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Sample records for ameliorates cognition deficits

  1. Naringin ameliorates cognitive deficits in streptozotocin-induced diabetic rats

    PubMed Central

    Liu, Xianchu; Liu, Ming; Mo, Yanzhi; Peng, Huan; Gong, Jingbo; Li, Zhuang; Chen, Jiaxue; Xie, Jingtao

    2016-01-01

    Objective(s): Previous research demonstrated that diabetes is one of the leading causes of learning and memory deficits. Naringin, a bioflavonoid isolated from grapefruits and oranges, has potent protective effects on streptozotocin (STZ)-induced diabetic rats. Recently, the effects of naringin on learning and memory performances were monitored in many animal models of cognitive impairment. However, to date, no studies have investigated the ameliorative effects of naringin on diabetes-associated cognitive decline (DACD). In this study, we investigated the effects of naringin, using a STZ-injected rat model and explored its potential mechanism. Materials and Methods: Diabetic rats were treated with naringin (100 mg/kg/d) for 7 days. The learning and memory function were assessed by Morris water maze test. The oxidative stress indicators [superoxide dismutase (SOD) and malondialdehyde (MDA)] and inflammatory cytokines (TNF-a, IL-1β, and IL-6) were measured in hippocampus using corresponding commercial kits. The mRNA and protein levels of PPARγ were evaluated by real time (RT)-PCR and Western blot analysis. Results: The results showed that supplementation of naringin improved learning and memory performances compared with the STZ group. Moreover, naringin supplement dramatically increased SOD levels, reduced MDA levels, and alleviated TNF-α, IL-1β, and IL-6 compared with the STZ group in the hippocampus. The pretreatment with naringin also significantly increased PPARγ expression. Conclusion: Our results showed that naringin may be a promising therapeutic agent for improving cognitive decline in DACD. PMID:27279986

  2. Puerarin ameliorates cognitive deficits in streptozotocin-induced diabetic rats.

    PubMed

    Liu, Xianchu; Mo, Yanzhi; Gong, Jingbo; Li, Zhuang; Peng, Huan; Chen, Jiaxue; Wang, Qichao; Ke, Zhaowen; Xie, Jingtao

    2016-04-01

    Previous research has indicated that Diabetes is a high risk of learning and memory deficits. Puerarin, an isoflavonoid extracted from Kudzu roots, has been reported to possess antioxidant, anti-inflammatory, anti-apoptotic and anti-diabetic properties which are useful in the treatment of various diseases. Recently, Puerarin was found to have the effects on learning and memory performances in humans and animal models. However, up to now, there is no detailed evidence on the effect of Puerarin on diabetes-associated cognitive decline (DACD). In this study, we designed to assess the effects of Puerarin on diabetes-associated cognitive decline (DACD) using a streptozotocin (STZ)-injected rat model and exploring its potential mechanism. Diabetic rats were treated with Puerarin (100 mg/kg per d) for 7 days. The learning and memory function was evaluated by morris water maze test. The acetylcholinesterase (AChE), choline acetylase (ChAT), oxidative indicators [malondialdehyde (MDA) and superoxide dismutase (SOD)] and inflammatory cytokine (TNF-a, IL-1β and IL-6) were measured in hippocampus by using corresponding commercial kits. mRNA and Protein levels of Bcl-2 were analyzed by RT-PCR and Westernblot. The results showed that supplementation of Puerarin improved the learning and memory performances compared with the STZ group by the morris water maze test. In addition, Puerarin supplement significantly prevented AChE and MDA activities, increased ChAT and SOD activities, and alleviated the protein level of TNF-α, IL-1β and IL-6 in the hippocampus compared with the STZ group. Moreover, the pretreatment with Puerarin also significantly increased the Bcl-2 expression. It is concluded that Puerarin possesses neuroprotection to ameliorate cognitive deficits in streptozotocin-induced diabetic rats by anti-inflammatory, antioxidant and antiapototic effects. PMID:26686502

  3. Smart Soup, a Traditional Chinese Medicine Formula, Ameliorates Amyloid Pathology and Related Cognitive Deficits

    PubMed Central

    Li, Xiaohang; Cui, Jin; Ding, Jianqing; Wang, Ying; Zeng, Xianglu; Ling, Yun; Shen, Xiaoheng; Chen, Shengdi; Huang, Chenggang; Pei, Gang

    2014-01-01

    Alzheimer’s disease (AD) is a progressive neurodegenerative disease that causes substantial public health care burdens. Intensive efforts have been made to find effective and safe disease-modifying treatment and symptomatic intervention alternatives against AD. Smart Soup (SS), a Chinese medicine formula composed of Rhizoma Acori Tatarinowii (AT), Poria cum Radix Pini (PRP) and Radix Polygalae (RP), is a typical prescription against memory deficits. Here, we assessed the efficacy of SS against AD. Oral administration of SS ameliorated the cognitive impairment of AD transgenic mice, with reduced Aβ levels, retarded Aβ amyloidosis and reduced Aβ-induced gliosis and neuronal loss in the brains of AD mice. Consistently, SS treatment reduced amyloid-related locomotor dysfunctions and premature death of AD transgenic Drosophila. Mechanistic studies showed that RP reduced Aβ generation, whereas AT and PRP exerted neuroprotective effects against Aβ. Taken together, our study indicates that SS could be effective against AD, providing a practical therapeutic strategy against the disease. PMID:25386946

  4. ABT-089, but not ABT-107, ameliorates nicotine withdrawal-induced cognitive deficits in C57BL6/J mice

    PubMed Central

    Yildirim, Emre; Connor, David A.; Gould, Thomas J.

    2015-01-01

    Nicotine withdrawal produces cognitive deficits that can predict relapse. Amelioration of these cognitive deficits emerges as a target in current smoking cessation therapies. In rodents, withdrawal from chronic nicotine disrupts contextual fear conditioning (CFC), whereas acute nicotine enhances this hippocampus-specific learning and memory. These modifications are mediated by β2-subunit-containing (β2*) nicotinic acetylcholine receptors in the hippocampus. We aimed to test ABT-089, a partial agonist of α4β2*, and ABT-107, an α7 nicotinic acetylcholine receptor agonist, for amelioration of cognitive deficits induced by withdrawal from chronic nicotine in mice. Mice underwent chronic nicotine administration (12.6 mg/kg/day or saline for 12 days), followed by 24 h of withdrawal. At the end of withdrawal, mice received 0.3 or 0.6 mg/kg ABT-089 or 0.3 mg/kg ABT-107 (doses were determined through initial dose–response experiments and prior studies) and were trained and tested for CFC. Nicotine withdrawal produced deficits in CFC that were reversed by acute ABT-089, but not ABT-107. Cued conditioning was not affected. Taken together, our results suggest that modulation of hippocampal learning and memory using ABT-089 may be an effective component of novel therapeutic strategies for nicotine addiction. PMID:25426579

  5. Reducing HDAC6 ameliorates cognitive deficits in a mouse model for Alzheimer's disease

    PubMed Central

    Govindarajan, Nambirajan; Rao, Pooja; Burkhardt, Susanne; Sananbenesi, Farahnaz; Schlüter, Oliver M; Bradke, Frank; Lu, Jianrong; Fischer, André

    2013-01-01

    Histone deacetylases (HDACs) are currently being discussed as promising therapeutic targets to treat neurodegenerative diseases. However, the role of specific HDACs in cognition and neurodegeneration remains poorly understood. Here, we investigate the function of HDAC6, a class II member of the HDAC superfamily, in the adult mouse brain. We report that mice lacking HDAC6 are cognitively normal but reducing endogenous HDAC6 levels restores learning and memory and α-tubulin acetylation in a mouse model for Alzheimer's disease (AD). Our data suggest that this therapeutic effect is, at least in part, linked to the observation that loss of HDAC6 renders neurons resistant to amyloid-β-mediated impairment of mitochondrial trafficking. Thus, our study suggests that targeting HDAC6 could be a suitable strategy to ameliorate cognitive decline observed in AD. PMID:23184605

  6. A coimmunization vaccine of Aβ42 ameliorates cognitive deficits without brain inflammation in an Alzheimer’s disease model

    PubMed Central

    2014-01-01

    Introduction Vaccination against amyloid-β protein (Aβ42) induces high levels of antibody, making it a promising strategy for treating Alzheimer’s disease (AD). One drawback in the past was that clinical trial approval was withheld because of speculation that the Aβ42 vaccine induces CD4+ T cell infiltrations into the central nervous system. To reduce T-cell activation while concomitantly maintaining high anti-Aβ42 titers is a great challenge in immunology. Methods We aimed to demonstrate that coimmunization with Aβ42 protein and expression plasmid can be beneficial in a mouse AD model and can prevent inflammation. We immunized the AD mice with the coimmunization vaccine and assessed behavior change and Aβ42 deposition. Furthermore, to determine the safety of the coimmunization vaccine, we used an induced Aβ42-EAE model to mimic the meningoencephalitis that happened in the AN-1792 vaccine clinical phase II trial and tested whether the coimmunization vaccine could ameliorate T-cell-mediated brain inflammation. Results The coimmunization vaccination reduced Aβ plaques and significantly ameliorated cognitive deficit while inhibiting T-cell-mediated brain inflammation and infiltration. These studies demonstrate that the coimmunization strategy that we describe in this article can ameliorate AD pathology without notable adverse effects in mice. Conclusions A coimmunization strategy leading to the development of a safe immunotherapeutic/preventive protocol against AD in humans is warranted. PMID:24987466

  7. Edaravone injection ameliorates cognitive deficits in rat model of Alzheimer's disease.

    PubMed

    Yang, Rui; Wang, Qingjun; Li, Fang; Li, Jian; Liu, Xuewen

    2015-11-01

    Oxidative stress plays important role in the pathogenesis of Alzheimer's disease (AD). Edaravone is a potent free radical scavenger that exerts antioxidant effects. Therefore, in this study we aimed to investigate neuroprotective effects of edaravone for AD. Wistar rats were randomly divided into three groups (n = 15): control group, model group, and treatment group, which were injected with phosphate buffered saline, Aβ1-40, and Aβ1-40 together with 5 mg/kg edaravone, respectively, into the right hippocampal dentate gyrus. Spatial learning and memory of the rats were examined by Morris water maze test. 4-Hydroxynonenal (4-HNE) level in rat hippocampus was analyzed by immunohistochemistry. Acetylcholinesterase (AChE) and choline acetylase (ChAT) activities were assayed by commercial kits. We found that edaravone ameliorated spatial learning and memory deficits in the rats. 4-HNE level in the hippocampus as well as AChE and ChAT activities in the hippocampus was significantly lower in treatment group than in model group. In conclusion, edaravone may be developed as a novel agent for the treatment of AD for improving cholinergic system and protecting neurons from oxidative toxicity. PMID:26163224

  8. Huperzine A ameliorates cognitive deficits in streptozotocin-induced diabetic rats.

    PubMed

    Mao, Xiao-Yuan; Cao, Dan-Feng; Li, Xi; Yin, Ji-Ye; Wang, Zhi-Bin; Zhang, Ying; Mao, Chen-Xue; Zhou, Hong-Hao; Liu, Zhao-Qian

    2014-01-01

    The present study was designed to probe the effects of Huperzine A (HupA) on diabetes-associated cognitive decline (DACD) using a streptozotocin (STZ)-injected rat model. Diabetic rats were treated with HupA (0.05 and 0.1 mg/kg) for seven weeks. Memory functions were evaluated by the water maze test. Nissl staining was selected for detecting neuronal loss. Protein and mRNA levels of brain-derived neurotrophic factor (BDNF) were analyzed by ELISA and real-time PCR, respectively. The activities of choline acetylase (ChAT), Acetylcholinesterase (AChE), malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT), NF-κB p65 unit, TNF-α, IL-1β, IL-6 and caspase-3 were measured using corresponding kits. After seven weeks, diabetic rats exhibited remarkable reductions in: body weight, percentage of time spent in target quadrant, number of times crossing the platform, ChAT and BDNF levels, SOD, GSH-Px and CAT accompanied with increases in neuronal damage, plasma glucose levels, escape latency, mean path length, AChE, MDA level as well as CAT, NF-κB p65 unit, TNF-α, IL-1β, IL-6 and caspase-3 in cerebral cortex and hippocampus. Supplementation with HupA significantly and dose-dependently reversed the corresponding values in diabetes. It is concluded that HupA ameliorates DACD via modulating BDNF, oxidative stress, inflammation and apoptosis. PMID:24857910

  9. Lignans from Schisandra chinensis ameliorate cognition deficits and attenuate brain oxidative damage induced by D-galactose in rats.

    PubMed

    Yan, Tingxu; Shang, Lei; Wang, Mengshi; Zhang, Chenning; Zhao, Xu; Bi, Kaishun; Jia, Ying

    2016-06-01

    The aim of this study was to explore the neuroprotective effects of active compounds from Schisandra chinensis (Trucz.) Baill. (Magnoliaceae) against the D-galactose (D-gal)-induced neurotoxicity in rat. The Wistar rats were subcutaneously injected with D-gal (150 mg/(kg day)) for six weeks and orally administered with water extract or 95 % ethanol extract (partitioned with petroleum ether (PE), chloroform (CF), ethyl acetate (EA) and n-Butanol (NB), respectively) of the fruits of Schisandra chinensis simultaneously. The alteration of cognitive functions was assessed by using Morris water maze and Step-down type passive avoidance test. The results demonstrated that PE fraction was the most effective fraction to ameliorate cognitive deficits. Further biochemical examination indicated that PE could attenuate the activities decreasing of superoxide dismutase (SOD), catalase (CAT), the total antioxidant (T-AOC) induced by D-gal, and maintain the normal levels of glutathione (GSH), malondialdehyde (MDA) and nitric oxide (NO) in the serum, prefrontal cortex, striatum and hippocampus of the brain of related rat, selectively. Meanwhile, the compounds of PE fraction were also identified as mainly lignans, thus, these results suggest that lignans from the PE fraction of Schisandra chinensis represented a potential source of medicine for the treatment of the aging-associated neurodegenerative diseases. PMID:26847610

  10. Naringin ameliorates cognitive deficits via oxidative stress, proinflammatory factors and the PPARγ signaling pathway in a type 2 diabetic rat model.

    PubMed

    Qi, Zhonghua; Xu, Yinghui; Liang, Zhanhua; Li, Sheng; Wang, Jie; Wei, Yi; Dong, Bin

    2015-11-01

    Naringenin is a flavonoid polyphenolic compound, which facilitates the removal of free radicals, oxidative stress and inflammation. The present study aimed to obtain a better understanding of the effects of curcumin on the regulation of diabetes‑associated cognitive decline, and its underlying mechanisms. An experimental diabetes mellitus (DM) rat model was induced by streptozoticin (50 mg/kg). Following treatment with naringin (100 and 200 mg/kg) for 16 weeks, the body weight and blood glucose levels of the DM rats were measured. A morris water maze test was used to analyze the effects of naringin on the cognitive deficit of the DM rats. The levels of oxidative stress, proinflammatory factors, caspase‑3 and caspase‑9, and the protein expression of peroxisome proliferator‑activated receptor γ (PPARγ) were quantified in the DM rats using a commercially‑available kit and western blot assay, respectively. In addition, a GW9662 PPARγ inhibitor (0.3 mg/kg) was administered to the DM rats to determine whether PPARγ affected the effects of naringin on the cognitive deficit of the DM rats. The results demonstrated that naringin increased the body weight, blood glucose levels, and cognitive deficits of the DM rats. The levels of oxidative stress and proinflammatory factors in the naringin‑treated rats were significantly lower, compared with those of the DM rats. In addition, naringin activated the protein expression of PPARγ, and administration of the PPARγ inhibitor decreased the protein expression of PPARγ, and attenuated the effects of naringin on cognitive deficit. The results also demonstrated that naringin decreased the expression levels of caspase‑3 and caspase‑9 in the DM rats. These results suggested that naringin ameliorated cognitive deficits via oxidative stress, proinflammatory factors and the PPARγ signaling pathway in the type 2 diabetic rat model. Furthermore, oxidative stress, proinflammatory factors and PPARγ signaling may be

  11. Long-term exposure to ELF-MF ameliorates cognitive deficits and attenuates tau hyperphosphorylation in 3xTg AD mice.

    PubMed

    Hu, Yu; Lai, Jinsheng; Wan, Baoquan; Liu, Xingfa; Zhang, Yemao; Zhang, Jiangong; Sun, Dongsheng; Ruan, Guoran; Liu, Enjie; Liu, Gong-Ping; Chen, Chen; Wang, Dao Wen

    2016-03-01

    Although numerous studies have reported the influence of extremely low frequency magnetic field (ELF-MF) exposure on human health, its effects on cognitive deficits in Alzheimer's disease (AD) have remained under debate. Moreover, the influence of ELF-MF on hyperphosphorylated tau, which is one of the most common pathological hallmarks of AD, has not been reported to date. Therefore, transgenic mice (3xTg) were used in the present study. 3xTg mice, which express an APP/PS1 mutation combined with a tau (P301L) mutation and that develop cognitive deficits at 6 months of age, were subjected to ELF-MF (50Hz, 500μT) exposure or sham exposure daily for 3 months. We discovered that ELF-MF exposure ameliorated cognitive deficits and increased synaptic proteins in 3xTg mice. The protective effects of ELF-MF exposure may have also been caused by the inhibition of apoptosis and/or decreased oxidative stress levels that were observed in the hippocampus tissues of treated mice. Furthermore, tau hyperphosphorylation was decreased in vivo because of ELF-MF exposure, and this decrease was induced by the inhibition of GSK3β and CDK5 activities and activation of PP2Ac. We are the first to report that exposure to ELF-MF can attenuate tau phosphorylation. These findings suggest that ELF-MF exposure could act as a valid therapeutic strategy for ameliorating cognitive deficits and attenuating tau hyperphosphorylation in AD. PMID:26945731

  12. Salidroside ameliorates arthritis-induced brain cognition deficits by regulating Rho/ROCK/NF-κB pathway.

    PubMed

    Zhu, Lingpeng; Chen, Tong; Chang, Xiayun; Zhou, Rui; Luo, Fen; Liu, Jingyan; Zhang, Kai; Wang, Yue; Yang, Ying; Long, Hongyan; Liu, Yu; Yan, Tianhua; Ma, Chunhua

    2016-04-01

    The prevalence of cognitive impairment in rheumatoid arthritis (RA) patients was increasingly serious nowadays. The purpose of the current study was to explore whether salidroside (Sal) could alleviate arthritis-induced cognition deficits and examine the relationship between the impairment and Rho/ROCK/NF-κB pathway. Collagen-induced arthritis (CIA) was established by the injection of chicken type II collagen (CII), complete Freund's adjuvant (CFA) and incomplete Freund's adjuvant (IFA). Arthritic lesions of CIA rats were assessed by arthritis index score, swelling of paws and histological analysis. Cognitive deficits symptoms of CIA rats were monitored through Morris water maze test. The contents of pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β) and interleukin-6 (IL-6) in hippocampus and serum were significantly reduced with salidroside (20 mg/kg, 40 mg/kg) treatment compared with those in the CIA group. In parallel, we demonstrated that the expressions of RhoA, ROCK1, ROCK2, p-NF-κBp65, p-IκBα, p-IKKα and p-IKKβ were enhanced accompanying the investigation arthritis-induced cognition deficits, which were remarkably down-regulated by salidroside and confirmed by the results obtained from western blot and immunohistochemistry. LC-MS/MS results ascertained that Sal could enter into the blood and brain tissues to exhibit the protective effect on arthritis-induced cognitive dysfunction. Therefore, it was assumed that Sal might be a potential therapeutic candidate to treat arthritis-induced brain cognition deficits through the regulation of Rho/ROCK/NF-κB signaling. PMID:26690894

  13. Guanfacine ameliorates hypobaric hypoxia induced spatial working memory deficits.

    PubMed

    Kauser, H; Sahu, S; Kumar, S; Panjwani, U

    2014-01-17

    Hypobaric hypoxia (HH) observed at high altitude causes mild cognitive impairment specifically affecting attention and working memory. Adrenergic dysregulation and neuronal damage in prefrontal cortex (PFC) has been implicated in hypoxia induced memory deficits. Optimal stimulation of alpha 2A adrenergic receptor in PFC facilitates the spatial working memory (SWM) under the conditions of adrenergic dysregulation. Therefore the present study was designed to test the efficacy of alpha 2A adrenergic agonist, Guanfacine (GFC), to restore HH induced SWM deficits and PFC neuronal damage. The rats were exposed to chronic HH equivalent to 25,000ft for 7days in an animal decompression chamber and received daily treatment of GFC at a dose of 1mg/kg body weight via the intramuscular route during the period of exposure. The cognitive performance was assessed by Delayed Alternation Task (DAT) using T-Maze and PFC neuronal damage was studied by apoptotic and neurodegenerative markers. Percentage of correct choice decreased significantly while perseverative errors showed a significant increase after 7days HH exposure, GFC significantly ameliorated the SWM deficits and perseveration. There was a marked and significant increase in chromatin condensation, DNA fragmentation, neuronal pyknosis and fluoro Jade positive cells in layer II of the medial PFC in hypoxia exposed group, administration of GFC significantly reduced the magnitude of these changes. Modulation of adrenergic mechanisms by GFC may serve as an effective countermeasure in amelioration of prefrontal deficits and neurodegenerative changes during HH. PMID:24184415

  14. Acetylcholinesterase inhibition ameliorates deficits in motivational drive

    PubMed Central

    2012-01-01

    Background Apathy is frequently observed in numerous neurological disorders, including Alzheimer's and Parkinson's, as well as neuropsychiatric disorders including schizophrenia. Apathy is defined as a lack of motivation characterized by diminished goal-oriented behavior and self-initiated activity. This study evaluated a chronic restraint stress (CRS) protocol in modeling apathetic behavior, and determined whether administration of an anticholinesterase had utility in attenuating CRS-induced phenotypes. Methods We assessed behavior as well as regional neuronal activity patterns using FosB immunohistochemistry after exposure to CRS for 6 h/d for a minimum of 21 d. Based on our FosB findings and recent clinical trials, we administered an anticholinesterase to evaluate attenuation of CRS-induced phenotypes. Results CRS resulted in behaviors that reflect motivational loss and diminished emotional responsiveness. CRS-exposed mice showed differences in FosB accumulation, including changes in the cholinergic basal forebrain system. Facilitating cholinergic signaling ameliorated CRS-induced deficits in initiation and motivational drive and rescued immediate early gene activation in the medial septum and nucleus accumbens. Conclusions Some CRS protocols may be useful for studying deficits in motivation and apathetic behavior. Amelioration of CRS-induced behaviors with an anticholinesterase supports a role for the cholinergic system in remediation of deficits in motivational drive. PMID:22433906

  15. Yam (Dioscorea pseudojaponica Yamamoto) ameliorates cognition deficit and attenuates oxidative damage in senescent mice induced by D-galactose.

    PubMed

    Chiu, Chuan-Sung; Deng, Jeng-Shyan; Hsieh, Ming-Tsuen; Fan, Ming-Jen; Lee, Min-Min; Chueh, Fu-Shin; Han, Chien-Kuo; Lin, Ying-Chih; Peng, Wen-Huang

    2009-01-01

    This study attempted to access the neuroprotective effect of yam (Dioscorea pseudojaponica Yamamoto) on the senescent mice induced by D-gal. The mice in the experiments were administered orally with yam (20, 100 or 500 mg/kg for 4 weeks, from the sixth week). The learning and memory abilities of the mice in Morris water maze test and the mechanisms involved in the neuroprotective effect of yam on the mice brain tissue were investigated. The content of diosgenin in the yam was also detected by using HPLC. Mice treated with yam were found to significantly improve their learning and memory abilities in Morris water maze test compared to those treated with D-gal (200 mg/kg for 10 weeks). In addition, yam was also found to increase the activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx) and decrease the malondialdehyde (MDA) level on the brains of D-gal treated mice. Finally, the amount of diosgenin in the yam was 5.49 mg/g extract. To sum up, these results indicate that yam had the potential to be a useful treatment for cognitive impairment in TCM. Its beneficial effect may be partly mediated via enhancing endogenous antioxidant enzymatic activities. PMID:19885949

  16. Quercetin ameliorates ischemia/reperfusion-induced cognitive deficits by inhibiting ASK1/JNK3/caspase-3 by enhancing the Akt signaling pathway.

    PubMed

    Pei, Bing; Yang, Miaomiao; Qi, Xiaoyan; Shen, Xin; Chen, Xing; Zhang, Fayong

    2016-09-01

    Cerebral ischemia/reperfusion (I/R) is a major cause of severe disability and death all worldwide. However, therapeutic options to minimize the detrimental effects of cerebral I/R injury are limited. Recent research has demonstrated that quercetin mediates neuroprotective effects associated with the activation of the Akt signaling pathway in the cerebral I/R brain. Therefore, the aim of this study was to further investigate the mechanisms of cognitive deficits induced by cerebral I/R injury and the effects of quercetin on these mechanisms. First, we assessed anxiety-like behavioral and cognitive impairment using the open field test and the Morris water maze test, respectively. Next, we examined the severity of apoptosis by staining hippocampal neurons by the Cresyl violet method. Third, we used western blot analysis to investigate the expression of total and phosphorylated Akt, ASK1, JNK3, c-Jun and caspase-3 after I/R injury. Our results revealed that mice subjected to bilateral common carotid occlusion exhibited severe anxiety-like behavior, learning and memory impairment, cell damage and apoptosis. These severe effects were attenuated by administration of quercetin. Further, western blot analysis revealed that quercetin increased p-Akt expression and decreased p-ASK1, p-JNK3 and cleaved caspase-3 expression after cerebral I/R injury and led to inhibition of neuronal apoptosis. Conversely, treatment with LY294002 (a selective inhibitor of Akt1) reversed the effects of quercetin. In conclusion, these findings highlight the important role of quercetin in protecting against cognitive deficits and inhibiting neuronal apoptosis via the Akt signaling pathway. We believe that quercetin might prove to be a useful therapeutic component in treating cerebral I/R diseases in the near future. PMID:27450812

  17. [Cognitive deficits in bipolar disorder].

    PubMed

    Sachs, Gabriele; Schaffer, Markus; Winklbaur, Bernadette

    2007-01-01

    Bipolar disorders are often associated with cognitive deficits which have an influence on social functioning and the course of the illness. These deficits have an impact on occupational ability and social integration. To date, specific cognitive domains have been found which characterize bipolar affective disorders. However, there is evidence of stable and lasting cognitive impairment in all phases of the disorder, including the remission phase, in the following domains: sustained attention, memory and executive functions (e.g. cognitive flexibility and problem solving). Although their cognitive deficits are comparable the deficits in patients with schizophrenia are more severe than those with bipolar disorder. Recent brain imaging findings indicate structural and functional abnormalities in the cortical and limbic networks of the brain in patients with bipolar disorder compared to healthy controls. Mood stabilizer and atypical antipsychotics may reduce cognitive deficits in certain domains (e.g. executive functions and word fluency) and may have a positive effect on quality of life and social functioning. PMID:17640495

  18. Selective PCAF inhibitor ameliorates cognitive and behavioral deficits by suppressing NF-κB-mediated neuroinflammation induced by Aβ in a model of Alzheimer's disease.

    PubMed

    Park, Soo-Yeon; Kim, Mi-Jeong; Kim, Young Jun; Lee, Yoo-Hyun; Bae, Donghyuk; Kim, Sunoh; Na, Younghwa; Yoon, Ho-Geun

    2015-04-01

    Several recent studies have reported an association between neurodegeneration and histone modifications, such as acetylation, deacetylation and methylation. In addition, questions have been raised regarding a potential functional role for the histone acetylation enzymes in β-amyloid (Aβ)-mediated neurotoxicity, particularly the p300/CBP-associated factor (PCAF) enzyme. We recently reported the potential utility of a PCAF inhibitor in the suppression of Aβ-induced neuronal cell death, although the in vivo effectiveness of the PCAF inhibitor remained unclear. In this study, we modified the PCAF inhibitor by chemical derivatization and selected compound C-30-27 as the most potent PCAF inhibitor. We demonstrated that C-30-27 selectively inhibited acetylation-dependent nuclear factor-κB (NF-κB) at Lys-122 and suppressed the NF-κB-mediated inflammatory response induced by lipopolysaccharide (LPS) or Aβ in both BV2 and Neuro-2A (N2A) cells. Finally, we demonstrated that C-30-27 improved cognitive deficits, as well as the capacity for locomotion and the damaged cholinergic system in the Aβ-treated rats. In conclusion, our results demonstrate that this selective PCAF inhibitor has the potential to reduce the neuroinflammatory response induced by Aβ. PMID:25672970

  19. Bushen-Yizhi formula ameliorates cognition deficits and attenuates oxidative stress-related neuronal apoptosis in scopolamine-induced senescence in mice

    PubMed Central

    HOU, XUE-QIN; WU, DIAN-WEI; ZHANG, CHUN-XIA; YAN, RONG; YANG, CONG; RONG, CUI-PING; ZHANG, LEI; CHANG, XIANG; SU, RU-YU; ZHANG, SHI-JIE; HE, WEN-QING; QU, ZHAO; LI, SHI; SU, ZI-REN; CHEN, YUN-BO; WANG, QI; FANG, SHU-HUAN

    2014-01-01

    Bushen-Yizhi formula (BSYZ), a traditional Chinese medicine formula consisting of six herbs has been reported to possess a neuroprotective effect. The present study aimed to investigate the effects of BSYZ on learning and memory abilities, as well as oxidative stress and neuronal apoptosis in the hippocampus of scopolamine (SCOP)-induced senescence in mice, in order to reveal whether BSYZ is a potential therapeutic agent for Alzheimer’s disease (AD). A high-performance liquid chromatography (HPLC) fingerprint was applied to provide a chemical profile of BSYZ. Extracts of BSYZ were orally administered to mice with SCOP-induced memory impairment for two weeks. The learning and memory abilities were determined by the Morris water maze test. The oxidant stress-related indices, such as activity of superoxide dismutase (SOD) and levels of glutathione (GSH) and malondialdehyde (MDA) were examined in hippocampus of SCOP-treated mice. The cell death ratio was assessed by TUNEL staining, while apoptotic-related proteins including Bcl-2 and Bax were determined by immunofluorescent staining and western blot analysis. Caspase-3 was determined by western blot analysis. Consequently, a chromatographic condition, which was conducted at 35°C with a flow rate of 0.8 ml/min on the Gemini C18 column with mobile phase of acetonitrile and water-phosphoric acid (100:0.1, v/v), was established to yield common fingerprint chromatography under 203 nm with a similarity index of 0.986 within 10 batches of BSYZ samples. BSYZ at a dose of 2.92 g/kg significantly improved the cognitive ability, restored the abnormal activity of SOD and increased the levels of MDA and GSH induced by SCOP. Moreover, the neural apoptosis in the hippocampus of SCOP-treated mice was reversed by BSYZ by regulating the expression of Bcl-2, Bax and caspase-3. The results demonstrated that BSYZ had neuroprotective effects in SCOP-induced senescence in mice by ameliorating oxidative stress and neuronal apoptosis in the

  20. Cholinesterase inhibitors ameliorate behavioral deficits induced by MK-801 in mice.

    PubMed

    Csernansky, John G; Martin, Maureen; Shah, Renu; Bertchume, Amy; Colvin, Jenny; Dong, Hongxin

    2005-12-01

    Enhancing cholinergic function has been suggested as a possible strategy for ameliorating the cognitive deficits of schizophrenia. The purpose of this study was to examine the effects of acetylcholinesterase (AChE) inhibitors in mice treated with the noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist, MK-801, which has been suggested as an animal model of the cognitive deficits of schizophrenia. Three separate experiments were conducted to test the effects of physostigmine, donepezil, or galantamine on deficits in learning and memory induced by MK-801. In each experiment, MK-801 (0.05 or 0.10 mg/kg) or saline was administered i.p. 20 min prior to behavioral testing over a total of 12 days. At 30 min prior to administration of MK-801 or saline, one of three doses of the AChE inhibitor (ie physostigmine-0.03, 0.10, or 0.30 mg/kg; donepezil-0.10, 0.30, or 1.00 mg/kg; or galantamine-0.25, 0.50, or 1.00 mg/kg) or saline was administered s.c. Behavioral testing was performed in all experimental animals using the following sequence: (1) spatial reversal learning, (2) locomotion, (3) fear conditioning, and (4) shock sensitivity. Both doses of MK-801 produced impairments in spatial reversal learning and in contextual and cued memory, as well as hyperlocomotion. Physostigmine and donepezil, but not galantamine, ameliorated MK-801-induced deficits in spatial reversal learning and in contextual and cued memory in a dose-dependent manner. Also, physostigmine, but not donepezil or galantamine, reversed MK-801-induced hyperlocomotion. Galantamine, but not physostigmine or donepezil, altered shock sensitivity. These results suggest that AChE inhibitors may differ in their capacity to ameliorate learning and memory deficits produced by MK-801 in mice, which may have relevance for the cognitive effects of cholinomimetic drugs in patients with schizophrenia. PMID:15956997

  1. Transthyretin stabilization by iododiflunisal promotes amyloid-β peptide clearance, decreases its deposition, and ameliorates cognitive deficits in an Alzheimer's disease mouse model.

    PubMed

    Ribeiro, Carlos A; Oliveira, Sandra Marisa; Guido, Luis F; Magalhães, Ana; Valencia, Gregorio; Arsequell, Gemma; Saraiva, Maria João; Cardoso, Isabel

    2014-01-01

    Alzheimer's disease (AD) is the most common form of dementia and now represents 50-70% of total dementia cases. Over the last two decades, transthyretin (TTR) has been associated with AD and, very recently, a novel concept of TTR stability has been established in vitro as a key factor in TTR/amyloid-β (Aβ) interaction. Small compounds, TTR stabilizers (usually non-steroid anti-inflammatory drugs), bind to the thyroxine (T4) central binding channel, increasing TTR tetrameric stability and TTR/Aβ interaction. In this work, we evaluated in vivo the effects of one of the TTR stabilizers identified as improving TTR/Aβ interaction, iododiflunisal (IDIF), in Aβ deposition and other AD features, using AβPPswe/PS1A246E transgenic mice, either carrying two or just one copy of the TTR gene (AD/TTR+/+ or AD/TTR+/-, respectively), available and characterized in our laboratory. The results showed that IDIF administered orally bound TTR in plasma and stabilized the protein, as assessed by T4 displacement assays, and was able to enter the brain as revealed by mass spectrometry analysis of cerebrospinal fluid. TTR levels, both in plasma and cerebrospinal fluid, were not altered. In AD/TTR+/- mice, IDIF administration resulted not only in decreased brain Aβ levels and deposition but also in improved cognitive function associated with the AD-like neuropathology in this mouse model, although no improvements were detectable in the AD/TTR+/+ animals. Further, in AD/TTR+/- mice, Aβ levels were reduced in plasma suggesting TTR promoted Aβ clearance from the brain and from the periphery. Taken together, these results strengthen the importance of TTR stability in the design of therapeutic drugs, highlighting the capacity of IDIF to be used in AD treatment to prevent and to slow the progression of the disease. PMID:24169237

  2. Cognitive deficits and functional outcome in schizophrenia

    PubMed Central

    Bowie, Christopher R; Harvey, Philip D

    2006-01-01

    Cognitive dysfunction is a core feature of schizophrenia. Deficits are moderate to severe across several domains, including attention, working memory, verbal learning and memory, and executive functions. These deficits pre-date the onset of frank psychosis and are stable throughout the course of the illness in most patients. Over the past decade, the focus on these deficits has increased dramatically with the recognition that they are consistently the best predictor of functional outcomes across outcome domains and patient samples. Recent treatment studies, both pharmacological and behavioral, suggest that cognitive deficits are malleable. Other research calls into question the meaningfulness of cognitive change in schizophrenia. In this article, we review cognitive deficits in schizophrenia and focus on their treatment and relationship to functional outcome. PMID:19412501

  3. Gastrodin Attenuates Cognitive Deficits Induced by 3,3'-Iminodipropionitrile.

    PubMed

    Wang, Xiaona; Li, Peng; Liu, Jingsheng; Jin, Xunbo; Li, Lianjun; Zhang, Dong; Sun, Peng

    2016-06-01

    3,3'-Iminodipropionitrile (IDPN), one of the nitrile derivatives, can induce persistent neurotoxicity, and therefore cause dyskinesia and cognitive impairments. Gastrodin, a main bioactive ingredient of Gastrodia elata Blume, is shown to greatly improve cognitive function. The aim of this study was to further determine whether administration of gastrodin can ameliorate IDPN-induced cognitive deficits in the Morris water maze (MWM) and novel object recognition (NOR) task, and to explore the underlying mechanisms. Results showed that exposure to IDPN (100 mg/kg/day, for 8 days) significantly impaired spatial and object recognition memory and that repeated treatment with gastrodin (150 mg/kg/day, for 6 weeks) could effectively alleviate the IDPN-induced cognitive impairments as indicated by increased spatial memory and discrimination ratio in the MWM and NOR tests. Gastrodin treatment also reverted IDPN-induced decreases of γ-aminobutyric acid (GABA) levels and increases of a2 GABAA receptor protein expression in the prefrontal cortex and hippocampus of IDPN-treated rats. These results suggest that gastrodin treatment may provide a novel pharmacological strategy for IDPN-induced cognitive deficits, which was mediated, at least in part, by normalizing the GABAergic system. PMID:26869041

  4. Effects of Stimulant Drugs on Attention and Cognitive Deficits.

    ERIC Educational Resources Information Center

    Gadow, Kenneth D.

    1981-01-01

    Research on the effects of stimulant drugs on attention and cognitive deficits in children with hyperactivity is reviewed. Topics covered include: attention and impulsivity, paired associate learning, school achievement, and drug induced attention and cognitive deficits. (CL)

  5. Oridonin ameliorates neuropathological changes and behavioural deficits in a mouse model of cerebral amyloidosis.

    PubMed

    Zhang, Zhi-Yuan; Daniels, Rolf; Schluesener, Hermann J

    2013-12-01

    Alzheimer's disease (AD) is the most common form of neurodegeneration and the major cause of dementia. This multifactorial disorder is clinically defined by progressive behavioural and cognitive deficits, and neuropathologically characterized by β-amyloid aggregation, hyperphosphorylated tau and neuroinflammation. Oridonin, a diterpenoid isolated from Chinese herb Rabdosia rubescens, has multiple biological properties, especially anti-inflammatory and neuroregulatory activities. Potential therapeutic effects of Oridonin were investigated in an animal model of cerebral amyloidosis for AD, transgenic APP/PS1 mice. Oridonin was suspended in carboxymethylcellulose or loaded with a nanostructured emulsion, and was orally administrated or injected. Before, during and following the experimental treatments, behavioural tests were performed with these transgenic mice and their naive littermates. Following relatively short-term treatments of 10 days, brain tissue of mice were removed for immunohistochemical assays. The results indicate that both oral treatment and injection of Oridonin significantly attenuated β-amyloid deposition, plaque-associated APP expression and microglial activation in brain of transgenic mice. Furthermore, injection of Oridonin-nanoemulsion ameliorated deficits in nesting, an important affiliative behaviour, and in social interaction. Additional in vitro studies indicated that Oridonin effectively attenuated inflammatory reaction of macrophage and microglial cell lines. Our results suggest that Oridonin might be considered a promising therapeutic option for human AD or other neurodegenerative diseases. PMID:24034629

  6. Nicotine ameliorates NMDA receptor antagonist-induced deficits in contextual fear conditioning through high-affinity nicotinic acetylcholine receptors in the hippocampus.

    PubMed

    André, Jessica M; Leach, Prescott T; Gould, Thomas J

    2011-03-01

    NMDA glutamate receptors (NMDARs) and nicotinic acetylcholine receptors (nAChRs) are both involved in learning and synaptic plasticity. Increasing evidence suggests processes mediated by these receptors may interact to modulate learning; however, little is known about the neural substrates involved in these interactive processes. The present studies investigated the effects of nicotine on MK-801 hydrogen maleate (MK-801) and DL-2-Amino-5-phosphonovaleric acid (APV)-induced disruption of contextual fear conditioning in male C57BL/6J mice, using direct drug infusion and selective nAChR antagonists to define the brain regions and the nAChR subtypes involved. Mice treated with MK-801 showed a deficit in contextual fear conditioning that was ameliorated by nicotine. Direct drug infusion demonstrated that the NMDAR antagonists disrupted hippocampal function and that nicotine acted in the dorsal hippocampus to ameliorate the deficit in learning. The high-affinity nAChR antagonist Dihydro-β-erythroidine hydrobromide (DhβE) blocked the effects of nicotine on MK-801-induced deficits while the α7 nAChR antagonist methyllycaconitine citrate salt hydrate (MLA) did not. These results suggest that NMDARs and nAChRs may mediate similar hippocampal processes involved in contextual fear conditioning. Furthermore, these results may have implications for developing effective therapeutics for the cognitive deficits associated with schizophrenia because a large subset of patients with schizophrenia exhibit cognitive deficits that may be related to NMDAR dysfunction and smoke at much higher rates than the healthy population, which may be an attempt to ameliorate cognitive deficits. PMID:21167848

  7. Characterization of Cognitive Deficits in Mice With an Alternating Hemiplegia-Linked Mutation

    PubMed Central

    2015-01-01

    Cognitive impairment is a prominent feature in a range of different movement disorders. Children with Alternating Hemiplegia of Childhood are prone to developmental delay, with deficits in cognitive functioning becoming progressively more evident as they grow older. Heterozygous mutations of the ATP1A3 gene, encoding the Na+,K+-ATPase α3 subunit, have been identified as the primary cause of Alternating Hemiplegia. Heterozygous Myshkin mice have an amino acid change (I810N) in Na+,K+-ATPase α3 that is also found in Alternating Hemiplegia. To investigate whether Myshkin mice exhibit learning and memory deficits resembling the cognitive impairments of patients with Alternating Hemiplegia, we subjected them to a range of behavioral tests that interrogate various cognitive domains. Myshkin mice showed impairments in spatial memory, spatial habituation, locomotor habituation, object recognition, social recognition, and trace fear conditioning, as well as in the visible platform version of the Morris water maze. Increasing the duration of training ameliorated the deficit in social recognition but not in spatial habituation. The deficits of Myshkin mice in all of the learning and memory tests used are consistent with the cognitive impairment of the vast majority of AHC patients. These mice could thus help advance our understanding of the underlying neural mechanisms influencing cognitive impairment in patients with ATP1A3-related disorders. PMID:26501181

  8. A Multiple Deficit Model of Reading Disability and Attention-Deficit/Hyperactivity Disorder: Searching for Shared Cognitive Deficits

    ERIC Educational Resources Information Center

    McGrath, Lauren M.; Pennington, Bruce F.; Shanahan, Michelle A.; Santerre-Lemmon, Laura E.; Barnard, Holly D.; Willcutt, Erik G.; DeFries, John C.; Olson, Richard K.

    2011-01-01

    Background: This study tests a multiple cognitive deficit model of reading disability (RD), attention-deficit/hyperactivity disorder (ADHD), and their comorbidity. Methods: A structural equation model (SEM) of multiple cognitive risk factors and symptom outcome variables was constructed. The model included phonological awareness as a unique…

  9. Should cognitive deficit be a diagnostic criterion for schizophrenia?

    PubMed Central

    Lewis, Ralph

    2004-01-01

    This review examines the question of whether cognitive deficits in schizophrenia are sufficiently reliable, stable and specific to warrant inclusion in the diagnostic criteria for schizophrenia. The literature provides evidence that cognitive deficits are highly prevalent and fairly marked in adult patients with schizophrenia. Similar deficits have been found in children and adolescents with schizophrenia, and in children before they exhibit the signs and symptoms of schizophrenia. These deficits may in fact be central to the pathophysiology underlying the development of overt psychosis in schizophrenia. The deficits appear to be relatively stable across the course of the illness. They are generally more severe in schizophrenia than in affective disorders and may have a relatively specific pattern in schizophrenia. It is concluded that the evidence that cognitive deficits are a core feature of schizophrenia is sufficiently compelling to warrant inclusion of these deficits in the diagnostic criteria for schizophrenia, at least as a nonessential criterion. PMID:15069464

  10. Amelioration of deficit syndrome of schizophrenia by norepinephrine reuptake inhibitor

    PubMed Central

    Shoja Shafti, Saeed; Jafarabad, Mohammad Sadeghe; Azizi, Reza

    2015-01-01

    Objective: Negative symptoms are a significant barrier to successful functional outcome and recovery in individuals with schizophrenia and their management is not unproblematic. Reboxetine is a norepinephrine reuptake inhibitor (NRI). Previous studies regarding the useful effects of reboxetine on deficit symptoms of schizophrenia have resulted in inconsistent results. The present study therefore evaluated the effectiveness of reboxetine as an adjunctive treatment in a group of schizophrenic patients with prominent negative symptoms. Method: A total of 50 male inpatients meeting diagnosis of schizophrenia entered into a 12-week parallel group, double-blind study for random assignment to reboxetine (n = 25 patients) or placebo (n = 25 patients). The inclusion criterion, in addition to the diagnosis of schizophrenia, was the existence of obvious negative symptoms for a duration of at least 2 years. The Scale for Assessment of Negative Symptoms (SANS) was used as the primary outcome measure. The Scale for Assessment of Positive Symptoms (SAPS), Simpson Angus Scale (SAS), Hamilton Rating Scale for Depression (HAM-D) and Mini-Mental Status Examination (MMSE) were used for comparison of the intervening parameters in this study. Results: According to the findings, 76% of patients in the target group showed some positive response to reboxetine compared with 24% in the control group (p < 0.01). The mean total score of SANS in the reboxetine group decreased significantly from 79.94 ± 1.20 to 74.23 ± 4.07 (p < 0.0001) at the end of the study; such an improvement was not significant in the placebo group with a decrease from 80.42 ± 2.46 to 79.08 ± 5.83 (p < 0.29). Changes of SAPS were insignificant in both groups. Effect size analysis for changes of SANS at the end of assessment indicated a large improvement with reboxetine (Cohen’s d = 2.91). Conclusion: Reboxetine, as an adjuvant to haloperidol, may have a helpful effect on the deficit syndrome of schizophrenia. PMID

  11. Diet-Induced Cognitive Deficits: The Role of Fat and Sugar, Potential Mechanisms and Nutritional Interventions

    PubMed Central

    Beilharz, Jessica E.; Maniam, Jayanthi; Morris, Margaret J.

    2015-01-01

    It is of vital importance to understand how the foods which are making us fat also act to impair cognition. In this review, we compare the effects of acute and chronic exposure to high-energy diets on cognition and examine the relative contributions of fat (saturated and polyunsaturated) and sugar to these deficits. Hippocampal-dependent memory appears to be particularly vulnerable to the effects of high-energy diets and these deficits can occur rapidly and prior to weight gain. More chronic diet exposure seems necessary however to impair other sorts of memory. Many potential mechanisms have been proposed to underlie diet-induced cognitive decline and we will focus on inflammation and the neurotrophic factor, brain-derived neurotrophic factor (BDNF). Finally, given supplementation of diets with omega-3 and curcumin has been shown to have positive effects on cognitive function in healthy ageing humans and in disease states, we will discuss how these nutritional interventions may attenuate diet-induced cognitive decline. We hope this approach will provide important insights into the causes of diet-induced cognitive deficits, and inform the development of novel therapeutics to prevent or ameliorate such memory impairments. PMID:26274972

  12. Mitochondria-Targeted Peptide Reverses Mitochondrial Dysfunction and Cognitive Deficits in Sepsis-Associated Encephalopathy.

    PubMed

    Wu, Jing; Zhang, Mingqiang; Hao, Shuangying; Jia, Ming; Ji, Muhuo; Qiu, Lili; Sun, Xiaoyan; Yang, Jianjun; Li, Kuanyu

    2015-08-01

    Sepsis-associated encephalopathy (SAE) is associated with increased mortality, morbidity, and long-term cognitive impairments. Its pathophysiology remains to be determined and an effective pharmacologic treatment is lacking. The goal of this study was to investigate the effects of the mitochondria-targeted peptide SS-31 on mitochondrial function and cognitive deficits in SAE mice. C57BL/6 male mice were randomly divided into sham, sham + SS-31, cecal ligation and puncture (CLP), and CLP + SS-31 groups. Peptide SS-31 (5 mg/kg) was intraperitoneally administrated immediately after operation and afterwards once daily for six consecutive days. Surviving mice were subjected to behavioral tests and the hippocampus was collected for biochemical analysis 7 days after operation. The results showed that CLP resulted in high mortality rate and cognitive deficits, representative characteristics of SAE. A physiological mechanistic investigation revealed that mitochondrial function of hippocampus was severely impaired, coupled with reactive oxygen species (ROS) generation, triggering neuronal apoptosis and inflammation. Notably, administration of peptide SS-31 protected the integrity of mitochondria, reversed the mitochondrial dysfunction, inhibited the apoptosis resulting from the release of cytochrome c, diminished the response of inflammation, and ultimately reversed the behavior deficits in the SAE mice. In conclusion, our data demonstrate that daily treatment with mitochondria-targeted peptide SS-31 reduces mortality rate and ameliorates cognitive deficits, which is possibly through a mechanism of reversing mitochondrial dysfunction and partial inhibition of neuronal apoptosis and inflammation in the hippocampus of the SAE mice. PMID:25288156

  13. Arctigenin isolated from the seeds of Arctium lappa ameliorates memory deficits in mice.

    PubMed

    Lee, In-Ah; Joh, Eun-Ha; Kim, Dong-Hyun

    2011-09-01

    The seeds of Arctium lappa L. (AL, family Asteraceae), the main constituents of which are arctiin and arctigenin, have been used as an herbal medicine or functional food to treat inflammatory diseases. These main constituents were shown to inhibit acetylcholinesterase (AChE) activity. Arctigenin more potently inhibited AChE activity than arctiin. Arctigenin at doses of 30 and 60 mg/kg (p. o.) potently reversed scopolamine-induced memory deficits by 62 % and 73 %, respectively, in a passive avoidance test. This finding is comparable with that of tacrine (10 mg/kg p. o.). Arctigenin also significantly reversed scopolamine-induced memory deficits in the Y-maze and Morris water maze tests. On the basis of these findings, arctigenin may ameliorate memory deficits by inhibiting AChE. PMID:21308615

  14. Chronic oleoylethanolamide treatment improves spatial cognitive deficits through enhancing hippocampal neurogenesis after transient focal cerebral ischemia.

    PubMed

    Yang, Li-Chao; Guo, Han; Zhou, Hao; Suo, Da-Qin; Li, Wen-Jun; Zhou, Yu; Zhao, Yun; Yang, Wu-Shuang; Jin, Xin

    2015-04-15

    Oleoylethanolamide (OEA) has been shown to have neuroprotective effects after acute cerebral ischemic injury. The aim of this study was to investigate the effects of chronic OEA treatment on ischemia-induced spatial cognitive impairments, electrophysiology behavior and hippocampal neurogenesis. Daily treatments of 30 mg/kg OEA significantly ameliorated spatial cognitive deficits and attenuated the inhibition of long-term potentiation (LTP) in the middle cerebral artery occlusion (MCAO) rat model. Moreover, OEA administration improved cognitive function in a manner associated with enhanced neurogenesis in the hippocampus. Further study demonstrated that treatment with OEA markedly increased the expressions of brain-derived neurotrophic factor (BDNF) and peroxisome proliferator-activated receptors α (PPARα). Our data suggest that chronic OEA treatment can exert functional recovery of cognitive impairments and neuroprotective effects against cerebral ischemic insult in rats via triggering of neurogenesis in the hippocampus, which supports the therapeutic use of OEA for cerebral ischemia. PMID:25748831

  15. Common Cognitive Deficits in Children with Attention-Deficit/Hyperactivity Disorder and Autism: Working Memory and Visual-Motor Integration

    ERIC Educational Resources Information Center

    Englund, Julia A.; Decker, Scott L.; Allen, Ryan A.; Roberts, Alycia M.

    2014-01-01

    Cognitive deficits in working memory (WM) are characteristic features of Attention-Deficit/Hyperactivity Disorder (ADHD) and autism. However, few studies have investigated cognitive deficits using a wide range of cognitive measures. We compared children with ADHD ("n" = 49) and autism ("n" = 33) with a demographically matched…

  16. GLYX-13 (rapastinel) ameliorates subchronic phencyclidine- and ketamine-induced declarative memory deficits in mice

    PubMed Central

    Rajagopal, Lakshmi; Burgdorf, Jeffrey S.; Moskal, Joseph R.; Meltzer, Herbert Y.

    2016-01-01

    GLYX-13 (rapastinel), a tetrapeptide (Thr-Pro-Pro-Thr-amide), has been reported to have fast acting antidepressant properties in man based upon its N-methyl-d-aspartate receptor (NMDAR) glycine site functional partial agonism. Ketamine, a non-competitive NMDAR antagonist, also reported to have fast acting antidepressant properties, produces cognitive impairment in rodents and man, whereas rapastinel has been reported to have cognitive enhancing properties in rodents, without impairing cognition in man, albeit clinical testing has been limited. The goal of this study was to compare the cognitive impairing effects of rapastinel and ketamine in novel object recognition (NOR), a measure of declarative memory, in male C57BL/6J mice treated with phencyclidine (PCP), another NMDAR noncompetitive antagonist known to severely impair cognition, in both rodents and man. C57BL/6J mice given a single dose or subchronic ketamine (30 mg/kg. i.p.) showed acute or persistent deficits in NOR, respectively. Acute i.v. rapastinel (1.0 mg/kg), did not induce NOR deficit. Pre-treatment with rapastinel significantly prevented acute ketamine-induced NOR deficit. Rapastinel (1.0 mg/kg, but not 0.3 mg/kg, iv) significantly reversed both subchronic ketamine- and subchronic PCP-induced NOR deficits. Rapastinel also potentiated the atypical antipsychotic drug with antidepressant properties, lurasidone, to restore NOR in subchronic ketamine-treated mice. These findings indicate that rapastinel, unlike ketamine, does not induce a declarative memory deficit in mice, and can prevent or reverse the ketamine-induced NOR deficit. Further study is required to determine if these differences translate during clinical use of ketamine and rapastinel as fast acting antidepressant drugs and if rapastinel could have non-ionotropic effects as an add-on therapy with antipsychotic/antidepressant medications. PMID:26632337

  17. Oculomotor Performance Identifies Underlying Cognitive Deficits in Attention-Deficit/Hyperactivity Disorder

    ERIC Educational Resources Information Center

    Loe, Irene M.; Feldman, Heidi M.; Yasui, Enami; Luna, Beatriz

    2009-01-01

    The evaluation of the cognitive control in children with attention-deficit hyperactivity disorder through the use of oculomotor tests reveal that this group showed susceptibility to peripheral distractors and deficits in response inhibition. All subjects were found to have intact sensorimotor function and working memory.

  18. Cognitive Mapping Deficits in Schizophrenia: A Critical Overview

    PubMed Central

    Bose, Anushree; Agarwal, Sri Mahavir; Kalmady, Sunil V.; Venkatasubramanian, Ganesan

    2014-01-01

    Hippocampal deficits are an established feature of schizophrenia and are complementary with recent evidences of marked allocentric processing deficits being reported in this disorder. By “Cognitive mapping” we intend to refer to the concepts from the seminal works of O’Keefe and Nadel (1978) that led to the development of cognitive map theory of hippocampal function. In this review, we summarize emerging evidences and issues that indicate that “Cognitive mapping deficits” form one of the important cognitive aberrations in schizophrenia. The importance has been placed upon hippocampally mediated allocentric processing deficits and their role in pathology of schizophrenia, for spatial/representational cognitive deficits and positive symptoms in particular. It is modestly summarized that emerging evidences point toward a web of spatial and cognitive representation errors concurrent with pronounced hippocampal dysfunction. In general, it can be stated that there are clear and consistent evidences that favor the cognitive mapping theory in explaining certain deficits of schizophrenia and for drawing out a possible and promising endophenotype/biomarkers. Further research in this regard demands attention. PMID:24701005

  19. Cognitive control in alcohol use disorder: deficits and clinical relevance

    PubMed Central

    Wilcox, Claire E.; Dekonenko, Charlene J.; Mayer, Andrew R.; Bogenschutz, Michael P.; Turner, Jessica A.

    2014-01-01

    Cognitive control refers to the internal representation, maintenance, and updating of context information in the service of exerting control over thoughts and behavior. Deficits in cognitive control likely contribute to difficulty in maintaining abstinence in individuals with alcohol use disorders (AUD). In this article, we define three cognitive control processes in detail (response inhibition, distractor interference control, and working memory), review the tasks measuring performance in these areas, and summarize the brain networks involved in carrying out these processes. Next, we review evidence of deficits in these processes in AUD, including both metrics of task performance and functional neuroimaging. Finally, we explore the clinical relevance of these deficits by identifying predictors of clinical outcome and markers that appear to change (improve) with treatment. We observe that individuals with AUD experience deficits in some, but not all, metrics of cognitive control. Deficits in cognitive control may predict clinical outcome in AUD, but more work is necessary to replicate findings. It is likely that performance on tasks requiring cognitive control improves with abstinence, and with some psychosocial and medication treatments. Future work should clarify which aspects of cognitive control are most important to target during treatment of AUD. PMID:24361772

  20. The smallest stroke: Occlusion of one penetrating vessel leads to infarction and a cognitive deficit

    PubMed Central

    Shih, Andy Y.; Blinder, Pablo; Tsai, Philbert S.; Friedman, Beth; Stanley, Geoffrey; Lyden, Patrick D.; Kleinfeld, David

    2014-01-01

    Microinfarctions are present in the aged and injured human brain. Their clinical significance is controversial, with postulated sequelae ranging from cognitive sparing to vascular dementia. To address the consequences of microinfarcts, we used controlled optical methods to create occlusions of individual penetrating arterioles or venules within rat cortex. Single microinfarcts, targeted to encompass all or part of a cortical column, impaired performance in a macrovibrissa-based behavioral task. Further, multiple targeted vessels caused tissue damage that coalesced across cortex, even though the intervening penetrating vessels were acutely patent. Post-occlusion administration of Memantine, a glutamate receptor antagonist that reduces cognitive decline in Alzheimer’s disease, ameliorated tissue damage and perceptual deficits. Collectively, these data imply that microinfarcts are likely contributors to cognitive decline. Strategies that have received limited success in the treatment of ischemic injury, which include therapeutics against excitotoxicity, may be successful against the progressive nature of vascular dementia. PMID:23242312

  1. Premorbid Cognitive Deficits in Young Relatives of Schizophrenia Patients

    PubMed Central

    Keshavan, Matcheri S.; Kulkarni, Shreedhar; Bhojraj, Tejas; Francis, Alan; Diwadkar, Vaibhav; Montrose, Debra M.; Seidman, Larry J.; Sweeney, John

    2009-01-01

    Neurocognitive deficits in schizophrenia (SZ) are thought to be stable trait markers that predate the illness and manifest in relatives of patients. Adolescence is the age of maximum vulnerability to the onset of SZ and may be an opportune “window” to observe neurocognitive impairments close to but prior to the onset of psychosis. We reviewed the extant studies assessing neurocognitive deficits in young relatives at high risk (HR) for SZ and their relation to brain structural alterations. We also provide some additional data pertaining to the relation of these deficits to psychopathology and brain structural alterations from the Pittsburgh Risk Evaluation Program (PREP). Cognitive deficits are noted in the HR population, which are more severe in first-degree relatives compared to second-degree relatives and primarily involve psychomotor speed, memory, attention, reasoning, and social-cognition. Reduced general intelligence is also noted, although its relationship to these specific domains is underexplored. Premorbid cognitive deficits may be related to brain structural and functional abnormalities, underlining the neurobiological basis of this illness. Cognitive impairments might predict later emergence of psychopathology in at-risk subjects and may be targets of early remediation and preventive strategies. Although evidence for neurocognitive deficits in young relatives abounds, further studies on their structural underpinnings and on their candidate status as endophenotypes are needed. PMID:20300465

  2. [Differentiation of deficit and non-deficit schizophrenia based on cognitive functions].

    PubMed

    Polgár, Patrícia

    2011-03-30

    Cognitive dysfunction is a core feature in schizophrenia and has a great impact on psychosocial functioning. Still it remains unclear, whether the different diagnostic subgroups have a specific cognitive profile. The topic of this research was to investigate the neurocognitive characteristics of deficit and non-deficit schizophrenia, and to examine if the two diagnostic subgroups have a qualitative difference in cognitive functioning. In Study 1., 275 patient and 130 healthy controls completed the WCST (Wisconsin Card Sorting Test). We performed an exploratory factor analytic study on the variables for the total group and each subgroups, then we assessed the ability of the factors to distinguish between the deficit, non deficit and control groups. In Study 2., I used the Kilroy-test to investigate procedural and context-dependent learning. 78 patients and 30 healthy controls completed the test, which has two phases: while the training phase is dominantly related to basal ganglia circuits, the context-dependent probe phase requires intact medial-temporal lobe functioning. Thus the two interactive memory systems can be examined separately within one test. Study 1.: Results of the exploratory factor analysis of the whole sample yielded two factors which together explained approximately 95% of the total variance. Comparison of the diagnostic groups on each of the factors revealed that both schizophrenia groups showed executive function impairment in comparison to controls. Deficit patients suffer from a more severe degree of impairment on the "General executive function" factor (conceptualization, flexibility, set shifting) than non-deficit patients. On the other hand, non-perseverative error type (factor 2.) seems to be less typical to deficit than to the non-deficit patients. Study 2.: Results revealed that deficit and non-deficit patients were similarly impaired on the probe phase compared with controls. However, the training phase was not compromised in non-deficit

  3. Japanese Huperzia serrata extract and the constituent, huperzine A, ameliorate the scopolamine-induced cognitive impairment in mice.

    PubMed

    Ohba, Takuya; Yoshino, Yuta; Ishisaka, Mitsue; Abe, Naohito; Tsuruma, Kazuhiro; Shimazawa, Masamitsu; Oyama, Masayoshi; Tabira, Takeshi; Hara, Hideaki

    2015-01-01

    Huperzia serrata has been used as a Chinese folk medicine for many years. It contains huperzine A, which has a protective effect against memory deficits in animal models; however, it is unclear if H. serrata extract exerts any effects in Alzheimer's disease (AD) models. We used H. serrata collected in Japan and determined its huperzine A content using HPLC. We determined its inhibitory effects on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activity. H. serrata extract (30 mg/kg/day) and donepezil (10 mg/kg/day) were orally administrated for 7 days. After repeated administration, we performed the Y-maze and passive avoidance tests. H. serrata extract contained 0.5% huperzine A; H. serrata extract inhibited AChE, but not BuChE. H. serrata extract ameliorated cognitive function in mice. These results indicate that Japanese H. serrata extract ameliorates cognitive function deficits by inhibiting AChE. Therefore, H. serrata extract may be valuable for the prevention or treatment of dementia in AD. PMID:26059088

  4. N-Acetylcysteine improves mitochondrial function and ameliorates behavioral deficits in the R6/1 mouse model of Huntington's disease

    PubMed Central

    Wright, D J; Renoir, T; Smith, Z M; Frazier, A E; Francis, P S; Thorburn, D R; McGee, S L; Hannan, A J; Gray, L J

    2015-01-01

    Huntington's disease (HD) is a neurodegenerative disorder, involving psychiatric, cognitive and motor symptoms, caused by a CAG-repeat expansion encoding an extended polyglutamine tract in the huntingtin protein. Oxidative stress and excitotoxicity have previously been implicated in the pathogenesis of HD. We hypothesized that N-acetylcysteine (NAC) may reduce both excitotoxicity and oxidative stress through its actions on glutamate reuptake and antioxidant capacity. The R6/1 transgenic mouse model of HD was used to investigate the effects of NAC on HD pathology. It was found that chronic NAC administration delayed the onset and progression of motor deficits in R6/1 mice, while having an antidepressant-like effect on both R6/1 and wild-type mice. A deficit in the astrocytic glutamate transporter protein, GLT-1, was found in R6/1 mice. However, this deficit was not ameliorated by NAC, implying that the therapeutic effect of NAC is not due to rescue of the GLT-1 deficit and associated glutamate-induced excitotoxicity. Assessment of mitochondrial function in the striatum and cortex revealed that R6/1 mice show reduced mitochondrial respiratory capacity specific to the striatum. This deficit was rescued by chronic treatment with NAC. There was a selective increase in markers of oxidative damage in mitochondria, which was rescued by NAC. In conclusion, NAC is able to delay the onset of motor deficits in the R6/1 model of Huntington's disease and it may do so by ameliorating mitochondrial dysfunction. Thus, NAC shows promise as a potential therapeutic agent in HD. Furthermore, our data suggest that NAC may also have broader antidepressant efficacy. PMID:25562842

  5. Speech deficits in serious mental illness: a cognitive resource issue?

    PubMed

    Cohen, Alex S; McGovern, Jessica E; Dinzeo, Thomas J; Covington, Michael A

    2014-12-01

    Speech deficits, notably those involved in psychomotor retardation, blunted affect, alogia and poverty of content of speech, are pronounced in a wide range of serious mental illnesses (e.g., schizophrenia, unipolar depression, bipolar disorders). The present project evaluated the degree to which these deficits manifest as a function of cognitive resource limitations. We examined natural speech from 52 patients meeting criteria for serious mental illnesses (i.e., severe functional deficits with a concomitant diagnosis of schizophrenia, unipolar and/or bipolar affective disorders) and 30 non-psychiatric controls using a range of objective, computer-based measures tapping speech production ("alogia"), variability ("blunted vocal affect") and content ("poverty of content of speech"). Subjects produced natural speech during a baseline condition and while engaging in an experimentally-manipulated cognitively-effortful task. For correlational analysis, cognitive ability was measured using a standardized battery. Generally speaking, speech deficits did not differ as a function of SMI diagnosis. However, every speech production and content measure was significantly abnormal in SMI versus control groups. Speech variability measures generally did not differ between groups. For both patients and controls as a group, speech during the cognitively-effortful task was sparser and less rich in content. Relative to controls, patients were abnormal under cognitive load with respect only to average pause length. Correlations between the speech variables and cognitive ability were only significant for this same variable: average pause length. Results suggest that certain speech deficits, notably involving pause length, may manifest as a function of cognitive resource limitations. Implications for treatment, research and assessment are discussed. PMID:25464920

  6. Speech Deficits in Serious mental Illness: A Cognitive Resource Issue?

    PubMed Central

    Cohen, Alex S.; McGovern, Jessica E.; Dinzeo, Thomas J.; Covington, Michael A.

    2014-01-01

    Speech deficits, notably those involved in psychomotor retardation, blunted affect, alogia and poverty of content of speech, are pronounced in a wide range of serious mental illnesses (e.g., schizophrenia, unipolar depression, bipolar disorders). The present project evaluated the degree to which these deficits manifest as a function of cognitive resource limitations. We examined natural speech from 52 patients meeting criteria for serious mental illnesses (i.e., severe functional deficits with a concomitant diagnosis of schizophrenia, unipolar and/or bipolar affective disorders) and 30 non-psychiatric controls using a range of objective, computer-based measures tapping speech production (“alogia”), variability (“blunted vocal affect”) and content (“poverty of content of speech”). Subjects produced natural speech during a baseline condition and while engaging in an experimentally-manipulated cognitively-effortful task. For correlational analysis, cognitive ability was measured using a standardized battery. Generally speaking, speech deficits did not differ as a function of SMI diagnosis. However, every speech production and content measure was significantly abnormal in SMI versus control groups. Speech variability measures generally did not differ between groups. For both patients and controls as a group, speech during the cognitively-effortful task was sparser and less rich in content. Relative to controls, patients were abnormal under cognitive load with respect only to average pause length. Correlations between the speech variables and cognitive ability were only significant for this same variable: average pause length. Results suggest that certain speech deficits, notably involving pause length, may manifest as a function of cognitive resource limitations. Implications for treatment, research and assessment are discussed. PMID:25464920

  7. LXR agonist treatment ameliorates amyloid pathology and memory deficits caused by high fat diet in APP23 mice

    PubMed Central

    Fitz, Nicholas F.; Cronican, Andrea; Pham, Tam; Fogg, Allison; Fauq, Abdul H.; Chapman, Robert; Lefterov, Iliya; Koldamova, Radosveta

    2010-01-01

    High fat diet and certain dietary patterns are associated with higher incidence of sporadic Alzheimer’s disease (AD) and cognitive decline. However, no specific therapy has been suggested to ameliorate the negative effects of high fat/high cholesterol levels on cognition and amyloid pathology. Here we show that in 9 month old APP23 mice, a high fat/high cholesterol (HF) diet provided for 4 months exacerbates the AD phenotype evaluated by behavioral, morphological and biochemical assays. To examine the therapeutic potential of Liver X Receptor (LXR) ligands, APP23 mice were fed HF diet supplemented with synthetic LXR agonist T0901317 (T0). Our results demonstrate that LXR ligand treatment causes a significant reduction of memory deficits observed during both acquisition and retention phases of the Morris Water Maze. Moreover, the effects of T0 on cognition correlate with AD-like morphological and biochemical parameters. We found a significant decrease in amyloid plaque load, insoluble Aβ and soluble Aβ oligomers. In vitro experiments with primary glia demonstrated that Abca1 is essential for the proper lipidation of ApoE and mediates the effects of T0 on Aβ degradation by microglia. Microdialysis experiments performed on awake freely moving mice showed that T0 decreased Aβ level in the interstitial fluid of the hippocampus, supporting the conclusion that this treatment increases Aβ clearance. The data presented conclusively shows that LXR activation in the context of a metabolic challenge has critical effects on AD phenotype progression by attenuating Aβ deposition and facilitating its clearance. PMID:20484628

  8. [Neurocognitive and social cognition deficits in patients with anorexia nervosa].

    PubMed

    Kułakowska, Dorota; Biernacka, Katarzyna; Wilkos, Ewelina; Rybakowski, Filip; Kucharska-Pietura, Katarzyna

    2014-01-01

    In the first part of the article the authors present a set of the actual concepts explaining problems of cognitive functions and social cognition currently observed in patients with anorexia nervosa (AN). It is possible; through the neuroimaging research, to get better understanding of the brain specifics in these individuals. Even though, the AN remains a disease with very complex and multifactorial etiology which remains a huge medical challenge. Currently, popular is the view that takes into consideration the integrating role of the insula and subcortical structures (such as hippocampus, amygdala, thalamus) in the regulation of cognitive and emotional processes in people suffering from AN. There is still an open problem, however, of the selection of therapeutic interventions targeting these deficits. The second part of the article presents the attempt to describe deficits in neurocognitive and social cognition in people with AN occurring prior to illness, during and after the recovery. Particular attention has been paid to the most frequently described in the literature--neurocognitive deficits such as rigidity of thinking, weak central coherence, and deficits in social cognition, including mental processes of perception and expression of emotions, disorders of the theory of mind (ToM) and empathy. The results of previous studies, their scarcity in Poland, do not give a satisfactory answer to the question whether the above mentioned disorders are a feature of endophenotype or condition in an episode of the disease. Research point to the more permanent nature, which may be more resistant to therapeutic modifications. PMID:25204093

  9. The molecular basis of cognitive deficits in pervasive developmental disorders

    PubMed Central

    Bhattacharya, Aditi; Klann, Eric

    2012-01-01

    Persons with pervasive developmental disorders (PDD) exhibit a range of cognitive deficits that hamper their quality of life, including difficulties involving communication, sociability, and perspective-taking. In recent years, a variety of studies in mice that model genetic syndromes with a high risk of PDD have provided insights into the underlying molecular mechanisms associated with these disorders. What is less appreciated is how the molecular anomalies affect neuronal and circuit function to give rise to the cognitive deficits associated with PDD. In this review, we describe genetic mutations that cause PDD and discuss how they alter fundamental social and cognitive processes. We then describe efforts to correct cognitive impairments associated with these disorders and identify areas of further inquiry in the search for molecular targets for therapeutics for PDD. PMID:22904374

  10. DOCOSAHEXAENOIC ACID PARTIALLY AMELIORATES DEFICITS IN SOCIAL BEHAVIOR AND ULTRASONIC VOCALIZATIONS CAUSED BY PRENATAL ETHANOL EXPOSURE

    PubMed Central

    Wellmann, Kristen A.; George, Finney; Brnouti, Fares; Mooney, Sandra M.

    2015-01-01

    Prenatal ethanol exposure disrupts social behavior in humans and rodents. One system particularly important for social behavior is the somatosensory system. Prenatal ethanol exposure alters the structure and function of this area. Docosahexaenoic acid (DHA), an omega 3 polyunsaturated fatty acid, is necessary for normal brain development and brains from ethanol-exposed animals are DHA deficient. Thus, we determined whether postnatal DHA supplementation ameliorated behavioral deficits induced by prenatal ethanol exposure. Timed pregnant Long-Evans rats were assigned to one of three groups: ad libitum access to an ethanol-containing liquid diet, pair fed an isocaloric isonutritive non-alcohol liquid diet, or ad libitum access to chow and water. Pups were assigned to one of two postnatal treatment groups; gavaged intragastrically once per day between postnatal day (P)11 and P20 with DHA (10 g/kg in artificial rat milk) or artificial rat milk. A third group was left untreated. Isolation-induced ultrasonic vocalizations (iUSVs) were recorded on P14. Social behavior and play-induced USVs were tested on P28 or P42. Somatosensory performance was tested with a gap crossing test around P33 or on P42. Anxiety was tested on elevated plus maze around P35. Animals exposed to ethanol prenatally vocalized less, play fought less, and crossed a significantly shorter gap than control-treated animals. Administration of DHA ameliorated these ethanol-induced deficits such that the ethanol-exposed animals given DHA were no longer significantly different to control-treated animals. Thus, DHA administration may have therapeutic value to reverse some of ethanol’s damaging effects. PMID:25746516

  11. CHOLINE AMELIORATES DEFICITS IN BALANCE CAUSED BY ACUTE NEONATAL ETHANOL EXPOSURE

    PubMed Central

    Bearer, Cynthia F.; Wellmann, Kristen A.; Tang, Ningfeng; He, Min; Mooney, Sandra M.

    2015-01-01

    Fetal alcohol spectrum disorder (FASD) is estimated to occur in 1% of all live births. The developing cerebellum is vulnerable to the toxic effects of alcohol. People with FASD have cerebellar hypoplasia and developmental deficits associated with cerebellar injury. Choline is an essential nutrient but many diets in the USA are choline deficient. In rats, choline given with or following alcohol exposure reduces many alcohol-induced neurobehavioral deficits, but not those associated with cerebellar function. Our objective was to determine if choline supplementation prior to alcohol exposure would ameliorate the impact of ethanol on a cerebellar-associated behavioral test in mice. Pregnant C57Bl6/J mice were maintained on a choline deficient diet from embryonic day 4.5. On postnatal day 1 (P1), pups were assigned to one of 8 treatment groups: choline (C) or saline (S) pre-treatment from P1-5, ethanol (6 g/kg) or Intralipid® on P5, C or S post-treatment from P6-20. On P30, balance and coordination were tested using the dowel crossing test. Overall, there was a significant effect of treatment and females crossed longer distances than males. Ethanol exposure significantly reduced the total distance crossed. Choline pre-treatment increased the distance crossed by males, and both pre- and post-treatment with choline significantly increased total distance crossed for females and males. There was no effect of choline on Intralipid®-exposed animals. This is the first study to show that choline ameliorates ethanol-induced effects on balance and coordination when given before ethanol exposure. Choline fortification of common foodstuffs may reduce the effects of alcohol. PMID:26085462

  12. Docosahexaenoic acid partially ameliorates deficits in social behavior and ultrasonic vocalizations caused by prenatal ethanol exposure.

    PubMed

    Wellmann, Kristen A; George, Finney; Brnouti, Fares; Mooney, Sandra M

    2015-06-01

    Prenatal ethanol exposure disrupts social behavior in humans and rodents. One system particularly important for social behavior is the somatosensory system. Prenatal ethanol exposure alters the structure and function of this area. Docosahexaenoic acid (DHA), an omega 3 polyunsaturated fatty acid, is necessary for normal brain development and brains from ethanol-exposed animals are DHA deficient. Thus, we determined whether postnatal DHA supplementation ameliorated behavioral deficits induced by prenatal ethanol exposure. Timed pregnant Long-Evans rats were assigned to one of three groups: ad libitum access to an ethanol-containing liquid diet, pair fed an isocaloric isonutritive non-alcohol liquid diet, or ad libitum access to chow and water. Pups were assigned to one of two postnatal treatment groups; gavaged intragastrically once per day between postnatal day (P)11 and P20 with DHA (10g/kg in artificial rat milk) or artificial rat milk. A third group was left untreated. Isolation-induced ultrasonic vocalizations (iUSVs) were recorded on P14. Social behavior and play-induced USVs were tested on P28 or P42. Somatosensory performance was tested with a gap crossing test around P33 or on P42. Anxiety was tested on elevated plus maze around P35. Animals exposed to ethanol prenatally vocalized less, play fought less, and crossed a significantly shorter gap than control-treated animals. Administration of DHA ameliorated these ethanol-induced deficits such that the ethanol-exposed animals given DHA were no longer significantly different to control-treated animals. Thus, DHA administration may have therapeutic value to reverse some of ethanol's damaging effects. PMID:25746516

  13. Ameliorative effects of amide derivatives of 1,3,4-thiadiazoles on scopolamine induced cognitive dysfunction.

    PubMed

    Kulshreshtha, Akanksha; Piplani, Poonam

    2016-10-21

    The present study reports the effect of amide derivatives of 1,3,4-thiadizoles on scopolamine induced deficit cholinergic neurotransmission and oxidative stress serving as promising leads for the therapeutics of cognitive dysfunction. Fourteen compounds (2c-8d) have been synthesised and evaluated against behavioural alterations using step down passive avoidance protocol and morris water maze and at a dose of 0.5 mg/kg with reference to the standard, Rivastigmine. All the synthesised compounds were evaluated for their in vitro acetylcholinesterase (AChE) inhibition at five different concentrations using mice brain homogenate as the source of the enzyme. Biochemical estimation of markers of oxidative stress (lipid peroxidation, superoxide dismutase, glutathione, plasma nitrite, catalase) has also been carried out to assess the role of synthesised molecules on the oxidative damage induced by scopolamine. The compounds 5c, 6c and 8c displayed appreciable activity with an IC50 value of 3 μM, 3.033 μM and 2.743 μM, respectively towards acetylcholinesterase inhibition. These compounds also decreased scopolamine induced oxidative stress, thus serving as promising leads for the amelioration of oxidative stress induced cognitive decline. The molecular docking study performed to predict the binding mode of the compounds also suggested that these compounds bind appreciably with the amino acids present in the active site of recombinant human acetylcholinesterase (rhAChE). The results indicated that these compounds could be further traversed as inhibitors of AChE and oxidative stress for the treatment of cognitive dysfunction. PMID:27448914

  14. Cognitive Deficits in Adults with ADHD Go beyond Comorbidity Effects

    ERIC Educational Resources Information Center

    Silva, Katiane L.; Guimaraes-da-Silva, Paula O.; Grevet, Eugenio H.; Victor, Marcelo M.; Salgado, Carlos A. I.; Vitola, Eduardo S.; Mota, Nina R.; Fischer, Aline G.; Contini, Veronica; Picon, Felipe A.; Karam, Rafael G.; Belmonte-de-Abreu, Paulo; Rohde, Luis A.; Bau, Claiton H. D.

    2013-01-01

    Objective: This study addresses if deficits in cognitive, attention, and inhibitory control performance in adults with ADHD are better explained by the disorder itself or by comorbid conditions. Method Adult patients with ADHD ("n" = 352) and controls ("n" = 94) were evaluated in the ADHD program of a tertiary hospital. The…

  15. Withdrawal From Chronic Nicotine Reduces Thyroid Hormone Levels and Levothyroxine Treatment Ameliorates Nicotine Withdrawal-Induced Deficits in Hippocampus-Dependent Learning in C57BL/6J Mice

    PubMed Central

    Leach, Prescott T.; Holliday, Erica; Kutlu, Munir G.

    2015-01-01

    Introduction: Cigarette smoking alters a variety of endocrine systems including thyroid hormones. Altered thyroid hormone signaling may lead to a subclinical or overt hypothyroid condition that could contribute to nicotine withdrawal-related symptoms, such as cognitive deficits. Thus, normalizing thyroid hormone levels may represent a novel therapeutic target for ameliorating nicotine withdrawal-associated cognitive deficits. Methods: The current studies conducted an analysis of serum thyroid hormone levels after chronic and withdrawal from chronic nicotine treatment in C57BL/6J mice using an enzyme-linked immunosorbent assay. The present studies also evaluated the effect of synthetic thyroid hormone (levothyroxine) on contextual and cued memory. Results: The current studies found that nicotine withdrawal reduces secreted thyroid hormone levels by 9% in C57BL/6J mice. Further, supplemental thyroid hormone not only enhanced memory in naïve animals, but also ameliorated deficits in hippocampus-dependent learning associated with nicotine withdrawal. Conclusions: These results suggest that smokers attempting to quit should be monitored closely for changes in thyroid function. If successfully treated, normalization of thyroid hormone levels may ameliorate some deficits associated with nicotine withdrawal and this may lead to higher rates of successful abstinence. PMID:25358661

  16. Assessment of basic cognitive abilities in relation to cognitive deficits.

    PubMed

    Detterman, D K; Mayer, J D; Caruso, D R; Legree, P J; Conners, F A; Taylor, R

    1992-11-01

    A modal model of information-processing was used to select a battery of nine tasks of basic cognitive ability (learning, relearning, reaction time, probe recall, Sternberg search, self-paced probe, stimulus discrimination, tachistoscopic full report, tachistoscopic partial report). Parameters from these tasks operationalized the model. After extensive pilot testing of the tasks to establish reliability, we tested 40 subjects (20 with mental retardation and 20 college students) on all tasks and the WAIS-R. The parameters from the tasks were generally reliable (.7 through .9) and had low correlations with IQ (average about .37). Nearly all of the major cognitive parameters differentiated significantly between groups. A subset of the basic cognitive parameters predicted IQ with an estimated multiple correlation in the general population of .72. Prediction of IQ using basic cognitive parameters was better for subjects with mental retardation than for college students. A modified version of the modal model was supported. Results show that individual differences in higher mental processes are highly dependent on basic cognitive abilities and can be predicted from them. These findings have substantial implications for the development of models of information-processing. PMID:1449729

  17. Cognitive planning deficit in patients with cerebellar atrophy.

    PubMed

    Grafman, J; Litvan, I; Massaquoi, S; Stewart, M; Sirigu, A; Hallett, M

    1992-08-01

    We compared the performance of 12 patients with cerebellar atrophy (CA) and 12 normal controls matched for age and education on the Tower of Hanoi, a nine-problem task that requires cognitive planning. CA patients performed significantly worse than controls on this task despite no difference in planning and between-move pause times. A reanalysis of the data using just the subgroup of patients with pure cerebellar cortical atrophy (CCA) (N = 9) replicated the above results and also showed that CCA patients had significantly increased planning times compared with controls. Neither age, sex, education level, severity of dementia, word fluency, response time, memory, nor visuomotor procedural learning predicted CA or CCA performance. This deficit in cognitive planning suggests a functional link between the cerebellum, basal ganglia, and the frontal lobe concerning specific cognitive processes. However, the exact role of the cerebellum in cognitive planning remains undetermined. PMID:1641142

  18. Neurally dissociable cognitive components of reading deficits in subacute stroke.

    PubMed

    Boukrina, Olga; Barrett, A M; Alexander, Edward J; Yao, Bing; Graves, William W

    2015-01-01

    According to cognitive models of reading, words are processed by interacting orthographic (spelling), phonological (sound), and semantic (meaning) information. Despite extensive study of the neural basis of reading in healthy participants, little group data exist on patients with reading deficits from focal brain damage pointing to critical neural systems for reading. Here, we report on one such study. We have performed neuropsychological testing and magnetic resonance imaging on 11 patients with left-hemisphere stroke (<=5 weeks post-stroke). Patients completed tasks assessing cognitive components of reading such as semantics (matching picture or word choices to a target based on meaning), phonology (matching word choices to a target based on rhyming), and orthography (a two-alternative forced choice of the most plausible non-word). They also read aloud pseudowords and words with high or low levels of usage frequency, imageability, and spelling-sound consistency. As predicted by the cognitive model, when averaged across patients, the influence of semantics was most salient for low-frequency, low-consistency words, when phonological decoding is especially difficult. Qualitative subtraction analyses revealed lesion sites specific to phonological processing. These areas were consistent with those shown previously to activate for phonology in healthy participants, including supramarginal, posterior superior temporal, middle temporal, inferior frontal gyri, and underlying white matter. Notable divergence between this analysis and previous functional imaging is the association of lesions in the mid-fusiform gyrus and anterior temporal lobe with phonological reading deficits. This study represents progress toward identifying brain lesion-deficit relationships in the cognitive components of reading. Such correspondences are expected to help not only better understand the neural mechanisms of reading, but may also help tailor reading therapy to individual neurocognitive

  19. Neurally dissociable cognitive components of reading deficits in subacute stroke

    PubMed Central

    Boukrina, Olga; Barrett, A. M.; Alexander, Edward J.; Yao, Bing; Graves, William W.

    2015-01-01

    According to cognitive models of reading, words are processed by interacting orthographic (spelling), phonological (sound), and semantic (meaning) information. Despite extensive study of the neural basis of reading in healthy participants, little group data exist on patients with reading deficits from focal brain damage pointing to critical neural systems for reading. Here, we report on one such study. We have performed neuropsychological testing and magnetic resonance imaging on 11 patients with left-hemisphere stroke (<=5 weeks post-stroke). Patients completed tasks assessing cognitive components of reading such as semantics (matching picture or word choices to a target based on meaning), phonology (matching word choices to a target based on rhyming), and orthography (a two-alternative forced choice of the most plausible non-word). They also read aloud pseudowords and words with high or low levels of usage frequency, imageability, and spelling-sound consistency. As predicted by the cognitive model, when averaged across patients, the influence of semantics was most salient for low-frequency, low-consistency words, when phonological decoding is especially difficult. Qualitative subtraction analyses revealed lesion sites specific to phonological processing. These areas were consistent with those shown previously to activate for phonology in healthy participants, including supramarginal, posterior superior temporal, middle temporal, inferior frontal gyri, and underlying white matter. Notable divergence between this analysis and previous functional imaging is the association of lesions in the mid-fusiform gyrus and anterior temporal lobe with phonological reading deficits. This study represents progress toward identifying brain lesion-deficit relationships in the cognitive components of reading. Such correspondences are expected to help not only better understand the neural mechanisms of reading, but may also help tailor reading therapy to individual neurocognitive

  20. Inhibition of inflammation by astaxanthin alleviates cognition deficits in diabetic mice.

    PubMed

    Zhou, Xiaoyan; Zhang, Fang; Hu, Xiaotong; Chen, Jing; Wen, Xiangru; Sun, Ying; Liu, Yonghai; Tang, Renxian; Zheng, Kuiyang; Song, Yuanjian

    2015-11-01

    Neurons in the hippocampal and cortical functional regions are more susceptible to damage induced by hyperglycemia, which can result in severe spatial learning and memory impairment. Neuroprotection ameliorates cognitive impairment induced by hyperglycemia in diabetic encephalopathy (DE). Astaxanthin has been widely studied in diabetes mellitus and diabetic complications due to its hypoglycemic, antioxidant and anti-apoptotic effects. However, whether astaxanthin can alleviate cognition deficits induced by DE and its precise mechanisms remain undetermined. In this study, DE was induced by streptozotocin (STZ, 150 mg/kg) in ICR mice. We observed the effect of astaxanthin on cognition and investigated its potential mechanisms in DE mice. Results showed that astaxanthin treatment significantly decreased the latency and enhanced the distance and time spent in the target quadrant in the Morris water maze test. Furthermore, neuronal survival was significantly increased in the hippocampal CA3 region and the frontal cortex following treatment with astaxanthin. Meanwhile, immunoblotting was used to observe the nuclear translocation of nuclear factor-kappaB (NF-κB) p65 and the expression of tumor necrosis factor-α (TNF-α) in the hippocampus and frontal cortex. The results indicated that astaxanthin could inhibit NF-κB nuclear translocation and downregulate TNF-α expression in the hippocampus and frontal cortex. Overall, the present study implied that astaxanthin could improve cognition by protecting neurons against inflammation injury potentially through inhibiting the nuclear translocation of NF-κB and down-regulating TNF-α. PMID:26272354

  1. Relations of symptoms to cognitive deficits in schizophrenia.

    PubMed

    Strauss, M E

    1993-01-01

    Schizophrenia is characterized by a variety of cognitive dysfunctions. Information-processing dysfunctions differ between clinical subtypes such that nonparanoid schizophrenia patients attend less than paranoid schizophrenia patients to connotative or contextual aspects of stimuli. The positive and negative symptom dimensions are also associated with distinct cognitive deficits. In general, positive symptoms are related to auditory-processing deficits and negative symptoms to visual/motor dysfunctions. The interaction of frontal and septohippocampal brain systems, and failures of information-processing automaticity and self-monitoring, have been proposed as the bases of positive symptoms. Negative symptoms are thought to arise from abnormalities in the complex interactions of frontal and striatal systems. Recent theoretical analyses have recommended a focus on the cognitive and neuropsychological analysis of specific symptoms (e.g., hallucinations and delusions) instead of on the more heterogeneous symptom clusters or dimensions. Studies of specific symptoms indicate that patients with hallucinations have deficits in discriminating the source of information. Delusions have been related to abnormal inference processes as well as abnormal perceptual experiences. Studies should now examine the links between information-processing abnormalities and symptoms over time, as the latter change, within the framework of explicit, disconfirmable theoretical models. PMID:8322033

  2. Impaired auditory selective attention ameliorated by cognitive training with graded exposure to noise in patients with traumatic brain injury.

    PubMed

    Dundon, Neil M; Dockree, Suvi P; Buckley, Vanessa; Merriman, Niamh; Carton, Mary; Clarke, Sarah; Roche, Richard A P; Lalor, Edmund C; Robertson, Ian H; Dockree, Paul M

    2015-08-01

    Patients who suffer traumatic brain injury frequently report difficulty concentrating on tasks and completing routine activities in noisy and distracting environments. Such impairments can have long-term negative psychosocial consequences. A cognitive control function that may underlie this impairment is the capacity to select a goal-relevant signal for further processing while safeguarding it from irrelevant noise. A paradigmatic investigation of this problem was undertaken using a dichotic listening task (study 1) in which comprehension of a stream of speech to one ear was measured in the context of increasing interference from a second stream of irrelevant speech to the other ear. Controls showed an initial decline in performance in the presence of competing speech but thereafter showed adaptation to increasing audibility of irrelevant speech, even at the highest levels of noise. By contrast, patients showed linear decline in performance with increasing noise. Subsequently attempts were made to ameliorate this deficit (study 2) using a cognitive training procedure based on attention process training (APT) that included graded exposure to irrelevant noise over the course of training. Patients were assigned to adaptive and non-adaptive training schedules or to a no-training control group. Results showed that both types of training drove improvements in the dichotic listening and in naturalistic tasks of performance in noise. Improvements were also seen on measures of selective attention in the visual domain suggesting transfer of training. We also observed augmentation of event-related potentials (ERPs) linked to target processing (P3b) but no change in ERPs evoked by distractor stimuli (P3a) suggesting that training heightened tuning of target signals, as opposed to gating irrelevant noise. No changes in any of the above measures were observed in a no-training control group. Together these findings present an ecologically valid approach to measure selective

  3. Cognitive deficits in bipolar disorder: from acute episode to remission.

    PubMed

    Volkert, J; Schiele, M A; Kazmaier, Julia; Glaser, Friederike; Zierhut, K C; Kopf, J; Kittel-Schneider, S; Reif, A

    2016-04-01

    Considerable evidence demonstrates that neuropsychological deficits are prevalent in bipolar disorder during both acute episodes and euthymia. However, it is less clear whether these cognitive disturbances are state- or trait-related. We here present the first longitudinal study employing a within-subject pre- and post-testing examining acutely admitted bipolar patients (BP) in depression or mania and during euthymia, aiming to identify cognitive performance from acute illness to remission. Cognitive performance was measured during acute episodes and repeated after at least 3 months of remission. To do so, 55 BP (35 depressed, 20 hypo-/manic) and 55 healthy controls (HC) were tested with a neuropsychological test battery (attention, working memory, verbal memory, executive functioning). The results showed global impairments in acutely ill BP compared to HC: depressed patients showed a characteristic psychomotor slowing, while manic patients had severe deficits in executive functioning. Twenty-nine remitted BP could be measured in the follow-up (dropout rate 48 %), whose cognitive functions partially recovered, whereas working memory and verbal memory were still impaired. However, we found that subthreshold depressive symptoms and persisting sleep disturbances in euthymic BP were associated with reduced speed, deficits in attention and verbal memory, while working memory was correlated with psychotic symptoms (lifetime). This result indicates working memory as trait related for a subgroup of BP with psychotic symptoms. In contrast, attention and verbal memory are negatively influenced by state factors like residual symptoms, which should be more considered as possible confounders in the search of cognitive endophenotypes in remitted BP. PMID:26611783

  4. Donepezil Improved Cognitive Deficits in a Patient With Neurosyphilis.

    PubMed

    Wu, Yi-Shan; Lane, Hsien-Yuan; Lin, Chieh-Hsin

    2015-01-01

    A large number of patients with neurosyphilis present dementia with a progressive course and psychiatric symptoms such as depression, mania, and psychosis. Despite prompt and proper antibiotic treatment, the recovery is often incomplete, especially when tissue damage has occurred. We reported a patient with persisted cognitive decline associated with neurosyphilis that improved substantially after donepezil therapy. A 43-year-old man manifested significant psychiatric symptoms such as mania, psychosis, and cognitive impairment due to neurosyphilis. Subsequently, the patient was treated with antipsychotics and donepezil concurrent with an adequate antibiotic treatment for neurosyphilis. During the 1-year follow-up, his rapid plasma reagin titer approached from 1:256 to 1:64. His Mini-Mental State Examination (MMSE) and Alzheimer's Disease Assessment Scale-cognitive subscale scores improved from 12 to 25 and 42.3 to 6.3, respectively, after a 6-month donepezil treatment. Donepezil was discontinued. Three months later, worsening of cognitive impairment (MMSE score, 23) was noted. After donepezil was started again for 3 months, his MMSE score improved to 26. Persistent cognitive impairment is commonly associated with neurosyphilis despite adequate penicillin treatment. Treatment of the cognitive impairment is important but difficult. Cholinergic pathways are considered as involving in the cognitive deficit induced by neurosyphilis and donepezil, a cholinesterase inhibitor, which may be useful for the improvement of cognition. In this case report, we described for the first time the successful use of donepezil in treating cognitive impairment associated with neurosyphilis. The role of cholinesterase inhibitors in the treatment of cognitive impairments caused by neurosyphilis needs further studies. PMID:26166240

  5. Ovarian hormones ameliorate memory impairment, cholinergic deficit, neuronal apoptosis and astrogliosis in a rat model of Alzheimer's disease

    PubMed Central

    HU, ZHIYING; YANG, YANG; GAO, KEQIANG; RUDD, JOHN A.; FANG, MARONG

    2016-01-01

    Ovarian hormones, including progesterone (P4) and 17 β-estradiol (E2), have been shown to affect memory functions; however, the underlying mechanism whereby ovarian hormone replacement therapy may decrease the risk of Alzheimer's disease (AD) is currently unclear. The present study aimed to investigate the effects of P4 and E2 on spatial and learning memory in an ovariectomized rat model of AD. β-amyloid (Aβ) or saline were stereotaxically injected into the hippocampus of the rats and, after 1 day, ovariectomy or sham operations were performed. Subsequently, the rats were treated with P4 alone, E2 alone, or a combination of P4 and E2. Treatment with E2 and/or P4 was shown to improve the learning and memory functions of the rats, as demonstrated by the Morris water maze test. In addition, treatment with E2 and P4 was associated with increased expression levels of choline acetyltransferase and 5-hydroxytryptamine receptor 2A (5-HT2A), and decreased expression levels of the glial fibrillary acidic protein in the hippocampus of the rats. Furthermore, E2 and P4 treatment significantly attenuated neuronal cell apoptosis, as demonstrated by terminal deoxynucleotidyl transferase dUTP nick end labeling assays; thus suggesting that the ovarian hormones were able to protect against Aβ-induced neuronal cell toxicity. The results of the present study suggested that the neuroprotective effects of P4 and E2 were associated with amelioration of the cholinergic deficit, suppression of apoptotic signals and astrogliosis, and upregulation of 5-HT2A expression levels. Therefore, hormone replacement therapy may be considered an effective strategy for the treatment of patients with cognitive disorders and neurodegenerative diseases. PMID:26889223

  6. Novel 5-HT5A receptor antagonists ameliorate scopolamine-induced working memory deficit in mice and reference memory impairment in aged rats.

    PubMed

    Yamazaki, Mayako; Okabe, Mayuko; Yamamoto, Noriyuki; Yarimizu, Junko; Harada, Katsuya

    2015-03-01

    Despite the human 5-HT5A receptor being cloned in 1994, the biological function of this receptor has not been extensively characterized due to a lack of specific ligands. We recently reported that the selective 5-HT5A receptor antagonist ASP5736 ameliorated cognitive impairment in several animal models of schizophrenia. Given that areas of the brain with high levels of 5-HT5A receptor expression, such as the hippocampus and cerebral cortex, have important functions in cognition and memory, we evaluated the chemically diverse, potent and brain-penetrating 5-HT5A receptor antagonists ASP5736, AS2030680, and AS2674723 in rodent models of cognitive dysfunction associated with dementia. Each of these compounds exhibited a high affinity for recombinant 5-HT5A receptors that was comparable to that of the non-selective ligand of this receptor, lysergic acid diethylamide (LSD). Although each compound had a low affinity for other receptors, 5-HT5A was the only receptor for which all three compounds had a high affinity. Each of the three compounds ameliorated scopolamine-induced working memory deficit in mice and improved reference memory impairment in aged rats at similar doses. Further, ASP5736 decreased the binding of LSD to 5-HT5A receptors in the olfactory bulb of rats in a dose-dependent manner and occupied 15%-50% of brain 5-HT5A receptors at behaviorally effective doses. These results indicate that the 5-HT5A receptor is involved in learning and memory and that treatment with 5-HT5A receptor antagonists might be broadly effective for cognitive impairment associated with not only schizophrenia but also dementia. PMID:25837935

  7. Individually modifiable risk factors to ameliorate cognitive aging: a systematic review and meta-analysis.

    PubMed

    Lehert, P; Villaseca, P; Hogervorst, E; Maki, P M; Henderson, V W

    2015-10-01

    A number of health and lifestyle factors are thought to contribute to cognitive decline associated with age but cannot be easily modified by the individual patient. We identified 12 individually modifiable interventions that can be implemented during midlife or later with the potential to ameliorate cognitive aging. For ten of these, we used PubMed databases for a systematic review of long-duration (at least 6 months), randomized, controlled trials in midlife and older adults without dementia or mild cognitive impairment with objective measures of neuropsychological performance. Using network meta-analysis, we performed a quantitative synthesis for global cognition (primary outcome) and episodic memory (secondary outcome). Of 1038 publications identified by our search strategy, 24 eligible trials were included in the network meta-analysis. Results suggested that the Mediterranean diet supplemented by olive oil and tai chi exercise may improve global cognition, and the Mediterranean diet plus olive oil and soy isoflavone supplements may improve memory. Effect sizes were no more than small (standardized mean differences 0.11-0.22). Cognitive training may have cognitive benefit as well. Most individually modifiable risk factors have not yet been adequately studied. We conclude that some interventions that can be self-initiated by healthy midlife and older adults may ameliorate cognitive aging. PMID:26361790

  8. Diet-induced obesity attenuates endotoxin-induced cognitive deficits

    PubMed Central

    Setti, Sharay E.; Littlefield, Alyssa M.; Johnson, Samantha W.; Kohman, Rachel A.

    2015-01-01

    Activation of the immune system can impair cognitive function, particularly on hippocampus dependent tasks. Several factors such as normal aging and prenatal experiences can modify the severity of these cognitive deficits. One additional factor that may modulate the behavioral response to immune activation is obesity. Prior work has shown that obesity alters the activity of the immune system. Whether diet-induced obesity (DIO) influences the cognitive deficits associated with inflammation is currently unknown. The present study explored whether DIO alters the behavioral response to the bacterial endotoxin, lipopolysaccharide (LPS). Female C57BL/6J mice were fed a high-fat (60% fat) or control diet (10% fat) for a total of five months. After consuming their respective diets for four months, mice received an LPS or saline injection and were assessed for alterations in spatial learning. One month later, mice received a second injection of LPS or saline and tissue samples were collected to assess the inflammatory response within the periphery and central nervous system (CNS). Results showed that LPS administration impaired spatial learning in the control diet mice, but had no effect in DIO mice. This lack of a cognitive deficit in the DIO female mice is likely due to a blunted inflammatory response within the brain. While cytokine production within the periphery (i.e., plasma, adipose, and spleen) was similar between the DIO and control mice, the DIO mice failed to show an increase in IL-6 and CD74 in the brain following LPS administration. Collectively, these data indicate that DIO can reduce aspects of the neuroinflammatory response as well as blunt the behavioral reaction to an immune challenge. PMID:25542778

  9. Cognitive Deficits as a Mediator of Poor Occupational Function in Remitted Major Depressive Disorder Patients

    PubMed Central

    Woo, Young Sup; Rosenblat, Joshua D.; Kakar, Ron; Bahk, Won-Myong; McIntyre, Roger S.

    2016-01-01

    Cognitive deficits in major depressive disorder (MDD) patients have been described in numerous studies. However, few reports have aimed to describe cognitive deficits in the remitted state of MDD and the mediational effect of cognitive deficits on occupational outcome. The aim of the current review is to synthesize the literature on the mediating and moderating effects of specific domains of cognition on occupational impairment among people with remitted MDD. In addition, predictors of cognitive deficits found to be vocationally important will be examined. Upon examination of the extant literature, attention, executive function and verbal memory are areas of consistent impairment in remitted MDD patients. Cognitive domains shown to have considerable impact on vocational functioning include deficits in memory, attention, learning and executive function. Factors that adversely affect cognitive function related to occupational accommodation include higher age, late age at onset, residual depressive symptoms, history of melancholic/psychotic depression, and physical/psychiatric comorbidity, whereas higher levels of education showed a protective effect against cognitive deficit. Cognitive deficits are a principal mediator of occupational impairment in remitted MDD patients. Therapeutic interventions specifically targeting cognitive deficits in MDD are needed, even in the remitted state, to improve functional recovery, especially in patients who have a higher risk of cognitive deficit. PMID:26792035

  10. Tetrandrine ameliorates sevoflurane‑induced cognitive impairment via the suppression of inflammation and apoptosis in aged rats.

    PubMed

    Ma, Hongmei; Yao, Li; Pang, Ling; Li, Xingwei; Yao, Qun

    2016-06-01

    Tetrandrine is a bisbenzylisoquinoline alkaloid extracted from Stephania tetrandra, a traditional Chinese herbal medicine, which has been observed to exert anti‑inflammatory effects. The aim of the current study was to investigate whether tetrandrine was able to ameliorate sevoflurane‑induced cognitive impairment in aged rats. Male 20‑month‑old Sprague‑Dawley rats underwent sevoflurane‑induction in an environment containing 2% sevoflurane for 5 h. The Morris water maze test was used to measure the effect of tetrandrine on learning and memory in sevoflurane‑treated aged rats. Western blot analysis of the protein expression levels of cyclooxygenase‑2 (COX‑2), inducible nitric oxide synthase (iNOS) and Bcl‑2 was conducted. ELISAs were used to measure the levels of interleukin (IL)‑1β, tumor necrosis factor (TNF‑α), nuclear factor‑κB (NF‑κB) and caspase‑3. In the present study, tetrandrine improved the learning and memory deficits observed in sevoflurane‑treated aged rats. Treatment with tetrandrine reduced the expression levels of COX‑2, IL‑1β, TNF‑α, NF‑κB, iNOS and caspase‑3, and increased the Bcl‑2 protein expression in sevoflurane‑treated aged rats. In conclusion, the current study indicated that tetrandrine ameliorates sevoflurane‑induced cognitive impairment via the suppression of inflammation and apoptosis in aged rats. Thus, tetrandrine may be a potential novel candidate to protect against the effects of sevoflurane anesthesia on cognitive function. PMID:27082007

  11. Fluoxetine Ameliorates Behavioral and Neuropathological Deficits in a Transgenic Model Mouse of α-synucleinopathy

    PubMed Central

    Ubhi, Kiren; Inglis, Chandra; Mante, Michael; Patrick, Christina; Adame, Anthony; Spencer, Brian; Rockenstein, Edward; May, Verena; Winkler, Juergen; Masliah, Eliezer

    2013-01-01

    The term α-synucleinopathies refers to a group of age-related neurological disorders including Parkinson’s disease (PD), Dementia with Lewy Bodies (DLB) and Multiple System Atrophy (MSA) that display an abnormal accumulation of alpha-synuclein (α-syn). In contrast to the neuronal α-syn accumulation observed in PD and DLB, MSA is characterized by a widespread oligodendrocytic α-syn accumulation. Transgenic mice expressing human α-syn under the oligodendrocyte-specific myelin basic protein promoter (MBP1-hαsyn tg mice) model many of the behavioral and neuropathological alterations observed in MSA. Fluoxetine, a selective serotonin reuptake inhibitor, has been shown to be protective in toxin-induced models of PD, however its effects in an in vivo transgenic model of α-synucleinopathy remain unclear. In this context, this study examined the effect of fluoxetine in the MBP1-hαsyn tg mice, a model of MSA. Fluoxetine adminstration ameliorated motor deficits in the MBP1-hαsyn tg mice, with a concomitant decrease in neurodegenerative pathology in the basal ganglia, neocortex and hippocampus. Fluoxetine adminstration also increased levels of the neurotrophic factors, GDNF (glial-derived neurotrophic factor) and BDNF (brain-derived neurotrophic factor) in the MBP1-hαsyn tg mice compared to vehicle-treated tg mice. This fluoxetine-induced increase in GDNF and BDNF protein levels was accompanied by activation of the ERK signaling pathway. The effects of fluoxetine adminstration on myelin and serotonin markers were also examined. Collectively these results indicate that fluoxetine may represent a novel therapeutic intervention for MSA and other neurodegenerative disorders. PMID:22281106

  12. Neurocomputational models of motor and cognitive deficits in Parkinson's disease.

    PubMed

    Wiecki, Thomas V; Frank, Michael J

    2010-01-01

    We review the contributions of biologically constrained computational models to our understanding of motor and cognitive deficits in Parkinson's disease (PD). The loss of dopaminergic neurons innervating the striatum in PD, and the well-established role of dopamine (DA) in reinforcement learning (RL), enable neural network models of the basal ganglia (BG) to derive concrete and testable predictions. We focus in this review on one simple underlying principle - the notion that reduced DA increases activity and causes long-term potentiation in the indirect pathway of the BG. We show how this theory can provide a unified account of diverse and seemingly unrelated phenomena in PD including progressive motor degeneration as well as cognitive deficits in RL, decision making and working memory. DA replacement therapy and deep brain stimulation can alleviate some aspects of these impairments, but can actually introduce negative effects such as motor dyskinesias and cognitive impulsivity. We discuss these treatment effects in terms of modulation of specific mechanisms within the computational framework. In addition, we review neurocomputational interpretations of increased impulsivity in the face of response conflict in patients with deep-brain-stimulation. PMID:20696325

  13. Cognitive Deficits in Geriatric Depression: Clinical Correlates and Implications for Current and Future Treatment

    PubMed Central

    Morimoto, Sarah Shizuko; Alexopoulos, George S.

    2013-01-01

    Synopsis The purpose of this article is to identify the cognitive deficits commonly associated with geriatric depression, and describe their clinical significance. We then summarize the complex relationship between geriatric depression and dementia and discuss possible shared mechanisms. Last, we present evidence regarding whether the cognitive deficits in depression may be mitigated with medication or with computerized cognitive remediation. PMID:24229654

  14. Cognitive Neuroscience of Attention Deficit Hyperactivity Disorder: Current Status and Working Hypotheses

    ERIC Educational Resources Information Center

    Vaidya, Chandan J.; Stollstorff, Melanie

    2008-01-01

    Cognitive neuroscience studies of Attention Deficit Hyperactivity Disorder (ADHD) suggest multiple loci of pathology with respect to both cognitive domains and neural circuitry. Cognitive deficits extend beyond executive functioning to include spatial, temporal, and lower-level "nonexecutive" functions. Atypical functional anatomy extends beyond…

  15. Ameliorative effect of Asparagus racemosus root extract against pentylenetetrazol-induced kindling and associated depression and memory deficit.

    PubMed

    Pahwa, Priyanka; Goel, Rajesh Kumar

    2016-04-01

    Asparagus racemosus (A. racemosus) roots are extensively used in traditional medicine for the management of epilepsy. The aim of the present study was to investigate the ameliorative effect of A. racemosus root extract (ARE) against pentylenetetrazol-induced kindling and associated depression and memory deficit. Kindling was successfully induced by repeated administration of a subconvulsant dose of PTZ (35 mg/kg; i.p.) at an interval of 48 ± 2 h in 43 days (21 injections). Pretreatment with valproate (300 mg/kg; i.p.), a major antiepileptic drug as well as ARE significantly suppressed the progression of kindling. Moreover, ARE also ameliorated the kindling-associated depression and memory deficit as indicated by decreased immobility time and increased step-down latency, respectively, as compared to vehicle control animals. Further, these behavioral observations were complemented with analogous neurochemical changes. In conclusion, the results of the present study showed that ARE treatment has an ameliorative effect against PTZ-induced kindling and associated behavioral comorbidities. PMID:26970996

  16. Sulforaphane ameliorates neurobehavioral deficits and protects the brain from amyloid β deposits and peroxidation in mice with Alzheimer-like lesions.

    PubMed

    Zhang, Rui; Miao, Qian-Wei; Zhu, Chun-Xiao; Zhao, Yue; Liu, Li; Yang, Jun; An, Li

    2015-03-01

    Alzheimer's disease (AD) is a common neurodegenerative disease in the elderly individuals and its effective therapies are still unavailable. This study was designed to investigate the neuroprotection of sulforaphane (SFN) in AD-lesion mice induced by combined administration of d-galactose and aluminium. Results showed that SFN ameliorated spatial cognitive impairment and locomotor activity decrease in Morris water maze and open field test, respectively. And attenuated numbers of amyloid β (Aβ) plaques in both hippocampus and cerebral cortex of AD-lesion mice were detected by immunohistochemistry. According to spectrophotometry and quantitative reverse-transcriptase polymerase chain reaction results, a significant increase in carbonyl group level and obvious decreases in both activity and messenger RNA expression of glutathione peroxidase were found in brain of AD-lesion mice compared with control, but not in SFN-treated AD-lesion mice. In conclusion, SFN ameliorates neurobehavioral deficits and protects the brain from Aβ deposits and peroxidation in mice with Alzheimer-like lesions, suggesting SFN is likely a potential phytochemical to be used in AD therapeutics. PMID:25024455

  17. Methylene blue reduces Aβ levels and rescues early cognitive deficit by increasing proteasome activity

    PubMed Central

    Medina, David X.; Caccamo, Antonella; Oddo, Salvatore

    2010-01-01

    Promising results have emerged from a phase II clinical trial testing Methylene blue (MB) as a potential therapeutic for Alzheimer disease (AD), where improvements in cognitive functions of AD patients after 6 months of MB administration have been reported. Despite these reports, no preclinical testing of MB in mammals has been published, and thus its mechanism of action in relation to AD pathology remains unknown. In order to elucidate the effects of MB on AD pathology and to determine its mechanism of action, we used a mouse model (3xTg-AD) that develops age-dependent accumulation of Aβ and tau and cognitive decline. Here, we report that chronic dietary MB treatment reduces Aβ levels and improves learning and memory deficits in the 3xTg-AD mice. The mechanisms underlying the effects of MB on Aβ pathology appears to be mediated by an increase in Aβ clearance as we show that MB increases the chymotrypsin-and trypsin-like activities of the proteasome in the brain. To our knowledge, this is the first report showing that MB increases proteasome function and ameliorates AD-like pathology in vivo. Overall, the data presented here support the use of MB for the treatment of AD and offer a possible mechanism of action. PMID:20731659

  18. Phloroglucinol Attenuates the Cognitive Deficits of the 5XFAD Mouse Model of Alzheimer's Disease.

    PubMed

    Yang, Eun-Jeong; Ahn, Sangzin; Ryu, Junghwa; Choi, Moon-Seok; Choi, Shinkyu; Chong, Young Hae; Hyun, Jin-Won; Chang, Moon-Jeong; Kim, Hye-Sun

    2015-01-01

    Alzheimer's disease (AD) is the most common form of dementia among the elderly. Neuritic plaques whose primary component is amyloid beta peptide (Aβ) and neurofibrillary tangles which are composed of hyperphosphorylated tau, are known to be the neuropathological hallmarks of AD. In addition, impaired synaptic plasticity in neuronal networks is thought to be important mechanism underlying for the cognitive deficits observed in AD. Although various causative factors, including excitotoxicity, mitochondrial dysregulation and oxidative damage caused by Aβ, are involved in early onset of AD, fundamental therapeutics that can modify the progression of this disease are not currently available. In the present study, we investigated whether phloroglucinol (1, 3, 5-trihydroxybenzene), a component of phlorotannins, which are plentiful in Ecklonia cava, a marine brown alga species, displays therapeutic activities in AD. We found that phloroglucinol attenuates the increase in reactive oxygen species (ROS) accumulation induced by oligomeric Aβ1-42 (Aβ1-42) treatment in HT-22, hippocampal cell line. In addition, phloroglucinol was shown to ameliorate the reduction in dendritic spine density induced by Aβ1-42 treatment in rat primary hippocampal neuron cultures. We also found that the administration of phloroglucinol to the hippocampal region attenuated the impairments in cognitive dysfunction observed in 22-week-old 5XFAD (Tg6799) mice, which are used as an AD animal model. These results indicate that phloroglucinol displays therapeutic potential for AD by reducing the cellular ROS levels. PMID:26284625

  19. Phloroglucinol Attenuates the Cognitive Deficits of the 5XFAD Mouse Model of Alzheimer’s Disease

    PubMed Central

    Ryu, Junghwa; Choi, Moon-Seok; Choi, Shinkyu; Chong, Young Hae; Hyun, Jin-Won; Chang, Moon-Jeong; Kim, Hye-Sun

    2015-01-01

    Alzheimer’s disease (AD) is the most common form of dementia among the elderly. Neuritic plaques whose primary component is amyloid beta peptide (Aβ) and neurofibrillary tangles which are composed of hyperphosphorylated tau, are known to be the neuropathological hallmarks of AD. In addition, impaired synaptic plasticity in neuronal networks is thought to be important mechanism underlying for the cognitive deficits observed in AD. Although various causative factors, including excitotoxicity, mitochondrial dysregulation and oxidative damage caused by Aβ, are involved in early onset of AD, fundamental therapeutics that can modify the progression of this disease are not currently available. In the present study, we investigated whether phloroglucinol (1, 3, 5—trihydroxybenzene), a component of phlorotannins, which are plentiful in Ecklonia cava, a marine brown alga species, displays therapeutic activities in AD. We found that phloroglucinol attenuates the increase in reactive oxygen species (ROS) accumulation induced by oligomeric Aβ1–42 (Aβ1–42) treatment in HT-22, hippocampal cell line. In addition, phloroglucinol was shown to ameliorate the reduction in dendritic spine density induced by Aβ1–42 treatment in rat primary hippocampal neuron cultures. We also found that the administration of phloroglucinol to the hippocampal region attenuated the impairments in cognitive dysfunction observed in 22-week-old 5XFAD (Tg6799) mice, which are used as an AD animal model. These results indicate that phloroglucinol displays therapeutic potential for AD by reducing the cellular ROS levels. PMID:26284625

  20. Facilitative effects of bi-hemispheric tDCS in cognitive deficits of Parkinson disease patients.

    PubMed

    Leite, Jorge; Gonçalves, Oscar F; Carvalho, Sandra

    2014-02-01

    Parkinson's disease (PD) is a progressive neurodegenerative disorder, primarily characterized by motor symptoms such as tremor, rigidity, bradykinesia, stiffness, slowness and impaired equilibrium. Although the motor symptoms have been the focus in PD, slight cognitive deficits are commonly found in non-demented and non-depressed PD patients, even in early stages of the disease, which have been linked to the subsequent development of pathological dementia. Thus, strongly reducing the quality of life (QoL). Both levodopa therapy and deep brain stimulation (DBS) have yield controversial results concerning the cognitive symptoms amelioration in PD patients. That does not seems to be the case with transcranial direct current stimulation (tDCS), although better stimulation parameters are needed. Therefore we hypothesize that simultaneously delivering cathodal tDCS (or ctDCS), over the right prefrontal cortex delivered with anodal tDCS (or atDCS) to left prefrontal cortex could be potentially beneficial for PD patients, either by mechanisms of homeostatic plasticity and by increases in the extracellular dopamine levels over the striatum. PMID:24332532

  1. Environmental enrichment mitigates cognitive deficits in a mouse model of Alzheimer's disease.

    PubMed

    Jankowsky, Joanna L; Melnikova, Tatiana; Fadale, Daniel J; Xu, Guilian M; Slunt, Hilda H; Gonzales, Victoria; Younkin, Linda H; Younkin, Steven G; Borchelt, David R; Savonenko, Alena V

    2005-05-25

    Epidemiological studies suggest that individuals with greater education or more cognitively demanding occupations have diminished risk of developing dementia. We wanted to test whether this effect could be recapitulated in rodents using environmental enrichment, a paradigm well documented to attenuate behavioral deficits induced by various pathological insults. Here, we demonstrate that learning and memory deficits observed in a transgenic mouse model of Alzheimer's disease can be ameliorated by enrichment. Female transgenic mice overexpressing amyloid precursor protein and/or presenilin-1 and nontransgenic controls were placed into enriched or standard cages at 2 months of age and tested for cognitive behavior after 6 months of differential housing. Enrichment significantly improved performance of all genotypes in the radial water maze and in the classic and repeated-reversal versions of the Morris water maze. However, enrichment did not benefit all genotypes equally. Mice overproducing amyloid-beta (Abeta), particularly those with amyloid deposits, showed weaker memory for the platform location in the classic Morris water maze and learned new platform positions in the repeated-reversals task less quickly than their nontransgenic cagemates. Nonetheless, enrichment normalized the performance of Abeta-overproducing mice to the level of standard-housed nontransgenic mice. Moreover, this functional preservation occurred despite increased neuritic plaque burden in the hippocampus of double-transgenic animals and elevated steady-state Abeta levels, because both endogenous and transgene-derived Abeta are increased in enriched animals. These results demonstrate that the generation of Abeta in vivo and its impact on the function of the nervous system can be strongly modulated by environmental factors. PMID:15917461

  2. Attention and Other Cognitive Deficits in Aphasia: Presence and Relation to Language and Communication Measures

    ERIC Educational Resources Information Center

    Murray, Laura L.

    2012-01-01

    Purpose: This study was designed to further elucidate the relationship between cognition and aphasia, with a focus on attention. It was hypothesized that individuals with aphasia would display variable deficit patterns on tests of attention and other cognitive functions and that their attention deficits, particularly those of complex attention…

  3. Offenders with Cognitive Deficits in a Canadian Prison Population: Prevalence, Profile, and Outcomes.

    PubMed

    Stewart, Lynn A; Wilton, Geoff; Sapers, Jeremy

    2016-01-01

    Impaired cognitive function has been associated with criminal behavior. In Canada it is unknown the extent to which this disorder affects federal inmates or its impact on key correctional outcomes. In this study, 488 incoming male offenders were assessed on the Cognistat, a neuropsychological screening tool. Twenty-five percent of offenders were found to have some level of cognitive deficit. Lower levels of educational achievement, unstable employment history, learning disability, serious alcohol problems, and symptoms of Attention Deficit Hyperactivity Disorder (ADHD) were significantly associated with the presence of cognitive deficits in this sample. Although there was a significant trend for offenders with cognitive deficits to have more admissions to segregation, level of cognitive deficit was not consistently related to rates of institutional charges or rates of completion of required correctional programs. On release, cognitive deficits were not related to returns to custody or returns to custody with an offence. These results indicate that while offenders with cognitive deficits may require assistance with educational upgrading and employment to improve their reintegration potential, they do not pose a particular management problem in the community after release relative to offenders without cognitive deficits. PMID:26341309

  4. Nobiletin Ameliorates the Deficits in Hippocampal BDNF, TrkB, and Synapsin I Induced by Chronic Unpredictable Mild Stress

    PubMed Central

    Li, Jing; Zhou, Ying; Liu, Bin-Bin; Liu, Qing; Geng, Di; Weng, Lian-Jin; Yi, Li-Tao

    2013-01-01

    Background. Our previous study has demonstrated that nobiletin could reverse the behavioral alterations in stressed mice. However, the relation of its antidepressant-like action with neurotrophic molecular expression remains unknown. This study aimed to explore the antidepressant-like mechanism of nobiletin related to the neurotrophic system in rats exposed to chronic unpredictable mild stress (CUMS). Methods. Depressive-like anhedonia (assessed by sucrose preference) and serum corticosterone secretion were evaluated in the CUMS, followed by brain-derived neurotrophic factor (BDNF), its tropomyosin-related kinase receptor B (TrkB), and the downstream target synapsin I expressions in the hippocampus. Results. Anhedonia, which occurred within week 2, was rapidly ameliorated by nobiletin. While fluoxetine needed additional 2 weeks to improve the anhedonia. In addition, nobiletin administration for 5 weeks significantly ameliorated CUMS-induced increase in serum corticosterone levels. Furthermore, we also found that CUMS-induced deficits of hippocampal BDNF, TrkB, and synapsin I were ameliorated by nobiletin. Conclusions. Taken together, these findings suggest that nobiletin produces rapidly acting antidepressant-like responses in the CUMS and imply that BDNF-TrkB pathway may play an important role in the antidepressant-like effect of nobiletin. PMID:23573124

  5. Models of cognitive deficit and statistical hypotheses: multiple sclerosis, an example.

    PubMed

    Ryan, L; Clark, C M; Klonoff, H; Paty, D

    1993-07-01

    The purpose of the current study was to describe four models of cognitive deficit and to outline the statistical hypotheses underlying each model. The four models of cognitive deficit were (a) specific deficit; (b) subgroup deficit; (c) a syndrome dissociation model; and (d) a global function dissociation model. Neuropsychological data are analyzed to examine each of these four models in a sample of mild Multiple Sclerosis (MS) patients. The results suggest that for these subjects and tests, the specific deficit model best fits the data. The results are reviewed initially in the context of MS. There follows a consideration of statistical caveats and finally, general applications of the proposed procedures. PMID:8354709

  6. Self-Instructional Cognitive Training to Reduce Impulsive Cognitive Style in Children with Attention Deficit with Hyperactivity Disorder

    ERIC Educational Resources Information Center

    Rivera-Flores, Gladys Wilma

    2015-01-01

    Introduction: Children with attention deficit with hyperactivity disorder (ADHD) have an impulsive, rigid and field-dependent cognitive style. This study examines whether self-instructional cognitive training reduces impulsive cognitive style in children diagnosed with this disorder. Method: The subjects were 10 children between the ages of 6 and…

  7. Behavioral Response Inhibition in Psychotic Disorders: Diagnostic Specificity, Familiality and Relation to Generalized Cognitive Deficit

    PubMed Central

    Ethridge, Lauren E.; Soilleux, Melanie; Nakonezny, Paul A.; Reilly, James L.; Hill, S. Kristian; Keefe, Richard S. E.; Gershon, Elliot S.; Pearlson, Godfrey D.; Tamminga, Carol A.; Keshavan, Matcheri S.; Sweeney, John A.

    2014-01-01

    Difficulty inhibiting context-inappropriate behavior is a common deficit in psychotic disorders. The diagnostic specificity of this impairment, its familiality, and its degree of independence from the generalized cognitive deficit associated with psychotic disorders remain to be clarified. Schizophrenia, schizoaffective and bipolar patients with history of psychosis (n=523), their available first-degree biological relatives (n=656), and healthy participants (n=223) from the multi-site B-SNIP study completed a manual Stop Signal task. A nonlinear mixed model was used to fit logistic curves to success rates on Stop trials as a function of parametrically varied Stop Signal Delay. While schizophrenia patients had greater generalized cognitive deficit than bipolar patients, their deficits were similar on the Stop Signal task. Further, only bipolar patients showed impaired inhibitory control relative to healthy individuals after controlling for generalized cognitive deficit. Deficits accounted for by the generalized deficit were seen in relatives of schizophrenia and schizoaffective patients, but not in relatives of bipolar patients. In clinically stable patients with psychotic bipolar disorder, impaired inhibitory behavioral control was a specific cognitive impairment, distinct from the generalized neuropsychological impairment associated with psychotic disorders. Thus, in bipolar disorder with psychosis, a deficit in inhibitory control may contribute to risk for impulsive behavior. Because the deficit was not familial in bipolar families and showed a lack of independence from the generalized cognitive deficit in schizophrenia spectrum disorders, it appears to be a trait related to illness processes rather than one tracking familial risk factors. PMID:25261042

  8. Cerebrolysin Ameloriates Cognitive Deficits in Type III Diabetic Rats.

    PubMed

    Georgy, Gehan S; Nassar, Noha N; Mansour, Hanaa A; Abdallah, Dalaal M

    2013-01-01

    Cerebrolysin (CBL), a mixture of several active peptide fragments and neurotrophic factors including brain-derived neurotrophic factor (BDNF), is currently used in the management of cognitive alterations in patients with dementia. Since Cognitive decline as well as increased dementia are strongly associated with diabetes and previous studies addressed the protective effect of BDNF in metabolic syndrome and type 2 diabetes; hence this work aimed to evaluate the potential neuroprotective effect of CBL in modulating the complications of hyperglycaemia experimentally induced by streptozotocin (STZ) on the rat brain hippocampus. To this end, male adult Sprague Dawley rats were divided into (i) vehicle- (ii) CBL- and (iii) STZ diabetic-control as well as (iv) STZ+CBL groups. Diabetes was confirmed by hyperglycemia and elevated glycated haemoglobin (HbA1c%), which were associated by weight loss, elevated tumor necrosis factor (TNF)-α and decreased insulin growth factor (IGF)-1β in the serum. Uncontrolled hyperglycemia caused learning and memory impairments that corroborated degenerative changes, neuronal loss and expression of caspase (Casp)-3 in the hippocampal area of STZ-diabetic rats. Behavioral deficits were associated by decreased hippocampal glutamate (GLU), glycine, serotonin (5-HT) and dopamine. Moreover, diabetic rats showed an increase in hippocampal nitric oxide and thiobarbituric acid reactive substances versus decreased non-protein sulfhydryls. Though CBL did not affect STZ-induced hyperglycemia, it partly improved body weight as well as HbA1c%. Such effects were associated by enhancement in both learning and memory as well as apparent normal cellularity in CA1and CA3 areas and reduced Casp-3 expression. CBL improved serum TNF-α and IGF-1β, GLU and 5-HT as well as hampering oxidative biomarkers. In conclusion, CBL possesses neuroprotection against diabetes-associated cerebral neurodegeneration and cognitive decline via anti-inflammatory, antioxidant and

  9. Neuregulin 1 improves cognitive deficits and neuropathology in an Alzheimer’s disease model

    PubMed Central

    Xu, Jiqing; de Winter, Fred; Farrokhi, Catherine; Rockenstein, Edward; Mante, Michael; Adame, Anthony; Cook, Jonathan; Jin, Xin; Masliah, Eliezer; Lee, Kuo-Fen

    2016-01-01

    Several lines of evidence suggest that neuregulin 1 (NRG1) signaling may influence cognitive function and neuropathology in Alzheimer’s disease (AD). To test this possibility, full-length type I or type III NRG1 was overexpressed via lentiviral vectors in the hippocampus of line 41 AD mouse. Both type I and type III NRG1 improves deficits in the Morris water-maze behavioral task. Neuropathology was also significantly ameliorated. Decreased expression of the neuronal marker MAP2 and synaptic markers PSD95 and synaptophysin in AD mice was significantly reversed. Levels of Aβ peptides and plaques were markedly reduced. Furthermore, we showed that soluble ectodomains of both type I and type III NRG1 significantly increased expression of Aβ-degrading enzyme neprilysin (NEP) in primary neuronal cultures. Consistent with this finding, immunoreactivity of NEP was increased in the hippocampus of AD mice. These results suggest that NRG1 provides beneficial effects in candidate neuropathologic substrates of AD and, therefore, is a potential target for the treatment of AD. PMID:27558862

  10. Bacopaside I ameliorates cognitive impairment in APP/PS1 mice via immune-mediated clearance of β-amyloid

    PubMed Central

    Li, Yuanyuan; Yuan, Xing; Shen, Yunheng; Zhao, Jing; Yue, Rongcai; Liu, Fang; He, Weiwei; Wang, Rui; Shan, Lei; Zhang, Weidong

    2016-01-01

    Standardized extracts of Bacopa monniera (BME) have been shown to exert a neuroprotective effect against mental diseases, such as depression, anxiety and Alzheimer's disease (AD), in chronic administration studies. However, its mechanism of action has remained unclear. In this study, we evaluated the therapeutic effect of Bacopaside I (BS-I), a major triterpenoid saponin of BME, on the cognitive impairment and neuropathology in APP/PS1 transgenic mice and explored the possible mechanism from a biological systems perspective. We found that BS-I treatment significantly ameliorated learning deficits, improved long-term spatial memory, and reduced plaque load in APP/PS1 mice. We constructed BS-I's therapeutic effect network by mapping the nodes onto the protein-protein interaction (PPI) network constructed according to their functional categories based on genomic and proteomic data. Because many of the top enrichment categories related to the processes of the immune system and phagocytosis were detected, we proposed that BS-I promotes amyloid clearance via the induction of a suitable degree of innate immune stimulation and phagocytosis. Our research may help to clarify the neuroprotective effect of BME and indicated that natural saponins target the immune system, which may offer new research avenues to discover novel treatments for AD. PMID:26946062

  11. Pharmacological Cognitive Enhancement in Healthy Individuals: A Compensation for Cognitive Deficits or a Question of Personality?

    PubMed Central

    Maier, Larissa J.; Wunderli, Michael D.; Vonmoos, Matthias; Römmelt, Andreas T.; Baumgartner, Markus R.; Seifritz, Erich

    2015-01-01

    The ongoing bioethical debate on pharmacological cognitive enhancement (PCE) in healthy individuals is often legitimated by the assumption that PCE will widely spread and become desirable for the general public in the near future. This assumption was questioned as PCE is not equally save and effective in everyone. Additionally, it was supposed that the willingness to use PCE is strongly personality-dependent likely preventing a broad PCE epidemic. Thus, we investigated whether the cognitive performance and personality of healthy individuals with regular nonmedical methylphenidate (MPH) use for PCE differ from stimulant-naïve controls. Twenty-five healthy individuals using MPH for PCE were compared with 39 age-, sex-, and education-matched healthy controls regarding cognitive performance and personality assessed by a comprehensive neuropsychological test battery including social cognition, prosocial behavior, decision-making, impulsivity, and personality questionnaires. Substance use was assessed through self-report in an interview and quantitative hair and urine analyses. Recently abstinent PCE users showed no cognitive impairment but superior strategic thinking and decision-making. Furthermore, PCE users displayed higher levels of trait impulsivity, novelty seeking, and Machiavellianism combined with lower levels of social reward dependence and cognitive empathy. Finally, PCE users reported a smaller social network and exhibited less prosocial behavior in social interaction tasks. In conclusion, the assumption that PCE use will soon become epidemic is not supported by the present findings as PCE users showed a highly specific personality profile that shares a number of features with illegal stimulant users. Lastly, regular MPH use for PCE is not necessarily associated with cognitive deficits. PMID:26107846

  12. The Boehm Test of Basic Concepts: Exploring the Test Results for Cognitive Deficits.

    ERIC Educational Resources Information Center

    Spector, Cecile C.

    1979-01-01

    Analysis of errors by more than 300 kindergarten children on the Boehm Test of Basic Concepts suggested seven cognitive factors that appear to be involved, including complexity of directions, deficits in spatial perception, and inadequate auditory memory for sentences. (CL)

  13. Autologous transplantation of intestine-isolated glia cells improves neuropathology and restores cognitive deficits in β amyloid-induced neurodegeneration

    PubMed Central

    Esposito, Giuseppe; Sarnelli, Giovanni; Capoccia, Elena; Cirillo, Carla; Pesce, Marcella; Lu, Jie; Calì, Gaetano; Cuomo, Rosario; Steardo, Luca

    2016-01-01

    Alzheimer’s disease (AD) is characterized by chronic deposition of β-amyloid (Aβ) in the brain, progressive neurodegeneration and consequent cognitive and behavioral deficits that typify the disease. Astrocytes are pivotal in this process because they are activated in the attempt to digest Aβ which starts a neuroinflammatory response that further contributes to neurodegeneration. The intestine is a good source of astrocytes-like cells-referred to as enteric glial cells (EGCs). Here we show that the autologous transplantation of EGCs into the brain of Aβ-injected rats arrested the development of the disease after their engraftment. Transplanted EGCs showed anti-amyloidogenic activity, embanked Aβ-induced neuroinflammation and neurodegeneration, and released neutrophic factors. The overall result was the amelioration of the pathological hallmarks and the cognitive and behavioral deficits typical of Aβ-associated disease. Our data indicate that autologous EGCs transplantation may provide an efficient alternative for applications in cell-replacement therapies to treat neurodegeneration in AD. PMID:26940982

  14. Autophagy ameliorates cognitive impairment through activation of PVT1 and apoptosis in diabetes mice.

    PubMed

    Li, Zhigui; Hao, Shuang; Yin, Hongqiang; Gao, Jing; Yang, Zhuo

    2016-05-15

    The underlying mechanisms of cognitive impairment in diabetes remain incompletely characterized. Here we show that the autophagic inhibition by 3-methyladenine (3-MA) aggravates cognitive impairment in streptozotocin-induced diabetic mice, including exacerbation of anxiety-like behaviors and aggravation in spatial learning and memory, especially the spatial reversal memory. Further neuronal function identification confirmed that both long term potentiation (LTP) and depotentiation (DPT) were exacerbated by autophagic inhibition in diabetic mice, which indicating impairment of synaptic plasticity. However, no significant change of pair-pulse facilitation (PPF) was recorded in diabetic mice with autophagic suppression compared with the diabetic mice, which indicated that presynaptic function was not affected by autophagic inhibition in diabetes. Subsequent hippocampal neuronal cell death analysis showed that the apoptotic cell death, but not the regulated necrosis, significantly increased in autophagic suppression of diabetic mice. Finally, molecular mechanism that may lead to cell death was identified. The long non-coding RNA PVT1 (plasmacytoma variant translocation 1) expression was analyzed, and data revealed that PVT1 was decreased significantly by 3-MA in diabetes. These findings show that PVT1-mediated autophagy may protect hippocampal neurons from impairment of synaptic plasticity and apoptosis, and then ameliorates cognitive impairment in diabetes. These intriguing findings will help pave the way for exciting functional studies of autophagy in cognitive impairment and diabetes that may alter the existing paradigms. PMID:26971628

  15. Cognitive Patterns and Learning Disabilities in Cleft Palate Children with Verbal Deficits.

    ERIC Educational Resources Information Center

    Richman, Lynn C.

    1980-01-01

    The study examined patterns of cognitive ability in 57 cleft lip and palate children (ages 7 to 9) with verbal deficit, but without general intellectual retardation to evaluate whether the verbal disability displayed by these children was related primarily to a specific verbal expression deficit or a more general symbolic mediation problem.…

  16. Number Processing and Heterogeneity of Developmental Dyscalculia: Subtypes with Different Cognitive Profiles and Deficits

    ERIC Educational Resources Information Center

    Skagerlund, Kenny; Träff, Ulf

    2016-01-01

    This study investigated if developmental dyscalculia (DD) in children with different profiles of mathematical deficits has the same or different cognitive origins. The defective approximate number system hypothesis and the access deficit hypothesis were tested using two different groups of children with DD (11-13 years old): a group with…

  17. Temporal Processing Deficits of Language-Learning Impaired Children Ameliorated by Training

    NASA Astrophysics Data System (ADS)

    Merzenich, Michael M.; Jenkins, William M.; Johnston, Paul; Schreiner, Christoph; Miller, Steven L.; Tallal, Paula

    1996-01-01

    Children with language-based learning impairments (LLIs) have major deficits in their recognition of some rapidly successive phonetic elements and nonspeech sound stimuli. In the current study, LLI children were engaged in adaptive training exercises mounted as computer "games" designed to drive improvements in their "temporal processing" skills. With 8 to 16 hours of training during a 20-day period, LLI children improved markedly in their abilities to recognize brief and fast sequences of nonspeech and speech stimuli.

  18. Cross-training in hemispatial neglect: auditory sustained attention training ameliorates visual attention deficits.

    PubMed

    Van Vleet, Thomas M; DeGutis, Joseph M

    2013-03-01

    Prominent deficits in spatial attention evident in patients with hemispatial neglect are often accompanied by equally prominent deficits in non-spatial attention (e.g., poor sustained and selective attention, pronounced vigilance decrement). A number of studies now show that deficits in non-spatial attention influence spatial attention. Treatment strategies focused on improving vigilance or sustained attention may effectively remediate neglect. For example, a recent study employing Tonic and Phasic Alertness Training (TAPAT), a task that requires monitoring a constant stream of hundreds of novel scenes, demonstrated group-level (n=12) improvements after training compared to a test-retest control group or active treatment control condition on measures of visual search, midpoint estimation and working memory (DeGutis and Van Vleet, 2010). To determine whether the modality of treatment or stimulus novelty are key factors to improving hemispatial neglect, we designed a similar continuous performance training task in which eight patients with chronic and moderate to severe neglect were challenged to rapidly and continuously discriminate a limited set of centrally presented auditory tones once a day for 9 days (36-min/day). All patients demonstrated significant improvement in several, untrained measures of spatial and non-spatial visual attention, and as a group failed to demonstrate a lateralized attention deficit 24-h post-training compared to a control group of chronic neglect patients who simply waited during the training period. The results indicate that TAPAT-related improvements in hemispatial neglect are likely due to improvements in the intrinsic regulation of supramodal, non-spatial attentional resources. PMID:22578712

  19. Effect of Treating Anxiety Disorders on Cognitive Deficits and Behaviors Associated with Attention Deficit Hyperactivity Disorder: A Preliminary Study.

    PubMed

    Denis, Isabelle; Guay, Marie-Claude; Foldes-Busque, Guillaume; BenAmor, Leila

    2016-06-01

    Twenty-five percent of children with ADHD also have an anxiety disorder (AD). As per Quay and in light of Barkley's model, anxiety may have a protective effect on cognitive deficits and behaviors associated with ADHD. This study aimed to evaluate the effect of treating AD on cognitive deficits and behaviors associated with ADHD in children with both disorders. Twenty-four children with ADHD and AD were divided into two groups: treatment for AD, and wait list. Participants were assessed at pre-treatment, post-treatment, and 6-month follow-up with the ADIS-C, the CBCL, and neuropsychological measures. The results revealed a significant improvement in automatic response inhibition and flexibility, and a decrease in inattention/hyperactivity behaviors following the treatment for AD. No significant differences were observed in motor response inhibition, working memory, or attention deficits. The results do not seem to support Quay's hypothesis: treating AD did not exacerbate cognitive deficits and behaviors associated with ADHD in our sample. PMID:26323585

  20. High fat diet-induced diabetes in mice exacerbates cognitive deficit due to chronic hypoperfusion.

    PubMed

    Zuloaga, Kristen L; Johnson, Lance A; Roese, Natalie E; Marzulla, Tessa; Zhang, Wenri; Nie, Xiao; Alkayed, Farah N; Hong, Christine; Grafe, Marjorie R; Pike, Martin M; Raber, Jacob; Alkayed, Nabil J

    2016-07-01

    Diabetes causes endothelial dysfunction and increases the risk of vascular cognitive impairment. However, it is unknown whether diabetes causes cognitive impairment due to reductions in cerebral blood flow or through independent effects on neuronal function and cognition. We addressed this using right unilateral common carotid artery occlusion to model vascular cognitive impairment and long-term high-fat diet to model type 2 diabetes in mice. Cognition was assessed using novel object recognition task, Morris water maze, and contextual and cued fear conditioning. Cerebral blood flow was assessed using arterial spin labeling magnetic resonance imaging. Vascular cognitive impairment mice showed cognitive deficit in the novel object recognition task, decreased cerebral blood flow in the right hemisphere, and increased glial activation in white matter and hippocampus. Mice fed a high-fat diet displayed deficits in the novel object recognition task, Morris water maze and fear conditioning tasks and neuronal loss, but no impairments in cerebral blood flow. Compared to vascular cognitive impairment mice fed a low fat diet, vascular cognitive impairment mice fed a high-fat diet exhibited reduced cued fear memory, increased deficit in the Morris water maze, neuronal loss, glial activation, and global decrease in cerebral blood flow. We conclude that high-fat diet and chronic hypoperfusion impair cognitive function by different mechanisms, although they share commons features, and that high-fat diet exacerbates vascular cognitive impairment pathology. PMID:26661233

  1. Recurrent Moderate Hypoglycemia Ameliorates Brain Damage and Cognitive Dysfunction Induced by Severe Hypoglycemia

    PubMed Central

    Puente, Erwin C.; Silverstein, Julie; Bree, Adam J.; Musikantow, Daniel R.; Wozniak, David F.; Maloney, Susan; Daphna-Iken, Dorit; Fisher, Simon J.

    2010-01-01

    OBJECTIVE Although intensive glycemic control achieved with insulin therapy increases the incidence of both moderate and severe hypoglycemia, clinical reports of cognitive impairment due to severe hypoglycemia have been highly variable. It was hypothesized that recurrent moderate hypoglycemia preconditions the brain and protects against damage caused by severe hypoglycemia. RESEARCH DESIGN AND METHODS Nine-week-old male Sprague-Dawley rats were subjected to either 3 consecutive days of recurrent moderate (25–40 mg/dl) hypoglycemia (RH) or saline injections. On the fourth day, rats were subjected to a hyperinsulinemic (0.2 units · kg−1 · min−1) severe hypoglycemic (∼11 mg/dl) clamp for 60 or 90 min. Neuronal damage was subsequently assessed by hematoxylin-eosin and Fluoro-Jade B staining. The functional significance of severe hypoglycemia–induced brain damage was evaluated by motor and cognitive testing. RESULTS Severe hypoglycemia induced brain damage and striking deficits in spatial learning and memory. Rats subjected to recurrent moderate hypoglycemia had 62–74% less brain cell death and were protected from most of these cognitive disturbances. CONCLUSIONS Antecedent recurrent moderate hypoglycemia preconditioned the brain and markedly limited both the extent of severe hypoglycemia–induced neuronal damage and associated cognitive impairment. In conclusion, changes brought about by recurrent moderate hypoglycemia can be viewed, paradoxically, as providing a beneficial adaptive response in that there is mitigation against severe hypoglycemia–induced brain damage and cognitive dysfunction. PMID:20086229

  2. Dissociable long-term cognitive deficits after frontal versus sensorimotor cortical contusions.

    PubMed

    Lindner, M D; Plone, M A; Cain, C K; Frydel, B; Francis, J M; Emerich, D F; Sutton, R L

    1998-03-01

    Cognitive deficits are the most enduring and disabling sequelae of human traumatic brain injury (TBI), but quantifying the magnitude, duration, and pattern of cognitive deficits produced by different types of TBI has received little emphasis in preclinical animal models. The objective of the present study was to use a battery of behavioral tests to determine if different impact sites produce different patterns of behavioral deficits and to determine how long behavioral deficits can be detected after TBI. Prior to surgery, rats were trained to criteria on delayed nonmatching to position, radial arm maze, and rotarod tasks. Rats received sham surgery (controls), midline frontal contusions (frontal TBI, 2.25 m/sec impact), or unilateral sensorimotor cortex contusions (lateral TBI, 3.22 m/sec impact) at 12 months of age and were tested throughout the next 12 months. Cognitive deficits were more robust and more enduring than sensorimotor deficits for both lateral TBI and frontal TBI groups. Lateral TBI rats exhibited transient deficits in the forelimb placing and in the rotarod test of motor/ambulatory function, but cognitive deficits were apparent throughout the 12-month postsurgery period on tests of spatial learning and memory including: (1)reacquisition of a working memory version of the radial arm maze 6-7 months post-TBI, (2) performance in water maze probe trials 8 months post-TBI, and (3) repeated acquisition of the Morris water maze 8 and 11 months post-TBI. Frontal TBI rats exhibited a different pattern of deficits, with the most robust deficits in tests of attention/orientation such as: (1) the delayed nonmatching to position task (even with no delays) 1-11 weeks post-TBI, (2) the repeated acquisition version of the water maze--especially on the first "information" trial 8 months post-TBI, (3) a test of sensorimotor neglect or inattention 8.5 months post-TBI, and (4) a DRL20 test of timing and/or sustained attention 11 months after surgery. These results

  3. Satureja bachtiarica ameliorate beta-amyloid induced memory impairment, oxidative stress and cholinergic deficit in animal model of Alzheimer's disease.

    PubMed

    Soodi, Maliheh; Saeidnia, Soodabeh; Sharifzadeh, Mohammad; Hajimehdipoor, Homa; Dashti, Abolfazl; Sepand, Mohammad Reza; Moradi, Shahla

    2016-04-01

    Extracellular deposition of Beta-amyloid peptide (Aβ) is the main finding in the pathophysiology of Alzheimer's disease (AD), which damages cholinergic neurons through oxidative stress and reduces the cholinergic neurotransmission. Satureja bachtiarica is a medicinal plant from the Lamiaceae family which was widely used in Iranian traditional medicine. The aim of the present study was to investigate possible protective effects of S. bachtiarica methanolic extract on Aβ induced spatial memory impairment in Morris Water Maze (MWM), oxidative stress and cholinergic neuron degeneration. Pre- aggregated Aβ was injected into the hippocampus of each rat bilaterally (10 μg/rat) and MWM task was performed 14 days later to evaluate learning and memory function. Methanolic extract of S.bachtiarica (10, 50 and 100 mg/Kg) was injected intraperitoneally for 19 consecutive days, after Aβ injection. After the probe test the brain tissue were collected and lipid peroxidation, Acetylcholinesterase (AChE) activity and Cholin Acetyl Transferees (ChAT) immunorectivity were measured in the hippocampus. Intrahipocampal injection of Aβ impaired learning and memory in MWM in training days and probe trail. Methanolic extract of S. bachtiarica (50 and 100 mg/Kg) could attenuate Aβ-induced memory deficit. ChAT immunostaining revealed that cholinergic neurons were loss in Aβ- injected group and S. bachtiarica (100 mg/Kg) could ameliorate Aβ- induced ChAT reduction in the hippocampus. Also S. bachtiarica could ameliorate Aβ-induced lipid peroxidation and AChE activity increase in the hippocampus. In conclusion our study represent that S.bachtiarica methanolic extract can improve Aβ-induced memory impairment and cholinergic loss then we recommended this extract as a candidate for further investigation in treatment of AD. PMID:26638718

  4. Metacognition-augmented cognitive remediation training reduces jumping to conclusions and overconfidence but not neurocognitive deficits in psychosis

    PubMed Central

    Moritz, Steffen; Thoering, Teresa; Kühn, Simone; Willenborg, Bastian; Westermann, Stefan; Nagel, Matthias

    2015-01-01

    The majority of patients with schizophrenia display neurocognitive deficits (e.g., memory impairment) as well as inflated cognitive biases (e.g., jumping to conclusions). Both cognitive domains are implicated in the pathogenesis of the disorder and are known to compromise functional outcome. At present, there is a dearth of effective treatment options. A total of 90 patients with schizophrenia were recruited online (a diagnosis of schizophrenia had been confirmed in a large subgroup during a previous hospital admission). Subsequent to a baseline assessment encompassing psychopathology, self-reported cognition as well as objective memory and reasoning tests, patients were randomized to one of three conditions: standard cognitive remediation (mybraintraining), metacognition-augmented cognition remediation (CR) condition (variant of mybraintraining which encouraged patients to reduce speed of decision-making and attenuate response confidence when participants made high-confidence judgements and hasty incorrect decisions) and a waitlist control group. Patients were retested after 6 weeks and again 3 months after the second assessment. Groups did not differ on psychopathology and neurocognitive parameters at any timepoint. However, at follow-up the metacognitive-augmented CR group displayed a significant reduction on jumping to conclusions and overconfidence. Treatment adherence correlated with a reduction of depression; gains in the training exercises from the standard mybraintraining condition were correlated with improved objective memory performance. The study suggests that metacognition-augmented CR may ameliorate cognitive biases but not neurocognition. The study ties in well with prior research showing that neurocognitive dysfunctions are rather resistant to change; the failure to detect significant improvement of CR or metacognition-augmented CR on psychopathology and neurocognition over time may partly be attributed to a number of methodological limitations of

  5. Should Sluggish Cognitive Tempo Symptoms Be Included in the Diagnosis of Attention-Deficit/hyperactivity Disorder?

    ERIC Educational Resources Information Center

    Todd, Richard D.; Rasmussen, Erik R.; Wood, Catherine; Levy, Florence; Hay, David A.

    2004-01-01

    Objective: To determine the impact of including sluggish cognitive tempo items on the factor and latent class structure of attention-deficit/hyperactivity disorder (ADHD) subtypes in boys and girls. Method: Parent report of two sluggish cognitive tempo items on a population-based sample of 1,430 female twins and 1,414 male twins were analyzed…

  6. Cognitive-Linguistic Deficit and Speech Intelligibility in Chronic Progressive Multiple Sclerosis

    ERIC Educational Resources Information Center

    Mackenzie, Catherine; Green, Jan

    2009-01-01

    Background: Multiple sclerosis is a disabling neurological disease with varied symptoms, including dysarthria and cognitive and linguistic impairments. Association between dysarthria and cognitive-linguistic deficit has not been explored in clinical multiple sclerosis studies. Aims: In patients with chronic progressive multiple sclerosis, the…

  7. Specific cognitive deficits and differential domains of social functioning impairment in schizophrenia.

    PubMed

    Cohen, Alex S; Forbes, Courtney B; Mann, Monica C; Blanchard, Jack J

    2006-01-31

    There is considerable inconsistency in findings regarding the relationship between specific cognitive deficits and social impairment in patients with schizophrenia. This inconsistency may relate to variability across studies in how social functioning is measured and preliminary evidence suggests that different indices of social functioning (e.g., laboratory test, community assessment) may have different cognitive correlates. The present study examined this issue by evaluating the relationships between cognitive deficits (including social cognitive deficits), role-play test performance, and community social functioning in 28 inpatients with schizophrenia. We expected the two measures of social functioning to have only modest convergence with each other. Moreover, informed by the literature on cognitive functioning in schizophrenia, we identified specific cognitive processes that were hypothesized to be associated with role-play performance (delayed verbal memory and attentional vigilance) and social functioning in the community (delayed verbal memory and executive functioning). As expected, the two measures of social functioning were modestly correlated with each other. Community social functioning was associated with a relatively constrained pattern of cognitive deficits and received a significant contribution (Deltar2=0.24) from specific cognitive processes beyond that of general cognitive functioning and symptom severity. In contrast to our hypotheses, role-play test performance was associated with a wide range of cognitive impairments and received little contribution from the specific cognitive processes beyond the effects of general cognitive functioning. Community social functioning, but not role-play test performance, was significantly associated with social cognition. These findings highlight the importance of conceptualizing social functioning as a multidimensional construct for schizophrenia research. PMID:16260120

  8. GM1 ganglioside reverses the cognitive deficits induced by MK801 in mice.

    PubMed

    Ni, Yu-Fei; Zhang, Wei; Bao, Xiao-Feng; Wang, Wei; Song, Lu; Jiang, Bo

    2016-08-01

    Cognitive deficits are core symptoms of schizophrenia, but effective treatments are still lacking. Previous studies have reported that the brain-derived neurotrophic factor (BDNF) signaling is closely involved in learning and memory. Monosialotetrahexosylganglioside (GM1) is a ganglioside with wide-ranging pharmacologic effects that enhances the BDNF signaling cascade. This study aimed to assess the effects of GM1 on schizophrenia-related cognitive impairments. A brief disruption of N-methyl-D-aspartate receptors with MK801 was used to generate the animal model for cognitive deficits in schizophrenia. It was found that MK801-treated mice showed significant deficits in memory ability compared with control mice in different behavior tests, and this was accompanied by decreased hippocampal BDNF signaling pathway. Consecutive administration of GM1 fully restored the MK801-induced cognitive deficits and the impaired BDNF signaling in the hippocampus. Furthermore, a BDNF system inhibitor abolished the effects of GM1 in the MK801 model. Taken together, our results show that GM1 could reverse the MK801-induced cognitive deficits, suggesting a potential usefulness of GM1 in treating the schizophrenia-related cognitive impairments. PMID:26960162

  9. Cognitive deficits triggered by early life stress: The role of histone deacetylase 1.

    PubMed

    Adler, Samantha M; Schmauss, Claudia

    2016-10-01

    Studies showed that histone deacetylase (HDAC) inhibitors can reverse cognitive deficits found in neurodegenerative disorders and age-related memory decline. However, the role of HDACs in stress-induced cognitive deficits has not been investigated. In the stress-susceptible mouse strain Balb/c, early life stress triggers a persistent decrease in HDAC expression in the forebrain neocortex, including reduced expression of class I HDACs. The same mice show pronounced cognitive deficits in adulthood, namely deficits in working memory and attention set-shifting. Here we show that these mice also exhibit reduced association of HDAC1 with promotor III of the brain-derived neurotrophic factor (Bdnf) gene, and that cognitive testing leads to abnormally increased Bdnf mRNA expression. A pharmacological reduction of Bdnf-tropomyosine kinase B receptor signaling effectively reverses the cognitive deficits, indicating that enhanced transcriptional activation of the Bdnf gene contributes to their emergence. In contrast to Balb/c mice, C57Bl/6 mice only develop attention set-shifting deficits when raised by Balb/c foster mothers during the time the pups are exposed to early life stress. HDAC1 levels at Bdnf promotor III are unaltered in such C57Bl/6 mice, although they exhibit decreased levels of HDAC1 at the promotor of the early-growth response gene 2 (Egr2) and abnormally increased Egr2 mRNA expression after cognitive testing. Hence, contrary to the beneficial effects of HDAC inhibition in neurodegenerative diseases, the reduced HDAC1 levels at promotors of distinct plasticity-associated genes predispose animals exposed to early life stress to enhanced expression of these genes upon cognitive challenge, an effect that negatively influences cognitive task performance. PMID:27260837

  10. Epigenetic modifications by inhibiting histone deacetylases reverse memory impairment in insulin resistance induced cognitive deficit in mice.

    PubMed

    Sharma, Sorabh; Taliyan, Rajeev

    2016-06-01

    Insulin resistance has been reported as a strong risk factor for Alzheimer's disease. However the molecular mechanisms of association between these still remain elusive. Various studies have highlighted the involvement of histone deacetylases (HDACs) in insulin resistance and cognitive deficits. Thus, the present study was designed to investigate the possible neuroprotective role of HDAC inhibitor, suberoylanilide hydroxamic acid (SAHA) in insulin resistance induced cognitive impairment in mice. Mice were subjected to either normal pellet diet (NPD) or high fat diet (HFD) for 8 weeks. HFD fed mice were treated with SAHA at 25 and 50 mg/kg i.p. once daily for 2 weeks. Serum insulin, glucose, triglycerides, total cholesterol and HDL-cholesterol levels were measured. A battery of behavioral parameters was performed to assess cognitive functions. Level of tumour necrosis factor (TNF-α) was measured in hippocampus to assess neuroinflammation. To further explore the molecular mechanisms we measured the histone H3 acetylation and brain derived neurotrophic factor (BDNF) level. HFD fed mice exhibit characteristic features of insulin resistance. These mice also showed a severe deficit in learning and memory along with reduced histone H3 acetylation and BDNF levels. In contrast, the mice treated with SAHA showed significant and dose dependent improvement in insulin resistant condition. These mice also showed improved learning and memory performance. SAHA treatment ameliorates the HFD induced reduction in histone H3 acetylation and BDNF levels. Based upon these results, it could be suggested that HDAC inhibitors exert neuroprotective effects by increasing H3 acetylation and subsequently BDNF level. PMID:26805421

  11. Uncovering the Neural Bases of Cognitive and Affective Empathy Deficits in Alzheimer's Disease and the Behavioral-Variant of Frontotemporal Dementia.

    PubMed

    Dermody, Nadene; Wong, Stephanie; Ahmed, Rebekah; Piguet, Olivier; Hodges, John R; Irish, Muireann

    2016-05-30

    Loss of empathy is a core presenting feature of the behavioral-variant of frontotemporal dementia (bvFTD), resulting in socioemotional difficulties and behavioral transgressions. In contrast, interpersonal functioning remains relatively intact in Alzheimer's disease (AD), despite marked cognitive decline. The neural substrates mediating these patterns of loss and sparing in social functioning remain unclear, yet are relevant for our understanding of the social brain. We investigated cognitive versus affective aspects of empathy using the Interpersonal Reactivity Index (IRI) in 25 AD and 24 bvFTD patients and contrasted their performance with 22 age- and education-matched controls. Cognitive empathy was comparably compromised in AD and bvFTD, whereas affective empathy was impaired exclusively in bvFTD. While controlling for overall cognitive dysfunction ameliorated perspective-taking deficits in AD, empathy loss persisted across cognitive and affective domains in bvFTD. Voxel-based morphometry analyses revealed divergent neural substrates of empathy loss in each patient group. Perspective-taking deficits correlated with predominantly left-sided temporoparietal atrophy in AD, whereas widespread bilateral frontoinsular, temporal, parietal, and occipital atrophy was implicated in bvFTD. Reduced empathic concern in bvFTD was associated with atrophy in the left orbitofrontal, inferior frontal, and insular cortices, and the bilateral mid-cingulate gyrus. Our findings suggest that social cognitive deficits in AD arise largely as a consequence of global cognitive dysfunction, rather than a loss of empathy per se. In contrast, loss of empathy in bvFTD reflects the deterioration of a distributed network of frontoinsular and temporal structures that appear crucial for monitoring and processing social information. PMID:27258418

  12. Review of recent studies on interventions for cognitive deficits in patients with cancer.

    PubMed

    Gehring, Karin; Roukema, Jan Anne; Sitskoorn, Margriet M

    2012-02-01

    Research has demonstrated that patients with cancer experience cognitive deficits, often due to aggressive anticancer treatments. In this article, we critically review the interventional studies that have been conducted to investigate beneficial effects on cognitive function in cancer patients. Pharmacological agents that have been studied include psychostimulants, such as methylphenidate and modafinil, erythropoietin, and hormonal (supplement) treatments for patients who receive hormonal suppression therapy. In addition, several cognitive rehabilitation programs have been evaluated in cancer patients. Recently, the approach of physical exercise to treat cognitive deficits has received great interest, and findings from novel studies are keenly anticipated. Although, in general, the studies reviewed were well designed, future studies may wish to include larger sample sizes and pay more attention to the accurate assessment of cognitive function. PMID:22316373

  13. Reinforcement and Stimulant Medication Ameliorate Deficient Response Inhibition in Children with Attention-Deficit/Hyperactivity Disorder.

    PubMed

    Rosch, Keri S; Fosco, Whitney D; Pelham, William E; Waxmonsky, James G; Bubnik, Michelle G; Hawk, Larry W

    2016-02-01

    This study examined the degree to which reinforcement, stimulant medication, and their combination impact response inhibition in children with Attention-Deficit/Hyperactivity Disorder (ADHD). Across three studies, participants with ADHD (n = 111, 25 girls) and typically-developing (TD) controls (n = 33, 6 girls) completed a standard version of the stop signal task (SST) and/or a reinforcement-manipulation SST with performance-contingent points. In two of these studies, these tasks were performed under placebo or 0.3 and 0.6 mg/kg methylphenidate (MPH) conditions. Cross-study comparisons were conducted to test hypotheses regarding the separate and combined effects of reinforcement and methylphenidate on response inhibition among children with ADHD relative to TD controls. Baseline response inhibition was worse among children with ADHD compared to controls. MPH produced dose-related improvements in response inhibition in children with ADHD; compared to non-medicated TD controls, 0.3 mg/kg MPH normalized deficient response inhibition, and 0.6 mg/kg MPH resulted in better inhibition in children with ADHD. Reinforcement improved response inhibition to a greater extent for children with ADHD than for TD children, normalizing response inhibition. The combination of MPH and reinforcement improved response inhibition among children with ADHD compared to reinforcement alone and MPH alone, also resulting in normalization of response inhibition despite repeated task exposure. Deficient response inhibition commonly observed in children with ADHD is significantly improved with MPH and/or reinforcement, normalizing inhibition relative to TD children tested under standard conditions. PMID:25985978

  14. Single administration of a novel γ-secretase modulator ameliorates cognitive dysfunction in aged C57BL/6J mice.

    PubMed

    Hayama, Tatsuya; Murakami, Koji; Watanabe, Tomomichi; Maeda, Ryota; Kamata, Makoto; Kondo, Shinichi

    2016-02-15

    Mutations in presenilin 1 (PS1) and presenilin 2 (PS2) are known to cause early onset of Alzheimer's disease (AD). These proteins comprise the catalytic domain of γ-secretase, which catalyzes the cleavage of β-amyloid (Aβ) from amyloid precursor protein (APP). In recent reports, PS1 and PS2 were linked to the modulation of intracellular calcium ion (Ca(2+)) dynamics, a key regulator of synaptic function. Ca(2+) dysregulation and synaptic dysfunction are leading hypothesis of cognitive dysfunctions during aging and AD progression. Accordingly, manipulations of presenilins by small molecules may have therapeutic potential for the treatment of cognitive dysfunction. In an accompanying report, we showed that chronic treatment with compound-1, a novel γ-secretase modulator (GSM), reduced Aβ production and ameliorated cognitive dysfunction in Tg2576 APP transgenic mice. Accordingly, in the present study we showed that single oral administration of compound-1 at 1 and 3mg/kg ameliorated cognitive dysfunction in aged non-transgenic mice. Moreover, compound-1 enhanced synaptic plasticity in hippocampal slices from aged C57BL/6J mice and increased messenger RNA (mRNA) expression of the immediate early gene c-fos, which has been shown to be related to synaptic plasticity in vivo. Finally, compound-1 modulated Ca(2+) signals through PS1 in mouse embryonic fibroblast cells. Taken together, compound-1 ameliorates both Aβ pathology and age-related cognitive dysfunctions. Hence, compound-1 may have potential as an early intervention for the cognitive declines that are commonly diagnosed in aged subjects, such as mild cognitive impairment (MCI) and prodromal AD. PMID:26707406

  15. Ursolic acid improves domoic acid-induced cognitive deficits in mice

    SciTech Connect

    Wu, Dong-mei; Lu, Jun; Zhang, Yan-qiu; Zheng, Yuan-lin; Hu, Bin; Cheng, Wei; Zhang, Zi-feng; Li, Meng-qiu

    2013-09-01

    Our previous findings suggest that mitochondrial dysfunction is the mechanism underlying cognitive deficits induced by domoic acid (DA). Ursolic acid (UA), a natural triterpenoid compound, possesses many important biological functions. Evidence shows that UA can activate PI3K/Akt signaling and suppress Forkhead box protein O1 (FoxO1) activity. FoxO1 is an important regulator of mitochondrial function. Here we investigate whether FoxO1 is involved in the oxidative stress-induced mitochondrial dysfunction in DA-treated mice and whether UA inhibits DA-induced mitochondrial dysfunction and cognitive deficits through regulating the PI3K/Akt and FoxO1 signaling pathways. Our results showed that FoxO1 knockdown reversed the mitochondrial abnormalities and cognitive deficits induced by DA in mice through decreasing HO-1 expression. Mechanistically, FoxO1 activation was associated with oxidative stress-induced JNK activation and decrease of Akt phosphorylation. Moreover, UA attenuated the mitochondrial dysfunction and cognitive deficits through promoting Akt phosphorylation and FoxO1 nuclear exclusion in the hippocampus of DA-treated mice. LY294002, an inhibitor of PI3K/Akt signaling, significantly decreased Akt phosphorylation in the hippocampus of DA/UA mice, which weakened UA actions. These results suggest that UA could be recommended as a possible candidate for the prevention and therapy of cognitive deficits in excitotoxic brain disorders. - Highlights: • Ursolic acid (UA) is a naturally triterpenoid compound. • UA attenuated the mitochondrial dysfunction and cognitive deficits. • Mechanistically, UA activates PI3K/Akt signaling and suppresses FoxO1 activity. • UA could be recommended as a possible candidate for anti-excitotoxic brain disorders.

  16. Cognitive Deficits in Nonretarded Adults with Fetal Alcohol Syndrome.

    ERIC Educational Resources Information Center

    Kerns, Kimberley A.; Don, Audrey; Mateer, Catherine A.; Streissguth, Ann P.

    1997-01-01

    Sixteen nonretarded young adults with fetal alcohol syndrome were divided into two groups, one with average to above average IQ and one with borderline to low average IQ. Subjects in both groups manifested clear deficits on neuropsychological measures sensitive to complex attention, verbal learning, and executive function at a frequency and…

  17. Static and Dynamic Cognitive Deficits in Childhood Preceding Adult Schizophrenia: A 30-Year Study

    PubMed Central

    Reichenberg, Abraham; Caspi, Avshalom; Harrington, HonaLee; Houts, Renate; Keefe, Richard S.E.; Murray, Robin M.; Poulton, Richie; Moffitt, Terrie E.

    2013-01-01

    Objective Premorbid cognitive deficits in schizophrenia are well documented and have been interpreted as supporting a neurodevelopmental etiological model. The authors investigated the following three unresolved questions about premorbid cognitive deficits: What is their developmental course? Do all premorbid cognitive deficits follow the same course? Are premorbid cognitive deficits specific to schizophrenia or shared by other psychiatric disorders? Methods Participants were members of a representative cohort of 1,037 males and females born between 1972 and 1973 in Dunedin, New Zealand. Cohort members underwent follow-up evaluations at specific intervals from age 3 to 32 years, with a 96% retention rate. Cognitive development was analyzed and compared in children who later developed schizophrenia or recurrent depression as well as in healthy comparison subjects. Results Children who developed adult schizophrenia exhibited developmental deficits (i.e., static cognitive impairments that emerge early and remain stable) on tests indexing verbal and visual knowledge acquisition, reasoning, and conceptualization. In addition, these children exhibited developmental lags (i.e., growth that is slower relative to healthy comparison subjects) on tests indexing processing speed, attention, visual-spatial problem solving ability, and working memory. These two premorbid cognitive patterns were not observed in children who later developed recurrent depression. Conclusions These findings suggest that the origins of schizophrenia include two interrelated developmental processes evident from childhood to early adolescence (ages 7–13 years). Children who will grow up to develop adult schizophrenia enter primary school struggling with verbal reasoning and lag further behind their peers in working memory, attention, and processing speed as they get older. PMID:20048021

  18. Silymarin ameliorates memory deficits and neuropathological changes in mouse model of high-fat-diet-induced experimental dementia.

    PubMed

    Neha; Kumar, Amit; Jaggi, Amteshwar S; Sodhi, Rupinder K; Singh, Nirmal

    2014-08-01

    A huge body evidences suggest that obesity is the single great risk factor for the development of dementia. Recently, silymarin, a flavonoid, clinically in use as a hepatoprotectant, has been reported to prevent amyloid beta-induced memory impairment by reducing oxidative stress and inflammation in mice brain. However, its potential in high-fat-diet (HFD)-induced dementia has not yet been investigated. Therefore, the present study is designed to explore the role of silymarin in HFD-induced experimental dementia in mice. Morris water maze test was employed to assess learning and memory. Various biochemical estimations including brain acetylcholinerstarse activity (AchE), thiobarbituric acid-reactive species (TBARS) level, reduced glutathione level (GSH), nirate/nitrite, and myeloperoxidase (MPO) activity were measured. Serum cholesterol level was also determined. HFD significantly impaired the cognitive abilities, along with increasing brain AchE, TBARS, MPO, nitrate/nitrite, and serum cholesterol levels. Marked reduction of brain GSH levels was observed. On the contrary, silymarin significantly reversed HFD-induced cognitive deficits and the biochemical changes. The present study indicates strong potential of silymarin in HFD-induced experimental dementia. PMID:24866499

  19. Icariside II, a novel phosphodiesterase-5 inhibitor, attenuates streptozotocin-induced cognitive deficits in rats.

    PubMed

    Yin, Caixia; Deng, Yuanyuan; Gao, Jianmei; Li, Xiaohui; Liu, Yuangui; Gong, Qihai

    2016-07-22

    Beta-amyloid (Aβ) deposition and neuroinflammation are involved in Alzheimer's disease (AD)-type neurodegeneration with cognitive deficits. Phosphodiesterase-5 (PDE5) inhibitors have recently been studied as a potential target for cognitive enhancement by reducing inflammatory responses and Aβ levels. The present study was designed to investigate the effects of icariside II (ICS II), a novel PDE5 inhibitor derived from the traditional Chinese herb Epimedium brevicornum, on cognitive deficits, Aβ levels and neuroinflammation induced by intracerebroventricular-streptozotocin (ICV-STZ) in rats. The results demonstrated that ICV-STZ exhibited cognitive deficits and neuronal morphological damage, along with Aβ increase and neuroinflammation in the rat hippocampus. ICS II improved cognitive deficits, attenuated neuronal death, and decreased the levels of Aβ1-40, Aβ1-42 and PDE5 in the hippocampus of STZ rats. Furthermore, administration of ICS II at the dose of 10mg/kg for 21days significantly suppressed the expression of beta-amyloid precursor protein (APP), beta-secretase1 (BACE1) and increased the expressions of neprilysin (NEP) together with inhibited interleukin-1β (IL-1β), tumor necrosis factor (TNF)-α, cyclooxygenase-2 (COX-2) and transforming growth factor-β1 (TGF-β1) levels. In addition, ICS II exerted a beneficial effect on inhibition of IκB-α degradation and NF-κB activation induced by STZ. Taken together, the present study demonstrated that ICS II was a potential therapeutic agent for AD treatment. PMID:27109920

  20. Deficits in Domains of Social Cognition in Schizophrenia: A Meta-Analysis of the Empirical Evidence

    PubMed Central

    Savla, Gauri N.

    2013-01-01

    Objective: Social cognition is strongly associated with functional outcome in schizophrenia, making it an important target for treatment. Our goal was to examine the average magnitude of differences between schizophrenia patients (SCs) and normal comparison (NCs) patients across multiple domains of social cognition recognized by the recent NIMH consensus statement: theory of mind (ToM), social perception, social knowledge, attributional bias, emotion perception, and emotion processing. Method: We conducted a meta-analysis of peer-reviewed studies of social cognition in schizophrenia, published between 1980 and November, 2011. Results: 112 studies reporting results from 3908 SCs and 3570 NCs met our inclusion criteria. SCs performed worse than NCs across all domains, with large effects for social perception (g = 1.04), ToM (g = 0.96), emotion perception (g = 0.89), and emotion processing (g = 0.88). Regression analyses showed that statistically significant heterogeneity in effects within domains was not explained by age, education, or gender. Greater deficits in social and emotion perception were associated with inpatient status, and greater deficits in emotion processing were associated with longer illness duration. Conclusions: Despite the limitations of existing studies, including lack of standardization or psychometric validation of measures, the evidence for deficits across multiple social cognitive domains in schizophrenia is clear. Future research should examine the role of neurobiological and psychosocial factors in models linking various aspects of deficit in schizophrenia, including social cognition, in order to identify targets for intervention. PMID:22949733

  1. Anle138b Partly Ameliorates Motor Deficits Despite Failure of Neuroprotection in a Model of Advanced Multiple System Atrophy

    PubMed Central

    Fellner, Lisa; Kuzdas-Wood, Daniela; Levin, Johannes; Ryazanov, Sergey; Leonov, Andrei; Griesinger, Christian; Giese, Armin; Wenning, Gregor K.; Stefanova, Nadia

    2016-01-01

    The neurodegenerative disorder multiple system atrophy (MSA) is characterized by autonomic failure, cerebellar ataxia and parkinsonism in any combination associated with predominantly oligodendroglial α-synuclein (α-syn) aggregates (glial cytoplasmic inclusions = GCIs). To date, there is no effective disease modifying therapy. Previous experiments have shown that the aggregation inhibitor anle138b reduces neurodegeneration, as well as behavioral deficits in both transgenic and toxin mouse models of Parkinson's disease (PD). Here we analyzed whether anle138b improves motor skills and reduces neuronal loss, as well as oligodendroglial α-syn aggregation in the PLP-α-syn transgenic mouse challenged with the mitochondrial toxin 3-nitropropionic acid (3-NP) to model full-blown MSA. Following 1 month of treatment with anle138b, MSA mice showed signs of motor improvement affecting stride length, but not pole, grip strength, and beam test performance. Loss of dopaminergic nigral neurons and Purkinje cells was not attenuated and GCI density remained unchanged. These data suggest that the pathology in transgenic PLP-α-syn mice receiving 3-NP might be too advanced to detect significant effects of anle138b treatment on neuronal loss and intracytoplasmic α-syn inclusion bodies. However, the partial motor amelioration may indicate potential efficacy of anle138b treatment that may be mediated by its actions on α-syn oligomers or may reflect improvement of neuronal dysfunction in neural at risk populations. Further studies are required to address the efficacy of anle138b in transgenic α-syn models of early-stage MSA and in the absence of additional toxin application. PMID:27013960

  2. Amusia and cognitive deficits in schizophrenia: is there a relationship?

    PubMed

    Wen, Yi; Nie, Xueqing; Wu, Daxing; Liu, Hong; Zhang, Pin; Lu, Xuejing

    2014-08-01

    The current study explored the music perception ability of individuals diagnosed with schizophrenia and its relationship with other cognitive abilities and psychotic symptom severity. The persons with schizophrenia performed significantly worse than the control group on the Montreal Battery of Evaluation of Amusia (MBEA) (p<0.001). The music perception ability of persons with schizophrenia was related to other cognitive abilities (attention, verbal memory, spatial memory, and executive function) and the severity of psychotic symptoms. PMID:24957355

  3. Glatiramer acetate reverses cognitive deficits from cranial-irradiated rat by inducing hippocampal neurogenesis.

    PubMed

    He, Fen; Zou, Jun-Tao; Zhou, Qiong-Fang; Niu, Dao-Li; Jia, Wei-Hua

    2014-06-15

    Patients received cranial-irradiation can be affected with cognitive deficits and decreasing hippocampal neurogenesis. In this work, we characterized the cognitive ability and immune-induced neurogenesis of the pre- and post-treated cranial-irradiated rats with Glatiramer acetate (GA), known as a weak CNS auto-antigen. The GA-treated rats displayed better cognitive abilities in Morris water maze (MWM). The numbers of Iba-I-positive microglia, BrdU(+)/DCX(+) cells and BrdU(+)/NeuN(+) cells in hippocampus increased, which are accompanied with increased IFN-γ and decreased IL-6, IL-4. Furthermore, GA reverted the Th1/Th2 balance. GA treatment can reverse the cognitive deficits caused by cranial irradiation through a mechanism that likely involves immunomodulation. PMID:24713401

  4. Voluntary exercise does not ameliorate spatial learning and memory deficits induced by chronic administration of nandrolone decanoate in rats.

    PubMed

    Tanehkar, Fatemeh; Rashidy-Pour, Ali; Vafaei, Abbas Ali; Sameni, Hamid Reza; Haghighi, Saeed; Miladi-Gorji, Hossien; Motamedi, Fereshteh; Akhavan, Maziar Mohammad; Bavarsad, Kowsar

    2013-01-01

    Chronic exposure to the anabolic androgenic steroids (AAS) nandrolone decanoate (ND) in supra-physiological doses is associated with learning and memory impairments. Given the well-known beneficial effects of voluntary exercise on cognitive functions, we examined whether voluntary exercise would improve the cognitive deficits induced by chronic administration of ND. We also investigated the effects of ND and voluntary exercise on hippocampal BDNF levels. The rats were randomly distributed into 4 experimental groups: the vehicle-sedentary group, the ND-sedentary group, the vehicle-exercise group, and the ND-exercise group. The vehicle-exercise and the ND-exercise groups were allowed to freely exercise in a running wheel for 15 days. The vehicle-sedentary and the ND-sedentary groups were kept sedentary for the same period. Vehicle or ND injections were started 14 days prior to the voluntary exercise and continued throughout the 15 days of voluntary exercise. After the 15-day period, the rats were trained and tested on a water maze spatial task using four trials per day for 5 consecutive days followed by a probe trial two days later. Exercise significantly improved performance during both the training and retention of the water maze task, and enhanced hippocampal BDNF. ND impaired spatial learning and memory, and this effect was not rescued by exercise. ND also potentiated the exercise-induced increase in hippocampal BDNF levels. These results seem to indicate that voluntary exercise is unable to improve the disruption of cognitive functions by chronic ND. Moreover, increased levels of BDNF may play a role in ND-induced impairments in learning and memory. The harmful effects of ND and other AAS on learning and memory should be taken into account when athletes decide to use AAS for performance or body image improvement. PMID:23068768

  5. Cinnamomum loureirii Extract Inhibits Acetylcholinesterase Activity and Ameliorates Trimethyltin-Induced Cognitive Dysfunction in Mice.

    PubMed

    Kim, Cho Rong; Choi, Soo Jung; Kwon, Yoon Kyung; Kim, Jae Kyeom; Kim, Youn-Jung; Park, Gwi Gun; Shin, Dong-Hoon

    2016-01-01

    The pathogenesis of Alzheimer's disease (AD) has been linked to the deficiency of neurotransmitter acetylcholine (ACh) in the brain, and the main treatment strategy for improving AD symptoms is the inhibition of acetylcholinesterase (AChE) activity. In the present study, we aimed to identify potent AChE inhibitors from Cinnamomum loureirii extract via bioassay-guided fractionation. We demonstrated that the most potent AChE inhibitor present in the C. loureirii extract was 2,4-bis(1,1-dimethylethyl)phenol. To confirm the antiamnesic effects of the ethanol extract of C. loureirii, mice were intraperitoneally injected with the neurotoxin trimethyltin (2.5 mg/kg) to induce cognitive dysfunction, and performance in the Y-maze and passive avoidance tests was assessed. Treatment with C. loureirii extract significantly improved performance in both behavioral tests, suggesting that this extract may be neuroprotective and therefore beneficial in preventing or ameliorating the degenerative processes of AD, potentially by restoring cholinergic function. PMID:27374288

  6. Social cognitive deficits and their neural correlates in progressive supranuclear palsy

    PubMed Central

    Calder, Andrew J.; Peers, Polly V.; Lawrence, Andrew D.; Acosta-Cabronero, Julio; Pereira, João M.; Hodges, John R.; Rowe, James B.

    2012-01-01

    Although progressive supranuclear palsy is defined by its akinetic rigidity, vertical supranuclear gaze palsy and falls, cognitive impairments are an important determinant of patients’ and carers’ quality of life. Here, we investigate whether there is a broad deficit of modality-independent social cognition in progressive supranuclear palsy and explore the neural correlates for these. We recruited 23 patients with progressive supranuclear palsy (using clinical diagnostic criteria, nine with subsequent pathological confirmation) and 22 age- and education-matched controls. Participants performed an auditory (voice) emotion recognition test, and a visual and auditory theory of mind test. Twenty-two patients and 20 controls underwent structural magnetic resonance imaging to analyse neural correlates of social cognition deficits using voxel-based morphometry. Patients were impaired on the voice emotion recognition and theory of mind tests but not auditory and visual control conditions. Grey matter atrophy in patients correlated with both voice emotion recognition and theory of mind deficits in the right inferior frontal gyrus, a region associated with prosodic auditory emotion recognition. Theory of mind deficits also correlated with atrophy of the anterior rostral medial frontal cortex, a region associated with theory of mind in health. We conclude that patients with progressive supranuclear palsy have a multimodal deficit in social cognition. This deficit is due, in part, to progressive atrophy in a network of frontal cortical regions linked to the integration of socially relevant stimuli and interpretation of their social meaning. This impairment of social cognition is important to consider for those managing and caring for patients with progressive supranuclear palsy. PMID:22637582

  7. Female mice heterozygous for creatine transporter deficiency show moderate cognitive deficits.

    PubMed

    Hautman, Emily R; Kokenge, Amanda N; Udobi, Kenea C; Williams, Michael T; Vorhees, Charles V; Skelton, Matthew R

    2014-01-01

    Creatine transporter (CrT) deficiency (CTD) is an X-linked disorder characterized by intellectual disability and speech delay. There have been reports that show female carriers have clinical symptoms. We have created CrT knockout (CrT(-/y)) mice in which males show severe cognitive deficits as a model of this disorder. The purpose of this study was to examine if the female carrier mice show cognitive deficits. Reductions in Cr levels as well as CrT transcript were observed in the brains of the female CrT(+/-) mice. CrT(+/-) mice show hyperactivity and increased latency to find the cued platform in the Morris water maze (MWM). CrT(+/-) female mice showed deficits in MWM hidden platform acquisition but not during reversal testing. Memory deficits on probe trials were observed during both phases. Novel object recognition memory and contextual fear memory were not affected in female CrT(+/-) mice. Female CrT(+/-) mice show moderate cognitive deficits, which is consistent with some of the human data. Female CrT(+/-) mice could prove to be beneficial in further understanding CTD and testing therapeutic approaches. PMID:23716276

  8. The Relationship between Sluggish Cognitive Tempo, Subtypes of Attention-Deficit/Hyperactivity Disorder, and Anxiety Disorders

    ERIC Educational Resources Information Center

    Skirbekk, Benedicte; Hansen, Berit Hjelde; Oerbeck, Beate; Kristensen, Hanne

    2011-01-01

    The objective of the present study was to examine the relationship between sluggish cognitive tempo (SCT), subtypes of attention-deficit/hyperactivity disorder (ADHD), and anxiety disorders (AnxDs). One hundred and forty-one children (90 males, 51 females) aged 7-13 years were assigned to four groups, i.e., referred children with comorbid AnxDs…

  9. Understanding Cognitive Deficits in Parkinson's Disease: Lessons from Preclinical Animal Models

    ERIC Educational Resources Information Center

    Solari, Nicola; Bonito-Oliva, Alessandra; Fisone, Gilberto; Brambilla, Riccardo

    2013-01-01

    Parkinson's disease (PD) has been, until recently, mainly defined by the presence of characteristic motor symptoms, such as rigidity, tremor, bradykinesia/akinesia, and postural instability. Accordingly, pharmacological and surgical treatments have so far addressed these motor disturbances, leaving nonmotor, cognitive deficits an unmet…

  10. The Cognitive Profile and Multiple-Deficit Hypothesis in Chinese Developmental Dyslexia.

    ERIC Educational Resources Information Center

    Ho, Connie Suk-Han; Chan, David Wai-Ock; Tsang, Suk-Man; Lee, Suk-Han

    2002-01-01

    Examined cognitive profile and multiple-deficit hypothesis in Chinese developmental dyslexia. Compared 30 Chinese dyslexic children with average readers of the same chronological age (CA) and 30 average readers at the same reading level (RL) in several rapid naming, visual, phonological, and orthographic tasks. Found that dyslexic children…

  11. Specific Cognitive Deficits in ADHD: A Diagnostic Concern in Differential Diagnosis

    ERIC Educational Resources Information Center

    Gupta, Rashmi; Kar, Bhoomika R.

    2010-01-01

    We present a critical account of existing tools used to diagnose children with Attention Deficit Hyperactivity Disorder and to make a case for the assessment of cognitive impairments as a part of diagnostic system. Surveys have shown that clinicians rely almost entirely upon subjective reports or their own clinical judgment when arriving at…

  12. The Turner Syndrome: Cognitive Deficits, Affective Discrimination, and Behavior Problems.

    ERIC Educational Resources Information Center

    McCauley, Elizabeth; And Others

    1987-01-01

    The study attemped to link cognitive and social problems seen in girls with Turner syndrome by assessing the girls' ability to process affective cues. Seventeen 9- to 17-year-old girls diagnosed with Turner syndrome were compared to a matched control group on a task which required interpretation of affective intention from facial expression.…

  13. Ethanolic Extract of the Seed of Zizyphus jujuba var. spinosa Ameliorates Cognitive Impairment Induced by Cholinergic Blockade in Mice

    PubMed Central

    Lee, Hyung Eun; Lee, So Young; Kim, Ju Sun; Park, Se Jin; Kim, Jong Min; Lee, Young Woo; Jung, Jun Man; Kim, Dong Hyun; Shin, Bum Young; Jang, Dae Sik; Kang, Sam Sik; Ryu, Jong Hoon

    2013-01-01

    In the present study, we investigated the effect of ethanolic extract of the seed of Zizyphus jujuba var. spinosa (EEZS) on cholinergic blockade-induced memory impairment in mice. Male ICR mice were treated with EEZS. The behavioral tests were conducted using the passive avoidance, the Y-maze, and the Morris water maze tasks. EEZS (100 or 200 mg/kg, p.o.) significantly ameliorated the scopolamine-induced cognitive impairment in our present behavioral tasks without changes of locomotor activity. The ameliorating effect of EEZS on scopolamine-induced memory impairment was significantly reversed by a sub-effective dose of MK-801 (0.0125 mg/kg, s.c.). In addition, single administration of EEZS in normal naïve mouse enhanced latency time in the passive avoidance task. Western blot analysis was employed to confirm the mechanism of memory-ameliorating effect of EEZS. Administration of EEZS (200 mg/kg) increased the level of memory-related signaling molecules, including phosphorylation of extracellular signal-regulated kinase or cAMP response element-binding protein in the hippocampal region. Also, the time-dependent expression level of brain-derived neurotrophic factor by the administration of EEZS was markedly increased from 3 to 9 h. These results suggest that EEZS has memory-ameliorating effect on scopolamine-induced cognitive impairment, which is mediated by the enhancement of the cholinergic neurotransmitter system, in part, via NMDA receptor signaling, and that EEZS would be useful agent against cognitive dysfunction such as Alzheimer’s disease. PMID:24244815

  14. Cognitive mechanisms underlying achievement deficits in children with mathematical learning disability.

    PubMed

    Geary, David C; Hoard, Mary K; Byrd-Craven, Jennifer; Nugent, Lara; Numtee, Chattavee

    2007-01-01

    Using strict and lenient mathematics achievement cutoff scores to define a learning disability, respective groups of children who are math disabled (MLD, n=15) and low achieving (LA, n=44) were identified. These groups and a group of typically achieving (TA, n=46) children were administered a battery of mathematical cognition, working memory, and speed of processing measures (M=6 years). The children with MLD showed deficits across all math cognition tasks, many of which were partially or fully mediated by working memory or speed of processing. Compared with the TA group, the LA children were less fluent in processing numerical information and knew fewer addition facts. Implications for defining MLD and identifying underlying cognitive deficits are discussed. PMID:17650142

  15. Pyrroloquinoline quinone prevents MK-801-induced stereotypical behavior and cognitive deficits in mice.

    PubMed

    Zhou, Xingqin; Chen, Quancheng; Hu, Xindai; Mao, Shishi; Kong, Yanyan

    2014-01-01

    Pyrroloquinoline quinone (PQQ), an essential nutrient, antioxidant, redox modulator, and nerve growth factor, prevents cognitive deficits associated with oxidative stress-induced neurodegeneration. Previous molecular imaging studies also demonstrate that PQQ binds to N-methyl D-aspartate (NMDA) receptors. In this study, we investigated the effects of PQQ on stereotypical behaviors and cognitive deficits induced by MK-801, a non-competitive NMDA antagonist used to model schizophrenia. Mice were given repeated injections of MK-801 (0.5mg/kg/d) and PQQ (0.2, 2.0, or 20 μg/kg/d) for 60 days. Behavior was evaluated using a variety of motor, social, and cognitive tests. We found that PQQ administration significantly attenuated MK-801-induced increases in stereotypical behavior and ataxia, suggesting a protective role of PQQ against MK-801-induced neuronal dysfunction and psychiatric disorders. Future studies are necessary to elucidate the underlying mechanisms of PQQ. PMID:24149067

  16. Cognitive deficits induced by 56Fe radiation exposure.

    PubMed

    Shukitt-Hale, B; Casadesus, G; Cantuti-Castelvetri, I; Rabin, B M; Joseph, J A

    2003-01-01

    Exposing rats to particles of high energy and charge (e.g., 56Fe) disrupts neuronal systems and the behaviors mediated by them; these adverse behavioral and neuronal effects are similar to those seen in aged animals. Because cognition declines with age, and our previous study showed that radiation disrupted Morris water maze spatial learning and memory performance, the present study used an 8-arm radial maze (RAM) to further test the cognitive behavioral consequences of radiation exposure. Control rats or rats exposed to whole-body irradiation with 1.0 Gy of 1 GeV/n high-energy 56Fe particles (delivered at the alternating gradient synchrotron at Brookhaven National Laboratory) were tested nine months following exposure. Radiation adversely affected RAM performance, and the changes seen parallel those of aging. Irradiated animals entered baited arms during the first 4 choices significantly less than did controls, produced their first error sooner, and also tended to make more errors as measured by re-entries into non-baited arms. These results show that irradiation with high-energy particles produces age-like decrements in cognitive behavior that may impair the ability of astronauts to perform critical tasks during long-term space travel beyond the magnetosphere. PMID:12577981

  17. Cognitive deficits induced by 56Fe radiation exposure

    NASA Astrophysics Data System (ADS)

    Shukitt-Hale, B.; Casadesus, G.; Cantuti-Castelvetri, I.; Rabin, B. M.; Joseph, J. A.

    Exposing rats to particles of high energy and charge (e.g., 56Fe) disrupts neuronal systems and the behaviors mediated by them; these adverse behavioral and neuronal effects are similar to those seen in aged animals. Because cognition declines with age, and our previous study showed that radiation disrupted Morris water maze spatial learning and memory performance, the present study used an 8-arm radial maze (RAM) to further test the cognitive behavioral consequences of radiation exposure. Control rats or rats exposed to whole-body irradiation with 1.0 Gy of 1 GeV/n high-energy 56Fe particles (delivered at the alternating gradient synchrotron at Brookhaven National Laboratory) were tested nine months following exposure. Radiation adversely affected RAM performance, and the changes seen parallel those of aging. Irradiated animals entered baited arms during the first 4 choices significantly less than did controls, produced their first error sooner, and also tended to make more errors as measured by re-entries into non-baited arms. These results show that irradiation with high-energy particles produces age-like decrements in cognitive behavior that may impair the ability of astronauts to perform critical tasks during long-term space travel beyond the magnetosphere.

  18. Cognitive deficits induced by 56Fe radiation exposure

    NASA Technical Reports Server (NTRS)

    Shukitt-Hale, B.; Casadesus, G.; Cantuti-Castelvetri, I.; Rabin, B. M.; Joseph, J. A.

    2003-01-01

    Exposing rats to particles of high energy and charge (e.g., 56Fe) disrupts neuronal systems and the behaviors mediated by them; these adverse behavioral and neuronal effects are similar to those seen in aged animals. Because cognition declines with age, and our previous study showed that radiation disrupted Morris water maze spatial learning and memory performance, the present study used an 8-arm radial maze (RAM) to further test the cognitive behavioral consequences of radiation exposure. Control rats or rats exposed to whole-body irradiation with 1.0 Gy of 1 GeV/n high-energy 56Fe particles (delivered at the alternating gradient synchrotron at Brookhaven National Laboratory) were tested nine months following exposure. Radiation adversely affected RAM performance, and the changes seen parallel those of aging. Irradiated animals entered baited arms during the first 4 choices significantly less than did controls, produced their first error sooner, and also tended to make more errors as measured by re-entries into non-baited arms. These results show that irradiation with high-energy particles produces age-like decrements in cognitive behavior that may impair the ability of astronauts to perform critical tasks during long-term space travel beyond the magnetosphere. Published by Elsevier Science Ltd on behalf of COSPAR.

  19. Social Cognition Deficits and Associations with Drinking History in Alcoholic Men and Women

    PubMed Central

    Valmas, Mary M.; Ruiz, Susan Mosher; Gansler, David A.; Sawyer, Kayle S.; Oscar-Berman, Marlene

    2014-01-01

    . These findings extend into the social cognition domain, previous literature demonstrating the presence of cognitive deficits in alcoholism, their association with alcoholism severity, and variability by gender. Moreover, because impairments in social cognition can persist despite extended abstinence, they have important implications for relapse prevention. PMID:25581654

  20. Distinguishing Sources of L2 Development Problems in K-12: Language Deficit, Cognitive Deficit, and Cognitive Distance

    ERIC Educational Resources Information Center

    Stapp, Yvonne

    2007-01-01

    K-12 students with limited L2 proficiency who do not progress satisfactorily are often referred to special education and/or speech pathology services. Like the teachers who refer such students, the representatives of each service have a specific expertise (e.g., cognition) with little knowledge of the other types of proficiencies (e.g., L1…

  1. The profile of executive functioning in amnestic mild cognitive impairment: disproportionate deficits in inhibitory control.

    PubMed

    Johns, Erin K; Phillips, Natalie A; Belleville, Sylvie; Goupil, Diane; Babins, Lennie; Kelner, Nora; Ska, Bernadette; Gilbert, Brigitte; Massoud, Fadi; de Boysson, Chloé; Duncan, Hilary D; Chertkow, Howard

    2012-05-01

    Amnestic mild cognitive impairment (aMCI) represents a group of individuals who are highly likely to develop Alzheimer's disease (AD). Although aMCI is typically conceptualized as involving predominantly deficits in episodic memory, recent studies have demonstrated that deficits in executive functioning may also be present, and thorough categorization of cognitive functioning in MCI may improve early diagnosis and treatment of AD. We first provide an extensive review of neuropsychology studies that examined executive functioning in MCI. We then present data on executive functioning across multiple sub-domains (divided attention, working memory, inhibitory control, verbal fluency, and planning) in 40 aMCI patients (single or multiple domain) and 32 normal elderly controls (NECs). MCI patients performed significantly worse than NECs in all 5 sub-domains, and there was impairment (>1.0 SD below the mean of NECs) in all sub-domains. Impairment on each test was frequent, with 100% of MCI patients exhibiting a deficit in at least one sub-domain of executive functioning. Inhibitory control was the most frequently and severely impaired. These results indicate that executive dysfunction in multiple sub-domains is common in aMCI and highlights the importance of a comprehensive neuropsychological evaluation for fully characterizing the nature and extent of cognitive deficits in MCI. PMID:22370245

  2. Testing sensory and cognitive explanations of the antisaccade deficit in schizophrenia.

    PubMed

    Leonard, Carly J; Robinson, Benjamin M; Kaiser, Samuel T; Hahn, Britta; McClenon, Clara; Harvey, Alex N; Luck, Steven J; Gold, James M

    2013-11-01

    Recent research has suggested that people with schizophrenia (PSZ) have sensory deficits, especially in the magnocellular pathway, and this has led to the proposal that dysfunctional sensory processing may underlie higher-order cognitive deficits. Here we test the hypothesis that the antisaccade deficit in PSZ reflects dysfunctional magnocellular processing rather than impaired cognitive processing, as indexed by working memory capacity. This is a plausible hypothesis because oculomotor regions have direct magnocellular inputs, and the stimuli used in most antisaccade tasks strongly activate the magnocellular visual pathway. In the current study, we examined both prosaccade and antisaccade performance in PSZ (N = 22) and matched healthy control subjects (HCS; N = 22) with Gabor stimuli designed to preferentially activate the magnocellular pathway, the parvocellular pathway, or both pathways. We also measured working memory capacity. PSZ exhibited impaired antisaccade performance relative to HCS across stimulus types, with impairment even for stimuli that minimized magnocellular activation. Although both sensory thresholds and working memory capacity were impaired in PSZ, only working memory capacity was correlated with antisaccade accuracy, consistent with a cognitive rather than sensory origin for the antisaccade deficit. PMID:24364614

  3. Dissociations in visual attention deficits among persons with mild cognitive impairment.

    PubMed

    Okonkwo, Ozioma C; Wadley, Virginia G; Ball, Karlene; Vance, David E; Crowe, Michael

    2008-07-01

    Impairments in visual attention and visual information processing have been identified as part of the neuropsychological features of Alzheimer's disease (AD), even in its earliest stages. There is increasing recognition that these deficits may be selective rather than global, with some attentional subtypes being more vulnerable than others. The few studies that have investigated attentional deficits in mild cognitive impairment (MCI), a putatively prodromal phase of AD, have not satisfactorily addressed the possible selectivity in attentional deficits in MCI. This study examined potential dissociations in visual attention deficits in MCI using a measure that assesses simple, divided, and selective attention. The results indicated a hierarchy of attentional impairments, with divided attention being the most affected and simple attention the least. Among participants with MCI, 53% showed evidence of impairment in divided attention compared to 19% of controls (OR = 4.81, p < .001). Poorer visual attention was also associated with poorer overall cognitive status. The implications of these findings for early identification of MCI, prevention of functional decline in MCI, and delay/reversal of cognitive degradation in MCI are discussed. PMID:18584341

  4. Interaction of Cognitive Distortions and Cognitive Deficits in the Formulation and Treatment of Obsessive-Compulsive Behaviours in a Woman with an Intellectual Disability

    ERIC Educational Resources Information Center

    Willner, Paul; Goodey, Rebecca

    2006-01-01

    Aims: This case study describes the formulation and cognitive-behavioural treatment (CBT) of obsessive-compulsive thoughts and behaviours in a woman with an intellectual disability. The report aimed to distinguish the cognitive deficits that reflect her disability from the cognitive distortions integral to her obsessive-compulsive disorder. Case…

  5. Cognitive Rehabilitation for Attention Deficit/Hyperactivity Disorder (ADHD): Promises and Problems

    PubMed Central

    Tajik-Parvinchi, Diana; Wright, Leah; Schachar, Russell

    2014-01-01

    Objective: Cognitive training entails the repeated exercise of a specific cognitive process over a period of time to improve performance on the trained task as well as on tasks that were not specifically trained (transfer effect). Cognitive training shows promise in remediating deficits in children with attention deficit/hyperactivity disorder (ADHD) – a disorder believed to stem from deficient cognitive processes – where the focus has been primarily on training working memory and attention. We discuss evidence from studies that have produced broad, limited, or no transfer effects with the goal of identifying factors that may be responsible for this heterogeneity. Results: There are several implicit assumptions that appear to drive researchers’ decisions regarding both the selection of cognitive abilities to train as well as the training tasks chosen to target those abilities. We identify these implicit assumptions and their weaknesses. We also draw attention to design limitations that may be contributing to lack of transfer. Conclusion: Although the overall pattern of findings from these studies is promising, the methodological and theoretical limitations associated with the literature limit conclusions about the efficacy of cognitive training as a rehabilitation method for ADHD. We hypothesize several suggestions that may improve training effects and summarize the evidence which led to our hypotheses. PMID:25320614

  6. Reactive oxygen species mediate cognitive deficits in experimental temporal lobe epilepsy.

    PubMed

    Pearson, Jennifer N; Rowley, Shane; Liang, Li-Ping; White, Andrew M; Day, Brian J; Patel, Manisha

    2015-10-01

    Cognitive dysfunction is an important comorbidity of temporal lobe epilepsy (TLE). However, no targeted therapies are available and the mechanisms underlying cognitive impairment, specifically deficits in learning and memory associated with TLE remain unknown. Oxidative stress is known to occur in the pathogenesis of TLE but its functional role remains to be determined. Here, we demonstrate that oxidative stress and resultant processes contribute to cognitive decline associated with epileptogenesis. Using a synthetic catalytic antioxidant, we show that pharmacological removal of reactive oxygen species (ROS) prevents 1) oxidative stress, 2) deficits in mitochondrial oxygen consumption rates, 3) hippocampal neuronal loss and 4) cognitive dysfunction without altering the intensity of the initial status epilepticus (SE) or epilepsy development in a rat model of SE-induced TLE. Moreover, the effects of the catalytic antioxidant on cognition persisted beyond the treatment period suggestive of disease-modification. The data implicate oxidative stress as a novel mechanism by which cognitive dysfunction can arise during epileptogenesis and suggest a potential disease-modifying therapeutic approach to target it. PMID:26184893

  7. IL-33 ameliorates Alzheimer’s disease-like pathology and cognitive decline

    PubMed Central

    Fu, Amy K. Y.; Hung, Kwok-Wang; Yuen, Michael Y. F.; Zhou, Xiaopu; Mak, Deejay S. Y.; Chan, Ivy C. W.; Cheung, Tom H.; Zhang, Baorong; Fu, Wing-Yu; Liew, Foo Y.; Ip, Nancy Y.

    2016-01-01

    Alzheimer’s disease (AD) is a devastating condition with no known effective treatment. AD is characterized by memory loss as well as impaired locomotor ability, reasoning, and judgment. Emerging evidence suggests that the innate immune response plays a major role in the pathogenesis of AD. In AD, the accumulation of β-amyloid (Aβ) in the brain perturbs physiological functions of the brain, including synaptic and neuronal dysfunction, microglial activation, and neuronal loss. Serum levels of soluble ST2 (sST2), a decoy receptor for interleukin (IL)-33, increase in patients with mild cognitive impairment, suggesting that impaired IL-33/ST2 signaling may contribute to the pathogenesis of AD. Therefore, we investigated the potential therapeutic role of IL-33 in AD, using transgenic mouse models. Here we report that IL-33 administration reverses synaptic plasticity impairment and memory deficits in APP/PS1 mice. IL-33 administration reduces soluble Aβ levels and amyloid plaque deposition by promoting the recruitment and Aβ phagocytic activity of microglia; this is mediated by ST2/p38 signaling activation. Furthermore, IL-33 injection modulates the innate immune response by polarizing microglia/macrophages toward an antiinflammatory phenotype and reducing the expression of proinflammatory genes, including IL-1β, IL-6, and NLRP3, in the cortices of APP/PS1 mice. Collectively, our results demonstrate a potential therapeutic role for IL-33 in AD. PMID:27091974

  8. IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline.

    PubMed

    Fu, Amy K Y; Hung, Kwok-Wang; Yuen, Michael Y F; Zhou, Xiaopu; Mak, Deejay S Y; Chan, Ivy C W; Cheung, Tom H; Zhang, Baorong; Fu, Wing-Yu; Liew, Foo Y; Ip, Nancy Y

    2016-05-10

    Alzheimer's disease (AD) is a devastating condition with no known effective treatment. AD is characterized by memory loss as well as impaired locomotor ability, reasoning, and judgment. Emerging evidence suggests that the innate immune response plays a major role in the pathogenesis of AD. In AD, the accumulation of β-amyloid (Aβ) in the brain perturbs physiological functions of the brain, including synaptic and neuronal dysfunction, microglial activation, and neuronal loss. Serum levels of soluble ST2 (sST2), a decoy receptor for interleukin (IL)-33, increase in patients with mild cognitive impairment, suggesting that impaired IL-33/ST2 signaling may contribute to the pathogenesis of AD. Therefore, we investigated the potential therapeutic role of IL-33 in AD, using transgenic mouse models. Here we report that IL-33 administration reverses synaptic plasticity impairment and memory deficits in APP/PS1 mice. IL-33 administration reduces soluble Aβ levels and amyloid plaque deposition by promoting the recruitment and Aβ phagocytic activity of microglia; this is mediated by ST2/p38 signaling activation. Furthermore, IL-33 injection modulates the innate immune response by polarizing microglia/macrophages toward an antiinflammatory phenotype and reducing the expression of proinflammatory genes, including IL-1β, IL-6, and NLRP3, in the cortices of APP/PS1 mice. Collectively, our results demonstrate a potential therapeutic role for IL-33 in AD. PMID:27091974

  9. A cognitive psychometric model for the psychodiagnostic assessment of memory-related deficits.

    PubMed

    Alexander, Gregory E; Satalich, Timothy A; Shankle, W Rodman; Batchelder, William H

    2016-03-01

    Clinical tests used for psychodiagnostic purposes, such as the well-known Alzheimer's Disease Assessment Scale: Cognitive subscale (ADAS-Cog), include a free-recall task. The free-recall task taps into latent cognitive processes associated with learning and memory components of human cognition, any of which might be impaired with the progression of Alzheimer's disease (AD). A Hidden Markov model of free recall is developed to measure latent cognitive processes used during the free-recall task. In return, these cognitive measurements give us insight into the degree to which normal cognitive functions are differentially impaired by medical conditions, such as AD and related disorders. The model is used to analyze the free-recall data obtained from healthy elderly participants, participants diagnosed as having mild cognitive impairment, and participants diagnosed with early AD. The model is specified hierarchically to handle item differences because of the serial position curve in free recall, as well as within-group individual differences in participants' recall abilities. Bayesian hierarchical inference is used to estimate the model. The model analysis suggests that the impaired patients have the following: (1) long-term memory encoding deficits, (2) short-term memory (STM) retrieval deficits for all but very short time intervals, (3) poorer transfer into long-term memory for items successfully retrieved from STM, and (4) poorer retention of items encoded into long-term memory after longer delays. Yet, impaired patients appear to have no deficit in immediate recall of encoded words in long-term memory or for very short time intervals in STM. PMID:26214016

  10. The Outcome of a Social Cognitive Training for Mainstream Adolescents with Social Communication Deficits in a Chinese Community

    ERIC Educational Resources Information Center

    Lee, Kathy Y. S.; Crooke, Pamela J.; Lui, Aster L. Y.; Kan, Peggy P. K.; Mark, Yuen-mai; van Hasselt, Charles Andrew; Tong, Michael C. F.

    2016-01-01

    The use of cognitive-based strategies for improving social communication behaviours for individuals who have solid language and cognition is an important question. This study investigated the outcome of teaching Social Thinking®, a framework based in social-cognition, to Chinese adolescents with social communication deficits. Thirty-nine students…

  11. RPS23RG1 reduces Aβ oligomer-induced synaptic and cognitive deficits

    PubMed Central

    Yan, Li; Chen, Yaomin; Li, Wubo; Huang, Xiumei; Badie, Hedieh; Jian, Fan; Huang, Timothy; Zhao, Yingjun; Cohen, Stanley N.; Li, Limin; Zhang, Yun-wu; Luo, Huanmin; Tu, Shichun; Xu, Huaxi

    2016-01-01

    Alzheimer’s disease (AD) is the most common form of dementia in the elderly. It is generally believed that β-amyloidogenesis, tau-hyperphosphorylation, and synaptic loss underlie cognitive decline in AD. Rps23rg1, a functional retroposed mouse gene, has been shown to reduce Alzheimer’s β-amyloid (Aβ) production and tau phosphorylation. In this study, we have identified its human homolog, and demonstrated that RPS23RG1 regulates synaptic plasticity, thus counteracting Aβ oligomer (oAβ)-induced cognitive deficits in mice. The level of RPS23RG1 mRNA is significantly lower in the brains of AD compared to non-AD patients, suggesting its potential role in the pathogenesis of the disease. Similar to its mouse counterpart, human RPS23RG1 interacts with adenylate cyclase, activating PKA/CREB, and inhibiting GSK-3. Furthermore, we show that human RPS23RG1 promotes synaptic plasticity and offsets oAβ-induced synaptic loss in a PKA-dependent manner in cultured primary neurons. Overexpression of Rps23rg1 in transgenic mice consistently prevented oAβ-induced PKA inactivation, synaptic deficits, suppression of long-term potentiation, and cognitive impairment as compared to wild type littermates. Our study demonstrates that RPS23RG1 may reduce the occurrence of key elements of AD pathology and enhance synaptic functions to counteract oAβ-induced synaptic and cognitive deficits in AD. PMID:26733416

  12. Epilepsy, cognitive deficits and neuroanatomy in males with ZDHHC9 mutations

    PubMed Central

    Baker, Kate; Astle, Duncan E; Scerif, Gaia; Barnes, Jessica; Smith, Jennie; Moffat, Georgina; Gillard, Jonathan; Baldeweg, Torsten; Raymond, F Lucy

    2015-01-01

    Objective Systematic investigation of individuals with intellectual disability after genetic diagnosis can illuminate specific phenotypes and mechanisms relevant to common neurodevelopmental disorders. We report the neurological, cognitive and neuroanatomical characteristics of nine males from three families with loss-of-function mutations in ZDHHC9 (OMIM #300799). Methods All known cases of X-linked intellectual disability (XLID) due to ZDHHC9 mutation in the United Kingdom were invited to participate in a study of neurocognitive and neuroimaging phenotypes. Results Seven out of nine males with ZDHHC9 mutations had been diagnosed with epilepsy, exceeding epilepsy risk in XLID comparison subjects (P = 0.01). Seizure histories and EEG features amongst ZDHHC9 mutation cases shared characteristics with rolandic epilepsy (RE). Specific cognitive deficits differentiated males with ZDHHC9 mutations from XLID comparison subjects and converged with reported linguistic and nonlinguistic deficits in idiopathic RE: impaired oromotor control, reduced verbal fluency, and impaired inhibitory control on visual attention tasks. Consistent neuroanatomical abnormalities included thalamic and striatal volume reductions and hypoplasia of the corpus callosum. Interpretation Mutations in ZDHHC9 are associated with susceptibility to focal seizures and specific cognitive impairments intersecting with the RE spectrum. Neurocognitive deficits are accompanied by consistent abnormalities of subcortical structures and inter-hemispheric connectivity. The biochemical, cellular and network-level mechanisms responsible for the ZDHHC9-associated neurocognitive phenotype may be relevant to cognitive outcomes in RE. PMID:26000327

  13. Identifying learning disabilities through a cognitive deficit framework: can verbal memory deficits explain similarities between learning disabled and low achieving students?

    PubMed

    Callinan, Sarah; Theiler, Stephen; Cunningham, Everarda

    2015-01-01

    Traditionally, students with learning disabilities (LD) have been identified using an aptitude-achievement discrepancy or response to intervention approach. As profiles of the cognitive deficits of discrepancy-defined students with LD have already been developed using these approaches, these deficits can in turn be used to identify LD using the discrepancy approach as a benchmark for convergent validity. Australian Grade 3 (N = 172) students were administered cognitive processing tests to ascertain whether scores in these tests could accurately allocate students into discrepancy-defined groups using discriminant function analysis. Results showed that 77% to 82% of students could be correctly allocated into LD, low achievement, and regular achievement groups using only measures of phonological processing, rapid naming, and verbal memory. Furthermore, verbal memory deficits were found, along with phonological processing and rapid naming deficits, in students that would be designated as low achieving by the discrepancy method. Because a significant discrepancy or lack of response to intervention is a result of cognitive deficits rather than the other way around, it is argued that LD should be identified via cognitive deficits. PMID:23886581

  14. Cognitive Impairments Induced by Concussive Mild Traumatic Brain Injury in Mouse Are Ameliorated by Treatment with Phenserine via Multiple Non-Cholinergic and Cholinergic Mechanisms.

    PubMed

    Tweedie, David; Fukui, Koji; Li, Yazhou; Yu, Qian-Sheng; Barak, Shani; Tamargo, Ian A; Rubovitch, Vardit; Holloway, Harold W; Lehrmann, Elin; Wood, William H; Zhang, Yongqing; Becker, Kevin G; Perez, Evelyn; Van Praag, Henriette; Luo, Yu; Hoffer, Barry J; Becker, Robert E; Pick, Chaim G; Greig, Nigel H

    2016-01-01

    Traumatic brain injury (TBI), often caused by a concussive impact to the head, affects an estimated 1.7 million Americans annually. With no approved drugs, its pharmacological treatment represents a significant and currently unmet medical need. In our prior development of the anti-cholinesterase compound phenserine for the treatment of neurodegenerative disorders, we recognized that it also possesses non-cholinergic actions with clinical potential. Here, we demonstrate neuroprotective actions of phenserine in neuronal cultures challenged with oxidative stress and glutamate excitotoxicity, two insults of relevance to TBI. These actions translated into amelioration of spatial and visual memory impairments in a mouse model of closed head mild TBI (mTBI) two days following cessation of clinically translatable dosing with phenserine (2.5 and 5.0 mg/kg BID x 5 days initiated post mTBI) in the absence of anti-cholinesterase activity. mTBI elevated levels of thiobarbituric acid reactive substances (TBARS), a marker of oxidative stress. Phenserine counteracted this by augmenting homeostatic mechanisms to mitigate oxidative stress, including superoxide dismutase [SOD] 1 and 2, and glutathione peroxidase [GPx], the activity and protein levels of which were measured by specific assays. Microarray analysis of hippocampal gene expression established that large numbers of genes were exclusively regulated by each individual treatment with a substantial number of them co-regulated between groups. Molecular pathways associated with lipid peroxidation were found to be regulated by mTBI, and treatment of mTBI animals with phenserine effectively reversed injury-induced regulations in the 'Blalock Alzheimer's Disease Up' pathway. Together these data suggest that multiple phenserine-associated actions underpin this compound's ability to ameliorate cognitive deficits caused by mTBI, and support the further evaluation of the compound as a therapeutic for TBI. PMID:27254111

  15. Cognitive Impairments Induced by Concussive Mild Traumatic Brain Injury in Mouse Are Ameliorated by Treatment with Phenserine via Multiple Non-Cholinergic and Cholinergic Mechanisms

    PubMed Central

    Li, Yazhou; Yu, Qian-sheng; Barak, Shani; Tamargo, Ian A.; Rubovitch, Vardit; Holloway, Harold W.; Lehrmann, Elin; Wood, William H.; Zhang, Yongqing; Becker, Kevin G.; Perez, Evelyn; Van Praag, Henriette; Luo, Yu; Hoffer, Barry J.; Becker, Robert E.; Pick, Chaim G.; Greig, Nigel H.

    2016-01-01

    Traumatic brain injury (TBI), often caused by a concussive impact to the head, affects an estimated 1.7 million Americans annually. With no approved drugs, its pharmacological treatment represents a significant and currently unmet medical need. In our prior development of the anti-cholinesterase compound phenserine for the treatment of neurodegenerative disorders, we recognized that it also possesses non-cholinergic actions with clinical potential. Here, we demonstrate neuroprotective actions of phenserine in neuronal cultures challenged with oxidative stress and glutamate excitotoxicity, two insults of relevance to TBI. These actions translated into amelioration of spatial and visual memory impairments in a mouse model of closed head mild TBI (mTBI) two days following cessation of clinically translatable dosing with phenserine (2.5 and 5.0 mg/kg BID x 5 days initiated post mTBI) in the absence of anti-cholinesterase activity. mTBI elevated levels of thiobarbituric acid reactive substances (TBARS), a marker of oxidative stress. Phenserine counteracted this by augmenting homeostatic mechanisms to mitigate oxidative stress, including superoxide dismutase [SOD] 1 and 2, and glutathione peroxidase [GPx], the activity and protein levels of which were measured by specific assays. Microarray analysis of hippocampal gene expression established that large numbers of genes were exclusively regulated by each individual treatment with a substantial number of them co-regulated between groups. Molecular pathways associated with lipid peroxidation were found to be regulated by mTBI, and treatment of mTBI animals with phenserine effectively reversed injury-induced regulations in the ‘Blalock Alzheimer’s Disease Up’ pathway. Together these data suggest that multiple phenserine-associated actions underpin this compound’s ability to ameliorate cognitive deficits caused by mTBI, and support the further evaluation of the compound as a therapeutic for TBI. PMID:27254111

  16. PHOSPHOLIPASE A2 REDUCTION AMELIORATES COGNITIVE DEFICITS IN MOUSE MODEL OF ALZHEIMER’S DISEASE

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Neuronal expression of familial Alzheimer’s disease (AD)-mutant human amyloid precursor proteins (hAPP) and hAPP-derived amyloid-' (A') peptides causes synaptic dysfunction, inflammation, and abnormal cerebrovascular tone in transgenic mice. Fatty acids are involved in these processes, but their con...

  17. Xanthoceras sorbifolia extracts ameliorate dendritic spine deficiency and cognitive decline via upregulation of BDNF expression in a rat model of Alzheimer's disease.

    PubMed

    Li, Yinjie; Xu, Jikai; Xu, Pu; Song, Shijie; Liu, Peng; Chi, Tianyan; Ji, Xuefei; Jin, Ge; Qiu, Shimeng; Hou, Yapeng; Zheng, Chen; Wang, Lili; Meng, Dali; Zou, Libo

    2016-08-26

    Xanthoceras sorbifolia, a traditional Chinese folk medicine with anti-inflammatory effects, has been used for a long time in China, especially in the Inner Mongolian area for the treatment of rheumatism. Inflammation is one of the main causes of Alzheimer's disease (AD). AD is characterized by aggregation of amyloid β-peptide (Aβ) plaques, neurofibrillary tangle formation, synaptic dysfunction and neuronal loss. To investigate whether Xanthoceras sorbifolia extracts (XSE) improve cognition and protect dendritic spines, we performed behavioral tests to investigate learning and memory in an Aβ25-35-induced dementia animal model of AD as well as Golgi staining to observe dendritic spine formation in CA1 pyramidal neurons and western blots to test the expression levels of PSD95, BDNF and downstream signaling pathways. Our results indicated that oral treatment with XSE significantly reduced cognitive impairments in behavioral tests (passive avoidance test, novel object recognition test, Y-maze test and Morris water maze test). Golgi staining results revealed that XSE ameliorated dendritic spine density deficits in CA1 pyramidal neurons in the hippocampus. Western blot analysis suggested that XSE upregulated PSD95, which is the major scaffolding protein in synapses. BDNF levels and the ratio of p-TrkB/TrkB increased, and the expression of the RhoA, a member of the Rho-GTPase family, and its downstream target protein ROCK2 decreased in the dementia animal model following treatment with XSE. Therefore, the cognition-improving effects of XSE probably resulted from dendritic spine protection effects through regulation of BDNF signaling pathways. PMID:27412235

  18. Pharmacological treatment of cognitive deficits in Alzheimer's disease.

    PubMed

    Brodaty, H; Ames, D; Boundy, K L; Hecker, J; Snowdon, J; Storey, E; Yates, M W

    2001-09-17

    Clinical trials and independent reviews support the use of cholinesterase inhibitors for treating the symptoms of patients with mild to moderate Alzheimer's disease (AD). Before initiating cholinesterase inhibitor therapy, patients should be thoroughly assessed, and the diagnosis confirmed, preferably by a specialist. Compliance with cholinesterase inhibitor therapy should be monitored and the response (in global, cognitive, functional and behavioural domains) reassessed after 2-3 months of treatment. Vitamin E may be protective against AD, and therapy with 1000 IU twice daily may be considered. There is insufficient evidence to support the use of other antioxidant agents, anti-inflammatory agents, monoamine oxidase B inhibitors, folate/homocysteine or antihypertensive drugs in patients with AD, or hormone replacement therapy in affected women. PMID:11665948

  19. The Brewed Rice Vinegar Kurozu Increases HSPA1A Expression and Ameliorates Cognitive Dysfunction in Aged P8 Mice

    PubMed Central

    Kanouchi, Hiroaki; Kakimoto, Toshiaki; Nakano, Hideya; Suzuki, Masahiro; Nakai, Yuji; Shiozaki, Kazuhiro; Akikoka, Kohei; Otomaru, Konosuke; Nagano, Masanobu; Matsumoto, Mitsuharu

    2016-01-01

    Kurozu is a traditional Japanese rice vinegar. During fermentation and aging of the Kurozu liquid in an earthenware jar over 1 year, a solid residue called Kurozu Moromi is produced. In the present study, we evaluated whether concentrated Kurozu or Kurozu Moromi could ameliorate cognitive dysfunction in the senescence-accelerated P8 mouse. Senescence-accelerated P8 mice were fed 0.25% (w/w) concentrated Kurozu or 0.5% (w/w) Kurozu Moromi for 4 or 25 weeks. Kurozu suppressed cognitive dysfunction and amyloid accumulation in the brain, while Kurozu Moromi showed a tendency to ameliorate cognitive dysfunction, but the effect was not significant. We hypothesize that concentrated Kurozu has an antioxidant effect; however, the level of lipid peroxidation in the brain did not differ in senescence-accelerated P8 mice. DNA microarray analysis indicated that concentrated Kurozu increased HSPA1A mRNA expression, a protein that prevents protein misfolding and aggregation. The increase in HSPA1A expression by Kurozu was confirmed using quantitative real-time PCR and immunoblotting methods. The suppression of amyloid accumulation by concentrated Kurozu may be associated with HSPA1A induction. However, concentrated Kurozu could not increase HSPA1A expression in mouse primary neurons, suggesting it may not directly affect neurons. PMID:26943920

  20. The Brewed Rice Vinegar Kurozu Increases HSPA1A Expression and Ameliorates Cognitive Dysfunction in Aged P8 Mice.

    PubMed

    Kanouchi, Hiroaki; Kakimoto, Toshiaki; Nakano, Hideya; Suzuki, Masahiro; Nakai, Yuji; Shiozaki, Kazuhiro; Akikoka, Kohei; Otomaru, Konosuke; Nagano, Masanobu; Matsumoto, Mitsuharu

    2016-01-01

    Kurozu is a traditional Japanese rice vinegar. During fermentation and aging of the Kurozu liquid in an earthenware jar over 1 year, a solid residue called Kurozu Moromi is produced. In the present study, we evaluated whether concentrated Kurozu or Kurozu Moromi could ameliorate cognitive dysfunction in the senescence-accelerated P8 mouse. Senescence-accelerated P8 mice were fed 0.25% (w/w) concentrated Kurozu or 0.5% (w/w) Kurozu Moromi for 4 or 25 weeks. Kurozu suppressed cognitive dysfunction and amyloid accumulation in the brain, while Kurozu Moromi showed a tendency to ameliorate cognitive dysfunction, but the effect was not significant. We hypothesize that concentrated Kurozu has an antioxidant effect; however, the level of lipid peroxidation in the brain did not differ in senescence-accelerated P8 mice. DNA microarray analysis indicated that concentrated Kurozu increased HSPA1A mRNA expression, a protein that prevents protein misfolding and aggregation. The increase in HSPA1A expression by Kurozu was confirmed using quantitative real-time PCR and immunoblotting methods. The suppression of amyloid accumulation by concentrated Kurozu may be associated with HSPA1A induction. However, concentrated Kurozu could not increase HSPA1A expression in mouse primary neurons, suggesting it may not directly affect neurons. PMID:26943920

  1. Cognitive rehabilitation training in patients with brain tumor-related epilepsy and cognitive deficits: a pilot study.

    PubMed

    Maschio, Marta; Dinapoli, Loredana; Fabi, Alessandra; Giannarelli, Diana; Cantelmi, Tonino

    2015-11-01

    The aim of this pilot observational study was to evaluate effect of cognitive rehabilitation training (RehabTr) on cognitive performances in patients with brain tumor-related epilepsy (BTRE) and cognitive disturbances. Medical inclusion criteria: patients (M/F) ≥ 18 years ≤ 75 with symptomatic seizures due to primary brain tumors or brain metastases in stable treatment with antiepileptic drugs; previous surgical resection or biopsy; >70 Karnofsky Performance Status; stable oncological disease. Eligible patients recruited from 100 consecutive patients with BTRE at first visit to our Center from 2011 to 2012. All recruited patients were administered battery of neuropsychological tests exploring various cognitive domains. Patients considered to have a neuropsychological deficit were those with at least one test score for a given domain indicative of impairment. Thirty patients out of 100 showed cognitive deficits, and were offered participation in RehabTr, of which 16 accepted (5 low grade glioma, 4 high grade glioma, 2 glioblastoma, 2 meningioma and 3 metastases) and 14 declined for various reasons. The RehabTr consisted of one weekly individual session of 1 h, for a total of 10 weeks, carried out by a trained psychologist. The functions trained were: memory, attention, visuo-spatial functions, language and reasoning by means of Training NeuroPsicologico (TNP(®)) software. To evaluate the effect of the RehabTr, the same battery of tests was administered directly after cognitive rehabilitation (T1), and at six-month follow-up (T2). Statistical analysis with Student T test for paired data showed that short-term verbal memory, episodic memory, fluency and long term visuo-spatial memory improved immediately after the T1 and remained stable at T2. At final follow-up all patients showed an improvement in at least one domain that had been lower than normal at baseline. Our results demonstrated a positive effect of rehabilitative training at different times, and, for

  2. Levetiracetam might act as an efficacious drug to attenuate cognitive deficits of Alzheimer's disease.

    PubMed

    Xiao, Rong

    2016-01-01

    Levetiracetam is a homologue of piracetam with an a-ethyl side-chain substitution and it is a Food and Drug Administration (FDA) approved antiepileptic drug. Recently, several studies have found that levetiracetam was able to reduce seizure frequency in epileptic seizures patients without affecting their cognitive functions. In the present review, the effects of levetiracetam on cognitive improvement were summarized in epileptic seizures patients with or without Alzheimer's disease (AD), high-grade glioma (HGG) patients and amnestic mild cognitive impairment (aMCI) patients. In addition, levetiracetam was observed to improve the cognitive deficits in normal aged animals and the transgenic animal models with AD, suggesting that levetiracetam may be a better choice for the prevention or treatment of AD. PMID:26268327

  3. Vagal Recovery From Cognitive Challenge Moderates Age-Related Deficits in Executive Functioning.

    PubMed

    Crowley, Olga V; Kimhy, David; McKinley, Paula S; Burg, Matthew M; Schwartz, Joseph E; Lachman, Margie E; Tun, Patricia A; Ryff, Carol D; Seeman, Teresa E; Sloan, Richard P

    2016-05-01

    Decline in executive functioning (EF) is a hallmark of cognitive aging. We have previously reported that faster vagal recovery from cognitive challenge is associated with better EF. This study examined the association between vagal recovery from cognitive challenge and age-related differences in EF among 817 participants in the Midlife in the U.S. study (aged 35-86). Cardiac vagal control was measured as high-frequency heart rate variability. Vagal recovery moderated the association between age and EF (β = .811, p = .004). Secondary analyses revealed that older participants (aged 65-86) with faster vagal recovery had superior EF compared to their peers who had slower vagal recovery. In contrast, among younger (aged 35-54) and middle-aged (aged 55-64) participants, vagal recovery was not associated with EF. We conclude that faster vagal recovery from cognitive challenge is associated with reduced deficits in EF among older, but not younger individuals. PMID:26303063

  4. Vagal Recovery From Cognitive Challenge Moderates Age-Related Deficits in Executive Functioning

    PubMed Central

    Crowley, Olga V.; Kimhy, David; McKinley, Paula S.; Burg, Matthew M.; Schwartz, Joseph E.; Lachman, Margie E.; Tun, Patricia A.; Ryff, Carol D.; Seeman, Teresa E.; Sloan, Richard P.

    2015-01-01

    Decline in executive functioning (EF) is a hallmark of cognitive aging. We have previously reported that faster vagal recovery from cognitive challenge is associated with better EF. This study examined the association between vagal recovery from cognitive challenge and age-related differences in EF among 817 participants in the Midlife in the U.S. study (aged 35–86). Cardiac vagal control was measured as high-frequency heart rate variability. Vagal recovery moderated the association between age and EF (β = .811, p = .004). Secondary analyses revealed that older participants (aged 65–86) with faster vagal recovery had superior EF compared to their peers who had slower vagal recovery. In contrast, among younger (aged 35–54) and middle-aged (aged 55–64) participants, vagal recovery was not associated with EF. We conclude that faster vagal recovery from cognitive challenge is associated with reduced deficits in EF among older, but not younger individuals. PMID:26303063

  5. Social Cognition Deficits and Psychopathic Traits in Young People Seeking Mental Health Treatment

    PubMed Central

    van Zwieten, Anita; Meyer, Johanna; Hermens, Daniel F.; Hickie, Ian B.; Hawes, David J.; Glozier, Nicholas; Naismith, Sharon L.; Scott, Elizabeth M.; Lee, Rico S. C.; Guastella, Adam J.

    2013-01-01

    Antisocial behaviours and psychopathic traits place an individual at risk for criminality, mental illness, substance dependence, and psychosocial dysfunction. Social cognition deficits appear to be associated with psychopathic traits and are believed to contribute to interpersonal dysfunction. Most research investigating the relationship of these traits with social cognition has been conducted either in children or adult forensic settings. We investigated whether psychopathic traits were associated with social cognition in 91 young people presenting for mental healthcare (aged between 15 and 25 years). Participants completed symptom severity measures, neuropsychological tests, the Reading the Mind in the Eyes Test of social cognition (RMET), and the Antisocial Process Screening Device (APSD) to assess psychopathic personality traits. Correlation analyses showed poorer social cognition was associated with greater psychopathic traits (r = −.36, p = .01). Interestingly, social cognition performance predicted unique variance in concurrent psychopathic personality traits above gender, IQ sustained attention, and working memory performance. These findings suggest that social cognitive impairments are associated with psychopathic tendencies in young people presenting for community mental healthcare. Research is needed to establish the directionality of this relationship and to determine whether social cognition training is an effective treatment amongst young people with psychopathic tendencies. PMID:23861799

  6. Pretreatment cognitive deficits and treatment effects on attention in childhood absence epilepsy

    PubMed Central

    Masur, David; Shinnar, Shlomo; Cnaan, Avital; Shinnar, Ruth C.; Clark, Peggy; Wang, Jichuan; Weiss, Erica F.; Hirtz, Deborah G.

    2013-01-01

    Objective: To determine the neurocognitive deficits associated with newly diagnosed untreated childhood absence epilepsy (CAE), develop a model describing the factorial structure of items measuring academic achievement and 3 neuropsychological constructs, and determine short-term differential neuropsychological effects on attention among ethosuximide, valproic acid, and lamotrigine. Methods: Subjects with newly diagnosed CAE entering a double-blind, randomized controlled clinical trial had neuropsychological testing including assessments of general intellectual functioning, attention, memory, executive function, and achievement. Attention was reassessed at the week 16–20 visit. Results: At study entry, 36% of the cohort exhibited attention deficits despite otherwise intact neurocognitive functioning. Structural equation modeling of baseline neuropsychological data revealed a direct sequential effect among attention, memory, executive function, and academic achievement. At the week 16–20 visit, attention deficits persisted even if seizure freedom was attained. More subjects receiving valproic acid (49%) had attention deficits than subjects receiving ethosuximide (32%) or lamotrigine (24%) (p = 0.0006). Parental assessment did not reliably detect attention deficits before or after treatment (p < 0.0001). Conclusions: Children with CAE have a high rate of pretreatment attentional deficits that persist despite seizure freedom. Rates are disproportionately higher for valproic acid treatment compared with ethosuximide or lamotrigine. Parents do not recognize these attentional deficits. These deficits present a threat to academic achievement. Vigilant cognitive and behavioral assessment of these children is warranted. Classification of evidence: This study provides Class I evidence that valproic acid is associated with more significant attentional dysfunction than ethosuximide or lamotrigine in children with newly diagnosed CAE. PMID:24089388

  7. Resting fMRI measures are associated with cognitive deficits in schizophrenia assessed by the MATRICS consensus cognitive battery

    NASA Astrophysics Data System (ADS)

    He, Hao; Bustillo, Juan; Du, Yuhui; Yu, Qingbao; Jones, Thomas R.; Jiang, Tianzi; Calhoun, Vince D.; Sui, Jing

    2015-03-01

    The cognitive deficits of schizophrenia are largely resistant to current treatment, and are thus a life-long burden to patients. The MATRICS consensus cognitive battery (MCCB) provides a reliable and valid assessment of cognition across a comprehensive set of cognitive domains for schizophrenia. In resting-state fMRI, functional connectivity associated with MCCB has not yet been examined. In this paper, the interrelationships between MCCB and the abnormalities seen in two types of functional measures from resting-state fMRI—fractional amplitude of low frequency fluctuations (fALFF) and functional network connectivity (FNC) maps were investigated in data from 47 schizophrenia patients and 50 age-matched healthy controls. First, the fALFF maps were generated and decomposed by independent component analysis (ICA), and then the component showing the highest correlation with MCCB composite scores was selected. Second, the whole brain was separated into functional networks by group ICA, and the FNC maps were calculated. The FNC strengths with most significant correlations with MCCB were displayed and spatially overlapped with the fALFF component of interest. It demonstrated increased cognitive performance associated with higher fALFF values (intensity of regional spontaneous brain activity) in prefrontal regions, inferior parietal lobe (IPL) but lower ALFF values in thalamus, striatum, and superior temporal gyrus (STG). Interestingly, the FNC showing significant correlations with MCCB were in well agreement with the activated regions with highest z-values in fALFF component. Our results support the view that functional deficits in distributed cortico-striato-thalamic circuits and inferior parietal lobe may account for several aspects of cognitive impairment in schizophrenia.

  8. The allusive cognitive deficit in paranoia: the case for mental time travel or cognitive self-projection.

    PubMed

    Corcoran, R

    2010-08-01

    Delusional beliefs are characteristic of psychosis and, of the delusions, the paranoid delusion is the single most common type associated with psychosis. The many years of research focused on neurocognition in schizophrenia, using standardized neurocognitive tests, have failed to find conclusive cognitive deficits in relation to positive symptoms. However, UK-based psychological research has identified sociocognitive anomalies in relation to paranoid thinking in the form of theory of mind (ToM), causal reasoning and threat-related processing anomalies. Drawing from recent neuroscientific research on the default mode network, this paper asserts that the common theme running through the psychological tests that are sensitive to the cognitive impairment of paranoia is the need to cognitively project the self through time, referred to as mental time travel. Such an understanding of the cognitive roots of paranoid ideation provides a synthesis between psychological and biological accounts of psychosis while also retaining the powerful argument that understanding abnormal thinking must start with models of normal cognition. This is the core theme running through the cognitive psychological literature of psychiatric disorders that enables research from this area to inform psychological therapy. PMID:20594394

  9. Spatial cognition following early-life seizures in rats: Performance deficits are dependent on task demands.

    PubMed

    Barry, Jeremy M; Tian, Chengju; Spinella, Anthony; Page, Matias; Holmes, Gregory L

    2016-07-01

    Cognitive impairment is a common comorbidity in childhood epilepsy. Studies in rodents have demonstrated that frequent seizures during the first weeks of life result in impaired spatial cognition when the rats are tested as juvenile or adults. To determine if spatial cognitive deficits following early-life seizures are task-specific or similar across spatial tasks, we compared the effects of early-life seizures in two spatial assays: 1) the Morris water maze, a hippocampal-dependent task of spatial cognition and 2) the active avoidance task, a task that associates an aversive shock stimulus with a static spatial location that requires intact hippocampal-amygdala networks. Rats with early-life seizures tested as adults did not differ from control rats in the water maze. However, while animals with early-life seizures showed some evidence of learning the active avoidance task, they received significantly more shocks in later training trials, particularly during the second training day, than controls. One possibility for the performance differences between the tasks is that the active avoidance task requires multiple brain regions and that interregional communication could be affected by alterations in white matter integrity. However, there were no measurable group differences with regard to levels of myelination. The study suggests that elucidation of mild cognitive deficits seen following early-life seizures may be dependent on task features of active avoidance. PMID:27152463

  10. Cognitive deficits in schizophrenia: an updated metanalysis of the scientific evidence

    PubMed Central

    2012-01-01

    Background This is an update of a previous meta-analysis published in 2005. Methods It includes the data published up to march 2010 for a total of 247 papers and 18,300 cases. Cognitive deficits are examined in 5 different domains: Memory functioning (128 studies), Global cognitive functioning (131 studies), Language (70 studies), Executive function (67 studies), Attention (76 studies). Only controlled studies were included: patients vs. normal subjects. Results Results evidence that in all domains and in all different analyses performed within each domain, patients show a significant reduction of cognitive efficiency with respect to normal subjects. The between studies heterogeneity is very high in almost all domains. There are various sources of this heterogeneity (age, sex, sample size, type of patients, and type of measurement) which contribute to the high degree of not-overlapping information offered by the single studies. Conclusions Our results, based on the current scientific evidence, confirm the previous findings that there is a generalized impairment of various cognitive functions in patients with schizophrenia when compared to normal cases. The modalities with which these results are obtained have not changed over the years and the more recent studies do not modify the high heterogeneity previously found between the studies. This reduces the methodological quality of the results. In order to improve the methodological quality of the studies performed in the field of cognitive deficits of patients with schizophrenia, various factors should be taken into account and better managed in designing future studies. PMID:22715980

  11. Reelin supplementation recovers synaptic plasticity and cognitive deficits in a mouse model for Angelman syndrome

    PubMed Central

    Hethorn, Whitney R; Ciarlone, Stephanie L; Filonova, Irina; Rogers, Justin T; Aguirre, Daniela; Ramirez, Raquel A; Grieco, Joseph C; Peters, Melinda M; Gulick, Danielle; Anderson, Anne E; L Banko, Jessica; Lussier, April L; Weeber, Edwin J

    2015-01-01

    The Reelin signaling pathway is implicated in processes controlling synaptic plasticity and hippocampus-dependent learning and memory. A single direct in vivo application of Reelin enhances long-term potentiation, increases dendritic spine density and improves associative and spatial learning and memory. Angelman syndrome (AS) is a neurological disorder that presents with an overall defect in synaptic function, including decreased long-term potentiation, reduced dendritic spine density, and deficits in learning and memory, making it an attractive model in which to examine the ability of Reelin to recover synaptic function and cognitive deficits. In this study, we investigated the effects of Reelin administration on synaptic plasticity and cognitive function in a mouse model of AS and demonstrated that bilateral, intraventricular injections of Reelin recover synaptic function and corresponding hippocampus-dependent associative and spatial learning and memory. Additionally, we describe alteration of the Reelin profile in tissue from both the AS mouse and post-mortem human brain. PMID:25864922

  12. Central catecholamine metabolism in vivo and the cognitive and motor deficits in Parkinson's disease.

    PubMed Central

    Mann, J J; Stanley, M; Kaplan, R D; Sweeney, J; Neophytides, A

    1983-01-01

    Cerebrospinal fluid levels of homovanillic acid (HVA) in unmedicated patients with Parkinson's disease were 45% of levels in control subjects. Levels of 3-methoxy-4-hydroxyphenylglycol (MHPG) and platelet monoamine oxidase activity (MAO) did not differ. Within the Parkinson's disease group platelet MAO B activity correlated with HVA (an MAO B substrate) but not MHPG (an MAO A substrate). A mild global dementia was found that did not correlate with the more severe motor deficit. There was a negative correlation between the motor deficit and HVA levels but not with MHPG. Cognitive functioning correlated positively with platelet MAO, and the ratio of HVA to MHPG levels and negatively with MHPG alone. It is postulated that dopaminergic and noradrenergic activity or the functional balance between these systems may contribute to the observed cognitive dysfunction. PMID:6644314

  13. Self-perceived cognitive deficits and their relationship with internalized stigma and quality of life in patients with schizophrenia

    PubMed Central

    Shin, Yeon-Jeong; Joo, Yo-Han; Kim, Jong-Hoon

    2016-01-01

    Background We investigated self-perceived cognitive deficits and their relationship with internalized stigma and quality of life in patients with schizophrenia in order to shed light on the clinical correlates of subjective cognitive deficits in schizophrenia. Methods Seventy outpatients with schizophrenia were evaluated. Patients’ self-perceived cognitive deficits, internalized stigma, and subjective quality of life were assessed using the Scale to Investigate Cognition in Schizophrenia (SSTICS), the Internalized Stigma of Mental Illness Scale (ISMI), and the Schizophrenia Quality of Life Scale Revision 4 (SQLS-R4), respectively. Correlation and regression analyses controlling for the severity of symptoms of schizophrenia were performed, and a mediation analysis was conducted to examine the hypothesis that internalized stigma mediates the relationship between self-perceived cognitive deficits and subjective quality of life. Results Pearson’s partial correlation analysis showed significant correlations among the SSTICS, ISMI, and SQLS-R4 scores (P<0.01). Multiple regression analysis showed that the SSTICS and ISMI scores significantly predicted the SQLS-R4 score (P<0.01). Mediation analysis revealed that the strength of the association between the SSTICS and SQLS-R4 scores decreased from β=0.74 (P<0.01) to β=0.56 (P<0.01), when the ISMI score was statistically controlled. The Sobel test revealed that this difference was significant (P<0.01), indicating that internalized stigma partially mediated the relationship between self-perceived cognitive deficits and quality of life. Conclusion The present study indicates that self-perceived cognitive deficits are significantly associated with internalized stigma and quality of life. Furthermore, internalized stigma was identified as a partial mediator of the relationship between self-perceived cognitive deficits and quality of life. These findings suggest that clinicians should be aware that patients with

  14. Cognitive flexibility deficits in a mouse model for the absence of full-length dystrophin.

    PubMed

    Remmelink, E; Aartsma-Rus, A; Smit, A B; Verhage, M; Loos, M; van Putten, M

    2016-07-01

    Duchenne muscular dystrophy (DMD) is a progressive muscle-wasting disorder, caused by mutations in the DMD gene and the resulting lack of dystrophin. The DMD gene has seven promoters, giving rise to multiple full-length and shorter isoforms. Besides the expression of dystrophin in muscles, the majority of dystrophin isoforms is expressed in brain and dystrophinopathy can lead to cognitive deficits, including intellectual impairments and deficits in executive function. In contrast to the muscle pathology, the impact of the lack of dystrophin on the brain is not very well studied. Here, we study the behavioral consequences of a lack of full-length dystrophin isoforms in mdx mice, particularly with regard to domains of executive functions and anxiety. We observed a deficit in cognitive flexibility in mdx mice in the absence of motor dysfunction or general learning impairments using two independent behavioral tests. In addition, increased anxiety was observed, but its expression depended on the context. Overall, these results suggest that the absence of full-length dystrophin in mice has specific behavioral effects that compare well to deficits observed in DMD patients. PMID:27220066

  15. Modeling neurodevelopmental cognitive deficits in tasks with cross-species translational validity.

    PubMed

    Cope, Z A; Powell, S B; Young, J W

    2016-01-01

    Numerous psychiatric disorders whose cognitive dysfunction links to functional outcome have neurodevelopmental origins including schizophrenia, autism and bipolar disorder. Treatments are needed for these cognitive deficits, which require development using animal models. Models of neurodevelopmental disorders are as varied and diverse as the disorders themselves, recreating some but not all aspects of the disorder. This variety may in part underlie why purported procognitive treatments translated from these models have failed to restore functioning in the targeted patient populations. Further complications arise from environmental factors used in these models that can contribute to numerous disorders, perhaps only impacting specific domains, while diagnostic boundaries define individual disorders, limiting translational efficacy. The Research Domain Criteria project seeks to 'develop new ways to classify mental disorders based on behavioral dimensions and neurobiological measures' in hopes of facilitating translational research by remaining agnostic toward diagnostic borders derived from clinical presentation in humans. Models could therefore recreate biosignatures of cognitive dysfunction irrespective of disease state. This review highlights work within the field of neurodevelopmental models of psychiatric disorders tested in cross-species translational cognitive paradigms that directly inform this newly developing research strategy. By expounding on this approach, the hopes are that a fuller understanding of each model may be attainable in terms of the cognitive profile elicited by each manipulation. Hence, conclusions may begin to be drawn on the nature of cognitive neuropathology on neurodevelopmental and other disorders, increasing the chances of procognitive treatment development for individuals affected in specific cognitive domains. PMID:26667374

  16. Cognitive executive impairment and dopaminergic deficits in de novo Parkinson's disease.

    PubMed

    Siepel, Françoise J; Brønnick, Kolbjørn S; Booij, Jan; Ravina, Bernard M; Lebedev, Alexander V; Pereira, Joana B; Grüner, Renate; Aarsland, Dag

    2014-12-01

    Cognitive impairment in Parkinson's disease (PD) is common and does directly impact patients' everyday functioning. However, the underlying mechanisms of early cognitive decline are not known. This study explored the association between striatal dopaminergic deficits and cognitive impairment within a large cohort of early, drug-naïve PD patients and tested the hypothesis that executive dysfunction in PD is associated with striatal dopaminergic depletion. A cross-sectional multicenter cohort of 339 PD patients and 158 healthy controls from the Parkinson's Progression Markers Initiative study was analyzed. Each individual underwent cerebral single-photon emission CT (SPECT) and a standardized neuropsychological assessment with tests of memory as well as visuospatial and executive function. SPECT imaging was performed with [(123) I]FP-CIT, and specific binding ratios in left and right putamen and caudate nucleus were calculated. The association between specific binding ratios, cognitive domain scores, and age was analyzed using Pearson's correlations, partial correlation, and conditional process analysis. A small, but significant, positive association between total striatal dopamine transporter binding and the attention/executive domain was found (r = 0.141; P = 0.009) in PD, but this was not significant after adjusting for age. However, in a moderated mediation model, we found that cognitive executive differences between controls and patients with PD were mediated by an age-moderated striatal dopaminergic deficit. Our findings support the hypothesis that nigrostriatal dopaminergic deficit is associated with executive impairment, but not to memory or visuospatial impairment, in early PD. PMID:25284687

  17. Pharmacological and genetic reversal of age dependent cognitive deficits due to decreased presenilin function

    PubMed Central

    McBride, Sean M. J.; Choi, Catherine H.; Schoenfeld, Brian P.; Bell, Aaron J.; Liebelt, David A.; Ferreiro, David; Choi, Richard J.; Hinchey, Paul; Kollaros, Maria; Terlizzi, Allison M.; Ferrick, Neal J.; Koenigsberg, Eric; Rudominer, Rebecca L.; Sumida, Ai; Chiorean, Stephanie; Siwicki, Kathleen K.; Nguyen, Hanh T.; Fortini, Mark E.; McDonald, Thomas V.; Jongens, Thomas A.

    2010-01-01

    Alzheimer's disease is the leading cause of cognitive loss and neurodegeneration in the developed world. Although its genetic and environmental causes are not generally known, familial forms of the disease (FAD) are due to mutations in a single copy of the Presenilin (PS) and Amyloid Precursor Protein (APP) genes. The dominant inheritance pattern of FAD indicates that it may be due to gain or change of function mutations. Studies of FAD-linked forms of presenilin in model organisms, however, indicate that they are loss of function, leading to the possibility that a reduction in PS activity might contribute to FAD and that proper psn levels are important for maintaining normal cognition throughout life. To explore this issue further, we have tested the effect of reducing psn activity during aging in Drosophila melanogaster males. We have found that flies in which the dosage of psn function is reduced by 50% display age-onset impairments in learning and memory. Treatment with metabotropic glutamate receptor (mGluR) antagonists or lithium during the aging process prevented the onset of these deficits, and treatment of aged flies reversed the age-dependent deficits. Genetic reduction of DmGluRA, the inositol trisphosphate receptor (InsP3R) or IPPase also prevented these age-onset cognitive deficits. These findings suggest that reduced psn activity may contribute to the age onset cognitive loss observed with FAD. They also indicate that enhanced mGluR signaling and calcium release regulated by InsP3R as underlying causes of the age-dependent cognitive phenotypes observed when psn activity is reduced. PMID:20631179

  18. Cognitive and olfactory deficits in Machado-Joseph disease: a dopamine transporter study.

    PubMed

    Braga-Neto, Pedro; Felicio, Andre C; Hoexter, Marcelo Q; Pedroso, José Luiz; Dutra, Lívia Almeida; Alessi, Helena; Minett, Thaís; Santos-Galduroz, Ruth F; da Rocha, Antônio José; Garcia, Lucas A L; Bertolucci, Paulo Henrique F; Bressan, Rodrigo A; Barsottini, Orlando Graziani Povoas

    2012-08-01

    Cognitive and olfactory impairments have been demonstrated in patients with Machado-Joseph disease (MJD), and a possible relationship with dopaminergic dysfunction is implicated. However, there is still controversy regarding the pattern of striatal dopaminergic dysfunction in patients with MJD. In this study, we investigated whether these patients had different dopamine transporter (DAT) densities as compared to healthy subjects, and correlated these data with cognitive performance and sense of smell. Twenty-two MJD patients and 20 control subjects were enrolled. The neuropsychological assessment comprised the spatial span, symbol search, picture completion, stroop color word test, trail making test and phonemic verbal fluency test. The 16-item Sniffin' Sticks was used to evaluate odor identification. DAT imaging was performed using the SPECT radioligand [(99m)Tc]-TRODAT-1, alongside with Magnetic Resonance imaging. Patients with MJD showed significantly lower DAT density in the caudate (1.34 ± 0.27 versus 2.02 ± 0.50, p < 0.001), posterior putamen (0.81 ± 0.32 versus 1.32 ± 0.34, p < 0.001) and anterior putamen (1.10 ± 0.31 versus 1.85 ± 0.45, p < 0.001) compared with healthy controls. The putamen/caudate ratio was also significantly lower in patients compared with controls (0.73 ± 0.038 versus 0.85 ± 0.032, p = 0.027). Even though we had only two patients with parkinsonism, we detected striatal dopaminergic deficits in those patients. No significant correlations were detected between DAT density and cognitive performance or Sniffin' Sticks scores. The data suggests that striatal dopamine deficit is not involved in cognitive or sense of smell deficits. This finding raises the possibility of extra-striatal dopamine and other neurotransmitter system involvement or of cerebellum neurodegeneration exerting a direct influence on cognitive and sensorial information processing in MJD. PMID:22575233

  19. Cognitive deficits of executive functions and decision-making in obsessive-compulsive disorder.

    PubMed

    Dittrich, Winand H; Johansen, Thomas

    2013-10-01

    The nature of cognitive deficits in obsessive-compulsive disorder (OCD) is characterized by contradictory findings in terms of specific neuropsychological deficits. Selective impairments have been suggested to involve visuospatial memory, set shifting, decision-making and response inhibition. The aim of this study was to investigate cognitive deficits in decision-making and executive functioning in OCD. It was hypothesized that the OCD patients would be less accurate in their responses compared to the healthy controls in rational decision-making on a version of the Cambridge gambling task (CGT) and on the color-word interference test and on a version of the Tower of Hanoi test (tower test) of executive functioning. Thirteen participants with OCD were compared to a group of healthy controls (n = 13) matched for age, gender, education and verbal IQ. Results revealed significant differences between the OCD group and the healthy control group on quality of decision-making on the CGT and for achievement score on the tower test. On these two tasks the OCD group performed worse than the healthy control group. The symptom-dimension analysis revealed performance differences where safety checking patients were impaired on the tower test compared to contamination patients. Results are discussed in the framework of cognition and emotion processing and findings implicate that OCD models should address, specifically, the interaction between cognition and emotion. Here the emotional disruption hypothesis is forwarded to account for the dysfunctional behaviors in OCD. Further implications regarding methodological and inhibitory factors affecting cognitive information processing are highlighted. PMID:23841985

  20. Emotional bias of cognitive control in adults with childhood attention-deficit/hyperactivity disorder.

    PubMed

    Schulz, Kurt P; Bédard, Anne-Claude V; Fan, Jin; Clerkin, Suzanne M; Dima, Danai; Newcorn, Jeffrey H; Halperin, Jeffrey M

    2014-01-01

    Affect recognition deficits found in individuals with attention-deficit/hyperactivity disorder (ADHD) across the lifespan may bias the development of cognitive control processes implicated in the pathophysiology of the disorder. This study aimed to determine the mechanism through which facial expressions influence cognitive control in young adults diagnosed with ADHD in childhood. Fourteen probands with childhood ADHD and 14 comparison subjects with no history of ADHD were scanned with functional magnetic resonance imaging while performing a face emotion go/no-go task. Event-related analyses contrasted activation and functional connectivity for cognitive control collapsed over face valence and tested for variations in activation for response execution and inhibition as a function of face valence. Probands with childhood ADHD made fewer correct responses and inhibitions overall than comparison subjects, but demonstrated comparable effects of face emotion on response execution and inhibition. The two groups showed similar frontotemporal activation for cognitive control collapsed across face valence, but differed in the functional connectivity of the right dorsolateral prefrontal cortex, with fewer interactions with the subgenual cingulate cortex, inferior frontal gyrus, and putamen in probands than in comparison subjects. Further, valence-dependent activation for response execution was seen in the amygdala, ventral striatum, subgenual cingulate cortex, and orbitofrontal cortex in comparison subjects but not in probands. The findings point to functional anomalies in limbic networks for both the valence-dependent biasing of cognitive control and the valence-independent cognitive control of face emotion processing in probands with childhood ADHD. This limbic dysfunction could impact cognitive control in emotional contexts and may contribute to the social and emotional problems associated with ADHD. PMID:24918067

  1. Performances on a cognitive theory of mind task: specific decline or general cognitive deficits? Evidence from normal aging.

    PubMed

    Fliss, Rafika; Lemerre, Marion; Mollard, Audrey

    2016-06-01

    Compromised theory of mind (ToM) can be explained either by a failure to implement specific representational capacities (mental state representations) or by more general executive selection demands. In older adult populations, evidence supporting affected executive functioning and cognitive ToM in normal aging are reported. However, links between these two functions remain unclear. In the present paper, we address these shortcomings by using a specific task of ToM and classical executive tasks. We studied, using an original cognitive ToM task, the effect of age on ToM performances, in link with the progressive executive decline. 96 elderly participants were recruited. They were asked to perform a cognitive ToM task, and 5 executive tests (Stroop test and Hayling Sentence Completion Test to appreciate inhibitory process, Trail Making Test and Verbal Fluency for shifting assessment and backward span dedicated to estimate working memory capacity). The results show changes in cognitive ToM performance according to executive demands. Correlational studies indicate a significant relationship between ToM performance and the selected executive measures. Regression analyzes demonstrates that level of vocabulary and age as the best predictors of ToM performance. The results are consistent with the hypothesis that ToM deficits are related to age-related domain-general decline rather than as to a breakdown in specialized representational system. The implications of these findings for the nature of social cognition tests in normal aging are also discussed. PMID:27277154

  2. Cognitive Impairments of Children with Severe Arithmetic Difficulties: Cognitive Deficit or Developmental Lag?

    ERIC Educational Resources Information Center

    Berg, Derek H.

    2008-01-01

    An age-matched/achievement-matched design was utilized to examine the cognitive functioning of children with severe arithmetic difficulties. A battery of cognitive tasks was administered to three groups of elementary aged children: 20 children with severe arithmetic difficulties (SAD), 20 children matched in age (CAM) to the children with SAD, and…

  3. A Cross-Sectional Study of the Relationship of Physical Activity with Depression and Cognitive Deficit in Older Adults.

    PubMed

    Paulo T, R S; Tribess, Sheilla; Sasaki, Jeffer Eidi; Meneguci, Joilson; Martins, Cristiane A; Freitas, Ismael F; Romo-Perez, Vicente; Virtuoso, Jair S

    2016-04-01

    The aim of this study was to examine the association of physical activity with depression and cognition deficit, separately and combined, in Brazilian older adults. We analyzed data from 622 older adults. Physical activity was assessed using the International Physical Activity Questionnaire. Depressive symptoms were assessed using the Geriatric Depression Scale, while cognitive deficit was assessed using the Mini-Mental State Examination. Multinomial logistic regressions were used to assess associations of depression and cognitive deficit with sociodemographic, health, and behavioral variables. Prevalence of physical inactivity (< 150 min of moderate-to-vigorous physical activity/ week), depression, and cognitive deficit were 35.7%, 37.4%, and 16.7%. Physical inactivity was associated with depression (OR: 1.83, 95% CI: 1.14-2.94) and with depression and cognitive deficit combined (OR: 4.23, 95% CI: 2.01-8.91). Physically inactive participants were also more likely to present limitations in orientation and language functions. Physical inactivity was associated with depression and also with depression and cognitive deficit combined in older adults. PMID:26439455

  4. Involvement of Neuroinflammation during Brain Development in Social Cognitive Deficits in Autism Spectrum Disorder and Schizophrenia.

    PubMed

    Nakagawa, Yutaka; Chiba, Kenji

    2016-09-01

    Development of social cognition, a unique and high-order function, depends on brain maturation from childhood to adulthood in humans. Autism spectrum disorder (ASD) and schizophrenia have similar social cognitive deficits, although age of onset in each disorder is different. Pathogenesis of these disorders is complex and contains several features, including genetic risk factors, environmental risk factors, and sites of abnormalities in the brain. Although several hypotheses have been postulated, they seem to be insufficient to explain how brain alterations associated with symptoms in these disorders develop at distinct developmental stages. Development of ASD appears to be related to cerebellar dysfunction and subsequent thalamic hyperactivation in early childhood. By contrast, schizophrenia seems to be triggered by thalamic hyperactivation in late adolescence, whereas hippocampal aberration has been possibly initiated in childhood. One of the possible culprits is metal homeostasis disturbances that can induce dysfunction of blood-cerebrospinal fluid barrier. Thalamic hyperactivation is thought to be induced by microglia-mediated neuroinflammation and abnormalities of intracerebral environment. Consequently, it is likely that the thalamic hyperactivation triggers dysregulation of the dorsolateral prefrontal cortex for lower brain regions related to social cognition. In this review, we summarize the brain aberration in ASD and schizophrenia and provide a possible mechanism underlying social cognitive deficits in these disorders based on their distinct ages of onset. PMID:27384073

  5. Air pollution, cognitive deficits and brain abnormalities: a pilot study with children and dogs.

    PubMed

    Calderón-Garcidueñas, Lilian; Mora-Tiscareño, Antonieta; Ontiveros, Esperanza; Gómez-Garza, Gilberto; Barragán-Mejía, Gerardo; Broadway, James; Chapman, Susan; Valencia-Salazar, Gildardo; Jewells, Valerie; Maronpot, Robert R; Henríquez-Roldán, Carlos; Pérez-Guillé, Beatriz; Torres-Jardón, Ricardo; Herrit, Lou; Brooks, Diane; Osnaya-Brizuela, Norma; Monroy, Maria E; González-Maciel, Angelica; Reynoso-Robles, Rafael; Villarreal-Calderon, Rafael; Solt, Anna C; Engle, Randall W

    2008-11-01

    Exposure to air pollution is associated with neuroinflammation in healthy children and dogs in Mexico City. Comparative studies were carried out in healthy children and young dogs similarly exposed to ambient pollution in Mexico City. Children from Mexico City (n: 55) and a low polluted city (n:18) underwent psychometric testing and brain magnetic resonance imaging MRI. Seven healthy young dogs with similar exposure to Mexico City air pollution had brain MRI, measurement of mRNA abundance of two inflammatory genes cyclooxygenase-2, and interleukin 1 beta in target brain areas, and histopathological evaluation of brain tissue. Children with no known risk factors for neurological or cognitive disorders residing in a polluted urban environment exhibited significant deficits in a combination of fluid and crystallized cognition tasks. Fifty-six percent of Mexico City children tested showed prefrontal white matter hyperintense lesions and similar lesions were observed in dogs (57%). Exposed dogs had frontal lesions with vascular subcortical pathology associated with neuroinflammation, enlarged Virchow-Robin spaces, gliosis, and ultrafine particulate matter deposition. Based on the MRI findings, the prefrontal cortex was a target anatomical region in Mexico City children and its damage could have contributed to their cognitive dysfunction. The present work presents a groundbreaking, interdisciplinary methodology for addressing relationships between environmental pollution, structural brain alterations by MRI, and cognitive deficits/delays in healthy children. PMID:18550243

  6. Calycosin ameliorates diabetes-induced cognitive impairments in rats by reducing oxidative stress via the PI3K/Akt/GSK-3β signaling pathway.

    PubMed

    Wang, Xiang; Zhao, Linhui

    2016-04-29

    Diabetic encephalopathy is one of the most prevalent chronic complications of diabetes mellitus (DM), but there is currently no effective method of prevention nor proven therapeutic regimen for it. In this study, we investigated the effects of calycosin on cognitive behavior and the potential mechanism involved in streptozocin-induced diabetic rats. The effects of diabetes and calycosin treatment on spatial learning and memory were evaluated using the Morris Water Maze, passive avoidance and motor coordination tests. Histological analysis of the hippocampus cornu ammonis 1 (CA1) region was conducted in rats. The decreased expression of the synapsin (SYN) and postsynatptic density protein (PSD-95), as well as brain-derived neurotrophic factor (BDNF) in diabetic rats was measured by quantitative real-time PCR and western blot. Treatment with calycosin promoted a reduction in the expression of SYN, PSD-95 and BDNF. In addition, diabetic rats showed increased MDA levels, and decreased SOD levels and GSH-Px activities in the hippocampus, as well as increased AChE activity in the cerebral cortex; these changes were reversed by calycosin supplementation. Thus, the impairment of learning and memory in STZ-induced diabetic rats was alleviated by calycosin, and that the degree of alleviation was associated with oxidative stress. We also found that calycosin treatment significantly stimulated Akt phosphorylation and decreased GSK-3β and tau phosphorylation, and that these changes could be restored by the PI3K/Akt inhibitor LY294002. In conclusion, calycosin had a beneficial effect on the amelioration, prevention and treatment of diabetes-associated cognitive deficits, through its involvement in oxidative stress, synaptic function and the PI3K/Akt/GSK-3β pathway. PMID:26970304

  7. Total Lignans of Schisandra chinensis Ameliorates Aβ1-42-Induced Neurodegeneration with Cognitive Impairment in Mice and Primary Mouse Neuronal Cells.

    PubMed

    Zhao, Xu; Liu, Chunmei; Xu, Mengjie; Li, Xiaolong; Bi, Kaishun; Jia, Ying

    2016-01-01

    Lignan compounds extracted from Schisandra chinensis (Turcz.) Baill. have been reported to possess various biological activities, and have potential in the treatment of Alzheimer's disease. This study was designed to investigate the effects of total lignans of Schisandra chinensis (TLS) on cognitive function and neurodegeneration in the model of AD induced by Aβ1-42 in vivo and in vitro. It was found that intragastric infusion with TLS (50 and 200 mg/kg) to Aβ1-42-induced mice significantly increased the number of avoidances in the shuttle-box test and swimming time in the target quadrant in the Morris water maze test. TLS at dose of 200 mg/kg significantly restored the activities of total antioxidant capacity (T-AOC), as well as the level of malondialdehyde (MDA) both in the hippocampus and cerebral cortex in mice. Results of histopathological examination indicated that TLS noticeably ameliorated the neurodegeneration in the hippocampus in mice. On the other hand, TLS (100 μM) could protect the Aβ1-42-induced primary mouse neuronal cells by blocking the decrease of mitochondrial membrane potential (MMP), change the expressions of Bcl-2 (important regulator in the mitochondria apoptosis pathway). Moreover, TLS also decreased the activity of β-secretase 1 (BACE1), crucial protease contributes to the hydrolysis of amyloid precursor protein (APP), and inhibited the expression of JKN/p38, which involved in the MAPKs signaling pathways in both mice and primary mouse neuronal cells. In summary, TLS might protect against cognitive deficits and neurodegeneration by releasing the damage of oxidative stress, inhibiting the expression of BACE1 and the MAPKs inflammatory signaling pathways. PMID:27035824

  8. Total Lignans of Schisandra chinensis Ameliorates Aβ1-42-Induced Neurodegeneration with Cognitive Impairment in Mice and Primary Mouse Neuronal Cells

    PubMed Central

    Zhao, Xu; Liu, Chunmei; Xu, Mengjie; Li, Xiaolong; Bi, Kaishun; Jia, Ying

    2016-01-01

    Lignan compounds extracted from Schisandra chinensis (Turcz.) Baill. have been reported to possess various biological activities, and have potential in the treatment of Alzheimer’s disease. This study was designed to investigate the effects of total lignans of Schisandra chinensis (TLS) on cognitive function and neurodegeneration in the model of AD induced by Aβ1–42 in vivo and in vitro. It was found that intragastric infusion with TLS (50 and 200 mg/kg) to Aβ1–42-induced mice significantly increased the number of avoidances in the shuttle-box test and swimming time in the target quadrant in the Morris water maze test. TLS at dose of 200 mg/kg significantly restored the activities of total antioxidant capacity (T-AOC), as well as the level of malondialdehyde (MDA) both in the hippocampus and cerebral cortex in mice. Results of histopathological examination indicated that TLS noticeably ameliorated the neurodegeneration in the hippocampus in mice. On the other hand, TLS (100 μM) could protect the Aβ1–42-induced primary mouse neuronal cells by blocking the decrease of mitochondrial membrane potential (MMP), change the expressions of Bcl-2 (important regulator in the mitochondria apoptosis pathway). Moreover, TLS also decreased the activity of β-secretase 1 (BACE1), crucial protease contributes to the hydrolysis of amyloid precursor protein (APP), and inhibited the expression of JKN/p38, which involved in the MAPKs signaling pathways in both mice and primary mouse neuronal cells. In summary, TLS might protect against cognitive deficits and neurodegeneration by releasing the damage of oxidative stress, inhibiting the expression of BACE1 and the MAPKs inflammatory signaling pathways. PMID:27035824

  9. Overstimulation of newborn mice leads to behavioral differences and deficits in cognitive performance

    PubMed Central

    Christakis, D. A.; Ramirez, J. S. B.; Ramirez, J. M.

    2012-01-01

    Observational studies in humans have found associations between overstimulation in infancy via excessive television viewing and subsequent deficits in cognition and attention. We developed and tested a mouse model of overstimulation whereby p10 mice were subjected to audio (70 db) and visual stimulation (flashing lights) for six hours per day for a total of 42 days. 10 days later cognition and behavior were tested using the following tests: Light Dark Latency, Elevated Plus Maze, Novel Object Recognition, and Barnes Maze. In all tests, overstimulated mice performed significantly worse compared to controls suggesting increased activity and risk taking, diminished short term memory, and decreased cognitive function. These findings suggest that excessive non-normative stimulation during critical periods of brain development can have demonstrable untoward effects on subsequent neurocognitive function. PMID:22855702

  10. Prevention, Rehabilitation, and Mitigation Strategies of Cognitive Deficits in Aging with HIV: Implications for Practice and Research

    PubMed Central

    Vance, David E.

    2013-01-01

    Highly active antiretroviral therapy has given the chance to those living with HIV to keep on living, allowing them the opportunity to age and perhaps age successfully. Yet, there are severe challenges to successful aging with HIV, one of which is cognitive deficits. Nearly half of those with HIV experience cognitive deficits that can interfere with everyday functioning, medical decision making, and quality of life. Given that cognitive deficits develop with more frequency and intensity with increasing age, concerns mount that as people age with HIV, they may experience more severe cognitive deficits. These concerns become especially germane given that by 2015, 50% of those with HIV will be 50 and older, and this older cohort of adults is expected to grow. As such, this paper focuses on the etiologies of such cognitive deficits within the context of cognitive reserve and neuroplasticity. From this, evidence-based and hypothetical prevention (i.e., cognitive prescriptions), rehabilitation (i.e., speed of processing training), and mitigation (i.e., spaced retrieval method) strategies are reviewed. Implications for nursing practice and research are posited. PMID:23431469

  11. 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

  12. 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. PMID:25009697

  13. Cognitive deficits in patients with obsessive–compulsive disorder – electroencephalography correlates

    PubMed Central

    Kamaradova, Dana; Hajda, Miroslav; Prasko, Jan; Taborsky, Jiri; Grambal, Ales; Latalova, Klara; Ociskova, Marie; Brunovsky, Martin; Hlustik, Petr

    2016-01-01

    Background Obsessive–compulsive disorder (OCD) is associated with cognitive dysfunction. Although there are several studies focused on the neurobiology of OCD, little is known about the biological correlates of the cognitive deficit linked to this disorder. The aim of our study was to examine the association between cognitive impairment and current source density markers in patients with OCD. Methods Resting-state eyes-closed electroencephalography (EEG) data were recorded in 20 patients with OCD and 15 healthy controls who were involved in the study. Cortical EEG sources were estimated by standardized low-resolution electromagnetic tomography in seven frequency bands: delta (1.5–6 Hz), theta (6.5–8 Hz), alpha-1 (8.5–10 Hz), alpha-2 (10.5–12 Hz), beta-1 (12.5–18 Hz), beta-2 (18.5–21 Hz), and beta-3 (21.5–30 Hz). Cognitive performance was measured by the Trail-Making Test (versions A and B), Stroop CW Test, and D2 Test. Results Frontal delta and theta EEG sources showed significantly higher activity in the whole group of patients with OCD (N=20) than in control subjects (N=15). Subsequent analysis revealed that this excess of low-frequency activity was present only in the subgroup of eleven patients with cognitive impairment (based on the performance in the Trail-Making Test – A). The subgroup of patients with normal cognitive functions (N=9) did not differ in cortical EEG sources from healthy controls. Conclusion The present results suggest that frontal low-frequency cortical sources of resting-state EEG rhythms can distinguish groups of cognitively impaired and cognitively intact patients with OCD. Based on our results, future studies should consider whether the present methodological approach provides clinically useful information for the revelation of cognitive impairment in patients with OCD. PMID:27226716

  14. Mount Everest: a space analogue for speech monitoring of cognitive deficits and stress.

    PubMed

    Lieberman, Philip; Morey, Angie; Hochstadt, Jesse; Larson, Mara; Mather, Sandra

    2005-06-01

    In deep-space missions, the basal ganglia and hippocampus, subcortical structures of the brain that play critical roles in motor activity, cognition, and memory, will be vulnerable to damage from cosmic rays. These metabolically active structures are also sensitive to damage arising from the low oxygen content of air at extreme altitudes. We have, therefore, used Mount Everest as an analogue for deep space, where astronauts will be subject to danger and stress as well as neural damage. We can ethically obtain data because our climber-subjects already intend to climb Mt. Everest. We record speech and test cognitive and linguistic performance before, during, and after exposure to hypoxic conditions. From these data we have derived and validated computer-implemented acoustic voice measures that track slight as well as profound cognitive impairment. Vowel duration and speech motor sequencing errors increase as climbers ascend, reflecting degraded basal ganglia activity. These metrics detect deficits in language comprehension and the ability to change plans in changing circumstances. Preliminary analyses also reveal memory deficits reflecting hippocampal damage. Our speech metrics are unobtrusive and do not reveal the content of a verbal message; they could be derived automatically, allowing space crews to detect subtle motor and cognitive deficits and invoke countermeasures before performance is profoundly impaired. In future work we will be validating the voice metrics of stress in collaboration with the Dinges NSBRI laboratory study of task-induced stress. Our procedures can also be applied in general aviation and in the treatment of Parkinson's disease, Alzheimer's dementia, and other neurological disorders. PMID:15943213

  15. Effect of Neuroscience-Based Cognitive Skill Training on Growth of Cognitive Deficits Associated with Learning Disabilities in Children Grades 2-4

    ERIC Educational Resources Information Center

    Avtzon, Sarah Abitbol

    2012-01-01

    Working memory, executive functions, and cognitive processes associated with specific academic areas, are empirically identified as being the core underlying cognitive deficits in students with specific learning disabilities. Using Hebb's theory of neuroplasticity and the principle of automaticity as theoretical bases, this experimental study…

  16. Edaravone alleviates Alzheimer’s disease-type pathologies and cognitive deficits

    PubMed Central

    Jiao, Shu-Sheng; Yao, Xiu-Qing; Liu, Yu-Hui; Wang, Qing-Hua; Zeng, Fan; Lu, Jian-Jun; Liu, Jia; Zhu, Chi; Shen, Lin-Lin; Liu, Cheng-Hui; Wang, Ye-Ran; Zeng, Gui-Hua; Parikh, Ankit; Chen, Jia; Liang, Chun-Rong; Xiang, Yang; Bu, Xian-Le; Deng, Juan; Li, Jing; Xu, Juan; Zeng, Yue-Qin; Xu, Xiang; Xu, Hai-Wei; Zhong, Jin-Hua; Zhou, Hua-Dong; Zhou, Xin-Fu; Wang, Yan-Jiang

    2015-01-01

    Alzheimer’s disease (AD) is one of most devastating diseases affecting elderly people. Amyloid-β (Aβ) accumulation and the downstream pathological events such as oxidative stress play critical roles in pathogenesis of AD. Lessons from failures of current clinical trials suggest that targeting multiple key pathways of the AD pathogenesis is necessary to halt the disease progression. Here we show that Edaravone, a free radical scavenger that is marketed for acute ischemic stroke, has a potent capacity of inhibiting Aβ aggregation and attenuating Aβ-induced oxidation in vitro. When given before or after the onset of Aβ deposition via i.p. injection, Edaravone substantially reduces Aβ deposition, alleviates oxidative stress, attenuates the downstream pathologies including Tau hyperphosphorylation, glial activation, neuroinflammation, neuronal loss, synaptic dysfunction, and rescues the behavioral deficits of APPswe/PS1 mice. Oral administration of Edaravone also ameliorates the AD-like pathologies and memory deficits of the mice. These findings suggest that Edaravone holds a promise as a therapeutic agent for AD by targeting multiple key pathways of the disease pathogenesis. PMID:25847999

  17. Alpha-tocopherol quinine ameliorates spatial memory deficits by reducing beta-amyloid oligomers, neuroinflammation and oxidative stress in transgenic mice with Alzheimer's disease.

    PubMed

    Wang, Shao-Wei; Yang, Shi-Gao; Liu, Wen; Zhang, Yang-Xin; Xu, Peng-Xin; Wang, Teng; Ling, Tie-Jun; Liu, Rui-Tian

    2016-01-01

    The pathologies of Alzheimer's disease (AD) is associated with soluble beta-amyloid (Aβ) oligomers, neuroinflammation and oxidative stress. Decreasing the levels of Aβ oligomer, glial activation and oxidative stress are potential therapeutic approaches for AD treatment. We previously found alpha-tocopherol quinine (α-TQ) inhibited Aβ aggregation and cytotoxicity, decreased the release of inflammatory cytokines and reactive oxygen species (ROS) in vitro. However, whether α-TQ ameliorates memory deficits and other neuropathologies in mice or patients with AD remains unknown. In this study, we reported that orally administered α-TQ ameliorated memory impairment in APPswe/PS1dE9 transgenic mice, decreased oxidative stress and the levels of Aβ oligomer in the brains of mice, prevented the production of inducible nitric oxide synthase and inflammatory mediators, such as interleukin-6 and interleukin-1β, and inhibited microglial activation by inhibiting NF-κB signaling pathway. These findings suggest that α-TQ has potential therapeutic value for AD treatment. PMID:26358659

  18. Cognitive Deficits Associated with Nav1.1 Alterations: Involvement of Neuronal Firing Dynamics and Oscillations

    PubMed Central

    Bender, Alex C.; Luikart, Bryan W.; Lenck-Santini, Pierre-Pascal

    2016-01-01

    Brain oscillations play a critical role in information processing and may, therefore, be essential to uncovering the mechanisms of cognitive impairment in neurological disease. In Dravet syndrome (DS), a mutation in SCN1A, coding for the voltage-gated sodium channel Nav1.1, is associated with severe cognitive impairment and seizures. While seizure frequency and severity do not correlate with the extent of impairment, the slowing of brain rhythms may be involved. Here we investigate the role of Nav1.1 on brain rhythms and cognition using RNA interference. We demonstrate that knockdown of Nav1.1 impairs fast- and burst-firing properties of neurons in the medial septum in vivo. The proportion of neurons that fired phase-locked to hippocampal theta oscillations was reduced, and medial septal regulation of theta rhythm was disrupted. During a working memory task, this deficit was characterized by a decrease in theta frequency and was negatively correlated with performance. These findings suggest a fundamental role for Nav1.1 in facilitating fast-firing properties in neurons, highlight the importance of precise temporal control of theta frequency for working memory, and imply that Nav1.1 deficits may disrupt information processing in DS via a dysregulation of brain rhythms. PMID:26978272

  19. Emotion recognition and cognitive empathy deficits in adolescent offenders revealed by context-sensitive tasks

    PubMed Central

    Gonzalez-Gadea, Maria Luz; Herrera, Eduar; Parra, Mario; Gomez Mendez, Pedro; Baez, Sandra; Manes, Facundo; Ibanez, Agustin

    2014-01-01

    Emotion recognition and empathy abilities require the integration of contextual information in real-life scenarios. Previous reports have explored these domains in adolescent offenders (AOs) but have not used tasks that replicate everyday situations. In this study we included ecological measures with different levels of contextual dependence to evaluate emotion recognition and empathy in AOs relative to non-offenders, controlling for the effect of demographic variables. We also explored the influence of fluid intelligence (FI) and executive functions (EFs) in the prediction of relevant deficits in these domains. Our results showed that AOs exhibit deficits in context-sensitive measures of emotion recognition and cognitive empathy. Difficulties in these tasks were neither explained by demographic variables nor predicted by FI or EFs. However, performance on measures that included simpler stimuli or could be solved by explicit knowledge was either only partially affected by demographic variables or preserved in AOs. These findings indicate that AOs show contextual social-cognition impairments which are relatively independent of basic cognitive functioning and demographic variables. PMID:25374529

  20. Striatum morphometry is associated with cognitive control deficits and symptom severity in internet gaming disorder.

    PubMed

    Cai, Chenxi; Yuan, Kai; Yin, Junsen; Feng, Dan; Bi, Yanzhi; Li, Yangding; Yu, Dahua; Jin, Chenwang; Qin, Wei; Tian, Jie

    2016-03-01

    Internet gaming disorder (IGD), identified in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-V) Section III as a condition warranting more clinical research, may be associated with impaired cognitive control. Previous IGD-related studies had revealed structural abnormalities in the prefrontal cortex, an important part of prefrontal-striatal circuits, which play critical roles in cognitive control. However, little is known about the relationship between the striatal nuclei (caudate, putamen, and nucleus accumbens) volumes and cognitive control deficit in individuals with IGD. Twenty-seven adolescents with IGD and 30 age-, gender- and education-matched healthy controls participated in this study. The volume differences of the striatum were assessed by measuring subcortical volume in FreeSurfer. Meanwhile, the Stroop task was used to detect cognitive control deficits. Correlation analysis was used to investigate the relationship between striatal volumes and performance in the Stroop task as well as severity in IGD. Relative to controls, the IGD committed more incongruent condition response errors during the Stroop task and showed increased volumes of dorsal striatum (caudate) and ventral striatum (nucleus accumbens). In addition, caudate volume was correlated with Stroop task performance and nucleus accumbens (NAc) volume was associated with the internet addiction test (IAT) score in the IGD group. The increased volumes of the right caudate and NAc and their association with behavioral characteristics (i.e., cognitive control and severity) in IGD were detected in the present study. Our findings suggest that the striatum may be implicated in the underlying pathophysiology of IGD. PMID:25720356

  1. Characteristics of cognitive deficits and writing skills of Polish adults with developmental dyslexia.

    PubMed

    Bogdanowicz, Katarzyna Maria; Łockiewicz, Marta; Bogdanowicz, Marta; Pąchalska, Maria

    2014-07-01

    The present study was aimed at analysing cognitive deficits of dyslexic adults, and examining their written language skills in comparison with their peers. Our results confirm the presence of a certain profile of symptoms in adult dyslexics. We noticed deficits in: phonological (verbal) short-term memory, phonological awareness, rapid automatised naming (speed, self-corrections), visual perception and control, and visual-motor coordination. Moreover, the dyslexic participants, as compared with their nondyslexic peers, produced more word structure errors whilst writing an essay. However, there were no significant differences between the two groups in the length of the essay, the number of linguistic and punctuation errors, the number of adjectives, and stylistic devices. PMID:23524010

  2. Deficits of cognitive restructuring in major depressive disorder: Measured by textual micro-counseling dialogues.

    PubMed

    Jiang, Nengzhi; Yu, Fei; Zhang, Wencai; Zhang, Jianxin

    2016-04-30

    Cognitive restructuring is an important strategy in cognitive behavioral therapy (CBT). The present study aimed to observe cognitive restructuring in major depressive disorder (MDD) patients using textual micro-counseling dialogue situations. A set of textual micro-counseling dialogues was used to trigger cognitive restructuring in 25 MDD patients and 27 healthy adults. The participants read descriptions ("problems") and explanations ("solutions") for psychologically distressing situations. High-, low-, and zero-restructuring solutions were randomly matched to the problems. The participants evaluated the adaptability and emotional valence of the problems and the insightfulness, adaptability, novelty, and emotional valence of the solutions. Insightfulness ratings for high-restructuring solutions were significantly higher relative to those of low-restructuring solutions in healthy adults, while adaptability ratings for low-restructuring solutions were significantly higher relative to those of high-restructuring solutions in MDD patients. Insightfulness ratings for the solutions were significantly predicted by novelty and adaptability in healthy adults and emotional valence in MDD patients. Lower insightfulness in high-restructuring solutions and higher adaptability in low-restructuring solutions in MDD patients may reflect deficits in cognitive control. PMID:27086227

  3. Manganese exposure and cognitive deficits: A growing concern for manganese neurotoxicity⋆

    PubMed Central

    Roels, H.A.; Bowler, R.M.; Kim, Y.; Henn, B. Claus; Mergler, D.; Hoet, P.; Gocheva, V.V.; Bellinger, D.C.; Wright, R.O.; Harris, M.G.; Chang, Y.; Bouchard, M.F.; Riojas-Rodriguez, H.; Menezes-Filho, J.A.; Téllez-Rojo, Martha Maria

    2013-01-01

    This symposium comprised five oral presentations dealing with recent findings on Mn-related cognitive and motor changes from epidemiological studies across the life span. The first contribution highlighted the usefulness of functional neuroimaging of the central nervous system (CNS) to evaluate cognitive as well as motor deficits in Mn-exposed welders. The second dealt with results of two prospective studies in Mn-exposed workers or welders showing that after decrease of Mn exposure the outcome of reversibility in adverse CNS effects may differ for motor and cognitive function and, in addition the issue of plasma Mn as a reliable biomarker for Mn exposure in welders has been addressed. The third presentation showed a brief overview of the results of an ongoing study assessing the relationship between environmental airborne Mn exposure and neurological or neuropsychological effects in adult Ohio residents living near a Mn point source. The fourth paper focused on the association between blood Mn and neurodevelopment in early childhood which seems to be sensitive to both low and high Mn concentrations. The fifth contribution gave an overview of six studies indicating a negative impact of excess environmental Mn exposure from air and drinking water on children’s cognitive performance, with special attention to hair Mn as a potential biomarker of exposure. These studies highlight a series of questions about Mn neurotoxicity with respect to cognitive processes, forms and routes of exposure, adequate biomarkers of exposure, gender differences, susceptibility and exposure limits with regard to age. PMID:22498092

  4. Manganese exposure and cognitive deficits: a growing concern for manganese neurotoxicity.

    PubMed

    Roels, H A; Bowler, R M; Kim, Y; Claus Henn, B; Mergler, D; Hoet, P; Gocheva, V V; Bellinger, D C; Wright, R O; Harris, M G; Chang, Y; Bouchard, M F; Riojas-Rodriguez, H; Menezes-Filho, J A; Téllez-Rojo, Martha Maria

    2012-08-01

    This symposium comprised five oral presentations dealing with recent findings on Mn-related cognitive and motor changes from epidemiological studies across the life span. The first contribution highlighted the usefulness of functional neuroimaging of the central nervous system (CNS) to evaluate cognitive as well as motor deficits in Mn-exposed welders. The second dealt with results of two prospective studies in Mn-exposed workers or welders showing that after decrease of Mn exposure the outcome of reversibility in adverse CNS effects may differ for motor and cognitive function and, in addition the issue of plasma Mn as a reliable biomarker for Mn exposure in welders has been addressed. The third presentation showed a brief overview of the results of an ongoing study assessing the relationship between environmental airborne Mn exposure and neurological or neuropsychological effects in adult Ohio residents living near a Mn point source. The fourth paper focused on the association between blood Mn and neurodevelopment in early childhood which seems to be sensitive to both low and high Mn concentrations. The fifth contribution gave an overview of six studies indicating a negative impact of excess environmental Mn exposure from air and drinking water on children's cognitive performance, with special attention to hair Mn as a potential biomarker of exposure. These studies highlight a series of questions about Mn neurotoxicity with respect to cognitive processes, forms and routes of exposure, adequate biomarkers of exposure, gender differences, susceptibility and exposure limits with regard to age. PMID:22498092

  5. 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

  6. Calpain inhibitor AK295 attenuates motor and cognitive deficits following experimental brain injury in the rat.

    PubMed Central

    Saatman, K E; Murai, H; Bartus, R T; Smith, D H; Hayward, N J; Perri, B R; McIntosh, T K

    1996-01-01

    Marked increases in intracellular calcium may play a role in mediating cellular dysfunction and death following central nervous system trauma, in part through the activation of the calcium-dependent neutral protease calpain. In this study, we evaluated the effect of the calpain inhibitor AK295 [Z-Leu-aminobutyric acid-CONH(CH2)3-morpholine] on cognitive and motor deficits following lateral fluid percussion brain injury in rats. Before injury, male Sprague-Dawley rats (350-425 g) were trained to perform a beam-walking task and to learn a cognitive test using a Morris water maze paradigm. Animals were subjected to fluid percussion injury (2.2-2.4 atm; 1 atm = 101.3 kPa) and, beginning at 15 min postinjury, received a continuous intraarterial infusion of AK295 (120-140 mg/kg, n = 15) or vehicle (n= 16) for 48 hr. Sham (uninjured) animals received either drug (n = 5) or vehicle (n = 10). Animals were evaluated for neurobehavioral motor function at 48 hr and 7 days postinjury and were tested in the Morris water maze to evaluate memory retention at 7 days postinjury. At 48 hr, both vehicle- and AK295-treated injured animals showed significant neuromotor deficits (P< 0.005). At 7 days, injured animals that received vehicle continued to exhibit significant motor dysfunction (P< 0.01). However, brain-injured, AK295-treated animals showed markedly improved motor scores (P<0.02), which were not significantly different from sham (uninjured) animals. Vehicle-treated, injured animals demonstrated a profound cognitive deficit (P< 0.001), which was significantly attenuated by AK295 treatment (P< 0.05). To our knowledge, this study is the first to use a calpain inhibitor following brain trauma and suggests that calpain plays a role in the posttraumatic events underlying memory and neuromotor dysfunction. PMID:8622952

  7. Long-term cognitive dysfunction in the rat following docetaxel treatment is ameliorated by the phosphodiesterase-4 inhibitor, rolipram.

    PubMed

    Callaghan, Charlotte K; O'Mara, Shane M

    2015-09-01

    Clinical studies report evidence of long-term cognitive and other deficits following adjunctive chemotherapy treatment, which is often termed "chemobrain" or "chemo-fog". The neurological bases of these impairments are poorly understood. Here, we hypothesize that systemic chemotherapy treatment causes long-term neurobehavioral deficits, and that these deficits are reversed by manipulation of cAMP by the PDE4 inhibitor, rolipram. Male han Wistar rats were treated with docetaxel (an adjunctive chemotherapeutic agent (1mg/kg i.v.)) or control solution (ethanol/Tween 20/0.9% Saline - 5/5/90) once per week for 4 weeks. They were allowed to recover for 4 weeks, administration of rolipram (0.5mg/kg po) or vehicle (maple syrup) then began and continued daily for 4 weeks. At the end of the treatment regime animals were tested for spatial and recognition memory deficits with the object exploration task and for depressive- and anxiety-like behavior in the forced swim test (FST) and open field exploration. We report docetaxel treatment impaired spatial memory but not object recognition memory, compared to control rats. Docetaxel-treated rats also spent significantly more time immobile than controls in the FST. Chronic rolipram treatment attenuated all of these docetaxel-associated changes, recovering spatial memory and reducing immobility. In conclusion, docetaxel-treated rats exhibit alterations in spatial memory and depressive-like behavior, which are reversed following chronic rolipram administration. These results detect long-term cognitive and mood changes following docetaxel treatment and identify PDE4 inhibition as a target treatment of neuropsychological changes associated with "chemobrain". PMID:25940764

  8. Focal cerebral hypoperfusion and selective cognitive deficit in dementia of the Alzheimer type.

    PubMed Central

    Celsis, P; Agniel, A; Puel, M; Rascol, A; Marc-Vergnes, J P

    1987-01-01

    Regional cerebral blood flow was investigated using single photon emission computed tomography and xenon-133 intravenous injection in six patients with dementia of the Alzheimer type (DAT) with atypical focal clinical presentation, and in 20 age-matched healthy volunteers. The patients had a progressive and preponderant cognitive deficit and a focal hypoperfusion that correlated with the neuropsychological findings, whereas the average flow did not significantly differ from that of controls. The assessment of concordant haemodynamic and neuropsychological focal abnormalities could be useful in the diagnosis of atypical cases of DAT. Images PMID:3501801

  9. Tripchlorolide improves cognitive deficits by reducing amyloid β and upregulating synapse-related proteins in a transgenic model of Alzheimer's Disease.

    PubMed

    Zeng, Yuqi; Zhang, Jian; Zhu, Yuangui; Zhang, Jing; Shen, Hui; Lu, Jianping; Pan, Xiaodong; Lin, Nan; Dai, Xiaoman; Zhou, Meng; Chen, Xiaochun

    2015-04-01

    Alzheimer's disease (AD) is characterized by early impairments in memory and progressive neurodegeneration. Disruption of synaptic plasticity processes that underlie learning and memory contribute partly to this pathophysiology. Tripchlorolide (T4 ), an extract from a traditional Chinese herbal Tripterygium wilfordii Hook F, has been shown to be neuroprotective in animal models of Parkinson's disease and to improve cognitive deficits in senescence-accelerated mouse P8. In this study, we investigated the effect of T4 on cognitive decline and synaptic plasticity in five times familial AD (5XFAD) mice co-expressing mutated amyloid precursor protein and presenilin-1. Five-month-old 5XFAD mice and wild type littermates were intraperitoneally injected with T4 , 5 μg/kg or 25 μg/kg, every other day for 60 days. T4 treatment significantly improved spatial learning and memory, alleviated synaptic ultrastructure degradation, up-regulated expression of synapse-related proteins, including synaptophysin, post-synaptic density-95, N-methyl-D-aspartate receptor subunit 1, phosphorylation of calcium/calmodulin dependent protein kinase II α, and phosphorylation of cyclic AMP-response element binding protein, and promoted activation of the phophoinositide-3-kinase-Akt-mammalian target of rapamycin signaling pathway in 5XFAD mice. Accumulation of amyloid β (Aβ) may contribute to synapse dysfunction and memory impairment in AD. We found that T4 treatment significantly reduced cerebral Aβ deposits and lowered Aβ levels in brain homogenates. These effects coincided with a reduction in cleavage of β-carboxyl-terminal amyloid precursor protein (APP) fragment, levels of soluble APPβ, and protein expression of β-site APP cleaving enzyme 1. Taken together, our findings identify T4 as a potent negative regulator of brain Aβ levels and show that it significantly ameliorates synaptic degeneration and cognitive deficits in a mouse model of AD. PMID:25661995

  10. Prefrontal cognitive deficits in mice with altered cerebral cortical GABAergic interneurons.

    PubMed

    Bissonette, Gregory B; Bae, Mihyun H; Suresh, Tejas; Jaffe, David E; Powell, Elizabeth M

    2014-02-01

    Alterations of inhibitory GABAergic neurons are implicated in multiple psychiatric and neurological disorders, including schizophrenia, autism and epilepsy. In particular, interneuron deficits in prefrontal areas, along with presumed decreased inhibition, have been reported in several human patients. The majority of forebrain GABAergic interneurons arise from a single subcortical source before migrating to their final regional destination. Factors that govern the interneuron populations have been identified, demonstrating that a single gene mutation may globally affect forebrain structures or a single area. In particular, mice lacking the urokinase plasminogen activator receptor (Plaur) gene have decreased GABAergic interneurons in frontal and parietal, but not caudal, cortical regions. Plaur assists in the activation of hepatocyte growth factor/scatter factor (HGF/SF), and several of the interneuron deficits are correlated with decreased levels of HGF/SF. In some cortical regions, the interneuron deficit can be remediated by endogenous overexpression of HGF/SF. In this study, we demonstrate decreased parvalbumin-expressing interneurons in the medial frontal cortex, but not in the hippocampus or basal lateral amygdala in the Plaur null mouse. The Plaur null mouse demonstrates impaired medial frontal cortical function in extinction of cued fear conditioning and the inability to form attentional sets. Endogenous HGF/SF overexpression increased the number of PV-expressing cells in medial frontal cortical areas to levels greater than found in wildtype mice, but did not remediate the behavioral deficits. These data suggest that proper medial frontal cortical function is dependent upon optimum levels of inhibition and that a deficit or excess of interneuron numbers impairs normal cognition. PMID:24211452

  11. Prefrontal cognitive deficits in mice with altered cerebral cortical GABAergic interneurons

    PubMed Central

    Bissonette, Gregory B.; Bae, Mihyun H.; Suresh, Tejas; Jaffe, David E.; Powell, Elizabeth M.

    2013-01-01

    Alterations of inhibitory GABAergic neurons are implicated in multiple psychiatric and neurological disorders, including schizophrenia, autism and epilepsy. In particular, interneuron deficits in prefrontal areas, along with presumed decreased inhibition, have been reported in several human patients. The majority of forebrain GABAergic interneurons arise from a single subcortical source before migrating to their final regional destination. Factors that govern the interneuron populations have been identified, demonstrating that a single gene mutation may globally affect forebrain structures or a single area. In particular, mice lacking the urokinase plasminogen activator receptor (Plaur) gene have decreased GABAergic interneurons in frontal and parietal, but not caudal, cortical regions. Plaur assists in the activation of hepatocyte growth factor/scatter factor (HGF/SF), and several of the interneuron deficits are correlated with decreased levels of HGF/SF. In some cortical regions, the interneuron deficit can be remediated by endogenous overexpression of HGF/SF. In this study, we demonstrate decreased parvalbumin-expressing interneurons in the medial frontal cortex, but not in the hippocampus or basal lateral amygdala in the Plaur null mouse. The Plaur null mouse demonstrates impaired medial frontal cortical function in extinction of cued fear conditioning and the inability to form attentional sets. Endogenous HGF/SF overexpression increased the number of PV-expressing cells in medial frontal cortical areas to levels greater than found in wildtype mice, but did not remediate the behavioral deficits. These data suggest that proper medial frontal cortical function is dependent upon optimum levels of inhibition and that a deficit or excess of interneuron numbers impairs normal cognition. PMID:24211452

  12. Oxidative stress induced NMDA receptor alteration leads to spatial memory deficits in temporal lobe epilepsy: ameliorative effects of Withania somnifera and Withanolide A.

    PubMed

    Soman, Smijin; Korah, P K; Jayanarayanan, S; Mathew, Jobin; Paulose, C S

    2012-09-01

    In the present study we investigate the effect of Withania somnifera (WS) root extract and Withanolide A (WA) in restoring spatial memory deficit by inhibiting oxidative stress induced alteration in glutamergic neurotransmission. We demonstrate significant cellular loss in hippocampus of epileptic rats, visualized through decreased TOPRO stained neurons. Impaired spatial memory was observed in epileptic rats after Radial arm maze test. Treatment with WS and WA has resulted in increased number of TOPRO stained neurons. Enhanced performance of epileptic rats treated with WS and WA was observed in Radial arm maze test. The antioxidant activity of WS and WA was studied using superoxide dismutase (SOD) and Catalase (CAT) assays in the hippocampus of experimental rats. The SOD activity and CAT activity decreased significantly in epileptic group, treatment with WS and WA significantly reversed the enzymatic activities to near control. Real time gene expression studies of SOD and GPx showed significant up-regulation in epileptic group compared to control. Treatment with WS and WA showed significant reversal to near control. Lipid peroxidation quantified using TBARS assay, significantly increased in epileptic rats. Treatment with WS and WA showed significant reversal to near control. NMDA receptor expression decreased in epileptic rats. The treatment with WS and WA resulted in physiological expression of NMDA receptors. This data suggests that oxidative stress effects membrane constitution resulting in decreased NMDA receptor density leading to impaired spatial memory. Treatment with WS and WA has ameliorated spatial memory deficits by enhancing antioxidant system and restoring altered NMDA receptor density. PMID:22700086

  13. [The histaminergic system: a target for innovative treatments of cognitive deficits].

    PubMed

    Motawaj, Mouhammad; Burban, Aude; Davenas, Elisabeth; Gbahou, Florence; Faucard, Raphaël; Morisset, Séverine; Arrang, Jean-Michel

    2010-01-01

    The central effects of histamine are mediated by H(1), H(2) and H(3) receptors. The H(3) receptor inhibits histamine release in brain. Therefore, H(3) receptor inverse agonists, by suppressing this brake, enhance histamine neuron activity. The histaminergic system plays a major role in cognition and H(3) receptor inverse agonists are expected to be a potential therapeutics for cognitive deficits of Alzheimer's disease (AD). They are eagerly awaited inasmuch as other treatments of the disease, such as tacrine or memantine, also enhance, through different mechanisms, histaminergic neurotransmission. An important loss of histaminergic neurons has been observed in AD. In contrast, levels of the histamine metabolite in the CSF of AD patients show that their global activity is decreased by only 25%. This indicates that activating histamine neurons in AD can be envisaged. PMID:21144476

  14. Alzheimer's disease: role of size and location of white matter changes in determining cognitive deficits.

    PubMed

    Bracco, L; Piccini, C; Moretti, M; Mascalchi, M; Sforza, A; Nacmias, B; Cellini, E; Bagnoli, S; Sorbi, S

    2005-01-01

    This study investigated the contribution that white matter changes (WMCs) make to clinical and cognitive features in Alzheimer's disease (AD), independently of possible confounders such as cortical atrophy and the apolipoprotein E genotype as well as their relationship to vascular risk factors. We semiquantitatively assessed the degree and location of WMCs (global, periventricular and deep white matter), lacunes and global atrophy on brain MRI scans of 86 AD cases, extensively evaluated from a clinical and neuropsychological point of view. Multivariate logistic and linear regression analysis showed that age was the only significant predictor of all WMC measures and revealed a significant association of periventricular WMCs with performance on executive function tasks as well as of deep WMCs with history of mood depression. Our results underline the significance of WMC location over size in the occurrence of specific cognitive deficits in AD. PMID:16192726

  15. Can Exercise Ameliorate Aromatase Inhibitor-Induced Cognitive Decline in Breast Cancer Patients?

    PubMed

    Li, Cuicui; Zhou, Chenglin; Li, Rena

    2016-08-01

    Aromatase inhibitors (AIs) have been commonly used as an effective adjuvant therapy in treatment of breast cancer, especially for menopausal women with estrogen receptor-positive breast cancer. Due to the nature of aromatase, the key enzyme for endogenous estrogen synthesis, inhibitory of aromatase-induced side effects, such as cognitive impairment has been reported in both human and animal studies. While extensive evidence suggested that physical exercises can improve learning and memory activity and even prevent age-related cognitive decline, basic research revealed some common pathways between exercise and estrogen signaling that affected cognitive function. This review draws on clinical and basic studies to assess the potential impact of exercise in cognitive function from women treated with AIs for breast cancer and explore the potential mechanism and effects of exercise on estrogen-related cognition. PMID:26223800

  16. Blue-yellow colour vision impairment and cognitive deficits in occasional and dependent stimulant users.

    PubMed

    Hulka, Lea M; Wagner, Michael; Preller, Katrin H; Jenni, Daniela; Quednow, Boris B

    2013-04-01

    Specific blue-yellow colour vision impairment has been reported in dependent cocaine users and it was postulated that drug-induced changes in retinal dopamine neurotransmission are responsible. However, it is unclear whether these changes are confined to chronic cocaine users, whether they are specific for dopaminergic stimulants such as cocaine and amphetamine and whether they are related to cognitive functions such as working memory, encoding and consolidation. In 47 occasional and 29 dependent cocaine users, 23 MDMA (commonly known as 'ecstasy') users and 47 stimulant-naive controls, colour vision discrimination was measured with the Lanthony Desaturated Panel D-15 Test and memory performance with the Auditory Verbal Learning Test. Both occasional and dependent cocaine users showed higher colour confusion indices than controls. Users of the serotonergic stimulant MDMA (26%), occasional (30%) and dependent cocaine users (34%) exhibited more frequent blue-yellow colour vision disorders compared to controls (9%). Inferior performance of MDMA users was caused by a subgroup with high amphetamine co-use (55%), while MDMA use alone was not associated with decreased blue-yellow discrimination (0%). Cognitive performance was worse in cocaine users with colour vision disorder compared to users and controls with intact colour vision and both colour vision impairment and cognitive deficits were related to cocaine use. Occasional cocaine and amphetamine use might induce blue-yellow colour vision impairment, whereas the serotonergic stimulant MDMA does not impair colour vision. The association between colour vision impairment and cognitive deficits in cocaine users may reflect that retinal and cerebral dopamine alterations are linked to a certain degree. PMID:22704223

  17. Early detection of cognitive deficits in the 3xTg-AD mouse model of Alzheimer's disease.

    PubMed

    Stover, Kurt R; Campbell, Mackenzie A; Van Winssen, Christine M; Brown, Richard E

    2015-08-01

    Which behavioral test is the most sensitive for detecting cognitive deficits in the 3xTg-AD at 6.5 months of age? The 3xTg-AD mouse model of Alzheimer's disease (AD) has three transgenes (APPswe, PS1M146V, and Tau P301L) which cause the development of amyloid beta plaques, neurofibrillary tangles, and cognitive deficits with age. In order to determine which task is the most sensitive in the early detection of cognitive deficits, we compared male and female 3xTg-AD and B6129SF2 wildtype mice at 6.5 months of age on a test battery including spontaneous alternation in the Y-Maze, novel object recognition, spatial memory in the Barnes maze, and cued and contextual fear conditioning. The 3xTg-AD mice had impaired learning and memory in the Barnes maze but performed better than B6129SF2 wildtype mice in the Y-Maze and in contextual fear conditioning. Neither genotype demonstrated a preference in the novel object recognition task nor was there a genotype difference in cued fear conditioning but females performed better than males. From our results we conclude that the 3xTg-AD mice have mild cognitive deficits in spatial learning and memory and that the Barnes maze was the most sensitive test for detecting these cognitive deficits in 6.5-month-old mice. PMID:25896362

  18. Acupuncture ameliorates cognitive impairment and hippocampus neuronal loss in experimental vascular dementia through Nrf2-mediated antioxidant response.

    PubMed

    Wang, Xue-Rui; Shi, Guang-Xia; Yang, Jing-Wen; Yan, Chao-Qun; Lin, Li-Ting; Du, Si-Qi; Zhu, Wen; He, Tian; Zeng, Xiang-Hong; Xu, Qian; Liu, Cun-Zhi

    2015-12-01

    Emerging evidence suggests acupuncture could exert neuroprotection in the vascular dementia via anti-oxidative effects. However, the involvement of Nrf2, a master regulator of antioxidant defense, in acupuncture-induced neuroprotection in vascular dementia remains undetermined. The goal of our study was to investigate the contribution of Nrf2 in acupuncture and its effects on vascular dementia. Morris water maze and Nissl staining were used to assess the effect of acupuncture on cognitive function and hippocampal neurodegeneration in experimental vascular dementia. The distribution of Nrf2 in neurons in hippocampus, the protein expression of Nrf2 in both cytosol and nucleus, and the protein and mRNA levels of its downstream target genes NQO1 and HO-1 were detected by double immunofluorescent staining, Western blotting and realtime PCR analysis respectively. Cognitive function and microglia activation were measured in both wild-type and Nrf2 gene knockout mice after acupuncture treatment. We found that acupuncture could remarkably reverse the cognitive deficits, neuron cell loss, reactive oxygen species production, and decreased cerebral blood flow. It was notable that acupuncture enhanced nuclear translocation of Nrf2 in neurons and up-regulate the protein and mRNA levels of Nrf2 and its target genes HO-1 and NQO1. Moreover, acupuncture could significantly down-regulated the over-activation of microglia after common carotid artery occlusion surgery. However, the reversed cognitive deficits, neuron cell loss and microglia activation by acupuncture were abolished in Nrf2 gene knockout mice. In conclusion, these findings provide evidence that the neuroprotection of acupuncture in models of vascular dementia was via the Nrf2 activation and Nrf2-dependent microglia activation. PMID:26546103

  19. Canonical correlation analysis of synchronous neural interactions and cognitive deficits in Alzheimer's dementia

    NASA Astrophysics Data System (ADS)

    Karageorgiou, Elissaios; Lewis, Scott M.; Riley McCarten, J.; Leuthold, Arthur C.; Hemmy, Laura S.; McPherson, Susan E.; Rottunda, Susan J.; Rubins, David M.; Georgopoulos, Apostolos P.

    2012-10-01

    In previous work (Georgopoulos et al 2007 J. Neural Eng. 4 349-55) we reported on the use of magnetoencephalographic (MEG) synchronous neural interactions (SNI) as a functional biomarker in Alzheimer's dementia (AD) diagnosis. Here we report on the application of canonical correlation analysis to investigate the relations between SNI and cognitive neuropsychological (NP) domains in AD patients. First, we performed individual correlations between each SNI and each NP, which provided an initial link between SNI and specific cognitive tests. Next, we performed factor analysis on each set, followed by a canonical correlation analysis between the derived SNI and NP factors. This last analysis optimally associated the entire MEG signal with cognitive function. The results revealed that SNI as a whole were mostly associated with memory and language, and, slightly less, executive function, processing speed and visuospatial abilities, thus differentiating functions subserved by the frontoparietal and the temporal cortices. These findings provide a direct interpretation of the information carried by the SNI and set the basis for identifying specific neural disease phenotypes according to cognitive deficits.

  20. Stress acts cumulatively to precipitate Alzheimer's disease-like tau pathology and cognitive deficits.

    PubMed

    Sotiropoulos, Ioannis; Catania, Caterina; Pinto, Lucilia G; Silva, Rui; Pollerberg, G Elizabeth; Takashima, Akihiko; Sousa, Nuno; Almeida, Osborne F X

    2011-05-25

    Stressful life experiences are likely etiological factors in sporadic forms of Alzheimer's disease (AD). Many AD patients hypersecrete glucocorticoids (GCs), and their GC levels correlate with the rate of cognitive impairment and extent of neuronal atrophy. Severity of cognitive deficits in AD correlates strongly with levels of hyperphosphorylated forms of the cytoskeletal protein TAU, an essential mediator of the actions of amyloid β (Aβ), another molecule with a key pathogenic role in AD. Our objective was to investigate the sequential interrelationships between these various pathogenic elements, in particular with respect to the mechanisms through which stress might precipitate cognitive decline. We thus examined whether stress, through the mediation of GCs, influences TAU hyperphosphorylation, a critical and early event in the cascade of processes leading to AD pathology. Results from healthy, wild-type, middle-aged rats show that chronic stress and GC induce abnormal hyperphosphorylation of TAU in the hippocampus and prefrontal cortex (PFC), with contemporaneous impairments of hippocampus- and PFC-dependent behaviors. Exogenous GC potentiated the ability of centrally infused Aβ to induce hyperphosphorylation of TAU epitopes associated with AD and cytoplasmic accumulation of TAU, while previous exposure to stress aggravated the biochemical and behavioral effects of GC in Aβ-infused animals. Thus, lifetime stress/GC exposure may have a cumulative impact on the onset and progress of AD pathology, with TAU hyperphosphorylation serving to transduce the negative effects of stress and GC on cognition. PMID:21613497

  1. Cognitive heterogeneity in adult attention deficit/hyperactivity disorder: A systematic analysis of neuropsychological measurements.

    PubMed

    Mostert, Jeanette C; Onnink, A Marten H; Klein, Marieke; Dammers, Janneke; Harneit, Anais; Schulten, Theresa; van Hulzen, Kimm J E; Kan, Cornelis C; Slaats-Willemse, Dorine; Buitelaar, Jan K; Franke, Barbara; Hoogman, Martine

    2015-11-01

    Attention Deficit/Hyperactivity Disorder (ADHD) in childhood is associated with impaired functioning in multiple cognitive domains: executive functioning (EF), reward and timing. Similar impairments have been described for adults with persistent ADHD, but an extensive investigation of neuropsychological functioning in a large sample of adult patients is currently lacking. We systematically examined neuropsychological performance on tasks measuring EF, delay discounting, time estimation and response variability using univariate ANCOVA's comparing patients with persistent ADHD (N=133, 42% male, mean age 36) and healthy adults (N=132, 40% male, mean age 36). In addition, we tested which combination of variables provided the highest accuracy in predicting ADHD diagnosis. We also estimated for each individual the severity of neuropsychological dysfunctioning. Lastly, we investigated potential effects of stimulant medication and a history of comorbid major depressive disorder (MDD) on performance. Compared to healthy adults, patients with ADHD showed impaired EF, were more impulsive, and more variable in responding. However, effect sizes were small to moderate (range: 0.05-0.70) and 11% of patients did not show neuropsychological dysfunctioning. The best fitting model predicting ADHD included measures from distinct cognitive domains (82.1% specificity, 64.9% sensitivity). Furthermore, patients receiving stimulant medication or with a history of MDD were not distinctively impaired. To conclude, while adults with ADHD as a group are impaired on several cognitive domains, the results confirm that adult ADHD is neuropsychologically heterogeneous. This provides a starting point to investigate individual differences in terms of impaired cognitive pathways. PMID:26336867

  2. Cholesterol diet counteracts repeated anesthesia/infusion-induced cognitive deficits in male Brown Norway rats

    PubMed Central

    Hohsfield, Lindsay A.; Ehrlich, Daniela; Humpel, Christian

    2015-01-01

    A variety of cardiovascular and cerebrovascular diseases are associated with alterations in cholesterol levels and metabolism. Moreover, convincing evidence shows that high cholesterol diet can lead to learning and memory impairments. On the other hand, a significant body of research has also demonstrated that learning is improved by elevated dietary cholesterol. Despite these conflicting findings, it is clear that cholesterol plays an important role in these cognitive properties. However, it remains unclear how this blood-brain barrier (BBB)-impenetrable molecule affects the brain and under what circumstances it provides either detrimental or beneficial effects to learning and memory. The aim of this study was to characterize the effects of 5% cholesterol diet on six-month-old inbred Brown Norway rats. More important, we sought to examine the role that cholesterol can play when repeated anesthesia and intravenous infusion disrupts cognitive function. This present study supports previous work showing that enriched cholesterol diet leads to significant alterations in neuroinflammation and BBB disruption. Following repeated anesthesia and intravenous infusion of saline we observe that animals under normal diet conditions exhibit significant deficiencies in spatial learning and cholinergic neuron populations compared to animals under enriched cholesterol diet, which do not show such deficiencies. These findings indicate that cholesterol diet can protect against or counteract anesthesia/infusion-induced cognitive deficits. Ultimately, these results suggest that cholesterol homeostasis serves an important functional role in the brain and that altering this homeostasis can either exert positive or negative effects on cognitive properties. PMID:23973449

  3. The ameliorative effect of ascorbic acid and Ginkgo biloba on learning and memory deficits associated with fluoride exposure

    PubMed Central

    Raghuveer, Vasudeva C.; Rao, Mallikarjuna C.; Somayaji, Nagabhooshana S.; Babu, Prakash B.

    2013-01-01

    Chronic exposure to fluoride causes dental and skeletal fluorosis. Fluoride exposure is also detrimental to soft tissues and organs. The present study aimed at evaluation of the effect of Ginkgo biloba and ascorbic acid on learning and memory deficits caused by fluoride exposure. Male Wistar rats were divided into five groups (n=6). Group 1 control. Groups 2 to 5 received 100 ppm of sodium fluoride over 30 days. Groups 3, 4 and 5 were further treated for 15 days receiving respectively 1% gum acacia solution, 100 mg/kg body weight ascorbic acid, and 100mg/kg body weight Ginkgo biloba extract. After 45 days, all animals were subjected to behavioural tests. The results showed that fluoride affected learning and memory. Fluoride causes oxidative stress and neurodegeneration, thereby affecting learning and memory. Ascorbic acid and Ginkgo biloba were found to augment the reversal of learning and memory deficits caused by fluoride ingestion. PMID:24678261

  4. Number Processing and Heterogeneity of Developmental Dyscalculia: Subtypes With Different Cognitive Profiles and Deficits.

    PubMed

    Skagerlund, Kenny; Träff, Ulf

    2016-01-01

    This study investigated if developmental dyscalculia (DD) in children with different profiles of mathematical deficits has the same or different cognitive origins. The defective approximate number system hypothesis and the access deficit hypothesis were tested using two different groups of children with DD (11-13 years old): a group with arithmetic fact dyscalculia (AFD) and a group with general dyscalculia (GD). Several different aspects of number magnitude processing were assessed in these two groups and compared with age-matched typically achieving children. The GD group displayed weaknesses with both symbolic and nonsymbolic number processing, whereas the AFD group displayed problems only with symbolic number processing. These findings provide evidence that the origins of DD in children with different profiles of mathematical problems diverge. Children with GD have impairment in the innate approximate number system, whereas children with AFD suffer from an access deficit. These findings have implications for researchers' selection procedures when studying dyscalculia, and also for practitioners in the educational setting. PMID:24598147

  5. Cognitive deficits and anxiety induced by diisononyl phthalate in mice and the neuroprotective effects of melatonin

    PubMed Central

    Ma, Ping; Liu, Xudong; Wu, Jiliang; Yan, Biao; Zhang, Yuchao; Lu, Yu; Wu, Yang; Liu, Chao; Guo, Junhui; Nanberg, Eewa; Bornehag, Carl-Gustaf; Yang, Xu

    2015-01-01

    Diisononyl phthalate (DINP) is a plasticizer that is frequently used as a substitute for other plasticizers whose use is prohibited in certain products. In vivo studies on the neurotoxicity of DINP are however, limited. This work aims to investigate whether DINP causes neurobehavioral changes in mice and to provide useful advice on preventing the occurrence of these adverse effects. Behavioral analysis showed that oral administration of 20 or 200 mg/kg/day DINP led to mouse cognitive deficits and anxiety. Brain histopathological observations, immunohistochemistry assays (cysteine-aspartic acid protease 3 [caspase-3], glial fibrillary acidic protein [GFAP]), oxidative stress assessments (reactive oxygen species [ROS], glutathione [GSH], superoxide dismutase [SOD] activities, 8-hydroxy-2-deoxyguanosine [8-OH-dG] and DNA-protein crosslinks [DPC]), and assessment of inflammation (tumor necrosis factor alpha [TNF-а] and interleukin-1 beta [IL-1β]) of mouse brains showed that there were histopathological alterations in the brain and increased levels of oxidative stress, and inflammation for these same groups. However, some of these effects were blocked by administration of melatonin (50 mg/kg/day). Down-regulation of oxidative stress was proposed to explain the neuroprotective effects of melatonin. The data suggests that DINP could cause cognitive deficits and anxiety in mice, and that melatonin could be used to avoid these adverse effects. PMID:26424168

  6. Personality disturbances in amyotrophic lateral sclerosis: a case study demonstrating changes in personality without cognitive deficits.

    PubMed

    Waldron, Eric J; Barrash, Joseph; Swenson, Andrea; Tranel, Daniel

    2014-08-01

    Patients with amyotrophic lateral sclerosis (ALS) often show deficits on neuropsychological tests that tap functions related to the integrity of the prefrontal lobes. Various aspects of personality are also known to be mediated by prefrontal regions, particularly ventromedial prefrontal cortex (vmPFC). Other than apathy, personality changes have not been widely reported in patients with ALS, although clinical observations indicate such changes might be relatively common. Here, we report on a middle-aged woman with bulbar onset ALS (diagnosed 06/2011, examined in Spring, 2012) whose neuropsychological exam did not reveal cognitive deficits. She performed normally on tests of executive functioning. Self-report measures of mood and personality were unremarkable. However, significant personality changes subsequent to disease onset were reported by her husband and two daughters, and these changes were quantified with the Iowa Scales of Personality Change. Results show that personality disturbance may manifest in the absence of notable cognitive changes in ALS, and careful assessment of personality may be important for documenting early neurobehavioral changes in some ALS patients. Findings also show that patients with ALS may not have good insight into personality changes, underscoring the importance of acquiring collateral information. More generally, the results provide further evidence that ALS may compromise the integrity of ventromedial prefrontal regions. PMID:24854881

  7. Cognitive deficits and anxiety induced by diisononyl phthalate in mice and the neuroprotective effects of melatonin.

    PubMed

    Ma, Ping; Liu, Xudong; Wu, Jiliang; Yan, Biao; Zhang, Yuchao; Lu, Yu; Wu, Yang; Liu, Chao; Guo, Junhui; Nanberg, Eewa; Bornehag, Carl-Gustaf; Yang, Xu

    2015-01-01

    Diisononyl phthalate (DINP) is a plasticizer that is frequently used as a substitute for other plasticizers whose use is prohibited in certain products. In vivo studies on the neurotoxicity of DINP are however, limited. This work aims to investigate whether DINP causes neurobehavioral changes in mice and to provide useful advice on preventing the occurrence of these adverse effects. Behavioral analysis showed that oral administration of 20 or 200 mg/kg/day DINP led to mouse cognitive deficits and anxiety. Brain histopathological observations, immunohistochemistry assays (cysteine-aspartic acid protease 3 [caspase-3], glial fibrillary acidic protein [GFAP]), oxidative stress assessments (reactive oxygen species [ROS], glutathione [GSH], superoxide dismutase [SOD] activities, 8-hydroxy-2-deoxyguanosine [8-OH-dG] and DNA-protein crosslinks [DPC]), and assessment of inflammation (tumor necrosis factor alpha [TNF-а] and interleukin-1 beta [IL-1β]) of mouse brains showed that there were histopathological alterations in the brain and increased levels of oxidative stress, and inflammation for these same groups. However, some of these effects were blocked by administration of melatonin (50 mg/kg/day). Down-regulation of oxidative stress was proposed to explain the neuroprotective effects of melatonin. The data suggests that DINP could cause cognitive deficits and anxiety in mice, and that melatonin could be used to avoid these adverse effects. PMID:26424168

  8. Root extract of Anacyclus pyrethrum ameliorates seizures, seizure-induced oxidative stress and cognitive impairment in experimental animals.

    PubMed

    Pahuja, Monika; Mehla, Jogender; Reeta, K H; Joshi, Sujata; Gupta, Yogendra Kumar

    2012-02-01

    In Ayurveda, Anacyclus pyrethrum has been used as a brain tonic. The present study evaluates the effect of hydroalcoholic extract of A. pyrethrum (HEAP) root against seizures, seizure-induced oxidative stress and cognitive impairment in experimental models of seizures. Male Wistar rats were used in the study. HEAP was administered in doses of 50, 100, 250, 500 in pentylenetetrazole (PTZ) model and 250, 500 and 1000 mg/kg in maximal electroshock (MES) model. Myoclonic jerk latency and generalized tonic clonic seizures (GTCS) were noted in PTZ whereas occurrence of tonic hind limb extension (THLE) was observed in MES seizures. Cognitive deficit was assessed using elevated plus maze and passive avoidance tests. Whole brain reduced glutathione, malondialdehyde levels and cholinesterase activity were measured. HEAP showed 50, 66.7, 83.3 and 100% protection at 50,100, 250 and 500 mg/kg, respectively against GTCS in PTZ induced seizures. In MES induced seizures, HEAP produced 16.7, 33.3 and 50% protection against THLE at 250, 500 and 1000 mg/kg, respectively. HEAP administration significantly prevented seizure induced oxidative stress and cognitive impairment in a dose-dependent manner. HEAP also normalized the decrease in cholinesterase activity caused by seizures. Thus, HEAP showed protective effect against seizures, seizure-induced oxidative stress and cognitive impairment in rats. PMID:21993359

  9. Vitamin D3 attenuates oxidative stress and cognitive deficits in a model of toxic demyelination

    PubMed Central

    Tarbali, Sepideh; Khezri, Shiva

    2016-01-01

    Objective(s): Multiple sclerosis (MS) is a demyelinating disease. The prevalence of MS is highest where environmental supplies of vitamin D are low. Cognitive deficits have been observed in patients with MS. Oxidative damage may contribute to the formation of MS lesions. Considering the involvement of hippocampus in MS, an attempt is made in this study to investigate the effects of vitamin D3 on behavioral process and the oxidative status in the dorsal hippocampus (CA1 area) following the induction of experimental demyelination in rats. Materials and Methods: Animals were divided into six groups. Control group: animals received no surgery and treatment; saline group: animals received normal saline; sham group: animals received 150 μl sesame oil IP; vitamin D3 group: animals received 5 μg/kg vitamin D3 IP; lysophosphatidyl choline (LPC) group (toxic demyelination’s model): animals received LPC by stereotaxic intra-hippocampal injection of 2 μl LPC in CA1 area; Vitamin D3- treated group: animals were treated with vitamin D3 at doses of 5 μg/kg IP for 7 and 21 days post lesion. The spatial memory, biochemical parameters including catalase (CAT) activities and lipid peroxidation levels were investigated. Results: Animals in LPC group had more deficits in spatial memory than the control group in radial arm maze. Vitamin D3 significantly improved spatial memory compared to LPC group. Also, results indicated that vitamin D3 caused a decrease in lipid peroxidation levels and an increase in CAT activities. Conclusion: Current findings suggest that vitamin D3 may have a protective effect on cognitive deficits and oxidative stress in toxic demyelination’s model. PMID:27096068

  10. Chronic periadolescent alcohol consumption produces persistent cognitive deficits in rhesus macaques.

    PubMed

    Wright, M Jerry; Taffe, Michael A

    2014-11-01

    Although human alcoholics exhibit lasting cognitive deficits, it can be difficult to definitively rule out pre-alcohol performance differences. For example, individuals with a family history of alcoholism are at increased risk for alcoholism and are also behaviorally impaired. Animal models of controlled alcohol exposure permit balanced group assignment, thereby ruling out the effects of pre-existing differences. Periadolescent male rhesus macaques (N = 5) consumed alcohol during 200 drinking sessions (M-F) across a 10-month period (mean daily alcohol consumption: 1.38 g/kg/day). A control group (N = 5) consumed a fruit-flavored vehicle during the same period. Spatial working memory, visual discrimination learning and retention and response time behavioral domains were assessed with subtests of the Monkey CANTAB (CAmbridge Neuropsychological Test Automated Battery). Spatial working memory performance was impaired in the alcohol group after 120 drinking sessions (6 mo) in a manner that depended on retention interval. The chronic alcohol animals were also impaired in retaining a visual discrimination over 24 hrs when assessed 6-8 weeks after cessation of alcohol drinking. Finally, the presentation of distractors in the response time task impaired the response time and accuracy of the chronic alcohol group more than controls after 6 months of alcohol cessation. Chronic alcohol consumption over as little as 6 months produces cognitive deficits, with some domains still affected after acute (6-8 wks) and lasting (6 mo) discontinuation from drinking. Animals were matched on alcohol preference and behavioral performance prior to exposure, thus providing strong evidence for the causal role of chronic alcohol in these deficits. PMID:25018042

  11. Early deficits in motor coordination and cognitive dysfunction in a mouse model of the neurodegenerative lysosomal storage disorder, Sandhoff disease

    PubMed Central

    Gulinello, Maria; Chen, Fengying; Dobrenis, Kostantin

    2014-01-01

    Mouse models of lysosomal storage diseases, including Sandhoff disease, are frequently employed to test therapies directed at the central nervous system. We backbred such mice and conducted a behavioral test battery which included sensorimotor and cognitive assessments. This is the first report of short-term memory deficits in a murine model of Sandhoff disease. We also document early onset of motor deficits using the balance beam test. PMID:18611415

  12. Minocycline Transiently Reduces Microglia/Macrophage Activation but Exacerbates Cognitive Deficits Following Repetitive Traumatic Brain Injury in the Neonatal Rat.

    PubMed

    Hanlon, Lauren A; Huh, Jimmy W; Raghupathi, Ramesh

    2016-03-01

    Elevated microglial/macrophage-associated biomarkers in the cerebrospinal fluid of infant victims of abusive head trauma (AHT) suggest that these cells play a role in the pathophysiology of the injury. In a model of AHT in 11-day-old rats, 3 impacts (24 hours apart) resulted in spatial learning and memory deficits and increased brain microglial/macrophage reactivity, traumatic axonal injury, neuronal degeneration, and cortical and white-matter atrophy. The antibiotic minocycline has been effective in decreasing injury-induced microglial/macrophage activation while simultaneously attenuating cellular and functional deficits in models of neonatal hypoxic ischemia, but the potential for this compound to rescue deficits after impact-based trauma to the immature brain remains unexplored. Acute minocycline administration in this model of AHT decreased microglial/macrophage reactivity in the corpus callosum of brain-injured animals at 3 days postinjury, but this effect was lost by 7 days postinjury. Additionally, minocycline treatment had no effect on traumatic axonal injury, neurodegeneration, tissue atrophy, or spatial learning deficits. Interestingly, minocycline-treated animals demonstrated exacerbated injury-induced spatial memory deficits. These results contrast with previous findings in other models of brain injury and suggest that minocycline is ineffective in reducing microglial/macrophage activation and ameliorating injury-induced deficits following repetitive neonatal traumatic brain injury. PMID:26825312

  13. Early Cognitive Deficits in Type 2 Diabetes: A Population-Based Study

    PubMed Central

    Marseglia, Anna; Fratiglioni, Laura; Laukka, Erika J.; Santoni, Giola; Pedersen, Nancy L.; Bäckman, Lars; Xu, Weili

    2016-01-01

    Evidence links type 2 diabetes to dementia risk. However, our knowledge on the initial cognitive deficits in diabetic individuals and the factors that might promote such deficits is still limited. This study aimed to identify the cognitive domains initially impaired by diabetes and the factors that play a role in this first stage. Within the population-based Swedish National Study on Aging and Care–Kungsholmen, 2305 cognitively intact participants aged ≥60 y were identified. Attention/working memory, perceptual speed, category fluency, letter fluency, semantic memory, and episodic memory were assessed. Diabetes (controlled and uncontrolled) and prediabetes were ascertained by clinicians, who also collected information on vascular disorders (hypertension, heart diseases, and stroke) and vascular risk factors (VRFs, including smoking and overweight/obesity). Data were analyzed with linear regression models. Overall, 196 participants (8.5%) had diabetes, of which 144 (73.5%) had elevated glycaemia (uncontrolled diabetes); 571 (24.8%) persons had prediabetes. In addition, diabetes, mainly uncontrolled, was related to lower performance in perceptual speed (β – 1.10 [95% CI – 1.98, – 0.23]), category fluency (β – 1.27 [95% CI – 2.52, – 0.03]), and digit span forward (β – 0.35 [95% CI – 0.54, – 0.17]). Critically, these associations were present only among APOE ɛ4 non–carriers. The associations of diabetes with perceptual speed and category fluency were present only among participants with VRFs or vascular disorders. Diabetes, especially uncontrolled diabetes, is associated with poorer performance in perceptual speed, category fluency, and attention/primary memory. VRFs, vascular disorders, and APOE status play a role in these associations. PMID:27314527

  14. Nobiletin treatment improves motor and cognitive deficits seen in MPTP-induced Parkinson model mice.

    PubMed

    Yabuki, Y; Ohizumi, Y; Yokosuka, A; Mimaki, Y; Fukunaga, K

    2014-02-14

    Nobiletin, a polymethoxylated flavonoid found in citrus fruit peel, reportedly improves memory impairment in rodent models. Here we report its effect on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced motor and cognitive deficits. Nobiletin administration (50mg/kg i.p.) for 2 consecutive weeks improved motor deficits seen in MPTP-induced Parkinson model mice by 2weeks, an effect that continued until 2weeks after drug withdrawal. Drug treatment promoted similar rescue of MPTP-induced cognitive impairment at equivalent time points. Nonetheless, nobiletin treatment did not block loss of dopaminergic neurons seen in the MPTP-treated mouse midbrain, nor did it rescue decreased tyrosine hydroxylase (TH) protein levels seen in the striatum or hippocampal CA1 region of these mice. Interestingly, nobiletin administration (50mg/kg i.p.) rescued reduced levels of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) autophosphorylation and phosphorylation at Thr-34 of dopamine- and cAMP-regulated phosphoprotein-32 (DARPP-32) in striatum and hippocampal CA1 to levels seen in sham-operated mice. Likewise, CaMKII- and cAMP kinase-dependent TH phosphorylation was significantly restored by nobiletin treatment. MPTP-induced reduction of dopamine contents in the striatum and hippocampal CA1 region was improved by nobiletin administration (50mg/kg i.p.). Acute intraperitoneal administration of nobiletin also enhanced dopamine release in striatum and hippocampal CA1, an effect partially inhibited by treatment with nifedipine (a L-type Ca(2+) channel inhibitor) or NNC 55-0396 (a T-type Ca(2+) channel inhibitor) and completely abolished by combined treatment with both. Overall, our study describes a novel nobiletin activity in brain and suggests that nobiletin rescues motor and cognitive dysfunction in MPTP-induced Parkinson model mice, in part by enhancing dopamine release. PMID:24316474

  15. Intra-regional and inter-regional abnormalities and cognitive control deficits in young adult smokers.

    PubMed

    Feng, Dan; Yuan, Kai; Li, Yangding; Cai, Chenxi; Yin, Junsen; Bi, Yanzhi; Cheng, Jiadong; Guan, Yanyan; Shi, Sha; Yu, Dahua; Jin, Chenwang; Lu, Xiaoqi; Qin, Wei; Tian, Jie

    2016-06-01

    Tobacco use during later adolescence and young adulthood may cause serious neurophysiological changes; rationally, it is extremely important to study the relationship between brain dysfunction and behavioral performances in young adult smokers. Previous resting state studies investigated the neural mechanisms in smokers. Unfortunately, few studies focused on spontaneous activity differences between young adult smokers and nonsmokers from both intra-regional and inter-regional levels, less is known about the association between resting state abnormalities and behavioral deficits. Therefore, we used fractional amplitude of low frequency fluctuation (fALFF) and resting state functional connectivity (RSFC) to investigate the resting state spontaneous activity differences between young adult smokers and nonsmokers. A correlation analysis was carried out to assess the relationship between neuroimaging findings and clinical information (pack-years, cigarette dependence, age of onset and craving score) as well as cognitive control deficits measured by the Stroop task. Consistent with previous addiction findings, our results revealed the resting state abnormalities within frontostriatal circuits, i.e., enhanced spontaneous activity of the caudate and reduced functional strength between the caudate and anterior cingulate cortex (ACC) in young adult smokers. Moreover, the fALFF values of the caudate were correlated with craving and RSFC strength between the caudate and ACC was associated with the cognitive control impairments in young adult smokers. Our findings could lead to a better understanding of intrinsic functional architecture of baseline brain activity in young smokers by providing regional and brain circuit spontaneous neuronal activity properties as well as their association with cognitive control impairments. PMID:26164168

  16. Virtual environment navigation tasks and the assessment of cognitive deficits in individuals with brain injury.

    PubMed

    Livingstone, Sharon A; Skelton, Ronald W

    2007-12-11

    Navigation in real environments is often impaired by traumatic brain injury (TBI). These deficits in wayfinding appear to be due to disruption of cognitive processes underlying navigation and may in turn be due to damage to the hippocampus and frontal lobes. These wayfinding problems after TBI were investigated using a virtual simulation of a Morris Water Maze (MWM), a standard test of hippocampal function in laboratory animals. The virtual environment consisted of a large virtual arena in a very large virtual room whose walls provided views of a naturalistic landscape. Eleven community-dwelling TBI survivors and 12 comparison participants, matched for gender, age and education were tested to see if they could find a location in the arena marked by one of the following: (a) a visible platform, (b) a single proximal object, (c) a single proximal object among seven other distracter objects, or (d) distal features inside and outside the room. The proximal objects allowed participants to use egocentric (body-centered) navigational strategies that rely on relatively simple stimulus-response associations. The absence of proximal cues forced the participants to rely on distal features of the environment (room walls, landscape elements) and tested their ability to use allocentric (world-based) navigational strategies requiring cognitive mapping. Results indicated that the navigation of TBI survivors was not impaired when the proximal cues were present but was impaired when proximal cues were absent. These results provide more evidence that the navigational deficit after TBI is due to an inability to form, remember or use cognitive maps. PMID:17727970

  17. Cognitive Deficits in Long-Term Anabolic-Androgenic Steroid Users

    PubMed Central

    Kanayama, Gen; Kean, Joseph; Hudson, James I.; Pope, Harrison G.

    2012-01-01

    Background Millions of individuals worldwide have used anabolic-androgenic steroids (AAS) to gain muscle or improve athletic performance. Recently, in vitro investigations have suggested that supraphysiologic AAS doses cause apoptosis of neuronal cells. These findings raise the possibility, apparently still untested, that humans using high-dose AAS might eventually develop cognitive deficits. Methods We administered five cognitive tests from the computerized CANTAB battery (Pattern Recognition Memory, Verbal Recognition Memory, Paired Associates Learning, Choice Reaction Time, and Rapid Visual Information Processing) to 31 male AAS users and 13 non-AAS-using weightlifters age 29-55, recruited and studied in May 2012 in Middlesbrough, UK. Testers were blinded to participants’ AAS status and other historical data. Results Long-term AAS users showed no significant differences from nonusers on measures of response speed, sustained attention, and verbal memory. On visuospatial memory, however, AAS users performed significantly more poorly than nonusers, and within the user group, visuospatial performance showed a significant negative correlation with total lifetime AAS dose. These were large effects: on Pattern Recognition Memory, long-term AAS users underperformed nonusers by almost one standard deviation, based on normative population scores (adjusted mean difference in z-scores = 0.89; p = 0.036), and performance on this test declined markedly with increasing lifetime AAS dose (adjusted change in z-score = −0.13 per 100g of lifetime AAS dose; p = 0.002). These results remained stable in sensitivity analyses addressing potential confounding factors. Conclusions These preliminary findings raise the ominous possibility that long-term high-dose AAS exposure may cause cognitive deficits, notably in visuospatial memory. PMID:23253252

  18. Attention-deficit hyperactivity disorder (ADHD) stimulant medications as cognitive enhancers.

    PubMed

    Advokat, Claire; Scheithauer, Mindy

    2013-01-01

    Recent increases in attention deficit hyperactivity disorder (ADHD) diagnoses, and the escalation of stimulant prescriptions, has raised concern about diversion and abuse of stimulants, as well as the ethics of using these drugs as "cognitive enhancers."Such concern appears misplaced in the face of substantial evidence that stimulant drugs do not improve the academic performance of ADHD-diagnosed students. Moreover, numerous studies have found little or no benefit of stimulants on neuropsychological tests of ADHD-diagnosed as well as normal, individuals. This paper examines the apparent paradox: why don't drugs that improve "attention," produce better academic outcomes in ADHD-diagnosed students? We found that stimulant drugs significantly improved impairment of episodic memory in ADHD-diagnosed undergraduate students. Nevertheless, we also found consistent academic deficits between ADHD students and their non-ADHD counterparts, regardless of whether or not they used stimulant medications. We reviewed the current literature on the behavioral effects of stimulants, to try to find an explanation for these conflicting phenomena. Across a variety of behavioral tasks, stimulants have been shown to reduce emotional reactions to frustration, improve the ability to detect errors, and increase effortful behavior. However, all of these effects would presumably enhance academic performance. On the other hand, the drugs were also found to promote "risky behavior" and to increase susceptibility to environmental distraction. Such negative effects, including the use of drugs to promote wakefulness for last minute study, might explain the lack of academic benefit in the "real world," despite their cognitive potential. Like many drugs, stimulants influence behavior in multiple ways, depending on the environmental contingencies. Depending on the circumstances, stimulants may, or may not, enhance cognition. PMID:23754970

  19. Ceftriaxone ameliorates tau pathology and cognitive decline via restoration of glial glutamate transporter in a mouse model of Alzheimer's disease.

    PubMed

    Zumkehr, Joannee; Rodriguez-Ortiz, Carlos J; Cheng, David; Kieu, Zanett; Wai, Thin; Hawkins, Charlesice; Kilian, Jason; Lim, Siok Lam; Medeiros, Rodrigo; Kitazawa, Masashi

    2015-07-01

    Glial glutamate transporter, GLT-1, is the major Na(+)-driven glutamate transporter to control glutamate levels in synapses and prevent glutamate-induced excitotoxicity implicated in neurodegenerative disorders including Alzheimer's disease (AD). Significant functional loss of GLT-1 has been reported to correlate well with synaptic degeneration and severity of cognitive impairment among AD patients, yet the underlying molecular mechanism and its pathological consequence in AD are not well understood. Here, we find the temporal decrease in GLT-1 levels in the hippocampus of the 3xTg-AD mouse model and that the pharmacological upregulation of GLT-1 significantly ameliorates the age-dependent pathological tau accumulation, restores synaptic proteins, and rescues cognitive decline with minimal effects on Aβ pathology. In primary neuron and astrocyte coculture, naturally secreted Aβ species significantly downregulate GLT-1 steady-state and expression levels. Taken together, our data strongly suggest that GLT-1 restoration is neuroprotective and Aβ-induced astrocyte dysfunction represented by a functional loss of GLT-1 may serve as one of the major pathological links between Aβ and tau pathology. PMID:25964214

  20. Atorvastatin ameliorates cognitive impairment, Aβ1-42 production and Tau hyperphosphorylation in APP/PS1 transgenic mice.

    PubMed

    Zhou, Dongsheng; Liu, Huaxia; Li, Chenli; Wang, Fangyan; Shi, Yaosheng; Liu, Lingjiang; Zhao, Xin; Liu, Aiming; Zhang, Junfang; Wang, Chuang; Chen, Zhongming

    2016-06-01

    Amyloid-beta (Aβ) interacts with the serine/threonine protein kinase AKT (also known as protein kinase B)/glycogen synthase kinase 3β (GSK3β) pathway and deactivates GSK3β signaling, which result in microtubule protein tau phosphorylation. Atorvastatin, a HMG-CoA reductase inhibitor, has been proven to improve learning and memory performance, reduce Aβ and phosphorylated tau levels in mouse model of Alzheimer's disease (AD). However, it still remains unclear whether atorvastatin is responsible for regulation of AKT/GSK3β signaling and contributes to subsequent down-regulation of Aβ1-42 and phosphorylated tau in APP/PS1 transgenic (Tg APP/PS1) mice. Herein, we aimed to investigate the possible impacts of atorvastatin (10 mg/kg, p.o.) on the memory deficit by behavioral tests and changes of AKT/GSK3β signaling in hippocampus and prefrontal cortex by western blot test in Tg APP/PS1 mice. The results showed that treatment with atorvastatin significantly reversed the memory deficit in the Tg APP/PS1 mice in a novel object recognition and the Morris water maze tests. Moreover, atorvastatin significantly attenuated Aβ1-42 accumulation and phosphorylation of tau (Ser396) in the hippocampus and prefrontal cortex of Tg APP/PS1 mice. In addition, atorvastatin treatment also increased phosphorylation of AKT, inhibited GSK3β activity by increasing phosphorylation of GSK3β (Ser9) and decreasing the beta-site APP cleaving enzyme 1 (BACE1) expression. These results indicated that the memory ameliorating effect of atorvastatin may be, in part, by regulation the AKT/GSK3β signaling which may contribute to down-regulation of Aβ1-42 and tau hyperphosphorylation. PMID:26883430

  1. Cognitive Training at a Young Age Attenuates Deficits in the zQ175 Mouse Model of HD.

    PubMed

    Curtin, Paul C P; Farrar, Andrew M; Oakeshott, Stephen; Sutphen, Jane; Berger, Jason; Mazzella, Matthew; Cox, Kimberly; He, Dansha; Alosio, William; Park, Larry C; Howland, David; Brunner, Daniela

    2015-01-01

    Huntington's Disease (HD) is a progressive neurodegenerative disorder that causes motor, cognitive, and psychiatric symptoms. In these experiments, we tested if operant training at an early age affected adult cognitive deficits in the zQ175 KI Het (zQ175) mouse model of HD. In Experiment 1 we trained zQ175 mice in a fixed-ratio/progressive ratio (FR/PR) task to assay learning and motivational deficits. We found pronounced deficits in response rates and task engagement in naïve adult zQ175 mice (32-33 weeks age), while deficits in zQ175 mice trained from 6-7 weeks age were either absent or less severe. When those mice were re-tested as adults, FR/PR performance deficits were absent or otherwise less severe than deficits observed in naïve adult zQ175 relative to wild type (WT) mice. In Experiment 2, we used a Go/No-go operant task to assess the effects of early cognitive testing on response inhibition deficits in zQ175 mice. We found that zQ175 mice that began testing at 7-8 weeks did not exhibit deficits in Go/No-go testing, but when re-tested at 28-29 weeks age exhibited an initial impairment that diminished with training. These transient deficits were nonetheless mild relative to deficits observed among adult zQ175 mice without prior testing experience. In Experiment 3 we trained mice in a two-choice visual discrimination test to evaluate cognitive flexibility. As in prior experiments, we found performance deficits were mild or absent in mice that started training at 6-9 weeks of age, while deficits in naive mice exposed to training at 28-29 weeks were severe. Re-testing mice at 28-29 weeks age, were previously trained starting at 6-9 weeks, revealed that deficits in learning and cognitive flexibility were absent or reduced relative to effects observed in naive adults. In Experiment 4, we tested working memory deficits with a delayed non-match to position (DNMTP) test. Mice with prior experience exhibited mild working memory deficits, with males zQ175 exhibiting

  2. Cognitive Training at a Young Age Attenuates Deficits in the zQ175 Mouse Model of HD

    PubMed Central

    Curtin, Paul C. P.; Farrar, Andrew M.; Oakeshott, Stephen; Sutphen, Jane; Berger, Jason; Mazzella, Matthew; Cox, Kimberly; He, Dansha; Alosio, William; Park, Larry C.; Howland, David; Brunner, Daniela

    2016-01-01

    Huntington's Disease (HD) is a progressive neurodegenerative disorder that causes motor, cognitive, and psychiatric symptoms. In these experiments, we tested if operant training at an early age affected adult cognitive deficits in the zQ175 KI Het (zQ175) mouse model of HD. In Experiment 1 we trained zQ175 mice in a fixed-ratio/progressive ratio (FR/PR) task to assay learning and motivational deficits. We found pronounced deficits in response rates and task engagement in naïve adult zQ175 mice (32–33 weeks age), while deficits in zQ175 mice trained from 6–7 weeks age were either absent or less severe. When those mice were re-tested as adults, FR/PR performance deficits were absent or otherwise less severe than deficits observed in naïve adult zQ175 relative to wild type (WT) mice. In Experiment 2, we used a Go/No-go operant task to assess the effects of early cognitive testing on response inhibition deficits in zQ175 mice. We found that zQ175 mice that began testing at 7–8 weeks did not exhibit deficits in Go/No-go testing, but when re-tested at 28–29 weeks age exhibited an initial impairment that diminished with training. These transient deficits were nonetheless mild relative to deficits observed among adult zQ175 mice without prior testing experience. In Experiment 3 we trained mice in a two-choice visual discrimination test to evaluate cognitive flexibility. As in prior experiments, we found performance deficits were mild or absent in mice that started training at 6–9 weeks of age, while deficits in naive mice exposed to training at 28–29 weeks were severe. Re-testing mice at 28–29 weeks age, were previously trained starting at 6–9 weeks, revealed that deficits in learning and cognitive flexibility were absent or reduced relative to effects observed in naive adults. In Experiment 4, we tested working memory deficits with a delayed non-match to position (DNMTP) test. Mice with prior experience exhibited mild working memory deficits, with males

  3. Acute cocaine induced deficits in cognitive performance in rhesus macaque monkeys treated with baclofen

    PubMed Central

    Porrino, Linda J.; Hampson, Robert E.; Opris, Ioan; Deadwyler, Samuel A.

    2013-01-01

    Rationale Acute and/or chronic exposure to cocaine can affect cognitive performance, which may influence rate of recovery during treatment. Objective Effects of the GABA-B receptor agonist baclofen were assessed for potency to reverse the negative influence of acute, pre-session, intravenous (IV) injection of cocaine on cognitive performance in Macaca mulatta nonhuman primates. Methods Animals were trained to perform a modified delayed match to sample (DMS) task incorporating two types of trials with varying degrees of cognitive load that had different decision requirements in order to correctly utilize information retained over the delay interval. The effects of cocaine (0.2, 0.4, and 0.6 mg/kg, IV) alone and in combination with baclofen (0.29 and 0.40 mg/kg, IV) were examined with respect to sustained performance levels. Brain metabolic activity during performance of the task was assessed using PET imaged uptake of [18F]-fluorodeoxyglucose. Results Acute cocaine injections produced a dose-dependent decline in DMS performance selective for trials of high cognitive load. The GABA-receptor agonist baclofen, co-administered with cocaine, reversed task performance back to nondrug (saline IV) control levels. Simultaneous assessment of PET-imaged brain metabolic activity in prefrontal cortex (PFC) showed alterations by cocaine compared to PFC metabolic activation in nondrug (saline, IV) control DMS sessions, but like performance, PFC activation was returned to control levels by baclofen (0.40 mg/kg, IV) injected with cocaine. Conclusions The results show that baclofen, administered at a relatively high dose, reversed the cognitive deficits produced by acute cocaine intoxication that may have implications for use in chronic drug exposure. PMID:22836369

  4. Time may not fully attenuate solvent-associated cognitive deficits in highly exposed workers

    PubMed Central

    Gutierrez, Laure-Anne; Okechukwu, Cassandra A.; Singh-Manoux, Archana; Amieva, Hélène; Goldberg, Marcel; Zins, Marie; Berr, Claudine

    2014-01-01

    Objective: To test the effects of lifetime occupational solvent exposure, as measured by dose and timing, on performance on multiple cognitive tests among retired French utility workers. Methods: A total of 2,143 retirees in the GAZEL cohort underwent cognitive testing in 2010. Lifetime exposure to chlorinated solvents, petroleum solvents, and benzene was assessed using a job exposure matrix. We modeled effects of lifetime solvent dose, timing of last exposure, and a combination of these metrics on risk for cognitive impairment. Results: Thirty-three percent of participants were exposed to chlorinated solvents, 26% to benzene, and 25% to petroleum solvents. High exposure to solvents was significantly associated with poor cognition; for example, those highly exposed to chlorinated solvents were at risk of impairment on the Mini-Mental State Examination (risk ratio 1.18; 95% confidence interval 1.06, 1.31), the Digit Symbol Substitution Test (1.54; 1.31, 1.82), semantic fluency test (1.33; 1.14, 1.55), and the Trail Making Test B (1.49; 1.25, 1.77). Retirees at greatest risk for deficits had both high lifetime exposure to solvents and were last exposed 12 to 30 years before testing. Risk was somewhat elevated among those with high lifetime exposure who were last exposed 31 to 50 years before testing. Those with high, recent exposure exhibited impairment in almost all domains, including those not typically associated with solvent exposure. Conclusions: While risk of cognitive impairment among moderately exposed workers may attenuate with time, this may not be fully true for those with higher exposure. This has implications for physicians working with formerly solvent-exposed patients as well as for workplace exposure limit policies. PMID:24821933

  5. Smaller than expected cognitive deficits in schizophrenia patients from the population-representative ABC catchment cohort.

    PubMed

    Lennertz, Leonhard; An der Heiden, Wolfram; Kronacher, Regina; Schulze-Rauschenbach, Svenja; Maier, Wolfgang; Häfner, Heinz; Wagner, Michael

    2016-08-01

    Most neuropsychological studies on schizophrenia suffer from sample selection bias, with male and chronic patients being overrepresented. This probably leads to an overestimation of cognitive impairments. The present study aimed to provide a less biased estimate of cognitive functions in schizophrenia using a population-representative catchment area sample. Schizophrenia patients (N = 89) from the prospective Mannheim ABC cohort were assessed 14 years after disease onset and first diagnosis, using a comprehensive neuropsychological test battery. A healthy control group (N = 90) was carefully matched according to age, gender, and geographic region (city, rural surrounds). The present sample was representative for the initial ABC cohort. In the comprehensive neuropsychological assessment, the schizophrenia patients were only moderately impaired as compared to the healthy control group (d = 0.56 for a general cognitive index, d = 0.42 for verbal memory, d = 0.61 for executive functions, d = 0.69 for attention). Only 33 % of the schizophrenia patients scored one standard deviation unit below the healthy control group in the general cognitive index. Neuropsychological performance did not correlate with measures of the clinical course including age at onset, number of hospital admissions, and time in paid work. Thus, in this population-representative sample of schizophrenia patients, neuropsychological deficits were less pronounced than expected from meta-analyses. In agreement with other epidemiological studies, this suggests a less devastating picture of cognition in schizophrenia. PMID:26233432

  6. Tandospirone, a 5-HT1A partial agonist, ameliorates aberrant lactate production in the prefrontal cortex of rats exposed to blockade of N-methy-D-aspartate receptors; Toward the therapeutics of cognitive impairment of schizophrenia

    PubMed Central

    Uehara, Takashi; Matsuoka, Tadasu; Sumiyoshi, Tomiki

    2014-01-01

    Rationale: Augmentation therapy with serotonin-1A (5-HT1A) receptor partial agonists has been suggested to improve cognitive impairment in patients with schizophrenia. Decreased activity of prefrontal cortex may provide a basis for cognitive deficits of the disease. Lactate plays a significant role in the supply of energy to the brain, and glutamatergic neurotransmission contributes to lactate production. Objectives and methods: The purposes of this study were to examine the effect of repeated administration (once a daily for 4 days) of tandospirone (0.05 or 5 mg/kg) on brain energy metabolism, as represented by extracellular lactate concentration (eLAC) in the medial prefrontal cortex (mPFC) of a rat model of schizophrenia. Results: Four-day treatment with MK-801, an NMDA-R antagonist, prolonged eLAC elevation induced by foot-shock stress (FS). Co-administration with the high-dose tandospirone suppressed prolonged FS-induced eLAC elevation in rats receiving MK-801, whereas tandospirone by itself did not affected eLAC increment. Conclusions: These results suggest that stimulation of 5-HT1A receptors ameliorates abnormalities of energy metabolism in the mPFC due to blockade of NMDA receptors. These findings provide a possible mechanism, based on brain energy metabolism, by which 5-HT1A agonism improve cognitive impairment of schizophrenia and related disorders. PMID:25232308

  7. Candida albicans exposures, sex specificity and cognitive deficits in schizophrenia and bipolar disorder.

    PubMed

    Severance, Emily G; Gressitt, Kristin L; Stallings, Catherine R; Katsafanas, Emily; Schweinfurth, Lucy A; Savage, Christina L; Adamos, Maria B; Sweeney, Kevin M; Origoni, Andrea E; Khushalani, Sunil; Leweke, F Markus; Dickerson, Faith B; Yolken, Robert H

    2016-01-01

    Immune aberrations in schizophrenia and bipolar disorder have led to the hypotheses that infectious agents or corresponding immune responses might contribute to psychiatric etiopathogeneses. We investigated case-control differences in exposure to the opportunistic fungal pathogen, Candida albicans, and examined associations with cognition, medication, lifestyle, and somatic conditions. We quantified C. albicans IgG antibodies in two cohorts totaling 947 individuals and evaluated odds ratios (OR) of exposure with psychiatric disorder using multivariate regressions. The case-control cohort included 261 with schizophrenia, 270 with bipolar disorder, and 277 non-psychiatric controls; the second included 139 with first-episode schizophrenia, 78 of whom were antipsychotic naive. No differences in C. albicans exposures were found until diagnostic groups were stratified by sex. In males, C. albicans seropositivity conferred increased odds for a schizophrenia diagnosis (OR 2.04-9.53, P⩽0.0001). In females, C. albicans seropositivity conferred increased odds for lower cognitive scores on Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) in schizophrenia (OR 1.12, P⩽0.004), with significant decreases on memory modules for both disorders (P⩽0.0007-0.03). C. albicans IgG levels were not impacted by antipsychotic medications. Gastrointestinal (GI) disturbances were associated with elevated C. albicans in males with schizophrenia and females with bipolar disorder (P⩽0.009-0.02). C. albicans exposure was associated with homelessness in bipolar males (P⩽0.0015). In conclusion, sex-specific C. albicans immune responses were evident in psychiatric disorder subsets. Inquiry regarding C. albicans infection or symptoms may expedite amelioration of this treatable comorbid condition. Yeast exposure as a risk factor for schizophrenia and its associated cognitive and GI effects require further investigation including the possible contribution of gut

  8. Candida albicans exposures, sex specificity and cognitive deficits in schizophrenia and bipolar disorder

    PubMed Central

    Severance, Emily G; Gressitt, Kristin L; Stallings, Catherine R; Katsafanas, Emily; Schweinfurth, Lucy A; Savage, Christina L; Adamos, Maria B; Sweeney, Kevin M; Origoni, Andrea E; Khushalani, Sunil; Leweke, F Markus; Dickerson, Faith B; Yolken, Robert H

    2016-01-01

    Immune aberrations in schizophrenia and bipolar disorder have led to the hypotheses that infectious agents or corresponding immune responses might contribute to psychiatric etiopathogeneses. We investigated case–control differences in exposure to the opportunistic fungal pathogen, Candida albicans, and examined associations with cognition, medication, lifestyle, and somatic conditions. We quantified C. albicans IgG antibodies in two cohorts totaling 947 individuals and evaluated odds ratios (OR) of exposure with psychiatric disorder using multivariate regressions. The case–control cohort included 261 with schizophrenia, 270 with bipolar disorder, and 277 non-psychiatric controls; the second included 139 with first-episode schizophrenia, 78 of whom were antipsychotic naive. No differences in C. albicans exposures were found until diagnostic groups were stratified by sex. In males, C. albicans seropositivity conferred increased odds for a schizophrenia diagnosis (OR 2.04–9.53, P⩽0.0001). In females, C. albicans seropositivity conferred increased odds for lower cognitive scores on Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) in schizophrenia (OR 1.12, P⩽0.004), with significant decreases on memory modules for both disorders (P⩽0.0007–0.03). C. albicans IgG levels were not impacted by antipsychotic medications. Gastrointestinal (GI) disturbances were associated with elevated C. albicans in males with schizophrenia and females with bipolar disorder (P⩽0.009–0.02). C. albicans exposure was associated with homelessness in bipolar males (P⩽0.0015). In conclusion, sex-specific C. albicans immune responses were evident in psychiatric disorder subsets. Inquiry regarding C. albicans infection or symptoms may expedite amelioration of this treatable comorbid condition. Yeast exposure as a risk factor for schizophrenia and its associated cognitive and GI effects require further investigation including the possible contribution of

  9. Pathologic and imaging correlates of cognitive deficits in multiple sclerosis: changing the paradigm of diagnosis and prognosis.

    PubMed

    Shi, Jiong; Baxter, Leslie C; Kuniyoshi, Sandra M

    2014-03-01

    From 1868, when Charcot first described the clinical features and the pathologic correlates, up till the present day, multiple sclerosis (MS) has commonly been characterized by the symptoms caused by inflammatory plaques in the white matter of the brain and spinal cord. Early use of magnetic resonance imaging (MRI) to diagnose MS focused on detecting these white matter lesions. By the 1990s, researchers recognized that many patients with MS have cognitive deficits that can cause severe disability, and also determined the associated pathology; these findings shed more light on both the pathogenesis and progression. Since 2004, several lines of evidence have shown that the extent of white matter plaques identified on MRI does not correlate well with cognitive deficits. High-resolution MRI and advances in immunohistochemical techniques have enabled detection of cortical demyelination early in the course, correlating with cognitive deficits. Late in the course, pathologic changes in normal-looking white and gray matter correlate more closely with progressive cognitive deficits than with visual, sensory, and motor symptoms. This finding implies the need to redefine the disease and its progression. In this review, we discuss the histopathologic studies of cortical plaques in MS and early indications about their role in disease definition and progression, describe the role of high-resolution MRI in staging and determining progression of cognitive symptoms, and discuss how advances in these areas are forcing us to rethink diagnosis and determination of progression. PMID:24674960

  10. 16p11.2 Deletion mice display cognitive deficits in touchscreen learning and novelty recognition tasks

    PubMed Central

    Lewis, Freeman C.; Sarvi, Michael S.; Foley, Gillian M.; Crawley, Jacqueline N.

    2015-01-01

    Chromosomal 16p11.2 deletion syndrome frequently presents with intellectual disabilities, speech delays, and autism. Here we investigated the Dolmetsch line of 16p11.2 heterozygous (+/−) mice on a range of cognitive tasks with different neuroanatomical substrates. Robust novel object recognition deficits were replicated in two cohorts of 16p11.2+/− mice, confirming previous findings. A similarly robust deficit in object location memory was discovered in +/−, indicating impaired spatial novelty recognition. Generalizability of novelty recognition deficits in +/− mice extended to preference for social novelty. Robust learning deficits and cognitive inflexibility were detected using Bussey–Saksida touchscreen operant chambers. During acquisition of pairwise visual discrimination, +/− mice required significantly more training trials to reach criterion than wild-type littermates (+/+), and made more errors and correction errors than +/+. In the reversal phase, all +/+ reached criterion, whereas most +/− failed to reach criterion by the 30-d cutoff. Contextual and cued fear conditioning were normal in +/−. These cognitive phenotypes may be relevant to some aspects of cognitive impairments in humans with 16p11.2 deletion, and support the use of 16p11.2+/− mice as a model system for discovering treatments for cognitive impairments in 16p11.2 deletion syndrome. PMID:26572653

  11. 16p11.2 Deletion mice display cognitive deficits in touchscreen learning and novelty recognition tasks.

    PubMed

    Yang, Mu; Lewis, Freeman C; Sarvi, Michael S; Foley, Gillian M; Crawley, Jacqueline N

    2015-12-01

    Chromosomal 16p11.2 deletion syndrome frequently presents with intellectual disabilities, speech delays, and autism. Here we investigated the Dolmetsch line of 16p11.2 heterozygous (+/-) mice on a range of cognitive tasks with different neuroanatomical substrates. Robust novel object recognition deficits were replicated in two cohorts of 16p11.2+/- mice, confirming previous findings. A similarly robust deficit in object location memory was discovered in +/-, indicating impaired spatial novelty recognition. Generalizability of novelty recognition deficits in +/- mice extended to preference for social novelty. Robust learning deficits and cognitive inflexibility were detected using Bussey-Saksida touchscreen operant chambers. During acquisition of pairwise visual discrimination, +/- mice required significantly more training trials to reach criterion than wild-type littermates (+/+), and made more errors and correction errors than +/+. In the reversal phase, all +/+ reached criterion, whereas most +/- failed to reach criterion by the 30-d cutoff. Contextual and cued fear conditioning were normal in +/-. These cognitive phenotypes may be relevant to some aspects of cognitive impairments in humans with 16p11.2 deletion, and support the use of 16p11.2+/- mice as a model system for discovering treatments for cognitive impairments in 16p11.2 deletion syndrome. PMID:26572653

  12. The effects of sigma (σ1) receptor-selective ligands on muscarinic receptor antagonist-induced cognitive deficits in mice

    PubMed Central

    Malik, Maninder; Rangel-Barajas, Claudia; Sumien, Nathalie; Su, Chang; Singh, Meharvan; Chen, Zhenglan; Huang, Ren-Qi; Meunier, Johann; Maurice, Tangui; Mach, Robert H; Luedtke, Robert R

    2015-01-01

    Background and Purpose Cognitive deficits in patients with Alzheimer's disease, Parkinson's disease, traumatic brain injury and stroke often involve alterations in cholinergic signalling. Currently available therapeutic drugs provide only symptomatic relief. Therefore, novel therapeutic strategies are needed to retard and/or arrest the progressive loss of memory. Experimental Approach Scopolamine-induced memory impairment provides a rapid and reversible phenotypic screening paradigm for cognition enhancement drug discovery. Male C57BL/6J mice given scopolamine (1 mg·kg−1) were used to evaluate the ability of LS-1–137, a novel sigma (σ1) receptor-selective agonist, to improve the cognitive deficits associated with muscarinic antagonist administration. Key Results LS-1–137 is a high-affinity (Ki = 3.2 nM) σ1 receptor agonist that is 80-fold selective for σ1, compared with σ2 receptors. LS-1–137 binds with low affinity at D2-like (D2, D3 and D4) dopamine and muscarinic receptors. LS-1–137 was found to partially reverse the learning deficits associated with scopolamine administration using a water maze test and an active avoidance task. LS-1–137 treatment was also found to trigger the release of brain-derived neurotrophic factor from rat astrocytes. Conclusions and Implications The σ1 receptor-selective compound LS-1–137 may represent a novel candidate cognitive enhancer for the treatment of muscarinic receptor-dependent cognitive deficits. PMID:25573298

  13. The effects of human corticotrophin releasing factor on motor and cognitive deficits after impact acceleration injury.

    PubMed

    Beaumont, A; Marmarou, C; Marmarou, A

    2000-10-01

    Corticotrophin releasing factor has been shown in several models of tissue injury to be an effective treatment for edema. In a previous study we demonstrated this ability in two models of traumatic brain injury (TBI). The aim of this study was to assess whether human corticotrophin releasing factor (hCRF) could additionally improve motor and cognitive deficits. Adult male Sprague-Dawley rats were randomised into five groups and injured with the Impact Acceleration Model of TBI. Groups I and II received sham injury followed by treatment with either drug vehicle or 100 micrograms kg-1 hCRF respectively. Group III was injured with no treatment; Group IV animals were injured and treated with 50 micrograms kg-1 hCRF and Group V were injured and treated with 100 micrograms kg-1 hCRF. Animals were assessed both before and after injury with a battery of standardised neuropsychological tests including the Morris Water Maze, the Beam Walk Test, the Beam Balance Test and the Inclined Plane Test. Both 50 micrograms kg-1 and 100 micrograms kg-1 hCRF caused significant improvements in motor and cognitive functioning, confirming that in addition to edema-reducing properties, human corticotrophin releasing factor is also capable of improving motor and cognitive functioning. Given the beneficial experimental effects of this compound, hCRF may be a useful clinical treatment, which requires formal evaluation. PMID:11091970

  14. Cognitive deficits are associated with unemployment in adults with sickle cell anemia.

    PubMed

    Sanger, Maureen; Jordan, Lori; Pruthi, Sumit; Day, Matthew; Covert, Brittany; Merriweather, Brenda; Rodeghier, Mark; DeBaun, Michael; Kassim, Adetola

    2016-08-01

    An estimated 25-60% of adults with sickle cell disease (SCD) are unemployed. Factors contributing to the high unemployment rate in this population are not well studied. With the known risk of cognitive deficits associated with SCD, we tested the hypothesis that unemployment is related to decrements in intellectual functioning. We conducted a retrospective chart review of 50 adults with sickle cell anemia who completed cognitive testing, including the Wechsler Adult Intelligence Scale-IV, as part of standard care. Employment status was recorded at the time of testing. Medical variables examined as possible risk factors for unemployment included disease phenotype, cerebral infarction, and pain frequency. The mean age of the sample was 30.7 years (range = 19-59); 56% were women. Almost half of the cohort (44%) were unemployed. In a multivariate logistic regression model, lower IQ scores (odds ratio = 0.88; p = .002, 95% confidence interval, CI [0.82, 0.96]) and lower educational attainment (odds ratio = 0.13; p = .012, 95% CI [0.03, 0.65]) were associated with increasing odds of unemployment. The results suggest that cognitive impairment in adults with sickle cell anemia may contribute to the risk of unemployment. Helping these individuals access vocational rehabilitation services may be an important component of multidisciplinary care. PMID:27167865

  15. Cognitive deficits in first-degree relatives of bipolar patients: the use of homogeneous subgroups in the search of cognitive endophenotypes.

    PubMed

    Volkert, Julia; Haubner, J; Kazmaier, J; Glaser, F; Kopf, J; Kittel-Schneider, S; Reif, A

    2016-08-01

    Previous studies have demonstrated impairments in attention, memory and executive functions in euthymic bipolar patients (BP) as well as their unaffected first-degree relatives, albeit in an attenuated form. Subsequently, cognitive deficits are discussed as a possible endophenotype of bipolar disorder. However, recent studies showed that only a subgroup of BP shows cognitive impairments. The aim of the present study was to investigate cognitive functioning in relatives compared to BP, to find out if the differentiation in a cognitive deficit vs. non-deficit subgroup is valid for relatives of BP, too. Therefore, the performance of 27 unaffected relatives of BP, 27 euthymic BP and 27 HC were compared using a neuropsychological test battery. The results showed that BP exhibited a reduced psychomotor speed and deficits in working memory compared to relatives and HC. Relatives performed significantly slower (psychomotor speed) as compared to HC (p = 0.024); performance in the other test measures lie between BP and HC. Furthermore, a detailed evaluation of the data indicated that only subgroups of BP and relatives exhibited cognitive impairments in the implemented tests. However, the deficit and non-deficit groups did not differ in sociodemographic and clinical variables from each other, possibly due to the small sample size. In conclusion, our results suggest that reduced psychomotor speed could serve as a potential endophenotype for bipolar disorder which should be investigated along the developmental trajectory of this disorder, also to examine whether abnormalities therein precede onset of the first mood episode. Furthermore, the division of relatives into subgroups aids in the identification of stable trait markers and high-risk bipolar groups and could enable early prevention strategies. As to that more research using distinct and homogeneous subgroups is necessary. PMID:27273092

  16. Bacopa monniera ameliorates cognitive impairment and neurodegeneration induced by intracerebroventricular-streptozotocin in rat: behavioral, biochemical, immunohistochemical and histopathological evidences.

    PubMed

    Khan, M Badruzzaman; Ahmad, Muzamil; Ahmad, Saif; Ishrat, Tauheed; Vaibhav, Kumar; Khuwaja, Gulrana; Islam, Fakhrul

    2015-02-01

    The standardized extract of Bacopa monniera (BM) is a complex mixture of ingredients with a uniquely wide spectrum of neuropharmacological influences upon the central nervous system including enhanced learning and memory with known antioxidant potential and protection of the brain from oxidative damage. The present study demonstrates the therapeutic efficacy of BM on cognitive impairment and oxidative damage, induced by intracerebroventricular injection of streptozotocin (ICV-STZ) in rat models. Male Wistar rats were pre-treated with BM at a selected dose (30 mg/Kg) given orally for 2 weeks and then were injected bilaterally with ICV-STZ (3 mg/Kg), while sham operated rats were received the same volume of vehicle. Behavioral parameters were subsequently monitored 2 weeks after the surgery using the Morris water maze (MWM) navigation task then were sacrificed for biochemical, immunohistochemical (Cu/Zn-SOD) and histopathological assays. ICV-STZ-infused rats showed significant loss in learning and memory ability, which were significantly improved by BM supplementation. A significant increase in thiobarbituric acid reactive species and a significant decrease in reduced glutathione, antioxidant enzymes in the hippocampus were observed in ICV-STZ rats. Moreover, decrease in Cu/Zn-SOD expression positive cells were observed in the hippocampus of ICV-STZ rats. BM supplementation significantly ameliorated all alterations induced by ICV-STZ in rats. The data suggest that ICV-STZ might cause its neurotoxic effects via the production of free radicals. Our study demonstrates that BM is a powerful antioxidant which prevents cognitive impairment, oxidative damage, and morphological changes in the ICV-STZ-infused rats. Thus, BM may have therapeutic value for the treatment of cognitive impairment. PMID:25037167

  17. Tinospora cordifolia ameliorates anxiety-like behavior and improves cognitive functions in acute sleep deprived rats

    PubMed Central

    Mishra, Rachana; Manchanda, Shaffi; Gupta, Muskan; Kaur, Taranjeet; Saini, Vedangana; Sharma, Anuradha; Kaur, Gurcharan

    2016-01-01

    Sleep deprivation (SD) leads to the spectrum of mood disorders like anxiety, cognitive dysfunctions and motor coordination impairment in many individuals. However, there is no effective pharmacological remedy to negate the effects of SD. The current study examined whether 50% ethanolic extract of Tinospora cordifolia (TCE) can attenuate these negative effects of SD. Three groups of adult Wistar female rats - (1) vehicle treated-sleep undisturbed (VUD), (2) vehicle treated-sleep deprived (VSD) and (3) TCE treated-sleep deprived (TSD) animals were tested behaviorally for cognitive functions, anxiety and motor coordination. TSD animals showed improved behavioral response in EPM and NOR tests for anxiety and cognitive functions, respectively as compared to VSD animals. TCE pretreatment modulated the stress induced-expression of plasticity markers PSA-NCAM, NCAM and GAP-43 along with proteins involved in the maintenance of LTP i.e., CamKII-α and calcineurin (CaN) in hippocampus and PC regions of the brain. Interestingly, contrary to VSD animals, TSD animals showed downregulated expression of inflammatory markers such as CD11b/c, MHC-1 and cytokines along with inhibition of apoptotic markers. This data suggests that TCE alone or in combination with other memory enhancing agents may help in managing sleep deprivation associated stress and improving cognitive functions. PMID:27146164

  18. Tinospora cordifolia ameliorates anxiety-like behavior and improves cognitive functions in acute sleep deprived rats.

    PubMed

    Mishra, Rachana; Manchanda, Shaffi; Gupta, Muskan; Kaur, Taranjeet; Saini, Vedangana; Sharma, Anuradha; Kaur, Gurcharan

    2016-01-01

    Sleep deprivation (SD) leads to the spectrum of mood disorders like anxiety, cognitive dysfunctions and motor coordination impairment in many individuals. However, there is no effective pharmacological remedy to negate the effects of SD. The current study examined whether 50% ethanolic extract of Tinospora cordifolia (TCE) can attenuate these negative effects of SD. Three groups of adult Wistar female rats - (1) vehicle treated-sleep undisturbed (VUD), (2) vehicle treated-sleep deprived (VSD) and (3) TCE treated-sleep deprived (TSD) animals were tested behaviorally for cognitive functions, anxiety and motor coordination. TSD animals showed improved behavioral response in EPM and NOR tests for anxiety and cognitive functions, respectively as compared to VSD animals. TCE pretreatment modulated the stress induced-expression of plasticity markers PSA-NCAM, NCAM and GAP-43 along with proteins involved in the maintenance of LTP i.e., CamKII-α and calcineurin (CaN) in hippocampus and PC regions of the brain. Interestingly, contrary to VSD animals, TSD animals showed downregulated expression of inflammatory markers such as CD11b/c, MHC-1 and cytokines along with inhibition of apoptotic markers. This data suggests that TCE alone or in combination with other memory enhancing agents may help in managing sleep deprivation associated stress and improving cognitive functions. PMID:27146164

  19. Erythropoietin ameliorates the motor and cognitive function impairments in a rat model of hepatic cirrhosis.

    PubMed

    Aghaei, Iraj; Nazeri, Masoud; Shabani, Mohammad; Mossavinasab, Marziehsadat; Mirhosseini, Fatemeh Khaleghi; Nayebpour, Mohsen; Dalili, Afshin

    2015-02-01

    Hepatic encephalopathy (HE) is a serious consequence of hepatic cirrhosis (HC). Previous studies have demonstrated cognitive impairments in both clinical and animal experiments of HC. Some potential therapeutic agents have been used to alleviate the cognitive symptoms in the animal models of HC. In the current study, the possible effect of erythropoietin (ERY) as a potent neuroprotective agent on motor and cognitive impairments induced by HC has been studied. Male Wistar rats (180-200 g) underwent bile duct ligation (BDL) or sham surgery. Administration of ERY (5,000 IU/kg, i.p., daily for three days) was initiated 2 weeks after surgery and lasted for the next 28 days. Open field, rotarod, Morris water maze and passive avoidance learning was used to evaluate the motor and cognitive function of the animals. ANOVA and repeated measures ANOVA were used to analyze the data. p < 0.05 was considered statistically significant. BDL rats had an increased level of hepatic enzymes and bilirubin. Impairment of balance function by BDL was reversed by ERY. Spatial and passive avoidance learning impairments observed in BDL rats were also reversed by chronic administration of ERY. ERY can be offered as a potential neuroprotective agent in the treatment of patients with HC that manifest mental dysfunctions. Though further studies are needed to clarify the exact mechanisms, the neuroprotective properties of ERY against BDL impairments were demonstrated in the current study. PMID:25115607

  20. The AT1 receptor antagonist, L-158,809, prevents or ameliorates fractionated whole-brain irradiation-induced cognitive impairment

    PubMed Central

    Robbins, Mike E.; Payne, Valerie; Tommasi, Ellen; Diz, Debra I; Hsu, Fang-Chi; Brown, William R.; Wheeler, Kenneth T.; Olson, John; Zhao, Weiling

    2009-01-01

    Purpose We hypothesized that administration of the angiotensin type 1 (AT1) receptor antagonist, L-158,809, to young adult male rats would prevent or ameliorate fractionated whole-brain irradiation (WBI)-induced cognitive impairment. Methods and Materials Groups of 80 young adult male Fischer 344 × Brown Norway (F344×BN) rats, 12–14 weeks old, received either: i] fractionated WBI; 40 Gy of γ rays in 4 weeks, 2 fractions/week, ii] sham-irradiation; iii] WBI plus L-158,809 (20 mg/L drinking water) starting 3 days prior, during and for 14, 28, or 54 weeks post-irradiation; and iv] sham-irradiation plus L-158,809 for 14, 28, or 54 weeks post-irradiation. An additional group of rats (n = 20) received L-158,809 prior to, during, and for 5 weeks post-irradiation, after which they received normal drinking water up to 28 weeks post-irradiation Results Administration of L-158,809 prior to, during, and for 28 or 54 weeks after fractionated WBI prevented or ameliorated the radiation-induced cognitive impairment observed 26 and 52 weeks post-irradiation. Moreover, giving L-158,809 prior to, during, and for only 5 weeks post-irradiation ameliorated the significant cognitive impairment observed 26 weeks post-irradiation. These radiation-induced cognitive impairments occurred without any changes in brain metabolites or gross histologic changes assessed at 28 and 54 weeks post-irradiation, respectively. Conclusions Administering L-158,809 prior to, during, and after fractionated WBI can prevent or ameliorate the chronic, progressive, cognitive impairment observed in rats at 26 and 52 weeks post-irradiation. These findings offer the promise of improving the quality of life for brain tumor patients. PMID:19084353

  1. The AT{sub 1} Receptor Antagonist, L-158,809, Prevents or Ameliorates Fractionated Whole-Brain Irradiation-Induced Cognitive Impairment

    SciTech Connect

    Robbins, Mike E. Payne, Valerie B.S.; Tommasi, Ellen B.S.; Diz, Debra I.; Hsu, Fang-Chi; Brown, William R.; Wheeler, Kenneth T.; Olson, John; Zhao Weiling

    2009-02-01

    Purpose: We hypothesized that administration of the angiotensin type 1 (AT1) receptor antagonist, L-158,809, to young adult male rats would prevent or ameliorate fractionated whole-brain irradiation (WBI)-induced cognitive impairment. Materials and Methods: Groups of 80 young adult male Fischer 344 x Brown Norway (F344xBN) rats, 12-14 weeks old, received either: (1) fractionated WBI; 40 Gy of {gamma} rays in 4 weeks, 2 fractions/week, (2) sham-irradiation; (3) WBI plus L-158,809 (20 mg/L drinking water) starting 3 days prior, during, and for 14, 28, or 54 weeks postirradiation; and (4) sham-irradiation plus L-158,809 for 14, 28, or 54 weeks postirradiation. An additional group of rats (n = 20) received L-158,809 before, during, and for 5 weeks postirradiation, after which they received normal drinking water up to 28 weeks postirradiation. Results: Administration of L-158,809 before, during, and for 28 or 54 weeks after fractionated WBI prevented or ameliorated the radiation-induced cognitive impairment observed 26 and 52 weeks postirradiation. Moreover, giving L-158,809 before, during, and for only 5 weeks postirradiation ameliorated the significant cognitive impairment observed 26 weeks postirradiation. These radiation-induced cognitive impairments occurred without any changes in brain metabolites or gross histologic changes assessed at 28 and 54 weeks postirradiation, respectively. Conclusions: Administering L-158,809 before, during, and after fractionated WBI can prevent or ameliorate the chronic, progressive, cognitive impairment observed in rats at 26 and 52 weeks postirradiation. These findings offer the promise of improving the quality of life for brain tumor patients.

  2. Midazolam Ameliorates the Behavior Deficits of a Rat Posttraumatic Stress Disorder Model through Dual 18 kDa Translocator Protein and Central Benzodiazepine Receptor and Neurosteroidogenesis

    PubMed Central

    Fang, Wei-Wu; Liu, Yan; Liu, Ji; Li, Bao-Wei; Wu, Wei; Li, Yun-Feng

    2014-01-01

    Post-traumatic stress disorder (PTSD) is a debilitating anxiety disorder that may develop after an individual has experienced or witnessed a severe traumatic event. It has been shown that the 18 kDa translocator protein (TSPO) may be correlated with PTSD and that the TSPO ligand improved the behavioral deficits in a mouse model of PTSD. Midazolam, a ligand for TSPO and central benzodiazepine receptor (CBR), induces anxiolytic- and anti-depressant-like effects in animal models. The present study aimed to determine whether midazolam ameliorates PTSD behavior in rats as assessed by the single prolonged stress (SPS) model. The SPS rats received daily Sertraline (Ser) (15 mg/kg, p.o.) and midazolam (0.125, 0.25, 0.5, and 1 mg/kg, p.o.) during the exposure to SPS and behavioral assessments, which included the open field (OF) test, the contextual fear paradigm (CFP), and the elevated plus-maze (EPM). The results showed that, like Ser (15 mg/kg, p.o.), midazolam (0.25 and 0.5 mg/kg, p.o.) significantly reversed the behavioral deficiencies of the SPS rats, including PTSD-associated freezing and anxiety-like behavior but not the effects on spontaneous locomotor activity. In addition, the anti-PTSD effects of midazolam (0.5 mg/kg, p.o.) were antagonized by the TSPO antagonist PK11195 (3 mg/kg, i.p.), the CBR antagonist flumazenil (15 mg/kg, p.o.) and the inhibitor of steroidogenic enzymes finasteride (30 mg/kg, p.o.), which by themselves had no effect on PTSD-associated freezing and anxiety-like behavior. In summary, this study demonstrated that midazolam improves the behavioral deficits in the SPS model through dual TSPO and CBR and neurosteroidogenesis. PMID:24988461

  3. Stimulation of 5-HT2C Receptors Improves Cognitive Deficits Induced by Human Tryptophan Hydroxylase 2 Loss of Function Mutation

    PubMed Central

    Del'Guidice, Thomas; Lemay, Francis; Lemasson, Morgane; Levasseur-Moreau, Jean; Manta, Stella; Etievant, Adeline; Escoffier, Guy; Doré, François Y; Roman, François S; Beaulieu, Jean-Martin

    2014-01-01

    Polymorphisms in the gene encoding the serotonin synthesis enzyme Tph2 have been identified in mental illnesses, including bipolar disorder, major depression, autism, schizophrenia, and ADHD. Deficits in cognitive flexibility and perseverative behaviors are shared common symptoms in these disorders. However, little is known about the impact of Tph2 gene variants on cognition. Mice expressing a human TPH2 variant (Tph2-KI) were used to investigate cognitive consequences of TPH2 loss of function and pharmacological treatments. We applied a recently developed behavioral assay, the automated H-maze, to study cognitive functions in Tph2-KI mice. This assay involves the consecutive discovery of three different rules: a delayed alternation task, a non-alternation task, and a delayed reversal task. Possible contribution of locomotion, reward, and sensory perception were also investigated. The expression of loss-of-function mutant Tph2 in mice was associated with impairments in reversal learning and cognitive flexibility, accompanied by perseverative behaviors similar to those observed in human clinical studies. Pharmacological restoration of 5-HT synthesis with 5-hydroxytryptophan or treatment with the 5-HT2C receptor agonist CP809.101 reduced cognitive deficits in Tph2-KI mice and abolished perseveration. In contrast, treatment with the psychostimulant methylphenidate exacerbated cognitive deficits in mutant mice. Results from this study suggest a contribution of TPH2 in the regulation of cognition. Furthermore, identification of a role for a 5-HT2 receptor agonist as a cognition-enhancing agent in mutant mice suggests a potential avenue to explore for the personalized treatment of cognitive symptoms in humans with reduced 5-HT synthesis and TPH2 polymorphisms. PMID:24196946

  4. Silencing PP2A inhibitor by lenti-shRNA interference ameliorates neuropathologies and memory deficits in tg2576 mice.

    PubMed

    Liu, Gong-Ping; Wei, Wei; Zhou, Xin; Shi, Hai-Rong; Liu, Xing-Hua; Chai, Gao-Shang; Yao, Xiu-Qing; Zhang, Jia-Yu; Peng, Cai-Xia; Hu, Juan; Li, Xia-Chun; Wang, Qun; Wang, Jian-Zhi

    2013-12-01

    Deficits of protein phosphatase-2A (PP2A) play a crucial role in tau hyperphosphorylation, amyloid overproduction, and synaptic suppression of Alzheimer's disease (AD), in which PP2A is inactivated by the endogenously increased inhibitory protein, namely inhibitor-2 of PP2A (I2(PP2A)). Therefore, in vivo silencing I2(PP2A) may rescue PP2A and mitigate AD neurodegeneration. By infusion of lentivirus-shRNA targeting I2(PP2A) (LV-siI2(PP2A)) into hippocampus and frontal cortex of 11-month-old tg2576 mice, we demonstrated that expression of LV-siI2(PP2A) decreased remarkably the elevated I2(PP2A) in both mRNA and protein levels. Simultaneously, the PP2A activity was restored with the mechanisms involving reduction of the inhibitory binding of I2(PP2A) to PP2A catalytic subunit (PP2AC), repression of the inhibitory Leu309-demethylation and elevation of PP2AC. Silencing I2(PP2A) induced a long-lasting attenuation of amyloidogenesis in tg2576 mice with inhibition of amyloid precursor protein hyperphosphorylation and β-secretase activity, whereas simultaneous inhibition of PP2A abolished the antiamyloidogenic effects of I2(PP2A) silencing. Finally, silencing I2(PP2A) could improve learning and memory of tg2576 mice with preservation of several memory-associated components. Our data reveal that targeting I2(PP2A) can efficiently rescue Aβ toxicities and improve the memory deficits in tg2576 mice, suggesting that I2(PP2A) could be a promising target for potential AD therapies. PMID:23922015

  5. Methylphenidate improves the behavioral and cognitive deficits of neurogranin knockout mice

    PubMed Central

    Huang, Freesia L.; Huang, Kuo-Ping

    2012-01-01

    Neurogranin (Ng), a brain-specific calmodulin-binding protein, is expressed highly in hippocampus, and is important for cognitive function. Deletion of the Ng gene from mice caused attenuation of signal reaction cascade in hippocampus, impairments in learning and memory and high frequency stimulation-induced long-term potentiation. Environmental enrichment alone failed to improve cognitive function. In the present study, behavioral testing revealed that Ng knockout mice were both hyperactive and socially withdrawn. Methylphenidate (MPH) was given to mice while they were also kept under an enrichment condition. MPH treatment reduced the hyperactivity of Ng knockout mice tested in both the open field and forced swim chamber. MPH improved their social abilities such that mice recognized and interacted better with novel subjects. The cognitive memories of MPH-treated mutants were improved in both water maze and contextual fear conditioning tests. High frequency stimulation-induced long-term potentiation of Ng knockout mice was also improved by MPH. The present treatment regimen, however, did not fully reverse the deficits of the mutant mice. In contrast, MPH exerted only a minimal effect on the wild type mice. At the cellular level, MPH increased the number of glial fibrillary acidic protein-positive cells in hippocampus, particularly within the dentate gyrus of Ng knockout mice. Therefore it will be of interest to determine the nature of MPH-mediated astrocyte activation and how it may modulate behavior in future studies. Taken together these Ng knockout mice may be useful for the development of better drug treatment to improve cognitive and behavioral impairments. PMID:22809330

  6. Inhibitor of the Tyrosine Phosphatase STEP Reverses Cognitive Deficits in a Mouse Model of Alzheimer's Disease

    PubMed Central

    Xu, Jian; Chatterjee, Manavi; Baguley, Tyler D.; Brouillette, Jonathan; Kurup, Pradeep; Ghosh, Debolina; Kanyo, Jean; Zhang, Yang; Seyb, Kathleen; Ononenyi, Chimezie; Foscue, Ethan; Anderson, George M.; Gresack, Jodi; Cuny, Gregory D.; Glicksman, Marcie A.; Greengard, Paul; Lam, TuKiet T.; Tautz, Lutz; Nairn, Angus C.; Ellman, Jonathan A.; Lombroso, Paul J.

    2014-01-01

    STEP (STriatal-Enriched protein tyrosine Phosphatase) is a neuron-specific phosphatase that regulates N-methyl-D-aspartate receptor (NMDAR) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) trafficking, as well as ERK1/2, p38, Fyn, and Pyk2 activity. STEP is overactive in several neuropsychiatric and neurodegenerative disorders, including Alzheimer's disease (AD). The increase in STEP activity likely disrupts synaptic function and contributes to the cognitive deficits in AD. AD mice lacking STEP have restored levels of glutamate receptors on synaptosomal membranes and improved cognitive function, results that suggest STEP as a novel therapeutic target for AD. Here we describe the first large-scale effort to identify and characterize small-molecule STEP inhibitors. We identified the benzopentathiepin 8-(trifluoromethyl)-1,2,3,4,5-benzopentathiepin-6-amine hydrochloride (known as TC-2153) as an inhibitor of STEP with an IC50 of 24.6 nM. TC-2153 represents a novel class of PTP inhibitors based upon a cyclic polysulfide pharmacophore that forms a reversible covalent bond with the catalytic cysteine in STEP. In cell-based secondary assays, TC-2153 increased tyrosine phosphorylation of STEP substrates ERK1/2, Pyk2, and GluN2B, and exhibited no toxicity in cortical cultures. Validation and specificity experiments performed in wild-type (WT) and STEP knockout (KO) cortical cells and in vivo in WT and STEP KO mice suggest specificity of inhibitors towards STEP compared to highly homologous tyrosine phosphatases. Furthermore, TC-2153 improved cognitive function in several cognitive tasks in 6- and 12-mo-old triple transgenic AD (3xTg-AD) mice, with no change in beta amyloid and phospho-tau levels. PMID:25093460

  7. Inhibitor of the tyrosine phosphatase STEP reverses cognitive deficits in a mouse model of Alzheimer's disease.

    PubMed

    Xu, Jian; Chatterjee, Manavi; Baguley, Tyler D; Brouillette, Jonathan; Kurup, Pradeep; Ghosh, Debolina; Kanyo, Jean; Zhang, Yang; Seyb, Kathleen; Ononenyi, Chimezie; Foscue, Ethan; Anderson, George M; Gresack, Jodi; Cuny, Gregory D; Glicksman, Marcie A; Greengard, Paul; Lam, TuKiet T; Tautz, Lutz; Nairn, Angus C; Ellman, Jonathan A; Lombroso, Paul J

    2014-08-01

    STEP (STriatal-Enriched protein tyrosine Phosphatase) is a neuron-specific phosphatase that regulates N-methyl-D-aspartate receptor (NMDAR) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) trafficking, as well as ERK1/2, p38, Fyn, and Pyk2 activity. STEP is overactive in several neuropsychiatric and neurodegenerative disorders, including Alzheimer's disease (AD). The increase in STEP activity likely disrupts synaptic function and contributes to the cognitive deficits in AD. AD mice lacking STEP have restored levels of glutamate receptors on synaptosomal membranes and improved cognitive function, results that suggest STEP as a novel therapeutic target for AD. Here we describe the first large-scale effort to identify and characterize small-molecule STEP inhibitors. We identified the benzopentathiepin 8-(trifluoromethyl)-1,2,3,4,5-benzopentathiepin-6-amine hydrochloride (known as TC-2153) as an inhibitor of STEP with an IC50 of 24.6 nM. TC-2153 represents a novel class of PTP inhibitors based upon a cyclic polysulfide pharmacophore that forms a reversible covalent bond with the catalytic cysteine in STEP. In cell-based secondary assays, TC-2153 increased tyrosine phosphorylation of STEP substrates ERK1/2, Pyk2, and GluN2B, and exhibited no toxicity in cortical cultures. Validation and specificity experiments performed in wild-type (WT) and STEP knockout (KO) cortical cells and in vivo in WT and STEP KO mice suggest specificity of inhibitors towards STEP compared to highly homologous tyrosine phosphatases. Furthermore, TC-2153 improved cognitive function in several cognitive tasks in 6- and 12-mo-old triple transgenic AD (3xTg-AD) mice, with no change in beta amyloid and phospho-tau levels. PMID:25093460

  8. Gray and White Matter Contributions to Cognitive Frontostriatal Deficits in Non-Demented Parkinson's Disease

    PubMed Central

    Price, Catherine C.; Tanner, Jared; Nguyen, Peter T.; Schwab, Nadine A.; Mitchell, Sandra; Slonena, Elizabeth; Brumback, Babette; Okun, Michael S.; Mareci, Thomas H.; Bowers, Dawn

    2016-01-01

    Objective This prospective investigation examined: 1) processing speed and working memory relative to other cognitive domains in non-demented medically managed idiopathic Parkinson’s disease, and 2) the predictive role of cortical/subcortical gray thickness/volume and white matter fractional anisotropy on processing speed and working memory. Methods Participants completed a neuropsychological protocol, Unified Parkinson’s Disease Rating Scale, brain MRI, and fasting blood draw to rule out vascular contributors. Within group a priori anatomical contributors included bilateral frontal thickness, caudate nuclei volume, and prefrontal white matter fractional anisotropy. Results Idiopathic Parkinson’s disease (n = 40; Hoehn & Yahr stages 1–3) and non-Parkinson’s disease ‘control’ peers (n = 40) matched on demographics, general cognition, comorbidity, and imaging/blood vascular metrics. Cognitively, individuals with Parkinson’s disease were significantly more impaired than controls on tests of processing speed, secondary deficits on working memory, with subtle impairments in memory, abstract reasoning, and visuoperceptual/spatial abilities. Anatomically, Parkinson’s disease individuals were not statistically different in cortical gray thickness or subcortical gray volumes with the exception of the putamen. Tract Based Spatial Statistics showed reduced prefrontal fractional anisotropy for Parkinson’s disease relative to controls. Within Parkinson’s disease, prefrontal fractional anisotropy and caudate nucleus volume partially explained processing speed. For controls, only prefrontal white matter was a significant contributor to processing speed. There were no significant anatomical predictors of working memory for either group. Conclusions Caudate nuclei volume and prefrontal fractional anisotropy, not frontal gray matter thickness, showed unique and combined significance for processing speed in Parkinson’s disease. Findings underscore the

  9. Separation of cognitive impairments in attention deficit hyperactivity disorder into two familial factors

    PubMed Central

    Kuntsi, J.; Wood, A.C.; Rijsdijk, F.; Johnson, K.A.; Andreou, P.; Albrecht, B.; Arias-Vasquez, A.; Buitelaar, J.K.; Mcloughlin, G.; Rommelse, N.N.J.; Sergeant, J.A.; Sonuga-Barke, E.J.S.; Uebel, H.; van der Meere, J.J.; Banaschewski, T.; Gill, M.; Manor, I.; Miranda, A.; Mulas, F.; Oades, R.D.; Roeyers, H.; Rothenberger, A.; Steinhausen, H.C.; Faraone, S.V.; Asherson, P.

    2013-01-01

    Context Attention deficit hyperactivity disorder (ADHD) is associated with widespread cognitive impairments, but it is not known whether the apparent multiple impairments share etiological roots, or whether separate etiological pathways exist. A better understanding of the etiological pathways is important for the development of targeted interventions and for identification of suitable intermediate phenotypes for molecular genetic investigations. Objective To determine, using a multivariate familial factor analysis approach, whether one or more familial factors underlie the slow and variable reaction times (RTs), impaired response inhibition and choice impulsivity that are associated with ADHD. Design An ADHD and control sibling-pair design. Setting Belgium, Germany, Ireland, Israel, Spain, Switzerland and the United Kingdom. Participants The sample consisted of 1265 participants, aged 6 to 18 years: 464 probands with ADHD and 456 of their siblings (524 with ADHD combined subtype), and 345 control participants. Main Outcome Measures Performance on a four-choice RT task, a go/no-go inhibition task and a choice-delay task. Results The final model consisted of two familial factors. The larger factor, reflecting 85% of the familial variance of ADHD, captured 98-100% of the familial influences on mean RT and RT variability. The second smaller factor, reflecting 12.5% of the familial variance of ADHD, captured 62-82% of the familial influences on commission and omission errors on the go/no-go task. Choice impulsivity was excluded in the final model, due to poor fit. Conclusions The findings suggest the existence of two familial pathways to cognitive impairments in ADHD and indicate promising cognitive targets for future molecular genetic investigations. The familial distinction between the two cognitive impairments is consistent with recent theoretical models – a developmental model and an arousal-attention model – on two separable underlying processes in ADHD

  10. Current Status of Cognitive Behavioral Therapy for Adult Attention-Deficit Hyperactivity Disorder

    PubMed Central

    Knouse, Laura E.; Safren, Steven A.

    2010-01-01

    Synopsis Attention-deficit / hyperactivity disorder (ADHD) is a valid and impairing psychological disorder that persists into adulthood in a majority of cases and is associated with chronic functional impairment and increased rates of comorbidity. Cognitive-behavioral therapy (CBT) approaches for this disorder have emerged relatively recently, and available evidence from open and randomized controlled trials suggests that these approaches are promising in producing significant symptom reduction. A conceptual model of how CBT may work for ADHD is reviewed along with existing efficacy studies. A preliminary comparison of effect sizes across intervention packages suggests that targeted learning and practice of specific behavioral compensatory strategies may be a critical “active ingredient” in CBT for adult ADHD. The article concludes with a discussion of future directions and critical questions that must be addressed in this area of clinical research. PMID:20599129

  11. Deficits in coordinated motor behavior and in nigrostriatal dopaminergic system ameliorated and VMAT2 expression up-regulated in aged male rats by administration of testosterone propionate.

    PubMed

    Wang, Li; Kang, Yunxiao; Zhang, Guoliang; Zhang, Yingbo; Cui, Rui; Yan, Wensheng; Tan, Huibing; Li, Shuangcheng; Wu, Baiyila; Cui, Huixian; Shi, Geming

    2016-06-01

    The effects of testosterone propionate (TP) supplements on the coordinated motor behavior and nigrostriatal dopaminergic (NSDA) system were analyzed in aged male rats. The present study showed the coordinated motor behavioral deficits, the reduced activity of NSDA system and the decreased expression of vesicular monoamine transporter 2 (VMAT2) in 24month-old male rats. Long term TP treatment improved the motor coordination dysfunction with aging. Increased tyrosine hydroxylase and dopamine transporter, as well as dopamine and its metabolites were found in the NSDA system of TP-treated 24month-old male rats, indicative of the amelioratory effects of TP supplements on NSDA system of aged male rats. The enhancement of dopaminergic (DAergic) activity of NSDA system by TP supplements might underlie the amelioration of the coordinated motor dysfunction in aged male rats. TP supplements up-regulated VMAT2 expression in NSDA system of aged male rats. Up-regulation of VMAT2 expression in aged male rats following chronic TP treatment might be involved in the maintenance of DAergic function of NSDA system in aged male rats. PMID:26956479

  12. Impaired retention is responsible for temporal order memory deficits in mild cognitive impairment.

    PubMed

    Gillis, M Meredith; Quinn, Kristen M; Phillips, Pamela A T; Hampstead, Benjamin M

    2013-05-01

    Temporal order memory, or remembering the order of events, is critical for everyday functioning and is difficult for patients with mild cognitive impairment (MCI). It is currently unclear whether these patients have difficulty acquiring and/or retaining such information and whether deficits in these patients are in excess of "normal" age-related declines. Therefore, the current study examined age and disease-related changes in temporal order memory as well as whether memory load played a role in such changes. Young controls (n=25), older controls (n=34), and MCI patients (n=32) completed an experimental task that required the reconstruction of sequences that were 3, 4, or 5 items in length both immediately after presentation (i.e., immediate recall) and again after a 10-min delay (i.e., delayed recall). During the immediate recall phase, there was an effect of age largely due to reduced performance at the two longest span lengths. Older controls and MCI patients only differed during the five span (controls>MCI). During the delayed recall, however, there were significant effects of both age and MCI regardless of span length. In MCI patients, immediate recall was significantly correlated with measures of executive functioning, whereas delayed recall performance was only related to other memory tests. These findings suggest that MCI patients experience initial temporal order memory deficits at the point when information begins to exceed working memory capacity and become dependent on medial temporal lobe functioning. Longer-term deficits are due to an inability to retain information, consistent with the characteristic medial temporal lobe dysfunction in MCI. PMID:23542809

  13. Riluzole rescues glutamate alterations, cognitive deficits, and tau pathology associated with P301L tau expression.

    PubMed

    Hunsberger, Holly C; Weitzner, Daniel S; Rudy, Carolyn C; Hickman, James E; Libell, Eric M; Speer, Rebecca R; Gerhardt, Greg A; Reed, Miranda N

    2015-10-01

    Hyperexcitability of the hippocampus is a commonly observed phenomenon in the years preceding a diagnosis of Alzheimer's disease (AD). Our previous work suggests a dysregulation in glutamate neurotransmission may mediate this hyperexcitability, and glutamate dysregulation correlates with cognitive deficits in the rTg(TauP301L)4510 mouse model of AD. To determine whether improving glutamate regulation would attenuate cognitive deficits and AD-related pathology, TauP301L mice were treated with riluzole (~ 12.5 mg/kg/day p.o.), an FDA-approved drug for amyotrophic lateral sclerosis that lowers extracellular glutamate levels. Riluzole-treated TauP301L mice exhibited improved performance in the water radial arm maze and the Morris water maze, associated with a decrease in glutamate release and an increase in glutamate uptake in the dentate gyrus, cornu ammonis 3 (CA3), and cornu ammonis 1 (CA1) regions of the hippocampus. Riluzole also attenuated the TauP301L-mediated increase in hippocampal vesicular glutamate transporter 1, which packages glutamate into vesicles and influences glutamate release; and the TauP301L-mediated decrease in hippocampal glutamate transporter 1, the major transporter responsible for removing glutamate from the extracellular space. The TauP301L-mediated reduction in PSD-95 expression, a marker of excitatory synapses in the hippocampus, was also rescued by riluzole. Riluzole treatment reduced total levels of tau, as well as the pathological phosphorylation and conformational changes in tau associated with the P301L mutation. These findings open new opportunities for the development of clinically applicable therapeutic approaches to regulate glutamate in vulnerable circuits for those at risk for the development of AD. PMID:26146790

  14. Autism-Relevant Social Abnormalities and Cognitive Deficits in Engrailed-2 Knockout Mice

    PubMed Central

    Brielmaier, Jennifer; Matteson, Paul G.; Silverman, Jill L.; Senerth, Julia M.; Kelly, Samantha; Genestine, Matthieu; Millonig, James H.

    2012-01-01

    ENGRAILED 2 (En2), a homeobox transcription factor, functions as a patterning gene in the early development and connectivity of rodent hindbrain and cerebellum, and regulates neurogenesis and development of monoaminergic pathways. To further understand the neurobiological functions of En2, we conducted neuroanatomical expression profiling of En2 wildtype mice. RTQPCR assays demonstrated that En2 is expressed in adult brain structures including the somatosensory cortex, hippocampus, striatum, thalamus, hypothalamus and brainstem. Human genetic studies indicate that EN2 is associated with autism. To determine the consequences of En2 mutations on mouse behaviors, including outcomes potentially relevant to autism, we conducted comprehensive phenotyping of social, communication, repetitive, and cognitive behaviors. En2 null mutants exhibited robust deficits in reciprocal social interactions as juveniles and adults, and absence of sociability in adults, replicated in two independent cohorts. Fear conditioning and water maze learning were impaired in En2 null mutants. High immobility in the forced swim test, reduced prepulse inhibition, mild motor coordination impairments and reduced grip strength were detected in En2 null mutants. No genotype differences were found on measures of ultrasonic vocalizations in social contexts, and no stereotyped or repetitive behaviors were observed. Developmental milestones, general health, olfactory abilities, exploratory locomotor activity, anxiety-like behaviors and pain responses did not differ across genotypes, indicating that the behavioral abnormalities detected in En2 null mutants were not attributable to physical or procedural confounds. Our findings provide new insight into the role of En2 in complex behaviors and suggest that disturbances in En2 signaling may contribute to neuropsychiatric disorders marked by social and cognitive deficits, including autism spectrum disorders. PMID:22829897

  15. Amelioration of scopolamine induced cognitive dysfunction and oxidative stress by Inonotus obliquus - a medicinal mushroom.

    PubMed

    Giridharan, Vijayasree Vayalanellore; Thandavarayan, Rajarajan Amirthalingam; Konishi, Tetsuya

    2011-06-01

    The present study was aimed to investigate the cognitive enhancing and anti-oxidant activities of Inonotus obliquus (Chaga) against scopolamine-induced experimental amnesia. Methanolic extract of Chaga (MEC) at 50 and 100 mg kg (-1)doses were administered orally for 7 days to amnesic mice. Learning and memory was assessed by passive avoidance task (PAT) and Morris water maze (MWM) test. Tacrine (THA, 10 mg kg (-1), orally (p.o)) used as a reference drug. To elucidate the mechanism of the cognitive enhancing activity of MEC, the activities of acetylcholinesterase (AChE), anti-oxidant enzymes, the levels of acetylcholine (ACh) and nitrite of mice brain homogenates were evaluated. MEC treatment for 7 days significantly improved the learning and memory as measured by PAT and MWM paradigms. Further, MEC significantly reduced the oxidative-nitritive stress, as evidenced by a decrease in malondialdehyde and nitrite levels and restored the glutathione and superoxide dismutase levels in a dose dependent manner. In addition, MEC treatment significantly decreased the AChE activity in both the salt and detergent-soluble fraction of brain homogenates. Further, treatment with MEC restored the levels of ACh as did THA. Thus, the significant cognitive enhancement observed in mice after MEC administration is closely related to higher brain anti-oxidant properties and inhibition of AChE activity. These findings stress the critical impact of Chaga, a medicinal mushroom, on the higher brain functions like learning and memory. PMID:21779570

  16. Salidroside ameliorates cognitive impairment in a d-galactose-induced rat model of Alzheimer's disease.

    PubMed

    Gao, Jin; He, He; Jiang, Wenjiao; Chang, Xiayun; Zhu, Lingpeng; Luo, Fen; Zhou, Rui; Ma, Chunhua; Yan, Tianhua

    2015-10-15

    The purpose of the present study was to investigate possible preventive effects of salidroside (sal) on a rat model of Alzheimer's disease and to explore its possible mechanism. Sub-acute aging was induced in male SD rats by subcutaneous injection of d-gal (120mg/kg) for 42 days, and the rats were treated with sal (20, 40mg/kg) or normal saline for 28 days after 14 days of d-gal injection. Morris water maze (MWM) test and step-down passive avoidance test were conducted to evaluate the cognitive function of the rats. The levels of inflammatory cytokines including tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β) in hippocampus were assayed by enzyme-linked immunosorbent assay (ELISA) to assess the anti-inflammatory effect of sal. Further, we estimated the expression levels of thioredoxin (Trx), thioredoxin interacting protein (Txnip/vitamin D3 up-regulated protein/thioredoxin binding protein-2), Bax, Bcl-2, caspase-9 and related-proteins of nuclear factor kappa B (NF-κB) signaling pathway by western blot assay. It showed that administration of sal significantly attenuated all the d-gal-induced changes in the hippocampus, including cognitive impairment and neuroinflammation. These analytical results provides evidence that sal can improve cognitive capacity by inhibiting neuroinflammation and affecting apoptosis-related proteins in hippocampus. PMID:26192909

  17. High cognitive reserve is associated with a reduced age-related deficit in spatial conflict resolution

    PubMed Central

    Puccioni, Olga; Vallesi, Antonino

    2012-01-01

    Several studies support the existence of a specific age-related difficulty in suppressing potentially distracting information. The aim of the present study is to investigate whether spatial conflict resolution is selectively affected by aging. The way aging affects individuals could be modulated by many factors determined by the socieconomic status: we investigated whether factors such as cognitive reserve (CR) and years of education may play a compensatory role against age-related deficits in the spatial domain. A spatial Stroop task with no feature repetitions was administered to a sample of 17 non-demented older adults (69–79 years-old) and 18 younger controls (18–34 years-old) matched for gender and years of education. The two age groups were also administered with measures of intelligence and CR. The overall spatial Stroop effect did not differ according to age, neither for speed nor for accuracy. The two age groups equally showed sequential effects for congruent trials: reduced response times (RTs) if another congruent trial preceded them, and accuracy at ceiling. For incongruent trials, older adults, but not younger controls, were influenced by congruency of trialn−1, since RTs increased with preceding congruent trials. Interestingly, such an age-related modulation negatively correlated with CR. These findings suggest that spatial conflict resolution in aging is predominantly affected by general slowing, rather than by a more specific deficit. However, a high level of CR seems to play a compensatory role for both factors. PMID:23248595

  18. Delta9-Tetrahydrocannabinol-induced cognitive deficits are reversed by olanzapine but not haloperidol in rats.

    PubMed

    Egashira, Nobuaki; Ishigami, Noriko; Mishima, Kenichi; Iwasaki, Katsunori; Oishi, Ryozo; Fujiwara, Michihiro

    2008-02-15

    Cannabis is the most widely used illicit substance. Delta9-Tetrahydrocannabinol (THC), the major psychoactive component of cannabis, is known to induce cognitive impairment that closely resembles the impairment observed in schizophrenic patients. THC has also been known to impair spatial memory in rats tested in the eight-arm radial maze. We previously reported that microinjection of THC (20 microg/side) into the rat dorsal hippocampus impaired spatial memory and that i.p. injection of THC (6 mg/kg) decreased the extracellular levels of acetylcholine (ACh) in the dorsal hippocampus. In the present study, we compared the effects of olanzapine, an atypical antipsychotic, with those of haloperidol, a typical neuroleptic, on the impairments of spatial memory and decreased ACh levels induced by THC (6 mg/kg, i.p.) in rats. We found that olanzapine (0.1 mg/kg, i.p.) reversed the THC-induced memory deficits and decrease in extracellular ACh levels, whereas haloperidol (0.03-0.3 mg, i.p.) had no effect. These results suggest that olanzapine may improve the THC-induced impairment of spatial memory, partly by enhancing ACh release in the dorsal hippocampus. Therefore, olanzapine could attenuate the acute short-term and working memory deficits induced by cannabis. PMID:18029074

  19. Critical Role of Acetylation in Tau-Mediated Neurodegeneration and Cognitive Deficits

    PubMed Central

    Min, Sang-Won; Chen, Xu; Tracy, Tara E; Li, Yaqiao; Zhou, Yungui; Wang, Chao; Shirakawa, Kotaro; Minami, S. Sakura; Defensor, Erwin; Mok, Sue Ann; Sohn, Peter Dongmin; Schilling, Birgit; Cong, Xin; Ellerby, Lisa; Gibson, Bradford W.; Johnson, Jeffrey; Krogan, Nevan; Shamloo, Mehrdad; Gestwicki, Jason; Masliah, Eliezer; Verdin, Eric; Gan, Li

    2015-01-01

    Tauopathies, including frontotemporal dementia (FTD) and Alzheimer’s disease (AD), are neurodegenerative diseases in which tau fibrils accumulate. Recent evidence supports soluble tau species as the major toxic species. How soluble tau accumulates and how it causes neurodegeneration remains unclear. Here we identified tau acetylation at K174 as an early change in AD brains and as a critical determinant in tau homeostasis and toxicity in mice. An acetyl-mimicking mutant (K174Q) slows down tau turnover and induces cognitive deficits in vivo. The acetyltransferase p300-induced tau acetylation is inhibited by a prescription drug salsalate/salicylate, which enhances tau turnover and reduces tau levels. In the PS19 transgenic mouse model of FTD, administering salsalate after disease onset inhibited p300 activity, lowered ac-K174 and total tau levels, rescued tau-induced memory deficits and prevented hippocampal atrophy. The tau-lowering and protective effects of salsalate/salicylate are diminished in neurons expressing K174Q tau. Targeting tau acetylation could be a new therapeutic strategy against human tauopathies. PMID:26390242

  20. Critical role of acetylation in tau-mediated neurodegeneration and cognitive deficits.

    PubMed

    Min, Sang-Won; Chen, Xu; Tracy, Tara E; Li, Yaqiao; Zhou, Yungui; Wang, Chao; Shirakawa, Kotaro; Minami, S Sakura; Defensor, Erwin; Mok, Sue Ann; Sohn, Peter Dongmin; Schilling, Birgit; Cong, Xin; Ellerby, Lisa; Gibson, Bradford W; Johnson, Jeffrey; Krogan, Nevan; Shamloo, Mehrdad; Gestwicki, Jason; Masliah, Eliezer; Verdin, Eric; Gan, Li

    2015-10-01

    Tauopathies, including frontotemporal dementia (FTD) and Alzheimer's disease (AD), are neurodegenerative diseases in which tau fibrils accumulate. Recent evidence supports soluble tau species as the major toxic species. How soluble tau accumulates and causes neurodegeneration remains unclear. Here we identify tau acetylation at Lys174 (K174) as an early change in AD brains and a critical determinant in tau homeostasis and toxicity in mice. The acetyl-mimicking mutant K174Q slows tau turnover and induces cognitive deficits in vivo. Acetyltransferase p300-induced tau acetylation is inhibited by salsalate and salicylate, which enhance tau turnover and reduce tau levels. In the PS19 transgenic mouse model of FTD, administration of salsalate after disease onset inhibited p300 activity, lowered levels of total tau and tau acetylated at K174, rescued tau-induced memory deficits and prevented hippocampal atrophy. The tau-lowering and protective effects of salsalate were diminished in neurons expressing K174Q tau. Targeting tau acetylation could be a new therapeutic strategy against human tauopathies. PMID:26390242

  1. High Suicide Risk after the Development of Cognitive and Working Memory Deficits Caused by Cannabis, Cocaine and Ecstasy Use

    ERIC Educational Resources Information Center

    Pompili, Maurizio; Lester, David; Girardi, Paolo; Tatarelli, Roberto

    2007-01-01

    We report the case of attempted suicide by a 30-year-old man who had significant cognitive deficits that developed after at least three years of polysubstance use with cannabis, methylenedioxymethamphetamine (MDMA, "ecstasy") and cocaine. The patient reported increasing difficulties in his professional and interpersonal life which may have been…

  2. The Relationship between Prenatal and Postnatal Exposure to Polychlorinated Biphenyls (PCBs) and Cognitive, Neuropsychological, and Behavioral Deficits: A Critical Appraisal

    ERIC Educational Resources Information Center

    Cicchetti, Domenic V.; Kaufman, Alan S.; Sparrow, Sara S.

    2004-01-01

    Our purpose in this report is to evaluate scientifically that body of literature relating the effects of prenatal and postnatal exposure to polychlorinated biphenyls (PCBs) upon neurobehavioral, health-related, and cognitive deficits in neonates, developing infants, children, and adults. The data derive from seven cohorts: six cohorts of mothers…

  3. Quantitative EEG Magnitudes in Children with and without Attention Deficit Disorder during Neurological Screening and Cognitive Tasks.

    ERIC Educational Resources Information Center

    Crawford, Helen J.; Barabasz, Marianne

    1996-01-01

    Quantitative EEG magnitude data were obtained from children with and without attention deficit disorder (ADD). The data suggest that the right fronto-centro-temporal region is not as "cognitively activated" relative to the left hemisphere in those children with ADD. Neurotherapy training of the right frontal and central regions in ADD children was…

  4. Spelling Difficulties in School-Aged Girls with Attention-Deficit/Hyperactivity Disorder: Behavioral, Psycholinguistic, Cognitive, and Graphomotor Correlates

    ERIC Educational Resources Information Center

    Åsberg Johnels, Jakob; Kopp, Svenny; Gillberg, Christopher

    2014-01-01

    Writing difficulties are common among children with attention-deficit/hyperactivity disorder (ADHD), but the nature of these difficulties has not been well studied. Here we relate behavioral, psycholinguistic, cognitive (memory/executive), and graphomotor measures to spelling skills in school-age girls with ADHD (n = 30) and an age-matched group…

  5. A Case Study of the Cognitive and Behavioral Deficits of Temporal Lobe Damage in Herpes Simplex Encephalitis.

    ERIC Educational Resources Information Center

    Greer, Margaret K.; And Others

    1989-01-01

    This case study illustrates the highly significant language difficulties, marked memory deficits, and propensity for physical aggression following temporal lobe damage brought about by herpes encephalitis, and presents the usefulness of a new diagnostic measure in delineating such a variable cognitive pattern. (Author)

  6. An Investigation of an Evaluation Method and Retraining Procedures for Emotionally Handicapped Children with Cognitive-Motor Deficits. Final Report.

    ERIC Educational Resources Information Center

    Rubin, Eli Z.; And Others

    To assess the effects of specialized retraining of cognitive, perceptual, and motor (CPM) deficits, a battery of tests was prepared and used with 200 behaviorally maladjusted and 200 problem-free children. The composite score indicated that 40% of the maladjusted group manifested major dysfunction whereas none of the problem-free group…

  7. Berry fruit can improve age-associated neuronal and cognitive deficits: from the laboratory to the clinic

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Research has demonstrated, in both human and animals, that cognitive functioning decreases with age, to include deficits in processing speed, executive function, memory, and spatial learning. The cause of these functional declines is not entirely understood; however, neuronal losses and the associat...

  8. 16p11.2 Deletion Mice Display Cognitive Deficits in Touchscreen Learning and Novelty Recognition Tasks

    ERIC Educational Resources Information Center

    Yang, Mu; Lewis, Freeman C.; Sarvi, Michael S.; Foley, Gillian M.; Crawley, Jacqueline N.

    2015-01-01

    Chromosomal 16p11.2 deletion syndrome frequently presents with intellectual disabilities, speech delays, and autism. Here we investigated the Dolmetsch line of 16p11.2 heterozygous (+/-) mice on a range of cognitive tasks with different neuroanatomical substrates. Robust novel object recognition deficits were replicated in two cohorts of 16p11.2…

  9. Numerical and Arithmetical Cognition: A Longitudinal Study of Process and Concept Deficits in Children with Learning Disability.

    ERIC Educational Resources Information Center

    Geary, David C.; Hamson, Carmen O.; Hoard, Mary K.

    2000-01-01

    Compared performance of first and second graders with normal intelligence but with learning disabilities (LD) in mathematics, reading, or both and children with variable achievement test performance to that of academically normal peers on experimental and psychometric tasks. Found that LD groups showed specific cognitive deficit patterns; children…

  10. An Integrative, Cognitive-Behavioral, Systemic Approach to Working with Students Diagnosed with Attention Deficit Hyperactive Disorder

    ERIC Educational Resources Information Center

    Shillingford, Margaret Ann; Lambie, Glenn W.; Walter, Sara Meghan

    2007-01-01

    Attention deficit hyperactive disorder (ADHD) is a prevalent diagnostic disorder for many students, which correlates with negative academic, social, and personal consequences. This article presents an integrative, cognitive-behavioral, systemic approach that offers behaviorally based interventions for professional school counselors to support…

  11. Pharmacologic blockade of 12/15-lipoxygenase ameliorates memory deficits, Aβ and tau neuropathology in the triple-transgenic mice.

    PubMed

    Chu, J; Li, J-G; Giannopoulos, P F; Blass, B E; Childers, W; Abou-Gharbia, M; Praticò, D

    2015-11-01

    The 12/15-lipoxygenase (12/15LO) enzyme is widely distributed within the central nervous system. Previous work showed that this protein is upregulated in Alzheimer's disease (AD), and plays an active role in the development of brain amyloidosis in amyloid beta (Aβ)-precursor protein transgenic mice (Tg2576). In the present paper, we studied the effect of its pharmacologic inhibition on the AD-like phenotype of a mouse model with plaques and tangles, the triple-transgenic mice. Compared with mice receiving placebo, the group treated with PD146176, a specific 12/15LO inhibitor, manifested a significant improvement of their memory deficits. The same animals had a significant reduction in Aβ levels and deposition, which was secondary to a decrease in the β-secretase pathway. In addition, while total tau-soluble levels were unchanged for both groups, PD146176-treated mice had a significant reduction in its phosphorylation state and insoluble fraction, which specifically associated with decrease in stress-activated protein kinase/c-Jun N-terminal kinase activity. In vitro study showed that the effect on tau and Aβ were independent from each other. These data establish a functional role for 12/15LO in the pathogenesis of the full spectrum of the AD-like phenotype and represent the successful completion of the initial step for the preclinical development of 12/15LO inhibitors as novel therapeutic agents for AD. PMID:25560760

  12. Atorvastatin attenuates cognitive deficits through Akt1/caspase-3 signaling pathway in ischemic stroke.

    PubMed

    Yang, Jie; Pan, Ying; Li, Xuejing; Wang, Xianying

    2015-12-10

    Neuronal damage in the hippocampal formation is more sensitive to ischemic stimulation and easily injured, causing severe learning and memory impairment. Therefore, protection of hippocampal neuronal damage is the main contributor for learning and memory impairment during cerebral ischemia. Atorvastatin has been reported to ameliorate ischemic brain damage after ischemia reperfusion (I/R). However, its molecular mechanism has not been elucidated clearly. In this study, we established four-vessel occlusion model in rats with cerebral ischemia. Here, we demonstrated that atorvastatin significantly improves the behavior of I/R-rat in open field tasks. We also found that atorvastatin significantly shortens the distance and time of loading onto the hidden platform in the positioning navigation process, decreases the latency in the space exploration process when cognitive testing with Morris water maze was performed during ischemic stroke in rats. Furthermore, the survival rate of neurons in the CA1 area of the hippocampus and the phosphorylation of Akt (Ser473) in the neurons are increased, whereas the expression of caspase-3 are inhibited by atorvastatin. However, after an intracerebroventricular injection of LY294002 (an inhibitor of Akt1), the above neuroprotective effects of atorvastatin are attenuated. In summary, our results imply atorvastatin may improve the survival rate of hippocampal neurons and reduce the impairment of learning and memory by downregulating the activation of the caspase-3 via increasing the phosphorylation of Akt1 during ischemia/reperfusion. PMID:26597376

  13. Protective roles of selenium and zinc against postnatal protein-undernutrition-induced alterations in Ca(2+)-homeostasis leading to cognitive deficits in Wistar rats.

    PubMed

    Adebayo, Olusegun L; Sandhir, Rajat; Adenuga, Gbenga A

    2015-06-01

    Postnatal protein-undernutrition impacts on mental development and cognition in children and can lead to problem with attention and unresponsiveness which compromise children's ability to learn. These behavioral disorders might be due to alteration in calcium homeostasis as calcium plays critical roles in fundamental functions of neuron. The role of low protein diet as well as Se and Zn supplementation on intracellular calcium concentration ([Ca(2+)]i), Ca(2+)-ATPase, Na(+)-K(+)-ATPase, calpain and caspase-3 activities from rat cortex and cerebellum were investigated. Well-fed (WF) and low protein diet-fed (LPDF) rats were given diets containing 16% and 5% casein, respectively, for a period of 10 weeks. Then, the rats were supplemented with Se and Zn at a concentration of 0.15 mgL(-1) and 227 mgL(-1), respectively, in drinking water for 3 weeks. The results obtained from the study showed a significant increase in [Ca(2+)]i; calpain and caspase-3 activities as well as increase transfer latency in water maze study and reductions in Ca(2+)-ATPase and Na(+)-K(+)-ATPase activities for LPDF rats compared to WF rats. Se and Zn supplementation to LPDF rats reversed the elevation in [Ca(2+)]i, calpain and caspase-3 activities and restored the cognitive deficits and the activities of Ca(2+)-ATPase and Na(+)-K(+)-ATPase. Conclusively, protein-undernutrition results in the accumulation of synaptosomal calcium and inhibition of calcium transporters presumably via free radical generations and results in cognitive impairment which also probably results from neuronal death in rats through calpain activation and the caspase cascade mechanisms. However, Se and Zn supplementations ameliorated the anomalies observed. PMID:25794607

  14. Oligodendrocyte and Interneuron Density in Hippocampal Subfields in Schizophrenia and Association of Oligodendrocyte Number with Cognitive Deficits

    PubMed Central

    Falkai, Peter; Steiner, Johann; Malchow, Berend; Shariati, Jawid; Knaus, Andreas; Bernstein, Hans-Gert; Schneider-Axmann, Thomas; Kraus, Theo; Hasan, Alkomiet; Bogerts, Bernhard; Schmitt, Andrea

    2016-01-01

    In schizophrenia, previous stereological post-mortem investigations of anterior, posterior, and total hippocampal subfields showed no alterations in total neuron number but did show decreased oligodendrocyte numbers in CA4, an area that corresponds to the polymorph layer of the dentate gyrus (DG). However, these investigations identified oligodendrocytes only on the basis of morphological criteria in Nissl staining and did not assess alterations of interneurons with immunohistochemical markers. Moreover, the association of findings in the posterior hippocampus with cognitive deficits remains unknown. On the basis of the available clinical records, we compared patients with definite and possible cognitive dysfunction; nine patients had evidence in their records of either definite (n = 4) or possible (n = 5) cognitive dysfunction. Additionally, we assessed the density of two oligodendrocyte subpopulations immunostained by the oligodendrocyte transcription factors Olig1 and Olig2 and of interneurons immunolabeled by parvalbumin. We investigated posterior hippocampal subregions in the post-mortem brains of the same schizophrenia patients (SZ; n = 10) and healthy controls (n = 10) we examined in our previously published stereological studies. Our stereological studies found that patients with definite cognitive deficits had decreased total/Nissl-stained oligodendrocyte numbers in the left (p = 0.014) and right (p = 0.050) CA4, left CA2/3 (p = 0.050), left CA1 (p = 0.027), and left (p = 0.050) and right (p = 0.014) subiculum of the anterior part of the hippocampus compared to patients with possible cognitive deficits. In the present study, we found no significant influence of definite cognitive deficits in the posterior part of the hippocampus, whereas in the entire hippocampus SZ with definite cognitive deficits showed decreased oligodendrocyte numbers in the left (p = 0.050) and right (p = 0.050) DG and left CA2/3 (p = 0.050). We did not find significant differences in

  15. Effectiveness of nootropic drugs with cholinergic activity in treatment of cognitive deficit: a review

    PubMed Central

    Colucci, Luisa; Bosco, Massimiliano; Rosario Ziello, Antonio; Rea, Raffaele; Amenta, Francesco; Fasanaro, Angiola Maria

    2012-01-01

    Nootropics represent probably the first “smart drugs” used for the treatment of cognitive deficits. The aim of this paper is to verify, by a systematic analysis of the literature, the effectiveness of nootropics in this indication. The analysis was limited to nootropics with cholinergic activity, in view of the role played by acetylcholine in learning and memory. Acetylcholine was the first neurotransmitter identified in the history of neuroscience and is the main neurotransmitter of the peripheral, autonomic, and enteric nervous systems. We conducted a systematic review of the literature for the 5-year period 2006–2011. From the data reported in the literature, it emerges that nootropics may be an effective alternative for strengthening and enhancing cognitive performance in patients with a range of pathologies. Although nootropics, and specifically the cholinergic precursors, already have a long history behind them, according to recent renewal of interest, they still seem to have a significant therapeutic role. Drugs with regulatory indications for symptomatic treatment of Alzheimer’s disease, such as cholinesterase inhibitors and memantine, often have transient effects in dementia disorders. Nootropics with a cholinergic profile and documented clinical effectiveness in combination with cognate drugs such as cholinesterase inhibitors or alone in patients who are not suitable for these inhibitors should be taken into account and evaluated further.

  16. The Coumarin Derivative Osthole Stimulates Adult Neural Stem Cells, Promotes Neurogenesis in the Hippocampus, and Ameliorates Cognitive Impairment in APP/PS1 Transgenic Mice.

    PubMed

    Kong, Liang; Hu, Yu; Yao, Yingjia; Jiao, Yanan; Li, Shaoheng; Yang, Jingxian

    2015-01-01

    It is believed that neuronal death caused by abnormal deposition of amyloid-beta peptide is the major cause of the cognitive decline in Alzheimer's disease. Adult neurogenesis plays a key role in the rescue of impaired neurons and amelioration of cognitive impairment. In the present study, we demonstrated that osthole, a natural coumarin derivative, was capable of promoting neuronal stem cell (NSC) survival and inducing NSC proliferation in vitro. In osthole-treated APP/PS1 transgenic mice, a significant improvement in learning and memory function was seen, which was associated with a significant increase in the number of new neurons (Ki67(+)/NF-M(+)) and a decrease in apoptotic cells in the hippocampal region of the brain. These observations suggested that osthole promoted NSC proliferation, supported neurogenesis, and thus efficiently rescued impaired neurons in the hippocampus and ameliorated cognitive impairment. We also found that osthole treatment activated the Notch pathway and upregulated the expression of self-renewal genes Notch 1 and Hes 1 mRNA in NSCs. However, when Notch activity was blocked by the γ-secretase inhibitor DAPT, the augmentation of Notch 1 and Hes 1 protein was ameliorated, and the proliferation-inducing effect of osthole was abolished, suggesting that the effects of osthole are at least in part mediated by activation of the Notch pathway. PMID:26328484

  17. CCR2 antagonism alters brain macrophage polarization and ameliorates cognitive dysfunction induced by traumatic brain injury.

    PubMed

    Morganti, Josh M; Jopson, Timothy D; Liu, Sharon; Riparip, Lara-Kirstie; Guandique, Cristian K; Gupta, Nalin; Ferguson, Adam R; Rosi, Susanna

    2015-01-14

    Traumatic brain injury (TBI) is a major risk factor for the development of multiple neurodegenerative diseases. With respect to the increasing prevalence of TBI, new therapeutic strategies are urgently needed that will prevent secondary damage to primarily unaffected tissue. Consistently, neuroinflammation has been implicated as a key mediator of secondary damage following the initial mechanical insult. Following injury, there is uncertainty regarding the role that accumulating CCR2(+) macrophages play in the injury-induced neuroinflammatory sequelae and cognitive dysfunction. Using CX3CR1(GFP/+)CCR2(RFP/+) reporter mice, we show that TBI initiated a temporally restricted accumulation of peripherally derived CCR2(+) macrophages, which were concentrated in the hippocampal formation, a region necessary for learning and memory. Multivariate analysis delineated CCR2(+) macrophages' neuroinflammatory response while identifying a novel therapeutic treatment window. As a proof of concept, targeting CCR2(+) macrophages with CCX872, a novel Phase I CCR2 selective antagonist, significantly reduced TBI-induced inflammatory macrophage accumulation. Concomitantly, there was a significant reduction in multiple proinflammatory and neurotoxic mediators with this treatment paradigm. Importantly, CCR2 antagonism resulted in a sparing of TBI-induced hippocampal-dependent cognitive dysfunction and reduced proinflammatory activation profile 1 month after injury. Thus, therapeutically targeting the CCR2(+) subset of monocytes/macrophages may provide a new avenue of clinical intervention following TBI. PMID:25589768

  18. CCR2 Antagonism Alters Brain Macrophage Polarization and Ameliorates Cognitive Dysfunction Induced by Traumatic Brain Injury

    PubMed Central

    Jopson, Timothy D.; Liu, Sharon; Riparip, Lara-Kirstie; Guandique, Cristian K.; Gupta, Nalin; Ferguson, Adam R.

    2015-01-01

    Traumatic brain injury (TBI) is a major risk factor for the development of multiple neurodegenerative diseases. With respect to the increasing prevalence of TBI, new therapeutic strategies are urgently needed that will prevent secondary damage to primarily unaffected tissue. Consistently, neuroinflammation has been implicated as a key mediator of secondary damage following the initial mechanical insult. Following injury, there is uncertainty regarding the role that accumulating CCR2+ macrophages play in the injury-induced neuroinflammatory sequelae and cognitive dysfunction. Using CX3CR1GFP/+CCR2RFP/+ reporter mice, we show that TBI initiated a temporally restricted accumulation of peripherally derived CCR2+ macrophages, which were concentrated in the hippocampal formation, a region necessary for learning and memory. Multivariate analysis delineated CCR2+ macrophages' neuroinflammatory response while identifying a novel therapeutic treatment window. As a proof of concept, targeting CCR2+ macrophages with CCX872, a novel Phase I CCR2 selective antagonist, significantly reduced TBI-induced inflammatory macrophage accumulation. Concomitantly, there was a significant reduction in multiple proinflammatory and neurotoxic mediators with this treatment paradigm. Importantly, CCR2 antagonism resulted in a sparing of TBI-induced hippocampal-dependent cognitive dysfunction and reduced proinflammatory activation profile 1 month after injury. Thus, therapeutically targeting the CCR2+ subset of monocytes/macrophages may provide a new avenue of clinical intervention following TBI. PMID:25589768

  19. Social cognitive and neurocognitive deficits in inpatients with unilateral thalamic lesions – pilot study

    PubMed Central

    Wilkos, Ewelina; Brown, Timothy JB; Slawinska, Ksenia; Kucharska, Katarzyna A

    2015-01-01

    worse performance on Reading the Mind in the Eyes Test, revised version II. Neuropsychological assessment demonstrated some statistically significant deficits in learning and remembering both verbal and visual material, long-term information storing, problem solving, and executive functions such as verbal fluency. Conclusion Patients at early stage of unilateral thalamic stroke showed both neurocognitive and social cognitive deficits. Further research is needed to increase understanding about diagnosis, early treatment, and prognosis of patients with thalamic lesions. PMID:25914535

  20. Differential profiles in auditory social cognition deficits between adults with autism and schizophrenia spectrum disorders: A preliminary analysis.

    PubMed

    Tobe, Russell H; Corcoran, Cheryl M; Breland, Melissa; MacKay-Brandt, Anna; Klim, Casimir; Colcombe, Stanley J; Leventhal, Bennett L; Javitt, Daniel C

    2016-08-01

    Impairment in social cognition, including emotion recognition, has been extensively studied in both Autism Spectrum Disorders (ASD) and Schizophrenia (SZ). However, the relative patterns of deficit between disorders have been studied to a lesser degree. Here, we applied a social cognition battery incorporating both auditory (AER) and visual (VER) emotion recognition measures to a group of 19 high-functioning individuals with ASD relative to 92 individuals with SZ, and 73 healthy control adult participants. We examined group differences and correlates of basic auditory processing and processing speed. Individuals with SZ were impaired in both AER and VER while ASD individuals were impaired in VER only. In contrast to SZ participants, those with ASD showed intact basic auditory function. Our finding of a dissociation between AER and VER deficits in ASD relative to Sz support modality-specific theories of emotion recognition dysfunction. Future studies should focus on visual system-specific contributions to social cognitive impairment in ASD. PMID:27131617

  1. Sex Differences in Adult Cognitive Deficits after Adolescent Nicotine Exposure in Rats

    PubMed Central

    Pickens, Laura R. G.; Rowan, James D.; Bevins, Rick A.; Fountain, Stephen B.

    2013-01-01

    This study was designed to determine whether deficits in adult serial pattern learning caused by adolescent nicotine exposure persist as impairments in asymptotic performance, whether adolescent nicotine exposure differentially retards learning about pattern elements that are inconsistent with “perfect” pattern structure, and whether there are sex differences in rats’ response to adolescent nicotine exposure as assessed by a serial multiple choice task. The current study replicated the results of our initial report (Fountain, Rowan, Kelley, Willey, & Nolley, 2008) using this task by showing that adolescent nicotine exposure (1.0 mg/kg/day nicotine for 35 days) produced a specific cognitive impairment in male rats that persisted into adulthood at least a month after adolescent nicotine exposure ended. In addition, sex differences were observed even in controls, with additional evidence that adolescent nicotine exposure significantly impaired learning relative to same-sex controls for chunk boundary elements in males and for violation elements in females. All nicotine-induced impairments were overcome by additional training so that groups did not differ at asymptote. An examination of the types of errors rats made indicated that adolescent nicotine exposure slowed learning without affecting rats’ cognitive strategy in the task. This data pattern suggests that exposure to nicotine in adolescence may have impaired different aspects of adult stimulus-response discrimination learning processes in males and females, but left abstract rule learning processes relatively spared in both sexes. These effects converge with other findings in the field and reinforce the concern that adolescent nicotine exposure poses an important threat to cognitive capacity in adulthood. PMID:23673345

  2. Modulation of Intestinal Microbiota by the Probiotic VSL#3 Resets Brain Gene Expression and Ameliorates the Age-Related Deficit in LTP

    PubMed Central

    Distrutti, Eleonora; O’Reilly, Julie-Ann; McDonald, Claire; Cipriani, Sabrina; Renga, Barbara; Lynch, Marina A.; Fiorucci, Stefano

    2014-01-01

    The intestinal microbiota is increasingly recognized as a complex signaling network that impacts on many systems beyond the enteric system modulating, among others, cognitive functions including learning, memory and decision-making processes. This has led to the concept of a microbiota-driven gut–brain axis, reflecting a bidirectional interaction between the central nervous system and the intestine. A deficit in synaptic plasticity is one of the many changes that occurs with age. Specifically, the archetypal model of plasticity, long-term potentiation (LTP), is reduced in hippocampus of middle-aged and aged rats. Because the intestinal microbiota might change with age, we have investigated whether the age-related deficit in LTP might be attenuated by changing the composition of intestinal microbiota with VSL#3, a probiotic mixture comprising 8 Gram-positive bacterial strains. Here, we report that treatment of aged rats with VSL#3 induced a robust change in the composition of intestinal microbiota with an increase in the abundance of Actinobacteria and Bacterioidetes, which was reduced in control-treated aged rats. VSL#3 administration modulated the expression of a large group of genes in brain tissue as assessed by whole gene expression, with evidence of a change in genes that impact on inflammatory and neuronal plasticity processes. The age-related deficit in LTP was attenuated in VSL#3-treated aged rats and this was accompanied by a modest decrease in markers of microglial activation and an increase in expression of BDNF and synapsin. The data support the notion that intestinal microbiota can be manipulated to positively impact on neuronal function. PMID:25202975

  3. β2-Adrenergic receptor agonist ameliorates phenotypes and corrects microRNA-mediated IGF1 deficits in a mouse model of Rett syndrome.

    PubMed

    Mellios, Nikolaos; Woodson, Jonathan; Garcia, Rodrigo I; Crawford, Benjamin; Sharma, Jitendra; Sheridan, Steven D; Haggarty, Stephen J; Sur, Mriganka

    2014-07-01

    Rett syndrome is a severe childhood onset neurodevelopmental disorder caused by mutations in methyl-CpG-binding protein 2 (MECP2), with known disturbances in catecholamine synthesis. Here, we show that treatment with the β2-adrenergic receptor agonist clenbuterol increases survival, rescues abnormalities in respiratory function and social recognition, and improves motor coordination in young male Mecp2-null (Mecp2(-/y)) mice. Importantly, we demonstrate that short-term treatment with clenbuterol in older symptomatic female heterozygous (Mecp2(-/+)) mice rescues respiratory, cognitive, and motor coordination deficits, and induces an anxiolytic effect. In addition, we reveal abnormalities in a microRNA-mediated pathway, downstream of brain-derived neurotrophic factor that affects insulin-like growth factor 1 (IGF1) expression in Mecp2(-/y) mice, and show that treatment with clenbuterol restores the observed molecular alterations. Finally, cotreatment with clenbuterol and recombinant human IGF1 results in additional increases in survival in male null mice. Collectively, our data support a role for IGF1 and other growth factor deficits as an underlying mechanism of Rett syndrome and introduce β2-adrenergic receptor agonists as potential therapeutic agents for the treatment of the disorder. PMID:24958851

  4. Emotion Perception or Social Cognitive Complexity: What Drives Face Processing Deficits in Autism Spectrum Disorder?

    ERIC Educational Resources Information Center

    Walsh, Jennifer A.; Creighton, Sarah E.; Rutherford, M. D.

    2016-01-01

    Some, but not all, relevant studies have revealed face processing deficits among those with autism spectrum disorder (ASD). In particular, deficits are revealed in face processing tasks that involve emotion perception. The current study examined whether either deficits in processing emotional expression or deficits in processing social cognitive…

  5. Erythropoietin Ameliorates Neonatal Hypoxia-Ischemia-Induced Neurobehavioral Deficits, Neuroinflammation, and Hippocampal Injury in the Juvenile Rat

    PubMed Central

    Lan, Kuo-Mao; Tien, Lu-Tai; Cai, Zhengwei; Lin, Shuying; Pang, Yi; Tanaka, Sachiko; Rhodes, Philip G.; Bhatt, Abhay J.; Savich, Renate D.; Fan, Lir-Wan

    2016-01-01

    The hematopoietic growth factor erythropoietin (EPO) has been shown to be neuroprotective against hypoxia-ischemia (HI) in Postnatal Day 7 (P7)–P10 or adult animal models. The current study was aimed to determine whether EPO also provides long-lasting neuroprotection against HI in P5 rats, which is relevant to immature human infants. Sprague-Dawley rats at P5 were subjected to right common carotid artery ligation followed by an exposure to 6% oxygen with balanced nitrogen for 1.5 h. Human recombinant EPO (rEPO, at a dose of 5 units/g) was administered intraperitoneally one hour before or immediately after insult, followed by additional injections at 24 and 48 h post-insult. The control rats were injected with normal saline following HI. Neurobehavioral tests were performed on P8 and P20, and brain injury was examined on P21. HI insult significantly impaired neurobehavioral performance including sensorimotor, locomotor activity and cognitive ability on the P8 and P20 rats. HI insult also resulted in brain inflammation (as indicated by microglia activation) and neuronal death (as indicated by Jade B positive staining) in the white matter, striatum, cortex, and hippocampal areas of the P21 rat. Both pre- and post-treatment with rEPO significantly improved neurobehavioral performance and protected against the HI-induced neuronal death, microglia activation (OX42+) as well as loss of mature oligodendrocytes (APC-CC1+) and hippocampal neurons (Nissl+). The long-lasting protective effects of rEPO in the neonatal rat HI model suggest that to exert neurotrophic activity in the brain might be an effective approach for therapeutic treatment of neonatal brain injury induced by hypoxia-ischemia. PMID:26927081

  6. Erythropoietin Ameliorates Neonatal Hypoxia-Ischemia-Induced Neurobehavioral Deficits, Neuroinflammation, and Hippocampal Injury in the Juvenile Rat.

    PubMed

    Lan, Kuo-Mao; Tien, Lu-Tai; Cai, Zhengwei; Lin, Shuying; Pang, Yi; Tanaka, Sachiko; Rhodes, Philip G; Bhatt, Abhay J; Savich, Renate D; Fan, Lir-Wan

    2016-01-01

    The hematopoietic growth factor erythropoietin (EPO) has been shown to be neuroprotective against hypoxia-ischemia (HI) in Postnatal Day 7 (P7)-P10 or adult animal models. The current study was aimed to determine whether EPO also provides long-lasting neuroprotection against HI in P5 rats, which is relevant to immature human infants. Sprague-Dawley rats at P5 were subjected to right common carotid artery ligation followed by an exposure to 6% oxygen with balanced nitrogen for 1.5 h. Human recombinant EPO (rEPO, at a dose of 5 units/g) was administered intraperitoneally one hour before or immediately after insult, followed by additional injections at 24 and 48 h post-insult. The control rats were injected with normal saline following HI. Neurobehavioral tests were performed on P8 and P20, and brain injury was examined on P21. HI insult significantly impaired neurobehavioral performance including sensorimotor, locomotor activity and cognitive ability on the P8 and P20 rats. HI insult also resulted in brain inflammation (as indicated by microglia activation) and neuronal death (as indicated by Jade B positive staining) in the white matter, striatum, cortex, and hippocampal areas of the P21 rat. Both pre- and post-treatment with rEPO significantly improved neurobehavioral performance and protected against the HI-induced neuronal death, microglia activation (OX42+) as well as loss of mature oligodendrocytes (APC-CC1+) and hippocampal neurons (Nissl+). The long-lasting protective effects of rEPO in the neonatal rat HI model suggest that to exert neurotrophic activity in the brain might be an effective approach for therapeutic treatment of neonatal brain injury induced by hypoxia-ischemia. PMID:26927081

  7. Longitudinal characterization of motor and cognitive deficits in a model of penetrating ballistic-like brain injury.

    PubMed

    Shear, Deborah A; Lu, Xi-Chun May; Bombard, Matthew C; Pedersen, Rebecca; Chen, Zhiyong; Davis, Angela; Tortella, Frank C

    2010-10-01

    Traumatic brain injury (TBI) produces a wide range of motor and cognitive changes. While some neurological symptoms may respond to therapeutic intervention during the initial recovery period, others may persist for many years after the initial insult, and often have a devastating impact on quality of life for the TBI victim. The aim of the current study was to develop neurobehavioral testing parameters designed to provide a longitudinal assessment of neurofunctional deficits in a rodent model of penetrating ballistic-like brain injury (PBBI). We report here a series of experiments in which unilateral frontal PBBI was induced in rats, and motor/cognitive abilities were assessed using a battery of tests ranging from 30 min to 10 weeks post-injury. The results showed that PBBI produced consistent and significant (1) neurological deficits (neuroscore examination: 30 min to 10 weeks post-PBBI), (2) sensorimotor dysfunction in the contralateral forelimb (forelimb asymmetry task: 7 and 21 days), (3) motor dysfunction (balance beam task: 3-7 days; and fixed-speed rotarod task: 3-28 days), and (4) spatial learning deficits in the Morris water maze (MWM) task out to 10 weeks post-injury. Overall, the results of this study demonstrate that PBBI produces enduring motor and cognitive deficits, and identifies the optimal task and testing parameters for facilitating longitudinal screening of promising therapeutic interventions in this brain injury model. PMID:20684676

  8. Characterization of cognitive deficits in a transgenic mouse model of Alzheimer's disease and effects of donepezil and memantine.

    PubMed

    Nagakura, Akira; Shitaka, Yoshitsugu; Yarimizu, Junko; Matsuoka, Nobuya

    2013-03-01

    Alzheimer's disease is characterized by a progressive decline in cognitive function and involves β-amyloid (Aβ) in its pathogenesis. To characterize cognitive deficits associated with Aβ accumulation, we analyzed PS1/APP mice overexpressing mutant presenilin-1 (PS1, M146L; line 6.2) and amyloid precursor protein (APP, K670N/M671L; line Tg2576), a mouse model of Alzheimer's disease with accelerated Aβ production. Age-dependent changes in working and spatial memory behaviors were investigated using Y-maze and Morris water maze tasks, respectively, in female PS1/APP mice at ages of 2, 4, 6, and 12 months. Significant deficits in working and spatial memory were observed from 4 and 6 months of age, respectively. Acute single-dose administrations of memantine, a low-to-moderate-affinity N-methyl-d-aspartate (NMDA) antagonist, showed improvements in working memory deficits at 4 months of age, whereas donepezil, an acetylcholinesterase (AChE) inhibitor, did not. However, both drugs improved spatial memory dysfunction at 6 months of age at therapeutically relevant doses. No age-related dramatic changes were observed in expression levels of several proteins relating to memory dysfunction and also the mechanisms of donepezil and memantine in the cerebral cortex of PS1/APP mice until 6 months of age. Taken together, these results suggest dysfunctions in cholinergic and/or glutamatergic transmissions may be involved in the cognitive deficits associated with Aβ toxicity. Since donepezil and memantine have been widely used for treating patients of Alzheimer's disease, these results also suggest that cognitive deficits in PS1/APP mice assessed in the Y-maze and Morris water maze tasks are a useful animal model for evaluating novel Alzheimer's disease therapeutics. PMID:23276665

  9. Cluster analysis of cognitive deficits may mark heterogeneity in schizophrenia in terms of outcome and response to treatment

    PubMed Central

    Gilbert, Elsa; Mérette, Chantal; Jomphe, Valérie; Émond, Claudia; Rouleau, Nancie; Bouchard, Roch-Hugo; Roy, Marc-André; Paccalet, Thomas

    2016-01-01

    Cognitive impairments are central to schizophrenia, but their clinical utility for tagging heterogeneity in lifetime outcome and response to treatment is not conclusive. By exploiting four cognitive domains consistently showing large deficits in studies, we tested whether cluster analysis would define separate subsets of patients and then whether the disease heterogeneity marked by these clusters would be related to lifetime outcome and response to treatment. A total of 112 schizophrenia patients completed a neuropsychological evaluation. The PANSS, GAF-S and GAF-F were rated at the onset and endpoint of the illness trajectory. A blind judgment of the lifetime response to treatment was made. The first cluster presented near-normal cognitive performance. Two other clusters of severely impaired patients were identified: one generally impaired in the four cognitive domains and another selectively impaired in visual episodic memory and processing speed, each relating to a different lifetime evolution of disease and treatment response. Although the two impaired clusters were clinically indistinguishable in symptom severity and functioning at disease onset, patients with selective cognitive impairments demonstrated better improvement at outcome, whereas the generally impaired patients were more likely to be treatment refractory. The findings have implications for the management of patients and for clinical trials since particular combinations of cognitive deficits in patients would influence their treatment response. PMID:24173295

  10. Cognition and the compassion deficit: the social psychology of helping behaviour in nursing.

    PubMed

    Paley, John

    2014-10-01

    This paper discusses compassion failure and compassion deficits in health care, using two major reports by Robert Francis in the UK as a point of reference. Francis enquired into events at the Mid Staffordshire Hospital between 2005 and 2009, events that unequivocally warrant the description 'appalling care'. These events prompted an intense national debate, along with proposals for significant changes in the regulation of nursing and nurse education. The circumstances are specific to the UK, but the issues are international. I suggest that social psychology provides numerous hints about the mechanisms that might have been involved at Mid Staffs and about the reasons why outsiders are blind to these mechanisms. However, there have been few references to social psychology in the post-Francis debate (the Francis Report itself makes no reference to it at all). It is an enormously valuable resource, and it has been overlooked. Drawing on the social psychology literature, I express scepticism about the idea that there was a compassion deficit among the Mid Staff nurses - the assumption that the appalling care had something to do with the character, attitudes, and values of nurses - and argue that the Francis Report's emphasis on a 'culture of compassion and caring in nurse recruitment, training and education' is misconceived. It was not a 'failure of compassion' that led to the events in Mid Staffs but an interlocking set of contextual factors that are known to affect social cognition. These factors cannot be corrected or compensated for by teaching ethics, empathy, and compassion to student nurses. PMID:24447716

  11. Cholesterol-loaded nanoparticles ameliorate synaptic and cognitive function in Huntington's disease mice.

    PubMed

    Valenza, Marta; Chen, Jane Y; Di Paolo, Eleonora; Ruozi, Barbara; Belletti, Daniela; Ferrari Bardile, Costanza; Leoni, Valerio; Caccia, Claudio; Brilli, Elisa; Di Donato, Stefano; Boido, Marina M; Vercelli, Alessandro; Vandelli, Maria A; Forni, Flavio; Cepeda, Carlos; Levine, Michael S; Tosi, Giovanni; Cattaneo, Elena

    2015-12-01

    Brain cholesterol biosynthesis and cholesterol levels are reduced in mouse models of Huntington's disease (HD), suggesting that locally synthesized, newly formed cholesterol is less available to neurons. This may be detrimental for neuronal function, especially given that locally synthesized cholesterol is implicated in synapse integrity and remodeling. Here, we used biodegradable and biocompatible polymeric nanoparticles (NPs) modified with glycopeptides (g7) and loaded with cholesterol (g7-NPs-Chol), which per se is not blood-brain barrier (BBB) permeable, to obtain high-rate cholesterol delivery into the brain after intraperitoneal injection in HD mice. We report that g7-NPs, in contrast to unmodified NPs, efficiently crossed the BBB and localized in glial and neuronal cells in different brain regions. We also found that repeated systemic delivery of g7-NPs-Chol rescued synaptic and cognitive dysfunction and partially improved global activity in HD mice. These results demonstrate that cholesterol supplementation to the HD brain reverses functional alterations associated with HD and highlight the potential of this new drug-administration route to the diseased brain. PMID:26589247

  12. Maternal dexamethasone exposure ameliorates cognition and tau pathology in the offspring of triple transgenic AD mice.

    PubMed

    Di Meco, A; Joshi, Y B; Lauretti, E; Praticò, D

    2016-03-01

    Dysregulation of stress hormones, such as glucocorticoids, in adult life increases the risk to develop Alzheimer's disease (AD). However, the effect of prenatal glucocorticoids exposure on AD development in the offspring remains unknown. We studied how gestational dexamethasone exposure influences the AD-like phenotype in the offspring of triple transgenic AD mice (3 × Tg). To this end, female mice received dexamethasone or vehicle during the entire pregnancy time in the drinking water. Offspring from vehicle-treated 3 × Tg (controls) were compared with offspring from dexamethasone-treated 3 × Tg later in life for their memory, learning ability and brain pathology. Compared with controls, offspring from dexamethasone-treated mothers displayed improvement in their memory as assessed by fear conditioning test, both in the cue and recall phases. The same animals had a significant reduction in the insoluble fraction of tau, which was associated with an increase in autophagy. In addition, they showed an activation of the transcription factor cellular response element-binding protein and an increase in brain-derived neurotrophic factor and c-FOS protein levels, key regulators of synaptic plasticity and memory. We conclude that dexamethasone exposure during pregnancy provides long-lasting protection against the onset and development of the AD-like phenotype by improving cognition and tau pathology. PMID:26077691

  13. Lack of association between mutation size and cognitive/behavior deficits in fragile X males: A brief report

    SciTech Connect

    Fisch, G.S.; Simensen, R.

    1996-08-09

    Previously, researchers reported molecular-neurobehavioral or molecular-cognitive associations in individuals with fra(X) (fragile X) mutation. However, not all investigators have noted molecular-behavioral relationships. Consequently, we examined prospectively 30 fra(X) males age 3-15 years from four testing sites to determine whether there was a relationship between mutation size and degree of either cognitive or adaptive behavior deficit. To measure cognitive abilities, all individuals were administered the Stanford-Binet (4th edition) IQ test. To evaluate adaptive behavior (DQ) skills, all individuals were assessed using the Vineland Adaptive Behavior Scale. To determine fra(X) status, genomic DNA from all individuals was extracted and digested with EcoRI and EagI restriction enzymes. Southern blots were prepared and hybridized with the pE5.1 probe. The Pearson correlation coefficient between full mutation size and composite IQ score revealed a non-significant, near-zero association (r = 0.06; P > .76). The Pearson coefficient between mutation size and DQ also showed a non-significant, near-zero association (r = 0.06; P >.73). We conclude that while fra(X) mutation produces cognitive and behavior deficits in males who inherit the defective gene, there is no relationship between mutation size and degree of deficit. 14 refs., 2 figs.

  14. Bilobalide alleviates depression-like behavior and cognitive deficit induced by chronic unpredictable mild stress in mice.

    PubMed

    Wu, Ruiyong; Shui, Li; Wang, Siyang; Song, Zhenzhen; Tai, Fadao

    2016-10-01

    Bilobalide (BB), a unique constituent of Ginkgo biloba, has powerful neuroprotection and stress-alleviating properties. However, whether BB exerts a positive effect on depression and cognitive deficit induced by chronic stress is not known. The present study was designed to investigate the influence of BB on depression and cognitive impairments induced by chronic unpredictable mild stress (CUMS) in mice. During daily exposure to stressors for 5 consecutive weeks, mice were administered BB at the doses of 0, 3, or 6 mg/kg/day intraperitoneally. We replicated the finding that CUMS induced depression-like behavior and cognitive deficits as the CUMS+vehicle (VEH) group showed a significant increase in immobility in the tail suspension test, a decrease in the discrimination index of the novel object recognition task, and increased latency to platform and decreased number of platform crossings in the Morris water maze compared with the control+VEH group. Chronic administration of BB effectively reversed these alterations. In addition, the CUMS+VEH group showed significantly higher levels of baseline serum corticosterone than those of the control+VEH group and BB dose-dependently inhibited this effect. Our results suggest that BB may be useful for inhibition of depression-like behavior and cognitive deficits, and this protective effect was possibly exerted partly through an action on the hypothalamic-pituitary-adrenal axis. PMID:27509313

  15. Lack of association between mutation size and cognitive/behavior deficits in fragile X males: a brief report.

    PubMed

    Fisch, G S; Carpenter, N; Howard-Peebles, P N; Maddalena, A; Simensen, R; Tarleton, J; Julien-Inalsingh, C; Chalifoux, M; Holden, J J

    1996-08-01

    Previously, researchers reported molecular-neurobehavioral or molecular-cognitive associations in individuals with fra(X) (fragile X) mutation. However, not all investigators have noted molecular-behavioral relationships. Consequently, we examined prospectively 30 fra(X) males age 3-15 years from four testing sites to determine whether there was a relationship between mutation size and degree of either cognitive or adaptive behavior deficit. To measure cognitive abilities, all individuals were administered the Stanford-Binet (4th edition) IQ test. To evaluate adaptive behavior (DQ) skills, all individuals were assessed using the Vineland Adaptive Behavior Scale. To determine fra(X) status, genomic DNA from all individuals was extracted and digested with EcoRI and EagI restriction enzymes. Southern blots were prepared and hybridized with the pE5.1 probe. The Pearson correlation coefficient between full mutation size and composite IQ score revealed a nonsignificant, near-zero association (r = 0.06; P > .76). The Pearson coefficient between mutation size and DQ also showed a nonsignificant, near-zero association (r = 0.06; P > .73). We conclude that while fra(X) mutation produces cognitive and behavior deficits in males who inherit the defective gene, there is no relationship between mutation size and degree of deficit. PMID:8844081

  16. Early treatment with high-dose interferon beta-1a reverses cognitive and cortical plasticity deficits in multiple sclerosis

    PubMed Central

    Mori, Francesco; Kusayanagi, Hajime; Buttari, Fabio; Centini, Barbara; Monteleone, Fabrizia; Nicoletti, Carolina Gabri; Bernardi, Giorgio; Di Cantogno, Elisabetta Verdun; Marciani, Maria Grazia; Centonze, Diego

    2012-01-01

    Summary Acute inflammation is associated with cognitive deficits and alterations of cortical plasticity in multiple sclerosis (MS). We tested whether early treatment with high-dose interferon (IFN) beta-1a, known to reduce inflammatory activity, improves cortical function and cognitive deficits in MS. Eighty treatment-naïve relapsing-remitting MS (RRMS) patients received IFN beta-1a (44 mcg) subcutaneously three times per week. Cognitive performance and cortical plasticity were measured through the paced auditory serial addition test (PASAT) and intermittent theta burst stimulation (iTBS) before and up to two years after IFN beta-1a initiation. Before treatment, patients with gadolinium-enhancing lesions (Gd+) on MRI performed worse on the PASAT, and showed lower iTBS-induced plasticity, compared with Gd− patients. Six months after treatment initiation both PASAT and iTBS-induced plasticity improved in Gd+ and remained stable in Gd− patients. These results suggest that cognitive and synaptic plasticity deficits may be rescued during high-dose IFN beta-1a treatment in newly-diagnosed RRMS patients with Gd+ lesions. PMID:23402677

  17. Tongluo Xingnao Effervescent Tablet preserves mitochondrial energy metabolism and attenuates cognition deficits in APPswe/PS1De9 mice.

    PubMed

    Dai, Yuan; Ma, Tao; Ren, Xiangyi; Wei, Jiangping; Fu, Wenjun; Ma, Yuntong; Xu, Shijun; Zhang, Zhanjun

    2016-09-01

    Tongluo Xingnao Effervescent Tablet (TXET), a traditional Chinese herbal formula composed of Ligusticum chuanxiong hor, Scutellaria baicalensis Georgi and Angelica sinensis, has been widely used to treat Alzheimer's disease (AD) and related dementias for decades in China. In the present study, we investigated the effects of TXET on mitochondrial function, energy metabolism and cognitive amelioration in the APPswe/PS1De9 transgenetic mouse model of AD. The energy charge and phosphocreatine, activity of the mitochondrial electron transport chain complexes, mitochondrial membrane potential, activity of Na(+)-K(+) ATPase and the expression levels of Bcl-2 and Bax in the brains were measured, respectively. TXET exhibits significant protection on mitochondrial function and energy supply in addition to ameliorating cognitive decline in APPswe/PS1De9 mice. TXET rescues mitochondrial function by increasing the mitochondrial membrane potential, energy charge levels, activity of respiratory chain complexes and Na(+)-K(+) ATPase activity. These findings suggest that TXET may attenuate cognition impairment through the restoration of mitochondrial function and energy metabolism in the brains in APPswe/PS1De9 mice. PMID:27461792

  18. Sensation-to-Cognition Cortical Streams in Attention-Deficit/Hyperactivity Disorder

    PubMed Central

    Carmona, Susana; Hoekzema, Elseline; Castellanos, Francisco X.; García-García, David; Lage-Castellanos, Agustín; Dijk, Koene R.A.Van; Navas-Sánchez, Francisco J.; Martínez, Kenia; Desco, Manuel; Sepulcre, Jorge

    2015-01-01

    We sought to determine whether functional connectivity streams that link sensory, attentional, and higher-order cognitive circuits are atypical in attention-deficit/hyperactivity disorder (ADHD). We applied a graph-theory method to the resting-state functional magnetic resonance imaging data of 120 children with ADHD and 120 age-matched typically developing children (TDC). Starting in unimodal primary cortex—visual, auditory, and somatosensory—we used stepwise functional connectivity to calculate functional connectivity paths at discrete numbers of relay stations (or link-step distances). First, we characterized the functional connectivity streams that link sensory, attentional, and higher-order cognitive circuits in TDC and found that systems do not reach the level of integration achieved by adults. Second, we searched for stepwise functional connectivity differences between children with ADHD and TDC. We found that, at the initial steps of sensory functional connectivity streams, patients display significant enhancements of connectivity degree within neighboring areas of primary cortex, while connectivity to attention-regulatory areas is reduced. Third, at subsequent link-step distances from primary sensory cortex, children with ADHD show decreased connectivity to executive processing areas and increased degree of connections to default mode regions. Fourth, in examining medication histories in children with ADHD, we found that children medicated with psychostimulants present functional connectivity streams with higher degree of connectivity to regions subserving attentional and executive processes compared to medication-naïve children. We conclude that predominance of local sensory processing and lesser influx of information to attentional and executive regions may reduce the ability to organize and control the balance between external and internal sources of information in ADHD. PMID:25821110

  19. Sensation-to-cognition cortical streams in attention-deficit/hyperactivity disorder.

    PubMed

    Carmona, Susana; Hoekzema, Elseline; Castellanos, Francisco X; García-García, David; Lage-Castellanos, Agustín; Van Dijk, Koene R A; Navas-Sánchez, Francisco J; Martínez, Kenia; Desco, Manuel; Sepulcre, Jorge

    2015-07-01

    We sought to determine whether functional connectivity streams that link sensory, attentional, and higher-order cognitive circuits are atypical in attention-deficit/hyperactivity disorder (ADHD). We applied a graph-theory method to the resting-state functional magnetic resonance imaging data of 120 children with ADHD and 120 age-matched typically developing children (TDC). Starting in unimodal primary cortex-visual, auditory, and somatosensory-we used stepwise functional connectivity to calculate functional connectivity paths at discrete numbers of relay stations (or link-step distances). First, we characterized the functional connectivity streams that link sensory, attentional, and higher-order cognitive circuits in TDC and found that systems do not reach the level of integration achieved by adults. Second, we searched for stepwise functional connectivity differences between children with ADHD and TDC. We found that, at the initial steps of sensory functional connectivity streams, patients display significant enhancements of connectivity degree within neighboring areas of primary cortex, while connectivity to attention-regulatory areas is reduced. Third, at subsequent link-step distances from primary sensory cortex, children with ADHD show decreased connectivity to executive processing areas and increased degree of connections to default mode regions. Fourth, in examining medication histories in children with ADHD, we found that children medicated with psychostimulants present functional connectivity streams with higher degree of connectivity to regions subserving attentional and executive processes compared to medication-naïve children. We conclude that predominance of local sensory processing and lesser influx of information to attentional and executive regions may reduce the ability to organize and control the balance between external and internal sources of information in ADHD. PMID:25821110

  20. Flupirtine attenuates chronic restraint stress-induced cognitive deficits and hippocampal apoptosis in male mice.

    PubMed

    Huang, Pengcheng; Li, Cai; Fu, Tianli; Zhao, Dan; Yi, Zhen; Lu, Qing; Guo, Lianjun; Xu, Xulin

    2015-07-15

    Chronic restraint stress (CRS) causes hippocampal neurodegeneration and hippocampus-dependent cognitive deficits. Flupirtine represents neuroprotective effects and we have previously shown that flupirtine can protect against memory impairment induced by acute stress. The present study aimed to investigate whether flupirtine could alleviate spatial learning and memory impairment and hippocampal apoptosis induced by CRS. CRS mice were restrained in well-ventilated Plexiglass tubes for 6h daily beginning from 10:00 to 16:00 for 21 consecutive days. Mice were injected with flupirtine (10mg/kg and 25mg/kg) or vehicle (10% DMSO) 30min before restraint stress for 21 days. After stressor cessation, the spatial learning and memory, dendritic spine density, injured neurons and the levels of Bcl-2, Bax, p-Akt, p-GSK-3β, p-Erk1/2 and synaptophysin of hippocampal tissues were examined. Our results showed that flupirtine significantly prevented spatial learning and memory impairment induced by CRS in the Morris water maze. In addition, flupirtine (10mg/kg and 25mg/kg) treatment alleviated neuronal apoptosis and the reduction of dendritic spine density and synaptophysin expression in the hippocampal CA1 region of CRS mice. Furthermore, flupirtine (10mg/kg and 25mg/kg) treatment significantly decreased the expression of Bax and increased the p-Akt and p-GSK-3β, and flupirtine (25mg/kg) treatment up-regulated the p-Erk1/2 in the hippocampus of CRS mice. These results suggested that flupirtine exerted protective effects on the CRS-induced cognitive impairment and hippocampal neuronal apoptosis, which is possibly associated with the activation of Akt/GSK-3β and Erk1/2 signaling pathways. PMID:25869780

  1. Hypercholesterolemic diet applied to rat dams protects their offspring against cognitive deficits. Simulated neonatal anoxia model.

    PubMed

    Bohr, Iwo

    2004-09-30

    There is accumulating data suggesting a neuroprotective activity of cholesterol, especially in stroke and Alzheimer's disease (AD). In the present study, a protective activity of this lipid in simulated neonatal anoxia was investigated. Rats were subjected to high cholesterol by feeding their dams with a diet enriched with cholesterol. Half of these rats were subjected to anoxia. One and a half months later, the rats were tested for their ability to acquire a spatial memory, one group on the linear maze and the other on the Morris water maze. After these assessments, the level of total plasma cholesterol was measured. Rats from dams subjected to neonatal anoxia on standard diet performed worse than control rats in both types of behavioral experiments, whereas anoxic rats from dams were housed on hypercholesterolemic diet performed as control animals. It suggests that dietetic cholesterol applied by their dams protected rats against cognitive deficits elicited by neonatal anoxia. Furthermore, offspring of anoxic rats housed on standard diet had elevated levels of blood cholesterol in relation to control animals. Generally, anoxia affected the concentration of this lipid much stronger than hypercholesterolemic diet of their dams. It might mean that the anoxia-related rise of cholesterol could be involved in physiological phenomenon being an adaptive response to neurotoxic processes. This concept is discussed in relation to pathological mechanisms in AD. PMID:15327920

  2. MDM2 inhibition rescues neurogenic and cognitive deficits in a mouse model of fragile X syndrome.

    PubMed

    Li, Yue; Stockton, Michael E; Bhuiyan, Ismat; Eisinger, Brian E; Gao, Yu; Miller, Jessica L; Bhattacharyya, Anita; Zhao, Xinyu

    2016-04-27

    Fragile X syndrome, the most common form of inherited intellectual disability, is caused by loss of the fragile X mental retardation protein (FMRP). However, the mechanism remains unclear, and effective treatment is lacking. We show that loss of FMRP leads to activation of adult mouse neural stem cells (NSCs) and a subsequent reduction in the production of neurons. We identified the ubiquitin ligase mouse double minute 2 homolog (MDM2) as a target of FMRP. FMRP regulates Mdm2 mRNA stability, and loss of FMRP resulted in elevated MDM2 mRNA and protein. Further, we found that increased MDM2 expression led to reduced P53 expression in adult mouse NSCs, leading to alterations in NSC proliferation and differentiation. Treatment with Nutlin-3, a small molecule undergoing clinical trials for treating cancer, specifically inhibited the interaction of MDM2 with P53, and rescued neurogenic and cognitive deficits in FMRP-deficient mice. Our data reveal a potential regulatory role for FMRP in the balance between adult NSC activation and quiescence, and identify a potential new treatment for fragile X syndrome. PMID:27122614

  3. Inhibitory Interneuron Deficit Links Altered Network Activity and Cognitive Dysfunction in Alzheimer Model

    PubMed Central

    Verret, Laure; Mann, Edward O.; Hang, Giao B.; Barth, Albert M. I.; Cobos, Inma; Ho, Kaitlyn; Devidze, Nino; Masliah, Eliezer; Kreitzer, Anatol C.; Mody, Istvan; Mucke, Lennart; Palop, Jorge J.

    2012-01-01

    SUMMARY Alzheimer's disease (AD) results in cognitive decline and altered network activity, but the mechanisms are unknown. To identify such mechanisms, we studied human amyloid precursor protein (hAPP) transgenic mice, which simulate key aspects of AD. Electroencephalographic recordings in hAPP mice revealed spontaneous epileptiform discharges, indicating network hypersynchrony, primarily during reduced gamma oscillatory activity. Because this oscillatory rhythm is generated by inhibitory parvalbumin (PV) cells, network dysfunction in hAPP mice might arise from impaired PV cells. Supporting this hypothesis, hAPP mice and AD patients had decreased levels of the interneuron-specific and PV cell–predominant voltage-gated sodium channel subunit Nav1.1. Restoring Nav1.1 levels in hAPP mice by Nav1.1-BAC expression increased inhibitory synaptic activity and gamma oscillations and reduced hypersynchrony, memory deficits, and premature mortality. We conclude that reduced Nav1.1 levels and PV cell dysfunction critically contribute to abnormalities in oscillatory rhythms, network synchrony, and memory in hAPP mice and possibly in AD. PMID:22541439

  4. Thalamic damage in periventricular leukomalacia: novel pathologic observations relevant to cognitive deficits in survivors of prematurity.

    PubMed

    Ligam, Poonam; Haynes, Robin L; Folkerth, Rebecca D; Liu, Lena; Yang, May; Volpe, Joseph J; Kinney, Hannah C

    2009-05-01

    Despite major advances in the long-term survival of premature infants, cognitive deficits occur in 30-50% of very preterm (<32 gestational weeks) survivors. Impaired working memory and attention despite average global intelligence are central to the academic difficulties of the survivors. Periventricular leukomalacia (PVL), characterized by periventricular necrosis and diffuse gliosis in the cerebral white matter, is the major brain pathology in preterm infants. We tested the novel hypothesis that pathology in thalamic nuclei critical for working memory and attention, i.e. mediodorsal nucleus and reticular nucleus, respectively, occurs in PVL. In 22 PVL cases (gestational age 32.5 +/- 4.8 wk) and 16 non-PVL controls (36.7 +/- 5.2 wk) who died within infancy, the incidence of thalamic pathology was significantly higher in PVL cases (59%; 13/22) compared with controls (19%; 3/16) (p = 0.01), with substantial involvement of the mediodorsal, and reticular nuclei in PVL. The prevention of thalamic damage may be required for the eradication of defects in survivors with PVL. PMID:19127204

  5. Hippocampal Aβ expression, but not phosphorylated tau, predicts cognitive deficits following repeated peripheral poly I:C administration.

    PubMed

    White, J D; Eimerbrink, M J; Hayes, H B; Hardy, A; Van Enkevort, E A; Peterman, J L; Chumley, M J; Boehm, G W

    2016-10-15

    Alzheimer's disease is marked by the accumulation of the amyloid-beta (Aβ) peptide, and increases in phosphorylation of the microtubule associated protein, tau. Changes in these proteins are considered responsible, in part, for the progressive neuronal degeneration and cognitive deficits seen in AD. We examined the effect of repeated consecutive peripheral poly I:C injections on cognitive deficits, central Aβ, and phosphorylated tau accumulation, following three treatment durations: 7, 14, and 21 days. Forty-eight hours after the final injection, animals were trained in a contextual fear-conditioning paradigm, and tested 24h later. Immediately after testing, the hippocampus was collected to quantify Aβ and phosphorylated tau accumulation. Results showed that, although poly I:C-induced Aβ was significantly elevated at all time points examined, poly I:C only disrupted cognition after 14 and 21 days of administration. Moreover, elevations in phosphorylated tau were not seen until the 14-day time point. Interestingly, phosphorylated tau expression then declined at the 21-day time point. Finally, we demonstrated that Aβ levels are a stronger predictor of cognitive dysfunction, explaining 37% of the variance, whereas phosphorylated tau levels only accounted for 0.2%. Taken together, these results support the hypothesis that inflammation-induced elevation in Aβ disrupts cognition, independently of phosphorylated tau, and suggest that long-term administration of poly I:C may provide a model to investigate the contribution of long-term inflammation toward the development of Alzheimer's-like pathology. PMID:27449203

  6. Concussive Brain Trauma in the Mouse Results in Acute Cognitive Deficits and Sustained Impairment of Axonal Function

    PubMed Central

    Creed, Jennifer A.; DiLeonardi, Ann Mae; Fox, Douglas P.; Tessler, Alan R.

    2011-01-01

    Abstract Concussive brain injury (CBI) accounts for approximately 75% of all brain-injured people in the United States each year and is particularly prevalent in contact sports. Concussion is the mildest form of diffuse traumatic brain injury (TBI) and results in transient cognitive dysfunction, the neuropathologic basis for which is traumatic axonal injury (TAI). To evaluate the structural and functional changes associated with concussion-induced cognitive deficits, adult mice were subjected to an impact on the intact skull over the midline suture that resulted in a brief apneic period and loss of the righting reflex. Closed head injury also resulted in an increase in the wet weight:dry weight ratio in the cortex suggestive of edema in the first 24 h, and the appearance of Fluoro-Jade-B-labeled degenerating neurons in the cortex and dentate gyrus of the hippocampus within the first 3 days post-injury. Compared to sham-injured mice, brain-injured mice exhibited significant deficits in spatial acquisition and working memory as measured using the Morris water maze over the first 3 days (p<0.001), but not after the fourth day post-injury. At 1 and 3 days post-injury, intra-axonal accumulation of amyloid precursor protein in the corpus callosum and cingulum was accompanied by neurofilament dephosphorylation, impaired transport of Fluoro-Gold and synaptophysin, and deficits in axonal conductance. Importantly, deficits in retrograde transport and in action potential of myelinated axons continued to be observed until 14 days post-injury, at which time axonal degeneration was apparent. These data suggest that despite recovery from acute cognitive deficits, concussive brain trauma leads to axonal degeneration and a sustained perturbation of axonal function. PMID:21299360

  7. Fingolimod protects against neonatal white matter damage and long-term cognitive deficits caused by hyperoxia.

    PubMed

    Serdar, Meray; Herz, Josephine; Kempe, Karina; Lumpe, Katharina; Reinboth, Barbara S; Sizonenko, Stéphane V; Hou, Xinlin; Herrmann, Ralf; Hadamitzky, Martin; Heumann, Rolf; Hansen, Wiebke; Sifringer, Marco; van de Looij, Yohan; Felderhoff-Müser, Ursula; Bendix, Ivo

    2016-02-01

    Cerebral white matter injury is a leading cause of adverse neurodevelopmental outcome in prematurely born infants involving cognitive deficits in later life. Despite increasing knowledge about the pathophysiology of perinatal brain injury, therapeutic options are limited. In the adult demyelinating disease multiple sclerosis the sphingosine-1-phosphate (S1P) receptor modulating substance fingolimod (FTY720) has beneficial effects. Herein, we evaluated the neuroprotective potential of FTY720 in a neonatal model of oxygen-toxicity, which is associated with hypomyelination and impaired neuro-cognitive outcome. A single dose of FTY720 (1mg/kg) at the onset of neonatal hyperoxia (24h 80% oxygen on postnatal day 6) resulted in improvement of neuro-cognitive development persisting into adulthood. This was associated with reduced microstructural white matter abnormalities 4 months after the insult. In search of the underlying mechanisms potential non-classical (i.e. lymphocyte-independent) pathways were analysed shortly after the insult, comprising modulation of oxidative stress and local inflammatory responses as well as myelination, oligodendrocyte degeneration and maturation. Treatment with FTY720 reduced hyperoxia-induced oxidative stress, microglia activation and associated pro-inflammatory cytokine expression. In vivo and in vitro analyses further revealed that oxygen-induced hypomyelination is restored to control levels, which was accompanied by reduced oligodendrocyte degeneration and enhanced maturation. Furthermore, hyperoxia-induced elevation of S1P receptor 1 (S1P1) protein expression on in vitro cultured oligodendrocyte precursor cells was reduced by activated FTY720 and protection from degeneration is abrogated after selective S1P1 blockade. Finally, FTY720s' classical mode of action (i.e. retention of immune cells within peripheral lymphoid organs) was analysed demonstrating that FTY720 diminished circulating lymphocyte counts independent from hyperoxia

  8. Cerebrolysin modulates pronerve growth factor/nerve growth factor ratio and ameliorates the cholinergic deficit in a transgenic model of Alzheimer's disease.

    PubMed

    Ubhi, Kiren; Rockenstein, Edward; Vazquez-Roque, Ruben; Mante, Michael; Inglis, Chandra; Patrick, Christina; Adame, Anthony; Fahnestock, Margaret; Doppler, Edith; Novak, Philip; Moessler, Herbert; Masliah, Eliezer

    2013-02-01

    Alzheimer's disease (AD) is characterized by degeneration of neocortex, limbic system, and basal forebrain, accompanied by accumulation of amyloid-β and tangle formation. Cerebrolysin (CBL), a peptide mixture with neurotrophic-like effects, is reported to improve cognition and activities of daily living in patients with AD. Likewise, CBL reduces synaptic and behavioral deficits in transgenic (tg) mice overexpressing the human amyloid precursor protein (hAPP). The neuroprotective effects of CBL may involve multiple mechanisms, including signaling regulation, control of APP metabolism, and expression of neurotrophic factors. We investigate the effects of CBL in the hAPP tg model of AD on levels of neurotrophic factors, including pro-nerve growth factor (NGF), NGF, brain-derived neurotrophic factor (BDNF), neurotropin (NT)-3, NT4, and ciliary neurotrophic factor (CNTF). Immunoblot analysis demonstrated that levels of pro-NGF were increased in saline-treated hAPP tg mice. In contrast, CBL-treated hAPP tg mice showed levels of pro-NGF comparable to control and increased levels of mature NGF. Consistently with these results, immunohistochemical analysis demonstrated increased NGF immunoreactivity in the hippocampus of CBL-treated hAPP tg mice. Protein levels of other neurotrophic factors, including BDNF, NT3, NT4, and CNTF, were unchanged. mRNA levels of NGF and other neurotrophins were also unchanged. Analysis of neurotrophin receptors showed preservation of the levels of TrKA and p75(NTR) immunoreactivity per cell in the nucleus basalis. Cholinergic cells in the nucleus basalis were reduced in the saline-treated hAPP tg mice, and treatment with CBL reduced these cholinergic deficits. These results suggest that the neurotrophic effects of CBL might involve modulation of the pro-NGF/NGF balance and a concomitant protection of cholinergic neurons. PMID:23152192

  9. Enriched endogenous n-3 polyunsaturated fatty acids alleviate cognitive and behavioral deficits in a mice model of Alzheimer's disease.

    PubMed

    Wu, Kefeng; Gao, Xiang; Shi, Baoyan; Chen, Shiyu; Zhou, Xin; Li, Zhidong; Gan, Yuhong; Cui, Liao; Kang, Jing Xuan; Li, Wende; Huang, Ren

    2016-10-01

    Alzheimer's disease (AD) is a progressive neurodegenerative disorder that accompanied by memory deficits and neuropsychiatric dysfunction. Omega-3 polyunsaturated fatty acids (n-3 PUFAs) have seemly therapeutic potential in AD, but the benefit of n-3 PUFAs is still in debates. Here, we employed a transgenic mice carry fat-1 gene to encode n-3 desaturase from Caenorhabditis elegans, which increase endogenous n-3 PUFAs by converting n-6 PUFAs to n-3 PUFAs crossed with amyloid precursor protein (APP) Tg mice to evaluate the protective effects of endogenous n-3 PUFAs on cognitive and behavioral deficits of APP Tg mice. We fed APP, APP/fat-1 and fat-1 mice with n-6 PUFAs rich diet. Brain tissues were collected at 3, 9 and 12 months for fatty acid and gene expression analysis, histology and protein assays. Morris Water Maze Test, open field test and elevated plus maze test were performed to measure the behavior capability. From the results, the expression of fat-1 transgene increased cortical n-3: n-6 PUFAs ratio and n-3 PUFAs concentrations, and sensorimotor dysfunction and cognitive deficits in AD were significantly less severe in APP/fat-1 mice with endogenous n-3 PUFAs than in APP mice controls. The protection against disturbance of spontaneous motor activity and cognitive deficits in AD was strongly correlated with increased n-3: n-6 PUFAs ratio and endogenous n-3 PUFAs, reduced APP generation, inhibited amyloid β peptide aggregation, suppressed nuclear factor-kappa B and astroglia activation, and reduced death of neurons in the cortex of APP/fat-1 mice compared with APP mice controls. In conclusion, our study demonstrates that an available medication with the maintenance of enriched n-3 PUFAs in the brain could slow down cognitive decline and prevent neuropsychological disorder in AD. PMID:27474225

  10. Cognitive deficits caused by a disease-mutation in the α3 Na(+)/K(+)-ATPase isoform.

    PubMed

    Holm, Thomas Hellesøe; Isaksen, Toke Jost; Glerup, Simon; Heuck, Anders; Bøttger, Pernille; Füchtbauer, Ernst-Martin; Nedergaard, Steen; Nyengaard, Jens Randel; Andreasen, Mogens; Nissen, Poul; Lykke-Hartmann, Karin

    2016-01-01

    The Na(+)/K(+)-ATPases maintain Na(+) and K(+) electrochemical gradients across the plasma membrane, a prerequisite for electrical excitability and secondary transport in neurons. Autosomal dominant mutations in the human ATP1A3 gene encoding the neuron-specific Na(+)/K(+)-ATPase α3 isoform cause different neurological diseases, including rapid-onset dystonia-parkinsonism (RDP) and alternating hemiplegia of childhood (AHC) with overlapping symptoms, including hemiplegia, dystonia, ataxia, hyperactivity, epileptic seizures, and cognitive deficits. Position D801 in the α3 isoform is a mutational hotspot, with the D801N, D801E and D801V mutations causing AHC and the D801Y mutation causing RDP or mild AHC. Despite intensive research, mechanisms underlying these disorders remain largely unknown. To study the genotype-to-phenotype relationship, a heterozygous knock-in mouse harboring the D801Y mutation (α3(+/D801Y)) was generated. The α3(+/D801Y) mice displayed hyperactivity, increased sensitivity to chemically induced epileptic seizures and cognitive deficits. Interestingly, no change in the excitability of CA1 pyramidal neurons in the α3(+/D801Y) mice was observed. The cognitive deficits were rescued by administration of the benzodiazepine, clonazepam, a GABA positive allosteric modulator. Our findings reveal the functional significance of the Na(+)/K(+)-ATPase α3 isoform in the control of spatial learning and memory and suggest a link to GABA transmission. PMID:27549929

  11. Cognitive deficits caused by a disease-mutation in the α3 Na+/K+-ATPase isoform

    PubMed Central

    Holm, Thomas Hellesøe; Isaksen, Toke Jost; Glerup, Simon; Heuck, Anders; Bøttger, Pernille; Füchtbauer, Ernst-Martin; Nedergaard, Steen; Nyengaard, Jens Randel; Andreasen, Mogens; Nissen, Poul; Lykke-Hartmann, Karin

    2016-01-01

    The Na+/K+-ATPases maintain Na+ and K+ electrochemical gradients across the plasma membrane, a prerequisite for electrical excitability and secondary transport in neurons. Autosomal dominant mutations in the human ATP1A3 gene encoding the neuron-specific Na+/K+-ATPase α3 isoform cause different neurological diseases, including rapid-onset dystonia-parkinsonism (RDP) and alternating hemiplegia of childhood (AHC) with overlapping symptoms, including hemiplegia, dystonia, ataxia, hyperactivity, epileptic seizures, and cognitive deficits. Position D801 in the α3 isoform is a mutational hotspot, with the D801N, D801E and D801V mutations causing AHC and the D801Y mutation causing RDP or mild AHC. Despite intensive research, mechanisms underlying these disorders remain largely unknown. To study the genotype-to-phenotype relationship, a heterozygous knock-in mouse harboring the D801Y mutation (α3+/D801Y) was generated. The α3+/D801Y mice displayed hyperactivity, increased sensitivity to chemically induced epileptic seizures and cognitive deficits. Interestingly, no change in the excitability of CA1 pyramidal neurons in the α3+/D801Y mice was observed. The cognitive deficits were rescued by administration of the benzodiazepine, clonazepam, a GABA positive allosteric modulator. Our findings reveal the functional significance of the Na+/K+-ATPase α3 isoform in the control of spatial learning and memory and suggest a link to GABA transmission. PMID:27549929

  12. Allicin improves endoplasmic reticulum stress-related cognitive deficits via PERK/Nrf2 antioxidative signaling pathway.

    PubMed

    Zhu, Yao-Feng; Li, Xian-Hui; Yuan, Zhi-Peng; Li, Chun-Yan; Tian, Rong-Bo; Jia, Wei; Xiao, Zhu-Ping

    2015-09-01

    Endoplasmic reticulum (ER) stress is involved in neurodegenerative diseases including Alzheimer's disease (AD), in which dysregulation of double-stranded RNA-dependent protein kinase (PKR)-like ER-resident kinase (PERK) is considered to play a critical role. Allicin, a garlic extract, has been demonstrated a protective role in AD model. The present study was designed to investigate the possible protective effect of allicin on ER stress-induced cognitive deficits and underlying mechanisms in rats. In this study, 72h of lateral ventricular infusion of tunicamycin (TM), an ER stress stimulator, induced significant cognitive deficits. TM increased tau phosphorylation, Aβ42 deposit, and oxidative stress, and reduced antioxidative enzymes activity in the hippocampus. TM moderately elevated the expression of PERK and its downstream substrate nuclear factor erythroid-derived 2-like 2 (Nrf2) in the hippocampus. All these impaired changes by TM were significantly improved by allicin pretreatment. Allicin markedly increased PERK and Nrf2 expression in the hippocampus. Thus, our data demonstrate the protective role of allicin in ER stress-related cognitive deficits, and suggest that PERK/Nrf2 antioxidative signaling pathway underlies the action mechanism. PMID:26049013

  13. Rosemary extract improves cognitive deficits in a rats model of repetitive mild traumatic brain injury associated with reduction of astrocytosis and neuronal degeneration in hippocampus.

    PubMed

    Song, Hai; Xu, Lincheng; Zhang, Rongping; Cao, Zhenzhen; Zhang, Huan; Yang, Li; Guo, Zeyun; Qu, Yongqiang; Yu, Jianyun

    2016-05-27

    In this study, we investigated whether Rosemary extract (RE) improved cognitive deficits in repetitive mild Traumatic brain injury (rmTBI) rats and its potential mechanisms. The present results showed that rmTBI caused cognitive deficits, such as increased latency to find platform and decreased time spent in target quadrant in Morris water maze (MWM). These behavioral alterations were accompanying with the increased neuronal degeneration and glial fibrillary acidic protein (GFAP)-positive cells, increased Reactive oxygen species (ROS) generation, decreased activity of Superoxide Dismutase (SOD), Glutathione Peroxidase (GPx) and Catalase (CAT), elevated protein level of IL-1β, IL-6 and TNF-α in hippocampus. Treatment with RE prevented these changes above. Our findings confirmed the effect of rosemary extract on improvement of cognitive deficits and suggested its mechanisms might be mediated by anti-oxidative and anti-inflammatory. Therefore, rosemary extract may be a potential treatment to improve cognitive deficits in rmTBI patients. PMID:27113205

  14. The effect of erythropoietin on cognition in affective disorders - Associations with baseline deficits and change in subjective cognitive complaints.

    PubMed

    Ott, Caroline Vintergaard; Vinberg, Maj; Kessing, Lars V; Miskowiak, Kamilla W

    2016-08-01

    This is a secondary data analysis from our erythropoietin (EPO) trials. We examine (I) whether EPO improves speed of complex cognitive processing across bipolar and unipolar disorder, (II) if objective and subjective baseline cognitive impairment increases patients׳ chances of treatment-efficacy and (III) if cognitive improvement correlates with better subjective cognitive function, quality of life and socio-occupational capacity. Patients with unipolar or bipolar disorder were randomized to eight weekly EPO (N=40) or saline (N=39) infusions. Cognition, mood, quality of life and socio-occupational capacity were assessed at baseline (week 1), after treatment completion (week 9) and at follow-up (week 14). We used repeated measures analysis of covariance to investigate the effect of EPO on speed of complex cognitive processing. With logistic regression, we examined whether baseline cognitive impairment predicted treatment-efficacy. Pearson correlations were used to assess associations between objective and subjective cognition, quality of life and socio-occupational capacity. EPO improved speed of complex cognitive processing across affective disorders at weeks 9 and 14 (p≤0.05). In EPO-treated patients, baseline cognitive impairment increased the odds of treatment-efficacy on cognition at weeks 9 and 14 by a factor 9.7 (95% CI:1.2-81.1) and 9.9 (95% CI:1.1-88.4), respectively (p≤0.04). Subjective cognitive complaints did not affect chances of treatment-efficacy (p≥0.45). EPO-associated cognitive improvement correlated with reduced cognitive complaints but not with quality of life or socio-occupational function. As the analyses were performed post-hoc, findings are only hypothesis-generating. In conclusion, pro-cognitive effects of EPO occurred across affective disorders. Neuropsychological screening for cognitive dysfunction may be warranted in future cognition trials. PMID:27349944

  15. Advantages of the multiple case series approach to the study of cognitive deficits in autism spectrum disorder

    PubMed Central

    Towgood, Karren J.; Meuwese, Julia D.I.; Gilbert, Sam J.; Turner, Martha S.; Burgess, Paul W.

    2009-01-01

    In the neuropsychological case series approach, tasks are administered that tap different cognitive domains, and differences within rather than across individuals are the basis for theorising; each individual is effectively their own control. This approach is a mainstay of cognitive neuropsychology, and is particularly suited to the study of populations with heterogeneous deficits. However it has very rarely been applied to the study of cognitive differences in autism spectrum disorder (ASD). Here, we investigate whether this approach can yield information beyond that given by the typical group study method, when applied to an ASD population. Twenty-one high-functioning adult ASD participants and 22 IQ, age, and gender-matched control participants were administered a large battery of neuropsychological tests that would represent a typical neuropsychological assessment for neurological patients in the United Kingdom. The data were analysed using both group and single-case study methods. The group analysis revealed a limited number of deficits, principally on tests with a large executive function component, with no impairment in more routine abilities such as basic attending, language and perception. Single-case study analysis proved more fruitful revealing evidence of considerable variation in abilities both between and within ASD participants. Both sub-normal and supra-normal performance were observed, with the most defining feature of the ASD group being this variability. We conclude that the use of group-level analysis alone in the study of cognitive deficits in ASD risks missing cognitive characteristics that may be vitally important both theoretically and clinically, and even may be misleading because of averaging artifact. PMID:19580821

  16. Advantages of the multiple case series approach to the study of cognitive deficits in autism spectrum disorder.

    PubMed

    Towgood, Karren J; Meuwese, Julia D I; Gilbert, Sam J; Turner, Martha S; Burgess, Paul W

    2009-11-01

    In the neuropsychological case series approach, tasks are administered that tap different cognitive domains, and differences within rather than across individuals are the basis for theorising; each individual is effectively their own control. This approach is a mainstay of cognitive neuropsychology, and is particularly suited to the study of populations with heterogeneous deficits. However it has very rarely been applied to the study of cognitive differences in autism spectrum disorder (ASD). Here, we investigate whether this approach can yield information beyond that given by the typical group study method, when applied to an ASD population. Twenty-one high-functioning adult ASD participants and 22 IQ, age, and gender-matched control participants were administered a large battery of neuropsychological tests that would represent a typical neuropsychological assessment for neurological patients in the United Kingdom. The data were analysed using both group and single-case study methods. The group analysis revealed a limited number of deficits, principally on tests with a large executive function component, with no impairment in more routine abilities such as basic attending, language and perception. Single-case study analysis proved more fruitful revealing evidence of considerable variation in abilities both between and within ASD participants. Both sub-normal and supra-normal performance were observed, with the most defining feature of the ASD group being this variability. We conclude that the use of group-level analysis alone in the study of cognitive deficits in ASD risks missing cognitive characteristics that may be vitally important both theoretically and clinically, and even may be misleading because of averaging artifact. PMID:19580821

  17. Cognitive Deficits, Changes in Synaptic Function, and Brain Pathology in a Mouse Model of Normal Aging1,2,3

    PubMed Central

    Wu, Tiffany; Hanson, Jesse E.; Alam, Nazia M.; Ngu, Hai; Lauffer, Benjamin E.; Lin, Han H.; Dominguez, Sara L.; Reeder, Jens; Tom, Jennifer; Steiner, Pascal; Foreman, Oded; Prusky, Glen T.

    2015-01-01

    Abstract Age is the main risk factor for sporadic Alzheimer’s disease. Yet, cognitive decline in aged rodents has been less well studied, possibly due to concomitant changes in sensory or locomotor function that can complicate cognitive tests. We tested mice that were 3, 11, and 23 months old in cognitive, sensory, and motor measures, and postmortem measures of gliosis and neural activity (c-Fos). Hippocampal synaptic function was also examined. While age-related impairments were detectable in tests of spatial memory, greater age-dependent effects were observed in tests of associative learning [active avoidance (AA)]. Gross visual function was largely normal, but startle responses to acoustic stimuli decreased with increased age, possibly due to hearing impairments. Therefore, a novel AA variant in which light alone served as the conditioning stimuli was used. Age-related deficits were again observed. Mild changes in vision, as measured by optokinetic responses, were detected in 19- versus 4-month-old mice, but these were not correlated to AA performance. Thus, deficits in hearing or vision are unlikely to account for the observed deficits in cognitive measures. Increased gliosis was observed in the hippocampal formation at older ages. Age-related changes in neural function and plasticity were observed with decreased c-Fos in the dentate gyrus, and decreased synaptic strength and paired-pulse facilitation in CA1 slices. This work, which carefully outlines age-dependent impairments in cognitive and synaptic function, c-Fos activity, and gliosis during normal aging in the mouse, suggests robust translational measures that will facilitate further study of the biology of aging. PMID:26473169

  18. Training of attentional control in mild cognitive impairment with executive deficits: results from a double-blind randomised controlled study.

    PubMed

    Gagnon, Lyssa G; Belleville, Sylvie

    2012-01-01

    This study evaluated the efficacy of a cognitive intervention for attentional control in older adults with mild cognitive impairment (MCI) with an executive deficit. It also sought to verify if the benefits of training generalised to primary and secondary outcome measures. Participants (n = 24) were randomly assigned to a training programme or active control condition. The experimental group completed a computer-based training programme involving Variable Priority (VP) coordination of both components of a dual task, to which was added a self-regulatory strategy designed to augment meta-cognition. The active control group performed Fixed Priority (FP) training: rote practice of the same dual task involving a visual detection task combined with an alpha-arithmetic task. Six one-hour training sessions were held three times a week for two weeks. Participants were tested pre- and post-training to detect improvement and transfer effects. Both groups improved on the visual detection and alpha-arithmetic tasks completed in focused attention, but only participants receiving VP training significantly improved their dual-task cost in accuracy for the visual detection task. As for transfer effects, both FP and VP training produced improvements on select outcome measures: focused attention, speed of processing, and switching abilities. No reliable advantage for generalisability of VP over FP training was found. Overall, these findings indicate that cognitive intervention may improve attentional control in persons with MCI and an executive deficit. PMID:22712452

  19. Mori Folium and Mori Fructus Mixture Attenuates High-Fat Diet-Induced Cognitive Deficits in Mice

    PubMed Central

    Jeong, Hyun Uk; Park, Gunhyuk; Kim, Hocheol; Lim, Yunsook; Oh, Myung Sook

    2015-01-01

    Obesity has become a global health problem, contributing to various diseases including diabetes, hypertension, cancer, and dementia. Increasing evidence suggests that obesity can also cause neuronal damage, long-term memory loss, and cognitive impairment. The leaves and the fruits of Morus alba L., containing active phytochemicals, have been shown to possess antiobesity and hypolipidemic properties. Thus, in the present study, we assessed their effects on cognitive functioning in mice fed a high-fat diet by performing immunohistochemistry, using antibodies against c-Fos, synaptophysin, and postsynaptic density protein 95 and a behavioral test. C57BL/6 mice fed a high-fat diet for 21 weeks exhibited increased body weight, but mice coadministered an optimized Mori Folium and Mori Fructus extract mixture (2 : 1; MFE) for the final 12 weeks exhibited significant body weight loss. Additionally, obese mice exhibited not only reduced neural activity, but also decreased presynaptic and postsynaptic activities, while MFE-treated mice exhibited recovery of these activities. Finally, cognitive deficits induced by the high-fat diet were recovered by cotreatment with MFE in the novel object recognition test. Our findings suggest that the antiobesity effects of MFE resulted in recovery of the cognitive deficits induced by the high-fat diet by regulation of neural and synaptic activities. PMID:25945108

  20. Prenatal exposure to vapors of gasoline-ethanol blends causes few cognitive deficits in adult rats.

    PubMed

    Oshiro, W M; Beasley, T E; McDaniel, K L; Evansky, P A; Martin, S A; Moser, V C; Gilbert, M E; Bushnell, P J

    2015-01-01

    any choice reaction time measure. Finally, no response inhibition deficit was observed in a differential reinforcement of low rate (DRL) response schedule in males or females in the E15 or E85 experiments. In summary, prenatal exposure to these fuel blends produced few deficits in adult offspring on these cognitive tests. Significant effects found during a water maze probe trial and choice reaction time tests were observed at vapor concentrations of 6000 ppm or higher, a concentration that is 4-6 orders of magnitude higher than those associated with normal automotive fueling operations and garages. Similar effects were not consistently observed in a previous study of inhaled ethanol, and thus these effects cannot be attributed to the concentration of ethanol in the mixture. PMID:25876165

  1. Chronic behavioral and cognitive deficits in a rat survival model of paraoxon toxicity

    PubMed Central

    Deshpande, Laxmikant S.; Phillips, Kristin; Huang, Beverly; DeLorenzo, Robert J.

    2014-01-01

    Organophosphate (OP) compounds, including paraoxon (POX), are similar to nerve agents such as sarin. There is a growing concern that OP agents could be weaponized to cause mass civilian causalities. We have developed a rodent survival model of POX toxicity that is being used to evaluate chronic morbidity and to screen for medical countermeasures against severe OP exposure. It is well known that the survivors of nerve gas and chronic OP exposure exhibit neurobehavioral deficits such as mood changes, depression, and memory impairments. In this study we investigated whether animals surviving severe POX exposure exhibited long-term neurological impairments. POX exposure produced overt signs of cholinergic toxicity. Rats were rescued using an optimized atropine, 2-PAM and diazepam therapy. Surviving rats were studied using established behavioral assays for identifying symptoms of depression and memory impairment 3-months after POX exposure. In the forced swim test, POX rats exhibited increased immobility time indicative of a despair-like state. In the sucrose preference test, POX rats consumed significantly less sucrose water indicating anhedonia-like condition. POX rats also displayed increased anxiety as characterized by significantly lower performance in the open arm of the elevated plus maze. Further, when tested with a novel object recognition paradigm, POX rats exhibited a negative discrimination ratio indicative of impaired recognition memory. The results indicate that this model of survival from severe POX exposure can be employed to study some of the molecular bases for OP-induced chronic behavioral and cognitive comorbidities and develop therapies for their treatment. PMID:25172410

  2. Down syndrome: genes, model systems, and progress towards pharmacotherapies and clinical trials for cognitive deficits.

    PubMed

    Busciglio, J; Capone, G; O'Bryan, J; O'Byran, J P; Gardiner, K J

    2013-01-01

    Down syndrome (DS) is caused by an extra copy of all or part of the long arm of human chromosome 21 (HSA21). While the complete phenotype is both complex, involving most organs and organ systems, and variable in severity among individuals, intellectual disability (ID) is seen in all people with DS and may have the most significant impact on quality of life. Because the worldwide incidence of DS remains at approximately 1 in 1,000 live births, DS is the most common genetic cause of ID. In recent years, there have been important advances in our understanding of the functions of genes encoded by HSA21 and in the number and utility of in vitro and in vivo systems for modeling DS. Of particular importance, several pharmacological treatments have been shown to rescue learning and memory deficits in one mouse model of DS, the Ts65Dn. Because adult mice were used in the majority of these experiments, there is considerable interest in extending the studies to human clinical trials, and a number of trials have been completed, are in progress or are being planned. A recent conference brought together researchers with a diverse array of expertise and interests to discuss (1) the functions of HSA21 genes with relevance to ID in DS, (2) the utility of model systems including Caenorhabditis elegans, zebrafish and mouse, as well as human neural stem cells and induced pluripotent stems cells, for studies relevant to ID in DS, (3) outcome measures used in pharmacological treatment of mouse models of DS and (4) outcome measures suitable for clinical trials for cognition in adults and children with DS. PMID:24008277

  3. Prefrontal cortex cognitive deficits in children treated early and continuously for PKU.

    PubMed

    Diamond, A; Prevor, M B; Callender, G; Druin, D P

    1997-01-01

    To begin to study the importance of dopamine for executive function abilities dependent on prefrontal cortex during early childhood, the present investigation studied children in whom we predicted reduced dopamine in prefrontal cortex but otherwise normal brains. These are children treated early and continuously for the metabolic disorder phenylketonuria (PKU). Untreated PKU is the most common biochemical cause of mental retardation. The root problem is an inability to convert one amino acid, phenylalanine (Phe), into another, tyrosine (Tyr), the precursor of dopamine. Phe levels in the bloodstream soar; Tyr levels fall. Treatment with a diet low in Phe reduces the Phe:Tyr imbalance but cannot eliminate it. We hypothesized that the resultant modest elevation in the ratio of Phe to Tyr in the blood, which results in slightly less Tyr reaching the brain, uniquely affects the cognitive functions dependent on prefrontal cortex because of the special sensitivity of prefrontally projecting dopamine neurons to small decreases in Tyr. In a 4-year longitudinal study, we found that PKU children whose plasma Phe levels were three to five times normal (6-10 mg/dl) performed worse than other PKU children with lower Phe levels, matched controls, their own siblings, and children from the general population on tasks that required the working memory and inhibitory control abilities dependent on dorsolateral prefrontal cortex. The impairment was as evident in our oldest age range (3 1/2-7 years) as it was in the youngest (6-12 months). The higher a child's Phe level, the worse that child's performance. Girls were more adversely affected than boys. The deficit appears to be selective, affecting principally one neural system, since even PKU children with Phe levels three to five times normal performed well on the 13 control tasks. Clinical implications for the treatment of PKU and other neurodevelopmental disorders are discussed. PMID:9421921

  4. Identification of a strategic brain network underlying processing speed deficits in vascular cognitive impairment.

    PubMed

    Duering, Marco; Gonik, Mariya; Malik, Rainer; Zieren, Nikola; Reyes, Sonia; Jouvent, Eric; Hervé, Dominique; Gschwendtner, Andreas; Opherk, Christian; Chabriat, Hugues; Dichgans, Martin

    2013-02-01

    Patients with vascular cognitive impairment (VCI) commonly exhibit deficits in processing speed. This has been attributed to a disruption of frontal-subcortical neuronal circuits by ischemic lesions, but the exact mechanisms and underlying anatomical structures are poorly understood. We set out to identify a strategic brain network for processing speed by applying graph-based data-mining techniques to MRI lesion maps from patients with small vessel disease. We studied 235 patients with CADASIL, a genetic small vessel disease causing pure VCI. Using a probabilistic atlas in standard space we first determined the regional volumes of white matter hyperintensities (WMH) and lacunar lesions (LL) within major white matter tracts. Conditional dependencies between the regional lesion volumes and processing speed were then examined using Bayesian network analysis. Exploratory analysis identified a network of five imaging variables as the best determinant of processing speed. The network included LL in the left anterior thalamic radiation and the left cingulum as well as WMH in the left forceps minor, the left parahippocampal white matter and the left corticospinal tract. Together these variables explained 34% of the total variance in the processing speed score. Structural equation modeling confirmed the findings obtained from the Bayesian models. In summary, using graph-based models we identified a strategic brain network having the highest predictive value for processing speed in our cohort of patients with pure small vessel disease. Our findings confirm and extend previous results showing a role of frontal-subcortical neuronal circuits, in particular dorsolateral prefrontal and cingulate circuits, in VCI. PMID:23153965

  5. Emotional face recognition deficit in amnestic patients with mild cognitive impairment: behavioral and electrophysiological evidence

    PubMed Central

    Yang, Linlin; Zhao, Xiaochuan; Wang, Lan; Yu, Lulu; Song, Mei; Wang, Xueyi

    2015-01-01

    Amnestic mild cognitive impairment (MCI) has been conceptualized as a transitional stage between healthy aging and Alzheimer’s disease. Thus, understanding emotional face recognition deficit in patients with amnestic MCI could be useful in determining progression of amnestic MCI. The purpose of this study was to investigate the features of emotional face processing in amnestic MCI by using event-related potentials (ERPs). Patients with amnestic MCI and healthy controls performed a face recognition task, giving old/new responses to previously studied and novel faces with different emotional messages as the stimulus material. Using the learning-recognition paradigm, the experiments were divided into two steps, ie, a learning phase and a test phase. ERPs were analyzed on electroencephalographic recordings. The behavior data indicated high emotion classification accuracy for patients with amnestic MCI and for healthy controls. The mean percentage of correct classifications was 81.19% for patients with amnestic MCI and 96.46% for controls. Our ERP data suggest that patients with amnestic MCI were still be able to undertake personalizing processing for negative faces, but not for neutral or positive faces, in the early frontal processing stage. In the early time window, no differences in frontal old/new effect were found between patients with amnestic MCI and normal controls. However, in the late time window, the three types of stimuli did not elicit any old/new parietal effects in patients with amnestic MCI, suggesting their recollection was impaired. This impairment may be closely associated with amnestic MCI disease. We conclude from our data that face recognition processing and emotional memory is impaired in patients with amnestic MCI. Such damage mainly occurred in the early coding stages. In addition, we found that patients with amnestic MCI had difficulty in post-processing of positive and neutral facial emotions. PMID:26347065

  6. Effects of cariprazine, a novel antipsychotic, on cognitive deficit and negative symptoms in a rodent model of schizophrenia symptomatology.

    PubMed

    Neill, Jo C; Grayson, Ben; Kiss, Béla; Gyertyán, István; Ferguson, Paul; Adham, Nika

    2016-01-01

    Negative symptoms and cognitive impairment associated with schizophrenia are strongly associated with poor functional outcome and reduced quality of life and remain an unmet clinical need. Cariprazine is a dopamine D3/D2 receptor partial agonist with preferential binding to D3 receptors, recently approved by the FDA for the treatment of schizophrenia and manic or mixed episodes associated with bipolar I disorder. The aim of this study is to evaluate effects of cariprazine in an animal model of cognitive deficit and negative symptoms of schizophrenia. Following sub-chronic PCP administration (2mg/kg, IP for 7 days followed by 7 days drug-free), female Lister Hooded rats were administered cariprazine (0.05, 0.1, or 0.25mg/kg, PO) or risperidone (0.16 or 0.1mg/kg, IP) before testing in novel object recognition (NOR), reversal learning (RL), and social interaction (SI) paradigms. As we have consistently demonstrated, sub-chronic PCP significantly impaired behavior in these tests. Deficits were significantly improved by cariprazine, in a dose dependent manner in the operant RL test with efficacy at lower doses in the NOR and SI tests. Locomotor activity was reduced at the highest doses of 0.1mg/kg and 0.25mg/kg in NOR and SI. Risperidone also reversed the PCP-induced deficit in all tests. In conclusion, cariprazine was effective to overcome PCP-induced deficits in cognition and social behavior in a thoroughly validated rat model in tests representing specific symptom domains in schizophrenia patients. These findings support very recent results showing efficacy of cariprazine in the treatment of negative symptoms in schizophrenia patients. PMID:26655189

  7. Long-term oral galactose treatment prevents cognitive deficits in male Wistar rats treated intracerebroventricularly with streptozotocin.

    PubMed

    Salkovic-Petrisic, Melita; Osmanovic-Barilar, Jelena; Knezovic, Ana; Hoyer, Siegfried; Mosetter, Kurt; Reutter, Werner

    2014-02-01

    Basic and clinical research has demonstrated that dementia of sporadic Alzheimer's disease (sAD) type is associated with dysfunction of the insulin-receptor (IR) system followed by decreased glucose transport via glucose transporter GLUT4 and decreased glucose metabolism in brain cells. An alternative source of energy is d-galactose (the C-4-epimer of d-glucose) which is transported into the brain by insulin-independent GLUT3 transporter where it might be metabolized to glucose via the Leloir pathway. Exclusively parenteral daily injections of galactose induce memory deterioration in rodents and are used to generate animal aging model, but the effects of oral galactose treatment on cognitive functions have never been tested. We have investigated the effects of continuous daily oral galactose (200 mg/kg/day) treatment on cognitive deficits in streptozotocin-induced (STZ-icv) rat model of sAD, tested by Morris Water Maze and Passive Avoidance test, respectively. One month of oral galactose treatment initiated immediately after the STZ-icv administration, successfully prevented development of the STZ-icv-induced cognitive deficits. Beneficial effect of oral galactose was independent of the rat age and of the galactose dose ranging from 100 to 300 mg/kg/day. Additionally, oral galactose administration led to the appearance of galactose in the blood. The increase of galactose concentration in the cerebrospinal fluid was several times lower after oral than after parenteral administration of the same galactose dose. Oral galactose exposure might have beneficial effects on learning and memory ability and could be worth investigating for improvement of cognitive deficits associated with glucose hypometabolism in AD. PMID:24055495

  8. Activated Microglia-Induced Deficits in Excitatory Synapses Through IL-1β: Implications for Cognitive Impairment in Sepsis.

    PubMed

    Moraes, Carolina A; Santos, Gabriel; de Sampaio e Spohr, Tania Cristina Leite; D'Avila, Joana C; Lima, Flávia Regina Souza; Benjamim, Claudia Farias; Bozza, Fernando A; Gomes, Flávia Carvalho Alcantara

    2015-08-01

    Recent clinical studies have shown that sepsis survivors may develop long-term cognitive impairments. The cellular and molecular mechanisms involved in these events are not well understood. This study investigated synaptic deficits in sepsis and the involvement of glial cells in this process. Septic animals showed memory impairment and reduced numbers of hippocampal and cortical excitatory synapses, identified by synaptophysin/PSD-95 co-localization, 9 days after disease onset. The behavioral deficits and synaptophysin/PSD-95 co-localization were rescued to normal levels within 30 days post-sepsis. Septic mice presented activation of microglia and reactive astrogliosis, which are hallmarks of brain injury and could be involved in the associated synaptic deficits. We treated neuronal cultures with conditioned medium derived from cultured astrocytes (ACM) and microglia (MCM) that were either non-stimulated or stimulated with lipopolysaccharide (LPS) to investigate the molecular mechanisms underlying synaptic deficits in sepsis. ACM and MCM increased the number of synapses between cortical neurons in vitro, and these effects were antagonized by LPS stimulation. LPS-MCM reduced the number of synapses by 50%, but LPS-ACM increased the number of synapses by 500%. Analysis of the composition of these conditioned media revealed increased levels of IL-1β in LPS-MCM. Furthermore, inhibition of IL-1β signaling through the addition of a soluble IL-1β receptor antagonist (IL-1 Ra) fully prevented the synaptic deficit induced by LPS-MCM. These results suggest that sepsis induces a transient synaptic deficit associated with memory impairments mediated by IL-1β secreted by activated microglia. PMID:25257696

  9. Cognitive deficits in progressive supranuclear palsy, Parkinson's disease, and multiple system atrophy in tests sensitive to frontal lobe dysfunction.

    PubMed Central

    Robbins, T W; James, M; Owen, A M; Lange, K W; Lees, A J; Leigh, P N; Marsden, C D; Quinn, N P; Summers, B A

    1994-01-01

    Groups of patients with idiopathic Parkinson's disease, multiple system atrophy, and progressive supranuclear palsy or Steele-Richardson-Olszewski syndrome, matched for overall clinical disability, were compared using three computerised cognitive tests previously shown to be sensitive to frontal lobe dysfunction. On a test of planning based on the Tower of London task, all three groups were impaired, but in different ways. The groups with palsy and Parkinson's disease were slower in the measure of initial thinking time, whereas the group with multiple system atrophy was only slower in a measure of thinking time subsequent to the first move, resembling patients with frontal lobe damage. On a test of spatial working memory, each group showed deficits relative to their matched control groups, but the three groups differed in their strategy for dealing with this task. On a test of attentional set shifting, each group was again impaired, mainly at the extradimensional shifting stage, but the group with Steele-Richardson-Olszewski syndrome exhibited the greatest deficit. The results are compared with previous findings in patients with Alzheimer's disease or frontal lobe damage. It is concluded that these basal ganglia disorders share a distinctive pattern of cognitive deficits on tests of frontal lobe dysfunction, but there are differences in the exact nature of the impairments, in comparison not only with frontal lobe damage but also with one another. PMID:8301310

  10. Sleep Disturbance and Cognitive Deficits in Bipolar Disorder: Toward An Integrated Examination of Disorder Maintenance and Functional Impairment

    PubMed Central

    Boland, Elaine M.; Alloy, Lauren B.

    2012-01-01

    Bipolar disorder is frequently associated with a number of poor outcomes including, but not limited to, a significant impairment in the ability to return to premorbid levels of occupational and psychosocial functioning, often despite the remission of mood symptoms. Sleep disturbance is an oft-reported residual symptom of manic and depressive episodes that has likewise been associated with the onset of manic episodes. Also present during affective episodes as well as the inter-episode periods are reports of deficits in cognitive functioning, which many reports have shown to play an important role in this persistent disability. Despite the presence of deficits in these two domains of functioning during affective episodes as well as the inter-episode phase, there has been no evaluation of the degree to which these systems may interact to maintain such high rates of functional disability. The aim of this review is to examine evidence for the study of the relationship between sleep disturbance and cognitive impairments in bipolar disorder as well as the ways in which deficits in these domains may work together to maintain functional impairment. PMID:23123569

  11. The Neural Substrates of Cognitive Control Deficits in Autism Spectrum Disorders

    ERIC Educational Resources Information Center

    Solomon, Marjorie; Ozonoff, Sally J.; Ursu, Stefan; Ravizza, Susan; Cummings, Neil; Ly, Stanford; Carter, Cameron S.

    2009-01-01

    Executive function deficits are among the most frequently reported symptoms of autism spectrum disorders (ASDs), however, there have been few functional magnetic resonance imaging (fMRI) studies that investigate the neural substrates of executive function deficits in ASDs, and only one in adolescents. The current study examined cognitive…

  12. The Cognitive Deficits Responsible for Developmental Dyslexia: Review of Evidence for a Selective Visual Attentional Disorder

    ERIC Educational Resources Information Center

    Valdois, Sylviane; Bosse, Marie-Line; Tainturier, Marie-Josephe

    2004-01-01

    There is strong converging evidence suggesting that developmental dyslexia stems from a phonological processing deficit. However, this hypothesis has been challenged by the widely admitted heterogeneity of the dyslexic population, and by several reports of dyslexic individuals with no apparent phonological deficit. In this paper, we discuss the…

  13. Parallels in Cognitive-Perceptual Deficit between Alcoholics and Antisocial Psychiatric Patients.

    ERIC Educational Resources Information Center

    Gorenstein, Ethan E.

    Theorists have hypothesized that alcoholism, antisocial behavior, and childhood hyperactivity are part of a spectrum of disorders that have a common etiologic component, i.e., neuropsychological deficits to the structures (limbic system, frontal lobes) which regulate impulses. To examine the similarities in neuropsychological deficits between…

  14. Comparison of the Recovery Patterns of Language and Cognitive Functions in Patients with Post-Traumatic Language Processing Deficits and in Patients with Aphasia Following a Stroke

    ERIC Educational Resources Information Center

    Vukovic, Mile; Vuksanovic, Jasmina; Vukovic, Irena

    2008-01-01

    In this study we investigated the recovery patterns of language and cognitive functions in patients with post-traumatic language processing deficits and in patients with aphasia following a stroke. The correlation of specific language functions and cognitive functions was analyzed in the acute phase and 6 months later. Significant recovery of the…

  15. Induction of cognitive deficits by immunization with cholinergic cell bodies: the influence of age and integrity of the blood-brain barrier.

    PubMed

    Alroy, G; Chapman, J; Feldon, J; Michaelson, D M

    1991-01-01

    We have recently shown that prolonged immunization of young rats for one year with cholinergic cell bodies (perikarya, PK) purified from Torpedo electric lobe results in the accumulation of IgG in specific brain areas such as the hippocampus and induces behavioral deficits in spatial orientation and short term memory /1, 7/. We presently studied the rate of development of the cognitive deficit in older (12 months old) Sprague Dawley rats which were immunized for periods of up to one year with either Torpedo cholinergic PK or adjuvant (controls). T-maze alternation and Morris swim maze tests revealed a small deficit in the performance of the PK immunized rats after 6 months whereas significant deficits were observed after 12 months of immunization. These results suggest that the duration of immunization is a more significant factor than the age of the animals in the development of the behavioral deficit. In order to examine whether permeability of the blood-brain barrier to IgG influences the rate of development of the cognitive deficit, we disrupted the blood-brain barrier of PK immunized rats by hypercapnia. This treatment repeated weekly for 2 months was found not to accelerate the rate of appearance of deficits in performance of the rats in the T-maze alternation and Morris swim test. These results suggest that penetration of IgG via the blood-brain barrier does not determine the rate of appearance of the cognitive deficits. PMID:1797094

  16. Experimental ‘Jet Lag’ Inhibits Adult Neurogenesis and Produces Long-Term Cognitive Deficits in Female Hamsters

    PubMed Central

    Gibson, Erin M.; Wang, Connie; Tjho, Stephanie; Khattar, Neera; Kriegsfeld, Lance J.

    2010-01-01

    Background Circadian disruptions through frequent transmeridian travel, rotating shift work, and poor sleep hygiene are associated with an array of physical and mental health maladies, including marked deficits in human cognitive function. Despite anecdotal and correlational reports suggesting a negative impact of circadian disruptions on brain function, this possibility has not been experimentally examined. Methodology/Principal Findings In the present study, we investigated whether experimental ‘jet lag’ (i.e., phase advances of the light∶dark cycle) negatively impacts learning and memory and whether any deficits observed are associated with reductions in hippocampal cell proliferation and neurogenesis. Because insults to circadian timing alter circulating glucocorticoid and sex steroid concentrations, both of which influence neurogenesis and learning/memory, we assessed the contribution of these endocrine factors to any observed alterations. Circadian disruption resulted in pronounced deficits in learning and memory paralleled by marked reductions in hippocampal cell proliferation and neurogenesis. Significantly, deficits in hippocampal-dependent learning and memory were not only seen during the period of the circadian disruption, but also persisted well after the cessation of jet lag, suggesting long-lasting negative consequences on brain function. Conclusions/Significance Together, these findings support the view that circadian disruptions suppress hippocampal neurogenesis via a glucocorticoid-independent mechanism, imposing pronounced and persistent impairments on learning and memory. PMID:21152025

  17. Soluble Aβ levels correlate with cognitive deficits in the 12-month-old APPswe/PS1dE9 mouse model of Alzheimer's disease.

    PubMed

    Zhang, Wei; Hao, Jian; Liu, Rui; Zhang, Zhuo; Lei, Gesheng; Su, Changjun; Miao, Jianting; Li, Zhuyi

    2011-09-23

    Amyloid-beta peptide (Aβ) is believed to be central in the pathogenesis of Alzheimer's disease (AD) characterized by cognitive deficits. However, it remains uncertain which form(s) of Aβ pathology is responsible for the cognitive deficits in AD. In the present study, the cognitive deficits and the profiles of Aβ pathology were characterized in the 12-month-old APPswe/PS1dE9 double transgenic mice, and their correlations were examined. Compared with non-transgenic littermates, the middle-aged APPswe/PS1dE9 mice exhibited spatial learning and memory deficits in the water maze test and long-term contextual memory deficits in the step-down passive avoidance test. Among the middle-aged APPswe/PS1dE9 mice, hippocampal soluble Aβ1-40 and Aβ1-42 levels were highly correlated with spatial learning deficits and long-term contextual memory deficits, as well as cortical and hippocampal soluble Aβ1-40 and Aβ1-42 levels were strongly correlated with spatial memory deficits. By contrast, no significant correlations were observed between three measures of cognitive functions and amyloid plaque burden (total Aβ plaque load and fibrillar Aβ plaque load), total Aβ levels (Aβ1-40 and Aβ1-42), as well as insoluble Aβ levels (Aβ1-40 and Aβ1-42). Stepwise multiple regression analysis identified hippocampal soluble Aβ1-40 and Aβ1-42 levels as independent factors for predicting the spatial learning deficits and the long-term contextual memory deficits, as well as hippocampal and cortical soluble Aβ1-40 and Aβ1-42 levels as independent factors for predicting the spatial memory deficits in transgenic mice. These results demonstrate that cognitive deficits are highly related to the levels of soluble Aβ in middle-aged APPswe/PS1dE9 mice, in which soluble Aβ levels are only a tiny fraction of the amount of total Aβ levels. Consequently, our findings provide further evidence that soluble Aβ might primarily contribute to cognitive deficits in AD, suggesting that reducing

  18. Docosahexaenoic Acid-Phosphatidylcholine Improves Cognitive Deficits in an Aβ23-35-Induced Alzheimer's Disease Rat Model.

    PubMed

    Qu, Mei-Hua; Yang, Xiaoyun; Wang, Yuming; Tang, Qingjuan; Han, Hailin; Wang, Jia; Wang, Guo-Du; Xue, Changhu; Gao, Zhiqin

    2016-01-01

    Both Docosahexaenoic acid (DHA) and Phosphatidylcholine (PC) have been shown to halt the pathogenesis of Alzheimer disease (AD) and vascular dementia. This study aimed to investigate the role of DHA-containing PC (DHA-PC) in the improvement of Aβ25-35-induced cognitive deficits in rats. Aβ25-35-induced AD rats were treated for 30 days with DHA-PC, which was extracted from Sthenoteuthis oualaniensis spawns. Cognitive improvement of the AD rats was detected using the Morris water maze (MWM). The results demonstrated that DHA-PC could improve the learning and memory abilities of AD rats in a dose-dependent pattern. Further analyses showed that expression of phosphorylated tau decreased, and the neuronal morphology recovered in brains of DHA-PC-treated AD rats, as compared with mock-treated AD rats. In addition, DHAPC treatment increased the activity of GSH-Px and SOD in the cortex and hippocampus of AD rats. Taken together, these data suggest that DHA-PC is able to improve the cognitive deficits in AD rats, probably through decreasing the phosphorylation of tau in the cortex and hippocampus CA1 area, and increasing the GSH-Px and SOD activities in the brain of AD rats. PMID:26268328

  19. Auditory and cognitive deficits associated with acquired amusia after stroke: a magnetoencephalography and neuropsychological follow-up study.

    PubMed

    Särkämö, Teppo; Tervaniemi, Mari; Soinila, Seppo; Autti, Taina; Silvennoinen, Heli M; Laine, Matti; Hietanen, Marja; Pihko, Elina

    2010-01-01

    Acquired amusia is a common disorder after damage to the middle cerebral artery (MCA) territory. However, its neurocognitive mechanisms, especially the relative contribution of perceptual and cognitive factors, are still unclear. We studied cognitive and auditory processing in the amusic brain by performing neuropsychological testing as well as magnetoencephalography (MEG) measurements of frequency and duration discrimination using magnetic mismatch negativity (MMNm) recordings. Fifty-three patients with a left (n = 24) or right (n = 29) hemisphere MCA stroke (MRI verified) were investigated 1 week, 3 months, and 6 months after the stroke. Amusia was evaluated using the Montreal Battery of Evaluation of Amusia (MBEA). We found that amusia caused by right hemisphere damage (RHD), especially to temporal and frontal areas, was more severe than amusia caused by left hemisphere damage (LHD). Furthermore, the severity of amusia was found to correlate with weaker frequency MMNm responses only in amusic RHD patients. Additionally, within the RHD subgroup, the amusic patients who had damage to the auditory cortex (AC) showed worse recovery on the MBEA as well as weaker MMNm responses throughout the 6-month follow-up than the non-amusic patients or the amusic patients without AC damage. Furthermore, the amusic patients both with and without AC damage performed worse than the non-amusic patients on tests of working memory, attention, and cognitive flexibility. These findings suggest domain-general cognitive deficits to be the primary mechanism underlying amusia without AC damage whereas amusia with AC damage is associated with both auditory and cognitive deficits. PMID:21152040

  20. Remission of Cognitive Deficits in Parkinson's Disease: Recovery from a Nonamnestic Mild Cognitive Impairment or Psychiatric Symptoms Remission?

    PubMed Central

    de Paula, Jonas Jardim; Cintra, Marco Túlio Gualberto; Miranda, Débora Marques; Bicalho, Maria Aparecida Camargos; Moares, Edgar Nunes; Malloy-Diniz, Leandro Fernandes

    2012-01-01

    Mild cognitive impairment is a clinical condition more frequent in patients with Parkinson's disease than in general population. The nonamnestic presentations, usually characterized by executive dysfunction, are most prevalent. We present a case report of a Parkinson's disease patient diagnosed with nonamnestic mild cognitive impairment that showed complete remission of cognitive symptoms after one year. We discuss the possible causes for the remission, focusing on the treatment of medical conditions such as a major depressive episode and vitamin B12 deficiency, in addition to the change of pharmacological treatment. In a third assessment, cognitive performance remained normal. The case report highlights the importance of controlling clinical comorbidities on the assessment and followup of mild cognitive impairment, especially on Parkinson's disease. PMID:23193494

  1. Effect of exercise-induced neurogenesis on cognitive function deficit in a rat model of vascular dementia

    PubMed Central

    CHOI, DONG-HEE; LEE, KYOUNG-HEE; LEE, JONGMIN

    2016-01-01

    Chronic cerebral hypoperfusion (CCH) is strongly correlated with progressive cognitive decline in neurological diseases, such as vascular dementia (VaD) and Alzheimer's disease. Exercise can enhance learning and memory, and delay age-related cognitive decline. However, exercise-induced hippocampal neurogenesis in experimental animals submitted to CCH has not been investigated. The present study aimed to investigate whether hippocampal neurogenesis induced by exercise can improve cognitive deficit in a rat model of VaD. Male Wistar rats (age, 8 weeks; weight, 292±3.05 g; n=12–13/group) were subjected to bilateral common carotid artery occlusion (2VO) or sham-surgery and each group was then subdivided randomly into no exercise and treadmill exercise groups. Exercise groups performed treadmill exercise daily at 15 m/min for 30 min for 4 weeks from the third to the seventh week after 2VO. It was demonstrated that the number of neural progenitor cells and mature neurons in the subgranular zone of 2VO rats was increased by exercise, and cognitive impairment in 2VO rats was attenuated by treadmill exercise. In addition, mature brain-derived neurotrophic factor (BDNF) levels in the hippocampus were increased in the exercise groups. Thus the present study suggests that exercise delays cognitive decline by the enhancing neurogenesis and increasing BDNF expression in the context of VaD. PMID:26934837

  2. Activation of type 5 metabotropic glutamate receptors attenuates deficits in cognitive flexibility induced by NMDA receptor blockade

    PubMed Central

    Stefani, Mark R.; Moghaddam, Bita

    2010-01-01

    Metabotropic glutamate (mGlu) receptors provide a mechanism by which the function of NMDA glutamate receptors can be modulated. As NMDA receptor hypofunction is implicated in the etiology of psychiatric disorders, including schizophrenia, the pharmacological regulation of mGlu receptor activity represents a promising therapeutic approach. We examined the effects of the positive allosteric mGlu5 receptor modulator 3- cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB), alone and in combination with the NMDA receptor antagonist MK-801, on a task measuring cognitive set-shifting ability. This task measures NMDA receptor-dependent cognitive abilities analogous to those impaired in schizophrenia. Systemic administration of CDPPB (10 & 30 mg/kg i.p) blocked MK-801 (0.1 mg/kg, i.p.)-induced impairments in set-shifting ability. The effect on learning was dose-dependent, with the 30 mg/kg dose having a greater effect than the 10 mg/kg dose across all trials. This ameliorative effect of CDPPB reflected a reduction in MK-801-induced perseverative responding. These results add to the evidence that mGlu5 receptors interact functionally with NMDA receptors to regulate behavior, and suggest that positive modulators of mGlu5 receptors may have therapeutic potential in the treatment of disorders, like schizophrenia, characterized by impairments in cognitive flexibility and memory. PMID:20371234

  3. Amelioration of Metabolic Syndrome-Associated Cognitive Impairments in Mice via a Reduction in Dietary Fat Content or Infusion of Non-Diabetic Plasma.

    PubMed

    Johnson, Lance A; Zuloaga, Kristen L; Kugelman, Tara L; Mader, Kevin S; Morré, Jeff T; Zuloaga, Damian G; Weber, Sydney; Marzulla, Tessa; Mulford, Amelia; Button, Dana; Lindner, Jonathan R; Alkayed, Nabil J; Stevens, Jan F; Raber, Jacob

    2016-01-01

    Obesity, metabolic syndrome (MetS) and type 2 diabetes (T2D) are associated with decreased cognitive function. While weight loss and T2D remission result in improvements in metabolism and vascular function, it is less clear if these benefits extend to cognitive performance. Here, we highlight the malleable nature of MetS-associated cognitive dysfunction using a mouse model of high fat diet (HFD)-induced MetS. While learning and memory was generally unaffected in mice with type 1 diabetes (T1D), multiple cognitive impairments were associated with MetS, including deficits in novel object recognition, cued fear memory, and spatial learning and memory. However, a brief reduction in dietary fat content in chronic HFD-fed mice led to a complete rescue of cognitive function. Cerebral blood volume (CBV), a measure of vascular perfusion, was decreased during MetS, was associated with long term memory, and recovered following the intervention. Finally, repeated infusion of plasma collected from age-matched, low fat diet-fed mice improved memory in HFD mice, and was associated with a distinct metabolic profile. Thus, the cognitive dysfunction accompanying MetS appears to be amenable to treatment, related to cerebrovascular function, and mitigated by systemic factors. PMID:26870815

  4. Amelioration of Metabolic Syndrome-Associated Cognitive Impairments in Mice via a Reduction in Dietary Fat Content or Infusion of Non-Diabetic Plasma

    PubMed Central

    Johnson, Lance A.; Zuloaga, Kristen L.; Kugelman, Tara L.; Mader, Kevin S.; Morré, Jeff T.; Zuloaga, Damian G.; Weber, Sydney; Marzulla, Tessa; Mulford, Amelia; Button, Dana; Lindner, Jonathan R.; Alkayed, Nabil J.; Stevens, Jan F.; Raber, Jacob

    2015-01-01

    Obesity, metabolic syndrome (MetS) and type 2 diabetes (T2D) are associated with decreased cognitive function. While weight loss and T2D remission result in improvements in metabolism and vascular function, it is less clear if these benefits extend to cognitive performance. Here, we highlight the malleable nature of MetS-associated cognitive dysfunction using a mouse model of high fat diet (HFD)-induced MetS. While learning and memory was generally unaffected in mice with type 1 diabetes (T1D), multiple cognitive impairments were associated with MetS, including deficits in novel object recognition, cued fear memory, and spatial learning and memory. However, a brief reduction in dietary fat content in chronic HFD-fed mice led to a complete rescue of cognitive function. Cerebral blood volume (CBV), a measure of vascular perfusion, was decreased during MetS, was associated with long term memory, and recovered following the intervention. Finally, repeated infusion of plasma collected from age-matched, low fat diet-fed mice improved memory in HFD mice, and was associated with a distinct metabolic profile. Thus, the cognitive dysfunction accompanying MetS appears to be amenable to treatment, related to cerebrovascular function, and mitigated by systemic factors. PMID:26870815

  5. Attention-deficit/hyperactivity disorder and sluggish cognitive tempo dimensions in relation to executive functioning in adolescents with ADHD.

    PubMed

    Becker, Stephen P; Langberg, Joshua M

    2014-02-01

    Previous research has failed to find a consistent relation between Sluggish Cognitive Tempo (SCT) and executive function (EF) in youth with Attention-Deficit/Hyperactivity Disorder (ADHD) when laboratory-based neuropsychological tasks of EF are used, whereas recent research with youth and adults suggests a significant relation between SCT and ratings of EF. The purpose of this study was to examine ADHD dimensions and SCT symptoms in relation to ratings of EF in adolescents with ADHD. Fifty-two adolescents (ages 12-16; 70 % male) participated in this study. Parents and teachers completed validated measures of SCT, ADHD symptoms, and EF in daily life. Adolescents' intelligence and academic achievement were also assessed. ADHD and SCT symptoms were significantly correlated with ratings of EF. Regression analyses demonstrated that, as hypothesized, ADHD hyperactive-impulsive symptoms were strongly associated with behavioral regulation EF deficits, with ADHD inattentive and SCT symptoms unrelated to behavioral regulation EF when hyperactive-impulsivity symptoms were included in the model. The parent-reported SCT Slow scale measuring motivation, initiative, and apathy predicted both parent- and teacher-reported metacognitive EF deficits above and beyond youth characteristics and ADHD symptoms. In contrast, teacher-reported ADHD inattention was most clearly associated with teacher-reported metacognitive EF deficits. This study provides preliminary evidence for the importance of SCT symptoms in relation to metacognitive EF deficits among adolescents with ADHD and the need to further investigate the overlap and distinctiveness of SCT/ADHD. Further research is needed to replicate and extend these findings. PMID:23443466

  6. Mechanisms underlying cognitive enhancement and reversal of cognitive deficits in nonhuman primates by the ampakine CX717

    PubMed Central

    Hampson, R. E.; España, R. A.; Rogers, G. A.; Porrino, L. J.; Deadwyler, S. A.

    2011-01-01

    Rationale Performance of cognitive tasks in nonhuman primates (NHPs) requires specific brain regions to make decisions under different degrees of difficulty or “cognitive load.” Objective Local cerebral metabolic activity ([18F]FDG PET imaging) in dorsolateral prefrontal cortex (DLPFC), medial temporal lobe (MTL), and dorsal striatum (DStr) is examined in NHPs performing a delayed-match-to-sample (DMS) task with variable degrees of cognitive load. Materials and methods Correlations between cognitive load and degree of brain metabolic activity were obtained with respect to the influence of the ampakine CX717 (Cortex Pharmaceuticals), using brain imaging and recordings of neuronal activity in NHPs and measures of intracellular calcium release in rat hippocampal slices. Results Activation of DLPFC, MTL, and DStr reflected changes in performance related to cognitive load within the DMS task and were engaged primarily on high load trials. Similar increased activation patterns and improved performance were also observed following administration of CX717. Sleep deprivation in NHPs produced impaired performance and reductions in brain activation which was reversed by CX717. One potential basis for this facilitation of cognition by CX717 was increased firing of task-specific hippocampal cells. Synaptic mechanisms affected by CX717 were examined in rat hippocampal slices which showed that N-methyl-d-aspartic acid-mediated release of intracellular calcium was reduced in slices from sleep-deprived rats and reversed by application of CX717 to the bathing medium. Conclusions The findings provide insight into how cognition is enhanced by CX717 in terms of brain, and underlying neural, processes that are activated on high vs. low cognitive load trials. PMID:18985324

  7. 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. PMID:26944333

  8. Effects of Pycnogenol and vitamin E on cognitive deficits and oxidative damage induced by intracerebroventricular streptozotocin in rats.

    PubMed

    Ishrat, Tauheed; Parveen, Kehkashan; Hoda, Md Nasrul; Khan, Mohammad Badruzzaman; Yousuf, Seema; Ansari, Mubeen Ahmad; Saleem, Sofiyan; Islam, Fakhrul

    2009-10-01

    Oxidative stress plays a crucial role in the progression of cognitive decline in Alzheimer's disease (AD). Considerable attention has been focused on increasing the internal antioxidant defenses in response to AD. This study was designed to examine and compare the pretreatment effects of Pycnogenol (PYC) and vitamin E (Vit E) on cognitive deficits and oxidative damage in the hippocampus and cerebral cortex of intracerebroventricular streptozotocin (ICV-STZ)-infused rats. Rats pretreated with PYC (10 mg/kg), Vit E (100 mg/kg), and vehicle (intraperitoneal; once daily for 3 weeks) were bilaterally injected with ICV-STZ (3 mg/kg), whereas sham rats received the same volume of vehicle. After 2 weeks of ICV-STZ infusion, rats were tested for cognitive performance using passive avoidance and water maze tasks, and then killed for biochemical assays. ICV-STZ induced significant declines in cognitive performance and choline acetyltransferase activity in the hippocampus, which were significantly attenuated with PYC and Vit E. Pretreatment with PYC and Vit E produced a significantly enhanced glutathione level and Na+/K+-ATPase activity and decreased thiobarbituric acid reactive substances and protein carbonyl. These findings suggest that PYC and Vit E may provide a promising approach for the treatment of oxidative stress-related neurodegeneration in conditions such as AD. PMID:19654508

  9. Guizhi-Fuling-Wan, a Traditional Chinese Herbal Medicine, Ameliorates Memory Deficits and Neuronal Apoptosis in the Streptozotocin-Induced Hyperglycemic Rodents via the Decrease of Bax/Bcl2 Ratio and Caspase-3 Expression.

    PubMed

    Wu, Kuo-Jen; Chen, Yuh-Fung; Tsai, Huei-Yann; Wu, Chi-Rei; Wood, W Gibson

    2012-01-01

    Brain neuronal apoptosis and cognitive impairment are associated with hyperglycemia and diabetes mellitus. The present study determined if the Chinese herbal medicine Guizhi-Fuling-Wan (GFW) would reduce memory loss and neuronal apoptosis in streptozotocin- (STZ-) induced hyperglycemic rodents. Two weeks after STZ induction, GFW was orally administered once daily for 7 days. GFW significantly improved spatial memory deficits in STZ-induced hyperglycemic mice. GFW decreased TUNEL-positive cells and caspase-3 positive cells in STZ-induced hyperglycemic rats. It also was found that GFW treatment reduced caspase-3 protein levels and increased levels of the antiapoptotic protein Bcl-2 that were indicative of neuroprotection. The protective therapeutic effects of GFW on neuronal apoptosis and cognition deficits caused by STZ-induced hyperglycemia may be due in part to inhibition of the cellular apoptosis pathway. GFW may have therapeutic effects in patients with diabetes-mellitus-induced neuropathology. PMID:23304209

  10. A functional magnetic resonance imaging study of cognitive control and neurosensory deficits in mild traumatic brain injury.

    PubMed

    Mayer, Andrew R; Hanlon, Faith M; Dodd, Andrew B; Ling, Josef M; Klimaj, Stefan D; Meier, Timothy B

    2015-11-01

    Mild traumatic brain injury patients (mTBI) frequently report symptoms of increased distractability and sensory disturbances during mutisensory stimulation. These common post-concussive symptoms could putatively result from dysfunction within the cognitive control network (CCN; top-down) or from unisensory cortex (bottom-up) itself. Functional magnetic resonance imaging (fMRI) and high-resolution structural data were therefore prospectively collected during a multisensory (audio-visual) cognitive control task from 46 mTBI patients within 3 weeks of injury and 46 matched healthy controls (HC), with a subset of participants returning at 4 months. Multisensory stimuli were presented at two frequencies to manipulate cognitive and perceptual load. Patients self-reported more cognitive, emotional, somatic, vestibular and visual symptoms relative to HC, which improved, but did not entirely resolve, over the 4 month follow-up period. There were no group differences in behavior or functional activation during cognitive control (incongruent--congruent trials). In contrast, patients exhibited abnormal activation within different regions of visual cortex that depended on whether attention was focused on auditory or visual information streams. Patients also exhibited increased activation within bilateral inferior parietal lobules during higher cognitive/perceptual loads, suggesting a compensatory mechanism to achieve similar levels of behavioral performance. Functional abnormalities within the visual cortex and inferior parietal lobules were only partially resolved at 4 months post-injury, suggesting that neural abnormalities may take longer to resolve than behavioral measures used in most clinical settings. In summary, current results indicate that abnormalities within unisensory cortex (particularly visual areas) following mTBI, which likely contribute to deficits commonly reported during multisensory stimulation. PMID:26493161

  11. Odor identification deficit in mild cognitive impairment and Alzheimer's disease is associated with hippocampal and deep gray matter atrophy.

    PubMed

    Hagemeier, Jesper; Woodward, Matthew R; Rafique, Usama A; Amrutkar, Chaitanya V; Bergsland, Niels; Dwyer, Michael G; Benedict, Ralph; Zivadinov, Robert; Szigeti, Kinga

    2016-09-30

    Even in early stages, Alzheimer's disease (AD) is associated with olfactory deficit. We assess the association of volumetric differences in subcortical deep gray matter (DGM) structures and odor identification deficit (OID) in subjects with amnestic mild cognitive impairment (aMCI), AD and normal controls (NCs), and relate findings to the current gold standard right sided memory measure, visual reproduction. Eighty subjects (19 aMCI; 42 CE; 19 NC) were included in this study. We obtained olfactory testing and normalized structural brain volumes from 3T T1 MRI scans. Associations between MRI, olfactory- and memory impairment were studied using Pearson- and partial-correlation adjusted for age. AD patients had significantly higher olfactory deficits, lower visual reproduction scores, and reduced brain volumes (p<0.05). Within aMCI, OID was associated with lower right hippocampal- and left amygdala volume (p<0.05). In AD, OID was associated with bilaterally lower hippocampus and left amygdala volumes. In contrast, visual reproduction was associated with bilateral volume loss regardless of study group. OID is a more specific marker of early pathological right mesial-temporal involvement than the currently regarded gold standard of right sided-memory (visual reproduction). OID may be valuable in the longitudinal evaluation of disease modifying treatments in early disease course. PMID:27567325

  12. Designing websites for persons with cognitive deficits: Design and usability of a psychoeducational intervention for persons with severe mental illness.

    PubMed Central

    Rotondi, Armando J.; Sinkule, Jennifer; Haas, Gretchen L.; Spring, Michael B.; Litschge, Christine M.; Newhill, Christina E.; Ganguli, Rohan; Anderson, Carol M.

    2013-01-01

    The purpose of this study was to develop an understanding of the design elements that influence the ability of persons with severe mental illness (SMI) and cognitive deficits to use a website, and to use this knowledge to design a web-based telehealth application to deliver a psychoeducation program to persons with schizophrenia and their families. Usability testing was conducted with 98 persons with SMI. First, individual website design elements were tested. Based on these results, theoretical website design models were used to create several alternative websites. These designs were tested for their ability to facilitate use by persons with SMI. The final website design is presented. The results indicate that commonly prescribed design models and guidelines produce websites that are poorly suited and confusing to persons with SMI. Our findings suggest an alternative model that should be considered when designing websites and other telehealth interventions for this population. Implications for future studies addressing the characteristics of accessible designs for persons with SMI and cognitive deficits are discussed. PMID:26321884

  13. Cognitive deficits and decreased locomotor activity induced by single-walled carbon nanotubes and neuroprotective effects of ascorbic acid.

    PubMed

    Liu, Xudong; Zhang, Yuchao; Li, Jinquan; Wang, Dong; Wu, Yang; Li, Yan; Lu, Zhisong; Yu, Samuel C T; Li, Rui; Yang, Xu

    2014-01-01

    Single-walled carbon nanotubes (SWCNTs) have shown increasing promise in the field of biomedicine, especially in applications related to the nervous system. However, there are limited studies available on the neurotoxicity of SWCNTs used in vivo. In this study, neurobehavioral changes caused by SWCNTs in mice and oxidative stress were investigated. The results of ethological analysis (Morris water maze and open-field test), brain histopathological examination, and assessments of oxidative stress (reactive oxygen species [ROS], malondialdehyde [MDA], and glutathione [GSH]), inflammation (nuclear factor κB, tumor necrosis factor α, interleukin-1β), and apoptosis (cysteine-aspartic acid protease 3) in brains showed that 6.25 and 12.50 mg/kg/day SWCNTs in mice could induce cognitive deficits and decreased locomotor activity, brain histopathological alterations, and increased levels of oxidative stress, inflammation, and apoptosis in mouse brains; however, 3.125 mg/kg/day SWCNTs had zero or minor adverse effects in mice, and these effects were blocked by concurrent administration of ascorbic acid. Down-regulation of oxidative stress, inflammation, and apoptosis were proposed to explain the neuroprotective effects of ascorbic acid. This work suggests SWCNTs could induce cognitive deficits and decreased locomotor activity, and provides a strategy to avoid the adverse effects. PMID:24596461

  14. Distinguishing between autism spectrum disorder and attention deficit hyperactivity disorder by using behavioral checklists, cognitive assessments, and neuropsychological test battery.

    PubMed

    Matsuura, Naomi; Ishitobi, Makoto; Arai, Sumiyoshi; Kawamura, Kaori; Asano, Mizuki; Inohara, Keisuke; Narimoto, Tadamasa; Wada, Yuji; Hiratani, Michio; Kosaka, Hirotaka

    2014-12-01

    Children with attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) share many common symptoms, including attention deficit, behavioral problems, and difficulties with social skills. The aim of this study was to distinguish between ASD and ADHD by identifying the characteristic features of both the disorders, by using multidimensional assessments, including screening behavioral checklists, cognitive assessments, and comprehensive neurological battery. After screening for comorbid disorders, we carefully selected age-, sex-, IQ-, and socio-economic status-matched children with typical development (TD). In the Wechsler Intelligence Scale for children, a lower score was observed for the ASD group than for the TD group in Picture concept, which is a subscale of perceptual reasoning. A lower score was shown by the ADHD group than by the TD group in the spatial working memory test in the Cambridge Neuropsychological Test Automated Battery (CANTAB(®)). Although ASD and ADHD have many similar symptoms, they can be differentiated by focusing on the behavioral and cognitive characteristics of executive function. PMID:25440561

  15. Effectiveness of cognitive-functional (Cog-Fun) intervention with children with attention deficit hyperactivity disorder: a pilot study.

    PubMed

    Hahn-Markowitz, Jeri; Manor, Iris; Maeir, Adina

    2011-01-01

    The executive function (EF) deficits of children with attention deficit hyperactivity disorder (ADHD) hinder their performance of complex daily functions. Despite the existing evidence-based pharmacological interventions for ADHD symptoms, no intervention has yet been found that deals directly with EFs in daily tasks. Fourteen children and their parents participated in the Cognitive-Functional (Cog-Fun) program in occupational therapy, which is tailored to the executive dysfunction of ADHD and focuses on enabling cognitive strategies for occupational performance. The study included initial assessment of EFs (Behavior Rating Inventory of Executive Functions; Tower of London(DX)), occupational performance (Canadian Occupational Performance Measure), 10 sessions of Cog-Fun intervention with each child-parent dyad, and postintervention and 3-month follow-up assessments. We found significant improvements with medium to large effects on outcome measures after intervention, and most effects were maintained at follow-up. The findings warrant controlled studies examining the effectiveness of this intervention for children with ADHD. PMID:21834453

  16. Cognitive Training for Attention-Deficit/Hyperactivity Disorder: Meta-Analysis of Clinical and Neuropsychological Outcomes From Randomized Controlled Trials

    PubMed Central

    Cortese, Samuele; Ferrin, Maite; Brandeis, Daniel; Buitelaar, Jan; Daley, David; Dittmann, Ralf W.; Holtmann, Martin; Santosh, Paramala; Stevenson, Jim; Stringaris, Argyris; Zuddas, Alessandro; Sonuga-Barke, Edmund J.S.

    2015-01-01

    Objective The authors performed meta-analyses of randomized controlled trials to examine the effects of cognitive training on attention-deficit/hyperactivity disorder (ADHD) symptoms, neuropsychological deficits, and academic skills in children/adolescents with ADHD. Method The authors searched Pubmed, Ovid, Web of Science, ERIC, and CINAHAL databases through May 18, 2014. Data were aggregated using random-effects models. Studies were evaluated with the Cochrane risk of bias tool. Results Sixteen of 695 nonduplicate records were analyzed (759 children with ADHD). When all types of training were considered together, there were significant effects on total ADHD (standardized mean difference [SMD] = 0.37, 95% CI = 0.09–0.66) and inattentive symptoms (SMD = 0.47, 95% CI = 0.14–0.80) for reports by raters most proximal to the treatment setting (i.e., typically unblinded). These figures decreased substantially when the outcomes were provided by probably blinded raters (ADHD total: SMD = 0.20, 95% CI = 0.01–0.40; inattention: SMD = 0.32, 95% CI = −0.01 to 0.66). Effects on hyperactivity/impulsivity symptoms were not significant. There were significant effects on laboratory tests of working memory (verbal: SMD = 0.52, 95% CI = 0.24–0.80; visual: SMD = 0.47, 95% CI = 0.23–0.70) and parent ratings of executive function (SMD = 0.35, 95% CI = 0.08–0.61). Effects on academic performance were not statistically significant. There were no effects of working memory training, specifically on ADHD symptoms. Interventions targeting multiple neuropsychological deficits had large effects on ADHD symptoms rated by most proximal assessors (SMD = 0.79, 95% CI = 0.46–1.12). Conclusion Despite improving working memory performance, cognitive training had limited effects on ADHD symptoms according to assessments based on blinded measures. Approaches targeting multiple neuropsychological processes may optimize the transfer of effects from cognitive deficits to

  17. [Prognosis of cognitive deficit progression in aged patients with mild cognitive impairment under prolonged therapy (a three year observation)].

    PubMed

    Gavrilova, S I; Kolykhalov, I V; Fedorova, Ia B; Kalyn, Ia B; Selezneva, N D; Samorodov, A V; Miasoedov, S N; Boksha, I S

    2013-01-01

    The aim of the study was to predict treatment efficacy in patients with mild cognitive impairment (MCI) and to find the most reliable clinical tests for the prediction of dementia. Patients with amnestic MCI (n=53) were treated with cerebrolysin for three years and underwent regularly neurocognitive and clinical psychiatric tests. The data were analyzed using non-parametric statistics, cluster analysis, and linear discriminate analysis. The combination of statistical methods has enabled to predict the degree of cognitive impairment as well as the development of dementia. A "dementia risk group" with fast cognitive decline (i.e. the low efficacy of the treatment) was identified. The tests are ranked according to their predictive values. PMID:23612410

  18. ELEVATED LEVELS OF KYNURENIC ACID DURING GESTATION PRODUCE NEUROCHEMICAL, MORPHOLOGICAL, AND COGNITIVE DEFICITS IN ADULTHOOD: IMPLICATIONS FOR SCHIZOPHRENIA

    PubMed Central

    Pershing, Michelle L.; Bortz, David M.; Pocivavsek, Ana; Fredericks, Peter J.; Jørgensen, Christinna V.; Vunck, Sarah A.; Leuner, Benedetta; Schwarcz, Robert; Bruno, John P.

    2016-01-01

    The levels of kynurenic acid (KYNA), an endogenous negative modulator of alpha 7 nicotinic acetylcholine receptors (α7nAChRs), are elevated in the brains of patients with schizophrenia (SZ). We reported that increases of brain KYNA in rats, through dietary exposure to its precursor kynurenine from embryonic day (ED)15 to postnatal day (PD) 21, result in neurochemical and cognitive deficits in adulthood. The present experiments focused on the effects of prenatal exposure to elevated kynurenine on measures of prefrontal excitability known to be impaired in SZ. Pregnant dams were fed a mash containing kynurenine (100 mg/day; progeny = EKYNs) from ED15 until ED22. Controls were fed an unadulterated mash (progeny = ECONs). The dietary loading procedure elevated maternal and fetal plasma kynurenine (2223% and 693% above controls, respectively) and increased fetal KYNA (forebrain; 500% above controls) on ED21. Elevations in forebrain KYNA disappeared after termination of the loading (PD2), but KYNA levels in the prefrontal cortex (PFC) were unexpectedly increased again when measured in adults (PD56-80; 75% above controls). We also observed changes in several markers of prefrontal excitability, including expression of the α7nAChR (22% and 17% reductions at PD2 and PD56-80), expression of mGluR2 (31% and 24% reductions at ED21 and PD56-80), dendritic spine density (11–14% decrease at PD56-80), subsensitive mesolimbic stimulation of glutamate release in PFC, and reversal/extra-dimensional shift deficits in the prefrontally-mediated set-shifting task. These results highlight the deleterious impact of elevated KYNA levels during sensitive periods of early development, which model the pathophysiological and cognitive deficits seen in SZ. PMID:25446576

  19. Long-Term Cognitive Deficits in Chimpanzees Associated with Early Impoverished Rearing

    ERIC Educational Resources Information Center

    Davenport, Richard K.; And Others

    1973-01-01

    According to transfer index testing, chimpanzees who had been reared in restricted laboratory environments for the first two years of life were inferior in cognitive skills to wild born control subjects. Findings are discussed in terms of the role of early experience in cognitive development. (DP)

  20. Tetrahydrohyperforin prevents cognitive deficit, Aβ deposition, tau phosphorylation and synaptotoxicity in the APPswe/PSEN1ΔE9 model of Alzheimer's disease: a possible effect on APP processing

    PubMed Central

    Inestrosa, N C; Tapia-Rojas, C; Griffith, T N; Carvajal, F J; Benito, M J; Rivera-Dictter, A; Alvarez, A R; Serrano, F G; Hancke, J L; Burgos, P V; Parodi, J; Varela-Nallar, L

    2011-01-01

    Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive deterioration of cognitive abilities, amyloid-β peptide (Aβ) accumulation and synaptic alterations. Previous studies indicated that hyperforin, a component of the St John's Wort, prevents Aβ neurotoxicity and some behavioral impairments in a rat model of AD. In this study we examined the ability of tetrahydrohyperforin (IDN5607), a stable hyperforin derivative, to prevent the cognitive deficit and synaptic impairment in an in vivo model of AD. In double transgenic APPswe/PSEN1ΔE9 mice, IDN5706 improves memory and prevents the impairment of synaptic plasticity in a dose-dependent manner, inducing a recovery of long-term potentiation. In agreement with these findings, IDN5706 prevented the decrease in synaptic proteins in hippocampus and cortex. In addition, decreased levels of tau hyperphosphorylation, astrogliosis, and total fibrillar and oligomeric forms of Aβ were determined in double transgenic mice treated with IDN5706. In cultured cells, IDN5706 decreased the proteolytic processing of the amyloid precursor protein that leads to Aβ peptide generation. These findings indicate that IDN5706 ameliorates AD neuropathology and could be considered of therapeutic relevance in AD treatment. PMID:22832522

  1. Behavioral, Cognitive, and Motor Preparation Deficits in a Visual Cued Spatial Attention Task in Autism Spectrum Disorder.

    PubMed

    Sokhadze, Estate M; Tasman, Allan; Sokhadze, Guela E; El-Baz, Ayman S; Casanova, Manuel F

    2016-03-01

    Abnormalities in motor skills have been regarded as part of the symptomatology characterizing autism spectrum disorder (ASD). It has been estimated that 80 % of subjects with autism display "motor dyspraxia" or clumsiness that are not readily identified in a routine neurological examination. In this study we used behavioral measures, event-related potentials (ERP), and lateralized readiness potential (LRP) to study cognitive and motor preparation deficits contributing to the dyspraxia of autism. A modified Posner cueing task was used to analyze motor preparation abnormalities in children with autism and in typically developing children (N = 30/per group). In this task, subjects engage in preparing motor response based on a visual cue, and then execute a motor movement based on the subsequent imperative stimulus. The experimental conditions, such as the validity of the cue and the spatial location of the target stimuli were manipulated to influence motor response selection, preparation, and execution. Reaction time and accuracy benefited from validly cued targets in both groups, while main effects of target spatial position were more obvious in the autism group. The main ERP findings were prolonged and more negative early frontal potentials in the ASD in incongruent trials in both types of spatial location. The LRP amplitude was larger in incongruent trials and had stronger effect in the children with ASD. These effects were better expressed at the earlier stages of LRP, specifically those related to response selection, and showed difficulties at the cognitive phase of stimulus processing rather that at the motor execution stage. The LRP measures at different stages reflect the chronology of cognitive aspects of movement preparation and are sensitive to manipulations of cue correctness, thus representing very useful biomarker in autism dyspraxia research. Future studies may use more advance and diverse manipulations of movement preparation demands in testing more

  2. Do Social and Cognitive Deficits Curtail Musical Understanding? Evidence from Autism and Down Syndrome

    ERIC Educational Resources Information Center

    Heaton, Pamela; Allen, Rory; Williams, Kerry; Cummins, Omar; Happe, Francesca

    2008-01-01

    Children with autism experience difficulties in understanding social affective cues, and it has been suggested that such deficits will generalize to music. In order to investigate this proposal, typically developing individuals and children with autism and Down syndrome were compared on tasks measuring perception of affective and movement states…

  3. Cognitive Behavior Therapy for College Students with Attention-Deficit/Hyperactivity Disorder

    ERIC Educational Resources Information Center

    Ramsay, J. Russell; Rostain, Anthony L.

    2006-01-01

    Attention-Deficit/Hyperactivity Disorder (ADHD) is a developmental syndrome that persists into adulthood for the majority of children with ADHD. Other individuals may not experience the full negative effects of undiagnosed ADHD until they face the demands of adult life. College counseling centers in particular are seeing a rise in the number of…

  4. Systematic review of the relationship between amyloid-β levels and measures of transgenic mouse cognitive deficit in Alzheimer's disease.

    PubMed

    Foley, Avery M; Ammar, Zeena M; Lee, Robert H; Mitchell, Cassie S

    2015-01-01

    Amyloid-β (Aβ) is believed to directly affect memory and learning in Alzheimer's disease (AD). It is widely suggested that there is a relationship between Aβ40 and Aβ42 levels and cognitive performance. In order to explore the validity of this relationship, we performed a meta-analysis of 40 peer-reviewed, published AD transgenic mouse studies that quantitatively measured Aβ levels in brain tissue after assessing cognitive performance. We examined the relationship between Aβ levels (Aβ40, Aβ42, or the ratio of Aβ42 to Aβ40) and cognitive function as measured by escape latency times in the Morris water maze or exploratory preference percentage in the novel object recognition test. Our systematic review examined five mouse models (Tg2576, APP, PS1, 3xTg, APP(OSK)-Tg), gender, and age. The overall result revealed no statistically significant correlation between quantified Aβ levels and experimental measures of cognitive function. However, enough of the trends were of the same sign to suggest that there probably is a very weak qualitative trend visible only across many orders of magnitude. In summary, the results of the systematic review revealed that mice bred to show elevated levels of Aβ do not perform significantly worse in cognitive tests than mice that do not have elevated Aβ levels. Our results suggest two lines of inquiry: 1) Aβ is a biochemical "side effect" of the AD pathology; or 2) learning and memory deficits in AD are tied to the presence of qualitatively "high" levels of Aβ but are not quantitatively sensitive to the levels themselves. PMID:25362040

  5. Childhood abuse and neglect may induce deficits in cognitive precursors of psychosis in high-risk children

    PubMed Central

    Berthelot, Nicolas; Paccalet, Thomas; Gilbert, Elsa; Moreau, Isabel; Mérette, Chantal; Gingras, Nathalie; Rouleau, Nancie; Maziade, Michel

    2015-01-01

    Background Millions of children are born to parents affected by major psychoses. Cognitive dysfunctions seen in patients are already detectable in these children. In parallel, childhood maltreatment increases the risk of adult psychoses through unknown mechanisms. We investigated whether high-risk offspring exposed to abuse/neglect displayed more cognitive precursors of adult psychoses in childhood and adolescence than nonexposed offspring. Methods We used a stepwise selection strategy from a 25-year follow-up of 48 densely affected kindreds including 1500 adults (405 patients with schizophrenia or bipolar disorder) to select high-risk offspring aged 6–22 years for inclusion in our study. All offspring were assessed for childhood trauma from direct interviews with the offspring, parents and relatives and from the review of lifetime medical records of parents and children and administered a neuropsychological battery including IQ and 4 of the most impaired neuropsychological domains in psychoses. Results Our study included 66 high-risk offspring. Those who were exposed to abuse/neglect had significantly lower IQ (effect size [ES] = 0.61) than nonexposed offspring and displayed poorer cognitive performance in visual episodic memory (ES = 0.67) and in executive functions of initiation (ES = 1.01). Moreover, exposed offspring presented more combinations of cognitive deficits that were associated with lower Global Assessment of Functioning scores. Limitations Exposure to abuse/neglect was not assessed in the control group, thus the study could not test whether the effect of childhood maltreatment occured only in a high-risk setting and not in the general population. Conclusion In high-risk youths, maltreatment in childhood/adolescence may negatively impact cognitive domains known to be impaired in adults with psychoses, suggesting an early mediating effect in the association between abuse/neglect and adult psychoses. This finding provides a target for future

  6. Blind rats are not profoundly impaired in the reference memory Morris water maze and cannot be clearly discriminated from rats with cognitive deficits in the cued platform task.

    PubMed

    Lindner, M D; Plone, M A; Schallert, T; Emerich, D F

    1997-06-01

    The Morris water maze is commonly used to test cognitive function in rodent models of neurological disorders including age-related cognitive deficits. It is often assumed that the most profoundly impaired aged rats may be blind due to retinal degeneration, and it has been reported that animals with visual sensory deficits can be identified based on their performance in a cued platform task. The results of the present study demonstrate that blind rats can perform surprisingly well in the reference memory version of the Morris water maze, and that blind rats cannot be selectively excluded based on performance in the cued platform task since atropine-treated rats also perform poorly in the cued platform task. Future studies may be able to develop screening procedures that help to eliminate subjects with non-cognitive deficits, but the present results do not support the use of the cued platform or straight swim task as screening procedures. Experimenters must be careful to consider the role that visual sensory function and other non-cognitive factors may have in performance of the spatial learning Morris water maze, and also the role that severe cognitive deficits may have in performance of the cued platform task. PMID:9197520

  7. The heterogeneity of attention-deficit/hyperactivity disorder symptoms and conduct problems: Cognitive inhibition, emotion regulation, emotionality, and disorganized attachment.

    PubMed

    Forslund, Tommie; Brocki, Karin C; Bohlin, Gunilla; Granqvist, Pehr; Eninger, Lilianne

    2016-09-01

    This study examined the contributions of several important domains of functioning to attention-deficit/hyperactivity disorder (ADHD) symptoms and conduct problems. Specifically, we investigated whether cognitive inhibition, emotion regulation, emotionality, and disorganized attachment made independent and specific contributions to these externalizing behaviour problems from a multiple pathways perspective. The study included laboratory measures of cognitive inhibition and disorganized attachment in 184 typically developing children (M age = 6 years, 10 months, SD = 1.7). Parental ratings provided measures of emotion regulation, emotionality, and externalizing behaviour problems. Results revealed that cognitive inhibition, regulation of positive emotion, and positive emotionality were independently and specifically related to ADHD symptoms. Disorganized attachment and negative emotionality formed independent and specific relations to conduct problems. Our findings support the multiple pathways perspective on ADHD, with poor regulation of positive emotion and high positive emotionality making distinct contributions to ADHD symptoms. More specifically, our results support the proposal of a temperamentally based pathway to ADHD symptoms. The findings also indicate that disorganized attachment and negative emotionality constitute pathways specific to conduct problems rather than to ADHD symptoms. PMID:26895773

  8. Repeated mild traumatic brain injury causes chronic neuroinflammation, changes in hippocampal synaptic plasticity, and associated cognitive deficits

    PubMed Central

    Aungst, Stephanie L; Kabadi, Shruti V; Thompson, Scott M; Stoica, Bogdan A; Faden, Alan I

    2014-01-01

    Repeated mild traumatic brain injury (mTBI) can cause sustained cognitive and psychiatric changes, as well as neurodegeneration, but the underlying mechanisms remain unclear. We examined histologic, neurophysiological, and cognitive changes after single or repeated (three injuries) mTBI using the rat lateral fluid percussion (LFP) model. Repeated mTBI caused substantial neuronal cell loss and significantly increased numbers of activated microglia in both ipsilateral and contralateral hippocampus on post-injury day (PID) 28. Long-term potentiation (LTP) could not be induced on PID 28 after repeated mTBI in ex vivo hippocampal slices from either hemisphere. N-Methyl-D-aspartate (NMDA) receptor-mediated responses were significantly attenuated after repeated mTBI, with no significant changes in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated responses. Long-term potentiation was elicited in slices after single mTBI, with potentiation significantly increased in ipsilateral versus contralateral hippocampus. After repeated mTBI, rats displayed cognitive impairments in the Morris water maze (MWM) and novel object recognition (NOR) tests. Thus, repeated mTBI causes deficits in the hippocampal function and changes in excitatory synaptic neurotransmission, which are associated with chronic neuroinflammation and neurodegeneration. PMID:24756076

  9. Increased hippocampal NgR1 signaling machinery in aged rats with deficits of spatial cognition

    PubMed Central

    VanGuilder Starkey, Heather D.; Sonntag, William E.; Freeman, Willard M.

    2013-01-01

    Myelin-associated inhibitor/NgR1 signaling has important roles in modulation of synaptic plasticity, with demonstrated effects on cognitive function. We have previously demonstrated that NgR1 and its ligands are upregulated in the hippocampus of aged rats with impaired spatial learning and memory, but it is unknown whether increased expression of these proteins indicates a potential increase in pathway signaling because NgR1 requires co-receptors for signal transduction through RhoA. Two co-receptor complexes have been identified to date, comprised of NgR1 and LINGO-1, and either p75 or TROY. In this study, we assessed the expression of LINGO-1, p75 and TROY, and the downstream effector RhoA in mature adult (12 months) and aged (26 months) male Fischer 344/Brown Norway hybrid rats classified as cognitively impaired or cognitively intact by Morris water maze testing. The hippocampal distribution of NgR1 and its co-receptors was assessed to determine whether receptor/co-receptor interaction, and therefore signaling through this pathway, is possible. Protein expression of LINGO-1, p75, TROY, and RhoA was significantly elevated in cognitively impaired, but not intact, aged rats compared to mature adults, and expression levels correlated significantly with water maze performance. Co-localization of NgR1 with LINGO-1, p75 and TROY was observed in hippocampal neurons of aged, cognitively impaired rats. Further, expression profiles of NgR1 pathway components were demonstrated to classify rats as cognitively intact or cognitively impaired with high accuracy. Together, this suggests that hippocampal induction of this pathway is a conserved phenomenon in cognitive decline that may impair learning and memory by suppressing neuronal plasticity. PMID:23438185

  10. Gender differences in cognitive deficits in schizophrenia with and without diabetes.

    PubMed

    Zhang, Bao Hua; Han, Mei; Zhang, Xiang Yang; Hui, Li; Jiang, Shu Rong; Yang, Fu De; Tan, Yun Long; Wang, Zhi Ren; Li, Juan; Huang, Xu Feng

    2015-11-01

    This study investigated gender differences in cognition in schizophrenia with and without diabetes. Cognition was assessed in 263 individuals with schizophrenia with age range (40-68): 67 males and 34 females with schizophrenia with diabetes; and 125 males and 37 females with schizophrenia without diabetes according to the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Fasting glucose, hemoglobin A1c (HbA1c) and lipid levels were measured. Results showed that male individuals performed worse on most cognitive tasks, especially attention, in schizophrenia with than without diabetes. This result was not observed in female individuals. Also, individuals of both genders showed higher fasting glucose and HbA1c in schizophrenia with than without diabetes. In schizophrenia with diabetes, males had significantly worse cognition than females in all cognitive domains. Higher HbA1c, lower high-density lipoprotein, and an earlier age of onset of schizophrenia were found in males compared with female individuals. HbA1c was negatively associated with attention and the RBANS total score for males but not for females. In schizophrenia without diabetes, males showed worse performance in immediate and delayed memory than females. This study support cognition was worse for males with schizophrenia irrespective of whether they have diabetes. However, diabetes exemplified the gender differences, especially in attention. PMID:26555485

  11. Hyperbaric Oxygen and Ginkgo Biloba Extract Ameliorate Cognitive and Memory Impairment via Nuclear Factor Kappa-B Pathway in Rat Model of Alzheimer's Disease

    PubMed Central

    Zhang, Li-Da; Ma, Li; Zhang, Li; Dai, Jian-Guo; Chang, Li-Gong; Huang, Pei-Lin; Tian, Xiao-Qiang

    2015-01-01

    Background: Hyperbaric oxygen (HBO) and Ginkgo biloba extract (e.g., EGB 761) were shown to ameliorate cognitive and memory impairment in Alzheimer's disease (AD). However, the exact mechanism remains elusive. The aim of the present study was to investigate the possible mechanisms of HBO and EGB 761 via the function of nuclear factor kappa-B (NF-κB) pathway. Methods: AD rats were induced by injecting β-amyloid 25–35 into the hippocampus. All animals were divided into six groups: Normal, sham, AD model, HBO (2 atmosphere absolute; 60 min/d), EGB 761 (20 mg·kg−1·d−1), and HBO/EGB 761 groups. Morris water maze tests were used to assess cognitive, and memory capacities of rats; TdT-mediated dUTP Nick-End Labeling staining and Western blotting were used to analyze apoptosis and NF-κB pathway-related proteins in hippocampus tissues. Results: Morris water maze tests revealed that EGB 761 and HBO significantly improved the cognitive and memory ability of AD rats. In addition, the protective effect of combinational therapy (HBO/EGB 761) was superior to either HBO or EGB 761 alone. In line, reduced apoptosis with NF-κB pathway activation was observed in hippocampus neurons treated by HBO and EGB 761. Conclusions: Our results suggested that HBO and EGB 761 improve cognitive and memory capacity in a rat model of AD. The protective effects are associated with the reduced apoptosis with NF-κB pathway activation in hippocampus neurons. PMID:26608991

  12. Defining the Optimal Window for Cranial Transplantation of Human Induced Pluripotent Stem Cell-Derived Cells to Ameliorate Radiation-Induced Cognitive Impairment

    PubMed Central

    Acharya, Munjal M.; Martirosian, Vahan; Christie, Lori-Ann; Riparip, Lara; Strnadel, Jan; Parihar, Vipan K.

    2015-01-01

    Past preclinical studies have demonstrated the capability of using human stem cell transplantation in the irradiated brain to ameliorate radiation-induced cognitive dysfunction. Intrahippocampal transplantation of human embryonic stem cells and human neural stem cells (hNSCs) was found to functionally restore cognition in rats 1 and 4 months after cranial irradiation. To optimize the potential therapeutic benefits of human stem cell transplantation, we have further defined optimal transplantation windows for maximizing cognitive benefits after irradiation and used induced pluripotent stem cell-derived hNSCs (iPSC-hNSCs) that may eventually help minimize graft rejection in the host brain. For these studies, animals given an acute head-only dose of 10 Gy were grafted with iPSC-hNSCs at 2 days, 2 weeks, or 4 weeks following irradiation. Animals receiving stem cell grafts showed improved hippocampal spatial memory and contextual fear-conditioning performance compared with irradiated sham-surgery controls when analyzed 1 month after transplantation surgery. Importantly, superior performance was evident when stem cell grafting was delayed by 4 weeks following irradiation compared with animals grafted at earlier times. Analysis of the 4-week cohort showed that the surviving grafted cells migrated throughout the CA1 and CA3 subfields of the host hippocampus and differentiated into neuronal (∼39%) and astroglial (∼14%) subtypes. Furthermore, radiation-induced inflammation was significantly attenuated across multiple hippocampal subfields in animals receiving iPSC-hNSCs at 4 weeks after irradiation. These studies expand our prior findings to demonstrate that protracted stem cell grafting provides improved cognitive benefits following irradiation that are associated with reduced neuroinflammation. PMID:25391646

  13. Harpagoside ameliorates the amyloid-β-induced cognitive impairment in rats via up-regulating BDNF expression and MAPK/PI3K pathways.

    PubMed

    Li, J; Ding, X; Zhang, R; Jiang, W; Sun, X; Xia, Z; Wang, X; Wu, E; Zhang, Y; Hu, Y

    2015-09-10

    So far, no effective disease-modifying therapies for Alzheimer's disease (AD) aiming at protecting or reversing neurodegeneration of the disease have been established yet. The present work aims to elucidate the effect of Harpagoside (abbreviated HAR), an iridoid glycosides purified from the Chinese medicinal herb Scrophularia ningpoensis, on neurodegeneration induced by β-amyloid peptide (Aβ) and the underlying molecular mechanism. Here we show that HAR exerts neuroprotective effects against Aβ neurotoxicity. Rats injected aggregated Aβ₁₋₄₀ into the bilateral hippocampus displayed impaired spatial learning and memory ability in a Y-maze test and novel object recognition test, while HAR treatment ameliorated Aβ₁₋₄₀-induced behavioral deficits. Moreover, administration of HAR increased the expression levels of brain-derived neurotrophic factor (BDNF) and activated the extracellular-regulated protein kinase (ERK) and the phosphatidylinositol 3-kinase (PI3-kinase) pathways both in the cerebral cortex and hippocampus of the Aβ₁₋₄₀-insulted rat model. Furthermore, in cultured primary cortical neurons, Aβ₁₋₄₂ induced significant decrease of choline acetyltransferase (ChAT)-positive neuron number and neurite outgrowth length, both of which were dose dependently increased by HAR. In addition, HAR pretreatment also significantly attenuated the decrease of cell viability in Aβ₁₋₄₂-injured primary cortical neurons. Finally, when K252a, an inhibitor of Trk tyrosine kinases, and a BDNF neutralizing antibody were added to the culture medium 2 h prior to HAR addition, the protective effect of HAR on Aβ₁₋₄₂-induced neurodegeneration in the primary cortical neuron was almost inhibited. Taken together, HAR exerting neuroprotection effect and ameliorating learning and memory deficit appears to be associated, at least in part, with up-regulation of BDNF content as well as activating its downstream signaling pathways, e.g., MAPK

  14. Docosahexaenoic acid intake ameliorates ketamine-induced impairment of spatial cognition and learning ability in ICR mice.

    PubMed

    Huang, Shucai; Dai, Yuanyuan; Zhang, Zhiwen; Hao, Wei; Chen, Hongxian

    2014-09-19

    Several studies have reported the ketamine-induced cognitive impairment. Docosahexaenoic acid (DHA) supplementation improves cognitive function in human infants and protects against learning impairment in patients with Alzheimer's disease (AD). In this study, we investigated the effect of DHA on ketamine-induced impairment of spatial cognition and learning ability in Institute of Cancer Research (ICR) mice. Morris water maze (MWM) was used to assess spatial learning and memory. Gamma-aminobutyric acid (GABA) levels in the hippocampus and prefrontal cortex were measured using high-performance liquid chromatography (HPLC). The results showed that intraperitoneal injection of ketamine (30mg/kg, twice per day) for 4 weeks led to the decline of spatial cognitive ability in mice, and 420mg/(kgd) DHA supplementation for 6 weeks improved ketamine-induced spatial cognitive impairment to a certain extent. The up-regulation of GABA levels in the hippocampus and prefrontal cortex was related to the improvement in spatial learning. Our results suggested that DHA supplementation would be a promising intervention to improve ketamine-induced spatial memory and cognitive dysfunction, and this effect of DHA might be correlated with the up-regulation of GABA levels. PMID:25123439

  15. The aging memory: Modulating epigenetic modifications to improve cognitive function.

    PubMed

    Fonseca, Rosalina

    2016-09-01

    Age-related cognitive decline is a major concern in society. Here, I discuss recent evidence that shows an age-related modulation of gene transcription by epigenetic modifications. Epigenetic modifications, such as histone acetylation, is unbalanced in aging, with an increase in histone deacetylation, that limits the expression of plasticity-related genes. By modifying the balance towards histone acetylation, histone deacetylase inhibitors present a new pharmacological approach to ameliorate age-related cognitive deficits. PMID:27390098

  16. Developing treatments for cognitive deficits in schizophrenia: the challenge of translation.

    PubMed

    Young, J W; Geyer, M A

    2015-02-01

    Schizophrenia is a life-long debilitating mental disorder affecting tens of millions of people worldwide. The serendipitous discovery of antipsychotics focused pharmaceutical research on developing a better antipsychotic. Our understanding of the disorder has advanced however, with the knowledge that cognitive enhancers are required for patients in order to improve their everyday lives. While antipsychotics treat psychosis, they do not enhance cognition and hence are not antischizophrenics. Developing pro-cognitive therapeutics has been extremely difficult, however, especially when no approved treatment exists. In lieu of stumbling on an efficacious treatment, developing targeted compounds can be facilitated by understanding the neural mechanisms underlying altered cognitive functioning in patients. Equally importantly, these cognitive domains will need to be measured similarly in animals and humans so that novel targets can be tested prior to conducting expensive clinical trials. To date, the limited similarity of testing across species has resulted in a translational bottleneck. In this review, we emphasize that schizophrenia is a disorder characterized by abnormal cognitive behavior. Quantifying these abnormalities using tasks having cross-species validity would enable the quantification of comparable processes in rodents. This approach would increase the likelihood that the neural substrates underlying relevant behaviors will be conserved across species. Hence, we detail cross-species tasks which can be used to test the effects of manipulations relevant to schizophrenia and putative therapeutics. Such tasks offer the hope of providing a bridge between non-clinical and clinical testing that will eventually lead to treatments developed specifically for patients with deficient cognition. PMID:25516372

  17. Developing treatments for cognitive deficits in schizophrenia: The challenge of translation

    PubMed Central

    Young, J.W.; Geyer, M.A.

    2015-01-01

    Schizophrenia is a life-long debilitating mental disorder affecting tens of millions of people worldwide. The serendipitous discovery of antipsychotics focused pharmaceutical research on developing a better antipsychotic. Our understanding of the disorder has advanced however, with the knowledge that cognitive enhancers are required for patients in order to improve their everyday lives. Whilst antipsychotics treat psychosis, they do not enhance cognition and hence are not antischizophrenics. Developing pro-cognitive therapeutics has been extremely difficult however, especially when no approved treatment exists. In lieu of stumbling on an efficacious treatment, developing targeted compounds can be facilitated by understanding the neural mechanisms underlying altered cognitive functioning in patients. Equally importantly, these cognitive domains will need to be measured similarly in animals and humans so that novel targets can be tested prior to conducting expensive clinical trials. To date, the limited similarity of testing across species has resulted in a translational bottleneck. In this review, we emphasize that schizophrenia is a disorder characterized by abnormal cognitive behavior. Quantifying these abnormalities using tasks having cross-species validity would enable the quantification of comparable processes in rodents. This approach would increase the likelihood that the neural substrates underlying relevant behaviors will be conserved across species. Hence, we detail cross-species tasks which can be used to test the effects of manipulations relevant to schizophrenia and putative therapeutics. Such tasks offer the hope of providing a bridge between non-clinical and clinical testing that will eventually lead to treatments developed specifically for patients with deficient cognition. PMID:25516372

  18. Assessing Social-Cognitive Deficits in Schizophrenia With the Mayer-Salovey-Caruso Emotional Intelligence Test

    PubMed Central

    Eack, Shaun M.; Greeno, Catherine G.; Pogue-Geile, Michael F.; Newhill, Christina E.; Hogarty, Gerard E.

    2010-01-01

    The emotion management subscale of the Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT) has recently been recommended by the National Institute of Mental Health Measurement and Treatment Research to Improve Cognition in Schizophrenia committee as the sole measure of social cognition for trials of cognitive enhancement in schizophrenia, yet the psychometric properties of this subscale and the larger instrument in schizophrenia patients have not been thoroughly examined. This research presents a psychometric investigation of the MSCEIT in a sample of 64 early course outpatients with schizophrenia, schizoaffective, or schizophreniform disorder. Results demonstrated that the MSCEIT possesses adequate internal consistency reliability among its branch and total scales and that patients’ branch and overall test performance was significantly below normative levels. Estimates of discriminant and concurrent validity indicated that the MSCEIT diverged from measures of neurocognitive functioning and psychopathology, but was only modestly related with objective measures of functional outcome. Convergent validity estimates suggested that, contrary to expectations, the MSCEIT did not correlate with a behavioral measure of social cognition. Finally, exploratory factor analyses suggested the possibility of a shift in the latent structure of emotional intelligence in schizophrenia, compared with studies with healthy individuals. These findings support the use of the MSCEIT as a reliable and potentially valid method of assessing the emotional components of social cognition in schizophrenia, but also point to a need for additional measurement development efforts to assess broader social-cognitive domains that may exhibit stronger relations with functional outcome. Further investigation is warranted to examine the instrument's latent factor structure and convergence with other measures of social cognition. PMID:18648021

  19. Deregulated semantic cognition contributes to object-use deficits in Alzheimer's disease: A comparison with semantic aphasia and semantic dementia.

    PubMed

    Corbett, Faye; Jefferies, Elizabeth; Burns, Alistair; Lambon Ralph, Matthew A

    2015-09-01

    Executive control is impaired from the early stages of Alzheimer's Disease (AD) and this produces deregulated semantic cognition (Corbett, Jefferies, Burns, & Lambon Ralph, ; Perry, Watson, & Hodges, ). While control deficits should affect semantic retrieval across all modalities, previous studies have typically focused on verbal semantic tasks. Even when non-verbal semantic tasks have been used, these have typically employed simple picture-matching tasks, which may be influenced by abnormalities in covert naming. Therefore, in the present study, we examined 10 patients with AD on a battery of object-use tasks, in order to advance our understanding of the origins of non-verbal semantic deficits in this population. The AD patients' deficits were contrasted with previously published performance on the same tasks within two additional groups of patients, displaying either semantic degradation (semantic dementia) or deregulation of semantic retrieval (semantic aphasia; Corbett, Jefferies, Ehsan, & Lambon Ralph, ). While overall accuracy was comparable to the scores in both other groups, the AD patients' object-use impairment most closely resembled that observed in SA; they exhibited poorer performance on comprehension tasks that placed strong demands on executive control. A similar pattern was observed in the expressive domain: the AD and SA groups were relatively good at straightforward object use compared to executively demanding, mechanical puzzles. Error types also differed: while all patients omitted essential actions, the SA and AD groups' demonstrations also featured unrelated intrusions. An association between AD patients' object use and their scores on standard executive measures suggested that control deficits contributed to their non-verbal semantic deficits. Moreover, in a task specifically designed to manipulate executive demand, patients with AD (and SA) exhibited difficulty in thinking flexibly about the non-canonical uses of everyday objects, especially

  20. Assessing Specific Cognitive Deficits Associated with Dementia in Older Adults with Down Syndrome: Use and Validity of the Arizona Cognitive Test Battery (ACTB)

    PubMed Central

    Sinai, Amanda; Hassiotis, Angela; Rantell, Khadija; Strydom, Andre

    2016-01-01

    Background Down syndrome is associated with specific cognitive deficits. Alongside this, older adults with Down syndrome are a high risk group for dementia. The Arizona Cognitive Test Battery (ACTB), a cognitive assessment battery specifically developed for use with individuals with Down syndrome, has been proposed for use as outcome measures for clinical trials in this population. It has not been validated in older adults with Down syndrome. This study aims to assess the use and validity of the ACTB in older adults with Down syndrome. Methods Participants with Down syndrome aged 45 and over were assessed using the ACTB, standard tabletop tests and informant ratings. Results Assessment outcomes of 49 participants were analysed. Of these, 19 (39%) had a diagnosis of dementia or possible dementia. Most participants were able to attempt most of the tasks, although some tasks had high floor effects (including CANTAB Intra-Extra Dimensional shift stages completed and Modified Dots Task). Of the ACTB tasks, statistically significant differences were observed between the dementia and no dementia groups on CANTAB Simple Reaction Time median latency, NEPSY Visuomotor Precision—Car and Motorbike and CANTAB Paired Associates Learning stages completed. No significant differences were observed for CANTAB Intra-Extra Dimensional Shift, Modified Dots Task, Finger Sequencing, NEPSY Visuomotor precision—Train and Car and CANTAB Paired Associates Learning first trial memory score. Several of the tasks in the ACTB can be used in older adults with Down syndrome and have mild to moderate concurrent validity when compared to tabletop tests and informant ratings, although this varies on a test by test basis. Conclusions Overall, scores for a number of tests in the ACTB were similar when comparing dementia and no dementia groups of older adults with Down syndrome, suggesting that it would not be an appropriate outcome measure of cognitive function for clinical trials of dementia

  1. A randomized, placebo-controlled study investigating the nicotinic α7 agonist, RG3487, for cognitive deficits in schizophrenia.

    PubMed

    Umbricht, Daniel; Keefe, Richard S E; Murray, Stephen; Lowe, David A; Porter, Richard; Garibaldi, George; Santarelli, Luca

    2014-06-01

    Effective treatments for cognitive impairment associated with schizophrenia (CIAS) remain an unmet need. Nicotinic α7 receptor agonists may be effective in CIAS. This 8-week (week 1, inpatient; weeks 2-8, outpatient), double-blind, randomized study used Measurement And Treatment Research to Improve Cognition in Schizophrenia (MATRICS) guidelines to investigate the nicotinic α7 partial agonist RG3487 (formerly MEM3454) in CIAS; 215 patients with chronic stable schizophrenia received placebo or RG3487 (5, 15, or 50 mg) added to ongoing treatment with risperidone, paliperidone, or aripiprazole. Primary end point was baseline to week 8 change in MATRICS Consensus Cognitive Battery (MCCB) composite t-score. Secondary outcomes were change in MCCB domain and negative symptom assessment (NSA) scores. The study did not allow for evaluation of nonsmokers. Each RG3487 dose was evaluated using a mixed-effects model repeated measures approach. Mean (SD) baseline MCCB composite t-score was 28.3 (12.0). No significant effect on MCCB composite t-scores was observed with RG3487 (adjusted mean difference (SE) vs placebo: 5 mg: 0.11 (1.39); 15 mg: -1.95 (1.39); 50 mg: -1.13 (1.37); p = 0.2-0.9). RG3487 did not improve MCCB domain scores. In a post hoc analysis of patients with moderate negative symptoms, 5 and 50 mg RG3487 vs placebo significantly improved NSA total (-4.45 (p = 0.04) and -4.75 (p = 0.02), respectively) and global (-0.39 (p = 0.04) and -0.55 (p = 0.003), respectively) scores. The MCCB did not lead to higher than expected patient withdrawal. RG3487 was generally well tolerated. In patients with stable schizophrenia, RG3487 did not improve cognitive deficits, as assessed by the MCCB; however, in patients with moderate negative symptoms, a post hoc analysis revealed significant improvement of negative symptoms. PMID:24549101

  2. Preadolescent girls with attention-deficit/hyperactivity disorder: I. Background characteristics, comorbidity, cognitive and social functioning, and parenting practices.

    PubMed

    Hinshaw, Stephen P

    2002-10-01

    This study investigated a diverse sample of girls (6-12 years of age) with attention-deficit/hyperactivity disorder (ADHD), combined type (n = 93) and inattentive type (n = 47), plus age- and ethnicity-matched comparison girls (n = 88), who participated in research summer programs. Speech and language problems, grade retention, and adoption characterized the ADHD sample; documented abuse characterized the combined type. Girls with ADHD showed dysfunction in terms of externalizing and internalizing behaviors and comorbidities, cognitive and academic performance, authoritarian parenting, and peer status. The inattentive type was more socially isolated but less rejected by peers than the combined type. ADHD-related impairment was independent of age and disruptive comorbidity. Further examination of processes related to psychopathology and competencies in girls with ADHD is needed. PMID:12362959

  3. A diet containing grape powder ameliorates the cognitive decline in aged rats with a long-term high-fructose-high-fat dietary pattern.

    PubMed

    Chou, Liang-Mao; Lin, Ching-I; Chen, Yue-Hwa; Liao, Hsiang; Lin, Shyh-Hsiang

    2016-08-01

    Research has suggested that the consumption of foods rich in polyphenols is beneficial to the cognitive functions of the elderly. We investigated the effects of grape consumption on spatial learning, memory performance and neurodegeneration-related protein expression in aged rats fed a high-fructose-high-fat (HFHF) diet. Six-week-old Wistar rats were fed an HFHF diet to 66 weeks of age to establish a model of an HFHF dietary pattern, before receiving intervention diets containing different amounts of grape powder for another 12 weeks in the second part of the experiment. Spatial learning, memory performance and cortical and hippocampal protein expression levels were assessed. After consuming the HFHF diet for a year, results showed that the rats fed a high grape powder-containing diet had significantly better spatial learning and memory performance, lower expression of β-amyloid and β-secretase and higher expression of α-secretase than the rats fed a low grape powder-containing diet. Therefore, long-term consumption of an HFHF diet caused a decline in cognitive functions and increased the risk factors for neurodegeneration, which could subsequently be ameliorated by the consumption of a polyphenol-rich diet. PMID:27206221

  4. The origins of repetitive thought in rumination: Separating cognitive style from deficits in inhibitory control over memory

    PubMed Central

    Fawcett, Jonathan M.; Benoit, Roland G.; Gagnepain, Pierre; Salman, Amna; Bartholdy, Savani; Bradley, Caroline; Chan, Daniel K.-Y.; Roche, Ayesha; Brewin, Chris R.; Anderson, Michael C.

    2015-01-01

    Background and objectives Rumination is a major contributor to the maintenance of affective disorders and has been linked to memory control deficits. However, ruminators often report intentionally engaging in repetitive thought due to its perceived benefits. Deliberate re-processing may lead to the appearance of a memory control deficit that is better explained as a difference in cognitive style. Methods Ninety-six undergraduate students volunteered to take part in a direct-suppression variant of the Think/No-Think paradigm after which they completed self-report measures of rumination and the degree to which they deliberately re-processed the to-be-suppressed items. Results We demonstrate a relation between rumination and impaired suppression-induced forgetting. This relation is robust even when controlling for deliberate re-processing of the to-be-suppressed items, a behavior itself related to both rumination and suppression. Therefore, whereas conscious fixation on to-be-suppressed items reduced memory suppression, it did not fully account for the relation between rumination and memory suppression. Limitations The current experiment employed a retrospective measure of deliberate re-processing in the context of an unscreened university sample; future research might therefore generalize our findings using an online measure of deliberate re-processing or within a clinical population. Conclusions We provide evidence that deliberate re-processing accounts for some – but not all – of the relation between rumination and suppression-induced forgetting. The present findings, observed in a paradigm known to engage top-down inhibitory modulation of mnemonic processing, provide the most theoretically focused evidence to date for the existence of a memory control deficit in rumination. PMID:25462596

  5. Deficits in narrative discourse elicited by visual stimuli are already present in patients with mild cognitive impairment

    PubMed Central

    Drummond, Cláudia; Coutinho, Gabriel; Fonseca, Rochele Paz; Assunção, Naima; Teldeschi, Alina; de Oliveira-Souza, Ricardo; Moll, Jorge; Tovar-Moll, Fernanda; Mattos, Paulo

    2015-01-01

    Language batteries used to assess the skills of elderly individuals, such as naming and semantic verbal fluency, present some limitations in differentiating healthy controls from patients with amnestic mild cognitive impairment (a-MCI). Deficits in narrative discourse occur early in dementia caused by Alzheimer's disease (AD), and the narrative discourse abilities of a-MCI patients are poorly documented. The present study sought to propose and evaluate parameters for investigating narrative discourse in these populations. After a pilot study of 30 healthy subjects who served as a preliminary investigation of macro- and micro-linguistic aspects, 77 individuals (patients with AD and a-MCI and a control group) were evaluated. The experimental task required the participants to narrate a story based on a sequence of actions visually presented. The Control and AD groups differed in all parameters except narrative time and the total number of words recalled. The a-MCI group displayed mild discursive difficulties that were characterized as an intermediate stage between the Control and AD groups' performances. The a-MCI and Control groups differed from the AD group with respect to global coherence, discourse type and referential cohesion. The a-MCI and AD groups were similar to one another but differed from the Control group with respect to the type of words recalled, the repetition of words in the same sentence, the narrative structure and the inclusion of irrelevant propositions in the narrative. The narrative parameter that best distinguished the three groups was the speech effectiveness index. The proposed task was able to reveal differences between healthy controls and groups with cognitive decline. According to our findings, patients with a-MCI already present narrative deficits that are characterized by mild discursive difficulties that are less severe than those found in patients with AD. PMID:26074814

  6. Baduk (the Game of Go) Improved Cognitive Function and Brain Activity in Children with Attention Deficit Hyperactivity Disorder

    PubMed Central

    Kim, Se Hee; Lee, Young Sik; Kim, Bung-Nyun; Cheong, Jae Hoon; Han, Sang Ho

    2014-01-01

    Objective Attention deficit hyperactivity disorder (ADHD) symptoms are associated with the deficit in executive functions. Playing Go involves many aspect of cognitive function and we hypothesized that it would be effective for children with ADHD. Methods Seventeen drug naïve children with ADHD and seventeen age and sex matched comparison subjects were participated. Participants played Go under the instructor's education for 2 hours/day, 5 days/week. Before and at the end of Go period, clinical symptoms, cognitive functions, and brain EEG were assessed with Dupaul's ADHD scale (ARS), Child depression inventory (CDI), digit span, the Children's Color Trails Test (CCTT), and 8-channel QEEG system (LXE3208, Laxtha Inc., Daejeon, Korea). Results There were significant improvements of ARS total score (z=2.93, p<0.01) and inattentive score (z=2.94, p<0.01) in children with ADHD. However, there was no significant change in hyperactivity score (z=1.33, p=0.18). There were improvement of digit total score (z=2.60, p<0.01; z=2.06, p=0.03), digit forward score (z=2.21, p=0.02; z=2.02, p=0.04) in both ADHD and healthy comparisons. In addition, ADHD children showed decreased time of CCTT-2 (z=2.21, p=0.03). The change of theta/beta right of prefrontal cortex during 16 weeks was greater in children with ADHD than in healthy comparisons (F=4.45, p=0.04). The change of right theta/beta in prefrontal cortex has a positive correlation with ARS-inattention score in children with ADHD (r=0.44, p=0.03). Conclusion We suggest that playing Go would be effective for children with ADHD by activating hypoarousal prefrontal function and enhancing executive function. PMID:24843369

  7. "I Know that You Know that I Know": Neural Substrates Associated with Social Cognition Deficits in DM1 Patients.

    PubMed

    Serra, Laura; Cercignani, Mara; Bruschini, Michela; Cipolotti, Lisa; Mancini, Matteo; Silvestri, Gabriella; Petrucci, Antonio; Bucci, Elisabetta; Antonini, Giovanni; Licchelli, Loretta; Spanò, Barbara; Giacanelli, Manlio; Caltagirone, Carlo; Meola, Giovanni; Bozzali, Marco

    2016-01-01

    Myotonic dystrophy type-1 (DM1) is a genetic multi-systemic disorder involving several organs including the brain. Despite the heterogeneity of this condition, some patients with non-congenital DM1 can present with minimal cognitive impairment on formal testing but with severe difficulties in daily-living activities including social interactions. One explanation for this paradoxical mismatch can be found in patients' dysfunctional social cognition, which can be assessed in the framework of the Theory of Mind (ToM). We hypothesize here that specific disease driven abnormalities in DM1 brains may result in ToM impairments. We recruited 20 DM1 patients who underwent the "Reading the Mind in the Eyes" and the ToM-story tests. These patients, together with 18 healthy controls, also underwent resting-state functional MRI. A composite Theory of Mind score was computed for all recruited patients and correlated with their brain functional connectivity. This analysis provided the patients' "Theory of Mind-network", which was compared, for its topological properties, with that of healthy controls. We found that DM1 patients showed deficits in both tests assessing ToM. These deficits were associated with specific patterns of abnormal connectivity between the left inferior temporal and fronto-cerebellar nodes in DM1 brains. The results confirm the previous suggestions of ToM dysfunctions in patients with DM1 and support the hypothesis that difficulties in social interactions and personal relationships are a direct consequence of brain abnormalities, and not a reaction symptom. This is relevant not only for a better pathophysiological comprehension of DM1, but also for non-pharmacological interventions to improve clinical aspects and impact on patients' success in life. PMID:27258100

  8. Deficits in narrative discourse elicited by visual stimuli are already present in patients with mild cognitive impairment.

    PubMed

    Drummond, Cláudia; Coutinho, Gabriel; Fonseca, Rochele Paz; Assunção, Naima; Teldeschi, Alina; de Oliveira-Souza, Ricardo; Moll, Jorge; Tovar-Moll, Fernanda; Mattos, Paulo

    2015-01-01

    Language batteries used to assess the skills of elderly individuals, such as naming and semantic verbal fluency, present some limitations in differentiating healthy controls from patients with amnestic mild cognitive impairment (a-MCI). Deficits in narrative discourse occur early in dementia caused by Alzheimer's disease (AD), and the narrative discourse abilities of a-MCI patients are poorly documented. The present study sought to propose and evaluate parameters for investigating narrative discourse in these populations. After a pilot study of 30 healthy subjects who served as a preliminary investigation of macro- and micro-linguistic aspects, 77 individuals (patients with AD and a-MCI and a control group) were evaluated. The experimental task required the participants to narrate a story based on a sequence of actions visually presented. The Control and AD groups differed in all parameters except narrative time and the total number of words recalled. The a-MCI group displayed mild discursive difficulties that were characterized as an intermediate stage between the Control and AD groups' performances. The a-MCI and Control groups differed from the AD group with respect to global coherence, discourse type and referential cohesion. The a-MCI and AD groups were similar to one another but differed from the Control group with respect to the type of words recalled, the repetition of words in the same sentence, the narrative structure and the inclusion of irrelevant propositions in the narrative. The narrative parameter that best distinguished the three groups was the speech effectiveness index. The proposed task was able to reveal differences between healthy controls and groups with cognitive decline. According to our findings, patients with a-MCI already present narrative deficits that are characterized by mild discursive difficulties that are less severe than those found in patients with AD. PMID:26074814

  9. Cognitive performance deficits in a simulated climb of Mount Everest - Operation Everest II

    NASA Technical Reports Server (NTRS)

    Kennedy, R. S.; Dunlap, W. P.; Banderet, L. E.; Smith, M. G.; Houston, C. S.

    1989-01-01

    Cognitive function at simulated altitude was investigated in a repeated-measures within-subject study of performance by seven volunteers in a hypobaric chamber, in which atmospheric pressure was systematically lowered over a period of 40 d to finally reach a pressure equivalent to 8845 m, the approximate height of Mount Everest. The automated performance test system employed compact computer design; automated test administrations, data storage, and retrieval; psychometric properties of stability and reliability; and factorial richness. Significant impairments of cognitive function were seen for three of the five tests in the battery; on two tests, grammatical reasoning and pattern comparison, every subject showed a substantial decrement.

  10. Uncovering a clinical portrait of sluggish cognitive tempo within an evaluation for attention-deficit/hyperactivity disorder: A case study.

    PubMed

    Becker, Stephen P; Ciesielski, Heather A; Rood, Jennifer E; Froehlich, Tanya E; Garner, Annie A; Tamm, Leanne; Epstein, Jeffery N

    2016-01-01

    Despite the burgeoning scientific literature examining the sluggish cognitive tempo (SCT) construct, very little is known about the clinical presentation of SCT. In clinical cases where SCT is suspected, it is critical to carefully assess not only for attention-deficit/hyperactivity disorder (ADHD) but also for other comorbidities that may account for the SCT-related behaviors, especially internalizing symptoms and sleep problems. The current case study provides a clinical description of SCT in a 7-year-old girl, offering a real-life portrait of SCT while also providing an opportunity to qualitatively differentiate between SCT and ADHD, other psychopathologies (e.g. depression, anxiety), and potentially related domains of functioning (e.g. sleep, executive functioning [EF]). "Jessica" was described by herself, parents, and teacher as being much slower than her peers in completing schoolwork, despite standardized testing showing Jessica to have above average intelligence and academic achievement. Jessica's parents completed rating scales indicating high levels of SCT symptoms and daytime sleepiness, as well as mildly elevated EF deficits. More research is needed to determine how to best conceptualize, assess, and treat SCT, and Jessica's case underscores the importance of further work in this area. PMID:25326531

  11. Learning to Read Against All Odds: Using Precision Reading to Enhance Literacy in Students with Cognitive Impairments, Extreme Academic Deficits, and Severe Social, Emotional, and Psychiatric Problems

    ERIC Educational Resources Information Center

    Freeze, Rick; Cook, Paula

    2005-01-01

    The purpose of this study was to assess the efficacy and practicality of precision reading, a constructive reading intervention, with students with cognitive impairments, extreme academic deficits in reading, and severe social, emotional, and psychiatric problems. As precision reading had shown promise with students with low achievement, learning…

  12. Randomized Controlled Trial of Osmotic-Release Methylphenidate with Cognitive-Behavioral Therapy in Adolescents with Attention-Deficit/Hyperactivity Disorder and Substance Use Disorders

    ERIC Educational Resources Information Center

    Riggs, Paula D.; Winhusen, Theresa; Davies, Robert D.; Leimberger, Jeffrey D.; Mikulich-Gilbertson, Susan; Klein, Constance; Macdonald, Marilyn; Lohman, Michelle; Bailey, Genie L.; Haynes, Louise; Jaffee, William B.; Haminton, Nancy; Hodgkins, Candace; Whitmore, Elizabeth; Trello-Rishel, Kathlene; Tamm, Leanne; Acosta, Michelle C.; Royer-Malvestuto, Charlotte; Subramaniam, Geetha; Fishman, Marc; Holmes, Beverly W.; Kaye, Mary Elyse; Vargo, Mark A.; Woody, George E.; Nunes, Edward V.; Liu, David

    2011-01-01

    Objective: To evaluate the efficacy and safety of osmotic-release methylphenidate (OROS-MPH) compared with placebo for attention-deficit/hyperactivity disorder (ADHD), and the impact on substance treatment outcomes in adolescents concurrently receiving cognitive-behavioral therapy (CBT) for substance use disorders (SUD). Method: This was a…

  13. Cognitive Performance Is Highly Sensitive to Prior Experience in Mice with a Learning and Memory Deficit: Failure Leads to More Failure

    ERIC Educational Resources Information Center

    Hebda-Bauer, Elaine K.; Watson, Stanley J.; Akil, Huda

    2005-01-01

    The impact of a previously successful or unsuccessful experience on the subsequent acquisition of a related task is not well understood. The nature of past experience may have even greater impact in individuals with learning deficits, as their cognitive processes can be easily disrupted. Mice with a targeted disruption of the [alpha] and [delta]…

  14. Effects on the visual system might contribute to some of the cognitive deficits of cancer chemotherapy-induced ‘chemo-fog’

    PubMed Central

    Raffa, R. B.; Tallarida, R. J.

    2011-01-01

    SUMMARY The diminution in certain aspects of cognitive function that is reported to occur in some patients during or after adjuvant cancer chemotherapy is variously known as ‘chemo-fog’, ‘chemo-brain’ or other such term. In addition to reported deficits in attention, concentration and other functions, most, if not all, of the studies report deficits involving visual-spatial function or visual memory. Since the visual system is part of the nervous system, it seems reasonable to ask if it is susceptible to some of the deleterious effects produced by adjuvant chemotherapeutic drugs. We propose here the possibility that some portion of the vision-related aspects of the ‘chemo-fog’ spectrum of cognitive deficits results from a direct action of the adjuvant drugs on the visual system or from drug / drug or site / site interaction between effects on the visual system and other critical brain regions. PMID:20831527

  15. The brain structural and cognitive basis of odor identification deficits in mild cognitive impairment and Alzheimer’s disease

    PubMed Central

    2014-01-01

    Background The objectives of this study were to explore the relationship between olfactory impairment, cognitive measures, and brain structure volumes in healthy elderly individuals, compared to patients with amnestic mild cognitive impairment (aMCI) or early Alzheimer’s disease (AD). The primary aim was to elucidate possible differences in cognitive scores and brain structure volumes between aMCI/AD patients with relatively intact odor identification (OI) ability and those with reduced ability. Methods Twelve patients with aMCI, six with early AD, and 30 control subjects were included. OI abilities were assessed with the Brief Smell Identification Test (B-SIT) and Sniffin Sticks Identification Test (SSIT). Neuropsychological tests of executive functions and memory were performed. Brain structural volumes were obtained from T1 weighted 3D MRI at 3 Tesla. Statistical comparisons between the patients with aMCI and AD indicated no significant differences in performance on most tests. Since the groups were small and AD patients were in an early phase of disease, all patients were subsequently considered together as a single group for studying OI. Patients were subdivided into relatively intact (scores >50%) and reduced OI (≤ 50% score) on the olfactory tests. Results The aMCI/AD group with reduced OI ability, as measured by both B-SIT and SSIT, had significantly smaller hippocampal volume as compared to the patient group with OI scores > 50%. There was a significant association between OI scores and hippocampal volume in the patient (not the control) group. Similar changes with tests of executive function and memory were not found. Low OI scores on B-SIT were associated with conversion from aMCI to AD in patients. The reduced OI patient group was significantly faster on Rey complex figure copying than the fairly intact OI group. Conclusion The results from this pilot study suggest that the reduction in the size of hippocampus in connection with early AD is

  16. Cognitive Deficits Associated with Acquired Amusia after Stroke: A Neuropsychological Follow-Up Study

    ERIC Educational Resources Information Center

    Sarkamo, Teppo; Tervaniemi, Mari; Soinila, Seppo; Autti, Taina; Silvennoinen, Heli M.; Laine, Matti; Hietanen, Marja

    2009-01-01

    Recent evidence on amusia suggests that our ability to perceive music might be based on the same neural resources that underlie other higher cognitive functions, such as speech perception and spatial processing. We studied the neural correlates of acquired amusia by performing extensive neuropsychological assessments on 53 stroke patients with a…

  17. Dimensions and Correlates of Attention Deficit/Hyperactivity Disorder and Sluggish Cognitive Tempo

    ERIC Educational Resources Information Center

    Garner, Annie A.; Marceaux, Janice; Mrug, Sylvie; Patterson, Cryshelle; Hodgens, Bart

    2010-01-01

    The present study examined Sluggish Cognitive Tempo (SCT) in relation to ADHD symptoms, clinical diagnosis, and multiple aspects of adjustment in a clinical sample. Parent and teacher reports were gathered for 322 children and adolescents evaluated for behavioral, emotional, and/or learning problems at a university clinic. Confirmatory factor…

  18. Cognitive Set Shifting Deficits and Their Relationship to Repetitive Behaviors in Autism Spectrum Disorder

    ERIC Educational Resources Information Center

    Miller, Haylie L.; Ragozzino, Michael E.; Cook, Edwin H.; Sweeney, John A.; Mosconi, Matthew W.

    2015-01-01

    The neurocognitive impairments associated with restricted and repetitive behaviors (RRBs) in autism spectrum disorder (ASD) are not yet clear. Prior studies indicate that individuals with ASD show reduced cognitive flexibility, which could reflect difficulty shifting from a previously learned response pattern or a failure to maintain a new…

  19. Prefrontal Cortex Cognitive Deficits in Children Treated Early and Continuously for PKU.

    ERIC Educational Resources Information Center

    Diamond, Adele; Prevor, Meredith B.; Druin, Donald P.; Callender, Glenda

    1997-01-01

    Hypothesized that elevated ratio of phenylalanine to tyrosine in blood of children with phenylketonuria uniquely affects cognitive functions dependent on prefrontal cortex because of the special sensitivity of prefrontally projecting dopamine neurons to small decreases in tyrosine. Found that children whose phenylalanine levels were three to five…

  20. A Multimodal Assessment of Behavioral and Cognitive Deficits in Abused and Neglected Preschoolers.

    ERIC Educational Resources Information Center

    Hoffman-Plotkin, Debbie; Twentyman, Craig T.

    1984-01-01

    Multiple measures of social and cognitive functioning were obtained to investigate whether abused and neglected children demonstrate serious psychological disturbances following instances of child maltreatment. Participants were 42 preschool children who had a previous history of physical abuse, serious neglect, or no maltreatment. (Author/RH)

  1. Prenatal exposure to vapors of gasoline-ethanol blends causes few cognitive deficits in adult rats

    EPA Science Inventory

    Developmental exposure to inhaled ethanol-gasoline fuel blends is a potential public health concern. Here we assessed cognitive functions in adult offspring of pregnant rats that were exposed to vapors of gasoline blended with a range of ethanol concentrations, including gasoli...

  2. Cognitive mediational deficits and the role of coping styles in pedophile and ephebophile Roman Catholic clergy.

    PubMed

    Ryan, Gregory P; Baerwald, Jeffrey P; McGlone, Gerard

    2008-01-01

    This study was designed to examine hypothesized differences between sex offending and nonoffending Roman Catholic clergy on cognitive mediation abilities as measured by the Rorschach Inkblot Test (H. Rorschach, 1921/1942). This study compared 78 priest pedophiles and 77 priest ephebophiles with 80 nonoffending priest controls on the Inkblot test using J. E. Exner's (2003) Comprehensive System. The three groups were compared on seven variables that constitute Exner's Cognitive Mediation cluster. Additionally, the groups' coping styles were compared to examine the interaction of coping style and cognitive mediational abilities. We found interactions between coping style and offending status across most of the cognitive variables indicating impairment in the mild to pathological ranges. Moreover, significantly higher unusual thinking styles (Xu%) and significantly lower conventional thinking styles (X+%) in offenders compared to nonoffenders. Those with an Extratensive style (n=31) showed significantly higher distorted thinking when compared to the Introversive (n=81), Ambitent (n=73), and Avoidant (n=50) coping styles. This study suggests that offenders display significantly higher distorted thinking styles than do nonoffenders. Possible reasons for these discrepancies and the role of coping styles in abusive behaviors were discussed. PMID:18161043

  3. Beyond Stimulus Deprivation: Iron Deficiency and Cognitive Deficits in Postinstitutionalized Children

    ERIC Educational Resources Information Center

    Doom, Jenalee R.; Gunnar, Megan R.; Georgieff, Michael K.; Kroupina, Maria G.; Frenn, Kristin; Fuglestad, Anita J.; Carlson, Stephanie M.

    2014-01-01

    Children adopted from institutions have been studied as models of the impact of stimulus deprivation on cognitive development (Nelson, Bos, Gunnar, & Sonuga-Barke, 2011), but these children may also suffer from micronutrient deficiencies (Fuglestad et al., 2008). The contributions of iron deficiency (ID) and duration of deprivation on…

  4. Piperine, the main alkaloid of Thai black pepper, protects against neurodegeneration and cognitive impairment in animal model of cognitive deficit like condition of Alzheimer's disease.

    PubMed

    Chonpathompikunlert, Pennapa; Wattanathorn, Jintanaporn; Muchimapura, Supaporn

    2010-03-01

    Recently, numerous medicinal plants possessing profound central nervous system effects and antioxidant activity have received much attention as food supplement to improve cognitive function against cognitive deficit condition including in Alzheimer's disease condition. Based on this information, the effect of piperine, a main active alkaloid in fruit of Piper nigrum, on memory performance and neurodegeneration in animal model of Alzheimer's disease have been investigated. Adult male Wistar rats (180-220 g) were orally given piperine at various doses ranging from 5, 10 and 20mg/kg BW at a period of 2 weeks before and 1 week after the intracerebroventricular administration of ethylcholine aziridinium ion (AF64A) bilaterally. The results showed that piperine at all dosage range used in this study significantly improved memory impairment and neurodegeneration in hippocampus. The possible underlying mechanisms might be partly associated with the decrease lipid peroxidation and acetylcholinesterase enzyme. Moreover, piperine also demonstrated the neurotrophic effect in hippocampus. However, further researches about the precise underlying mechanism are still required. PMID:20034530

  5. Anti-Human α-Synuclein N-Terminal Peptide Antibody Protects against Dopaminergic Cell Death and Ameliorates Behavioral Deficits in an AAV-α-Synuclein Rat Model of Parkinson’s Disease

    PubMed Central

    Shahaduzzaman, Md; Nash, Kevin; Hudson, Charles; Sharif, Masroor; Grimmig, Bethany; Lin, Xiaoyang; Bai, Ge; Liu, Hui; Ugen, Kenneth E.; Cao, Chuanhai; Bickford, Paula C.

    2015-01-01

    The protein α-synuclein (α-Syn) has a central role in the pathogenesis of Parkinson’s disease (PD) and immunotherapeutic approaches targeting this molecule have shown promising results. In this study, novel antibodies were generated against specific peptides from full length human α-Syn and evaluated for effectiveness in ameliorating α-Syn-induced cell death and behavioral deficits in an AAV-α-Syn expressing rat model of PD. Fisher 344 rats were injected with rAAV vector into the right substantia nigra (SN), while control rats received an AAV vector expressing green fluorescent protein (GFP). Beginning one week after injection of the AAV-α-Syn vectors, rats were treated intraperitoneally with either control IgG or antibodies against the N-terminal (AB1), or central region (AB2) of α-Syn. An unbiased stereological estimation of TH+, NeuN+, and OX6 (MHC-II) immunostaining revealed that the α-Syn peptide antibodies (AB1 and AB2) significantly inhibited α-Syn-induced dopaminergic cell (DA) and NeuN+ cell loss (one-way ANOVA (F (3, 30) = 5.8, p = 0.002 and (F (3, 29) = 7.92, p = 0.002 respectively), as well as decreasing the number of activated microglia in the ipsilateral SN (one-way ANOVA F = 14.09; p = 0.0003). Antibody treated animals also had lower levels of α-Syn in the ipsilateral SN (one-way ANOVA F (7, 37) = 9.786; p = 0.0001) and demonstrated a partial intermediate improvement of the behavioral deficits. Our data suggest that, in particular, an α-Syn peptide antibody against the N-terminal region of the protein can protect against DA neuron loss and, to some extent behavioral deficits. As such, these results may be a potential therapeutic strategy for halting the progression of PD. PMID:25658425

  6. Intracerebroventricular Injection of Amyloid-β Peptides in Normal Mice to Acutely Induce Alzheimer-like Cognitive Deficits.

    PubMed

    Kim, Hye Yun; Lee, Dongkeun K; Chung, Bo-Ryehn; Kim, Hyunjin V; Kim, YoungSoo

    2016-01-01

    Amyloid-β (Aβ) is a major pathological mediator of both familial and sporadic Alzheimer's disease (AD). In the brains of AD patients, progressive accumulation of Aβ oligomers and plaques is observed. Such Aβ abnormalities are believed to block long-term potentiation, impair synaptic function, and induce cognitive deficits. Clinical and experimental evidences have revealed that the acute increase of Aβ levels in the brain allows development of Alzheimer-like phenotypes. Hence, a detailed protocol describing how to acutely generate an AD mouse model via the intracerebroventricular (ICV) injection of Aβ is necessary in many cases. In this protocol, the steps of the experiment with an Aβ-injected mouse are included, from the preparation of peptides to the testing of behavioral abnormalities. The process of preparing the tools and animal subjects before the injection, of injecting the Aβ into the mouse brain via ICV injection, and of assessing the degree of cognitive impairment are easily explained throughout the protocol, with an emphasis on tips for effective ICV injection of Aβ. By mimicking certain aspects of AD with a designated injection of Aβ, researchers can bypass the aging process and focus on the downstream pathology of Aβ abnormalities. PMID:27023127

  7. Cerebellum proteomics addressing the cognitive deficit of rats perinatally exposed to the food-relevant polychlorinated biphenyl 138.

    PubMed

    Campagna, Roberta; Brunelli, Laura; Airoldi, Luisa; Fanelli, Roberto; Hakansson, Helen; Heimeier, Rachel A; De Boever, Patrick; Boix, Jordi; Llansola, Marta; Felipo, Vicente; Pastorelli, Roberta

    2011-09-01

    Developmental exposure to polychlorinated biphenyls (PCBs) has been associated with cognitive deficits in humans and laboratory animals by mechanisms that remain unknown. Recently, it has been shown that developmental exposure to 2,2',3,4,4',5'-hexachlorobiphenyl (PCB138), a food-relevant PCB congener, decreases the learning ability of young rats. The aim of this study was to characterize the effect of perinatal exposure to PCB138 on the brain proteome profile in young rats in order to gain insight into the mechanisms underlying PCB138 neurotoxicity. Comparison of the cerebellum proteome from 3-month-old unexposed and PCB138-exposed male offspring was performed using state-of-the-art label-free semiquantitative mass spectrometry method. Biological pathways associated with Ca(2+) homeostasis and androgen receptor signaling pathways were primarily disrupted. These perturbations may contribute toward a premature ageing-like proteome profile of the cerebellum that is triggered by PCB138 exposure in males. Our proteomic data provide insights into the phenomena that may be contributing to the PCB138 neurotoxicity effects observed in laboratory rodents and correlate with PCB exposure and decreased cognitive functions in humans. As such, this study highlights the importance of PCB138 as a risk factor in developmental neurotoxicity in laboratory rodents and humans. PMID:21673325

  8. Pretreatment with Resveratrol Prevents Neuronal Injury and Cognitive Deficits Induced by Perinatal Hypoxia-Ischemia in Rats

    PubMed Central

    Arteaga, Olatz; Revuelta, Miren; Urigüen, Leyre; Álvarez, Antonia; Montalvo, Haizea; Hilario, Enrique

    2015-01-01

    Despite advances in neonatal care, hypoxic-ischemic brain injury is still a serious clinical problem, which is responsible for many cases of perinatal mortality, cerebral palsy, motor impairment and cognitive deficits. Resveratrol, a natural polyphenol with important anti-oxidant and anti-inflammatory properties, is present in grapevines, peanuts and pomegranates. The aim of the present work was to evaluate the possible neuroprotective effect of resveratrol when administered before or immediately after a hypoxic-ischemic brain event in neonatal rats by analyzing brain damage, the mitochondrial status and long-term cognitive impairment. Our results indicate that pretreatment with resveratrol protects against brain damage, reducing infarct volume, preserving myelination and minimizing the astroglial reactive response. Moreover its neuroprotective effect was found to be long lasting, as behavioral outcomes were significantly improved at adulthood. We speculate that one of the mechanisms for this neuroprotection may be related to the maintenance of the mitochondrial inner membrane integrity and potential, and to the reduction of reactive oxygen species. Curiously, none of these protective features was observed when resveratrol was administered immediately after hypoxia-ischemia. PMID:26544861

  9. The study of social cognition with neuroimaging methods as a means to explore future directions of deficit evaluation in schizophrenia?

    PubMed

    Brunet-Gouet, Eric; Achim, Amélie M; Vistoli, Damien; Passerieux, Christine; Hardy-Baylé, Marie-Christine; Jackson, Philip L

    2011-11-30

    This article discusses the important advances in a recent field of science dealing with the brain processes implicated in understanding social situations and interacting with others. Many behavioral studies on schizophrenia have shown the impairment of these processes and their preferential relation with disorganization and negative syndromes. Brain imaging is a powerful method to identify brain systems participating in these processes in healthy subjects and will be used increasingly to study mental disorders such as schizophrenia. A few preliminary studies have opened this field of research and allowed for the drawing of some limited conclusions. We emphasize the importance of developing an integrated neurocognitive framework to account for the multifaceted nature of social cognition deficits in schizophrenia. Inspired by contemporary models of empathy and social cognition that identify different components such as shared representation, mentalizing, self/other distinction, we show how schizophrenia affects these components at the behavioral and functional levels. We also outline the interest of this model to understand putative abnormalities of contextual integration within the area of mentalization. Finally, we discuss how specialized measures of brain functions during the performance of these precisely defined mental processes might be used as outcome predictors. PMID:21185085

  10. Cognitive deficits and brain myo-Inositol are early biomarkers of epileptogenesis in a rat model of epilepsy.

    PubMed

    Pascente, Rosaria; Frigerio, Federica; Rizzi, Massimo; Porcu, Luca; Boido, Marina; Davids, Joe; Zaben, Malik; Tolomeo, Daniele; Filibian, Marta; Gray, William P; Vezzani, Annamaria; Ravizza, Teresa

    2016-09-01

    One major unmet clinical need in epilepsy is the identification of therapies to prevent or arrest epilepsy development in patients exposed to a potential epileptogenic insult. The development of such treatments has been hampered by the lack of non-invasive biomarkers that could be used to identify the patients at-risk, thereby allowing to design affordable clinical studies. Our goal was to test the predictive value of cognitive deficits and brain astrocyte activation for the development of epilepsy following a potential epileptogenic injury. We used a model of epilepsy induced by pilocarpine-evoked status epilepticus (SE) in 21-day old rats where 60-70% of animals develop spontaneous seizures after around 70days, although SE is similar in all rats. Learning was evaluated in the Morris water-maze at days 15 and 65 post-SE, each time followed by proton magnetic resonance spectroscopy for measuring hippocampal myo-Inositol levels, a marker of astrocyte activation. Rats were video-EEG monitored for two weeks at seven months post-SE to detect spontaneous seizures, then brain histology was done. Behavioral and imaging data were retrospectively analysed in epileptic rats and compared with non-epileptic and control animals. Rats displayed spatial learning deficits within three weeks from SE. However, only epilepsy-prone rats showed accelerated forgetting and reduced learning rate compared to both rats not developing epilepsy and controls. These deficits were associated with reduced hippocampal neurogenesis. myo-Inositol levels increased transiently in the hippocampus of SE-rats not developing epilepsy while this increase persisted until spontaneous seizures onset in epilepsy-prone rats, being associated with a local increase in S100β-positive astrocytes. Neuronal cell loss was similar in all SE-rats. Our data show that behavioral deficits, together with a non-invasive marker of astrocyte activation, predict which rats develop epilepsy after an acute injury. These measures

  11. Cognitive deficits in patients after soft tissue injury of the cervical spine.

    PubMed

    Radanov, B P; Dvorák, J; Valach, L

    1992-02-01

    Fifty-one patients suffering from soft tissue injury of the cervical spine underwent clinical and psychometric examination. Clinical interview evaluated subjective complaints and formal testing of self-estimated cognitive impairment, divided attention, and speed of information processing. Results indicated at least two different syndromes: 1) the "cervicoencephalic syndrome," characterized by headache, fatigue, dizziness, poor concentration, disturbed accommodation, and impaired adaptation to light intensity; and 2) the "lower cervical spine syndrome," which is accompanied by cervical and cervicobrachial pain. When comparing patients with either of these two syndromes, those suffering from cervicoencephalic syndrome had significantly poorer results when tested for divided attention. Speed of information processing was reduced to a comparable extent in both syndromes. These findings were not related to the length of the post-traumatic interval. Reduced processing of working memory is assumed, which may account for more global cognitive problems as well as secondary neurotic reaction. PMID:1553581

  12. Hippocampal expression of myelin-associated inhibitors is induced with age-related cognitive decline and correlates with deficits of spatial learning and memory

    PubMed Central

    VanGuilder, Heather D.; Bixler, Georgina V.; Sonntag, William E.; Freeman, Willard M.

    2012-01-01

    Impairment of cognitive functions including hippocampus-dependent spatial learning and memory affects nearly half of the aged population. Age-related cognitive decline is associated with synaptic dysfunction that occurs in the absence of neuronal cell loss, suggesting that impaired neuronal signaling and plasticity may underlie age-related deficits of cognitive function. Expression of myelin-associated inhibitors (MAIs) of synaptic plasticity, including the ligands MAG, Nogo-A, and OMgp, and their common receptor, NgR1, was examined in hippocampal synaptosomes and CA1, CA3 and DG subregions derived from adult (12–13 months) and aged (26–28 months) Fischer 344 × Brown Norway rats. Rats were behaviorally phenotyped by Morris water maze testing and classified as aged cognitively intact (n=7–8) or aged cognitively impaired (n=7–10) relative to adults (n=5–7). MAI protein expression was induced in cognitively impaired, but not cognitively intact, aged rats and correlated with cognitive performance in individual rats. Immunohistochemical experiments demonstrated that upregulation of MAIs occurs, in part, in hippocampal neuronal axons and somata. While a number of pathways and processes are altered with brain aging, we report a coordinated induction of myelin-associated inhibitors of functional and structural plasticity only in cognitively impaired aged rats. Induction of MAIs may decrease stimulus-induced synaptic strengthening and structural remodeling, ultimately impairing synaptic mechanisms of spatial learning and memory and resulting in cognitive decline. PMID:22269040

  13. Pharmacological intervention for cognitive deficits and aggression in frontal lobe injury.

    PubMed

    Sugden, Steven G; Kile, Shawn J; Farrimond, Derald D; Hilty, Donald M; Bourgeois, James A

    2006-01-01

    We present a case that promotes early intervention and pharmacological treatment for the neuropsychiatric sequelae (frontal lobe syndrome, including cognitive impairment and aggressive behavior) associated with traumatic brain injury (TBI) and delirium. The patient, who sustained significant systemic complications related to his trauma, was previously diagnosed with alcohol and drug dependence and antisocial personality disorder. These antecedent conditions and prolonged systemic complications likely played a complicating role in his course of recovery. PMID:16720932

  14. Striatal Activity is Associated with Deficits of Cognitive Control and Aberrant Salience for Patients with Schizophrenia

    PubMed Central

    Ceaser, Alan E.; Barch, Deanna M.

    2016-01-01

    A recent meta-analysis has shown that a large dopamine abnormality exists in the striatum when comparing patients with schizophrenia and controls, and this abnormality is thought to contribute to aberrant salience assignment (or a misattribution of relevance to irrelevant stimuli). This abnormality may also disrupt striatal contributions to cognitive control processing. We examined the relationship between striatal involvement in cognition and aberrant salience symptoms using a task of cognitive control that involves updating, interference control, and simple maintenance. The current study included a sample of 22 patients with schizophrenia and 20 healthy controls and used a slow event-related fMRI design. We predicted that (1) aberrant salience symptoms would be greater for patient's, (2) patients would demonstrate increased errors during interference control trials, given that patients may be inappropriately assigning salience to distracters, and (3) striatal activity during those errors would be correlated with aberrant salience symptoms. We found a trend toward a significant difference between patients and controls on aberrant salience symptoms, and a significant difference between groups on select task conditions. During interference control trials, patients were more likely to inappropriately encode distracters. For patients, both prefrontal and striatal activity was significantly greater when patients inappropriately identified the distracter as correct compared to activity during distracter rejection. During updating, patient prefrontal and striatal activity was significantly lower for incorrect than correct updating trials. Finally, as predicted, for patients the increase of activity during incorrect distracter trials was positively correlated with aberrant salience symptoms, but only for the striatal region. These relationships may have implications for treatments that improve cognitive function and reduce symptom expression. PMID:26869912

  15. Protective effect of menthol on β-amyloid peptide induced cognitive deficits in mice.

    PubMed

    Bhadania, Mital; Joshi, Hanumanthachar; Patel, Purva; Kulkarni, Venkatrao H

    2012-04-15

    Cognitive impairment is a multidimensional concept that subsumes the attention and concentration, learning and memory, problem-solving ability, visuospatial abilities, mental flexibility, psychomotor efficiency and manual dexterity. The intrinsic mechanisms of the behavioural effects may involve neuronal damage in the brain structure. A lower concentration of glutamate receptor co-agonists in the striatum indicates the general malfunction of the brain glutamatergic system. It is suggested that a selective decrease in hippocampal glutamate concentration may account for deterioration in learning and memory process, considering the important role of this neurotransmitter in the cognitive functions. Nootropic agents like piracetam and anticholinesterase inhibitors are commonly used for improving memory, mood and behaviours. The present study was undertaken to assess the nootropic potential of menthol on learning and memory employing exteroceptive and interoceptive behavioral model in young and aged mice. To delineate the mechanism by which menthol decreases cognitive impairment and protect the brain, various biochemical parameters such as brain glutamate, glycine, glutathione and thiobarbituric acid reactive substances were determined. Menthol produced significant improvement in learning and memory. Menthol exhibited excellent antioxidant effect and maintain glutamate concentration in various region of the mouse brain for management of preliminary symptoms of memory impairment. PMID:22329901

  16. Intranasal Insulin Improves Age-Related Cognitive Deficits and Reverses Electrophysiological Correlates of Brain Aging.

    PubMed

    Maimaiti, Shaniya; Anderson, Katie L; DeMoll, Chris; Brewer, Lawrence D; Rauh, Benjamin A; Gant, John C; Blalock, Eric M; Porter, Nada M; Thibault, Olivier

    2016-01-01

    Peripheral insulin resistance is a key component of metabolic syndrome associated with obesity, dyslipidemia, hypertension, and type 2 diabetes. While the impact of insulin resistance is well recognized in the periphery, it is also becoming apparent in the brain. Recent studies suggest that insulin resistance may be a factor in brain aging and Alzheimer's disease (AD) whereby intranasal insulin therapy, which delivers insulin to the brain, improves cognition and memory in AD patients. Here, we tested a clinically relevant delivery method to determine the impact of two forms of insulin, short-acting insulin lispro (Humalog) or long-acting insulin detemir (Levemir), on cognitive functions in aged F344 rats. We also explored insulin effects on the Ca(2+)-dependent hippocampal afterhyperpolarization (AHP), a well-characterized neurophysiological marker of aging which is increased in the aged, memory impaired animal. Low-dose intranasal insulin improved memory recall in aged animals such that their performance was similar to that seen in younger animals. Further, because ex vivo insulin also reduced the AHP, our results suggest that the AHP may be a novel cellular target of insulin in the brain, and improved cognitive performance following intranasal insulin therapy may be the result of insulin actions on the AHP. PMID:25659889

  17. Luteolin protects against high fat diet-induced cognitive deficits in obesity mice.

    PubMed

    Liu, Yi; Fu, Xiaobin; Lan, Nuo; Li, Sai; Zhang, Jingzheng; Wang, Shuaishuai; Li, Cheng; Shang, Yanguo; Huang, Tonghui; Zhang, Ling

    2014-07-01

    The epidemic and experimental studies have confirmed that the obesity can lead to neuroinflammation, neurodegenerative diseases and adversely affect cognition. Despite the numerous elucidations on the impact of obesity on cognition decline, the contributors to the impairments in obesity remain unclear. Male C57BL/6J mice were fed either a control or high-fat diet (HFD) for 16 weeks and then randomized into four groups treated with their respective diets for 4 weeks including control diet (CD); control diet+luteolin (CDL); high-fat diet (HFD), high-fat diet+luteolin (HFDL). The dose of luteolin was 10mg/kg, oral. We showed that adding luteolin in high-fat diet can significantly reduce body weight gain, food intake and plasma cytokines as well as improving glucose metabolism of mice on HFD. Importantly, we showed that luteolin treatment had the effects of alleviating neuroinflammation, oxidative stress and neuronal insulin resistance in the mouse brain, restored blood adipocytokines level to normal. Furthermore, luteolin increased the level of brain-derived neurotrophic factor (BDNF), the action of synapsin I (SYP) and postsynaptic density protein 95 (PSD-95) in the cortex and hippocampus as to that the behavioral performance in Morris water maze (MWM) and step-through task were significantly improved. These results indicate a previously unrecognized potential of luteolin in alleviating obesity-induced cognitive impairment for type-2 diabetes mellitus and Alzheimer disease (AD). PMID:24667364

  18. Dysregulated peripheral endocannabinoid system signaling is associated with cognitive deficits in first-episode psychosis.

    PubMed

    Bioque, Miquel; Cabrera, Bibiana; García-Bueno, Borja; Mac-Dowell, Karina S; Torrent, Carla; Saiz, Pilar A; Parellada, Mara; González-Pinto, Ana; Lobo, Antonio; Leza, Juan C; Bernardo, Miguel

    2016-04-01

    Among etiological explanations for psychosis, several hypotheses involving alterations on the immune/inflammatory system have been proposed. The endocannabinoid system (ECS) is an endogenous neuroprotective, anti-inflammatory system that modulates cognitive processes. Its altered expression has been associated with psychotic disorders. 73 patients with a first episode of psychoses (FEP) and 67 healthy controls were recruited in 5 university centers in Spain. The protein expression of the main peripheral ECS components was determined in peripheral blood mononuclear cells. The cognition function was assessed following the MATRICS consensus. After controlling for potential confounding factors, working memory statistically correlated to the peripheral N-acyl phosphatidylethanolamine phospholipase expression (p = 0.039). The short-term verbal memory correlated to the Diacylglycerol lipase (p = 0.043) and the fatty acid amide hydrolase (p = 0.026) expression. Finally, attention measures correlated to the Monoacylglycerol lipase expression, by means of the CPT-II commissions (p = 0.036) and detectability (p = 0.026) scores. The ECS may regulate the activation of key mediators in immune and inflammatory responses that may be involved in the primary neuronal stress phenomenon that occurs from the onset of psychotic illness. This study points a relationship between the ECS and the cognitive function in early psychosis and suggests the use of some of the ECS elements as biomarkers and/or pharmacological targets for FEP. PMID:26783729

  19. Cognitive Biases toward Internet Game-Related Pictures and Executive Deficits in Individuals with an Internet Game Addiction

    PubMed Central

    Zhou, Zhenhe; Yuan, Guozhen; Yao, Jianjun

    2012-01-01

    Background The cue-related go/no-go switching task provides an experimental approach to study individual’s flexibility in changing situations. Because Internet addiction disorder (IAD) belongs to the compulsive-impulsive spectrum of disorders, it should present cognitive bias and executive functioning deficit characteristics of some of these types of disorders. Until now, no studies have been reported on cognitive bias and executive function involving mental flexibility and response inhibition in IAD. Methodology/Principal Findings A total of 46 subjects who met the criteria of the modified Young’s Diagnostic Questionnaire for Internet addiction (YDQ) were recruited as an Internet game addiction (IGA) group, along with 46 healthy control individuals. All participants performed the Internet game-shifting task. Using hit rate, RT, d′ and C as the dependent measures, a three-way ANOVA (group × target × condition) was performed. For hit rate, a significant effect of group, type of target and condition were found. The group–target interaction effect was significant. For RT, significant effects were revealed for group and type of target. The group–target interaction effect was significant. Comparisons of the means revealed that the slowing down of IGA relative to NIA was more pronounced when the target stimuli were neutral as opposed to Internet game-related pictures. In addition, the group–condition interaction effect was significant. For d′, significant effects of group, type of target and condition were found. The group–target interaction effect was significant. For C, the type of target produced a significant effect. There was a positive correlation between the length of the addiction (number of years) and the severity of the cognitive bias. Conclusions IGA present cognitive biases towards information related to Internet gaming. These biases, as well as poor executive functioning skills (lower mental flexibility and response inhibition), might be

  20. Intrinsic Hippocampal Excitability Changes of Opposite Signs and Different Origins in CA1 and CA3 Pyramidal Neurons Underlie Aging-Related Cognitive Deficits

    PubMed Central

    Oh, M. Matthew; Simkin, Dina; Disterhoft, John F.

    2016-01-01

    Aging-related cognitive deficits have been attributed to dysfunction of neurons due to failures at synaptic or intrinsic loci, or both. Given the importance of the hippocampus for successful encoding of memory and that the main output of the hippocampus is via the CA1 pyramidal neurons, much of the research has been focused on identifying the aging-related changes of these CA1 pyramidal neurons. We and others have discovered that the postburst afterhyperpolarization (AHP) following a train of action potentials is greatly enlarged in CA1 pyramidal neurons of aged animals. This enlarged postburst AHP is a significant factor in reducing the intrinsic excitability of these neurons, and thus limiting their activity in the neural network during learning. Based on these data, it has largely been thought that aging-related cognitive deficits are attributable to reduced activity of pyramidal neurons. However, recent in vivo and ex vivo studies provide compelling evidence that aging-related deficits could also be due to a converse change in CA3 pyramidal neurons, which show increased activity with aging. In this review, we will incorporate these recent findings and posit that an interdependent dynamic dysfunctional change occurs within the hippocampal network, largely due to altered intrinsic excitability in CA1 and CA3 hippocampal pyramidal neurons, which ultimately leads to the aging-related cognitive deficits. PMID:27375440

  1. Cognitive Deficits in Healthy Elderly Population With "Normal" Scores on the Mini-Mental State Examination.

    PubMed

    Votruba, Kristen L; Persad, Carol; Giordani, Bruno

    2016-05-01

    This study investigated whether healthy older adults with Mini-Mental State Examination (MMSE) scores above 23 exhibit cognitive impairment on neuropsychological tests. Participants completed the MMSE and a neuropsychological battery including tests of 10 domains. Results were compared to published normative data. On neuropsychological testing, participants performed well on measures of naming and recall but showed mild to moderate impairment in working memory and processing speed and marked impairment in inhibition, sustained attention, and executive functioning. Almost everyone (91%) scored at least 1 standard deviation (SD) below the mean in at least 1 domain. The median number of domains in which individuals scored below 1 SD was 3.0 of 10.0, whereas over 21% scored below 1 SD in 5 domains or more. With the strictest of definitions for impairment, 20% of this population scored below 2.0 SDs below the norm in at least 2 domains, a necessary condition for a diagnosis of dementia. The finding that cognitive impairment, particularly in attention and executive functioning, is found in healthy older persons who perform well on the MMSE has clinical and research implications in terms of emphasizing normal variability in performance and early identification of possible impairment. PMID:26850856

  2. A Quantitative System Pharmacology Computer Model for Cognitive Deficits in Schizophrenia

    PubMed Central

    Geerts, H; Roberts, P; Spiros, A

    2013-01-01

    Although the positive symptoms of schizophrenia are reasonably well-controlled by current antipsychotics, cognitive impairment remains largely unaddressed. The Matrics initiative lays out a regulatory path forward and a number of targets have been tested in the clinic, so far without much success. To address this translational disconnect, we have developed a mechanism-based humanized computer model of a relevant key cortical brain network with schizophrenia pathology involved with the maintenance aspect of working memory (WM). The model is calibrated using published clinical experiments on N-back WM tests. We further simulate the opposite effect of γ-aminobutyric acid (GABA) modulators lorazepam and flumazenil and of a published augmentation trial of clozapine with risperidone, illustrating the introduction of new targets and the capacity of predicting the effects of polypharmacy. This humanized approach allows for early prospective and quantitative assessment of cognitive outcome in a central nervous system (CNS) research and development project, thereby hopefully increasing the success rate of clinical trials. PMID:23887686

  3. Green Tea Extract Ameliorates Learning and Memory Deficits in Ischemic Rats via Its Active Component Polyphenol Epigallocatechin-3-gallate by Modulation of Oxidative Stress and Neuroinflammation

    PubMed Central

    Wu, Kuo-Jen; Hsieh, Ming-Tsuen; Wu, Chi-Rei; Wood, W. Gibson; Chen, Yuh-Fung

    2012-01-01

    Ischemic stroke results in brain damage and behavioral deficits including memory impairment. Protective effects of green tea extract (GTex) and its major functional polyphenol (−)-epigallocatechin gallate (EGCG) on memory were examined in cerebral ischemic rats. GTex and EGCG were administered 1 hr before middle cerebral artery ligation in rats. GTex, EGCG, and pentoxifylline (PTX) significantly improved ishemic-induced memory impairment in a Morris water maze test. Malondialdehyde (MDA) levels, glutathione (GSH), and superoxide dismutase (SOD) activity in the cerebral cortex and hippocampus were increased by long-term treatment with GTex and EGCG. Both compounds were also associated with reduced cerebral infraction breakdown of MDA and GSH in the hippocampus. In in vitro experiments, EGCG had anti-inflammatory effects in BV-2 microglia cells. EGCG inhibited lipopolysaccharide- (LPS-) induced nitric oxide production and reduced cyclooxygenase-2 and inducible nitric oxide synthase expression in BV-2 cells. GTex and its active polyphenol EGCG improved learning and memory deficits in a cerebral ischemia animal model and such protection may be due to the reduction of oxidative stress and neuroinflammation. PMID:22919410

  4. 7, 8-Dihydroxyflavone induces synapse expression of AMPA GluA1 and ameliorates cognitive and spine abnormalities in a mouse model of fragile X syndrome.

    PubMed

    Tian, Mi; Zeng, Yan; Hu, Yilan; Yuan, Xiuxue; Liu, Shumin; Li, Jie; Lu, Pan; Sun, Yao; Gao, Lei; Fu, Daan; Li, Yi; Wang, Shasha; McClintock, Shawn M

    2015-02-01

    Fragile X syndrome (FXS) is characterized by immature dendritic spine architectures and cognitive impairment. 7, 8-Dihydroxyflavone (7, 8-DHF) has recently been identified as a high affinity tropomyosin receptor kinase B (TrkB) agonist. The purpose of this paper was to examine the utility of 7, 8-DHF as an effective pharmacotherapeutic agent that targets dendritic pathology and cognitive impairments in FXS mutant. We synthesized pharmacologic, behavioral, and biochemical approaches to examine the effects of 7, 8-DHF on spatial and fear memory functions, and morphological spine abnormalities in fragile X mental retardation 1 (Fmr1) gene knock-out mice. The study found that 4 weeks of treatment with 7, 8-DHF improved spatial and fear memory, and ameliorated morphological spine abnormalities including the number and elongation of spines in the hippocampus and amygdala. Further mechanism analysis revealed that 7, 8-DHF enhanced the expression of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) GluA1 receptor, but reduced the normal levels of GluA2 at the synapses in Fmr1. Potentially related to drug-induced changes in AMPA receptor subunits, 7, 8-DHF at the synapses led to phosphorylation of specific serine sites on subunits Ser818 and Ser813 of GluA1, and Ser880 of GluA2, as well as phosphorylation of TrkB, calcium/calmodulin-dependent protein kinase II, and protein kinase C. However, 7, 8-DHF neither affected behavioral performance nor increased TrkB phosphorylation in WT mice, which suggested that it had FXS-specific correcting effect. Altogether, these results demonstrated that 7, 8-DHF improved learning and memory, and reduced abnormalities in spine morphology, thus providing a potential pharmacotherapeutic strategy for FXS. PMID:25229717

  5. A Randomized, Placebo-Controlled Study Investigating the Nicotinic α7 Agonist, RG3487, for Cognitive Deficits in Schizophrenia

    PubMed Central

    Umbricht, Daniel; Keefe, Richard SE; Murray, Stephen; Lowe, David A; Porter, Richard; Garibaldi, George; Santarelli, Luca

    2014-01-01

    Effective treatments for cognitive impairment associated with schizophrenia (CIAS) remain an unmet need. Nicotinic α7 receptor agonists may be effective in CIAS. This 8-week (week 1, inpatient; weeks 2–8, outpatient), double-blind, randomized study used Measurement And Treatment Research to Improve Cognition in Schizophrenia (MATRICS) guidelines to investigate the nicotinic α7 partial agonist RG3487 (formerly MEM3454) in CIAS; 215 patients with chronic stable schizophrenia received placebo or RG3487 (5, 15, or 50 mg) added to ongoing treatment with risperidone, paliperidone, or aripiprazole. Primary end point was baseline to week 8 change in MATRICS Consensus Cognitive Battery (MCCB) composite t-score. Secondary outcomes were change in MCCB domain and negative symptom assessment (NSA) scores. The study did not allow for evaluation of nonsmokers. Each RG3487 dose was evaluated using a mixed-effects model repeated measures approach. Mean (SD) baseline MCCB composite t-score was 28.3 (12.0). No significant effect on MCCB composite t-scores was observed with RG3487 (adjusted mean difference (SE) vs placebo: 5 mg: 0.11 (1.39); 15 mg: −1.95 (1.39); 50 mg: −1.13 (1.37); p=0.2–0.9). RG3487 did not improve MCCB domain scores. In a post hoc analysis of patients with moderate negative symptoms, 5 and 50 mg RG3487 vs placebo significantly improved NSA total (−4.45 (p=0.04) and −4.75 (p=0.02), respectively) and global (−0.39 (p=0.04) and −0.55 (p=0.003), respectively) scores. The MCCB did not lead to higher than expected patient withdrawal. RG3487 was generally well tolerated. In patients with stable schizophrenia, RG3487 did not improve cognitive deficits, as assessed by the MCCB; however, in patients with moderate negative symptoms, a post hoc analysis revealed significant improvement of negative symptoms. PMID:24549101

  6. Cognitive Control Deficits in Shifting and Inhibition in Preschool Age Children are Associated with Increased Depression and Anxiety Over 7.5 Years of Development.

    PubMed

    Kertz, Sarah J; Belden, Andy C; Tillman, Rebecca; Luby, Joan

    2016-08-01

    Although depression and anxiety are common in youth (Costello et al. 2003), factors that put children at risk for such symptoms are not well understood. The current study examined associations between early childhood cognitive control deficits and depression and anxiety over the course of development through school age. Participants were 188 children (at baseline M = 5.42 years, SD = 0.79 years) and their primary caregiver. Caregivers completed ratings of children's executive functioning at preschool age and measures of depression and anxiety severity over seven assessment waves (a period of approximately 7.5 years). Longitudinal multilevel linear models were used to examine the effect of attention shifting and inhibition deficits on depression and anxiety. Inhibition deficits at preschool were associated with significantly greater depression severity scores at each subsequent assessment wave (up until 7.5 years later). Inhibition deficits were associated with greater anxiety severity from 3.5 to 7.5 years later. Greater shifting deficits at preschool age were associated with greater depression severity up to 5.5 years later. Shifting deficits were also associated with significantly greater anxiety severity up to 3.5 years later. Importantly, these effects were significant even after accounting for the influence of other key predictors including assessment wave/time, gender, parental education, IQ, and symptom severity at preschool age, suggesting that effects are robust. Overall, findings indicate that cognitive control deficits are an early vulnerability factor for developing affective symptoms. Timely assessment and intervention may be beneficial as an early prevention strategy. PMID:26607383

  7. A dual brain-targeting curcumin-loaded polymersomes ameliorated cognitive dysfunction in intrahippocampal amyloid-β1–42-injected mice

    PubMed Central

    Jia, Tingting; Sun, Zhiguo; Lu, Ying; Gao, Jie; Zou, Hao; Xie, Fangyuan; Zhang, Guoqing; Xu, Hao; Sun, Duxin; Yu, Yuan; Zhong, Yanqiang

    2016-01-01

    Due to the impermeability of the blood–brain barrier and the nonselective distribution of drugs in the brain, the therapeutic access to intractable neurological disorders is challenging. In this study, dual brain-targeting polymersomes (POs) functionalized by transferrin and Tet-1 peptide (Tf/Tet-1-POs) promoted the transportation of curcumin into the brain and provided neuroprotection. The modification of the ligands that bind to the surface of POs was revealed by X-ray photoelectron spectroscopy analysis. The cell uptake of a coculture model of mouse brain capillary endothelial cells with neurons showed that the Tf/Tet-1-POs had significant transportation properties and possessed affinity for neurons. The pharmacokinetic analysis showed that the blood–brain barrier permeability–surface efficiency of the Tf/Tet-1-POs was 0.28 mL/h/g and that the brain tissue uptake rate (% ID/g) was 0.08, which were significant compared with the controls (P<0.05). The curcumin-encapsulated Tf/Tet-1-POs provided neuroprotection and ameliorated cognitive dysfunction in intrahippocampal amyloid-β1–42-injected mice. These results suggest that the dual brain-targeting POs are more capable of drug delivery to the brain that can be exploited as a multiple noninvasive vehicle for targeting therapeutics. PMID:27540290

  8. A dual brain-targeting curcumin-loaded polymersomes ameliorated cognitive dysfunction in intrahippocampal amyloid-β1-42-injected mice.

    PubMed

    Jia, Tingting; Sun, Zhiguo; Lu, Ying; Gao, Jie; Zou, Hao; Xie, Fangyuan; Zhang, Guoqing; Xu, Hao; Sun, Duxin; Yu, Yuan; Zhong, Yanqiang

    2016-01-01

    Due to the impermeability of the blood-brain barrier and the nonselective distribution of drugs in the brain, the therapeutic access to intractable neurological disorders is challenging. In this study, dual brain-targeting polymersomes (POs) functionalized by transferrin and Tet-1 peptide (Tf/Tet-1-POs) promoted the transportation of curcumin into the brain and provided neuroprotection. The modification of the ligands that bind to the surface of POs was revealed by X-ray photoelectron spectroscopy analysis. The cell uptake of a coculture model of mouse brain capillary endothelial cells with neurons showed that the Tf/Tet-1-POs had significant transportation properties and possessed affinity for neurons. The pharmacokinetic analysis showed that the blood-brain barrier permeability-surface efficiency of the Tf/Tet-1-POs was 0.28 mL/h/g and that the brain tissue uptake rate (% ID/g) was 0.08, which were significant compared with the controls (P<0.05). The curcumin-encapsulated Tf/Tet-1-POs provided neuroprotection and ameliorated cognitive dysfunction in intrahippocampal amyloid-β1-42-injected mice. These results suggest that the dual brain-targeting POs are more capable of drug delivery to the brain that can be exploited as a multiple noninvasive vehicle for targeting therapeutics. PMID:27540290

  9. Ameliorative Effect of Quercetin on Neurochemical and Behavioral Deficits in Rotenone Rat Model of Parkinson's Disease: Modulating Autophagy (Quercetin on Experimental Parkinson's Disease).

    PubMed

    El-Horany, Hemat E; El-Latif, Rania N Abd; ElBatsh, Maha M; Emam, Marwa N

    2016-07-01

    Autophagy is necessary for neuronal homeostasis and its dysfunction has been implicated in Parkinson's disease (PD) as it can exacerbate endoplasmic reticulum (ER) stress and ER stress-induced apoptosis. Quercetin is a flavonoid known for its neuroprotective and antioxidant effects. The present study investigated the protective, autophagy-modulating effects of quercetin in the rotenone rat model of PD. Rotenone was intraperitoneally injected at dose of 2 ml/kg/day for 4 weeks. Simultaneous intraperitoneal injection of quercetin was given at a dose of 50 mg/kg/day also for 4 weeks. Neurobehavioral changes were studied. Oxidative/antioxidant status, C/EBP homologous protein (CHOP), Beclin-1, and dopamine levels were assessed. DNA fragmentation and histopathological changes were evaluated. This research work revealed that quercetin significantly attenuated rotenone-induced behavioral impairment, augmented autophagy, ameliorated ER stress- induced apoptosis with attenuated oxidative stress. From the current study, quercetin can act as an autophagy enhancer in PD rat model and modulates the microenvironment that leads to neuronal death. PMID:27252111

  10. Naringin and Sertraline Ameliorate Doxorubicin-Induced Behavioral Deficits Through Modulation of Serotonin Level and Mitochondrial Complexes Protection Pathway in Rat Hippocampus.

    PubMed

    Kwatra, Mohit; Jangra, Ashok; Mishra, Murli; Sharma, Yogita; Ahmed, Sahabuddin; Ghosh, Pinaki; Kumar, Vikas; Vohora, Divya; Khanam, Razia

    2016-09-01

    The present study was designed to investigate the neuroprotective effect of naringin (NR) alone as well as its combination with sertraline (SRT) against doxorubicin (DOX)-induced neurobehavioral and neurochemical anomalies. DOX (15 mg/kg; i.p.) administration caused behavioral alterations, oxidative stress, neuroinflammation, mitochondrial dysfunction and monoamines alteration in male Wistar rats. NR (50 and 100 mg/kg; i.p.) and SRT (5 mg/kg; i.p.) treatment significantly attenuated DOX-induced anxiety and depressive-like behavior as evident from elevated plus maze (EPM) and modified forced swimming test (mFST), respectively. NR treatment significantly attenuated DOX-induced raised plasma corticosterone (CORT), tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β) levels in the hippocampus (HC). Furthermore, we found that combination of NR and SRT regimen ameliorated DOX-induced behavioral anomalies through modulation of the 5-HT level and mitochondrial complexes protection pathway along with alleviation of oxidative stress in the HC region. Therefore, NR treatment alone or in combination with SRT could be beneficial against DOX-induced neurotoxicity. PMID:27209303

  11. Protective effects of myricetin on chronic stress-induced cognitive deficits.

    PubMed

    Wang, Qi-Min; Wang, Gui-Lin; Ma, Ze-Gang

    2016-06-15

    The aim of the present study is to investigate the possible effects of chronic administration of myricetin, a natural flavonoid, on chronic stress-induced learning and memory deficits in mice. The mice were restrained daily 4 h/day for 21 days in well-ventilated plexiglass tubes without access to food and water. These animals were injected with myricetin or vehicle 40 min before each restraint stress over a period of 21 days. Then, spatial learning and memory of the mice were evaluated by the Morris water maze task. We did not observe a significant difference in the escape latency in mice subjected to repeated restraint stress, which indicates that learning ability was not affected by restraint stress. However, the spatial memory ability was significantly impaired in the repeatedly restrained mice. Myricetin administration specifically increased the time spent in the target quadrant in mice exposed to chronic stress in the probe trial as tested in the Morris water maze task. Further studies showed that myricetin treatment decreased plasma adrenocorticotrophic hormone levels of those mice subjected to repeated restraint stress. The effect of myricetin on the levels of brain-derived neurotrophic factor (BDNF) in hippocampus was also investigated. The result showed that myricetin normalized the decreased BDNF levels in mice subjected to repeated restraint stress. These findings provide more evidence that chronic administration of myricetin improves spatial memory in repeatedly restrained mice and BDNF signaling in the hippocampus may be involved in the protective effects of myricetin. PMID:27171032

  12. Kaempferia parviflora extract ameliorates the cognitive impairments and the reduction in cell proliferation induced by valproic acid treatment in rats.

    PubMed

    Welbat, Jariya Umka; Chaisawang, Pornthip; Chaijaroonkhanarak, Wunnee; Prachaney, Parichat; Pannangrong, Wanassanun; Sripanidkulchai, Bungorn; Wigmore, Peter

    2016-07-01

    Kaempferia parviflora is a herbal plant whose rhizomes are used in traditional medicine. Investigations of this plant have shown it to have antidepressant activity and to improve learning and memory in animal models. The aim of the present investigation was to determine whether K. parviflora could protect the brain from the impairments in cognition and hippocampal neurogenesis which are caused by valproic acid (VPA). Male Sprague Dawley rats (180-200g) were given once daily K. parviflora extract (100mg/kg) via oral gavage for 21 days. Rats received twice daily intraperitoneal injections of valproic acid (300mg/kg) from days 8 to 21 of the experiment. Spatial memory was tested using the novel object location (N