potential mediational pathways through which social activity may relate to cognitive performance. A multilevel structural equation modeling approach to mediation was used to investigate whether cognitive activity, physical activity, depressive symptoms, and vascular health conditions mediate the association between social activity and cognitive function in older adults. Using data from the Victoria Longitudinal Study (VLS), we tested four cognitive outcomes: fluency, episodic memory, reasoning, and vocabulary. Three important findings emerged. First, the association between social activity and all four domains of cognitive function was significantly mediated by cognitive activity at the within-person level. Second, we observed a significant indirect effect of social activity on all domains of cognitive function through cognitive activity at the between-person level. Third, we found a within-person indirect relationship of social activity with episodic memory performance through physical activity. For these older adults, engagement in social activities was related to participation in everyday cognitive activities and in turn to better cognitive performance. This pattern is consistent with the interpretation that a lifestyle of social engagement may benefit cognitive performance by providing opportunities or motivation to participate in supportive cognitively stimulating activities. PMID:27929339

Cognitive activity mediates the association between social activity and cognitive performance: A longitudinal study.

PubMed

Brown, Cassandra L; Robitaille, Annie; Zelinski, Elizabeth M; Dixon, Roger A; Hofer, Scott M; Piccinin, Andrea M

2016-12-01

Social activity is 1 aspect of an active lifestyle and some evidence indicates it is related to preserved cognitive function in older adulthood. However, the potential mechanisms underlying this association remain unclear. We investigate 4 potential mediational pathways through which social activity may relate to cognitive performance. A multilevel structural equation modeling approach to mediation was used to investigate whether cognitive activity, physical activity, depressive symptoms, and vascular health conditions mediate the association between social activity and cognitive function in older adults. Using data from the Victoria Longitudinal Study, we tested 4 cognitive outcomes: fluency, episodic memory, reasoning, and vocabulary. Three important findings emerged. First, the association between social activity and all 4 domains of cognitive function was significantly mediated by cognitive activity at the within-person level. Second, we observed a significant indirect effect of social activity on all domains of cognitive function through cognitive activity at the between-person level. Third, we found a within-person indirect relationship of social activity with episodic memory performance through physical activity. For these older adults, engagement in social activities was related to participation in everyday cognitive activities and in turn to better cognitive performance. This pattern is consistent with the interpretation that a lifestyle of social engagement may benefit cognitive performance by providing opportunities or motivation to participate in supportive cognitively stimulating activities. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

Control of IP3-mediated Ca2+ puffs in Xenopus laevis oocytes by the Ca2+-binding protein parvalbumin

PubMed Central

John, Linu M; Mosquera-Caro, Monica; Camacho, Patricia; Lechleiter, James D

2001-01-01

Elementary events of Ca2+ release (Ca2+ puffs) can be elicited from discrete clusters of inositol 1,4,5 trisphosphate receptors (IP3Rs) at low concentrations of IP3. Ca2+ puffs have rarely been observed unless elicited by either hormone treatment or introduction of IP3 into the cell. However, cells appear to have sufficient concentrations of IP3 (0.1-3.0 μM) to induce Ca2+ release under resting conditions. Here, we investigated Ca2+ puff activity in non-stimulated Xenopus oocytes using confocal microscopy. The fluorescent Ca2+ dye indicators Calcium Green 1 and Oregon Green 488 BAPTA-2 were injected into oocytes to monitor basal Ca2+ activity. In this preparation, injection or overexpression of parvalbumin, an EF-hand Ca2+-binding protein (CaBP), induced Ca2+ puffs in resting Xenopus oocytes. This activity was inhibited by heparin, an IP3R channel blocker, and by mutation of the Ca2+-binding sites in parvalbumin. Ca2+ puff activity was also evoked by injection of low concentrations of the Ca2+ chelator EGTA, but not by calbindin D28k, another member of the EF-hand CaBP superfamily. BAPTA and the Ca2+ indicator dye Oregon Green 488 BAPTA-1 evoked Ca2+ puff activity, while the dextran conjugate of Oregon Green 488 BAPTA-1 did not. These data indicate that a Ca2+ buffer must be mobile in order to increase Ca2+ puff activity. Together, the data indicate that some IP3Rs spontaneously release Ca2+ under resting concentrations of IP3. These elementary Ca2+ events appear to be below the level of detection of current imaging techniques. We suggest that parvalbumin evokes Ca2+ puffs by coordinating the activity of elementary IP3R channel openings. We conclude that Ca2+ release can be evoked not only by hormone-induced increases in IP3, but also by expression of mobile cytosolic CaBPs under resting concentrations of IP3. PMID:11507154

Choline-mediated modulation of hippocampal sharp wave-ripple complexes in vitro.

PubMed

Fischer, Viktoria; Both, Martin; Draguhn, Andreas; Egorov, Alexei V

2014-06-01

The cholinergic system is critically involved in the modulation of cognitive functions, including learning and memory. Acetylcholine acts through muscarinic (mAChRs) and nicotinic receptors (nAChRs), which are both abundantly expressed in the hippocampus. Previous evidence indicates that choline, the precursor and degradation product of Acetylcholine, can itself activate nAChRs and thereby affects intrinsic and synaptic neuronal functions. Here, we asked whether the cellular actions of choline directly affect hippocampal network activity. Using mouse hippocampal slices we found that choline efficiently suppresses spontaneously occurring sharp wave-ripple complexes (SPW-R) and can induce gamma oscillations. In addition, choline reduces synaptic transmission between hippocampal subfields CA3 and CA1. Surprisingly, these effects are mediated by activation of both mAChRs and α7-containing nAChRs. Most nicotinic effects became only apparent after local, fast application of choline, indicating rapid desensitization kinetics of nAChRs. Effects were still present following block of choline uptake and are, therefore, likely because of direct actions of choline at the respective receptors. Together, choline turns out to be a potent regulator of patterned network activity within the hippocampus. These actions may be of importance for understanding state transitions in normal and pathologically altered neuronal networks. In this study we asked whether choline, the precursor and degradation product of acetylcholine, directly affects hippocampal network activity. Using mouse hippocampal slices we found that choline efficiently suppresses spontaneously occurring sharp wave-ripple complexes (SPW-R). In addition, choline reduces synaptic transmission between hippocampal subfields. These effects are mediated by direct activation of muscarinic as well as nicotinic cholinergic pathways. Together, choline turns out to be a potent regulator of patterned activity within hippocampal networks. © 2014 International Society for Neurochemistry.

Nitric oxide-dependent activation of CaMKII increases diastolic sarcoplasmic reticulum calcium release in cardiac myocytes in response to adrenergic stimulation.

PubMed

Curran, Jerry; Tang, Lifei; Roof, Steve R; Velmurugan, Sathya; Millard, Ashley; Shonts, Stephen; Wang, Honglan; Santiago, Demetrio; Ahmad, Usama; Perryman, Matthew; Bers, Donald M; Mohler, Peter J; Ziolo, Mark T; Shannon, Thomas R

2014-01-01

Spontaneous calcium waves in cardiac myocytes are caused by diastolic sarcoplasmic reticulum release (SR Ca(2+) leak) through ryanodine receptors. Beta-adrenergic (β-AR) tone is known to increase this leak through the activation of Ca-calmodulin-dependent protein kinase (CaMKII) and the subsequent phosphorylation of the ryanodine receptor. When β-AR drive is chronic, as observed in heart failure, this CaMKII-dependent effect is exaggerated and becomes potentially arrhythmogenic. Recent evidence has indicated that CaMKII activation can be regulated by cellular oxidizing agents, such as reactive oxygen species. Here, we investigate how the cellular second messenger, nitric oxide, mediates CaMKII activity downstream of the adrenergic signaling cascade and promotes the generation of arrhythmogenic spontaneous Ca(2+) waves in intact cardiomyocytes. Both SCaWs and SR Ca(2+) leak were measured in intact rabbit and mouse ventricular myocytes loaded with the Ca-dependent fluorescent dye, fluo-4. CaMKII activity in vitro and immunoblotting for phosphorylated residues on CaMKII, nitric oxide synthase, and Akt were measured to confirm activity of these enzymes as part of the adrenergic cascade. We demonstrate that stimulation of the β-AR pathway by isoproterenol increased the CaMKII-dependent SR Ca(2+) leak. This increased leak was prevented by inhibition of nitric oxide synthase 1 but not nitric oxide synthase 3. In ventricular myocytes isolated from wild-type mice, isoproterenol stimulation also increased the CaMKII-dependent leak. Critically, in myocytes isolated from nitric oxide synthase 1 knock-out mice this effect is ablated. We show that isoproterenol stimulation leads to an increase in nitric oxide production, and nitric oxide alone is sufficient to activate CaMKII and increase SR Ca(2+) leak. Mechanistically, our data links Akt to nitric oxide synthase 1 activation downstream of β-AR stimulation. Collectively, this evidence supports the hypothesis that CaMKII is regulated by nitric oxide as part of the adrenergic cascade leading to arrhythmogenesis.

Coupling of SK channels, L-type Ca2+ channels, and ryanodine receptors in cardiomyocytes.

PubMed

Zhang, Xiao-Dong; Coulibaly, Zana A; Chen, Wei Chun; Ledford, Hannah A; Lee, Jeong Han; Sirish, Padmini; Dai, Gu; Jian, Zhong; Chuang, Frank; Brust-Mascher, Ingrid; Yamoah, Ebenezer N; Chen-Izu, Ye; Izu, Leighton T; Chiamvimonvat, Nipavan

2018-03-16

Small-conductance Ca 2+ -activated K + (SK) channels regulate the excitability of cardiomyocytes by integrating intracellular Ca 2+ and membrane potentials on a beat-to-beat basis. The inextricable interplay between activation of SK channels and Ca 2+ dynamics suggests the pathology of one begets another. Yet, the exact mechanistic underpinning for the activation of cardiac SK channels remains unaddressed. Here, we investigated the intracellular Ca 2+ microdomains necessary for SK channel activation. SK currents coupled with Ca 2+ influx via L-type Ca 2+ channels (LTCCs) continued to be elicited after application of caffeine, ryanodine or thapsigargin to deplete SR Ca 2+ store, suggesting that LTCCs provide the immediate Ca 2+ microdomain for the activation of SK channels in cardiomyocytes. Super-resolution imaging of SK2, Ca v 1.2 Ca 2+ channel, and ryanodine receptor 2 (RyR2) was performed to quantify the nearest neighbor distances (NND) and localized the three molecules within hundreds of nanometers. The distribution of NND between SK2 and RyR2 as well as SK2 and Ca v 1.2 was bimodal, suggesting a spatial relationship between the channels. The activation mechanism revealed by our study paved the way for the understanding of the roles of SK channels on the feedback mechanism to regulate the activities of LTCCs and RyR2 to influence local and global Ca 2+ signaling.

Participation in recreation and cognitive activities as a predictor of cognitive performance of adults with/without Down syndrome.

PubMed

Lifshitz-Vahav, Hefziba; Shnitzer, Shlomit; Mashal, Nira

2016-09-01

The Cognitive Activity Theory suggests an association between participation in cognitive activities during midlife and cognitive functioning in the short term. We examined the impact of participation in cognitively stimulating activities conveyed during leisure activities on crystallized and fluid tests' performance among adults with intellectual disabilities (ID). Adults (n = 32; chronological age = 25-55) with non-specific ID and with Down syndrome rated the frequency of their participation in leisure activities. Pursuits included more cognitively involving (reading, participating in academic courses) and less cognitively involving (cooking, dancing) activities. Three judges ranked activities according to their cognitive load on a 1 (few cognitive components) to 5 (many cognitive components) points scale. The findings indicate two new scales: cognitively stimulating activities and recreational stimulating activities. The crystallized battery included phonemic fluency, synonyms, idioms, and verbal metaphors. The fluid battery included the Homophone Meaning Generation Test, Metaphoric Triad Test, Novel Metaphors Test, and Trail Making Test. Hierarchal regression with chronological and mental age, recreational, and cognitively stimulating activities indicated that participation in recreational activities contributed significantly to the explained variance of word fluency. Participation in cognitive activities contributed significantly to the explained variance of most of the crystallized and fluid tests. The findings support the Cognitive Activity Theory in populations with ID. The findings also support the Compensation Age Theory: not only endogenous factors (age, etiology, IQ level), but also exogenous factors such as life style determining the cognitive functioning of adults with ID. However, frequency and the cognitive load of the activities influenced their cognitive functioning.

Synthesis and evaluation of sulfonamide-bearing thiazole as carbonic anhydrase isoforms hCA I and hCA II.

PubMed

Kılıcaslan, Soner; Arslan, Mustafa; Ruya, Zeynep; Bilen, Çigdem; Ergün, Adem; Gençer, Nahit; Arslan, Oktay

2016-12-01

Sulfonamide-bearing thiazole compounds were synthesized and their inhibitory effects on the activity of purified human carbonic anhydrase I and II were evaluated. Human carbonic anhydrase isoenzymes (hCA-I and hCA-II) were purified from erythrocyte cells by affinity chromatography. The inhibitory effects of the 12 synthesized sulfonamide (5a-l) on the hydratase and esterase activities of these isoenzymes (hCA-I and hCA-II) were studied in vitro. In relation to these activities, the inhibition equilibrium constants (Ki) were determined. The results showed that all the synthesized compounds inhibited the CA isoenzyme activity. Among them 5b was found to be the most active (IC50 = 0.35 μM; Ki: 0.33 μM) for hCA I and hCA II.

Neural correlates of species-typical illogical cognitive bias in human inference.

PubMed

Ogawa, Akitoshi; Yamazaki, Yumiko; Ueno, Kenichi; Cheng, Kang; Iriki, Atsushi

2010-09-01

The ability to think logically is a hallmark of human intelligence, yet our innate inferential abilities are marked by implicit biases that often lead to illogical inference. For example, given AB ("if A then B"), people frequently but fallaciously infer the inverse, BA. This mode of inference, called symmetry, is logically invalid because, although it may be true, it is not necessarily true. Given pairs of conditional relations, such as AB and BC, humans reflexively perform two additional modes of inference: transitivity, whereby one (validly) infers AC; and equivalence, whereby one (invalidly) infers CA. In sharp contrast, nonhuman animals can handle transitivity but can rarely be made to acquire symmetry or equivalence. In the present study, human subjects performed logical and illogical inferences about the relations between abstract, visually presented figures while their brain activation was monitored with fMRI. The prefrontal, medial frontal, and intraparietal cortices were activated during all modes of inference. Additional activation in the precuneus and posterior parietal cortex was observed during transitivity and equivalence, which may reflect the need to retrieve the intermediate stimulus (B) from memory. Surprisingly, the patterns of brain activation in illogical and logical inference were very similar. We conclude that the observed inference-related fronto-parietal network is adapted for processing categorical, but not logical, structures of association among stimuli. Humans might prefer categorization over the memorization of logical structures in order to minimize the cognitive working memory load when processing large volumes of information.

Blood Biomarker Profile of TBI-Associated Cognitive Impairment Among Old and Young Veterans

DTIC Science & Technology

2015-10-01

associated with TBI remains unclear. Some studies link TBI to Alzheimer disease (AD) while others suggest the TBI-associated dementia is more similar to...encephalopathy (CTE), blood biomarkers, aging, cognitive impairment (CI), Alzheimer ’s disease (AD) Accomplishments • What were the major goals of the...Yountville, CA: Months 6-18  Data collection is currently ongoing at both sites. o Enroll 80 veterans with mild Alzheimer Disease (AD) at AFRH and VHC-Y

The use of antioxidants to prevent glutamate-induced derangement of calcium ion metabolism in rat cerebral cortex synaptosomes.

PubMed

Avrova, N F; Shestak, K I; Zakharova, I O; Sokolova, T V; Tyurina, Y Y; Tyurin, V A

2000-01-01

Glutamate is shown to induce increases in intracellular Ca2+ concentrations ([Ca2+]i), increases in 45Ca2+ influx, decreases in the activity of Na+,K+-ATPase activity, and activation of the Na+/Ca2+ exchanger in rat cerebral cortex synaptosomes. NMDA receptor antagonists virtually prevented these effects. Preincubation of synaptosomes with alpha-tocopherol, superoxide dismutase, and ganglioside GM1 normalized [Ca2+]i, 45Ca2+ influx, and Na+,K+-ATPase activity in rat cerebral cortex synaptosomes exposed to glutamate. Glutamate and GM1 activated the Na+/K+ exchanger, and their effects were additive. Calcium ions entering cerebral cortex nerve cells via NMDA receptors during exposure to high glutamate concentrations appeared to be only the trigger for the processes activating free-radical reactions. Activation of these reactions led to increases in Ca2+ influx into cells, decreases in Na+,K+-ATPase activity, and significant increases in [Ca2+]i, though this could be prevented by antioxidants and gangliosides.

A novel mechanism of tandem activation of ryanodine receptors by cytosolic and SR luminal Ca2+ during excitation-contraction coupling in atrial myocytes.

PubMed

Maxwell, Joshua T; Blatter, Lothar A

2017-06-15

In atrial myocytes excitation-contraction coupling is strikingly different from ventricle because atrial myocytes lack a transverse tubule membrane system: Ca 2+ release starts in the cell periphery and propagates towards the cell centre by Ca 2+ -induced Ca 2+ release from the sarcoplasmic reticulum (SR) Ca 2+ store. The cytosolic Ca 2+ sensitivity of the ryanodine receptor (RyRs) Ca 2+ release channel is low and it is unclear how Ca 2+ release can be activated in the interior of atrial cells. Simultaneous confocal imaging of cytosolic and intra-SR calcium revealed a transient elevation of store Ca 2+ that we termed 'Ca 2+ sensitization signal'. We propose a novel paradigm of atrial ECC that is based on tandem activation of the RyRs by cytosolic and luminal Ca 2+ through a 'fire-diffuse-uptake-fire' (or FDUF) mechanism: Ca 2+ uptake by SR Ca 2+ pumps at the propagation front elevates Ca 2+ inside the SR locally, leading to luminal RyR sensitization and lowering of the cytosolic Ca 2+ activation threshold. In atrial myocytes Ca 2+ release during excitation-contraction coupling (ECC) is strikingly different from ventricular myocytes. In many species atrial myocytes lack a transverse tubule system, dividing the sarcoplasmic reticulum (SR) Ca 2+ store into the peripheral subsarcolemmnal junctional (j-SR) and the much more abundant central non-junctional (nj-SR) SR. Action potential (AP)-induced Ca 2+ entry activates Ca 2+ -induced Ca 2+ release (CICR) from j-SR ryanodine receptor (RyR) Ca 2+ release channels. Peripheral elevation of [Ca 2+ ] i initiates CICR from nj-SR and sustains propagation of CICR to the cell centre. Simultaneous confocal measurements of cytosolic ([Ca 2+ ] i ; with the fluorescent Ca 2+ indicator rhod-2) and intra-SR ([Ca 2+ ] SR ; fluo-5N) Ca 2+ in rabbit atrial myocytes revealed that Ca 2+ release from j-SR resulted in a cytosolic Ca 2+ transient of higher amplitude compared to release from nj-SR; however, the degree of depletion of j-SR [Ca 2+ ] SR was smaller than nj-SR [Ca 2+ ] SR . Similarly, Ca 2+ signals from individual release sites of the j-SR showed a larger cytosolic amplitude (Ca 2+ sparks) but smaller depletion (Ca 2+ blinks) than release from nj-SR. During AP-induced Ca 2+ release the rise of [Ca 2+ ] i detected at individual release sites of the nj-SR preceded the depletion of [Ca 2+ ] SR , and during this latency period a transient elevation of [Ca 2+ ] SR occurred. We propose that Ca 2+ release from nj-SR is activated by cytosolic and luminal Ca 2+ (tandem RyR activation) via a novel 'fire-diffuse-uptake-fire' (FDUF) mechanism. This novel paradigm of atrial ECC predicts that Ca 2+ uptake by sarco-endoplasmic reticulum Ca 2+ -ATPase (SERCA) at the propagation front elevates local [Ca 2+ ] SR , leading to luminal RyR sensitization and lowering of the activation threshold for cytosolic CICR. © 2016 The Authors. The Journal of Physiology © 2016 The Physiological Society.

Characterization of carbonic anhydrase XIII in the erythrocytes of the Burmese python, Python molurus bivittatus.

PubMed

Esbaugh, A J; Secor, S M; Grosell, M

2015-09-01

Carbonic anhydrase (CA) is one of the most abundant proteins found in vertebrate erythrocytes with the majority of species expressing a low activity CA I and high activity CA II. However, several phylogenetic gaps remain in our understanding of the expansion of cytoplasmic CA in vertebrate erythrocytes. In particular, very little is known about isoforms from reptiles. The current study sought to characterize the erythrocyte isoforms from two squamate species, Python molurus and Nerodia rhombifer, which was combined with information from recent genome projects to address this important phylogenetic gap. Obtained sequences grouped closely with CA XIII in phylogenetic analyses. CA II mRNA transcripts were also found in erythrocytes, but found at less than half the levels of CA XIII. Structural analysis suggested similar biochemical activity as the respective mammalian isoforms, with CA XIII being a low activity isoform. Biochemical characterization verified that the majority of CA activity in the erythrocytes was due to a high activity CA II-like isoform; however, titration with copper supported the presence of two CA pools. The CA II-like pool accounted for 90 % of the total activity. To assess potential disparate roles of these isoforms a feeding stress was used to up-regulate CO2 excretion pathways. Significant up-regulation of CA II and the anion exchanger was observed; CA XIII was strongly down-regulated. While these results do not provide insight into the role of CA XIII in the erythrocytes, they do suggest that the presence of two isoforms is not simply a case of physiological redundancy. Copyright © 2015. Published by Elsevier Inc.

Quantitative analysis of the Ca2+ -dependent regulation of delayed rectifier K+ current IKs in rabbit ventricular myocytes.

PubMed

Bartos, Daniel C; Morotti, Stefano; Ginsburg, Kenneth S; Grandi, Eleonora; Bers, Donald M

2017-04-01

[Ca 2+ ] i enhanced rabbit ventricular slowly activating delayed rectifier K + current (I Ks ) by negatively shifting the voltage dependence of activation and slowing deactivation, similar to perfusion of isoproterenol. Rabbit ventricular rapidly activating delayed rectifier K + current (I Kr ) amplitude and voltage dependence were unaffected by high [Ca 2+ ] i . When measuring or simulating I Ks during an action potential, I Ks was not different during a physiological Ca 2+ transient or when [Ca 2+ ] i was buffered to 500 nm. The slowly activating delayed rectifier K + current (I Ks ) contributes to repolarization of the cardiac action potential (AP). Intracellular Ca 2+ ([Ca 2+ ] i ) and β-adrenergic receptor (β-AR) stimulation modulate I Ks amplitude and kinetics, but details of these important I Ks regulators and their interaction are limited. We assessed the [Ca 2+ ] i dependence of I Ks in steady-state conditions and with dynamically changing membrane potential and [Ca 2+ ] i during an AP. I Ks was recorded from freshly isolated rabbit ventricular myocytes using whole-cell patch clamp. With intracellular pipette solutions that controlled free [Ca 2+ ] i , we found that raising [Ca 2+ ] i from 100 to 600 nm produced similar increases in I Ks as did β-AR activation, and the effects appeared additive. Both β-AR activation and high [Ca 2+ ] i increased maximally activated tail I Ks , negatively shifted the voltage dependence of activation, and slowed deactivation kinetics. These data informed changes in our well-established mathematical model of the rabbit myocyte. In both AP-clamp experiments and simulations, I Ks recorded during a normal physiological Ca 2+ transient was similar to I Ks measured with [Ca 2+ ] i clamped at 500-600 nm. Thus, our study provides novel quantitative data as to how physiological [Ca 2+ ] i regulates I Ks amplitude and kinetics during the normal rabbit AP. Our results suggest that micromolar [Ca 2+ ] i , in the submembrane or junctional cleft space, is not required to maximize [Ca 2+ ] i -dependent I Ks activation during normal Ca 2+ transients. © 2016 The Authors. The Journal of Physiology © 2016 The Physiological Society.

Quantitative analysis of the Ca2+‐dependent regulation of delayed rectifier K+ current I Ks in rabbit ventricular myocytes

PubMed Central

Bartos, Daniel C.; Morotti, Stefano; Ginsburg, Kenneth S.; Grandi, Eleonora

2017-01-01

Key points [Ca2+]i enhanced rabbit ventricular slowly activating delayed rectifier K+ current (I Ks) by negatively shifting the voltage dependence of activation and slowing deactivation, similar to perfusion of isoproterenol.Rabbit ventricular rapidly activating delayed rectifier K+ current (I Kr) amplitude and voltage dependence were unaffected by high [Ca2+]i.When measuring or simulating I Ks during an action potential, I Ks was not different during a physiological Ca2+ transient or when [Ca2+]i was buffered to 500 nm. Abstract The slowly activating delayed rectifier K+ current (I Ks) contributes to repolarization of the cardiac action potential (AP). Intracellular Ca2+ ([Ca2+]i) and β‐adrenergic receptor (β‐AR) stimulation modulate I Ks amplitude and kinetics, but details of these important I Ks regulators and their interaction are limited. We assessed the [Ca2+]i dependence of I Ks in steady‐state conditions and with dynamically changing membrane potential and [Ca2+]i during an AP. I Ks was recorded from freshly isolated rabbit ventricular myocytes using whole‐cell patch clamp. With intracellular pipette solutions that controlled free [Ca2+]i, we found that raising [Ca2+]i from 100 to 600 nm produced similar increases in I Ks as did β‐AR activation, and the effects appeared additive. Both β‐AR activation and high [Ca2+]i increased maximally activated tail I Ks, negatively shifted the voltage dependence of activation, and slowed deactivation kinetics. These data informed changes in our well‐established mathematical model of the rabbit myocyte. In both AP‐clamp experiments and simulations, I Ks recorded during a normal physiological Ca2+ transient was similar to I Ks measured with [Ca2+]i clamped at 500–600 nm. Thus, our study provides novel quantitative data as to how physiological [Ca2+]i regulates I Ks amplitude and kinetics during the normal rabbit AP. Our results suggest that micromolar [Ca2+]i, in the submembrane or junctional cleft space, is not required to maximize [Ca2+]i‐dependent I Ks activation during normal Ca2+ transients. PMID:28008618

The Calcium-Sensing Receptor Increases Activity of the Renal NCC through the WNK4-SPAK Pathway.

PubMed

Bazúa-Valenti, Silvana; Rojas-Vega, Lorena; Castañeda-Bueno, María; Barrera-Chimal, Jonatan; Bautista, Rocío; Cervantes-Pérez, Luz G; Vázquez, Norma; Plata, Consuelo; Murillo-de-Ozores, Adrián R; González-Mariscal, Lorenza; Ellison, David H; Riccardi, Daniela; Bobadilla, Norma A; Gamba, Gerardo

2018-05-30

Background Hypercalciuria can result from activation of the basolateral calcium-sensing receptor (CaSR), which in the thick ascending limb of Henle's loop controls Ca 2+ excretion and NaCl reabsorption in response to extracellular Ca 2+ However, the function of CaSR in the regulation of NaCl reabsorption in the distal convoluted tubule (DCT) is unknown. We hypothesized that CaSR in this location is involved in activating the thiazide-sensitive NaCl cotransporter (NCC) to prevent NaCl loss. Methods We used a combination of in vitro and in vivo models to examine the effects of CaSR on NCC activity. Because the KLHL3-WNK4-SPAK pathway is involved in regulating NaCl reabsorption in the DCT, we assessed the involvement of this pathway as well. Results Thiazide-sensitive 22 Na + uptake assays in Xenopus laevis oocytes revealed that NCC activity increased in a WNK4-dependent manner upon activation of CaSR with Gd 3+ In HEK293 cells, treatment with the calcimimetic R-568 stimulated SPAK phosphorylation only in the presence of WNK4. The WNK4 inhibitor WNK463 also prevented this effect. Furthermore, CaSR activation in HEK293 cells led to phosphorylation of KLHL3 and WNK4 and increased WNK4 abundance and activity. Finally, acute oral administration of R-568 in mice led to the phosphorylation of NCC. Conclusions Activation of CaSR can increase NCC activity via the WNK4-SPAK pathway. It is possible that activation of CaSR by Ca 2+ in the apical membrane of the DCT increases NaCl reabsorption by NCC, with the consequent, well known decrease of Ca 2+ reabsorption, further promoting hypercalciuria. Copyright © 2018 by the American Society of Nephrology.

[Endoplasmic-mitochondrial Ca(2+)-functional unit: dependence of respiration of secretory cells on activity of ryanodine- and IP3 - sensitive Ca(2+)-channels].

PubMed

Velykopols'ka, O Iu; Man'ko, B O; Man'ko, V V

2012-01-01

Using Clark oxygen electrode, dependence of mitochondrial functions on Ca(2+)-release channels activity of Chironomus plumosus L. larvae salivary glands suspension was investigated. Cells were ATP-permeabilized in order to enable penetration of exogenous oxidative substrates. Activation of plasmalemmal P2X-receptors (as well as P2Y-receptors) per se does not modify the endogenous respiration of salivary gland suspension. That is, Ca(2+)-influx from extracellular medium does not influence functional activity of mitochondria, although they are located along the basal part of the plasma membrane. Activation of RyRs intensifies endogenous respiration and pyruvate-malate-stimulated respiration, but not succinate-stimulated respiration. Neither activation of IP3Rs (via P2Y-receptors activation), nor their inhibition alters endogenous respiration. Nevertheless, IP3Rs inhibition by 2-APB intensifies succinate-stimulated respiration. All abovementioned facts testify that Ca2+, released from stores via channels, alters functional activity of mitochondria, and undoubtedly confirm the existence of endoplasmic-mitochondrial Ca(2+)-functional unit in Ch. plumosus larvae salivary glands secretory cells. In steady state of endoplasmic-mitochondrial Ca(2+)-functional unit the spontaneous activity of IP3Rs is observed; released through IP3Rs, Ca2+ is accumulated in mitochondria via uniporter and modulates oxidative processes. Activation of RyRs induces the transition of endoplasmic-mitochondrial Ca(2+)-functional unit to the active state, which is required to intensify cell respiration and oxidative phosphorylation. As expected, the transition of endoplasmic-mitochondrial Ca(2+)-functional unit to inactivated state (i. e. inhibition of Ca(2+)-release channels at excessive [Ca2+]i) limits the duration of signal transduction, has protective nature and prevents apoptosis.

The other side of cardiac Ca2+ signaling: transcriptional control

PubMed Central

Domínguez-Rodríguez, Alejandro; Ruiz-Hurtado, Gema; Benitah, Jean-Pierre; Gómez, Ana M.

2012-01-01

Ca2+ is probably the most versatile signal transduction element used by all cell types. In the heart, it is essential to activate cellular contraction in each heartbeat. Nevertheless Ca2+ is not only a key element in excitation-contraction coupling (EC coupling), but it is also a pivotal second messenger in cardiac signal transduction, being able to control processes such as excitability, metabolism, and transcriptional regulation. Regarding the latter, Ca2+ activates Ca2+-dependent transcription factors by a process called excitation-transcription coupling (ET coupling). ET coupling is an integrated process by which the common signaling pathways that regulate EC coupling activate transcription factors. Although ET coupling has been extensively studied in neurons and other cell types, less is known in cardiac muscle. Some hints have been found in studies on the development of cardiac hypertrophy, where two Ca2+-dependent enzymes are key actors: Ca2+/Calmodulin kinase II (CaMKII) and phosphatase calcineurin, both of which are activated by the complex Ca2+/Calmodulin. The question now is how ET coupling occurs in cardiomyocytes, where intracellular Ca2+ is continuously oscillating. In this focused review, we will draw attention to location of Ca2+ signaling: intranuclear ([Ca2+]n) or cytoplasmic ([Ca2+]c), and the specific ionic channels involved in the activation of cardiac ET coupling. Specifically, we will highlight the role of the 1,4,5 inositol triphosphate receptors (IP3Rs) in the elevation of [Ca2+]n levels, which are important to locally activate CaMKII, and the role of transient receptor potential channels canonical (TRPCs) in [Ca2+]c, needed to activate calcineurin (Cn). PMID:23226134

Cytosolic calcium homeostasis in bovine parathyroid cells and its modulation by protein kinase C.

PubMed Central

Racke, F K; Nemeth, E F

1993-01-01

1. The effects of protein kinase C (PKC) activators and inhibitors on the mechanisms regulating cytosolic Ca2+ homeostasis in dissociated bovine parathyroid cells loaded with fura-2 were examined. 2. Stepwise increases in the concentration of extracellular Ca2+ (from 0.5 to 2 or 3 mM) elicited transient followed by sustained increases in the concentration of intracellular free Ca2+ ([Ca2+]i). Cytosolic Ca2+ transients reflected the mobilization of intracellular Ca2+ and influx of extracellular Ca2+ whereas sustained increases in [Ca2+]i resulted from the influx of extracellular Ca2+. Brief (1-2 min) pretreatment with phorbol myristate acetate (PMA) shifted the concentration-response curve for extracellular Ca(2+)-induced cytosolic Ca2+ transients to the right without affecting the maximal response. Cytosolic Ca2+ transients elicited by extracellular Mg2+ were similarly affected by PMA. 3. These effects of PMA were mimicked by various other activators of PKC with the rank order of potency PMA > phorbol dibutyrate > bryostatin , > (-)indolactam V > mezerein. Isomers or analogues of these compounds that do not alter PKC activity (4 alpha-phorbols and (+)indolactam V) did not alter [Ca2+]i. 4. PKC activators depressed evoked increases in [Ca2+]i when influx of extracellular Ca2+ was blocked with Gd3+. Cytosolic Ca2+ transients elicited by extracellular Mg2+ in the absence of extracellular Ca2+ were similarly inhibited by PKC activators. Activation of PKC thus inhibits the mobilization of intracellular Ca2+ elicited by extracellular divalent cations. 5. Increases in the concentration of extracellular Ca2+ caused corresponding increases in the formation of [3H]inositol 1,4,5-trisphosphate ([3H]InsP3). Pretreatment with PMA shifted the concentration-response curve for extracellular Ca(2+)-induced [3H]InsP3 formation to the right without affecting the maximal response. 6. PKC activators also caused some depression of steady-state increases in [Ca2+]i elicited by extracellular Ca2+. In contrast, PMA did not affect increases in [Ca2+]i elicited by ionomycin or thapsigargin. 7. Ba2+ was used to monitor divalent cation influx. PMA decreased the rate of rise of the fluorescent signal elicited by extracellular Ba2+. 8. All these effects of PKC activators on [Ca2+]i were blocked or reversed by staurosporine at concentrations (30-100 nM) that inhibited PKC activity in parathyroid cells. Staurosporine alone potentiated cytosolic Ca2+ responses evoked by submaximal concentrations of extracellular divalent cations. 9. PKC thus depresses both the mobilization of intracellular Ca2+ and the influx of extracellular Ca2+ in parathyroid cells. The effects on [Ca2+]i provide evidence for a Ca2+ receptor on the surface of parathyroid cells that uses transmembrane signalling mechanisms common to some other Ca(2+)-mobilizing receptors.(ABSTRACT TRUNCATED AT 400 WORDS) PMID:8254504

Focused Attention, Heart Rate Deceleration, and Cognitive Development in Preterm and Full-Term Infants

PubMed Central

Petrie Thomas, Julianne H.; Whitfield, Michael F.; Oberlander, Tim F.; Synnes, Anne R.; Grunau, Ruth E.

2012-01-01

The majority of children who are born very preterm escape major impairment, yet more subtle cognitive and attention problems are very common in this population. Previous research has linked infant focused attention during exploratory play to later cognition in children born full-term and preterm. Infant focused attention can be indexed by sustained decreases in heart rate (HR). However there are no preterm studies that have jointly examined infant behavioral attention and concurrent HR response during exploratory play in relation to developing cognition. We recruited preterm infants free from neonatal conditions associated with major adverse outcomes, and further excluded infants with developmental delay (Bayley Mental Development Index [MDI < 70]) at 8 months corrected age (CA). During infant exploratory play at 8 months CA, focused attention and concurrent HR response were compared in 83 preterm infants (born 23–32 weeks gestational age [GA]) who escaped major impairment to 46 full-term infants. Focused attention and HR response were then examined in relation to Bayley MDI, after adjusting for neonatal risk. MDI did not differ by group, yet full-term infants displayed higher global focused attention ratings. Among the extremely preterm infants born <29 weeks, fewer days on mechanical ventilation, mean longest focus, and greater HR deceleration during focused attention episodes, accounted for 49% of adjusted variance in predicting concurrent MDI. There were no significant associations for later-born gestational age (29–32 weeks) or full-term infants. Among extremely preterm infants who escape major impairment, our findings suggest unique relationships between focused attention, HR deceleration, and developing cognition. PMID:22487941

The Additional Contribution of White Matter Hyperintensity Location to Post-stroke Cognitive Impairment: Insights From a Multiple-Lesion Symptom Mapping Study.

PubMed

Zhao, Lei; Wong, Adrian; Luo, Yishan; Liu, Wenyan; Chu, Winnie W C; Abrigo, Jill M; Lee, Ryan K L; Mok, Vincent; Shi, Lin

2018-01-01

White matter hyperintensities (WMH) are common in acute ischemic stroke patients. Although WMH volume has been reported to influence post-stroke cognition, it is still not clear whether WMH location, independent of acute ischemic lesion (AIL) volume and location, contributes to cognitive impairment after stroke. Here, we proposed a multiple-lesion symptom mapping model that considers both the presence of WMH and AIL to measure the additional contribution of WMH locations to post-stroke cognitive impairment. Seventy-six first-ever stroke patients with AILs in the left hemisphere were examined by Montreal Cognitive Assessment (MoCA) at baseline and 1 year after stroke. The association between the location of AIL and WMH and global cognition was investigated by a multiple-lesion symptom mapping (MLSM) model based on support vector regression (SVR). To explore the relative merits of MLSM over the existing lesion-symptom mapping approaches with only AIL considered (mass-univariate VLSM and SVR-LSM), we measured the contribution of the significant AIL and/or WMH clusters from these models to post-stroke cognitive impairment. In addition, we compared the significant WMH locations identified by the optimal SVR-MLSM model for cognitive impairment at baseline and 1 year post stroke. The identified strategic locations of WMH significantly contributed to the prediction of MoCA at baseline (short-term) and 1 year (long-term) after stroke independent of the strategic locations of AIL. The significant clusters of WMH for short-term and long-term post-stroke cognitive impairment were mainly in the corpus callosum, corona radiata, and posterior thalamic radiation. We noted that in some regions, the AIL clusters that were significant for short-term outcome were no longer significant for long-term outcome, and interestingly more WMH clusters in these regions became significant for long-term outcome compared to short-term outcome. This indicated that there are some regions where local WMH burden has larger impact than AIL burden on the long-term post-stroke cognitive impairment. In consequence, SVR-MLSM was effective in identifying the WMH locations that have additional impact on post-stroke cognition on top of AIL locations. Such a method can also be applied to other lesion-behavior studies where multiple types of lesions may have potential contributions to a specific behavior.

Stochastic nature and red cell population distribution of the sickling-induced Ca2+ permeability.

PubMed

Lew, V L; Ortiz, O E; Bookchin, R M

1997-06-01

To explore basic properties of the sickling-induced cation permeability pathway, the Ca2+ component (Psickle-Ca) was studied in density-fractionated sickle cell anemia (SS) discocytes through its effects on the activity of the cells' Ca2+sensitive K+-channels (KCa). The instant state of KCa channel activation was monitored during continuous or cyclic deoxygenation of the cells using a novel thiocyanate-densecell formation method. Each deoxy pulse caused a reversible, sustained Psickle-Ca, which activated KCa channels in only 10-45% of cells at physiological [Ca2+]o ("activated cells"). After removal of cells activated by each previous deoxy pulse, subsequent pulses generated similar activated cell fractions, indicating a random determination rather than the response of a specific vulnerable subpopulation. The fraction of activated cells rose monotonically with [Ca2+]o along a curve reflecting the cells' distribution of Psickle-Ca, with values high enough in a small cell fraction to trigger near-maximal KCa channels. Consistent with the stochastic nature of Psickle-Ca, repeated deoxygenated-oxygenated pulsing led to progressive dense cell formation, whereas single long pulses caused one early density shift. Thus deoxygenation-induced Ca2+-permeabilization in SS cells is a probabilistic event with large cumulative dehydrating potential. The possible molecular nature of Psickle-Ca is discussed.

The TNFα-Transgenic Rat: Hippocampal Synaptic Integrity, Cognition, Function, and Post-Ischemic Cell Loss

PubMed Central

Pettigrew, L. Creed; Kryscio, Richard J.; Norris, Christopher M.

2016-01-01

The cytokine, tumor necrosis factor α (TNFα), is a key regulator of neuroinflammation linked to numerous neurodegenerative conditions and diseases. The present study used transgenic rats that overexpress a murine TNFα gene, under the control of its own promoter, to investigate the impact of chronically elevated TNFα on hippocampal synaptic function. Neuronal viability and cognitive recovery in TNFα Tg rats were also determined following an ischemic insult arising from reversible middle cerebral artery occlusion (MCAO). Basal CA3-CA1 synaptic strength, recorded in acute brain slices, was not significantly different between eight-week-old TNFα Tg rats and non-Tg rats. In contrast, slices from TNFα Tg rats showed significantly greater levels of long-term potentiation (LTP) in response to 100 Hz stimulation, suggesting that synaptic networks may be hyperexcitable in the context of elevated TNFα. Cognitive and motor deficits (assessed on the Morris Water Maze and Rotarod task, respectively) were present in TNFα Tg rats in the absence of significant differences in the loss of cortical and hippocampal neurons. TNF overexpression exacerbated MCAO-dependent deficits on the rotarod, but ameliorated cortical neuron loss in response to MCAO. PMID:27144978

Cortical thickness and surface area correlates with cognitive dysfunction among first-episode psychosis patients.

PubMed

Haring, L; Müürsepp, A; Mõttus, R; Ilves, P; Koch, K; Uppin, K; Tarnovskaja, J; Maron, E; Zharkovsky, A; Vasar, E; Vasar, V

2016-07-01

In studies using magnetic resonance imaging (MRI), some have reported specific brain structure-function relationships among first-episode psychosis (FEP) patients, but findings are inconsistent. We aimed to localize the brain regions where cortical thickness (CTh) and surface area (cortical area; CA) relate to neurocognition, by performing an MRI on participants and measuring their neurocognitive performance using the Cambridge Neuropsychological Test Automated Battery (CANTAB), in order to investigate any significant differences between FEP patients and control subjects (CS). Exploration of potential correlations between specific cognitive functions and brain structure was performed using CANTAB computer-based neurocognitive testing and a vertex-by-vertex whole-brain MRI analysis of 63 FEP patients and 30 CS. Significant correlations were found between cortical parameters in the frontal, temporal, cingular and occipital brain regions and performance in set-shifting, working memory manipulation, strategy usage and sustained attention tests. These correlations were significantly dissimilar between FEP patients and CS. Significant correlations between CTh and CA with neurocognitive performance were localized in brain areas known to be involved in cognition. The results also suggested a disrupted structure-function relationship in FEP patients compared with CS.

Endothelial CaMKII as a regulator of eNOS activity and NO-mediated vasoreactivity

PubMed Central

Murthy, Shubha; Koval, Olha M.; Ramiro Diaz, Juan M.; Kumar, Santosh; Nuno, Daniel; Scott, Jason A.; Allamargot, Chantal; Zhu, Linda J.; Broadhurst, Kim; Santhana, Velarchana; Kutschke, William J.; Irani, Kaikobad; Lamping, Kathryn G.; Grumbach, Isabella M.

2017-01-01

The multifunctional Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a serine/threonine kinase important in transducing intracellular Ca2+ signals. While in vitro data regarding the role of CaMKII in the regulation of endothelial nitric oxide synthase (eNOS) are contradictory, its role in endothelial function in vivo remains unknown. Using two novel transgenic models to express CaMKII inhibitor peptides selectively in endothelium, we examined the effect of CaMKII on eNOS activation, NO production, vasomotor tone and blood pressure. Under baseline conditions, CaMKII activation was low in the aortic wall. Consistently, systolic and diastolic blood pressure, heart rate and plasma NO levels were unaltered by endothelial CaMKII inhibition. Moreover, endothelial CaMKII inhibition had no significant effect on NO-dependent vasodilation. These results were confirmed in studies of aortic rings transduced with adenovirus expressing a CaMKII inhibitor peptide. In cultured endothelial cells, bradykinin treatment produced the anticipated rapid influx of Ca2+ and transient CaMKII and eNOS activation, whereas CaMKII inhibition blocked eNOS phosphorylation on Ser-1179 and dephosphorylation at Thr-497. Ca2+/CaM binding to eNOS and resultant NO production in vitro were decreased under CaMKII inhibition. Our results demonstrate that CaMKII plays an important role in transient bradykinin-driven eNOS activation in vitro, but does not regulate NO production, vasorelaxation or blood pressure in vivo under baseline conditions. PMID:29059213

CD147 reinforces [Ca2+]i oscillations and promotes oncogenic progression in hepatocellular carcinoma.

PubMed

Tang, Juan; Guo, Yun-Shan; Yu, Xiao-Ling; Huang, Wan; Zheng, Ming; Zhou, Ying-Hui; Nan, Gang; Wang, Jian-Chao; Yang, Hai-Jiao; Yu, Jing-Min; Jiang, Jian-Li; Chen, Zhi-Nan

2015-10-27

Oscillations in intracellular Ca2+ concentrations ([Ca2+]i) mediate various cellular function. Although it is known that [Ca2+]i oscillations are susceptible to dysregulation in tumors, the tumor-specific regulators of [Ca2+]i oscillations are poorly characterized. We discovered that CD147 promotes hepatocellular carcinoma (HCC) metastasis and proliferation by enhancing the amplitude and frequency of [Ca2+]i oscillations in HCC cells. CD147 activates two distinct signaling pathways to regulate [Ca2+]i oscillations. By activating FAK-Src-IP3R1 signaling pathway, CD147 promotes Ca2+ release from endoplasmic reticulum (ER) and enhances the amplitude of [Ca2+]i oscillations. Furthermore, CD147 accelerates ER Ca2+refilling and enhances the frequency of [Ca2+]i oscillations through activating CaMKP-PAK1-PP2A-PLB-SERCA signaling pathway. Besides, CD147-promoted ER Ca2+ release and refilling are tightly regulated by changing [Ca2+]i. CD147 may activate IP3R1 channel under low [Ca2+]i conditions and CD147 may activate SERCA pump under high [Ca2+]i conditions. CD147 deletion suppresses HCC tumorigenesis and increases the survival rate of liver-specific CD147 knockout mice by regulating [Ca2+]i oscillations in vivo. Together, these results reveal that CD147 functions as a critical regulator of ER-dependent [Ca2+]i oscillations to promote oncogenic progression in HCC.

CD147 reinforces [Ca2+]i oscillations and promotes oncogenic progression in hepatocellular carcinoma

PubMed Central

Zheng, Ming; Zhou, Ying-Hui; Nan, Gang; Wang, Jian-Chao; Yang, Hai-Jiao; Yu, Jing-Min; Jiang, Jian-Li; Chen, Zhi-Nan

2015-01-01

Oscillations in intracellular Ca2+ concentrations ([Ca2+]i) mediate various cellular function. Although it is known that [Ca2+]i oscillations are susceptible to dysregulation in tumors, the tumor-specific regulators of [Ca2+]i oscillations are poorly characterized. We discovered that CD147 promotes hepatocellular carcinoma (HCC) metastasis and proliferation by enhancing the amplitude and frequency of [Ca2+]i oscillations in HCC cells. CD147 activates two distinct signaling pathways to regulate [Ca2+]i oscillations. By activating FAK-Src-IP3R1 signaling pathway, CD147 promotes Ca2+ release from endoplasmic reticulum (ER) and enhances the amplitude of [Ca2+]i oscillations. Furthermore, CD147 accelerates ER Ca2+ refilling and enhances the frequency of [Ca2+]i oscillations through activating CaMKP-PAK1-PP2A-PLB-SERCA signaling pathway. Besides, CD147-promoted ER Ca2+ release and refilling are tightly regulated by changing [Ca2+]i. CD147 may activate IP3R1 channel under low [Ca2+]i conditions and CD147 may activate SERCA pump under high [Ca2+]i conditions. CD147 deletion suppresses HCC tumorigenesis and increases the survival rate of liver-specific CD147 knockout mice by regulating [Ca2+]i oscillations in vivo. Together, these results reveal that CD147 functions as a critical regulator of ER-dependent [Ca2+]i oscillations to promote oncogenic progression in HCC. PMID:26498680

Ionic regulation of the cardiac sodium-calcium exchanger.

PubMed

Reeves, John P; Condrescu, Madalina

2008-01-01

The Na(+)-Ca(2+) exchanger (NCX) links transmembrane movements of Ca(2+) ions to the reciprocal movement of Na(+) ions. It normally functions primarily as a Ca(2+) efflux mechanism in excitable tissues such as the heart, but it can also mediate Ca(2+) influx under certain conditions. Na(+) and Ca(2+) ions exert complex regulatory effects on NCX activity. Ca(2+) binds to two regulatory sites in the exchanger's central hydrophilic domain, and this interaction is normally essential for activation of exchange activity. High cytosolic Na(+) concentrations, however, can induce a constitutive activity that by-passes the need for allosteric Ca(2+) activation. Constitutive NCX activity can also be induced by high levels of phopshotidylinositol-4,5-bisphosphate (PIP₂) and by mutations affecting the regulatory calcium binding domains. In addition to promoting constitutive activity, high cytosolic Na(+) concentrations also induce an inactivated state of the exchanger (Na(+)-dependent inactivation) that becomes dominant when cytosolic pH and PIP₂ levels fall. Na(+)-dependent inactivation may provide a means of protecting cells from Ca(2+) overload due to NCX-mediated Ca(2+) influx during ischemia.

Improvement of postoperative cognitive dysfunction and attention network function of patients with ischemic cerebrovascular disease via dexmedetomidine.

PubMed

Zhang, Jingchao; Wang, Guoliang; Zhang, Fangxiang; Zhao, Qian

2018-03-01

The protective effect of dexmedetomidine on cognitive dysfunction and decreased attention network function of patients with ischemic cerebrovascular disease after stenting was investigated. Fifty-eight patients with ischemic cerebrovascular disease undergoing stenting in Guizhou Provincial People's Hospital were selected and randomly divided into control group (n=29) and dexmedetomidine group (n=29). The dexmedetomidine group was treated with dexmedetomidine before induced anesthesia, while the control group was given the same dose of normal saline; and the normal volunteers of the same age were selected as the normal group (n=29). At 3 days after operation, the levels of serum S100B and nerve growth factor (NGF) in each group were detected using the enzyme-linked immunosorbent assay, and the level of brain-derived neurotrophic factor (BDNF) was detected via western blotting. Montreal cognitive assessment (MoCA) and attention network test (ANT) were performed. Moreover, the cognitive function and attention network function, and the effects of dexmedetomidine on cognitive function and attention network function were evaluated. The concentrations of serum S100B and NGF in dexmedetomidine group was lower than those in control group (P<0.01). The results of western blotting showed that the levels of serum BDNF in control group and dexmedetomidine group were significantly lower than that in normal group (P<0.01), and it was higher in dexmedetomidine group than that in control group (P<0.01). Besides, both MoCA and ANT results revealed that the visual space and executive function scores, attention scores, delayed memory scores, targeted network efficiency and executive control network efficiency in dexmedetomidine group were obviously higher than those in control group (P<0.01). The cognitive function and attention network function of patients with ischemic cerebrovascular disease have a certain degree of damage, and the preoperative administration of dexmedetomidine can effectively improve the patient's cognitive dysfunction and attention network function after operation.

Calcium interacts with antifreeze proteins and chitinase from cold-acclimated winter rye.

PubMed

Stressmann, Maja; Kitao, Satoshi; Griffith, Marilyn; Moresoli, Christine; Bravo, León A; Marangoni, Alejandro G

2004-05-01

During cold acclimation, winter rye (Secale cereale) plants accumulate pathogenesis-related proteins that are also antifreeze proteins (AFPs) because they adsorb onto ice and inhibit its growth. Although they promote winter survival in planta, these dual-function AFPs proteins lose activity when stored at subzero temperatures in vitro, so we examined their stability in solutions containing CaCl2, MgCl2, or NaCl. Antifreeze activity was unaffected by salts before freezing, but decreased after freezing and thawing in CaCl2 and was recovered by adding a chelator. Ca2+ enhanced chitinase activity 3- to 5-fold in unfrozen samples, although hydrolytic activity also decreased after freezing and thawing in CaCl2. Native PAGE, circular dichroism, and Trp fluorescence experiments showed that the AFPs partially unfold after freezing and thawing, but they fold more compactly or aggregate in CaCl2. Ruthenium red, which binds to Ca(2+)-binding sites, readily stained AFPs in the absence of Ca2+, but less stain was visible after freezing and thawing AFPs in CaCl2. We conclude that the structure of AFPs changes during freezing and thawing, creating new Ca(2+)-binding sites. Once Ca2+ binds to those sites, antifreeze activity, chitinase activity and ruthenium red binding are all inhibited. Because free Ca2+ concentrations are typically low in the apoplast, antifreeze activity is probably stable to freezing and thawing in planta. Ca2+ may regulate chitinase activity if concentrations are increased locally by release from pectin or interaction with Ca(2+)-binding proteins. Furthermore, antifreeze activity can be easily maintained in vitro by including a chelator during frozen storage.

Learning through inter- and intradisciplinary problem solving: using cognitive apprenticeship to analyse doctor-to-doctor consultation.

PubMed

Pimmer, Christoph; Pachler, Norbert; Nierle, Julia; Genewein, Urs

2012-12-01

Today's healthcare can be characterised by the increasing importance of specialisation that requires cooperation across disciplines and specialities. In view of the number of educational programmes for interdisciplinary cooperation, surprisingly little is known on how learning arises from interdisciplinary work. In order to analyse the learning and teaching practices of interdisciplinary cooperation, a multiple case study research focused on how consults, i.e., doctor-to-doctor consultations between medical doctors from different disciplines were carried out: semi-structured interviews with doctors of all levels of seniority from two hospital sites in Switzerland were conducted. Starting with a priori constructs based on the 'methods' underpinning cognitive apprenticeship (CA), the transcribed interviews were analysed according to the principles of qualitative content analysis. The research contributes to three debates: (1) socio-cognitive and situated learning, (2) intra- and interdisciplinary learning in clinical settings, and (3), more generally, to cooperation and problem solving. Patient cases, which necessitate the cooperation of doctors in consults across boundaries of clinical specialisms, trigger intra- as well as interdisciplinary learning and offer numerous and varied opportunities for learning by requesting doctors as well as for on-call doctors, in particular those in residence. The relevance of consults for learning can also be verified from the perspective of CA which is commonly used by experts, albeit in varying forms, degrees of frequency and quality, and valued by learners. Through data analysis a model for collaborative problem-solving and help-seeking was developed which shows the interplay of pedagogical 'methods' of CA in informal clinical learning contexts.

Functional significance of the intermediate conductance Ca2+-activated K+ channel for the short-term survival of injured erythrocytes.

PubMed

Föller, Michael; Bobbala, Diwakar; Koka, Saisudha; Boini, Krishna M; Mahmud, Hasan; Kasinathan, Ravi S; Shumilina, Ekaterina; Amann, Kerstin; Beranek, Golo; Sausbier, Ulrike; Ruth, Peter; Sausbier, Matthias; Lang, Florian; Huber, Stephan M

2010-11-01

Increased cytosolic Ca(2+) concentrations activate Gardos K(+) channels in human erythrocytes with membrane hyperpolarization, efflux of K(+), Cl⁻, and osmotically obliged H₂O resulting in cell shrinkage, a phenomenon referred to as Gardos effect. We tested whether the Gardos effect delays colloid osmotic hemolysis of injured erythrocytes from mice lacking the Ca(2+)-activated K(+) channel K(Ca)3.1. To this end, we applied patch clamp and flow cytometry and determined in vitro as well as in vivo hemolysis. As a result, erythrocytes from K(Ca)3.1-deficient (K(Ca)3.1(-/-)) mice lacked Gardos channel activity and the Gardos effect. Blood parameters, reticulocyte count, or osmotic erythrocyte resistance, however, did not differ between K(Ca)3.1(-/-) mice and their wild-type littermates, suggesting low or absent Gardos channel activity in unstressed erythrocytes. Oxidative stress-induced Ca(2+) entry and phospholipid scrambling were significantly less pronounced in K(Ca)3.1(-/-) than in wild-type erythrocytes. Moreover, in vitro treatment with α-toxin from Staphylococcus aureus, which forms pores in the cellular membrane, resulted in significantly stronger hemolysis of K(Ca)3.1(-/-) than of wild-type erythrocytes. Intravenous injection of α-toxin induced more profound hemolysis in K(Ca)3.1(-/-) than in wild-type mice. Similarly, intra-peritoneal application of the redox-active substance phenylhydrazine, an agent for the induction of hemolytic anemia, was followed by a significantly stronger decrease of hematocrit in K(Ca)3.1(-/-) than in wild-type mice. Finally, malaria infection triggered the activation of K(Ca)3.1 and transient shrinkage of the infected erythrocytes. In conclusion, K(Ca)3.1 channel activity and Gardos effect counteract hemolysis of injured erythrocytes, thus decreasing hemoglobin release into circulating blood.

Substitution of the methionine residues of calmodulin with the unnatural amino acid analogs ethionine and norleucine: biochemical and spectroscopic studies.

PubMed Central

Yuan, T.; Vogel, H. J.

1999-01-01

Calmodulin (CaM) is a 148-residue regulatory calcium-binding protein that activates a wide range of target proteins and enzymes. Calcium-saturated CaM has a bilobal structure, and each domain has an exposed hydrophobic surface region where target proteins are bound. These two "active sites" of calmodulin are remarkably rich in Met residues. Here we have biosynthetically substituted (up to 90% incorporation) the unnatural amino acids ethionine (Eth) and norleucine (Nle) for the nine Met residues of CaM. The substituted proteins bind in a calcium-dependent manner to hydrophobic matrices and a synthetic peptide, encompassing the CaM-binding domain of myosin light-chain kinase (MLCK). Infrared and circular dichroism spectroscopy show that there are essentially no changes in the secondary structure of these proteins compared to wild-type CaM (WT-CaM). One- and two-dimensional NMR studies of the Eth-CaM and Nle-CaM proteins reveal that, while the core of the proteins is relatively unaffected by the substitutions, the two hydrophobic interaction surfaces adjust to accommodate the Eth and Nle residues. Enzyme activation studies with MLCK show that Eth-CaM and Nle-CaM activate the enzyme to 90% of its maximal activity, with little changes in dissociation constant. For calcineurin only 50% activation was obtained, and the K(D) for Nle-CaM also increased 3.5-fold compared with WT-CaM. These data show that the "active site" Met residues of CaM play a distinct role in the activation of different target enzymes, in agreement with site-directed mutagenesis studies of the Met residues of CaM. PMID:10210190

CaMKKβ Is Involved in AMP-Activated Protein Kinase Activation by Baicalin in LKB1 Deficient Cell Lines

PubMed Central

Wang, Ying; Du, Zhiyan; Liu, Daihua; Guo, Hongxia; Shen, Jingkang; Peng, Hongli

2012-01-01

AMP-activated protein kinase (AMPK) plays an important role in mediating energy metabolism and is controlled mainly by two upstream kinases, LKB1 or Ca2+/calmodulin-dependent protein kinase kinase-β (CaMKKβ). Previously, we found that baicalin, one of the major flavonoids in a traditional Chinese herb medicine, Scutellaria baicalensis, protects against the development of hepatic steatosis in rats feeding with a high-fat diet by the activation of AMPK, but, the underlying mechanism for AMPK activation is unknown. Here we show that in two LKB1-deficient cells, HeLa and A549 cells, baicalin activates AMPK by α Thr-172 phosphorylation and subsequent phosphorylation of its downstream target, acetyl CoA carboxylase, at Ser-79, to a similar degree as does in HepG2 cells (that express LKB1). Pharmacologic inhibition of CaMKKβ by its selective inhibitor STO-609 markedly inhibits baicalin-induced AMPK activation in both HeLa and HepG2 cells, indicating that CaMKKβ is the responsible AMPK kinase. We also show that treatment of baicalin causes a larger increase in intracellular Ca2+ concentration ([Ca2+]i), although the maximal level of [Ca2+]i is lower in HepG2 cells compared to HeLa cells. Chelation of intracellular free Ca2+ by EDTA and EGTA, or depletion of intracellular Ca2+ stores by the endoplasmic reticulum Ca2+-ATPase inhibitor thapsigargin abrogates baicalin-induced activation of AMPK in HeLa cells. Neither cellular ATP nor the production of reactive oxygen species is altered by baicalin. Finally, in HeLa cells, baicalin treatment no longer decreases intracellular lipid accumulation caused by oleic acid after inhibition of CaMKKβ by STO-609. These results demonstrate that a potential Ca2+/CaMKKβ dependent pathway is involved in the activation of AMPK by baicalin and suggest that CaMKKβ likely acts as an upstream kinase of AMPK in response to baicalin. PMID:23110126

Store-depletion and hyperforin activate distinct types of Ca(2+)-conducting channels in cortical neurons.

PubMed

Gibon, Julien; Tu, Peng; Bouron, Alexandre

2010-06-01

Cortical neurons embryos (E13) from murine brain have a wide diversity of plasma membrane Ca(2+)-conducting channels. For instance, they express several types of transient receptor potential channels of C-type (TRPC) and hyperforin, a potent TRPC6-channel activator, controls the activity of TRPC6-like channels. In addition, E13 cortical neurons possess plasma membrane channels activated in response to the depletion of internal Ca(2+) pools. Since some TRPC channels seem to be involved in the activity of store-depletion-activated channels, we investigated whether hyperforin and the depletion of the Ca(2+) stores control similar or distinct Ca(2+) routes. Calcium imaging experiments performed with the fluorescent Ca(2+) indicator Fluo-4 showed that the TRPC3 channel blocker Pyr3 potently inhibits with an IC(50) of 0.5microM the entry of Ca(2+) triggered in response to the thapsigargin-dependent depletion of the Ca(2+) stores. On the other hand, Pyr3 does not block the hyperforin-sensitive Ca(2+) entry. In contrast to the hyperforin responses, the Ca(2+) entry through the store-depletion-activated channels is down-regulated by the competitive tyrosine kinase inhibitors genistein and PP2. In addition, the immunosuppressant FK506, known to modulate several classes of Ca(2+)-conducting channels, strongly attenuates the entry of Ca(2+) through the store-depletion-activated channels, leaving the hyperforin-sensitive responses unaffected. Hence, the Zn(2+) chelator TPEN markedly attenuated the hyperforin-sensitive responses without modifying the thapsigargin-dependent Ca(2+) signals. Pyr3-insensitive channels are key components of the hyperforin-sensitive channels, whereas the thapsigargin-dependent depletion of the Ca(2+) stores of the endoplasmic reticulum activates Pyr3-sensitive channels. Altogether, these data support the notion that hyperforin and the depletion of the Ca(2+) pools control distinct plasma membrane Ca(2+)-conducting channels. This report further illustrates that, at the beginning of the corticogenesis, immature cortical neurons express diverse functional Ca(2+) channels. 2010 Elsevier Ltd. All rights reserved.

Novel nootropic drug sunifiram improves cognitive deficits via CaM kinase II and protein kinase C activation in olfactory bulbectomized mice.

PubMed

Moriguchi, Shigeki; Tanaka, Tomoya; Tagashira, Hideaki; Narahashi, Toshio; Fukunaga, Kohji

2013-04-01

Alzheimer's disease (AD) shows degeneration of the cholinergic system in the medial septum, thereby eliciting down-regulation of the olfactory function in patients. We have previously reported that olfactory bulbectomized (OBX) mice show hippocampus-dependent memory impairment as assessed by memory-related behavioral tasks and hippocampal long-term potentiation (LTP). In the present study, we focused whether novel pyrrolidone nootropic drug sunifiram improves both memory impairment and depression observed in OBX mice. OBX mice were administered once a day for 7-12 days with sunifiram (0.01-1.0mg/kg p.o.) from 10 days after operation with or without gavestinel (10mg/kg i.p.), which is glycine-binding site inhibitor of N-methyl-d-aspartate receptor (NMDAR). The spatial reference memory assessed by Y-maze and short-term memory assessed by novel object recognition task were significantly improved by sunifiram treatment in OBX mice. Sunifiram also restored hippocampal LTP injured in OBX mice without treatment with gavestinel. By contrast, sunifiram treatment did not ameliorate the depressive behaviors assessed by tail suspension task in OBX mice. Notably, sunifiram treatment restored CaMKIIα (Thr-286) autophosphorylation and GluR1 (Ser-831) phosphorylation in the hippocampal CA1 region from OBX mice to the levels of control mice. Likewise, sunifiram treatment improved PKCα (Ser-657) autophosphorylation and NR1 (Ser-896) phosphorylation to the control levels. Stimulation of CaMKII and PKC autophosphorylation by sunifiram was significantly inhibited by pre-treatment with gavestinel. However, sunifiram treatment did not affect the phosphorylation of CaMKIV (Thr-196) and ERK. Taken together, sunifiram ameliorates OBX-induced deficits of memory-related behaviors and impaired LTP in the hippocampal CA1 region via stimulation of glycine-binding site of NMDAR. Copyright © 2013 Elsevier B.V. All rights reserved.

Calcium-activated K(+) channel (K(Ca)3.1) activity during Ca(2+) store depletion and store-operated Ca(2+) entry in human macrophages.

PubMed

Gao, Ya-dong; Hanley, Peter J; Rinné, Susanne; Zuzarte, Marylou; Daut, Jurgen

2010-07-01

STIM1 'senses' decreases in endoplasmic reticular (ER) luminal Ca(2+) and induces store-operated Ca(2+) (SOC) entry through plasma membrane Orai channels. The Ca(2+)/calmodulin-activated K(+) channel K(Ca)3.1 (previously known as SK4) has been implicated as an 'amplifier' of the Ca(2+)-release activated Ca(2+) (CRAC) current, especially in T lymphocytes. We have previously shown that human macrophages express K(Ca)3.1, and here we used the whole-cell patch-clamp technique to investigate the activity of these channels during Ca(2+) store depletion and store-operated Ca(2+) influx. Using RT-PCR, we found that macrophages express the elementary CRAC channel components Orai1 and STIM1, as well as Orai2, Orai3 and STIM2, but not the putatively STIM1-activated channels TRPC1, TRPC3-7 or TRPV6. In whole-cell configuration, a robust Ca(2+)-induced outwardly rectifying K(+) current inhibited by clotrimazole and augmented by DC-EBIO could be detected, consistent with K(Ca)3.1 channel current (also known as intermediate-conductance IK1). Introduction of extracellular Ca(2+) following Ca(2+) store depletion via P2Y(2) receptors induced a robust charybdotoxin (CTX)- and 2-APB-sensitive outward K(+) current and hyperpolarization. We also found that SOC entry induced by thapsigargin treatment induced CTX-sensitive K(+) current in HEK293 cells transiently expressing K(Ca)3.1. Our data suggest that SOC and K(Ca)3.1 channels are tightly coupled, such that a small Ca(2+) influx current induces a much large K(Ca)3.1 channel current and hyperpolarization, providing the necessary electrochemical driving force for prolonged Ca(2+) signaling and store repletion. Copyright 2010 Elsevier Ltd. All rights reserved.

Cloud condensation nucleation activities of calcium carbonate and its atmospheric ageing products.

PubMed

Tang, M J; Whitehead, J; Davidson, N M; Pope, F D; Alfarra, M R; McFiggans, G; Kalberer, M

2015-12-28

Aerosol particles can serve as cloud condensation nuclei (CCN) to form cloud droplets, and its composition is a main factor governing whether an aerosol particle is an effective CCN. Pure mineral dust particles are poor CCN; however, changes in chemical composition of mineral dust aerosol particles, due to heterogeneous reactions with reactive trace gases in the troposphere, can modify their CCN properties. In this study we investigated the CCN activities of CaCO3 (as a surrogate for mineral dust) and its six atmospheric ageing products: Ca(NO3)2, CaCl2, CaSO4, Ca(CH3SO3)2, Ca(HCOO)2, and Ca(CH3COO)2. CaCO3 has a very low CCN activity with a hygroscopicity parameter (κ) of 0.001-0.003. The CCN activities of its potential atmospheric ageing products are significantly higher. For example, we determined that Ca(NO3)2, CaCl2 and Ca(HCOO)2 have κ values of ∼0.50, similar to that of (NH4)2SO4. Ca(CH3COO)2 has slightly lower CCN activity with a κ value of ∼0.40, and the κ value of CaSO4 is around 0.02. We further show that exposure of CaCO3 particles to N2O5 at 0% relative humidity (RH) significantly enhances their CCN activity, with κ values increasing to around 0.02-0.04. Within the experimental uncertainties, it appears that the variation in exposure to N2O5 from ∼550 to 15,000 ppbv s does not change the CCN activities of aged CaCO3 particles. This observation indicates that the CaCO3 surface may be already saturated at the shortest exposure. We also discussed the atmospheric implications of our study, and suggested that the rate of change in CCN activities of mineral dust particles in the troposphere is important to determine their roles in cloud formation.

Gender-Specific Potential Inhibitory Role of Ca2+/Calmodulin Dependent Protein Kinase Phosphatase (CaMKP) in Pressure-Overloaded Mouse Heart

PubMed Central

Prévilon, Miresta; Pezet, Mylène; Vinet, Laurent; Mercadier, Jean-Jacques; Rouet-Benzineb, Patricia

2014-01-01

Background Ca2+/calmodulin-dependent protein kinase phosphatase (CaMKP) has been proposed as a potent regulator of multifunctional Ca2+/calmodulin-dependent protein kinases (i.e., CaMKII). The CaMKII-dependent activation of myocyte enhancer factor 2 (MEF2) disrupts interactions between MEF2-histone deacetylases (HDACs), thereby de-repressing downstream gene transcription. Whether CaMKP modulates the CaMKII- MEF2 pathway in the heart is unknown. Here, we investigated the molecular and functional consequences of left ventricular (LV) pressure overload in the mouse of both genders, and in particular we evaluated the expression levels and localization of CaMKP and its association with CaMKII-MEF2 signaling. Methodology and Principal Findings Five week-old B6D1/F1 mice of both genders underwent a sham-operation or thoracic aortic constriction (TAC). Thirty days later, TAC was associated with pathological LV hypertrophy characterized by systolic and diastolic dysfunction. Gene expression was assessed by real-time PCR. Fetal gene program re-expression comprised increased RNA levels of brain natriuretic peptide and alpha-skeletal actin. Mouse hearts of both genders expressed both CaMKP transcript and protein. Activation of signalling pathways was studied by Western blot in LV lysates or subcellular fractions (nuclear and cytoplasmic). TAC was associated with increased CaMKP expression in male LVs whereas it tended to be decreased in females. The DNA binding activity of MEF2 was determined by spectrophotometry. CaMKP compartmentalization differed according to gender. In male TAC mice, nuclear CaMKP was associated with inactive CaMKII resulting in less MEF2 activation. In female TAC mice, active CaMKII (phospho-CaMKII) detected in the nuclear fraction, was associated with a strong MEF2 transcription factor-binding activity. Conclusions/Significance Gender-specific CaMKP compartmentalization is associated with CaMKII-mediated MEF2 activation in pressure-overloaded hearts. Therefore, CaMKP could be considered as an important novel cellular target for the development of new therapeutic strategies for heart diseases. PMID:24608696

Gender-specific potential inhibitory role of Ca2+/calmodulin dependent protein kinase phosphatase (CaMKP) in pressure-overloaded mouse heart.

PubMed

Prévilon, Miresta; Pezet, Mylène; Vinet, Laurent; Mercadier, Jean-Jacques; Rouet-Benzineb, Patricia

2014-01-01

Ca2+/calmodulin-dependent protein kinase phosphatase (CaMKP) has been proposed as a potent regulator of multifunctional Ca2+/calmodulin-dependent protein kinases (i.e., CaMKII). The CaMKII-dependent activation of myocyte enhancer factor 2 (MEF2) disrupts interactions between MEF2-histone deacetylases (HDACs), thereby de-repressing downstream gene transcription. Whether CaMKP modulates the CaMKII- MEF2 pathway in the heart is unknown. Here, we investigated the molecular and functional consequences of left ventricular (LV) pressure overload in the mouse of both genders, and in particular we evaluated the expression levels and localization of CaMKP and its association with CaMKII-MEF2 signaling. Five week-old B6D1/F1 mice of both genders underwent a sham-operation or thoracic aortic constriction (TAC). Thirty days later, TAC was associated with pathological LV hypertrophy characterized by systolic and diastolic dysfunction. Gene expression was assessed by real-time PCR. Fetal gene program re-expression comprised increased RNA levels of brain natriuretic peptide and alpha-skeletal actin. Mouse hearts of both genders expressed both CaMKP transcript and protein. Activation of signalling pathways was studied by Western blot in LV lysates or subcellular fractions (nuclear and cytoplasmic). TAC was associated with increased CaMKP expression in male LVs whereas it tended to be decreased in females. The DNA binding activity of MEF2 was determined by spectrophotometry. CaMKP compartmentalization differed according to gender. In male TAC mice, nuclear CaMKP was associated with inactive CaMKII resulting in less MEF2 activation. In female TAC mice, active CaMKII (phospho-CaMKII) detected in the nuclear fraction, was associated with a strong MEF2 transcription factor-binding activity. Gender-specific CaMKP compartmentalization is associated with CaMKII-mediated MEF2 activation in pressure-overloaded hearts. Therefore, CaMKP could be considered as an important novel cellular target for the development of new therapeutic strategies for heart diseases.

Ca2+/Calmodulin-Dependent Protein Kinase Kinases (CaMKKs) Effects on AMP-Activated Protein Kinase (AMPK) Regulation of Chicken Sperm Functions.

PubMed

Nguyen, Thi Mong Diep; Combarnous, Yves; Praud, Christophe; Duittoz, Anne; Blesbois, Elisabeth

2016-01-01

Sperm require high levels of energy to ensure motility and acrosome reaction (AR) accomplishment. The AMP-activated protein kinase (AMPK) has been demonstrated to be strongly involved in the control of these properties. We address here the question of the potential role of calcium mobilization on AMPK activation and function in chicken sperm through the Ca(2+)/calmodulin-dependent protein kinase kinases (CaMKKs) mediated pathway. The presence of CaMKKs and their substrates CaMKI and CaMKIV was evaluated by western-blotting and indirect immunofluorescence. Sperm were incubated in presence or absence of extracellular Ca(2+), or of CaMKKs inhibitor (STO-609). Phosphorylations of AMPK, CaMKI, and CaMKIV, as well as sperm functions were evaluated. We demonstrate the presence of both CaMKKs (α and β), CaMKI and CaMKIV in chicken sperm. CaMKKα and CaMKI were localized in the acrosome, the midpiece, and at much lower fluorescence in the flagellum, whereas CaMKKβ was mostly localized in the flagellum and much less in the midpiece and the acrosome. CaMKIV was only present in the flagellum. The presence of extracellular calcium induced an increase in kinases phosphorylation and sperm activity. STO-609 reduced AMPK phosphorylation in the presence of extracellular Ca(2+) but not in its absence. STO-609 did not affect CaMKIV phosphorylation but decreased CaMKI phosphorylation and this inhibition was quicker in the presence of extracellular Ca(2+) than in its absence. STO-609 efficiently inhibited sperm motility and AR, both in the presence and absence of extracellular Ca(2+). Our results show for the first time the presence of CaMKKs (α and β) and one of its substrate, CaMKI in different subcellular compartments in germ cells, as well as the changes in the AMPK regulation pathway, sperm motility and AR related to Ca(2+) entry in sperm through the Ca(2+)/CaM/CaMKKs/CaMKI pathway. The Ca(2+)/CaMKKs/AMPK pathway is activated only under conditions of extracellular Ca(2+) entry in the cells.

The role of calcium and calmodulin in freezing-induced freezing resistance of Populus tomentosa cuttings.

PubMed

Lin, Shan-Zhi; Zhang, Zhi-Yi; Lin, Yuan-Zhen; Zhang, Qian; Guo, Huan

2004-02-01

To explore the role of calcium-calmodulin messenger system in the transduction of low temperature signal in woody plants, Populus tomentosa cuttings after being treated with CaCl(2) (10 mmol/L), Ca(2+) chelator EGTA (3 mmol/L), Ca(2+) channel inhibitor LaCl(3) (100 mmol/L) or CaM antagonist CPZ (50 mmol/L) were used for freezing acclimation at -3 degrees C. The changes in the calmodulin (CaM) and malonaldehyde (MDA) contents, the activities of superoxide dismutase (SOD), peroxidase (POD) and Ca(2+)-dependent adenosinetriphosphatase (Ca(2+)-ATPase) of mitochondrial membrane as well as freezing resistance (expressed as LT(50)) of cuttings were investigated to elucidate the physiological mechanisms by which trees adapt to freezing. The results showed that freezing acclimation increased the CaM content, the activities of SOD, POD and Ca(2+)-ATPase of mitochondrial membrane as well as freezing resistance of cuttings, and decreased the MDA content as compared with control cuttings. Treatment with CaCl(2) at the time of freezing acclimation enhanced the effect of freezing acclimation on the above-mentioned indexes, but this enhancement was abolished by Ca(2+)chelator EGTA, Ca(2+) channel inhibitor LaCl(3) or CaM antagonist CPZ, indicating that the calcium-calmodulin messenger system was involved in the course of freezing resistance development. The presence of CaCl(2) at the same time of freezing acclimation also reduced the degree of decline in CaM content, and in SOD, POD and Ca(2+)-ATPase activities caused by freezing stress at -14 degrees C, and enhanced the level of increase in CaM content, and in SOD, POD and Ca(2+)-ATPase activity in the recovery periods at 25 degrees C . The change in CaM content was found to be closely correlated to the levels of SOD, POD and Ca(2+)-ATPase, and to the degree of freezing resistance of cuttings during freezing acclimation either with or without CaCl(2) treatment. It was suggested that the increase of CaM content induced by CaCl(2) treatment promote the formation of Ca(2+)-CaM complexes, which effectively activates the activities of SOD, POD and mitochondrial Ca(2+)-ATPase and then further result in the adaptive changes associated with the development and enhancement of freezing resistance. Thus, It could be concluded that Ca(2+)-calmodulin may be involved in the regulation of the increase in SOD, POD and Ca(2+)-ATPase activities, and the induction of freezing resistance of cuttings.

Subpopulation of store-operated Ca2+ channels regulate Ca2+-induced Ca2+ release in non-excitable cells.

PubMed

Yao, Jian; Li, Qin; Chen, Jin; Muallem, Shmuel

2004-05-14

Ca2+-induced Ca2+ release (CICR) is a well characterized activity in skeletal and cardiac muscles mediated by the ryanodine receptors. The present study demonstrates CICR in the non-excitable parotid acinar cells, which resembles the mechanism described in cardiac myocytes. Partial depletion of internal Ca2+ stores leads to a minimal activation of Ca2+ influx. Ca2+ influx through this pathway results in an explosive mobilization of Ca2+ from the majority of the stores by CICR. Thus, stimulation of parotid acinar cells in Ca2+ -free medium with 0.5 microm carbachol releases approximately 5% of the Ca2+ mobilizable by 1 mm carbachol. Addition of external Ca2+ induced the same Ca2+ release observed in maximally stimulated cells. Similar results were obtained by a short treatment with 2.5-10 microm cyclopiazonic acid, an inhibitor of the sarco/endoplasmic reticulum Ca2+ ATPase pump. The Ca2+ release induced by the addition of external Ca2+ was largely independent of IP(3)Rs because it was reduced by only approximately 30% by the inhibition of the inositol 1,4,5-trisphosphate receptors with caffeine or heparin. Measurements of Ca2+ -activated outward current and [Ca2+](i) suggested that most CICR triggered by Ca2+ influx occurred away from the plasma membrane. Measurement of the response to several concentrations of cyclopiazonic acid revealed that Ca2+ influx that regulates CICR is associated with a selective portion of the internal Ca2+ pool. The minimal activation of Ca2+ influx by partial store depletion was confirmed by the measurement of Mn2+ influx. Inhibition of Ca2+ influx with SKF96365 or 2-aminoethoxydiphenyl borate prevented activation of CICR observed on addition of external Ca2+. These findings provide evidence for activation of CICR by Ca2+ influx in non-excitable cells, demonstrate a previously unrecognized role for Ca2+ influx in triggering CICR, and indicate that CICR in non-excitable cells resembles CICR in cardiac myocytes with the exception that in cardiac cells Ca2+ influx is mediated by voltage-regulated Ca2+ channels whereas in non-excitable cells Ca2+ influx is mediated by store-operated channels.

Carbonic anhydrase activity in Arabidopsis thaliana thylakoid membrane and fragments enriched with PSI or PSII.

PubMed

Ignatova, Lyudmila K; Rudenko, Natalia N; Mudrik, Vilen A; Fedorchuk, Tat'yana P; Ivanov, Boris N

2011-12-01

The procedure of isolating the thylakoids and the thylakoid membrane fragments enriched with either photosystem I or photosystem II (PSI- and PSII-membranes) from Arabidopsis thaliana leaves was developed. It differed from the one used with pea and spinach in durations of detergent treatment and centrifugation, and in concentrations of detergent and Mg(2+) in the media. Both the thylakoid and the fragments preserved carbonic anhydrase (CA) activities. Using nondenaturing electrophoresis followed by detection of CA activity in the gel stained with bromo thymol blue, one low molecular mass carrier of CA activity was found in the PSI-membranes, and two carriers, a low molecular mass one and a high molecular mass one, were found in the PSII-membranes. The proteins in the PSII-membranes differed in their sensitivity to acetazolamide (AA), a specific CA inhibitor. AA at 5 × 10(-7) M inhibited the CA activity of the high molecular mass protein but stimulated the activity of the low molecular mass carrier in the PSII-membranes. At the same concentration, AA moderately inhibited, by 30%, the CA activity of PSI-membranes. CA activity of the PSII-membranes was almost completely suppressed by the lipophilic CA inhibitor, ethoxyzolamide at 10(-9) M, whereas CA activity of the PSI-membranes was inhibited by this inhibitor even at 5 × 10(-7) M just the same as for AA. The observed distribution of CA activity in the thylakoid membranes from A. thaliana was close to the one found in the membranes of pea, evidencing the general pattern of CA activity in the thylakoid membranes of C3-plants. © Springer Science+Business Media B.V. 2011