Regional ADC values of the normal brain: differences due to age, gender, and laterality.

PubMed

Naganawa, Shinji; Sato, Kimihide; Katagiri, Toshio; Mimura, Takeo; Ishigaki, Takeo

2003-01-01

The purpose of this study was to evaluate the stability of measurement for apparent diffusion coefficient (ADC) values in normal brain, to clarify the effect of aging on ADC values, to compare ADC values between men and women, and to compare ADC values between right and left sides of the brain. To evaluate the stability of measurements, five normal volunteers (four men and one woman) were examined five times on different days. Then, 294 subjects with normal MR imaging (147 men and 147 women; age range 20-89 years) were measured. The ADC measurement in normal volunteers was stable. The ADC values stayed within the 5% deviation of average values in all volunteers (mean+/-standard deviation 2.3+/-1.2%). The ADC values gradually increased by aging in all regions. In thalamus, no significant difference was seen between right and left in the subjects under 60 years; however, right side showed higher values in the subjects over 60 years (p<0.01). In the subjects under 60 years, women showed higher values in right frontal, bilateral thalamus, and temporal (p<0.01); however, in the subjects over 60 years, no region showed difference between men and women. The knowledge obtained in this study may be helpful to understand the developmental and aging mechanisms of normal brain and may be useful for the future quantitative study as a reference.

Brain tissue volumes in the general elderly population. The Rotterdam Scan Study.

PubMed

Ikram, M Arfan; Vrooman, Henri A; Vernooij, Meike W; van der Lijn, Fedde; Hofman, Albert; van der Lugt, Aad; Niessen, Wiro J; Breteler, Monique M B

2008-06-01

We investigated how volumes of cerebrospinal fluid (CSF), grey matter (GM) and white matter (WM) varied with age, sex, small vessel disease and cardiovascular risk factors in the Rotterdam Scan Study. Participants (n=490; 60-90 years) were non-demented and 51.0% had hypertension, 4.9% had diabetes mellitus, 17.8% were current smoker and 54.0% were former smoker. We segmented brain MR-images into GM, normal WM, white matter lesion (WML) and CSF. Brain infarcts were rated visually. Volumes were expressed as percentage of intra-cranial volume. With increasing age, volumes of total brain, normal WM and total WM decreased; that of GM remained unchanged; and that of WML increased, in both men and women. Excluding persons with infarcts did not alter these results. Persons with larger load of small vessel disease had smaller brain volume, especially normal WM volume. Diastolic blood pressure, diabetes mellitus and current smoking were also related to smaller brain volume. In the elderly, higher age, small vessel disease and cardiovascular risk factors are associated with smaller brain volume, especially WM volume.

X-ray diffraction evidence for myelin disorder in brain from humans with Alzheimer's disease.

PubMed

Chia, L S; Thompson, J E; Moscarello, M A

1984-09-05

Wide-angle X-ray diffraction studies revealed that the lipid phase transition temperature of myelin from brain tissue of humans with Alzheimer's disease was about 12 degrees C lower than that of normal age-matched controls, indicating differences in the physical organization of the myelin lipid bilayer. Elevated levels of malondialdehyde and conjugated diene were found in brain tissue from humans with Alzheimer's disease, indicating an increased amount of lipid peroxidation over the controls. An increase in myelin disorder and in lipid peroxidation can both be correlated with aging in human brain, but the changes in myelin from humans with Alzheimer's disease are more pronounced than in normal aging. These changes might represent severe or accelerated aging.

Determinants of iron accumulation in the normal aging brain.

PubMed

Pirpamer, Lukas; Hofer, Edith; Gesierich, Benno; De Guio, François; Freudenberger, Paul; Seiler, Stephan; Duering, Marco; Jouvent, Eric; Duchesnay, Edouard; Dichgans, Martin; Ropele, Stefan; Schmidt, Reinhold

2016-07-01

In a recent postmortem study, R2* relaxometry in gray matter (GM) of the brain has been validated as a noninvasive measure for iron content in brain tissue. Iron accumulation in the normal aging brain is a common finding and relates to brain maturation and degeneration. The goal of this study was to assess the determinants of iron accumulation during brain aging. The study cohort consisted of 314 healthy community-dwelling participants of the Austrian Stroke Prevention Study. Their age ranged from 38-82 years. Quantitative magnetic resonance imaging was performed on 3T and included R2* mapping, based on a 3D multi-echo gradient echo sequence. The median of R2* values was measured in all GM regions, which were segmented automatically using FreeSurfer. We investigated 25 possible determinants for cerebral iron deposition. These included demographics, brain volume, lifestyle factors, cerebrovascular risk factors, serum levels of iron, and single nucleotide polymorphisms related to iron regulating genes (rs1800562, rs3811647, rs1799945, and rs1049296). The body mass index (BMI) was significantly related to R2* in 15/32 analyzed brain regions with the strongest correlations found in the amygdala (p = 0.0091), medial temporal lobe (p = 0.0002), and hippocampus (p ≤ 0.0001). Further associations to R2* values were found in deep GM for age and smoking. No significant associations were found for gender, GM volume, serum levels of iron, or iron-associated genetic polymorphisms. In conclusion, besides age, the BMI and smoking are the only significant determinants of brain iron accumulation in normally aging subjects. Smoking relates to iron deposition in the basal ganglia, whereas higher BMI is associated with iron content in the neocortex following an Alzheimer-like distribution. Copyright © 2016 Elsevier Inc. All rights reserved.

Functional neuroimaging of normal aging: Declining brain, adapting brain.

PubMed

Sugiura, Motoaki

2016-09-01

Early functional neuroimaging research on normal aging brain has been dominated by the interest in cognitive decline. In this framework the age-related compensatory recruitment of prefrontal cortex, in terms of executive system or reduced lateralization, has been established. Further details on these compensatory mechanisms and the findings reflecting cognitive decline, however, remain the matter of intensive investigations. Studies in another framework where age-related neural alteration is considered adaptation to the environmental change are recently burgeoning and appear largely categorized into three domains. The age-related increase in activation of the sensorimotor network may reflect the alteration of the peripheral sensorimotor systems. The increased susceptibility of the network for the mental-state inference to the socioemotional significance may be explained by the age-related motivational shift due to the altered social perception. The age-related change in activation of the self-referential network may be relevant to the focused positive self-concept of elderly driven by a similar motivational shift. Across the domains, the concept of the self and internal model may provide the theoretical bases of this adaptation framework. These two frameworks complement each other to provide a comprehensive view of the normal aging brain. Copyright © 2016 Elsevier B.V. All rights reserved.

High brain lactate is a hallmark of aging and caused by a shift in the lactate dehydrogenase A/B ratio.

PubMed

Ross, Jaime M; Öberg, Johanna; Brené, Stefan; Coppotelli, Giuseppe; Terzioglu, Mügen; Pernold, Karin; Goiny, Michel; Sitnikov, Rouslan; Kehr, Jan; Trifunovic, Aleksandra; Larsson, Nils-Göran; Hoffer, Barry J; Olson, Lars

2010-11-16

At present, there are few means to track symptomatic stages of CNS aging. Thus, although metabolic changes are implicated in mtDNA mutation-driven aging, the manifestations remain unclear. Here, we used normally aging and prematurely aging mtDNA mutator mice to establish a molecular link between mitochondrial dysfunction and abnormal metabolism in the aging process. Using proton magnetic resonance spectroscopy and HPLC, we found that brain lactate levels were increased twofold in both normally and prematurely aging mice during aging. To correlate the striking increase in lactate with tissue pathology, we investigated the respiratory chain enzymes and detected mitochondrial failure in key brain areas from both normally and prematurely aging mice. We used in situ hybridization to show that increased brain lactate levels were caused by a shift in transcriptional activities of the lactate dehydrogenases to promote pyruvate to lactate conversion. Separation of the five tetrameric lactate dehydrogenase (LDH) isoenzymes revealed an increase of those dominated by the Ldh-A product and a decrease of those rich in the Ldh-B product, which, in turn, increases pyruvate to lactate conversion. Spectrophotometric assays measuring LDH activity from the pyruvate and lactate sides of the reaction showed a higher pyruvate → lactate activity in the brain. We argue for the use of lactate proton magnetic resonance spectroscopy as a noninvasive strategy for monitoring this hallmark of the aging process. The mtDNA mutator mouse allows us to conclude that the increased LDH-A/LDH-B ratio causes high brain lactate levels, which, in turn, are predictive of aging phenotypes.

Characterizing structural association alterations within brain networks in normal aging using Gaussian Bayesian networks.

PubMed

Guo, Xiaojuan; Wang, Yan; Chen, Kewei; Wu, Xia; Zhang, Jiacai; Li, Ke; Jin, Zhen; Yao, Li

2014-01-01

Recent multivariate neuroimaging studies have revealed aging-related alterations in brain structural networks. However, the sensory/motor networks such as the auditory, visual and motor networks, have obtained much less attention in normal aging research. In this study, we used Gaussian Bayesian networks (BN), an approach investigating possible inter-regional directed relationship, to characterize aging effects on structural associations between core brain regions within each of these structural sensory/motor networks using volumetric MRI data. We then further examined the discriminability of BN models for the young (N = 109; mean age =22.73 years, range 20-28) and old (N = 82; mean age =74.37 years, range 60-90) groups. The results of the BN modeling demonstrated that structural associations exist between two homotopic brain regions from the left and right hemispheres in each of the three networks. In particular, compared with the young group, the old group had significant connection reductions in each of the three networks and lesser connection numbers in the visual network. Moreover, it was found that the aging-related BN models could distinguish the young and old individuals with 90.05, 73.82, and 88.48% accuracy for the auditory, visual, and motor networks, respectively. Our findings suggest that BN models can be used to investigate the normal aging process with reliable statistical power. Moreover, these differences in structural inter-regional interactions may help elucidate the neuronal mechanism of anatomical changes in normal aging.

R2* mapping for brain iron: associations with cognition in normal aging.

PubMed

Ghadery, Christine; Pirpamer, Lukas; Hofer, Edith; Langkammer, Christian; Petrovic, Katja; Loitfelder, Marisa; Schwingenschuh, Petra; Seiler, Stephan; Duering, Marco; Jouvent, Eric; Schmidt, Helena; Fazekas, Franz; Mangin, Jean-Francois; Chabriat, Hugues; Dichgans, Martin; Ropele, Stefan; Schmidt, Reinhold

2015-02-01

Brain iron accumulates during aging and has been associated with neurodegenerative disorders including Alzheimer's disease. Magnetic resonance (MR)-based R2* mapping enables the in vivo detection of iron content in brain tissue. We investigated if during normal brain aging iron load relates to cognitive impairment in region-specific patterns in a community-dwelling cohort of 336 healthy, middle aged, and older adults from the Austrian Stroke Prevention Family Study. MR imaging and R2* mapping in the basal ganglia and neocortex were done at 3T. Comprehensive neuropsychological testing assessed memory, executive function, and psychomotor speed. We found the highest iron concentration in the globus pallidus, and pallidal and putaminal iron was significantly and inversely associated with cognitive performance in all cognitive domains, except memory. These associations were iron load dependent. Vascular brain lesions and brain volume did not mediate the relationship between iron and cognitive performance. We conclude that higher R2*-determined iron in the basal ganglia correlates with cognitive impairment during brain aging independent of concomitant brain abnormalities. The prognostic significance of this finding needs to be determined. Copyright © 2015 Elsevier Inc. All rights reserved.

Cerebral control of the bladder in normal and urge-incontinent women

PubMed Central

Griffiths, Derek; Tadic, Stasa D.; Schaefer, Werner; Resnick, Neil M.

2007-01-01

Aim: To identify age-related changes in the normal brain/bladder control system, and differences between urge incontinence in younger and older women, as shown by brain responses to bladder filling; and to use age, bladder volume, urge incontinence and detrusor overactivity (DO) as probes to reveal control-system function. Functional MRI was used to examine regional brain responses to bladder infusion in 21 females (26 – 85 years): 11 “cases” with urge incontinence and DO (proven previously) and 10 normal “controls”. Responses and their age dependence were determined at small and large bladder volumes, in whole brain and in regions of interest representing right insula and anterior cingulate (ACG). In “controls”, increasing bladder volume/sensation led to increasing insular responses; with increasing age, insular responses became weaker. In younger “cases”, ACG responded abnormally strongly at large bladder volumes/strong sensation. Elderly “cases” showed strong ACG responses even at small bladder volume, but more moderate responses at larger volumes; if DO occurred, pontine micturition center (PMC) activation did not increase. Conclusion: Among normal “controls”, increasing age leads to decreased responses in brain regions involved in bladder control, including right insula, consistent with its role in mapping normal bladder sensations. Strong ACG activation occurs in urge-incontinent “cases” and may be a sign of urgency, indicating recruitment of alternative pathways when loss of bladder control is feared. Easier ACG provocation in older “cases” reflects lack of physiological reserve or different etiology. ACG responses seem associated with PMC inhibition: reduced ACG activity accompanies failure of inhibition (DO). PMID:17574871

High brain lactate is a hallmark of aging and caused by a shift in the lactate dehydrogenase A/B ratio

PubMed Central

Ross, Jaime M.; Öberg, Johanna; Brené, Stefan; Coppotelli, Giuseppe; Terzioglu, Mügen; Pernold, Karin; Goiny, Michel; Sitnikov, Rouslan; Kehr, Jan; Trifunovic, Aleksandra; Larsson, Nils-Göran; Hoffer, Barry J.; Olson, Lars

2010-01-01

At present, there are few means to track symptomatic stages of CNS aging. Thus, although metabolic changes are implicated in mtDNA mutation-driven aging, the manifestations remain unclear. Here, we used normally aging and prematurely aging mtDNA mutator mice to establish a molecular link between mitochondrial dysfunction and abnormal metabolism in the aging process. Using proton magnetic resonance spectroscopy and HPLC, we found that brain lactate levels were increased twofold in both normally and prematurely aging mice during aging. To correlate the striking increase in lactate with tissue pathology, we investigated the respiratory chain enzymes and detected mitochondrial failure in key brain areas from both normally and prematurely aging mice. We used in situ hybridization to show that increased brain lactate levels were caused by a shift in transcriptional activities of the lactate dehydrogenases to promote pyruvate to lactate conversion. Separation of the five tetrameric lactate dehydrogenase (LDH) isoenzymes revealed an increase of those dominated by the Ldh-A product and a decrease of those rich in the Ldh-B product, which, in turn, increases pyruvate to lactate conversion. Spectrophotometric assays measuring LDH activity from the pyruvate and lactate sides of the reaction showed a higher pyruvate → lactate activity in the brain. We argue for the use of lactate proton magnetic resonance spectroscopy as a noninvasive strategy for monitoring this hallmark of the aging process. The mtDNA mutator mouse allows us to conclude that the increased LDH-A/LDH-B ratio causes high brain lactate levels, which, in turn, are predictive of aging phenotypes. PMID:21041631

Brain-Derived Neurotrophic Factor Expression in Individuals With Schizophrenia and Healthy Aging: Testing the Accelerated Aging Hypothesis of Schizophrenia.

PubMed

Islam, Farhana; Mulsant, Benoit H; Voineskos, Aristotle N; Rajji, Tarek K

2017-07-01

Schizophrenia has been hypothesized to be a syndrome of accelerated aging. Brain plasticity is vulnerable to the normal aging process and affected in schizophrenia: brain-derived neurotrophic factor (BDNF) is an important neuroplasticity molecule. The present review explores the accelerated aging hypothesis of schizophrenia by comparing changes in BDNF expression in schizophrenia with aging-associated changes. Individuals with schizophrenia show patterns of increased overall mortality, metabolic abnormalities, and cognitive decline normally observed later in life in the healthy population. An overall decrease is observed in BDNF expression in schizophrenia compared to healthy controls and in older individuals compared to a younger cohort. There is a marked decrease in BDNF levels in the frontal regions and in the periphery among older individuals and those with schizophrenia; however, data for BDNF expression in the occipital, parietal, and temporal cortices and the hippocampus is inconclusive. Accelerated aging hypothesis is supported based on frontal regions and peripheral studies; however, further studies are needed in other brain regions.

Regionally distinct responses of microglia and glial progenitor cells to whole brain irradiation in adult and aging rats.

PubMed

Hua, Kun; Schindler, Matthew K; McQuail, Joseph A; Forbes, M Elizabeth; Riddle, David R

2012-01-01

Radiation therapy has proven efficacy for treating brain tumors and metastases. Higher doses and larger treatment fields increase the probability of eliminating neoplasms and preventing reoccurrence, but dose and field are limited by damage to normal tissues. Normal tissue injury is greatest during development and in populations of proliferating cells but also occurs in adults and older individuals and in non-proliferative cell populations. To better understand radiation-induced normal tissue injury and how it may be affected by aging, we exposed young adult, middle-aged, and old rats to 10 Gy of whole brain irradiation and assessed in gray- and white matter the responses of microglia, the primary cellular mediators of radiation-induced neuroinflammation, and oligodendrocyte precursor cells, the largest population of proliferating cells in the adult brain. We found that aging and/or irradiation caused only a few microglia to transition to the classically "activated" phenotype, e.g., enlarged cell body, few processes, and markers of phagocytosis, that is seen following more damaging neural insults. Microglial changes in response to aging and irradiation were relatively modest and three markers of reactivity - morphology, proliferation, and expression of the lysosomal marker CD68- were regulated largely independently within individual cells. Proliferation of oligodendrocyte precursors did not appear to be altered during normal aging but increased following irradiation. The impacts of irradiation and aging on both microglia and oligodendrocyte precursors were heterogeneous between white- and gray matter and among regions of gray matter, indicating that there are regional regulators of the neural response to brain irradiation. By several measures, the CA3 region of the hippocampus appeared to be differentially sensitive to effects of aging and irradiation. The changes assessed here likely contribute to injury following inflammatory challenges like brain irradiation and represent important end-points for analysis in studies of therapeutic strategies to protect patients from neural dysfunction.

Between destiny and disease: genetics and molecular pathways of human central nervous system aging.

PubMed

Glorioso, Christin; Sibille, Etienne

2011-02-01

Aging of the human brain is associated with "normal" functional, structural, and molecular changes that underlie alterations in cognition, memory, mood and motor function, amongst other processes. Normal aging also imposes a robust constraint on the onset of many neurological diseases, ranging from late onset neurodegenerative diseases, such as Alzheimer's (AD) and Parkinson's diseases (PD), to early onset psychiatric disorders, such as bipolar disorder (BPD) and schizophrenia (SCZ). The molecular mechanisms and genetic underpinnings of age-related changes in the brain are understudied, and, while they share some overlap with peripheral mechanisms of aging, many are unique to the largely non-mitotic brain. Hence, understanding mechanisms of brain aging and identifying associated modulators may have profound consequences for the prevention and treatment of age-related impairments and diseases. Here we review current knowledge on age-related functional and structural changes, their molecular and genetic underpinnings, and discuss how these pathways may contribute to the vulnerability to develop age-related neurological diseases. We highlight recent findings from human post-mortem brain microarray studies, which we hypothesize, point to a potential genetically controlled transcriptional program underlying molecular changes and age-gating of neurological diseases. Finally, we discuss the implications of this model for understanding basic mechanisms of brain aging and for the future investigation of therapeutic approaches. Copyright © 2010 Elsevier Ltd. All rights reserved.

Total and regional brain volumes in a population-based normative sample from 4 to 18 years: the NIH MRI Study of Normal Brain Development.

PubMed

2012-01-01

Using a population-based sampling strategy, the National Institutes of Health (NIH) Magnetic Resonance Imaging Study of Normal Brain Development compiled a longitudinal normative reference database of neuroimaging and correlated clinical/behavioral data from a demographically representative sample of healthy children and adolescents aged newborn through early adulthood. The present paper reports brain volume data for 325 children, ages 4.5-18 years, from the first cross-sectional time point. Measures included volumes of whole-brain gray matter (GM) and white matter (WM), left and right lateral ventricles, frontal, temporal, parietal and occipital lobe GM and WM, subcortical GM (thalamus, caudate, putamen, and globus pallidus), cerebellum, and brainstem. Associations with cross-sectional age, sex, family income, parental education, and body mass index (BMI) were evaluated. Key observations are: 1) age-related decreases in lobar GM most prominent in parietal and occipital cortex; 2) age-related increases in lobar WM, greatest in occipital, followed by the temporal lobe; 3) age-related trajectories predominantly curvilinear in females, but linear in males; and 4) small systematic associations of brain tissue volumes with BMI but not with IQ, family income, or parental education. These findings constitute a normative reference on regional brain volumes in children and adolescents.

Early parental care is important for hippocampal maturation: evidence from brain morphology in humans.

PubMed

Rao, Hengyi; Betancourt, Laura; Giannetta, Joan M; Brodsky, Nancy L; Korczykowski, Marc; Avants, Brian B; Gee, James C; Wang, Jiongjiong; Hurt, Hallam; Detre, John A; Farah, Martha J

2010-01-01

The effects of early life experience on later brain structure and function have been studied extensively in animals, yet the relationship between childhood experience and normal brain development in humans remains largely unknown. Using a unique longitudinal data set including ecologically valid in-home measures of early experience during childhood (at age 4 and 8 years) and high-resolution structural brain imaging during adolescence (mean age 14 years), we examined the effects on later brain morphology of two dimensions of early experience: parental nurturance and environmental stimulation. Parental nurturance at age 4 predicts the volume of the left hippocampus in adolescence, with better nurturance associated with smaller hippocampal volume. In contrast, environmental stimulation did not correlate with hippocampal volume. Moreover, the association between hippocampal volume and parental nurturance disappears at age 8, supporting the existence of a sensitive developmental period for brain maturation. These findings indicate that variation in normal childhood experience is associated with differences in brain morphology, and hippocampal volume is specifically associated with early parental nurturance. Our results provide neuroimaging evidence supporting the important role of warm parental care during early childhood for brain maturation.

Energy Metabolism and Inflammation in Brain Aging and Alzheimer’s Disease

PubMed Central

Yin, Fei; Sancheti, Harsh; Patil, Ishan; Cadenas, Enrique

2016-01-01

The high energy demand of the brain renders it sensitive to changes in energy fuel supply and mitochondrial function. Deficits in glucose availability and mitochondrial function are well-known hallmarks of brain aging and are particularly accentuated in neurodegenerative disorders such as Alzheimer’s disease. As important cellular sources of H2O2, mitochondrial dysfunction is usually associated with altered redox status. Bioenergetic deficits and chronic oxidative stress are both major contributors to cognitive decline associated with brain aging and Alzheimer’s disease. Neuroinflammatory changes, including microglial activation and production of inflammatory cytokines, are observed in neurodegenerative diseases and normal aging. The bioenergetic hypothesis advocates for sequential events from metabolic deficits to propagation of neuronal dysfunction, to aging, and to neurodegeneration, while the inflammatory hypothesis supports microglia activation as the driving force for neuroinflammation. Nevertheless, growing evidence suggests that these diverse mechanisms have redox dysregulation as a common denominator and connector. An independent view of the mechanisms underlying brain aging and neurodegeneration is being replaced by one that entails multiple mechanisms coordinating and interacting with each other. This review focuses on the alterations in energy metabolism and inflammatory responses and their connection via redox regulation in normal brain aging and Alzheimer’s disease. Interactions of these systems is reviewed based on basic research and clinical studies. PMID:27154981

Association of Structural Global Brain Network Properties with Intelligence in Normal Aging

PubMed Central

Fischer, Florian U.; Wolf, Dominik; Scheurich, Armin; Fellgiebel, Andreas

2014-01-01

Higher general intelligence attenuates age-associated cognitive decline and the risk of dementia. Thus, intelligence has been associated with cognitive reserve or resilience in normal aging. Neurophysiologically, intelligence is considered as a complex capacity that is dependent on a global cognitive network rather than isolated brain areas. An association of structural as well as functional brain network characteristics with intelligence has already been reported in young adults. We investigated the relationship between global structural brain network properties, general intelligence and age in a group of 43 cognitively healthy elderly, age 60–85 years. Individuals were assessed cross-sectionally using Wechsler Adult Intelligence Scale-Revised (WAIS-R) and diffusion-tensor imaging. Structural brain networks were reconstructed individually using deterministic tractography, global network properties (global efficiency, mean shortest path length, and clustering coefficient) were determined by graph theory and correlated to intelligence scores within both age groups. Network properties were significantly correlated to age, whereas no significant correlation to WAIS-R was observed. However, in a subgroup of 15 individuals aged 75 and above, the network properties were significantly correlated to WAIS-R. Our findings suggest that general intelligence and global properties of structural brain networks may not be generally associated in cognitively healthy elderly. However, we provide first evidence of an association between global structural brain network properties and general intelligence in advanced elderly. Intelligence might be affected by age-associated network deterioration only if a certain threshold of structural degeneration is exceeded. Thus, age-associated brain structural changes seem to be partially compensated by the network and the range of this compensation might be a surrogate of cognitive reserve or brain resilience. PMID:24465994

Could linear MRI measurements of hippocampus differentiate normal brain aging in elderly persons from Alzheimer disease?

PubMed

Tarroun, Abdullah; Bonnefoy, Marc; Bouffard-Vercelli, Juliette; Gedeon, Claire; Vallee, Bernard; Cotton, François

2007-02-01

Although mild progressive specific structural brain changes are commonly associated with normal human aging, it is unclear whether automatic or manual measurements of these structures can differentiate normal brain aging in elderly persons from patients suffering from cognitive impairment. The objective of this study was primarily to define, with a standard high resolution MRI, the range of normal linear age-specific values for the hippocampal formation (HF), and secondarily to differentiate hippocampal atrophy in normal aging from that occurring in Alzheimer disease (AD). Two MRI-based linear measurements of the hippocampal formation at the level of the head and of the tail, standardized by the cranial dimensions, were obtained from coronal and sagittal T1-weighted MR images in 25 normal elderly subjects, and 26 patients with AD. In this study, dimensions of the HF have been standardized and they revealed normal distributions for each side and each sex: the width of the hippocampal head at the level of the amygdala was 16.42 +/- 1.9 mm, and its height 7.93 +/- 1.4 mm; the width of the tail at the level of the cerebral aqueduct was 8.54 +/- 1.2 mm, and the height 5.74 +/- 0.4 mm. There were no significant differences in standardized dimensions of the HF between sides, sexes, or in comparison to head dimensions in the two groups. In addition, the median inter-observer agreement index was 93%. In contrast, the dimensions of the hippocampal formation decreased gradually with increasing age, owing to physiological atrophy, but this atrophy is more significant in the group of AD.

Detection of Normal Aging Effects on Human Brain Metabolite Concentrations and Microstructure with Whole-Brain MR Spectroscopic Imaging and Quantitative MR Imaging.

PubMed

Eylers, V V; Maudsley, A A; Bronzlik, P; Dellani, P R; Lanfermann, H; Ding, X-Q

2016-03-01

Knowledge of age-related physiological changes in the human brain is a prerequisite to identify neurodegenerative diseases. Therefore, in this study whole-brain (1)H-MRS was used in combination with quantitative MR imaging to study the effects of normal aging on healthy human brain metabolites and microstructure. Sixty healthy volunteers, 21-70 years of age, were studied. Brain maps of the metabolites NAA, creatine and phosphocreatine, and Cho and the tissue irreversible and reversible transverse relaxation times T2 and T2' were derived from the datasets. The relative metabolite concentrations and the values of relaxation times were measured with ROIs placed within the frontal and parietal WM, centrum semiovale, splenium of the corpus callosum, hand motor area, occipital GM, putamen, thalamus, pons ventral/dorsal, and cerebellar white matter and posterior lobe. Linear regression analysis and Pearson correlation tests were used to analyze the data. Aging resulted in decreased NAA concentrations in the occipital GM, putamen, splenium of the corpus callosum, and pons ventral and decreased creatine and phosphocreatine concentrations in the pons dorsal and putamen. Cho concentrations did not change significantly in selected brain regions. T2 increased in the cerebellar white matter and decreased in the splenium of the corpus callosum with aging, while the T2' decreased in the occipital GM, hand motor area, and putamen, and increased in the splenium of the corpus callosum. Correlations were found between NAA concentrations and T2' in the occipital GM and putamen and between creatine and phosphocreatine concentrations and T2' in the putamen. The effects of normal aging on brain metabolites and microstructure are region-dependent. Correlations between both processes are evident in the gray matter. The obtained data could be used as references for future studies on patients. © 2016 by American Journal of Neuroradiology.

Estimating the brain pathological age of Alzheimer’s disease patients from MR image data based on the separability distance criterion

NASA Astrophysics Data System (ADS)

Li, Yongming; Li, Fan; Wang, Pin; Zhu, Xueru; Liu, Shujun; Qiu, Mingguo; Zhang, Jingna; Zeng, Xiaoping

2016-10-01

Traditional age estimation methods are based on the same idea that uses the real age as the training label. However, these methods ignore that there is a deviation between the real age and the brain age due to accelerated brain aging. This paper considers this deviation and searches for it by maximizing the separability distance value rather than by minimizing the difference between the estimated brain age and the real age. Firstly, set the search range of the deviation as the deviation candidates according to prior knowledge. Secondly, use the support vector regression (SVR) as the age estimation model to minimize the difference between the estimated age and the real age plus deviation rather than the real age itself. Thirdly, design the fitness function based on the separability distance criterion. Fourthly, conduct age estimation on the validation dataset using the trained age estimation model, put the estimated age into the fitness function, and obtain the fitness value of the deviation candidate. Fifthly, repeat the iteration until all the deviation candidates are involved and get the optimal deviation with maximum fitness values. The real age plus the optimal deviation is taken as the brain pathological age. The experimental results showed that the separability was apparently improved. For normal control-Alzheimer’s disease (NC-AD), normal control-mild cognition impairment (NC-MCI), and MCI-AD, the average improvements were 0.178 (35.11%), 0.033 (14.47%), and 0.017 (39.53%), respectively. For NC-MCI-AD, the average improvement was 0.2287 (64.22%). The estimated brain pathological age could be not only more helpful to the classification of AD but also more precisely reflect accelerated brain aging. In conclusion, this paper offers a new method for brain age estimation that can distinguish different states of AD and can better reflect the extent of accelerated aging.

Relationship of metabolic and endocrine parameters to brain glucose metabolism in older adults: do cognitively-normal older adults have a particular metabolic phenotype?

PubMed

Nugent, S; Castellano, C A; Bocti, C; Dionne, I; Fulop, T; Cunnane, S C

2016-02-01

Our primary objective in this study was to quantify whole brain and regional cerebral metabolic rates of glucose (CMRg) in young and older adults in order to determine age-normalized reference CMRg values for healthy older adults with normal cognition for age. Our secondary objectives were to--(i) report a broader range of metabolic and endocrine parameters including body fat composition that could form the basis for the concept of a 'metabolic phenotype' in cognitively normal, older adults, and (ii) to assess whether medications commonly used to control blood lipids, blood pressure or thyroxine affect CMRg values in older adults. Cognition assessed by a battery of tests was normal for age and education in both groups. Compared to the young group (25 years old; n = 34), the older group (72 years old; n = 41) had ~14% lower CMRg (μmol/100 g/min) specifically in the frontal cortex, and 18% lower CMRg in the caudate. Lower grey matter volume and cortical thickness was widespread in the older group. These differences in CMRg, grey matter volume and cortical thickness were present in the absence of any known evidence for prodromal Alzheimer's disease (AD). Percent total body fat was positively correlated with CMRg in many brain regions but only in the older group. Before and after controlling for body fat, HOMA2-IR was significantly positively correlated to CMRg in several brain regions in the older group. These data show that compared to a healthy younger adult, the metabolic phenotype of a cognitively-normal 72 year old person includes similar plasma glucose, insulin, cholesterol, triglycerides and TSH, higher hemoglobin A1c and percent body fat, lower CMRg in the superior frontal cortex and caudate, but the same CMRg in the hippocampus and white matter. Age-normalization of cognitive test results is standard practice and we would suggest that regional CMRg in cognitively healthy older adults should also be age-normalized.

Gene expression profiles in anatomically and functionally distinct regions of the normal aged human brain

PubMed Central

Liang, Winnie S.; Dunckley, Travis; Beach, Thomas G.; Grover, Andrew; Mastroeni, Diego; Walker, Douglas G.; Caselli, Richard J.; Kukull, Walter A.; McKeel, Daniel; Morris, John C.; Hulette, Christine; Schmechel, Donald; Alexander, Gene E.; Reiman, Eric M.; Rogers, Joseph; Stephan, Dietrich A.

2008-01-01

In this article, we have characterized and compared gene expression profiles from laser capture microdissected neurons in six functionally and anatomically distinct regions from clinically and histopathologically normal aged human brains. These regions, which are also known to be differentially vulnerable to the histopathological and metabolic features of Alzheimer’s disease (AD), include the entorhinal cortex and hippocampus (limbic and paralimbic areas vulnerable to early neurofibrillary tangle pathology in AD), posterior cingulate cortex (a paralimbic area vulnerable to early metabolic abnormalities in AD), temporal and prefrontal cortex (unimodal and heteromodal sensory association areas vulnerable to early neuritic plaque pathology in AD), and primary visual cortex (a primary sensory area relatively spared in early AD). These neuronal profiles will provide valuable reference information for future studies of the brain, in normal aging, AD and other neurological and psychiatric disorders. PMID:17077275

Prenatal Brain MR Imaging: Reference Linear Biometric Centiles between 20 and 24 Gestational Weeks.

PubMed

Conte, G; Milani, S; Palumbo, G; Talenti, G; Boito, S; Rustico, M; Triulzi, F; Righini, A; Izzo, G; Doneda, C; Zolin, A; Parazzini, C

2018-05-01

Evaluation of biometry is a fundamental step in prenatal brain MR imaging. While different studies have reported reference centiles for MR imaging biometric data of fetuses in the late second and third trimesters of gestation, no one has reported them in fetuses in the early second trimester. We report centiles of normal MR imaging linear biometric data of a large cohort of fetal brains within 24 weeks of gestation. From the data bases of 2 referral centers of fetal medicine, accounting for 3850 examinations, we retrospectively collected 169 prenatal brain MR imaging examinations of singleton pregnancies, between 20 and 24 weeks of gestational age, with normal brain anatomy at MR imaging and normal postnatal neurologic development. To trace the reference centiles, we used the CG-LMS method. Reference biometric centiles for the developing structures of the cerebrum, cerebellum, brain stem, and theca were obtained. The overall interassessor agreement was adequate for all measurements. Reference biometric centiles of the brain structures in fetuses between 20 and 24 weeks of gestational age may be a reliable tool in assessing fetal brain development. © 2018 by American Journal of Neuroradiology.

Age-Related Changes and Reference Values of Bicaudate Ratio and Sagittal Brainstem Diameters on MRI.

PubMed

Garbade, Sven F; Boy, Nikolas; Heringer, Jana; Kölker, Stefan; Harting, Inga

2018-06-05

Cranial magnetic resonance imaging (MRI) plays an important role in the diagnosis of neurometabolic diseases, and, in addition, temporal patterns of signal and volume changes allow insight into the underlying pathogenesis. While assessment of volume changes by visual inspection is subjective, volumetric approaches are often not feasible with rare neurometabolic diseases, where MRIs are often acquired with different scanners and protocols. Linear surrogate parameters of brain volume, for example, the bicaudate ratio, present a robust alternative that can be derived from standard imaging sequences. Due to the continuing postnatal brain and skull development and later brain involution, it is, however, necessary to compare patient values with age age-adapted normal values.In this article, we present age-dependent normal values derived from 993 standard scans of patients with normal MRI findings (age range: 0-80 years; mean = 19.9; median = 12.8 years) for bicaudate ratio as a measure of global supratentorial volume, as well as the maximal anteroposterior diameters of mesencephalon, pons, and medulla oblongata as parameters of brainstem volume. The provided data allow quantitative, objective assessment of brain volume changes instead of the usually performed visual and therefore subjective assessment. Georg Thieme Verlag KG Stuttgart · New York.

Energy metabolism and inflammation in brain aging and Alzheimer's disease.

PubMed

Yin, Fei; Sancheti, Harsh; Patil, Ishan; Cadenas, Enrique

2016-11-01

The high energy demand of the brain renders it sensitive to changes in energy fuel supply and mitochondrial function. Deficits in glucose availability and mitochondrial function are well-known hallmarks of brain aging and are particularly accentuated in neurodegenerative disorders such as Alzheimer's disease. As important cellular sources of H 2 O 2 , mitochondrial dysfunction is usually associated with altered redox status. Bioenergetic deficits and chronic oxidative stress are both major contributors to cognitive decline associated with brain aging and Alzheimer's disease. Neuroinflammatory changes, including microglial activation and production of inflammatory cytokines, are observed in neurodegenerative diseases and normal aging. The bioenergetic hypothesis advocates for sequential events from metabolic deficits to propagation of neuronal dysfunction, to aging, and to neurodegeneration, while the inflammatory hypothesis supports microglia activation as the driving force for neuroinflammation. Nevertheless, growing evidence suggests that these diverse mechanisms have redox dysregulation as a common denominator and connector. An independent view of the mechanisms underlying brain aging and neurodegeneration is being replaced by one that entails multiple mechanisms coordinating and interacting with each other. This review focuses on the alterations in energy metabolism and inflammatory responses and their connection via redox regulation in normal brain aging and Alzheimer's disease. Interaction of these systems is reviewed based on basic research and clinical studies. Copyright © 2016 Elsevier Inc. All rights reserved.

Glymphatic MRI in idiopathic normal pressure hydrocephalus.

PubMed

Ringstad, Geir; Vatnehol, Svein Are Sirirud; Eide, Per Kristian

2017-10-01

The glymphatic system has in previous studies been shown as fundamental to clearance of waste metabolites from the brain interstitial space, and is proposed to be instrumental in normal ageing and brain pathology such as Alzheimer's disease and brain trauma. Assessment of glymphatic function using magnetic resonance imaging with intrathecal contrast agent as a cerebrospinal fluid tracer has so far been limited to rodents. We aimed to image cerebrospinal fluid flow characteristics and glymphatic function in humans, and applied the methodology in a prospective study of 15 idiopathic normal pressure hydrocephalus patients (mean age 71.3 ± 8.1 years, three female and 12 male) and eight reference subjects (mean age 41.1 + 13.0 years, six female and two male) with suspected cerebrospinal fluid leakage (seven) and intracranial cyst (one). The imaging protocol included T1-weighted magnetic resonance imaging with equal sequence parameters before and at multiple time points through 24 h after intrathecal injection of the contrast agent gadobutrol at the lumbar level. All study subjects were kept in the supine position between examinations during the first day. Gadobutrol enhancement was measured at all imaging time points from regions of interest placed at predefined locations in brain parenchyma, the subarachnoid and intraventricular space, and inside the sagittal sinus. Parameters demonstrating gadobutrol enhancement and clearance in different locations were compared between idiopathic normal pressure hydrocephalus and reference subjects. A characteristic flow pattern in idiopathic normal hydrocephalus was ventricular reflux of gadobutrol from the subarachnoid space followed by transependymal gadobutrol migration. At the brain surfaces, gadobutrol propagated antegradely along large leptomeningeal arteries in all study subjects, and preceded glymphatic enhancement in adjacent brain tissue, indicating a pivotal role of intracranial pulsations for glymphatic function. In idiopathic normal pressure hydrocephalus, we found delayed enhancement (P < 0.05) and decreased clearance of gadobutrol (P < 0.05) at the Sylvian fissure. Parenchymal (glymphatic) enhancement peaked overnight in both study groups, possibly indicating a crucial role of sleep, and was larger in normal pressure hydrocephalus patients (P < 0.05 at inferior frontal gyrus). We interpret decreased gadobutrol clearance from the subarachnoid space, along with persisting enhancement in brain parenchyma, as signs of reduced glymphatic clearance in idiopathic normal hydrocephalus, and hypothesize that reduced glymphatic function is instrumental for dementia in this disease. The study shows promise for glymphatic magnetic resonance imaging as a method to assess human brain metabolic function and renders a potential for contrast enhanced brain extravascular space imaging. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain.

Biomechanical Analysis of Normal Brain Development during the First Year of Life Using Finite Strain Theory.

PubMed

Kim, Jeong Chul; Wang, Li; Shen, Dinggang; Lin, Weili

2016-12-02

The first year of life is the most critical time period for structural and functional development of the human brain. Combining longitudinal MR imaging and finite strain theory, this study aimed to provide new insights into normal brain development through a biomechanical framework. Thirty-three normal infants were longitudinally imaged using MRI from 2 weeks to 1 year of age. Voxel-wise Jacobian determinant was estimated to elucidate volumetric changes while Lagrange strains (both normal and shear strains) were measured to reveal directional growth information every 3 months during the first year of life. Directional normal strain maps revealed that, during the first 6 months, the growth pattern of gray matter is anisotropic and spatially inhomogeneous with higher left-right stretch around the temporal lobe and interhemispheric fissure, anterior-posterior stretch in the frontal and occipital lobes, and superior-inferior stretch in right inferior occipital and right inferior temporal gyri. In contrast, anterior lateral ventricles and insula showed an isotropic stretch pattern. Volumetric and directional growth rates were linearly decreased with age for most of the cortical regions. Our results revealed anisotropic and inhomogeneous brain growth patterns of the human brain during the first year of life using longitudinal MRI and a biomechanical framework.

The Brain as a Mixer, II. A Pilot Study of Central Auditory Integration Abilities of Normal and Retarded Children. Studies in Language and Language Behavior, Progress Report Number VII.

ERIC Educational Resources Information Center

Semmel, Melvyn I.; And Others

To explore the binaural integration abilities of six educable mentally retarded boys (ages 8 to 13) and six normal boys (ages 7 to 12) to detect possible brain inju"y, an adaptation of Matzker's (1958) technique involving separating words into high and low frequencies was used. One frequency filter system presented frequencies from 425 to 1275…

Progressive Disintegration of Brain Networking from Normal Aging to Alzheimer Disease: Analysis of Independent Components of 18F-FDG PET Data.

PubMed

Pagani, Marco; Giuliani, Alessandro; Öberg, Johanna; De Carli, Fabrizio; Morbelli, Silvia; Girtler, Nicola; Arnaldi, Dario; Accardo, Jennifer; Bauckneht, Matteo; Bongioanni, Francesca; Chincarini, Andrea; Sambuceti, Gianmario; Jonsson, Cathrine; Nobili, Flavio

2017-07-01

Brain connectivity has been assessed in several neurodegenerative disorders investigating the mutual correlations between predetermined regions or nodes. Selective breakdown of brain networks during progression from normal aging to Alzheimer disease dementia (AD) has also been observed. Methods: We implemented independent-component analysis of 18 F-FDG PET data in 5 groups of subjects with cognitive states ranging from normal aging to AD-including mild cognitive impairment (MCI) not converting or converting to AD-to disclose the spatial distribution of the independent components in each cognitive state and their accuracy in discriminating the groups. Results: We could identify spatially distinct independent components in each group, with generation of local circuits increasing proportionally to the severity of the disease. AD-specific independent components first appeared in the late-MCI stage and could discriminate converting MCI and AD from nonconverting MCI with an accuracy of 83.5%. Progressive disintegration of the intrinsic networks from normal aging to MCI to AD was inversely proportional to the conversion time. Conclusion: Independent-component analysis of 18 F-FDG PET data showed a gradual disruption of functional brain connectivity with progression of cognitive decline in AD. This information might be useful as a prognostic aid for individual patients and as a surrogate biomarker in intervention trials. © 2017 by the Society of Nuclear Medicine and Molecular Imaging.

Estimating brain age using high-resolution pattern recognition: Younger brains in long-term meditation practitioners.

PubMed

Luders, Eileen; Cherbuin, Nicolas; Gaser, Christian

2016-07-01

Normal aging is known to be accompanied by loss of brain substance. The present study was designed to examine whether the practice of meditation is associated with a reduced brain age. Specific focus was directed at age fifty and beyond, as mid-life is a time when aging processes are known to become more prominent. We applied a recently developed machine learning algorithm trained to identify anatomical correlates of age in the brain translating those into one single score: the BrainAGE index (in years). Using this validated approach based on high-dimensional pattern recognition, we re-analyzed a large sample of 50 long-term meditators and 50 control subjects estimating and comparing their brain ages. We observed that, at age fifty, brains of meditators were estimated to be 7.5years younger than those of controls. In addition, we examined if the brain age estimates change with increasing age. While brain age estimates varied only little in controls, significant changes were detected in meditators: for every additional year over fifty, meditators' brains were estimated to be an additional 1month and 22days younger than their chronological age. Altogether, these findings seem to suggest that meditation is beneficial for brain preservation, effectively protecting against age-related atrophy with a consistently slower rate of brain aging throughout life. Copyright © 2016 Elsevier Inc. All rights reserved.

Sex differences in normal age trajectories of functional brain networks.

PubMed

Scheinost, Dustin; Finn, Emily S; Tokoglu, Fuyuze; Shen, Xilin; Papademetris, Xenophon; Hampson, Michelle; Constable, R Todd

2015-04-01

Resting-state functional magnetic resonance image (rs-fMRI) is increasingly used to study functional brain networks. Nevertheless, variability in these networks due to factors such as sex and aging is not fully understood. This study explored sex differences in normal age trajectories of resting-state networks (RSNs) using a novel voxel-wise measure of functional connectivity, the intrinsic connectivity distribution (ICD). Males and females showed differential patterns of changing connectivity in large-scale RSNs during normal aging from early adulthood to late middle-age. In some networks, such as the default-mode network, males and females both showed decreases in connectivity with age, albeit at different rates. In other networks, such as the fronto-parietal network, males and females showed divergent connectivity trajectories with age. Main effects of sex and age were found in many of the same regions showing sex-related differences in aging. Finally, these sex differences in aging trajectories were robust to choice of preprocessing strategy, such as global signal regression. Our findings resolve some discrepancies in the literature, especially with respect to the trajectory of connectivity in the default mode, which can be explained by our observed interactions between sex and aging. Overall, results indicate that RSNs show different aging trajectories for males and females. Characterizing effects of sex and age on RSNs are critical first steps in understanding the functional organization of the human brain. © 2014 Wiley Periodicals, Inc.

Magnetic Resonance Elastography Demonstrates Increased Brain Stiffness in Normal Pressure Hydrocephalus

PubMed Central

N, Fattahi; A, Arani; A, Perry; F, Meyer; A, Manduca; K, Glaser; ML, Senjem; RL, Ehman; J, Huston

2015-01-01

Introduction Normal pressure hydrocephalus (NPH) is a reversible neurologic disorder characterized by a triad of cognitive impairment, gait abnormality and urinary incontinence that is commonly treated with ventriculoperitoneal shunt placement. However, there are multiple overlapping symptoms which often make it difficult to differentiate NPH from other types of dementia and improved diagnostic techniques would help patient management. MR elastography (MRE) is a novel diagnostic tool that could potentially identify patients with NPH. The purpose of this study was to assess brain stiffness changes in NPH patients compared with age- and sex-matched cognitively normal individuals. Methods MRE was performed on 10 NPH patients and 21 age- and sex-matched volunteers with no known neurologic disorders. Image acquisition was conducted on a 3T MRI scanner. Shear waves with 60Hz vibration frequency were transmitted into the brain by a pillow-like passive driver. A novel postprocessing technique resistant to noise and edge artifacts was implemented to determine regional brain stiffness. The Wilcoxon rank sum test and linear regression were used for statistical analysis. Results A significant increase in stiffness was observed in the cerebrum (p = 0.001), occipital lobe (p = 0.0002), parietal lobe (p= 0.001), and the temporal lobe (p = 0.02) in the NPH group compared with normal controls. However, no significant difference was noted in other regions of the brain including the frontal lobe (p = 0.07), deep gray and white matter (p = 0.43), or the cerebellum (p = 0.20). Conclusion This study demonstrates increased brain stiffness in NPH patients compared to age- and sex-matched normal controls which motivates future studies investigating the use of MRE for NPH diagnosis and efficacy of shunt therapy. PMID:26542235

High-Throughput Analysis of Age-Dependent Protein Changes in Layer II/III of the Human Orbitofrontal Cortex

NASA Astrophysics Data System (ADS)

Kapadia, Fenika

Studies on the orbitofrontal cortex (OFC) during normal aging have shown a decline in cognitive functions, a loss of spines/synapses in layer III and gene expression changes related to neural communication. Biological changes during the course of normal aging are summarized into 9 hallmarks based on aging in peripheral tissue. Whether these hallmarks apply to non-dividing brain tissue is not known. Therefore, we opted to perform large-scale proteomic profiling of the OFC layer II/III during normal aging from 15 young and 18 old male subjects. MaxQuant was utilized for label-free quantification and statistical analysis by the Random Intercept Model (RIM) identified 118 differentially expressed (DE) age-related proteins. Altered neural communication was the most represented hallmark of aging (54% of DE proteins), highlighting the importance of communication in the brain. Functional analysis showed enrichment in GABA/glutamate signaling and pro-inflammatory responses. The former may contribute to alterations in excitation/inhibition, leading to cognitive decline during aging.

Redox proteomics and the dynamic molecular landscape of the aging brain.

PubMed

Perluigi, Marzia; Swomley, Aaron M; Butterfield, D Allan

2014-01-01

It is well established that the risk to develop neurodegenerative disorders increases with chronological aging. Accumulating studies contributed to characterize the age-dependent changes either at gene and protein expression level which, taken together, show that aging of the human brain results from the combination of the normal decline of multiple biological functions with environmental factors that contribute to defining disease risk of late-life brain disorders. Finding the "way out" of the labyrinth of such complex molecular interactions may help to fill the gap between "normal" brain aging and development of age-dependent diseases. To this purpose, proteomics studies are a powerful tool to better understand where to set the boundary line of healthy aging and age-related disease by analyzing the variation of protein expression levels and the major post translational modifications that determine "protein" physio/pathological fate. Increasing attention has been focused on oxidative modifications due to the crucial role of oxidative stress in aging, in addition to the fact that this type of modification is irreversible and may alter protein function. Redox proteomics studies contributed to decipher the complexity of brain aging by identifying the proteins that were increasingly oxidized and eventually dysfunctional as a function of age. The purpose of this review is to summarize the most important findings obtained by applying proteomics approaches to murine models of aging with also a brief overview of some human studies, in particular those related to dementia. Copyright © 2014. Published by Elsevier B.V.

MRI Brain Volume Measurements in Infantile Neuronal Ceroid Lipofuscinosis

PubMed Central

Baker, Eva H.; Levin, Sondra W.; Zhang, Zhongjian; Mukherjee, Anil B.

2016-01-01

Background Infantile neuronal ceroid lipofuscinosis (INCL) is a devastating neurodegenerative storage disease caused by palmitoyl-protein thioesterase-1 (PPT1) deficiency. PPT1 deficiency impairs degradation of palmitoylated proteins (constituents of ceroid) by lysosomal hydrolases. Consequent lysosomal ceroid accumulation leads to neuronal injury, resulting in rapid neurodegeneration and childhood demise. As part of a project studying treatment benefits of a combination of cysteamine bitartrate and N-acetylcysteine, we made serial measurements of patients’ brain volumes using MRI. Methods Ten INCL patients participating in a treatment/follow-up study underwent brain MRI that included high resolution T1-weighted images. After manual placement of a mask delineating the surface of the brain, a maximum-likelihood classifier was applied to determine total brain volume, further subdivided as cerebrum, cerebellum, brainstem, and thalamus. Patients’ brain volumes were compared to those of a normal population. Results Major subdivisions of the brain followed similar trajectories with different timing. The cerebrum demonstrated early, rapid volume loss, and may never have been normal postnatally. The thalamus dropped out of the normal range around age 6 months, cerebellum around age 2 years, and brainstem around age 3 years. Discussion Rapid cerebral volume loss was expected based upon previous qualitative reports. Because our study did not include a non-treatment arm, and because progression of brain volumes in INCL has not previously been quantified, we could not determine whether our intervention had a beneficial effect on brain volumes. However, the level of quantitative detail in this study allows it to serve as a reference for evaluation of future therapeutic interventions. PMID:27765741

Hitting a Moving Target: Basic Mechanisms of Recovery from Acquired Developmental Brain Injury

PubMed Central

Giza, Christopher C.; Kolb, Bryan; Harris, Neil G.; Asarnow, Robert F.; Prins, Mayumi L.

2009-01-01

Acquired brain injuries represent a major cause of disability in the pediatric population. Understanding responses to developmental acquired brain injuries requires knowledge of the neurobiology of normal development, age-at-injury effects and experience-dependent neuroplasticity. In the developing brain, full recovery cannot be considered as a return to the premorbid baseline, since ongoing maturation means that cerebral functioning in normal individuals will continue to advance. Thus, the recovering immature brain has to ‘hit a moving target’ to achieve full functional recovery, defined as parity with age-matched uninjured peers. This review will discuss the consequences of developmental injuries such as focal lesions, diffuse hypoxia and traumatic brain injury (TBI). Underlying cellular and physiological mechanisms relevant to age-at-injury effects will be described in considerable detail, including but not limited to alterations in neurotransmission, connectivity/network functioning, the extracellular matrix, response to oxidative stress and changes in cerebral metabolism. Finally, mechanisms of experience-dependent plasticity will be reviewed in conjunction with their effects on neural repair and recovery. PMID:19956795

Genetic and Diagnostic Biomarker Development in ASD Toddlers Using Resting State Functional MRI

DTIC Science & Technology

2017-11-01

Integration Theory of intelligence (Jung and Haier, Behave Brain Sci, 2007...predicting a number of age-related phenotypes. Measures of white matter integrity in the brain are heritable and highly sensitive to both normal and...pathological aging processes. We consider the phenotypic and genetic interrelationships between epigenetic age acceleration and white matter integrity

Long live the axon. Parallels between ageing and pathology from a presynaptic point of view.

PubMed

Grillo, Federico W

2016-10-01

All animals have to find the right balance between investing resources into their reproductive cycle and protecting their tissues from age-related damage. In higher order organisms the brain is particularly vulnerable to ageing, as the great majority of post-mitotic neurons are there to stay for an entire life. While ageing is unavoidable, it may progress at different rates in different individuals of the same species depending on a variety of genetic and environmental factors. Inevitably though, ageing results in a cognitive and sensory-motor decline caused by changes in neuronal structure and function. Besides normal ageing, age-related pathological conditions can develop in a sizeable proportion of the population. While this wide array of diseases are considerably different compared to physiological ageing, the two processes share many similarities and are likely to interact. At the subcellular level, two key structures are involved in brain ageing: axons and their synapses. Here I highlight how the ageing process affects these structures in normal and neurodegenerative states in different brain areas. Copyright © 2016 Elsevier B.V. All rights reserved.

Glymphatic MRI in idiopathic normal pressure hydrocephalus

PubMed Central

Ringstad, Geir; Vatnehol, Svein Are Sirirud; Eide, Per Kristian

2017-01-01

Abstract The glymphatic system has in previous studies been shown as fundamental to clearance of waste metabolites from the brain interstitial space, and is proposed to be instrumental in normal ageing and brain pathology such as Alzheimer’s disease and brain trauma. Assessment of glymphatic function using magnetic resonance imaging with intrathecal contrast agent as a cerebrospinal fluid tracer has so far been limited to rodents. We aimed to image cerebrospinal fluid flow characteristics and glymphatic function in humans, and applied the methodology in a prospective study of 15 idiopathic normal pressure hydrocephalus patients (mean age 71.3 ± 8.1 years, three female and 12 male) and eight reference subjects (mean age 41.1 + 13.0 years, six female and two male) with suspected cerebrospinal fluid leakage (seven) and intracranial cyst (one). The imaging protocol included T1-weighted magnetic resonance imaging with equal sequence parameters before and at multiple time points through 24 h after intrathecal injection of the contrast agent gadobutrol at the lumbar level. All study subjects were kept in the supine position between examinations during the first day. Gadobutrol enhancement was measured at all imaging time points from regions of interest placed at predefined locations in brain parenchyma, the subarachnoid and intraventricular space, and inside the sagittal sinus. Parameters demonstrating gadobutrol enhancement and clearance in different locations were compared between idiopathic normal pressure hydrocephalus and reference subjects. A characteristic flow pattern in idiopathic normal hydrocephalus was ventricular reflux of gadobutrol from the subarachnoid space followed by transependymal gadobutrol migration. At the brain surfaces, gadobutrol propagated antegradely along large leptomeningeal arteries in all study subjects, and preceded glymphatic enhancement in adjacent brain tissue, indicating a pivotal role of intracranial pulsations for glymphatic function. In idiopathic normal pressure hydrocephalus, we found delayed enhancement (P < 0.05) and decreased clearance of gadobutrol (P < 0.05) at the Sylvian fissure. Parenchymal (glymphatic) enhancement peaked overnight in both study groups, possibly indicating a crucial role of sleep, and was larger in normal pressure hydrocephalus patients (P < 0.05 at inferior frontal gyrus). We interpret decreased gadobutrol clearance from the subarachnoid space, along with persisting enhancement in brain parenchyma, as signs of reduced glymphatic clearance in idiopathic normal hydrocephalus, and hypothesize that reduced glymphatic function is instrumental for dementia in this disease. The study shows promise for glymphatic magnetic resonance imaging as a method to assess human brain metabolic function and renders a potential for contrast enhanced brain extravascular space imaging. PMID:28969373

The endocannabinoid system in normal and pathological brain ageing

PubMed Central

Bilkei-Gorzo, Andras

2012-01-01

The role of endocannabinoids as inhibitory retrograde transmitters is now widely known and intensively studied. However, endocannabinoids also influence neuronal activity by exerting neuroprotective effects and regulating glial responses. This review centres around this less-studied area, focusing on the cellular and molecular mechanisms underlying the protective effect of the cannabinoid system in brain ageing. The progression of ageing is largely determined by the balance between detrimental, pro-ageing, largely stochastic processes, and the activity of the homeostatic defence system. Experimental evidence suggests that the cannabinoid system is part of the latter system. Cannabinoids as regulators of mitochondrial activity, as anti-oxidants and as modulators of clearance processes protect neurons on the molecular level. On the cellular level, the cannabinoid system regulates the expression of brain-derived neurotrophic factor and neurogenesis. Neuroinflammatory processes contributing to the progression of normal brain ageing and to the pathogenesis of neurodegenerative diseases are suppressed by cannabinoids, suggesting that they may also influence the ageing process on the system level. In good agreement with the hypothesized beneficial role of cannabinoid system activity against brain ageing, it was shown that animals lacking CB1 receptors show early onset of learning deficits associated with age-related histological and molecular changes. In preclinical models of neurodegenerative disorders, cannabinoids show beneficial effects, but the clinical evidence regarding their efficacy as therapeutic tools is either inconclusive or still missing. PMID:23108550

The endocannabinoid system in normal and pathological brain ageing.

PubMed

Bilkei-Gorzo, Andras

2012-12-05

The role of endocannabinoids as inhibitory retrograde transmitters is now widely known and intensively studied. However, endocannabinoids also influence neuronal activity by exerting neuroprotective effects and regulating glial responses. This review centres around this less-studied area, focusing on the cellular and molecular mechanisms underlying the protective effect of the cannabinoid system in brain ageing. The progression of ageing is largely determined by the balance between detrimental, pro-ageing, largely stochastic processes, and the activity of the homeostatic defence system. Experimental evidence suggests that the cannabinoid system is part of the latter system. Cannabinoids as regulators of mitochondrial activity, as anti-oxidants and as modulators of clearance processes protect neurons on the molecular level. On the cellular level, the cannabinoid system regulates the expression of brain-derived neurotrophic factor and neurogenesis. Neuroinflammatory processes contributing to the progression of normal brain ageing and to the pathogenesis of neurodegenerative diseases are suppressed by cannabinoids, suggesting that they may also influence the ageing process on the system level. In good agreement with the hypothesized beneficial role of cannabinoid system activity against brain ageing, it was shown that animals lacking CB1 receptors show early onset of learning deficits associated with age-related histological and molecular changes. In preclinical models of neurodegenerative disorders, cannabinoids show beneficial effects, but the clinical evidence regarding their efficacy as therapeutic tools is either inconclusive or still missing.

Ascorbic acid, cognitive function, and Alzheimer’s disease: a current review and future direction

PubMed Central

Bowman, Gene L.

2013-01-01

This narrative review appraises the human and animal studies implicating ascorbic acid (AA) in normal cognitive function and Alzheimer’s disease. A research framework for how nutrition affects brain aging is proposed with emphasis on AA intake, status, metabolism, and transport into brain tissue. A final synopsis highlights areas for future research regarding AA nourishment and healthy brain aging. PMID:22419527

The lack of age-pigments and the alterations in intracellular monovalent electrolytes in spontaneously hypertensive, stroke-prone (SHRsp) rats as revealed by electron microscopy and X-ray microanalysis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zs.-Nagy, I.; Zs.-Nagy, V.; Casoli, T.

1989-01-01

Male, spontaneously hypertensive, stroke-prone (SHRsp) rats established by Okamoto et al. were studied. About 80% of the males of this strain have a particularly short life span (33-41 weeks); they display a considerable hypertension (above 220 mmHg) and a tendency for plurifocal brain strokes. Hypertension and strokes can be provoked in an accelerated and synchronized fashion by supplementing 1% NaCl into their drinking water. Symptoms of the appearance of brain strokes can be judged from characteristic signs of motor disorders, and can be established also by pathohistology. Since hypertension and arteriosclerosis are frequently involved in aging, the question we intendedmore » to answer was whether these animals may represent a model of the normal aging process or not. Two approaches are described: (1) Accumulation of lipofuscin granules in their brain, liver and myocardium was followed by transmission electron microscopy before and after the appearance of strokes. It has been established that these tissues do not show any typical accumulation of lipofuscin granules, although submicroscopic signs of an enhanced damage of cell organelles (especially of mitochondria in liver and brain cells, but not in myocardium) were encountered. (2) The intracellular monovalent composition in the brain and liver was measured by using bulk-specimen X-ray microanalysis. The intracellular Na-content (mEq/kg water) was significantly higher (170-200%) in both the brain and liver cells, whereas the K-content increased only moderately (118-130%). The results suggest that although the SHRsp rats do not represent a direct model for the normal aging process from the point of view of lipofuscin accumulation, the shifts of the monovalent electrolyte contents in the brain and liver cells observed already in the youngest ages, are similar to those observed in aged normal rats.« less

Contribution of four lifelong factors of cognitive reserve on late cognition in normal aging and Parkinson's disease.

PubMed

Rouillard, Maud; Audiffren, Michel; Albinet, Cédric; Ali Bahri, Mohamed; Garraux, Gaëtan; Collette, Fabienne

2017-03-01

Cognitive reserve (CR) was proposed to explain how individual differences in brain function help to cope with the effects of normal aging and neurodegenerative diseases. Education, professional solicitations, and engagement in leisure and physical activities across the lifetime are considered as major determinants of this reserve. Using multiple linear regression analyses, we tested separately in healthy elderly and Parkinson's disease (PD) populations to what extent cognitive performance in several domains was explained by (a) any of these four environmental lifespan variables; (b) demographic and clinical variables (age, gender, depression score, and, for the PD group, duration of disease and dopaminergic drugs). We also tested for an interaction, if any, between these lifespan variables and brain pathology indexed by global atrophy measured from high-resolution anatomical magnetic resonance imaging. Age was negatively associated with cognitive performance in the PD group. In healthy elderly participants, we observed significant positive associations between cognitive performance and (a) education, (b) leisure activities, and (c) professional solicitation (decisional latitude). Furthermore, participants with greater brain atrophy benefited more from CR. In PD patients, education and professional solicitations contributed to cognitive performance but to a lesser extent than in controls. CR factors modulated the relationship between cognition and brain atrophy only in patients with a slight or moderate brain atrophy. Education is the CR factor that contributed the most to late cognitive functioning in both groups, closely followed by leisure activity in normal aging and professional solicitations in PD. Our results also provide evidence suggesting that the effects of CR does not express similarly in normal aging and PD. From a broader perspective, these results seem to indicate that CR factors the most consistently practiced across lifespan (education and professional solicitation) are those that are the more strongly associated to late cognitive efficiency.

Fatty aspirin: a new perspective in the prevention of dementia of Alzheimer's type?

PubMed

Pomponi, M; Di Gioia, A; Bria, P; Pomponi, M F L

2008-10-01

Alzheimer's disease (AD) leads to a dramatic decline in cognitive abilities and memory. A more modest disruption of memory often occurs in normal aging and the same circuits that are devastated through degeneration in AD are vulnerable to sub-lethal age-related changes that alter synaptic transmission. There are numerous indications that aberrant plasticity is critically involved in Alzheimer's. Is ageing itself the major risk factor for AD? Is AD an acceleration of normal ageing? We assume that the ability of the brain is to modify its own structural organization and functioning which is liable to become impaired in ageing until it becomes dramatically impaired in Alzheimer's. Moreover, ageing can compromise the conversion of dietary alpha-linolenic acid (ALA) to docosahexaenoic acid (DHA). DHA regulates synaptogenesis and affects the synaptic structure, and synapse density is reduced in ageing. DHA and newly identified DHA-derived messenger, neuroprotecting D1 (NPD1), protect synapses and decrease the number of activated microglia in the hippocampal system. Delaying AD onset by a few years would reduce the number of the cases of dementia in the community. DHA (and NPD1?) and aspirin induce brain-derived neurotrophic factor (BDNF) protein expression and this protein has a crucial role in neuronal survival. The authors--in view of the increased neuroinflammatory reaction frequently observed during normal brain ageing--suggest the long-term use of "fatty aspirin", an association of DHA and/or NPD1 and aspirin (or nitroaspirin), to postpone, or prevent, the structural neurodegeneration of the brain.

Reexpression of a developmentally regulated antigen in Down syndrome and Alzheimer disease

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wolozin, B.; Scicutella, A.; Davies, P.

1988-08-01

ALZ-50 is a monoclonal antibody that recognizes a protein of apparent molecular mass 68 kilodaltons (A68). The protein is present in the brains of patients with Alzheimer disease but is not detectable in normal adult brain tissue. The authors report that ALZ-50-reactive neurons are found in normal fetal and neonatal human brain and in brain tissue from neonatal individuals with Down syndrome. Reactive neurons decrease sharply in number after age 2 and reappear in older individuals with Down syndrome and in patients with Alzheimer disease.

Insulin-like Growth Factor 1 (IGF-1) as a marker of cognitive decline in normal ageing: A review.

PubMed

Frater, Julanne; Lie, David; Bartlett, Perry; McGrath, John J

2018-03-01

Insulin-like Growth Factor 1 (IGF-1) and its signaling pathway play a primary role in normal growth and ageing, however serum IGF-1 is known to reduce with advancing age. Recent findings suggest IGF-1 is essential for neurogenesis in the adult brain, and this reduction of IGF-1 with ageing may contribute to age-related cognitive decline. Experimental studies have shown manipulation of the GH/GF-1 axis can slow rates of cognitive decline in animals, making IGF-1 a potential biomarker of cognition, and/or its signaling pathway a possible therapeutic target to prevent or slow age-related cognitive decline. A systematic literature review and qualitative narrative summary of current evidence for IGF-1 as a biomarker of cognitive decline in the ageing brain was undertaken. Results indicate IGF-1 concentrations do not confer additional diagnostic information for those with cognitive decline, and routine clinical measurement of IGF-1 is not currently justified. In cases of established cognitive impairment, it remains unclear whether increasing circulating or brain IGF-1 may reverse or slow down the rate of further decline. Advances in neuroimaging, genetics, neuroscience and the availability of large well characterized biobanks will facilitate research exploring the role of IGF-1 in both normal ageing and age-related cognitive decline. Copyright © 2017 Elsevier B.V. All rights reserved.

Age-Related Gray and White Matter Changes in Normal Adult Brains

PubMed Central

Farokhian, Farnaz; Yang, Chunlan; Beheshti, Iman; Matsuda, Hiroshi; Wu, Shuicai

2017-01-01

Normal aging is associated with both structural changes in many brain regions and functional declines in several cognitive domains with advancing age. Advanced neuroimaging techniques enable explorative analyses of structural alterations that can be used as assessments of such age-related changes. Here we used voxel-based morphometry (VBM) to investigate regional and global brain volume differences among four groups of healthy adults from the IXI Dataset: older females (OF, mean age 68.35 yrs; n=69), older males (OM, 68.43 yrs; n=66), young females (YF, 27.09 yrs; n=71), and young males (YM, 27.91 yrs; n=71), using 3D T1-weighted MRI data. At the global level, we investigated the influence of age and gender on brain volumes using a two-way analysis of variance. With respect to gender, we used the Pearson correlation to investigate global brain volume alterations due to age in the older and young groups. At the regional level, we used a flexible factorial statistical test to compare the means of gray matter (GM) and white matter (WM) volume alterations among the four groups. We observed different patterns in both the global and regional GM and WM alterations in the young and older groups with respect to gender. At the global level, we observed significant influences of age and gender on global brain volumes. At the regional level, the older subjects showed a widespread reduction in GM volume in regions of the frontal, insular, and cingulate cortices compared to the young subjects in both genders. Compared to the young subjects, the older subjects showed a widespread WM decline prominently in the thalamic radiations, in addition to increased WM in pericentral and occipital areas. Knowledge of these observed brain volume differences and changes may contribute to the elucidation of mechanisms underlying aging as well as age-related brain atrophy and disease. PMID:29344423

Molecular insights into the pathogenesis of Alzheimer's disease and its relationship to normal aging.

PubMed

Podtelezhnikov, Alexei A; Tanis, Keith Q; Nebozhyn, Michael; Ray, William J; Stone, David J; Loboda, Andrey P

2011-01-01

Alzheimer's disease (AD) is a complex neurodegenerative disorder that diverges from the process of normal brain aging by unknown mechanisms. We analyzed the global structure of age- and disease-dependent gene expression patterns in three regions from more than 600 brains. Gene expression variation could be almost completely explained by four transcriptional biomarkers that we named BioAge (biological age), Alz (Alzheimer), Inflame (inflammation), and NdStress (neurodegenerative stress). BioAge captures the first principal component of variation and includes genes statistically associated with neuronal loss, glial activation, and lipid metabolism. Normally BioAge increases with chronological age, but in AD it is prematurely expressed as if some of the subjects were 140 years old. A component of BioAge, Lipa, contains the AD risk factor APOE and reflects an apparent early disturbance in lipid metabolism. The rate of biological aging in AD patients, which cannot be explained by BioAge, is associated instead with NdStress, which includes genes related to protein folding and metabolism. Inflame, comprised of inflammatory cytokines and microglial genes, is broadly activated and appears early in the disease process. In contrast, the disease-specific biomarker Alz was selectively present only in the affected areas of the AD brain, appears later in pathogenesis, and is enriched in genes associated with the signaling and cell adhesion changes during the epithelial to mesenchymal (EMT) transition. Together these biomarkers provide detailed description of the aging process and its contribution to Alzheimer's disease progression. © 2011 Podtelezhnikov et al.

Molecular Insights into the Pathogenesis of Alzheimer's Disease and Its Relationship to Normal Aging

PubMed Central

Podtelezhnikov, Alexei A.; Tanis, Keith Q.; Nebozhyn, Michael; Ray, William J.

2011-01-01

Alzheimer's disease (AD) is a complex neurodegenerative disorder that diverges from the process of normal brain aging by unknown mechanisms. We analyzed the global structure of age- and disease-dependent gene expression patterns in three regions from more than 600 brains. Gene expression variation could be almost completely explained by four transcriptional biomarkers that we named BioAge (biological age), Alz (Alzheimer), Inflame (inflammation), and NdStress (neurodegenerative stress). BioAge captures the first principal component of variation and includes genes statistically associated with neuronal loss, glial activation, and lipid metabolism. Normally BioAge increases with chronological age, but in AD it is prematurely expressed as if some of the subjects were 140 years old. A component of BioAge, Lipa, contains the AD risk factor APOE and reflects an apparent early disturbance in lipid metabolism. The rate of biological aging in AD patients, which cannot be explained by BioAge, is associated instead with NdStress, which includes genes related to protein folding and metabolism. Inflame, comprised of inflammatory cytokines and microglial genes, is broadly activated and appears early in the disease process. In contrast, the disease-specific biomarker Alz was selectively present only in the affected areas of the AD brain, appears later in pathogenesis, and is enriched in genes associated with the signaling and cell adhesion changes during the epithelial to mesenchymal (EMT) transition. Together these biomarkers provide detailed description of the aging process and its contribution to Alzheimer's disease progression. PMID:22216330

Estimated maximal and current brain volume predict cognitive ability in old age

PubMed Central

Royle, Natalie A.; Booth, Tom; Valdés Hernández, Maria C.; Penke, Lars; Murray, Catherine; Gow, Alan J.; Maniega, Susana Muñoz; Starr, John; Bastin, Mark E.; Deary, Ian J.; Wardlaw, Joanna M.

2013-01-01

Brain tissue deterioration is a significant contributor to lower cognitive ability in later life; however, few studies have appropriate data to establish how much influence prior brain volume and prior cognitive performance have on this association. We investigated the associations between structural brain imaging biomarkers, including an estimate of maximal brain volume, and detailed measures of cognitive ability at age 73 years in a large (N = 620), generally healthy, community-dwelling population. Cognitive ability data were available from age 11 years. We found positive associations (r) between general cognitive ability and estimated brain volume in youth (male, 0.28; females, 0.12), and in measured brain volume in later life (males, 0.27; females, 0.26). Our findings show that cognitive ability in youth is a strong predictor of estimated prior and measured current brain volume in old age but that these effects were the same for both white and gray matter. As 1 of the largest studies of associations between brain volume and cognitive ability with normal aging, this work contributes to the wider understanding of how some early-life factors influence cognitive aging. PMID:23850342

Diffusion Tensor Tractography Reveals Disrupted Structural Connectivity during Brain Aging

NASA Astrophysics Data System (ADS)

Lin, Lan; Tian, Miao; Wang, Qi; Wu, Shuicai

2017-10-01

Brain aging is one of the most crucial biological processes that entail many physical, biological, chemical, and psychological changes, and also a major risk factor for most common neurodegenerative diseases. To improve the quality of life for the elderly, it is important to understand how the brain is changed during the normal aging process. We compared diffusion tensor imaging (DTI)-based brain networks in a cohort of 75 healthy old subjects by using graph theory metrics to describe the anatomical networks and connectivity patterns, and network-based statistic (NBS) analysis was used to identify pairs of regions with altered structural connectivity. The NBS analysis revealed a significant network comprising nine distinct fiber bundles linking 10 different brain regions showed altered white matter structures in young-old group compare with middle-aged group (p < .05, family-wise error-corrected). Our results might guide future studies and help to gain a better understanding of brain aging.

IGF-1: The Jekyll & Hyde of the aging brain.

PubMed

Gubbi, Sriram; Quipildor, Gabriela Farias; Barzilai, Nir; Huffman, Derek M; Milman, Sofiya

2018-05-08

The IGF-1 signaling pathway has emerged as a major regulator of the aging process, from rodents to humans. However, given the pleiotropic actions of IGF-1, its role in the aging brain remains complex and controversial. While IGF-1 is clearly essential for normal development of the central nervous system, conflicting evidence has emerged from preclinical and human studies regarding its relationship to cognitive function, as well as cerebrovascular and neurodegenerative disorders. This review delves into the current state of the evidence examining the role of IGF-1 in the aging brain, encompassing preclinical and clinical studies. A broad examination of the data indicates that IGF-1 may indeed play opposing roles in the aging brain, depending on the underlying pathology and context. Some evidence suggests that in the setting of neurodegenerative diseases that manifest with abnormal protein deposition in the brain, such as Alzheimer's disease, reducing IGF-1 signaling may serve a protective role by slowing disease progression and augmenting clearance of pathologic proteins to maintain cellular homeostasis. In contrast, inducing IGF-1 deficiency has also been implicated in dysregulated function of cognition and the neurovascular system, suggesting that some IGF-1 signaling may be necessary for normal brain function. Furthermore, states of acute neuronal injury, which necessitate growth, repair and survival signals to persevere, typically demonstrate salutary effects of IGF-1 in that context. Appreciating the dual, at times opposing "Dr. Jekyll" and "Mr. Hyde" characteristics of IGF-1 in the aging brain, will bring us closer to understanding its impact and devising more targeted IGF-1-related interventions.

Complexity and Synchronicity of Resting State BOLD FMRI in Normal Aging and Cognitive Decline

PubMed Central

Liu, Collin Y; Krishnan, Anitha P; Yan, Lirong; Smith, Robert X; Kilroy, Emily; Alger, Jeffery R; Ringman, John M; Wang, Danny JJ

2012-01-01

Purpose To explore the use of approximate entropy (ApEn) as an index of the complexity and the synchronicity of resting state BOLD fMRI in normal aging and cognitive decline associated with familial Alzheimer’s disease (fAD). Materials and Methods Resting state BOLD fMRI data were acquired at 3T from 2 independent cohorts of subjects consisting of healthy young (age 23±2 years, n=8) and aged volunteers (age 66±3 years, n=8), as well as 22 fAD associated subjects (14 mutation carriers, age 41.2±15.8 years; and 8 non-mutation carrying family members, age 28.8±5.9 years). Mean ApEn values were compared between the two age groups, and correlated with cognitive performance in the fAD group. Cross-ApEn (C-ApEn) was further calculated to assess the asynchrony between precuneus and the rest of the brain. Results Complexity of brain activity measured by mean ApEn in gray and white matter decreased with normal aging. In the fAD group, cognitive impairment was associated with decreased mean ApEn in gray matter as well as decreased regional ApEn in right precuneus, right lateral parietal regions, left precentral gyrus, and right paracentral gyrus. A pattern of asynchrony between BOLD fMRI series emerged from C-ApEn analysis, with significant regional anti-correlation with cross-correlation coefficient of functional connectivity analysis. Conclusion ApEn and C-ApEn may be useful for assessing the complexity and synchronicity of brain activity in normal aging and cognitive decline associated with neurodegenerative diseases PMID:23225622

Effects of neuroinflammation on the regenerative capacity of brain stem cells.

PubMed

Russo, Isabella; Barlati, Sergio; Bosetti, Francesca

2011-03-01

In the adult brain, neurogenesis under physiological conditions occurs in the subventricular zone and in the dentate gyrus. Although the exact molecular mechanisms that regulate neural stem cell proliferation and differentiation are largely unknown, several factors have been shown to affect neurogenesis. Decreased neurogenesis in the hippocampus has been recognized as one of the mechanisms of age-related brain dysfunction. Furthermore, in pathological conditions of the central nervous system associated with neuroinflammation, inflammatory mediators such as cytokines and chemokines can affect the capacity of brain stem cells and alter neurogenesis. In this review, we summarize the state of the art on the effects of neuroinflammation on adult neurogenesis and discuss the use of the lipopolysaccharide-model to study the effects of inflammation and reactive-microglia on brain stem cells and neurogenesis. Furthermore, we discuss the possible causes underlying reduced neurogenesis with normal aging and potential anti-inflammatory, pro-neurogenic interventions aimed at improving memory deficits in normal and pathological aging and in neurodegenerative diseases. © 2011 The Authors. Journal of Neurochemistry © 2011 International Society for Neurochemistry.

Asymmetry of Hemispheric Network Topology Reveals Dissociable Processes between Functional and Structural Brain Connectome in Community-Living Elders

PubMed Central

Sun, Yu; Li, Junhua; Suckling, John; Feng, Lei

2017-01-01

Human brain is structurally and functionally asymmetrical and the asymmetries of brain phenotypes have been shown to change in normal aging. Recent advances in graph theoretical analysis have showed topological lateralization between hemispheric networks in the human brain throughout the lifespan. Nevertheless, apparent discrepancies of hemispheric asymmetry were reported between the structural and functional brain networks, indicating the potentially complex asymmetry patterns between structural and functional networks in aging population. In this study, using multimodal neuroimaging (resting-state fMRI and structural diffusion tensor imaging), we investigated the characteristics of hemispheric network topology in 76 (male/female = 15/61, age = 70.08 ± 5.30 years) community-dwelling older adults. Hemispheric functional and structural brain networks were obtained for each participant. Graph theoretical approaches were then employed to estimate the hemispheric topological properties. We found that the optimal small-world properties were preserved in both structural and functional hemispheric networks in older adults. Moreover, a leftward asymmetry in both global and local levels were observed in structural brain networks in comparison with a symmetric pattern in functional brain network, suggesting a dissociable process of hemispheric asymmetry between structural and functional connectome in healthy older adults. Finally, the scores of hemispheric asymmetry in both structural and functional networks were associated with behavioral performance in various cognitive domains. Taken together, these findings provide new insights into the lateralized nature of multimodal brain connectivity, highlight the potentially complex relationship between structural and functional brain network alterations, and augment our understanding of asymmetric structural and functional specializations in normal aging. PMID:29209197

Higher resting-state activity in reward-related brain circuits in obese versus normal-weight females independent of food intake.

PubMed

Hogenkamp, P S; Zhou, W; Dahlberg, L S; Stark, J; Larsen, A L; Olivo, G; Wiemerslage, L; Larsson, E-M; Sundbom, M; Benedict, C; Schiöth, H B

2016-11-01

In response to food cues, obese vs normal-weight individuals show greater activation in brain regions involved in the regulation of food intake under both fasted and sated conditions. Putative effects of obesity on task-independent low-frequency blood-oxygenation-level-dependent signals-that is, resting-state brain activity-in the context of food intake are, however, less well studied. To compare eyes closed, whole-brain low-frequency BOLD signals between severely obese and normal-weight females, as assessed by functional magnetic resonance imaging (fMRI). Fractional amplitude of low-frequency fluctuations were measured in the morning following an overnight fast in 17 obese (age: 39±11 years, body mass index (BMI): 42.3±4.8 kg m - 2 ) and 12 normal-weight females (age: 36±12 years, BMI: 22.7±1.8 kg m - 2 ), both before and 30 min after consumption of a standardized meal (~260 kcal). Compared with normal-weight controls, obese females had increased low-frequency activity in clusters located in the putamen, claustrum and insula (P<0.05). This group difference was not altered by food intake. Self-reported hunger dropped and plasma glucose concentrations increased after food intake (P<0.05); however, these changes did not differ between the BMI groups. Reward-related brain regions are more active under resting-state conditions in obese than in normal-weight females. This difference was independent of food intake under the experimental settings applied in the current study. Future studies involving males and females, as well as utilizing repeated post-prandial resting-state fMRI scans and various types of meals are needed to further investigate how food intake alters resting-state brain activity in obese humans.

Ageing and brain white matter structure in 3,513 UK Biobank participants

PubMed Central

Cox, Simon R.; Ritchie, Stuart J.; Tucker-Drob, Elliot M.; Liewald, David C.; Hagenaars, Saskia P.; Davies, Gail; Wardlaw, Joanna M.; Gale, Catharine R.; Bastin, Mark E.; Deary, Ian J.

2016-01-01

Quantifying the microstructural properties of the human brain's connections is necessary for understanding normal ageing and disease. Here we examine brain white matter magnetic resonance imaging (MRI) data in 3,513 generally healthy people aged 44.64–77.12 years from the UK Biobank. Using conventional water diffusion measures and newer, rarely studied indices from neurite orientation dispersion and density imaging, we document large age associations with white matter microstructure. Mean diffusivity is the most age-sensitive measure, with negative age associations strongest in the thalamic radiation and association fibres. White matter microstructure across brain tracts becomes increasingly correlated in older age. This may reflect an age-related aggregation of systemic detrimental effects. We report several other novel results, including age associations with hemisphere and sex, and comparative volumetric MRI analyses. Results from this unusually large, single-scanner sample provide one of the most extensive characterizations of age associations with major white matter tracts in the human brain. PMID:27976682

Multiple Brain Markers are Linked to Age-Related Variation in Cognition

PubMed Central

Hedden, Trey; Schultz, Aaron P.; Rieckmann, Anna; Mormino, Elizabeth C.; Johnson, Keith A.; Sperling, Reisa A.; Buckner, Randy L.

2016-01-01

Age-related alterations in brain structure and function have been challenging to link to cognition due to potential overlapping influences of multiple neurobiological cascades. We examined multiple brain markers associated with age-related variation in cognition. Clinically normal older humans aged 65–90 from the Harvard Aging Brain Study (N = 186) were characterized on a priori magnetic resonance imaging markers of gray matter thickness and volume, white matter hyperintensities, fractional anisotropy (FA), resting-state functional connectivity, positron emission tomography markers of glucose metabolism and amyloid burden, and cognitive factors of processing speed, executive function, and episodic memory. Partial correlation and mediation analyses estimated age-related variance in cognition shared with individual brain markers and unique to each marker. The largest relationships linked FA and striatum volume to processing speed and executive function, and hippocampal volume to episodic memory. Of the age-related variance in cognition, 70–80% was accounted for by combining all brain markers (but only ∼20% of total variance). Age had significant indirect effects on cognition via brain markers, with significant markers varying across cognitive domains. These results suggest that most age-related variation in cognition is shared among multiple brain markers, but potential specificity between some brain markers and cognitive domains motivates additional study of age-related markers of neural health. PMID:25316342

Stable olfactory sensory neuron in vivo physiology during normal aging.

PubMed

Kass, Marley D; Czarnecki, Lindsey A; McGann, John P

2018-05-08

Normal aging is associated with a number of smell impairments that are paralleled by age-dependent changes in the peripheral olfactory system, including decreases in olfactory sensory neurons (OSNs) and in the regenerative capacity of the epithelium. Thus, an age-dependent degradation of sensory input to the brain is one proposed mechanism for the loss of olfactory function in older populations. Here, we tested this hypothesis by performing in vivo optical neurophysiology in 6-, 12-, 18-, and 24-month-old mice. We visualized odor-evoked neurotransmitter release from populations of OSNs into olfactory bulb glomeruli, and found that these sensory inputs are actually quite stable during normal aging. Specifically, the magnitude and number of odor-evoked glomerular responses were comparable across all ages, and there was no effect of age on the sensitivity of OSN responses to odors or on the neural discriminability of different sensory maps. These results suggest that the brain's olfactory bulbs do not receive deteriorated input during aging and that local bulbar circuitry might adapt to maintain stable nerve input. Copyright © 2018 Elsevier Inc. All rights reserved.

Aging is associated with altered inflammatory, arachidonic acid cascade and synaptic markers, influenced by epigenetic modifications, in the human frontal cortex

PubMed Central

Keleshian, Vasken L.; Modi, Hiren R.; Rapoport, Stanley I.; Rao, Jagadeesh S.

2013-01-01

Aging is a risk factor for Alzheimer’s disease (AD) and is associated with cognitive decline. However, underlying molecular mechanisms of brain aging are not clear. Recent studies suggest epigenetic influences on gene expression in AD, since DNA methylation levels influence protein and mRNA expression in postmortem AD brain. We hypothesized that some of these changes occur with normal aging. To test this hypothesis, we measured markers of the arachidonic acid (AA) cascade, neuroinflammation, pro- and anti-apoptosis factors, and gene specific epigenetic modifications in postmortem frontal cortex from nine middle-aged (41 ± 1 (SEM) years) and ten aged subjects (70 ± 3 years). The aged compared with middle-aged brain showed elevated levels of neuroinflammatory and AA cascade markers, altered pro and anti-apoptosis factors and loss of synaptophysin. Some of these changes correlated with promoter hypermethylation of BDNF, CREB, and synaptophysin and hypomethylation of BAX. These molecular alterations in aging are different from or more subtle than changes associated with AD pathology. The degree to which they are related to changes in cognition or behavior during normal aging remains to be evaluated. PMID:23336521

Chemical mapping of anxiety in the brain of healthy humans: an in vivo 1H-MRS study on the effects of sex, age, and brain region.

PubMed

Grachev, I D; Apkarian, A V

2000-12-01

We recently presented results in an in vivo study of human brain chemistry in 'physiologic' anxiety, i.e., the anxiety of normal everyday life. Normal subjects with high anxiety demonstrated increased concentration of chemicals in orbital frontal cortex (OFC) as compared to lower anxiety. In a separate study of aging we demonstrated a decrease of total chemical concentration in OFC of middle-aged subjects, as compared with younger age. This brain region also showed gender dependence; men demonstrating decreased chemical concentration compared to women. We hypothesized that these sex- and age-dependent differences in OFC chemistry changes are a result of anxiety effects on this brain region. In the present study we examined these sex- and age-differential regional brain chemistry changes (as identified by localized in vivo proton magnetic resonance spectroscopy [1H-MRS]) in relation to the state-trait-anxiety (as measured by the State-Trait Anxiety Inventory) in 35 healthy subjects. The concentrations for all nine chemicals of 1H-MRS spectra were measured relative to creatine across multiple brain regions, including OFC in the left hemisphere. Analysis of variance showed anxiety-specific effects on chemical concentration changes in OFC, which were different for both sexes and age groups. Male subjects showed larger effect of anxiety on OFC chemistry as compared to females when the same sex high-anxiety subjects were compared to lower anxiety. Similarly, middle-aged subjects showed larger effect of anxiety on OFC chemistry as compared to younger age when the same age subjects with high anxiety were compared to lower anxiety. Largest effect of anxiety on OFC chemistry was due to changes of N-Acetyl aspartate. The results indicate that the state-trait anxiety has sex- and age-differential patterns on OFC chemistry in healthy humans, providing new information about the neurobiological roots of anxiety.

Efficient principal component analysis for multivariate 3D voxel-based mapping of brain functional imaging data sets as applied to FDG-PET and normal aging.

PubMed

Zuendorf, Gerhard; Kerrouche, Nacer; Herholz, Karl; Baron, Jean-Claude

2003-01-01

Principal component analysis (PCA) is a well-known technique for reduction of dimensionality of functional imaging data. PCA can be looked at as the projection of the original images onto a new orthogonal coordinate system with lower dimensions. The new axes explain the variance in the images in decreasing order of importance, showing correlations between brain regions. We used an efficient, stable and analytical method to work out the PCA of Positron Emission Tomography (PET) images of 74 normal subjects using [(18)F]fluoro-2-deoxy-D-glucose (FDG) as a tracer. Principal components (PCs) and their relation to age effects were investigated. Correlations between the projections of the images on the new axes and the age of the subjects were carried out. The first two PCs could be identified as being the only PCs significantly correlated to age. The first principal component, which explained 10% of the data set variance, was reduced only in subjects of age 55 or older and was related to loss of signal in and adjacent to ventricles and basal cisterns, reflecting expected age-related brain atrophy with enlarging CSF spaces. The second principal component, which accounted for 8% of the total variance, had high loadings from prefrontal, posterior parietal and posterior cingulate cortices and showed the strongest correlation with age (r = -0.56), entirely consistent with previously documented age-related declines in brain glucose utilization. Thus, our method showed that the effect of aging on brain metabolism has at least two independent dimensions. This method should have widespread applications in multivariate analysis of brain functional images. Copyright 2002 Wiley-Liss, Inc.

Normal lactate concentration range in the neonatal brain.

PubMed

Tomiyasu, Moyoko; Aida, Noriko; Shibasaki, Jun; Tachibana, Yasuhiko; Endo, Mamiko; Nozawa, Kumiko; Shimizu, Eiji; Tsuji, Hiroshi; Obata, Takayuki

2016-11-01

Lactate peaks are occasionally observed during in vivo magnetic resonance spectroscopy (MRS) scans of the neonatal brain, even in healthy patients. The purpose of this study was to investigate the normal range of neonatal brain lactate concentration, as a definitive normal range would be clinically valuable. Using a clinical 3T scanner (echo/repetition times, 30/5000ms), single-voxel MRS data were obtained from the basal ganglia (BG) and centrum semiovale (CS) in 48 healthy neonates (postconceptional age (PCA), 30-43weeks), nine infants (age, 1-12months old), and 20 children (age, 4-15years). Lactate concentrations were calculated using an MRS signal quantification program, LCModel. Correlations between regional lactate concentration and PCA (neonates), or age (all subjects) were investigated. Absolute lactate concentrations of the BG and CS were as follows: neonates, 0.77mM (0-2.02) [median (range)] and 0.77 (0-1.42), respectively; infants, 0.38 (0-0.79) and 0.49 (0.17-1.17); and children, 0.17 (0-0.76) and 0.22 (0-0.80). Overall, subjects' lactate concentrations decreased significantly with age (Spearman: BG, n=61, ρ=-0.38, p=0.003; CS, n=68, ρ=-0.57, p<0.001). However, during the neonatal period no correlations were detected between lactate concentration in either region and PCA. We determined normal ranges of neonatal lactate concentration, which may prove useful for diagnostic purposes. Further studies regarding changes in brain lactate concentration during development would help clarify the reasons for higher concentrations observed during the neonatal period, and contribute to improvements in diagnoses. Copyright © 2016 Elsevier Inc. All rights reserved.

Neuroimaging Studies Illustrate the Commonalities Between Ageing and Brain Diseases.

PubMed

Cole, James H

2018-07-01

The lack of specificity in neuroimaging studies of neurological and psychiatric diseases suggests that these different diseases have more in common than is generally considered. Potentially, features that are secondary effects of different pathological processes may share common neurobiological underpinnings. Intriguingly, many of these mechanisms are also observed in studies of normal (i.e., non-pathological) brain ageing. Different brain diseases may be causing premature or accelerated ageing to the brain, an idea that is supported by a line of "brain ageing" research that combines neuroimaging data with machine learning analysis. In reviewing this field, I conclude that such observations could have important implications, suggesting that we should shift experimental paradigm: away from characterizing the average case-control brain differences resulting from a disease toward methods that place individuals in their age-appropriate context. This will also lead naturally to clinical applications, whereby neuroimaging can contribute to a personalized-medicine approach to improve brain health. © 2018 WILEY Periodicals, Inc.

Life and death of neurons in the aging brain

NASA Technical Reports Server (NTRS)

Morrison, J. H.; Hof, P. R.; Bloom, F. E. (Principal Investigator)

1997-01-01

Neurodegenerative disorders are characterized by extensive neuron death that leads to functional decline, but the neurobiological correlates of functional decline in normal aging are less well defined. For decades, it has been a commonly held notion that widespread neuron death in the neocortex and hippocampus is an inevitable concomitant of brain aging, but recent quantitative studies suggest that neuron death is restricted in normal aging and unlikely to account for age-related impairment of neocortical and hippocampal functions. In this article, the qualitative and quantitative differences between aging and Alzheimer's disease with respect to neuron loss are discussed, and age-related changes in functional and biochemical attributes of hippocampal circuits that might mediate functional decline in the absence of neuron death are explored. When these data are viewed comprehensively, it appears that the primary neurobiological substrates for functional impairment in aging differ in important ways from those in neurodegenerative disorders such as Alzheimer's disease.

The diffusion tensor imaging (DTI) component of the NIH MRI study of normal brain development (PedsDTI).

PubMed

Walker, Lindsay; Chang, Lin-Ching; Nayak, Amritha; Irfanoglu, M Okan; Botteron, Kelly N; McCracken, James; McKinstry, Robert C; Rivkin, Michael J; Wang, Dah-Jyuu; Rumsey, Judith; Pierpaoli, Carlo

2016-01-01

The NIH MRI Study of normal brain development sought to characterize typical brain development in a population of infants, toddlers, children and adolescents/young adults, covering the socio-economic and ethnic diversity of the population of the United States. The study began in 1999 with data collection commencing in 2001 and concluding in 2007. The study was designed with the final goal of providing a controlled-access database; open to qualified researchers and clinicians, which could serve as a powerful tool for elucidating typical brain development and identifying deviations associated with brain-based disorders and diseases, and as a resource for developing computational methods and image processing tools. This paper focuses on the DTI component of the NIH MRI study of normal brain development. In this work, we describe the DTI data acquisition protocols, data processing steps, quality assessment procedures, and data included in the database, along with database access requirements. For more details, visit http://www.pediatricmri.nih.gov. This longitudinal DTI dataset includes raw and processed diffusion data from 498 low resolution (3 mm) DTI datasets from 274 unique subjects, and 193 high resolution (2.5 mm) DTI datasets from 152 unique subjects. Subjects range in age from 10 days (from date of birth) through 22 years. Additionally, a set of age-specific DTI templates are included. This forms one component of the larger NIH MRI study of normal brain development which also includes T1-, T2-, proton density-weighted, and proton magnetic resonance spectroscopy (MRS) imaging data, and demographic, clinical and behavioral data. Published by Elsevier Inc.

Estimated maximal and current brain volume predict cognitive ability in old age.

PubMed

Royle, Natalie A; Booth, Tom; Valdés Hernández, Maria C; Penke, Lars; Murray, Catherine; Gow, Alan J; Maniega, Susana Muñoz; Starr, John; Bastin, Mark E; Deary, Ian J; Wardlaw, Joanna M

2013-12-01

Brain tissue deterioration is a significant contributor to lower cognitive ability in later life; however, few studies have appropriate data to establish how much influence prior brain volume and prior cognitive performance have on this association. We investigated the associations between structural brain imaging biomarkers, including an estimate of maximal brain volume, and detailed measures of cognitive ability at age 73 years in a large (N = 620), generally healthy, community-dwelling population. Cognitive ability data were available from age 11 years. We found positive associations (r) between general cognitive ability and estimated brain volume in youth (male, 0.28; females, 0.12), and in measured brain volume in later life (males, 0.27; females, 0.26). Our findings show that cognitive ability in youth is a strong predictor of estimated prior and measured current brain volume in old age but that these effects were the same for both white and gray matter. As 1 of the largest studies of associations between brain volume and cognitive ability with normal aging, this work contributes to the wider understanding of how some early-life factors influence cognitive aging. Copyright © 2013 Elsevier Inc. All rights reserved.

Dynamic Bayesian network modeling for longitudinal brain morphometry

PubMed Central

Chen, Rong; Resnick, Susan M; Davatzikos, Christos; Herskovits, Edward H

2011-01-01

Identifying interactions among brain regions from structural magnetic-resonance images presents one of the major challenges in computational neuroanatomy. We propose a Bayesian data-mining approach to the detection of longitudinal morphological changes in the human brain. Our method uses a dynamic Bayesian network to represent evolving inter-regional dependencies. The major advantage of dynamic Bayesian network modeling is that it can represent complicated interactions among temporal processes. We validated our approach by analyzing a simulated atrophy study, and found that this approach requires only a small number of samples to detect the ground-truth temporal model. We further applied dynamic Bayesian network modeling to a longitudinal study of normal aging and mild cognitive impairment — the Baltimore Longitudinal Study of Aging. We found that interactions among regional volume-change rates for the mild cognitive impairment group are different from those for the normal-aging group. PMID:21963916

MRI-Based Measurement of Brain Stem Cross-Sectional Area in Relapsing-Remitting Multiple Sclerosis.

PubMed

Chivers, Tomos R; Constantinescu, Cris S; Tench, Christopher R

2015-01-01

To determine if patients with relapsing-remitting multiple sclerosis (RRMS) have a reduced brain stem cross-sectional area (CSA) compared to age- and sex-matched controls. The brain stem is a common site of involvement in MS. However, relatively few imaging studies have investigated brain stem atrophy. Brain magnetic resonance imaging (MRI) was performed on patients and controls using a 1.5T MRI scanner with a quadrature head coil. Three-dimensional magnetization-prepared rapid acquisition gradient-echo (MPRAGE) images with 128 contiguous slices, covering the whole brain and brain stem and a T2-weighted image with 3 mm transverse contiguous images were acquired. We measured the brain stem CSA at three sites, the midbrain, the pons, and the medulla oblongata in 35 RRMS patients and 35 controls using a semiautomated algorithm. CSA readings were normalized using the total external cranial volume to reduce normal population variance and increase statistical power. A significant CSA reduction was found in the midbrain (P ≤ .001), pons (P ≤ .001), and the medulla oblongata (P = .047) postnormalization. A CSA reduction of 9.3% was found in the midbrain, 8.7% in the pons, and 6.5% in the medulla oblongata. A significantly reduced, normalized brain stem CSA was detected in all areas of the brain stem of the RRMS patients, when compared to age- and gender-matched controls. Lack of detectable upper cervical cord atrophy in the same patients suggests some independence of the MS pathology in these regions. Copyright © 2015 by the American Society of Neuroimaging.

Primary central nervous system lymphoma in childhood presenting as progressive panhypopituitarism.

PubMed

Silfen, M E; Garvin, J H; Hays, A P; Starkman, H S; Aranoff, G S; Levine, L S; Feldstein, N A; Wong, B; Oberfield, S E

2001-02-01

We report a 15-year-old boy who had isolated central diabetes insipidus initially diagnosed at age 11 years. A brain magnetic resonance imaging (MRI) was normal at the time. At age 12 years, growth hormone (GH) testing was performed because of a decline in linear growth rate and demonstrated GH deficiency. After a repeat normal brain MRI, GH therapy was begun. Three years later, hormonal testing revealed prepubertal gonadotropins and low testosterone levels, free thyroxine index, and morning cortisol levels. Repeat brain MRI demonstrated a 9-mm enhancing lesion in the region of the pituitary stalk. The pathologic diagnosis was that of a high-grade malignant B-cell lymphoma, suggestive of Burkitt Lymphoma. Growth hormone therapy has not been associated with an increased incidence of lymphoma. This report underscores the need for vigilance in follow-up brain imaging and hormonal evaluation in children with diabetes insipidus, especially those with evolving anterior hormone deficiencies.

Network Analysis: Applications for the Developing Brain

PubMed Central

Chu-Shore, Catherine J.; Kramer, Mark A.; Bianchi, Matt T.; Caviness, Verne S.; Cash, Sydney S.

2011-01-01

Development of the human brain follows a complex trajectory of age-specific anatomical and physiological changes. The application of network analysis provides an illuminating perspective on the dynamic interregional and global properties of this intricate and complex system. Here, we provide a critical synopsis of methods of network analysis with a focus on developing brain networks. After discussing basic concepts and approaches to network analysis, we explore the primary events of anatomical cortical development from gestation through adolescence. Upon this framework, we describe early work revealing the evolution of age-specific functional brain networks in normal neurodevelopment. Finally, we review how these relationships can be altered in disease and perhaps even rectified with treatment. While this method of description and inquiry remains in early form, there is already substantial evidence that the application of network models and analysis to understanding normal and abnormal human neural development holds tremendous promise for future discovery. PMID:21303762

Modeling Early Postnatal Brain Growth and Development with CT: Changes in the Brain Radiodensity Histogram from Birth to 2 Years.

PubMed

Cauley, K A; Hu, Y; Och, J; Yorks, P J; Fielden, S W

2018-04-01

The majority of brain growth and development occur in the first 2 years of life. This study investigated these changes by analysis of the brain radiodensity histogram of head CT scans from the clinical population, 0-2 years of age. One hundred twenty consecutive head CTs with normal findings meeting the inclusion criteria from children from birth to 2 years were retrospectively identified from 3 different CT scan platforms. Histogram analysis was performed on brain-extracted images, and histogram mean, mode, full width at half maximum, skewness, kurtosis, and SD were correlated with subject age. The effects of scan platform were investigated. Normative curves were fitted by polynomial regression analysis. Average total brain volume was 360 cm 3 at birth, 948 cm 3 at 1 year, and 1072 cm 3 at 2 years. Total brain tissue density showed an 11% increase in mean density at 1 year and 19% at 2 years. Brain radiodensity histogram skewness was positive at birth, declining logarithmically in the first 200 days of life. The histogram kurtosis also decreased in the first 200 days to approach a normal distribution. Direct segmentation of CT images showed that changes in brain radiodensity histogram skewness correlated with, and can be explained by, a relative increase in gray matter volume and an increase in gray and white matter tissue density that occurs during this period of brain maturation. Normative metrics of the brain radiodensity histogram derived from routine clinical head CT images can be used to develop a model of normal brain development. © 2018 by American Journal of Neuroradiology.

The relationship between white matter brain metabolites and cognition in normal aging: the GENIE study.

PubMed

Charlton, R A; McIntyre, D J O; Howe, F A; Morris, R G; Markus, H S

2007-08-20

Magnetic resonance spectroscopy (MRS) has demonstrated age-related changes in brain metabolites that may underlie micro-structural brain changes, but few studies have examined their relationship with cognitive decline. We performed a cross-sectional study of brain metabolism and cognitive function in 82 healthy adults (aged 50-90) participating in the GENIE (St GEorge's Neuropsychology and Imaging in the Elderly) study. Absolute metabolite concentrations were measured by proton chemical shift imaging within voxels placed in the centrum semiovale white matter. Cognitive abilities assessed were executive function, working memory, information processing speed, long-term memory and fluid intelligence. Correlations showed that all cognitive domains declined with age. Total creatine (tCr) concentration increased with age (r=0.495, p<0.001). Regression analyses were performed for each cognitive variable, including estimated intelligence and the metabolites, with age then added as a final step. A significant relationship was observed between tCr and executive function, long-term memory, and fluid intelligence, although these relationships did not remain significant after age was added as a final step in the regression. The regression analysis also demonstrated a significant relationship between N-acetylaspartate (NAA) and executive function. As there was no age-related decline in NAA, this argues against axonal loss with age; however the relationship between NAA and executive function independent of age and estimated intelligence is consistent with white matter axonal integrity having an important role in executive function in normal individuals.

Sonographic assessment of normal and abnormal patterns of fetal cerebral lamination.

PubMed

Pugash, D; Hendson, G; Dunham, C P; Dewar, K; Money, D M; Prayer, D

2012-12-01

Prenatal development of the brain is characterized by gestational age-specific changes in the laminar structure of the brain parenchyma before 30 gestational weeks. Cerebral lamination patterns of normal fetal brain development have been described histologically, by postmortem in-vitro magnetic resonance imaging (MRI) and by in-vivo fetal MRI. The purpose of this study was to evaluate the sonographic appearance of laminar organization of the cerebral wall in normal and abnormal brain development. This was a retrospective study of ultrasound findings in 92 normal fetuses and 68 fetuses with abnormal cerebral lamination patterns for gestational age, at 17-38 weeks' gestation. We investigated the visibility of the subplate zone relative to the intermediate zone and correlated characteristic sonographic findings of cerebral lamination with gestational age in order to evaluate transient structures. In the normal cohort, the subplate zone-intermediate zone interface was identified as early as 17 weeks, and in all 57 fetuses examined up to 28 weeks. In all of these fetuses, the subplate zone appeared anechoic and the intermediate zone appeared homogeneously more echogenic than did the subplate zone. In the 22 fetuses between 28 and 34 weeks, there was a transition period when lamination disappeared in a variable fashion. The subplate zone-intermediate zone interface was not identified in any fetus after 34 weeks (n=13). There were three patterns of abnormal cerebral lamination: (1) no normal laminar pattern before 28 weeks (n=32), in association with severe ventriculomegaly, diffuse ischemia, microcephaly, teratogen exposure or lissencephaly; (2) focal disruption of lamination before 28 weeks (n=24), associated with hemorrhage, porencephaly, stroke, migrational abnormalities, thanatophoric dysplasia, meningomyelocele or encephalocele; (3) increased prominence and echogenicity of the intermediate zone before 28 weeks and/or persistence of a laminar pattern beyond 33 weeks (n=10), associated with Type 1 lissencephaly or CMV infection. There was a mixed focal/diffuse pattern in two fetuses. In CMV infection, the earliest indication of the infection was focal heterogeneity and increased echogenicity of the intermediate zone, which predated the development of microcephaly, ventriculomegaly and intracranial calcification. The fetal subplate and intermediate zones can be demonstrated reliably on routine sonography before 28 weeks and disappear after 34 weeks. These findings represent normal gestational age-dependent transient laminar patterns of cerebral development and are consistent with histological studies. Abnormal fetal cerebral lamination patterns for gestational age are also visible on sonography, and may indicate abnormal brain development. Copyright © 2012 ISUOG. Published by John Wiley & Sons, Ltd.

The effect of ingested sulfite on visual evoked potentials, lipid peroxidation, and antioxidant status of brain in normal and sulfite oxidase-deficient aged rats.

PubMed

Ozsoy, Ozlem; Aras, Sinem; Ozkan, Ayse; Parlak, Hande; Aslan, Mutay; Yargicoglu, Piraye; Agar, Aysel

2016-07-01

Sulfite, commonly used as a preservative in foods, beverages, and pharmaceuticals, is a very reactive and potentially toxic molecule which is detoxified by sulfite oxidase (SOX). Changes induced by aging may be exacerbated by exogenous chemicals like sulfite. The aim of this study was to investigate the effects of ingested sulfite on visual evoked potentials (VEPs) and brain antioxidant statuses by measuring superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activities. Brain lipid oxidation status was also determined via thiobarbituric acid reactive substances (TBARS) in normal- and SOX-deficient aged rats. Rats do not mimic the sulfite responses seen in humans because of their relatively high SOX activity level. Therefore this study used SOX-deficient rats since they are more appropriate models for studying sulfite toxicity. Forty male Wistar rats aged 24 months were randomly assigned to four groups: control (C), sulfite (S), SOX-deficient (D) and SOX-deficient + sulfite (DS). SOX deficiency was established by feeding rats with low molybdenum (Mo) diet and adding 200 ppm tungsten (W) to their drinking water. Sulfite in the form of sodium metabisulfite (25 mg kg(-1) day(-1)) was given by gavage. Treatment continued for 6 weeks. At the end of the experimental period, flash VEPs were recorded. Hepatic SOX activity was measured to confirm SOX deficiency. SOX-deficient rats had an approximately 10-fold decrease in hepatic SOX activity compared with the normal rats. The activity of SOX in deficient rats was thus in the range of humans. There was no significant difference between control and treated groups in either latence or amplitude of VEP components. Brain SOD, CAT, and GPx activities and brain TBARS levels were similar in all experimental groups compared with the control group. Our results indicate that exogenous administration of sulfite does not affect VEP components and the antioxidant/oxidant status of aged rat brains. © The Author(s) 2014.

Prediction of brain maturity based on cortical thickness at different spatial resolutions.

PubMed

Khundrakpam, Budhachandra S; Tohka, Jussi; Evans, Alan C

2015-05-01

Several studies using magnetic resonance imaging (MRI) scans have shown developmental trajectories of cortical thickness. Cognitive milestones happen concurrently with these structural changes, and a delay in such changes has been implicated in developmental disorders such as attention-deficit/hyperactivity disorder (ADHD). Accurate estimation of individuals' brain maturity, therefore, is critical in establishing a baseline for normal brain development against which neurodevelopmental disorders can be assessed. In this study, cortical thickness derived from structural magnetic resonance imaging (MRI) scans of a large longitudinal dataset of normally growing children and adolescents (n=308), were used to build a highly accurate predictive model for estimating chronological age (cross-validated correlation up to R=0.84). Unlike previous studies which used kernelized approach in building prediction models, we used an elastic net penalized linear regression model capable of producing a spatially sparse, yet accurate predictive model of chronological age. Upon investigating different scales of cortical parcellation from 78 to 10,240 brain parcels, we observed that the accuracy in estimated age improved with increased spatial scale of brain parcellation, with the best estimations obtained for spatial resolutions consisting of 2560 and 10,240 brain parcels. The top predictors of brain maturity were found in highly localized sensorimotor and association areas. The results of our study demonstrate that cortical thickness can be used to estimate individuals' brain maturity with high accuracy, and the estimated ages relate to functional and behavioural measures, underscoring the relevance and scope of the study in the understanding of biological maturity. Copyright © 2015 Elsevier Inc. All rights reserved.

Age- and sex-associated changes in cerebral glucose metabolism in normal healthy subjects: statistical parametric mapping analysis of F-18 fluorodeoxyglucose brain positron emission tomography.

PubMed

Kim, In-Ju; Kim, Seong-Jang; Kim, Yong-Ki

2009-12-01

The age- and sex-associated changes of brain development are unclear and controversial. Several previous studies showed conflicting results of a specific pattern of cerebral glucose metabolism or no differences of cerebral glucose metabolism in association with normal aging process and sex. To investigate the effects of age and sex on changes in cerebral glucose metabolism in healthy subjects using fluorine-18 fluorodeoxyglucose (F-18 FDG) brain positron emission tomography (PET) and statistical parametric mapping (SPM) analysis. Seventy-eight healthy subjects (32 males, mean age 46.6+/-18.2 years; 46 females, mean age 40.6+/-19.8 years) underwent F-18 FDG brain PET. Using SPM, age- and sex-associated changes in cerebral glucose metabolism were investigated. In males, a negative correlation existed in several gray matter areas, including the right temporopolar (Brodmann area [BA] 38), right orbitofrontal (BA 47), left orbitofrontal gyrus (BA 10), left dorsolateral frontal gyrus (BA 8), and left insula (BA 13) areas. A positive relationship existed in the left claustrum and left thalamus. In females, negative changes existed in the left caudate body, left temporopolar area (BA 38), right orbitofrontal gyri (BA 47 and BA 10), and right dorsolateral prefrontal cortex (BA 46). A positive association was demonstrated in the left subthalamic nucleus and the left superior frontal gyrus. In white matter, an age-associated decrease in FDG uptake in males was shown in the left insula, and increased FDG uptake was found in the left corpus callosum. The female group had an age-associated negative correlation of FDG uptake only in the right corpus callosum. Using SPM, we found not only similar areas of brain, but also sex-specific cerebral areas of age-associated changes of FDG uptake.

Brain stem and cerebellar atrophy in chronic progressive neuro-Behçet's disease.

PubMed

Kanoto, Masafumi; Hosoya, Takaaki; Toyoguchi, Yuuki; Oda, Atsuko

2013-01-01

Chronic progressive neuro-Behçet's disease (CPNBD) resembles multiple sclerosis (MS) on patient background and image findings, and therefore is difficult to diagnose. The purpose is to identify the characteristic magnetic resonance imaging (MRI) findings of CPNBD and to clarify the differences between the MRI findings of CPNBD and those of MS. The subjects consist of a CPNBD group (n=4; 1 male and 3 females; mean age, 51 y.o.), a MS group (n=19; 3 males and 16 females; mean age, 45 y.o.) and a normal control group (n=23; 10 males and 13 females; mean age, 45 y.o.). Brain stem atrophy, cerebellar atrophy, and leukoencephalopathy were retrospectively evaluated in each subjects. In middle sagittal brain MR images, the prepontine distance was measured as an indirect index of brain stem and cerebellar atrophy and the pontine and mesencephalic distance was measured as a direct index of brain stem atrophy. These indexes were statistically analyzed. Brain stem atrophy, cerebellar atrophy, and leukoencephalopathy were seen in all CPNBD cases. Prepontine distance was significantly different between the CPNBD group and the MS group (p<0.05), and between the CPNBD group and the normal control group (p<0.001). Pontine and mesencephalic distance were significantly different between the CPNBD group and the MS group (p<0.001, p<0.01 respectively), and between the CPNBD group and the normal control group (p<0.001). Chronic progressive neuro-Behçet's disease should be considered in patients with brain stem and cerebellar atrophy in addition to leukoencephalopathy similar to that seen in multiple sclerosis. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Brain tissue pulsatility mediates cognitive and electrophysiological changes in normal aging: Evidence from ultrasound tissue pulsatility imaging (TPI).

PubMed

Angel, Lucie; Bouazzaoui, Badiâa; Isingrini, Michel; Fay, Séverine; Taconnat, Laurence; Vanneste, Sandrine; Ledoux, Moïse; Gissot, Valérie; Hommet, Caroline; Andersson, Fréderic; Barantin, Laurent; Cottier, Jean-Philippe; Pasco, Jérémy; Desmidt, Thomas; Patat, Frédéric; Camus, Vincent; Remenieras, Jean-Pierre

2018-06-01

Aging is characterized by a cognitive decline of fluid abilities and is also associated with electrophysiological changes. The vascular hypothesis proposes that brain is sensitive to vascular dysfunction which may accelerate age-related brain modifications and thus explain age-related neurocognitive decline. To test this hypothesis, cognitive performance was measured in 39 healthy participants from 20 to 80 years, using tests assessing inhibition, fluid intelligence, attention and crystallized abilities. Brain functioning associated with attentional abilities was assessed by measuring the P3b ERP component elicited through an auditory oddball paradigm. To assess vascular health, we used an innovative measure of the pulsatility of deep brain tissue, due to variations in cerebral blood flow over the cardiac cycle. Results showed (1) a classical effect of age on fluid neurocognitive measures (inhibition, fluid intelligence, magnitude and latency of the P3b) but not on crystallized measures, (2) that brain pulsatility decreases with advancing age, (3) that brain pulsatility is positively correlated with fluid neurocognitive measures and (4) that brain pulsatility strongly mediated the age-related variance in cognitive performance and the magnitude of the P3b component. The mediating role of the brain pulsatility in age-related effect on neurocognitive measures supports the vascular hypothesis of cognitive aging. Copyright © 2018 Elsevier Inc. All rights reserved.

Neonatal Brain MRI and Motor Outcome at School Age in Children with Neonatal Encephalopathy: A Review of Personal Experience

PubMed Central

Mercuri, Eugenio; Barnett, Anna L.

2003-01-01

The aim of this paper is to review (i) the spectrum of neuromotor function at school age in children who had been born full-term and presented with neonatal encephalopathy (NE) and low Apgar scores and (ii) the relation between the presence/absence of such difficulties and neonatal brain MRI. Motor outcome appears to be mainly related to the severity of basal ganglia and internal capsule involvement. Severe basal ganglia lesions were always associated with the most severe outcome, microcephaly, tetraplegia, and severe global delay, whereas more discrete basal ganglia lesions were associated with athetoid cerebral palsy, with normal cognitive development or minor neuro-motor abnormalities. White matter lesions were associated with abnormal motor outcome only if the internal capsule was involved. Children with moderate white matter changes but normal internal capsule, had normal motor outcome at school age. PMID:14640307

Cortical thinning in cognitively normal elderly cohort of 60 to 89 year old from AIBL database and vulnerable brain areas

NASA Astrophysics Data System (ADS)

Lin, Zhongmin S.; Avinash, Gopal; Yan, Litao; McMillan, Kathryn

2014-03-01

Age-related cortical thinning has been studied by many researchers using quantitative MR images for the past three decades and vastly differing results have been reported. Although results have shown age-related cortical thickening in elderly cohort statistically in some brain regions under certain conditions, cortical thinning in elderly cohort requires further systematic investigation. This paper leverages our previously reported brain surface intensity model (BSIM)1 based technique to measure cortical thickness to study cortical changes due to normal aging. We measured cortical thickness of cognitively normal persons from 60 to 89 years old using Australian Imaging Biomarkers and Lifestyle Study (AIBL) data. MRI brains of 56 healthy people including 29 women and 27 men were selected. We measured average cortical thickness of each individual in eight brain regions: parietal, frontal, temporal, occipital, visual, sensory motor, medial frontal and medial parietal. Unlike the previous published studies, our results showed consistent age-related thinning of cerebral cortex in all brain regions. The parietal, medial frontal and medial parietal showed fastest thinning rates of 0.14, 0.12 and 0.10 mm/decade respectively while the visual region showed the slowest thinning rate of 0.05 mm/decade. In sensorimotor and parietal areas, women showed higher thinning (0.09 and 0.16 mm/decade) than men while in all other regions men showed higher thinning than women. We also created high resolution cortical thinning rate maps of the cohort and compared them to typical patterns of PET metabolic reduction of moderate AD and frontotemporal dementia (FTD). The results seemed to indicate vulnerable areas of cortical deterioration that may lead to brain dementia. These results validate our cortical thickness measurement technique by demonstrating the consistency of the cortical thinning and prediction of cortical deterioration trend with AIBL database.

Ascorbic Acid and the Brain: Rationale for the Use against Cognitive Decline

PubMed Central

Harrison, Fiona E.; Bowman, Gene L.; Polidori, Maria Cristina

2014-01-01

This review is focused upon the role of ascorbic acid (AA, vitamin C) in the promotion of healthy brain aging. Particular attention is attributed to the biochemistry and neuronal metabolism interface, transport across tissues, animal models that are useful for this area of research, and the human studies that implicate AA in the continuum between normal cognitive aging and age-related cognitive decline up to Alzheimer’s disease. Vascular risk factors and comorbidity relationships with cognitive decline and AA are discussed to facilitate strategies for advancing AA research in the area of brain health and neurodegeneration. PMID:24763117

Regional Fluid-Attenuated Inversion Recovery (FLAIR) at 7 Tesla correlates with amyloid beta in hippocampus and brainstem of cognitively normal elderly subjects

PubMed Central

Schreiner, Simon J.; Liu, Xinyang; Gietl, Anton F.; Wyss, Michael; Steininger, Stefanie C.; Gruber, Esmeralda; Treyer, Valerie; Meier, Irene B.; Kälin, Andrea M.; Leh, Sandra E.; Buck, Alfred; Nitsch, Roger M.; Pruessmann, Klaas P.; Hock, Christoph; Unschuld, Paul G.

2014-01-01

Background: Accumulation of amyloid beta (Aβ) may occur during healthy aging and is a risk factor for Alzheimer Disease (AD). While individual Aβ-accumulation can be measured non-invasively using Pittsburgh Compund-B positron emission tomography (PiB-PET), Fluid-attenuated inversion recovery (FLAIR) is a Magnetic Resonance Imaging (MRI) sequence, capable of indicating heterogeneous age-related brain pathologies associated with tissue-edema. In the current study cognitively normal elderly subjects were investigated for regional correlation of PiB- and FLAIR intensity. Methods: Fourteen healthy elderly subjects without known history of cognitive impairment received 11C-PiB-PET for estimation of regional Aβ-load. In addition, whole brain T1-MPRAGE and FLAIR-MRI sequences were acquired at high field strength of 7 Tesla (7T). Volume-normalized intensities of brain regions were assessed by applying an automated subcortical segmentation algorithm for spatial definition of brain structures. Statistical dependence between FLAIR- and PiB-PET intensities was tested using Spearman's rank correlation coefficient (rho), followed by Holm–Bonferroni correction for multiple testing. Results: Neuropsychological testing revealed normal cognitive performance levels in all participants. Mean regional PiB-PET and FLAIR intensities were normally distributed and independent. Significant correlation between volume-normalized PiB-PET signals and FLAIR intensities resulted for Hippocampus (right: rho = 0.86; left: rho = 0.84), Brainstem (rho = 0.85) and left Basal Ganglia vessel region (rho = 0.82). Conclusions: Our finding of a significant relationship between PiB- and FLAIR intensity mainly observable in the Hippocampus and Brainstem, indicates regional Aβ associated tissue-edema in cognitively normal elderly subjects. Further studies including clinical populations are necessary to clarify the relevance of our findings for estimating individual risk for age-related neurodegenerative processes such as AD. PMID:25249977

Epigenetic Age Acceleration Assessed with Human White-Matter Images.

PubMed

Hodgson, Karen; Carless, Melanie A; Kulkarni, Hemant; Curran, Joanne E; Sprooten, Emma; Knowles, Emma E; Mathias, Samuel; Göring, Harald H H; Yao, Nailin; Olvera, Rene L; Fox, Peter T; Almasy, Laura; Duggirala, Ravi; Blangero, John; Glahn, David C

2017-05-03

The accurate estimation of age using methylation data has proved a useful and heritable biomarker, with acceleration in epigenetic age predicting a number of age-related phenotypes. Measures of white matter integrity in the brain are also heritable and highly sensitive to both normal and pathological aging processes across adulthood. We consider the phenotypic and genetic interrelationships between epigenetic age acceleration and white matter integrity in humans. Our goal was to investigate processes that underlie interindividual variability in age-related changes in the brain. Using blood taken from a Mexican-American extended pedigree sample ( n = 628; age = 23.28-93.11 years), epigenetic age was estimated using the method developed by Horvath (2013). For n = 376 individuals, diffusion tensor imaging scans were also available. The interrelationship between epigenetic age acceleration and global white matter integrity was investigated with variance decomposition methods. To test for neuroanatomical specificity, 16 specific tracts were additionally considered. We observed negative phenotypic correlations between epigenetic age acceleration and global white matter tract integrity (ρ pheno = -0.119, p = 0.028), with evidence of shared genetic (ρ gene = -0.463, p = 0.013) but not environmental influences. Negative phenotypic and genetic correlations with age acceleration were also seen for a number of specific white matter tracts, along with additional negative phenotypic correlations between granulocyte abundance and white matter integrity. These findings (i.e., increased acceleration in epigenetic age in peripheral blood correlates with reduced white matter integrity in the brain and shares common genetic influences) provide a window into the neurobiology of aging processes within the brain and a potential biomarker of normal and pathological brain aging. SIGNIFICANCE STATEMENT Epigenetic measures can be used to predict age with a high degree of accuracy and so capture acceleration in biological age, relative to chronological age. The white matter tracts within the brain are also highly sensitive to aging processes. We show that increased biological aging (measured using epigenetic data from blood samples) is correlated with reduced integrity of white matter tracts within the human brain (measured using diffusion tensor imaging) with data from a large sample of Mexican-American families. Given the family design of the sample, we are also able to demonstrate that epigenetic aging and white matter tract integrity also share common genetic influences. Therefore, epigenetic age may be a potential, and accessible, biomarker of brain aging. Copyright © 2017 the authors 0270-6474/17/374735-09$15.00/0.

A biometric analysis of brain size in micrencephalics.

PubMed

Hofman, M A

1984-01-01

Brain weight and head circumference in micrencephalic patients were analysed as a function of age, height and sex in relation to normal human standards. A quantitative definition of micrencephaly is proposed, which is based on these analyses. Evidence is presented, furthermore, that micrencephalics have a significantly lower brain weight in adolescence than in early childhood, and that this cerebral dystrophy continues throughout adulthood, leading to death in more than 85% of the males and 78% of the females before they reach the age of 30 years. Since this decline in brain weight after approximately 3-5 years of age is not accompanied by a similar reduction in head circumference, the brains of elderly micrencephalic patients no longer occupy the entire cranial cavity. It is evident, therefore, that head circumference in the case of micrencephaly is an unsuitable parameter for estimating brain size.

Normal age-related brain morphometric changes: nonuniformity across cortical thickness, surface area and gray matter volume?

PubMed

Lemaitre, Herve; Goldman, Aaron L; Sambataro, Fabio; Verchinski, Beth A; Meyer-Lindenberg, Andreas; Weinberger, Daniel R; Mattay, Venkata S

2012-03-01

Normal aging is accompanied by global as well as regional structural changes. While these age-related changes in gray matter volume have been extensively studied, less has been done using newer morphological indexes, such as cortical thickness and surface area. To this end, we analyzed structural images of 216 healthy volunteers, ranging from 18 to 87 years of age, using a surface-based automated parcellation approach. Linear regressions of age revealed a concomitant global age-related reduction in cortical thickness, surface area and volume. Cortical thickness and volume collectively confirmed the vulnerability of the prefrontal cortex, whereas in other cortical regions, such as in the parietal cortex, thickness was the only measure sensitive to the pronounced age-related atrophy. No cortical regions showed more surface area reduction than the global average. The distinction between these morphological measures may provide valuable information to dissect age-related structural changes of the brain, with each of these indexes probably reflecting specific histological changes occurring during aging. Published by Elsevier Inc.

Resting-State Oscillatory Activity in Children Born Small for Gestational Age: An MEG Study

PubMed Central

Boersma, Maria; de Bie, Henrica M. A.; Oostrom, Kim J.; van Dijk, Bob W.; Hillebrand, Arjan; van Wijk, Bernadette C. M.; Delemarre-van de Waal, Henriëtte A.; Stam, Cornelis J.

2013-01-01

Growth restriction in utero during a period that is critical for normal growth of the brain, has previously been associated with deviations in cognitive abilities and brain anatomical and functional changes. We measured magnetoencephalography (MEG) in 4- to 7-year-old children to test if children born small for gestational age (SGA) show deviations in resting-state brain oscillatory activity. Children born SGA with postnatally spontaneous catch-up growth [SGA+; six boys, seven girls; mean age 6.3 year (SD = 0.9)] and children born appropriate for gestational age [AGA; seven boys, three girls; mean age 6.0 year (SD = 1.2)] participated in a resting-state MEG study. We calculated absolute and relative power spectra and used non-parametric statistics to test for group differences. SGA+ and AGA born children showed no significant differences in absolute and relative power except for reduced absolute gamma band power in SGA children. At the time of MEG investigation, SGA+ children showed significantly lower head circumference (HC) and a trend toward lower IQ, however there was no association of HC or IQ with absolute or relative power. Except for reduced absolute gamma band power, our findings suggest normal brain activity patterns at school age in a group of children born SGA in which spontaneous catch-up growth of bodily length after birth occurred. Although previous findings suggest that being born SGA alters brain oscillatory activity early in neonatal life, we show that these neonatal alterations do not persist at early school age when spontaneous postnatal catch-up growth occurs after birth. PMID:24068993

Low-frequency transcranial magnetic stimulation is beneficial for enhancing synaptic plasticity in the aging brain.

PubMed

Zhang, Zhan-Chi; Luan, Feng; Xie, Chun-Yan; Geng, Dan-Dan; Wang, Yan-Yong; Ma, Jun

2015-06-01

In the aging brain, cognitive function gradually declines and causes a progressive reduction in the structural and functional plasticity of the hippocampus. Transcranial magnetic stimulation is an emerging and novel neurological and psychiatric tool used to investigate the neurobiology of cognitive function. Recent studies have demonstrated that low-frequency transcranial magnetic stimulation (≤1 Hz) ameliorates synaptic plasticity and spatial cognitive deficits in learning-impaired mice. However, the mechanisms by which this treatment improves these deficits during normal aging are still unknown. Therefore, the current study investigated the effects of transcranial magnetic stimulation on the brain-derived neurotrophic factor signal pathway, synaptic protein markers, and spatial memory behavior in the hippocampus of normal aged mice. The study also investigated the downstream regulator, Fyn kinase, and the downstream effectors, synaptophysin and growth-associated protein 43 (both synaptic markers), to determine the possible mechanisms by which transcranial magnetic stimulation regulates cognitive capacity. Transcranial magnetic stimulation with low intensity (110% average resting motor threshold intensity, 1 Hz) increased mRNA and protein levels of brain-derived neurotrophic factor, tropomyosin receptor kinase B, and Fyn in the hippocampus of aged mice. The treatment also upregulated the mRNA and protein expression of synaptophysin and growth-associated protein 43 in the hippocampus of these mice. In conclusion, brain-derived neurotrophic factor signaling may play an important role in sustaining and regulating structural synaptic plasticity induced by transcranial magnetic stimulation in the hippocampus of aging mice, and Fyn may be critical during this regulation. These responses may change the structural plasticity of the aging hippocampus, thereby improving cognitive function.

Glial Modulation by N-acylethanolamides in Brain Injury and Neurodegeneration

PubMed Central

Herrera, María I.; Kölliker-Frers, Rodolfo; Barreto, George; Blanco, Eduardo; Capani, Francisco

2016-01-01

Neuroinflammation involves the activation of glial cells and represents a key element in normal aging and pathophysiology of brain damage. N-acylethanolamides (NAEs), naturally occurring amides, are known for their pro-homeostatic effects. An increase in NAEs has been reported in vivo and in vitro in the aging brain and in brain injury. Treatment with NAEs may promote neuroprotection and exert anti-inflammatory actions via PPARα activation and/or by counteracting gliosis. This review aims to provide an overview of endogenous and exogenous properties of NAEs in neuroinflammation and to discuss their interaction with glial cells. PMID:27199733

Glial Modulation by N-acylethanolamides in Brain Injury and Neurodegeneration.

PubMed

Herrera, María I; Kölliker-Frers, Rodolfo; Barreto, George; Blanco, Eduardo; Capani, Francisco

2016-01-01

Neuroinflammation involves the activation of glial cells and represents a key element in normal aging and pathophysiology of brain damage. N-acylethanolamides (NAEs), naturally occurring amides, are known for their pro-homeostatic effects. An increase in NAEs has been reported in vivo and in vitro in the aging brain and in brain injury. Treatment with NAEs may promote neuroprotection and exert anti-inflammatory actions via PPARα activation and/or by counteracting gliosis. This review aims to provide an overview of endogenous and exogenous properties of NAEs in neuroinflammation and to discuss their interaction with glial cells.

The muscle protein dysferlin accumulates in the Alzheimer brain

PubMed Central

Palamand, Divya; Strider, Jeff; Milone, Margherita; Pestronk, Alan

2006-01-01

Dysferlin is a transmembrane protein that is highly expressed in muscle. Dysferlin mutations cause limb-girdle dystrophy type 2B, Miyoshi myopathy and distal anterior compartment myopathy. Dysferlin has also been described in neural tissue. We studied dysferlin distribution in the brains of patients with Alzheimer disease (AD) and controls. Twelve brains, staged using the Clinical Dementia Rating were examined: 9 AD cases (mean age: 85.9 years and mean disease duration: 8.9 years), and 3 age-matched controls (mean age: 87.5 years). Dysferlin is a cytoplasmic protein in the pyramidal neurons of normal and AD brains. In addition, there were dysferlin-positive dystrophic neurites within Aβ plaques in the AD brain, distinct from tau-positive neurites. Western blots of total brain protein (RIPA) and sequential extraction buffers (high salt, high salt/Triton X-100, SDS and formic acid) of increasing protein extraction strength were performed to examine solubility state. In RIPA fractions, dysferlin was seen as 230–272 kDa bands in normal and AD brains. In serial extractions, there was a shift of dysferlin from soluble phase in high salt/Triton X-100 to the more insoluble SDS fraction in AD. Dysferlin is a new protein described in the AD brain that accumulates in association with neuritic plaques. In muscle, dysferlin plays a role in the repair of muscle membrane damage. The accumulation of dysferlin in the AD brain may be related to the inability of neurons to repair damage due to Aβ deposits accumulating in the AD brain. PMID:17024495

Aging exacerbates intracerebral hemorrhage-induced brain injury.

PubMed

Lee, Jae-Chul; Cho, Geum-Sil; Choi, Byung-Ok; Kim, Hyoung Chun; Kim, Won-Ki

2009-09-01

Aging may be an important factor affecting brain injury by intracerebral hemorrhage (ICH). In the present study, we investigated the responses of glial cells and monocytes to intracerebral hemorrhage in normal and aged rats. ICH was induced by microinjecting autologous whole blood (15 microL) into the striatum of young (4 month old) and aged (24 month old) Sprague-Dawley rats. Age-dependent relations of brain tissue damage with glial and macrophageal responses were evaluated. Three days after ICH, activated microglia/macrophages with OX42-positive processes and swollen cytoplasm were more abundantly distributed around and inside the hemorrhagic lesions. These were more dramatic in aged versus the young rats. Western blot and immunohistochemistry analyses showed that the expression of interleukin-1beta protein after ICH was greater in aged rats, whereas the expression of GFAP and ciliary neurotrophic factor protein after ICH was significantly lower in aged rats. These results suggest that ICH causes more severe brain injury in aged rats most likely due to overactivation of microglia/macrophages and concomitant repression of reactive astrocytes.

Gene expression in the aging human brain: an overview.

PubMed

Mohan, Adith; Mather, Karen A; Thalamuthu, Anbupalam; Baune, Bernhard T; Sachdev, Perminder S

2016-03-01

The review aims to provide a summary of recent developments in the study of gene expression in the aging human brain. Profiling differentially expressed genes or 'transcripts' in the human brain over the course of normal aging has provided valuable insights into the biological pathways that appear activated or suppressed in late life. Genes mediating neuroinflammation and immune system activation in particular, show significant age-related upregulation creating a state of vulnerability to neurodegenerative and neuropsychiatric disease in the aging brain. Cellular ionic dyshomeostasis and age-related decline in a host of molecular influences on synaptic efficacy may underlie neurocognitive decline in later life. Critically, these investigations have also shed light on the mobilization of protective genetic responses within the aging human brain that help determine health and disease trajectories in older age. There is growing interest in the study of pre and posttranscriptional regulators of gene expression, and the role of noncoding RNAs in particular, as mediators of the phenotypic diversity that characterizes human brain aging. Gene expression studies in healthy brain aging offer an opportunity to unravel the intricately regulated cellular underpinnings of neurocognitive aging as well as disease risk and resiliency in late life. In doing so, new avenues for early intervention in age-related neurodegenerative disease could be investigated with potentially significant implications for the development of disease-modifying therapies.

Accelerated Brain Aging in Schizophrenia: A Longitudinal Pattern Recognition Study.

PubMed

Schnack, Hugo G; van Haren, Neeltje E M; Nieuwenhuis, Mireille; Hulshoff Pol, Hilleke E; Cahn, Wiepke; Kahn, René S

2016-06-01

Despite the multitude of longitudinal neuroimaging studies that have been published, a basic question on the progressive brain loss in schizophrenia remains unaddressed: Does it reflect accelerated aging of the brain, or is it caused by a fundamentally different process? The authors used support vector regression, a supervised machine learning technique, to address this question. In a longitudinal sample of 341 schizophrenia patients and 386 healthy subjects with one or more structural MRI scans (1,197 in total), machine learning algorithms were used to build models to predict the age of the brain and the presence of schizophrenia ("schizophrenia score"), based on the gray matter density maps. Age at baseline ranged from 16 to 67 years, and follow-up scans were acquired between 1 and 13 years after the baseline scan. Differences between brain age and chronological age ("brain age gap") and between schizophrenia score and healthy reference score ("schizophrenia gap") were calculated. Accelerated brain aging was calculated from changes in brain age gap between two consecutive measurements. The age prediction model was validated in an independent sample. In schizophrenia patients, brain age was significantly greater than chronological age at baseline (+3.36 years) and progressively increased during follow-up (+1.24 years in addition to the baseline gap). The acceleration of brain aging was not constant: it decreased from 2.5 years/year just after illness onset to about the normal rate (1 year/year) approximately 5 years after illness onset. The schizophrenia gap also increased during follow-up, but more pronounced variability in brain abnormalities at follow-up rendered this increase nonsignificant. The progressive brain loss in schizophrenia appears to reflect two different processes: one relatively homogeneous, reflecting accelerated aging of the brain and related to various measures of outcome, and a more variable one, possibly reflecting individual variation and medication use. Differentiating between these two processes may not only elucidate the various factors influencing brain loss in schizophrenia, but also assist in individualizing treatment.

A Lifespan Approach to Neuroinflammatory and Cognitive Disorders: A Critical Role for Glia

PubMed Central

Bilbo, Staci D.; Smith, Susan H.; Schwarz, Jaclyn M.

2011-01-01

Cognitive decline is a common problem of aging. Whereas multiple neural and glial mechanisms may account for these declines, microglial sensitization and/or dystrophy has emerged as a leading culprit in brain aging and dysfunction. However, glial activation is consistently observed in normal brain aging as well, independent of frank neuroinflammation or functional impairment. Such variability suggests the existence of additional vulnerability factors that can impact neuronal-glial interactions and thus overall brain and cognitive health. The goal of this review is to elucidate our working hypothesis that an individual‘s risk or resilience to neuroinflammatory disorders and poor cognitive aging may critically depend on their early life experience, which can change immune reactivity within the brain for the remainder of the lifespan. For instance, early-life infection in rats can profoundly disrupt memory function in young adulthood, as well as accelerate age-related cognitive decline, both of which are linked to enduring changes in glial function that occur in response to the initial infection. We discuss these findings within the context of the growing literature on the role of immune molecules and neuroimmune crosstalk in normal brain development. We highlight the intrinsic factors (e.g., chemokines, hormones) that regulate microglial development and their colonization of the embryonic and postnatal brain, and the capacity for disruption or “re-programming” of this crucial process by external events (e.g, stress, infection). An impact on glia, which in turn alters neural development, has the capacity to profoundly impact cognitive and mental health function at all stages of life. PMID:21822589

Childhood and adolescent obesity and long-term cognitive consequences during aging.

PubMed

Wang, Jun; Freire, Daniel; Knable, Lindsay; Zhao, Wei; Gong, Bing; Mazzola, Paolo; Ho, Lap; Levine, Samara; Pasinetti, Giulio M

2015-04-01

The prevalence of childhood/adolescent obesity and insulin resistance has reached an epidemic level. Obesity's immediate clinical impacts have been extensively studied; however, current clinical evidence underscores the long-term implications. The current study explored the impacts of brief childhood/adolescent obesity and insulin resistance on cognitive function in later life. To mimic childhood/adolescent obesity and insulin resistance, we exposed 9-week-old C57BL/6J mice to a high-fat diet for 15 weeks, after which the mice exhibited diet-induced obesity and insulin resistance. We then put these mice back on a normal low-fat diet, after which the mice exhibited normal body weight and glucose tolerance. However, a spatial memory test in the forms of the Morris water maze (MWM) and contextual fear conditioning at 85 weeks of age showed that these mice had severe deficits in learning and long-term memory consolidation. Mechanistic investigations identified increased expression of histone deacetylases 5, accompanied by reduced expression of brain-derived neurotrophic factor, in the brains 61 weeks after the mice had been off the high-fat diet. Electrophysiology studies showed that hippocampal slices isolated from these mice are more susceptible to synaptic impairments compared with slices isolated from the control mice. We demonstrated that a 15-week occurrence of obesity and insulin resistance during childhood/adolescence induces irreversible epigenetic modifications in the brain that persist following restoration of normal metabolic homeostasis, leading to brain synaptic dysfunction during aging. Our study provides experimental evidence that limited early-life exposure to obesity and insulin resistance may have long-term deleterious consequences in the brain, contributing to the onset/progression of cognitive dysfunction during aging. © 2014 Wiley Periodicals, Inc.

In vivo NAD assay reveals the intracellular NAD contents and redox state in healthy human brain and their age dependences

PubMed Central

Zhu, Xiao-Hong; Lu, Ming; Lee, Byeong-Yeul; Ugurbil, Kamil; Chen, Wei

2015-01-01

NAD is an essential metabolite that exists in NAD+ or NADH form in all living cells. Despite its critical roles in regulating mitochondrial energy production through the NAD+/NADH redox state and modulating cellular signaling processes through the activity of the NAD+-dependent enzymes, the method for quantifying intracellular NAD contents and redox state is limited to a few in vitro or ex vivo assays, which are not suitable for studying a living brain or organ. Here, we present a magnetic resonance (MR) -based in vivo NAD assay that uses the high-field MR scanner and is capable of noninvasively assessing NAD+ and NADH contents and the NAD+/NADH redox state in intact human brain. The results of this study provide the first insight, to our knowledge, into the cellular NAD concentrations and redox state in the brains of healthy volunteers. Furthermore, an age-dependent increase of intracellular NADH and age-dependent reductions in NAD+, total NAD contents, and NAD+/NADH redox potential of the healthy human brain were revealed in this study. The overall findings not only provide direct evidence of declined mitochondrial functions and altered NAD homeostasis that accompany the normal aging process but also, elucidate the merits and potentials of this new NAD assay for noninvasively studying the intracellular NAD metabolism and redox state in normal and diseased human brain or other organs in situ. PMID:25730862

Functional brain development in growth-restricted and constitutionally small fetuses: a fetal magnetoencephalography case-control study.

PubMed

Morin, E C; Schleger, F; Preissl, H; Braendle, J; Eswaran, H; Abele, H; Brucker, S; Kiefer-Schmidt, I

2015-08-01

Fetal magnetoencephalography records fetal brain activity non-invasively. Delayed brain responses were reported for fetuses weighing below the tenth percentile. To investigate whether this delay indicates delayed brain maturation resulting from placental insufficiency, this study distinguished two groups of fetuses below the tenth percentile: growth-restricted fetuses with abnormal umbilical artery Doppler velocity (IUGR) and constitutionally small-for-gestational-age fetuses with normal umbilical artery Doppler findings (SGA) were compared with fetuses of adequate weight for gestational age (AGA), matched for age and behavioural state. A case-control study of matched pairs. Fetal magnetoencephalography-Center at the University Hospital of Tuebingen. Fourteen IUGR fetuses and 23 SGA fetuses were matched for gestational age and fetal behavioural state with 37 healthy, normal-sized fetuses. A 156-channel fetal magentoencephalography system was used to record fetal brain activity. Light flashes as visual stimulation were applied to the fetus. The Student's t-test for paired groups was performed. Latency of fetal visual evoked magnetic responses (VER). The IUGR fetuses showed delayed VERs compared with controls (IUGR, 233.1 ms; controls, 184.6 ms; P = 0.032). SGA fetuses had similar evoked response latencies compared with controls (SGA, 216.1 ms; controls, 219.9 ms; P = 0.828). Behavioural states were similarly distributed. Visual evoked responses are delayed in IUGR fetuses, but not in SGA. Fetal behavioural state as an influencing factor of brain response latency was accounted for in the comparison. This reinforces that delayed brain maturation is the result of placental insufficiency. © 2015 Royal College of Obstetricians and Gynaecologists.

Characterizing age-related decline of recognition memory and brain activation profile in mice.

PubMed

Belblidia, Hassina; Leger, Marianne; Abdelmalek, Abdelouadoud; Quiedeville, Anne; Calocer, Floriane; Boulouard, Michel; Jozet-Alves, Christelle; Freret, Thomas; Schumann-Bard, Pascale

2018-06-01

Episodic memory decline is one of the earlier deficits occurring during normal aging in humans. The question of spatial versus non-spatial sensitivity to age-related memory decline is of importance for a full understanding of these changes. Here, we characterized the effect of normal aging on both non-spatial (object) and spatial (object location) memory performances as well as on associated neuronal activation in mice. Novel-object (NOR) and object-location (OLR) recognition tests, respectively assessing the identity and spatial features of object memory, were examined at different ages. We show that memory performances in both tests were altered by aging as early as 15 months of age: NOR memory was partially impaired whereas OLR memory was found to be fully disrupted at 15 months of age. Brain activation profiles were assessed for both tests using immunohistochemical detection of c-Fos (neuronal activation marker) in 3and 15 month-old mice. Normal performances in NOR task by 3 month-old mice were associated to an activation of the hippocampus and a trend towards an activation in the perirhinal cortex, in a way that did significantly differ with 15 month-old mice. During OLR task, brain activation took place in the hippocampus in 3 month-old but not significantly in 15 month-old mice, which were fully impaired at this task. These differential alterations of the object- and object-location recognition memory may be linked to differential alteration of the neuronal networks supporting these tasks. Copyright © 2018 Elsevier Inc. All rights reserved.

Do glutathione levels decline in aging human brain?

PubMed

Tong, Junchao; Fitzmaurice, Paul S; Moszczynska, Anna; Mattina, Katie; Ang, Lee-Cyn; Boileau, Isabelle; Furukawa, Yoshiaki; Sailasuta, Napapon; Kish, Stephen J

2016-04-01

For the past 60 years a major theory of "aging" is that age-related damage is largely caused by excessive uncompensated oxidative stress. The ubiquitous tripeptide glutathione is a major antioxidant defense mechanism against reactive free radicals and has also served as a marker of changes in oxidative stress. Some (albeit conflicting) animal data suggest a loss of glutathione in brain senescence, which might compromise the ability of the aging brain to meet the demands of oxidative stress. Our objective was to establish whether advancing age is associated with glutathione deficiency in human brain. We measured reduced glutathione (GSH) levels in multiple regions of autopsied brain of normal subjects (n=74) aged one day to 99 years. Brain GSH levels during the infancy/teenage years were generally similar to those in the oldest examined adult group (76-99 years). During adulthood (23-99 years) GSH levels remained either stable (occipital cortex) or increased (caudate nucleus, frontal and cerebellar cortices). To the extent that GSH levels represent glutathione antioxidant capacity, our postmortem data suggest that human brain aging is not associated with declining glutathione status. We suggest that aged healthy human brains can maintain antioxidant capacity related to glutathione and that an age-related increase in GSH levels in some brain regions might possibly be a compensatory response to increased oxidative stress. Since our findings, although suggestive, suffer from the generic limitations of all postmortem brain studies, we also suggest the need for "replication" investigations employing the new (1)H MRS imaging procedures in living human brain. Copyright © 2016 Elsevier Inc. All rights reserved.

The impact of glucose disorders on cognition and brain volumes in the elderly: the Sydney Memory and Ageing Study.

PubMed

Samaras, Katherine; Lutgers, Helen L; Kochan, Nicole A; Crawford, John D; Campbell, Lesley V; Wen, Wei; Slavin, Melissa J; Baune, Bernard T; Lipnicki, Darren M; Brodaty, Henry; Trollor, Julian N; Sachdev, Perminder S

2014-04-01

Type 2 diabetes predicts accelerated cognitive decline and brain atrophy. We hypothesized that impaired fasting glucose (IFG) and incident glucose disorders have detrimental effects on global cognition and brain volume. We further hypothesized that metabolic and inflammatory derangements accompanying hyperglycaemia contribute to change in brain structure and function. This was a longitudinal study of a community-dwelling elderly cohort with neuropsychological testing (n = 880) and brain volumes by magnetic resonance imaging (n = 312) measured at baseline and 2 years. Primary outcomes were global cognition and total brain volume. Secondary outcomes were cognitive domains (processing speed, memory, language, visuospatial and executive function) and brain volumes (hippocampal, parahippocampal, precuneus and frontal lobe). Participants were categorised as normal, impaired fasting glucose at both assessments (stable IFG), baseline diabetes or incident glucose disorders (incident diabetes or IFG at 2 years). Measures included inflammatory cytokines and oxidative metabolites. Covariates were age, sex, education, non-English speaking background, smoking, blood pressure, lipid-lowering or antihypertensive medications, mood score, apolipoprotein E genotype and baseline cognition or brain volume. Participants with incident glucose disorders had greater decline in global cognition and visuospatial function compared to normal, similar to that observed in baseline diabetes. Homocysteine was independently associated with the observed effect of diabetes on executive function. Apolipoprotein E genotype did not influence the observed effects of diabetes on cognition. Incident glucose disorders and diabetes were also associated with greater 2-year decline in total brain volume, compared to normal (40.0 ± 4.2 vs. 46.7 ± 5.7 mm(3) vs. 18.1 ± 6.2, respectively, p < 0.005). Stable IFG did not show greater decline in global cognition or brain volumes compared to normal. Incident glucose disorders, like diabetes, are associated with accelerated decline in global cognition and brain volumes in non-demented elderly, whereas stable IFG is not. Preventing deterioration in glucose metabolism in the elderly may help preserve brain structure and function.

Brain volume and fatigue in patients with postpoliomyelitis syndrome.

PubMed

Trojan, Daria A; Narayanan, Sridar; Francis, Simon J; Caramanos, Zografos; Robinson, Ann; Cardoso, Mauro; Arnold, Douglas L

2014-03-01

Acute paralytic poliomyelitis is associated with encephalitis. Early brain inflammation may produce permanent neuronal injury with brain atrophy, which may result in symptoms such as fatigue. Brain volume has not been assessed in postpoliomyelitis syndrome (PPS). To determine whether brain volume is decreased compared with that in normal controls, and whether brain volume is associated with fatigue in patients with PPS. A cross-sectional study. Tertiary university-affiliated hospital postpolio and multiple sclerosis (MS) clinics. Forty-nine ambulatory patients with PPS, 28 normal controls, and 53 ambulatory patients with MS. We studied the brains of all study subjects with magnetic resonance imaging by using a 1.5 T Siemens Sonata machine. The subjects completed the Fatigue Severity Scale. Multivariable linear regression models were computed to evaluate the contribution of PPS and MS compared with controls to explain brain volume. Normalized brain volume (NBV) was assessed with the automated program Structured Image Evaluation, using Normalization, of Atrophy method from the acquired magnetic resonance images. This method may miss brainstem atrophy. Technically adequate NBV measurements were available for 42 patients with PPS, 27 controls, and 49 patients with MS. The mean (standard deviation) age was 60.9 ± 7.6 years for patients with PPS, 47.0 ± 14.6 years for controls, and 46.2 ± 9.4 years for patients with MS. In a multivariable model adjusted for age and gender, NBV was not significantly different in patients with PPS compared with that in controls (P = .28). As expected, when using a similar model for patients with MS, NBV was significantly decreased compared with that in controls (P = .006). There was no significant association between NBV and fatigue in subjects with PPS (Spearman ρ = 0.23; P = .19). No significant whole-brain atrophy was found, and no association of brain volume with fatigue in PPS. Brain atrophy was confirmed in MS. It is possible that brainstem atrophy was not recognized by this study. Copyright © 2014 American Academy of Physical Medicine and Rehabilitation. Published by Elsevier Inc. All rights reserved.

Physiological and biochemical effects of 17β estradiol in aging female rat brain.

PubMed

Kumar, Pardeep; Taha, Asia; Kale, R K; Cowsik, S M; Baquer, Najma Zaheer

2011-07-01

Aging in females and males is considered as the end of natural protection against age related diseases like osteoporosis, coronary heart disease, diabetes, Alzheimer's disease and Parkinson's disease. These changes increase during menopausal condition in females when the level of estradiol is decreased. The objective of this study was to observe the changes in activities of monoamine oxidase, glucose transporter-4 levels, membrane fluidity, lipid peroxidation levels and lipofuscin accumulation occurring in brains of female rats of 3 months (young), 12 months (adult) and 24 months (old) age groups, and to see whether these changes are restored to normal levels after exogenous administration of estradiol (0.1 μg/g body weight for 1 month). The results obtained in the present work revealed that normal aging was associated with significant increases in the activity of monoamine oxidase, lipid peroxidation levels and lipofuscin accumulation in the brains of aging female rats, and a decrease in glucose transporter-4 level and membrane fluidity. Our data showed that estradiol treatment significantly decreased monoamine oxidase activity, lipid peroxidation and lipofuscin accumulation in brain regions of aging rats, and a reversal of glucose transporter-4 levels and membrane fluidity was achieved, therefore it can be concluded from the present findings that estradiol's beneficial effects seemed to arise from its antilipofuscin, antioxidant and antilipidperoxidative effects, implying an overall anti-aging action. The results of this study will be useful for pharmacological modification of the aging process and applying new strategies for control of age related disorders. Copyright © 2011 Elsevier Inc. All rights reserved.

Phenotypic and Gene Expression Modification with Normal Brain Aging in GFAP-Positive Astrocytes and Neural Stem Cells

PubMed Central

Bernal, Giovanna M.; Peterson, Daniel A.

2011-01-01

Summary Astrocytes secrete growth factors that are both neuroprotective and supportive for the local environment. Identified by glial fibrillary acidic protein (GFAP) expression, astrocytes exhibit heterogeneity in morphology and in expression of phenotypic markers and growth factors throughout different adult brain regions. In adult neurogenic niches, astrocytes secrete vascular endothelial growth factor (VEGF) and fibroblast growth factor-2 (FGF-2) within the neurogenic niche, and are also a source of special GFAP-positive multipotent neural stem cells (NSCs). Normal aging is accompanied by a decline in CNS function and reduced neurogenesis. We asked if a decreased availability of astrocyte-derived factors may contribute to the age-related decline in neurogenesis. Determining alterations of astrocytic activity in the aging brain is crucial for understanding CNS homeostasis in aging and for assessing appropriate therapeutic targets for an aging population. We found region-specific alterations in gene expression of GFAP, VEGF and FGF-2 and their receptors in the aged brain corresponding to changes in astrocytic reactivity, supporting astrocytic heterogeneity and demonstrating a differential aging effect. We found that GFAP-positive NSCs uniquely coexpress both VEGF and its key mitotic receptor Flk-1 in both young and aged hippocampus, indicating a possible autocrine/paracrine signaling mechanism. VEGF expression is lost once NSCs commit to a neuronal fate, but Flk-1-mediated sensitivity to VEGF signaling is maintained. We propose that age-related astrocytic changes result in reduced VEGF and FGF-2 signaling, which in turn limits neural stem cell and progenitor cell maintenance and contributes to decreased neurogenesis. PMID:21385309

Normal variation in early parental sensitivity predicts child structural brain development.

PubMed

Kok, Rianne; Thijssen, Sandra; Bakermans-Kranenburg, Marian J; Jaddoe, Vincent W V; Verhulst, Frank C; White, Tonya; van IJzendoorn, Marinus H; Tiemeier, Henning

2015-10-01

Early caregiving can have an impact on brain structure and function in children. The influence of extreme caregiving experiences has been demonstrated, but studies on the influence of normal variation in parenting quality are scarce. Moreover, no studies to date have included the role of both maternal and paternal sensitivity in child brain maturation. This study examined the prospective relation between mothers' and fathers' sensitive caregiving in early childhood and brain structure later in childhood. Participants were enrolled in a population-based prenatal cohort. For 191 families, maternal and paternal sensitivity was repeatedly observed when the child was between 1 year and 4 years of age. Head circumference was assessed at 6 weeks, and brain structure was assessed using magnetic resonance imaging (MRI) measurements at 8 years of age. Higher levels of parental sensitivity in early childhood were associated with larger total brain volume (adjusted β = 0.15, p = .01) and gray matter volume (adjusted β = 0.16, p = .01) at 8 years, controlling for infant head size. Higher levels of maternal sensitivity in early childhood were associated with a larger gray matter volume (adjusted β = 0.13, p = .04) at 8 years, independent of infant head circumference. Associations with maternal versus paternal sensitivity were not significantly different. Normal variation in caregiving quality is related to markers of more optimal brain development in children. The results illustrate the important role of both mothers and fathers in child brain development. Copyright © 2015 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.

Physiological neuronal decline in healthy aging human brain - An in vivo study with MRI and short echo-time whole-brain (1)H MR spectroscopic imaging.

PubMed

Ding, Xiao-Qi; Maudsley, Andrew A; Sabati, Mohammad; Sheriff, Sulaiman; Schmitz, Birte; Schütze, Martin; Bronzlik, Paul; Kahl, Kai G; Lanfermann, Heinrich

2016-08-15

Knowledge of physiological aging in healthy human brain is increasingly important for neuroscientific research and clinical diagnosis. To investigate neuronal decline in normal aging brain eighty-one healthy subjects aged between 20 and 70years were studied with MRI and whole-brain (1)H MR spectroscopic imaging. Concentrations of brain metabolites N-acetyl-aspartate (NAA), choline (Cho), total creatine (tCr), myo-inositol (mI), and glutamine+glutamate (Glx) in ratios to internal water, and the fractional volumes of brain tissue were estimated simultaneously in eight cerebral lobes and in cerebellum. Results demonstrated that an age-related decrease in gray matter volume was the largest contribution to changes in brain volume. Both lobar NAA and the fractional volume of gray matter (FVGM) decreased with age in all cerebral lobes, indicating that the decreased NAA was predominantly associated with decreased gray matter volume and neuronal density or metabolic activity. In cerebral white matter Cho, tCr, and mI increased with age in association with increased fractional volume, showing altered cellular membrane turn-over, energy metabolism, and glial activity in human aging white matter. In cerebellum tCr increased while brain tissue volume decreased with age, showing difference to cerebral aging. The observed age-related metabolic and microstructural variations suggest that physiological neuronal decline in aging human brain is associated with a reduction of gray matter volume and neuronal density, in combination with cellular aging in white matter indicated by microstructural alterations and altered energy metabolism in the cerebellum. Copyright © 2016 Elsevier Inc. All rights reserved.

Subjective cognitive complaints, personality and brain amyloid-beta in cognitively normal older adults

PubMed Central

Snitz, Beth E.; Weissfeld, Lisa A.; Cohen, Ann D.; Lopez, Oscar L.; Nebes, Robert D.; Aizenstein, Howard J.; McDade, Eric; Price, Julie C.; Mathis, Chester A.; Klunk, William E.

2015-01-01

Objectives Subjective cognitive complaints in otherwise normal aging are common but may be associated with preclinical Alzheimer Disease in some individuals. Little is known about who is mostly likely to show associations between cognitive complaints and preclinical Alzheimer pathology. We sought to 1) demonstrate associations between subjective complaints and brain amyloid-β in cognitively normal older adults; 2) to explore personality factors as potential moderators of this association. Design Cross-sectional observational study. Setting Clinical neuroimaging research center. Participants Community volunteer sample of 92 healthy older adults, screened for normal cognition with comprehensive neuropsychological evaluation. Measurements Subjective cognitive self-report measures included the Memory Functioning Questionnaire, Cognitive Failures Questionnaire, and the Subjective Cognitive Complaint Scale. Personality was measured with the NEO Five Factor Inventory. Brain amyloid-β deposition was assessed with Pittsburgh compound B (PiB)-PET imaging. Results One of three cognitive complaint measures, the Memory Functioning Questionnaire, was associated with global PiB retention (standardized beta =−.230, p=.046, adjusting for age, sex and depressive symptoms). Neuroticism moderated this association such that only high neuroticism individuals showed the predicted pattern of high complaint – high amyloid-β association. Conclusions Evidence for association between subjective cognition and brain amyloid-β deposition in healthy older adults is demonstrable but measure-specific. Neuroticism may moderate the MFQ – amyloid-β association such that it is observed in the context of higher trait neuroticism. Subjective cognitive complaints and neuroticism may reflect a common susceptibility toward psychological distress and negative affect, which are in turn risk factors for cognitive decline in aging and incident Alzheimer Disease. PMID:25746485

MRI Brain Volume Measurements in Infantile Neuronal Ceroid Lipofuscinosis.

PubMed

Baker, E H; Levin, S W; Zhang, Z; Mukherjee, A B

2017-02-01

Infantile neuronal ceroid lipofuscinosis is a devastating neurodegenerative storage disease caused by palmitoyl-protein thioesterase 1 deficiency, which impairs degradation of palmitoylated proteins (constituents of ceroid) by lysosomal hydrolases. Consequent lysosomal ceroid accumulation leads to neuronal injury, resulting in rapid neurodegeneration and childhood death. As part of a project studying the treatment benefits of a combination of cysteamine bitartrate and N -acetyl cysteine, we made serial measurements of patients' brain volumes with MR imaging. Ten patients with infantile neuronal ceroid lipofuscinosis participating in a treatment/follow-up study underwent brain MR imaging that included high-resolution T1-weighted images. After manual placement of a mask delineating the surface of the brain, a maximum-likelihood classifier was applied to determine total brain volume, further subdivided as cerebrum, cerebellum, brain stem, and thalamus. Patients' brain volumes were compared with those of a healthy population. Major subdivisions of the brain followed similar trajectories with different timing. The cerebrum demonstrated early, rapid volume loss and may never have been normal postnatally. The thalamus dropped out of the normal range around 6 months of age; the cerebellum, around 2 years of age; and the brain stem, around 3 years of age. Rapid cerebral volume loss was expected on the basis of previous qualitative reports. Because our study did not include a nontreatment arm and because progression of brain volumes in infantile neuronal ceroid lipofuscinosis has not been previously quantified, we could not determine whether our intervention had a beneficial effect on brain volumes. However, the level of quantitative detail in this study allows it to serve as a reference for evaluation of future therapeutic interventions. © 2017 by American Journal of Neuroradiology.

Brain perfusion SPECT in the mouse: normal pattern according to gender and age.

PubMed

Apostolova, Ivayla; Wunder, Andreas; Dirnagl, Ulrich; Michel, Roger; Stemmer, Nina; Lukas, Mathias; Derlin, Thorsten; Gregor-Mamoudou, Betina; Goldschmidt, Jürgen; Brenner, Winfried; Buchert, Ralph

2012-12-01

Regional cerebral blood flow (rCBF) is a useful surrogate marker of neuronal activity and a parameter of primary interest in the diagnosis of many diseases. The increasing use of mouse models spawns the demand for in vivo measurement of rCBF in the mouse. Small animal SPECT provides excellent spatial resolution at adequate sensitivity and is therefore a promising tool for imaging the mouse brain. This study evaluates the feasibility of mouse brain perfusion SPECT and assesses the regional pattern of normal Tc-99m-HMPAO uptake and the impact of age and gender. Whole-brain kinetics was compared between Tc-99m-HMPAO and Tc-99m-ECD using rapid dynamic planar scans in 10 mice. Assessment of the regional uptake pattern was restricted to the more suitable tracer, HMPAO. Two HMPAO SPECTs were performed in 18 juvenile mice aged 7.5 ± 1.5weeks, and in the same animals at young adulthood, 19.1 ± 4.0 weeks (nanoSPECT/CTplus, general purpose mouse apertures: 1.2kcps/MBq, 0.7mm FWHM). The 3-D MRI Digital Atlas Database of an adult C57BL/6J mouse brain was used for region-of-interest (ROI) analysis. SPECT images were stereotactically normalized using SPM8 and a custom made, left-right symmetric HMPAO template in atlas space. For testing lateral asymmetry, each SPECT was left-right flipped prior to stereotactical normalization. Flipped and unflipped SPECTs were compared by paired testing. Peak brain uptake was similar for ECD and HMPAO: 1.8 ± 0.2 and 2.1 ± 0.6 %ID (p=0.357). Washout after the peak was much faster for ECD than for HMPAO: 24 ± 7min vs. 4.6 ± 1.7h (p=0.001). The general linear model for repeated measures with gender as an intersubject factor revealed an increase in relative HMPAO uptake with age in the neocortex (p=0.018) and the hippocampus (p=0.012). A decrease was detected in the midbrain (p=0.025). Lateral asymmetry, with HMPAO uptake larger in the left hemisphere, was detected primarily in the neocortex, both at juvenile age (asymmetry index AI=2.7 ± 1.7%, p=0.000) and at young adult age (AI=2.4 ± 1.7%, p=0.000). Gender had no effect on asymmetry. Voxel-wise testing confirmed the ROI-based findings. In conclusion, high-resolution HMPAO SPECT is a promising technique for measuring rCBF in preclinical research. It indicates lateral asymmetry of rCBF in the mouse brain as well as age-related changes during late maturation. ECD is not suitable as tracer for brain SPECT in the mouse because of its fast clearance from tissue indicating an interspecies difference in esterase activity between mice and humans. Copyright © 2012 Elsevier Inc. All rights reserved.

[Quantitative analysis method based on fractal theory for medical imaging of normal brain development in infants].

PubMed

Li, Heheng; Luo, Liangping; Huang, Li

2011-02-01

The present paper is aimed to study the fractal spectrum of the cerebral computerized tomography in 158 normal infants of different age groups, based on the calculation of chaotic theory. The distribution range of neonatal period was 1.88-1.90 (mean = 1.8913 +/- 0.0064); It reached a stable condition at the level of 1.89-1.90 during 1-12 months old (mean = 1.8927 +/- 0.0045); The normal range of 1-2 years old infants was 1.86-1.90 (mean = 1.8863 +/- 4 0.0085); It kept the invariance of the quantitative value among 1.88-1.91(mean = 1.8958 +/- 0.0083) during 2-3 years of age. ANOVA indicated there's no significant difference between boys and girls (F = 0.243, P > 0.05), but the difference of age groups was significant (F = 8.947, P < 0.001). The fractal dimension of cerebral computerized tomography in normal infants computed by box methods was maintained at an efficient stability from 1.86 to 1.91. It indicated that there exit some attractor modes in pediatric brain development.

Voxel-based statistical analysis of cerebral blood flow using Tc-99m ECD brain SPECT in patients with traumatic brain injury: group and individual analyses.

PubMed

Shin, Yong Beom; Kim, Seong-Jang; Kim, In-Ju; Kim, Yong-Ki; Kim, Dong-Soo; Park, Jae Heung; Yeom, Seok-Ran

2006-06-01

Statistical parametric mapping (SPM) was applied to brain perfusion single photon emission computed tomography (SPECT) images in patients with traumatic brain injury (TBI) to investigate regional cerebral abnormalities compared to age-matched normal controls. Thirteen patients with TBI underwent brain perfusion SPECT were included in this study (10 males, three females, mean age 39.8 +/- 18.2, range 21 - 74). SPM2 software implemented in MATLAB 5.3 was used for spatial pre-processing and analysis and to determine the quantitative differences between TBI patients and age-matched normal controls. Three large voxel clusters of significantly decreased cerebral blood perfusion were found in patients with TBI. The largest clusters were area including medial frontal gyrus (voxel number 3642, peak Z-value = 4.31, 4.27, p = 0.000) in both hemispheres. The second largest clusters were areas including cingulated gyrus and anterior cingulate gyrus of left hemisphere (voxel number 381, peak Z-value = 3.67, 3.62, p = 0.000). Other clusters were parahippocampal gyrus (voxel number 173, peak Z-value = 3.40, p = 0.000) and hippocampus (voxel number 173, peak Z-value = 3.23, p = 0.001) in the left hemisphere. The false discovery rate (FDR) was less than 0.04. From this study, group and individual analyses of SPM2 could clearly identify the perfusion abnormalities of brain SPECT in patients with TBI. Group analysis of SPM2 showed hypoperfusion pattern in the areas including medial frontal gyrus of both hemispheres, cingulate gyrus, anterior cingulate gyrus, parahippocampal gyrus and hippocampus in the left hemisphere compared to age-matched normal controls. Also, left parahippocampal gyrus and left hippocampus were additional hypoperfusion areas. However, these findings deserve further investigation on a larger number of patients to be performed to allow a better validation of objective SPM analysis in patients with TBI.

Minimal Brain Dysfunction and Otitis Media.

ERIC Educational Resources Information Center

Hersher, Leonard

1978-01-01

The frequency of otitis media among 22 hyperactive children (ages 7-to-13 years) with learning disorders was compared with the frequency of otitis media in a sample of 772 normal matched-age children. (Author/PHR)

Phospholipase A2 - nexus of aging, oxidative stress, neuronal excitability, and functional decline of the aging nervous system? Insights from a snail model system of neuronal aging and age-associated memory impairment.

PubMed

Hermann, Petra M; Watson, Shawn N; Wildering, Willem C

2014-01-01

The aging brain undergoes a range of changes varying from subtle structural and physiological changes causing only minor functional decline under healthy normal aging conditions, to severe cognitive or neurological impairment associated with extensive loss of neurons and circuits due to age-associated neurodegenerative disease conditions. Understanding how biological aging processes affect the brain and how they contribute to the onset and progress of age-associated neurodegenerative diseases is a core research goal in contemporary neuroscience. This review focuses on the idea that changes in intrinsic neuronal electrical excitability associated with (per)oxidation of membrane lipids and activation of phospholipase A2 (PLA2) enzymes are an important mechanism of learning and memory failure under normal aging conditions. Specifically, in the context of this special issue on the biology of cognitive aging we portray the opportunities offered by the identifiable neurons and behaviorally characterized neural circuits of the freshwater snail Lymnaea stagnalis in neuronal aging research and recapitulate recent insights indicating a key role of lipid peroxidation-induced PLA2 as instruments of aging, oxidative stress and inflammation in age-associated neuronal and memory impairment in this model system. The findings are discussed in view of accumulating evidence suggesting involvement of analogous mechanisms in the etiology of age-associated dysfunction and disease of the human and mammalian brain.

The Earliest Stage of Cognitive Impairment in Transition From Normal Aging to Alzheimer Disease Is Marked By Prominent RNA Oxidation in Vulnerable Neurons

PubMed Central

Nunomura, Akihiko; Tamaoki, Toshio; Motohashi, Nobutaka; Nakamura, Masao; McKeel, Daniel W.; Tabaton, Massimo; Lee, Hyoung-gon; Smith, Mark A.; Perry, George; Zhu, Xiongwei

2012-01-01

Although neuronal RNA oxidation is a prominent and established feature in age-associated neurodegenerative disorders such as Alzheimer disease (AD), oxidative damage to neuronal RNA in aging and in the transitional stages from normal elderly to the onset of AD has not been fully examined. In this study, we used an in situ approach to identify an oxidized RNA nucleoside 8-hydroxyguanosine (8OHG) in the cerebral cortex of 65 individuals without dementia ranging in age from 0.3 to 86 years. We also examined brain samples from 20 elderly who were evaluated for their premortem clinical dementia rating score and postmortem brain pathological diagnoses to investigate preclinical AD and mild cognitive impairment. Relative density measurements of 8OHG-immunoreactivity revealed a statistically significant increase in neuronal RNA oxidation during aging in the hippocampus and the temporal neocortex. In subjects with mild cognitive impairment but not preclinical AD, neurons of the temporal cortex showed a higher burden of oxidized RNA compared to age-matched controls. These results indicate that although neuronal RNA oxidation fundamentally occurs as an age-associated phenomenon, more prominent RNA damage than in normal aging correlates with the onset of cognitive impairment in the prodromal stage of AD. PMID:22318126

Periodontal disease associates with higher brain amyloid load in normal elderly

PubMed Central

Kamer, Angela R.; Pirraglia, Elizabeth; Tsui, Wai; Rusinek, Henry; Vallabhajosula, Shankar; Mosconi, Lisa; Yi, Li; McHugh, Pauline; Craig, Ronald G.; Svetcov, Spencer; Linker, Ross; Shi, Chen; Glodzik, Lidia; Williams, Schantel; Corby, Patricia; Saxena, Deepak; de Leon, Mony J.

2015-01-01

Background The accumulation of amyloid β plaques (Aβ) is a central feature of Alzheimer’s disease (AD). First reported in animal models, it remains uncertain if peripheral inflammatory/infectious conditions in humans can promote Aβ brain accumulation. Periodontal disease, a common chronic infection, has been previously reported to be associated with AD. Methods Thirty-eight cognitively normal, healthy, community residing elderly (mean age 61; 68% female) were examined in an Alzheimer’s Disease research center and a University-based Dental School. Linear regression models (adjusted for age, ApoE and smoking) were used to test the hypothesis that periodontal disease assessed by clinical attachment loss was associated with brain Aβ load using 11C-PIB PET imaging. Results After adjusting for confounders, clinical attachment loss (≥ 3mm), representing a history of periodontal inflammatory/infectious burden, was associated with increased 11C-PIB uptake in Aβ vulnerable brain regions (p=0.002). Conclusion We show for the first time in humans an association between periodontal disease and brain Aβ load. These data are consistent with prior animal studies showing that peripheral inflammation/infections are sufficient to produce brain Aβ accumulations. PMID:25491073

A Complex Interplay of Vitamin B1 and B6 Metabolism with Cognition, Brain Structure, and Functional Connectivity in Older Adults.

PubMed

Jannusch, Kai; Jockwitz, Christiane; Bidmon, Hans-Jürgen; Moebus, Susanne; Amunts, Katrin; Caspers, Svenja

2017-01-01

Aging is associated with brain atrophy, functional brain network reorganization and decline of cognitive performance, albeit characterized by high interindividual variability. Among environmental influencing factors accounting for this variability, nutrition and particularly vitamin supply is thought to play an important role. While evidence exists that supplementation of vitamins B6 and B1 might be beneficial for cognition and brain structure, at least in deficient states and neurodegenerative diseases, little is known about this relation during healthy aging and in relation to reorganization of functional brain networks. We thus assessed the relation between blood levels of vitamins B1 and B6 and cognitive performance, cortical folding, and functional resting-state connectivity in a large sample of older adults ( N > 600; age: 55-85 years), drawn from the population-based 1000BRAINS study. In addition to blood sampling, subjects underwent structural and functional resting-state neuroimaging as well as extensive neuropsychological testing in the domains of executive functions, (working) memory, attention, and language. Brain regions showing changes in the local gyrification index as calculated using FreeSurfer in relation to vitamin levels were used for subsequent seed-based resting-state functional connectivity analysis. For B6, a positive correlation with local cortical folding was found throughout the brain, while only slight changes in functional connectivity were observed. Contrarily, for B1, a negative correlation with cortical folding as well as problem solving and visuo-spatial working memory performance was found, which was accompanied by pronounced increases of interhemispheric and decreases of intrahemispheric functional connectivity. While the effects for B6 expand previous knowledge on beneficial effects of B6 supplementation on brain structure, they also showed that additional effects on cognition might not be recognizable in healthy older subjects with normal B6 blood levels. The cortical atrophy and pronounced functional reorganization associated with B1, contrarily, was more in line with the theory of a disturbed B1 metabolism in older adults, leading to B1 utilization deficits, and thus, an effective B1 deficiency in the brain, despite normal to high-normal blood levels.

A Complex Interplay of Vitamin B1 and B6 Metabolism with Cognition, Brain Structure, and Functional Connectivity in Older Adults

PubMed Central

Jannusch, Kai; Jockwitz, Christiane; Bidmon, Hans-Jürgen; Moebus, Susanne; Amunts, Katrin; Caspers, Svenja

2017-01-01

Aging is associated with brain atrophy, functional brain network reorganization and decline of cognitive performance, albeit characterized by high interindividual variability. Among environmental influencing factors accounting for this variability, nutrition and particularly vitamin supply is thought to play an important role. While evidence exists that supplementation of vitamins B6 and B1 might be beneficial for cognition and brain structure, at least in deficient states and neurodegenerative diseases, little is known about this relation during healthy aging and in relation to reorganization of functional brain networks. We thus assessed the relation between blood levels of vitamins B1 and B6 and cognitive performance, cortical folding, and functional resting-state connectivity in a large sample of older adults (N > 600; age: 55–85 years), drawn from the population-based 1000BRAINS study. In addition to blood sampling, subjects underwent structural and functional resting-state neuroimaging as well as extensive neuropsychological testing in the domains of executive functions, (working) memory, attention, and language. Brain regions showing changes in the local gyrification index as calculated using FreeSurfer in relation to vitamin levels were used for subsequent seed-based resting-state functional connectivity analysis. For B6, a positive correlation with local cortical folding was found throughout the brain, while only slight changes in functional connectivity were observed. Contrarily, for B1, a negative correlation with cortical folding as well as problem solving and visuo-spatial working memory performance was found, which was accompanied by pronounced increases of interhemispheric and decreases of intrahemispheric functional connectivity. While the effects for B6 expand previous knowledge on beneficial effects of B6 supplementation on brain structure, they also showed that additional effects on cognition might not be recognizable in healthy older subjects with normal B6 blood levels. The cortical atrophy and pronounced functional reorganization associated with B1, contrarily, was more in line with the theory of a disturbed B1 metabolism in older adults, leading to B1 utilization deficits, and thus, an effective B1 deficiency in the brain, despite normal to high-normal blood levels. PMID:29163003

Indestructible plastic: the neuroscience of the new aging brain.

PubMed

Holman, Constance; de Villers-Sidani, Etienne

2014-01-01

In recent years, research on experience-dependent plasticity has provided valuable insight on adaptation to environmental input across the lifespan, and advances in understanding the minute cellular changes underlying the brain's capacity for self-reorganization have opened exciting new possibilities for treating illness and injury. Ongoing work in this line of inquiry has also come to deeply influence another field: cognitive neuroscience of the normal aging. This complex process, once considered inevitable or beyond the reach of treatment, has been transformed into an arena of intense investigation and strategic intervention. However, important questions remain about this characterization of the aging brain, and the assumptions it makes about the social, cultural, and biological space occupied by cognition in the older individual and body. The following paper will provide a critical examination of the move from basic experiments on the neurophysiology of experience-dependent plasticity to the growing market for (and public conception of) cognitive aging as a medicalized space for intervention by neuroscience-backed technologies. Entangled with changing concepts of normality, pathology, and self-preservation, we will argue that this new understanding, led by personalized cognitive training strategies, is approaching a point where interdisciplinary research is crucial to provide a holistic and nuanced understanding of the aging process. This new outlook will allow us to move forward in a space where our knowledge, like our new conception of the brain, is never static.

Gene expression changes in the course of normal brain aging are sexually dimorphic

PubMed Central

Berchtold, Nicole C.; Cribbs, David H.; Coleman, Paul D.; Rogers, Joseph; Head, Elizabeth; Kim, Ronald; Beach, Tom; Miller, Carol; Troncoso, Juan; Trojanowski, John Q.; Zielke, H. Ronald; Cotman, Carl W.

2008-01-01

Gene expression profiles were assessed in the hippocampus, entorhinal cortex, superior-frontal gyrus, and postcentral gyrus across the lifespan of 55 cognitively intact individuals aged 20–99 years. Perspectives on global gene changes that are associated with brain aging emerged, revealing two overarching concepts. First, different regions of the forebrain exhibited substantially different gene profile changes with age. For example, comparing equally powered groups, 5,029 probe sets were significantly altered with age in the superior-frontal gyrus, compared with 1,110 in the entorhinal cortex. Prominent change occurred in the sixth to seventh decades across cortical regions, suggesting that this period is a critical transition point in brain aging, particularly in males. Second, clear gender differences in brain aging were evident, suggesting that the brain undergoes sexually dimorphic changes in gene expression not only in development but also in later life. Globally across all brain regions, males showed more gene change than females. Further, Gene Ontology analysis revealed that different categories of genes were predominantly affected in males vs. females. Notably, the male brain was characterized by global decreased catabolic and anabolic capacity with aging, with down-regulated genes heavily enriched in energy production and protein synthesis/transport categories. Increased immune activation was a prominent feature of aging in both sexes, with proportionally greater activation in the female brain. These data open opportunities to explore age-dependent changes in gene expression that set the balance between neurodegeneration and compensatory mechanisms in the brain and suggest that this balance is set differently in males and females, an intriguing idea. PMID:18832152

Cerebrospinal Fluid Concentration of Key Autophagy Protein Lamp2 Changes Little During Normal Aging

PubMed Central

Loeffler, David A.; Klaver, Andrea C.; Coffey, Mary P.; Aasly, Jan O.

2018-01-01

Autophagy removes both functional and damaged intracellular macromolecules from cells via lysosomal degradation. Three autophagic mechanisms, namely macroautophagy, chaperone-mediated autophagy (CMA), and microautophagy, have been described in mammals. Studies in experimental systems have found macroautophagy and CMA to decrease with normal aging, despite the fact that oxidative stress, which can activate both processes, increases with normal aging. Whether autophagic mechanisms decrease in the human brain during normal aging is unclear. The primary objective of this study was to examine the association of a major autophagy protein, lysosome-associated membrane glycoprotein (lamp2), with age in cerebrospinal fluid (CSF) samples from healthy subjects. Lamp2 consists of three isoforms, lamp2a, 2b and 2c, all of which participate in autophagy. Lamp2’s CSF concentration decreases in Parkinson’s disease (PD) and increases in Alzheimer’s disease (AD), but whether its CSF concentration changes during normal aging has not been investigated. Our secondary objectives were to examine the associations of lamp2’s CSF concentration with CSF levels of the molecular chaperone heat shock 70-kDa protein (HSPA8), which interacts with lamp2a in CMA, and oxidative stress markers 8-hydroxy-2′-deoxyguanosine (8-OHdG), 8-isoprostane (8-ISO) and Total Antioxidant Capacity (TAC) in healthy subjects. We found lamp2’s observed associations with these variables to be weak, with all Kendall’s tau-b absolute values ≤0.20. These results suggest that CSF lamp2 concentration changes little during normal aging and does not appear to be associated with HSPA8 or oxidative stress. Further studies are indicated to determine the relationship between CSF lamp2 concentration and brain autophagic processes.

Phenotypic and gene expression modification with normal brain aging in GFAP-positive astrocytes and neural stem cells.

PubMed

Bernal, Giovanna M; Peterson, Daniel A

2011-06-01

Astrocytes secrete growth factors that are both neuroprotective and supportive for the local environment. Identified by glial fibrillary acidic protein (GFAP) expression, astrocytes exhibit heterogeneity in morphology and in the expression of phenotypic markers and growth factors throughout different adult brain regions. In adult neurogenic niches, astrocytes secrete vascular endothelial growth factor (VEGF) and fibroblast growth factor-2 (FGF-2) within the neurogenic niche and are also a source of special GFAP-positive multipotent neural stem cells (NSCs). Normal aging is accompanied by a decline in CNS function and reduced neurogenesis. We asked whether a decreased availability of astrocyte-derived factors may contribute to the age-related decline in neurogenesis. Determining alterations of astrocytic activity in the aging brain is crucial for understanding CNS homeostasis in aging and for assessing appropriate therapeutic targets for an aging population. We found region-specific alterations in the gene expression of GFAP, VEGF, and FGF-2 and their receptors in the aged brain corresponding to changes in astrocytic reactivity, supporting astrocytic heterogeneity and demonstrating a differential aging effect. We found that GFAP-positive NSCs uniquely coexpress both VEGF and its key mitotic receptor Flk-1 in both young and aged hippocampus, indicating a possible autocrine/paracrine signaling mechanism. VEGF expression is lost once NSCs commit to a neuronal fate, but Flk-1-mediated sensitivity to VEGF signaling is maintained. We propose that age-related astrocytic changes result in reduced VEGF and FGF-2 signaling, which in turn limits NSC and progenitor cell maintenance and contributes to decreased neurogenesis. © 2011 The Authors. Aging Cell © 2011 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.

Mitochondrial base excision repair in mouse synaptosomes during normal aging and in a model of Alzheimer’s disease

PubMed Central

Gredilla, Ricardo; Weissman, Lior; Yang, Jenq-Lin; Bohr, Vilhelm A.; Stevnsner, Tinna

2010-01-01

Brain aging is associated with synaptic decline and cognitive impairment. Increased levels of oxidative DNA base damage and accumulation of mitochondrial DNA (mtDNA) mutations or deletions lead to mitochondrial dysfunction, playing an important role in the aging process and the pathogenesis of neurodegenerative diseases such as Alzheimer’s disease (AD). In mitochondria, base excision repair (BER) is the main DNA repair pathway for base modifications such as deamination and oxidation, and constitutes an important mechanism to avoid accumulation of mtDNA mutations. Synaptic function is highly dependent on mitochondria, and in the current study we have investigated BER in synaptosomes of mouse brain during normal aging and in an AD model. Synaptosomes are isolated synapses in membranous structures produced by subcellular fractionation of brain tissue. They include the whole presynaptic terminal as well as portions of the postsynaptic terminal. Synaptosomes contain the molecular machinery necessary for uptake, storage, and release of neurotransmitters, including synaptic vesicles and mitochondria. BER activities were measured in synaptosomal fractions from young and old mice and from pre-symptomatic and symptomatic AD mice harboring mutated APP, Tau and PS1 (3xTgAD). During normal aging, a reduction in the BER capacity was observed in the synaptosomal fraction, which was associated with a decrease in the level of BER proteins. However, we did not observe changes between the synaptosomal BER activities of pre-symptomatic and symptomatic AD mice. Our findings suggest that the age-related reduction in BER capacity in the synaptosomal fraction might contribute to mitochondrial and synaptic dysfunction during aging. The development of AD-like pathology in the 3xTgAD mouse model was, however, not associated with deficiencies of the BER mechanisms in the synaptosomal fraction when the whole brain was analyzed. PMID:20708822

Constructing and assessing brain templates from Chinese pediatric MRI data using SPM

NASA Astrophysics Data System (ADS)

Yin, Qingjie; Ye, Qing; Yao, Li; Chen, Kewei; Jin, Zhen; Liu, Gang; Wu, Xingchun; Wang, Tingting

2005-04-01

Spatial normalization is a very important step in the processing of magnetic resonance imaging (MRI) data. So the quality of brain templates is crucial for the accuracy of MRI analysis. In this paper, using the classical protocol and the optimized protocol plus nonlinear deformation, we constructed the T1 whole brain templates and apriori brain tissue data from 69 Chinese pediatric MRI data (age 7-16 years). Then we proposed a new assessment method to evaluate our templates. 10 pediatric subjects were chosen to do the assessment as the following steps. First, the cerebellum region, the region of interest (ROI), was located on both the pediatric volume and the template volume by an experienced neuroanatomist. Second, the pediatric whole brain was mapped to the template with affine and nonlinear deformation. Third, the parameter, derived from the second step, was used to only normalize the ROI of the child to the ROI of the template. Last, the overlapping ratio, which described the overlapping rate between the ROI of the template and the normalized ROI of the child, was calculated. The mean of overlapping ratio normalized to the classical template was 0.9687, and the mean normalized to the optimized template was 0.9713. The results show that the two Chinese pediatric brain templates are comparable and their accuracy is adequate to our studies.

Brain white matter development is associated with a human-specific haplotype increasing the synthesis of long chain fatty acids.

PubMed

Peters, Bart D; Voineskos, Aristotle N; Szeszko, Philip R; Lett, Tristram A; DeRosse, Pamela; Guha, Saurav; Karlsgodt, Katherine H; Ikuta, Toshikazu; Felsky, Daniel; John, Majnu; Rotenberg, David J; Kennedy, James L; Lencz, Todd; Malhotra, Anil K

2014-04-30

The genetic and molecular pathways driving human brain white matter (WM) development are only beginning to be discovered. Long chain polyunsaturated fatty acids (LC-PUFAs) have been implicated in myelination in animal models and humans. The biosynthesis of LC-PUFAs is regulated by the fatty acid desaturase (FADS) genes, of which a human-specific haplotype is strongly associated with ω-3 and ω-6 LC-PUFA concentrations in blood. To investigate the relationship between LC-PUFA synthesis and human brain WM development, we examined whether this FADS haplotype is associated with age-related WM differences across the life span in healthy individuals 9-86 years of age (n = 207). Diffusion tensor imaging was performed to measure fractional anisotropy (FA), a putative measure of myelination, of the cerebral WM tracts. FADS haplotype status was determined with a single nucleotide polymorphism (rs174583) that tags this haplotype. Overall, normal age-related WM differences were observed, including higher FA values in early adulthood compared with childhood, followed by lower FA values across older age ranges. However, individuals homozygous for the minor allele (associated with lower LC-PUFA concentrations) did not display these normal age-related WM differences (significant age × genotype interactions, p(corrected) < 0.05). These findings suggest that LC-PUFAs are involved in human brain WM development from childhood into adulthood. This haplotype and LC-PUFAs may play a role in myelin-related disorders of neurodevelopmental origin.

A methodological approach to studying resilience mechanisms: demonstration of utility in age and Alzheimer's disease-related brain pathology.

PubMed

Wolf, Dominik; Fischer, Florian Udo; Fellgiebel, Andreas

2018-05-01

The present work aims at providing a methodological approach for the investigation of resilience factors and mechanisms in normal aging, Alzheimer's disease (AD) and other neurodegenerative disorders. By expanding and re-conceptualizing traditional regression approaches, we propose an approach that not only aims at identifying potential resilience factors but also allows for a differentiation between general and dynamic resilience factors in terms of their association with pathology. Dynamic resilience factors are characterized by an increasing relevance with increasing levels of pathology, while the relevance of general resilience factors is independent of the amount of pathology. Utility of the approach is demonstrated in age and AD-related brain pathology by investigating widely accepted resilience factors, including education and brain volume. Moreover, the approach is used to test hippocampal volume as potential resilience factor. Education and brain volume could be identified as general resilience factors against age and AD-related pathology. Beyond that, analyses highlighted that hippocampal volume may not only be disease target but also serve as a potential resilience factor in age and AD-related pathology, particularly at higher levels of tau-pathology (i.e. dynamic resilience factor). Given its unspecific and superordinate nature the approach is suitable for the investigation of a wide range of potential resilience factors in normal aging, AD and other neurodegenerative disorders. Consequently, it may find a wide application and thereby promote the comparability between studies.

Brain and retinal ferroportin 1 dysregulation in polycythaemia mice.

PubMed

Iacovelli, Jared; Mlodnicka, Agnieska E; Veldman, Peter; Ying, Gui-Shuang; Dunaief, Joshua L; Schumacher, Armin

2009-09-15

Disruption of iron homeostasis within the central nervous system (CNS) can lead to profound abnormalities during both development and aging in mammals. The radiation-induced polycythaemia (Pcm) mutation, a 58-bp microdeletion in the promoter region of ferroportin 1 (Fpn1), disrupts transcriptional and post-transcriptional regulation of this pivotal iron transporter. This regulatory mutation induces dynamic alterations in peripheral iron homeostasis such that newborn homozygous Pcm mice exhibit iron deficiency anemia with increased duodenal Fpn1 expression while adult homozygotes display decreased Fpn1 expression and anemia despite organismal iron overload. Herein we report the impact of the Pcm microdeletion on iron homeostasis in two compartments of the central nervous system: brain and retina. At birth, Pcm homozygotes show a marked decrease in brain iron content and reduced levels of Fpn1 expression. Upregulation of transferrin receptor 1 (TfR1) in brain microvasculature appears to mediate the compensatory iron uptake during postnatal development and iron content in Pcm brain is restored to wild-type levels by 7 weeks of age. Similarly, changes in expression are transient and expression of Fpn1 and TfR1 is indistinguishable between Pcm homozygotes and wild-type by 12 weeks of age. Strikingly, the adult Pcm brain is effectively protected from the peripheral iron overload and maintains normal iron content. In contrast to Fpn1 downregulation in perinatal brain, the retina of Pcm homozygotes reveals increased levels of Fpn1 expression. While retinal morphology appears normal at birth and during early postnatal development, adult Pcm mice demonstrate a marked, age-dependent loss of photoreceptors. This phenotype demonstrates the importance of iron homeostasis in retinal health.

Brain and retinal ferroportin 1 dysregulation in polycythaemia mice

PubMed Central

Iacovelli, Jared; Mlodnicka, Agnieska E.; Veldman, Peter; Ying, Gui-Shuang; Dunaief, Joshua L.; Schumacher, Armin

2009-01-01

Disruption of iron homeostatsis within the central nervous system (CNS) can lead to profound abnormalities during both development and aging in mammals. The radiation-induced polycythaemia (Pcm) mutation, a 58-bp microdeletion in the promoter region of ferroportin 1 (Fpn1), disrupts transcriptional and post-transcriptional regulation of this pivotal iron transporter. This regulatory mutation induces dynamic alterations in peripheral iron homeostatis such that newborn homozygous Pcm mice exhibit iron deficiency anemia with increased duodenal Fpn1 expression while adult homozygotes display decreased Fpn1 expression and anemia despite organismal iron overload. Herein we report the impact of the Pcm microdeletion on iron homeostasis in two compartments of the the central nervous system: brain and retina. At birth, Pcm homozygotes show a marked decrease in brain iron content and reduced levels of Fpn1 expression. Upregulation of transferrin receptor 1 (TfR1) in brain microvasculature appears to mediate the compensatory iron uptake during postnatal development and iron content in Pcm brain is restored to wildtype levels by 7 weeks of age. Similarly, changes in expression are transient and expression of Fpn1 and TfR1 is indistinguishable between Pcm homozygotes and wildtype by 12 weeks of age. Strikingly, the adult Pcm brain is effectively protected from the peripheral iron overload and maintains normal iron content. In contrast to Fpn1 downregulation in perinatal brain, the retina of Pcm homozygotes reveals increased levels of Fpn1 expression. While retinal morphology appears normal at birth and during early postnatal development, adult Pcm mice demonstrate a marked, age-dependent loss of photoreceptors. This phenotype demonstrates the importance of iron homeostasis in retinal health. PMID:19596281

Putting age-related task activation into large-scale brain networks: A meta-analysis of 114 fMRI studies on healthy aging.

PubMed

Li, Hui-Jie; Hou, Xiao-Hui; Liu, Han-Hui; Yue, Chun-Lin; Lu, Guang-Ming; Zuo, Xi-Nian

2015-10-01

Normal aging is associated with cognitive decline and underlying brain dysfunction. Previous studies concentrated less on brain network changes at a systems level. Our goal was to examine these age-related changes of fMRI-derived activation with a common network parcellation of the human brain function, offering a systems-neuroscience perspective of healthy aging. We conducted a series of meta-analyses on a total of 114 studies that included 2035 older adults and 1845 young adults. Voxels showing significant age-related changes in activation were then overlaid onto seven commonly referenced neuronal networks. Older adults present moderate cognitive decline in behavioral performance during fMRI scanning, and hypo-activate the visual network and hyper-activate both the frontoparietal control and default mode networks. The degree of increased activation in frontoparietal network was associated with behavioral performance in older adults. Age-related changes in activation present different network patterns across cognitive domains. The systems neuroscience approach used here may be useful for elucidating the underlying network mechanisms of various brain plasticity processes during healthy aging. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

TOR on the Brain

PubMed Central

Garelick, Michael G.; Kennedy, Brian K.

2012-01-01

Signaling by target of rapamycin (mTOR in mammals) has been shown to modulate lifespan in several model organisms ranging from yeast to mice. In mice, reduced mTOR signaling by chronic rapamycin treatment leads to lifespan extension, raising the possibility that rapamycin and its analogs may benefit the aging brain and serve as effective treatments of age-related neurodegenerative diseases. Here, we review mTOR signaling and how neurons utilize mTOR to regulate brain function, including regulation of feeding, synaptic plasticity and memory formation. Additionally, we discuss recent findings that evaluate the mechanisms by which reduced mTOR activity might benefit the aging brain in normal and pathological states. We will focus on recent studies investigating mTOR and Alzheimer s disease, Parkinson s disease, and polyglutamine expansion syndromes such as Huntington s disease. PMID:20849946

Changes in neurocranium thickness in early childhood

NASA Astrophysics Data System (ADS)

Gajawelli, Niharika; Deoni, Sean; Shi, Jie; Xu, Liang; Dirks, Holly; Dean, Douglas; O'Muircheartaigh, Jonathan; Sawardekar, Siddhant; Ezis, Andrea; Nelson, Marvin D.; Wang, Yalin; Lepore, Natasha

2015-12-01

Several developmental disorders involve shape abnormalities of the neurocranium, the most common one being craniosynostosis, that affects about 1 in 2000 infants. A key step in determining how these disorders affect neurodevelopment is to establish how the brain and neurocranium co-evolve in the normally developing child. However, due to the scarcity of normally developing infant and pediatric imaging data, there have been a lack of imaging studies pertaining to normal neurocranial development. Here, taking advantage of a large data bank of high quality brain MRI from healthy children ages 0-4 years old, and of a novel conformal geometry-based analysis pipeline, we have been determining a set of statistical atlases of the neurocranium, divided into age groups. In this first part of the study, we focus more specifically on a comparison of 1 and 2 year old infants. Characterizing neurocranium shape changes will enable us to understand how the cranial bones develop in relation to brain development. This in turn will allow a better determination of the effects of neurocranial disorders, which will help inform treatment strategies.

Normative biometry of the fetal brain using magnetic resonance imaging.

PubMed

Kyriakopoulou, Vanessa; Vatansever, Deniz; Davidson, Alice; Patkee, Prachi; Elkommos, Samia; Chew, Andrew; Martinez-Biarge, Miriam; Hagberg, Bibbi; Damodaram, Mellisa; Allsop, Joanna; Fox, Matt; Hajnal, Joseph V; Rutherford, Mary A

2017-07-01

The fetal brain shows accelerated growth in the latter half of gestation, and these changes can be captured by 2D and 3D biometry measurements. The aim of this study was to quantify brain growth in normal fetuses using Magnetic Resonance Imaging (MRI) and to produce reference biometry data and a freely available centile calculator ( https://www.developingbrain.co.uk/fetalcentiles/ ). A total of 127 MRI examinations (1.5 T) of fetuses with a normal brain appearance (21-38 gestational weeks) were included in this study. 2D and 3D biometric parameters were measured from slice-to-volume reconstructed images, including 3D measurements of supratentorial brain tissue, lateral ventricles, cortex, cerebellum and extra-cerebral CSF and 2D measurements of brain biparietal diameter and fronto-occipital length, skull biparietal diameter and occipitofrontal diameter, head circumference, transverse cerebellar diameter, extra-cerebral CSF, ventricular atrial diameter, and vermis height, width, and area. Centiles were constructed for each measurement. All participants were invited for developmental follow-up. All 2D and 3D measurements, except for atrial diameter, showed a significant positive correlation with gestational age. There was a sex effect on left and total lateral ventricular volumes and the degree of ventricular asymmetry. The 5th, 50th, and 95th centiles and a centile calculator were produced. Developmental follow-up was available for 73.1% of cases [mean chronological age 27.4 (±10.2) months]. We present normative reference charts for fetal brain MRI biometry at 21-38 gestational weeks. Developing growth trajectories will aid in the better understanding of normal fetal brain growth and subsequently of deviations from typical development in high-risk pregnancies or following premature delivery.

Clinical Relevance of Discourse Characteristics after Right Hemisphere Brain Damage

ERIC Educational Resources Information Center

Blake, Margaret Lehman

2006-01-01

Purpose: Discourse characteristics of adults with right hemisphere brain damage are similar to those reported for healthy older adults, prompting the question of whether changes are due to neurological lesions or normal aging processes. The clinical relevance of potential differences across groups was examined through ratings by speech-language…

Fluid intelligence and brain functional organization in aging yoga and meditation practitioners

PubMed Central

Gard, Tim; Taquet, Maxime; Dixit, Rohan; Hölzel, Britta K.; de Montjoye, Yves-Alexandre; Brach, Narayan; Salat, David H.; Dickerson, Bradford C.; Gray, Jeremy R.; Lazar, Sara W.

2014-01-01

Numerous studies have documented the normal age-related decline of neural structure, function, and cognitive performance. Preliminary evidence suggests that meditation may reduce decline in specific cognitive domains and in brain structure. Here we extended this research by investigating the relation between age and fluid intelligence and resting state brain functional network architecture using graph theory, in middle-aged yoga and meditation practitioners, and matched controls. Fluid intelligence declined slower in yoga practitioners and meditators combined than in controls. Resting state functional networks of yoga practitioners and meditators combined were more integrated and more resilient to damage than those of controls. Furthermore, mindfulness was positively correlated with fluid intelligence, resilience, and global network efficiency. These findings reveal the possibility to increase resilience and to slow the decline of fluid intelligence and brain functional architecture and suggest that mindfulness plays a mechanistic role in this preservation. PMID:24795629

Positron Emission Tomography Reveals Abnormal Topological Organization in Functional Brain Network in Diabetic Patients.

PubMed

Qiu, Xiangzhe; Zhang, Yanjun; Feng, Hongbo; Jiang, Donglang

2016-01-01

Recent studies have demonstrated alterations in the topological organization of structural brain networks in diabetes mellitus (DM). However, the DM-related changes in the topological properties in functional brain networks are unexplored so far. We therefore used fluoro-D-glucose positron emission tomography (FDG-PET) data to construct functional brain networks of 73 DM patients and 91 sex- and age-matched normal controls (NCs), followed by a graph theoretical analysis. We found that both DM patients and NCs had a small-world topology in functional brain network. In comparison to the NC group, the DM group was found to have significantly lower small-world index, lower normalized clustering coefficients and higher normalized characteristic path length. Moreover, for diabetic patients, the nodal centrality was significantly reduced in the right rectus, the right cuneus, the left middle occipital gyrus, and the left postcentral gyrus, and it was significantly increased in the orbitofrontal region of the left middle frontal gyrus, the left olfactory region, and the right paracentral lobule. Our results demonstrated that the diabetic brain was associated with disrupted topological organization in the functional PET network, thus providing functional evidence for the abnormalities of brain networks in DM.

Caspase inhibition in select olfactory neurons restores innate attraction behavior in aged Drosophila.

PubMed

Chihara, Takahiro; Kitabayashi, Aki; Morimoto, Michie; Takeuchi, Ken-ichi; Masuyama, Kaoru; Tonoki, Ayako; Davis, Ronald L; Wang, Jing W; Miura, Masayuki

2014-06-01

Sensory and cognitive performance decline with age. Neural dysfunction caused by nerve death in senile dementia and neurodegenerative disease has been intensively studied; however, functional changes in neural circuits during the normal aging process are not well understood. Caspases are key regulators of cell death, a hallmark of age-related neurodegeneration. Using a genetic probe for caspase-3-like activity (DEVDase activity), we have mapped age-dependent neuronal changes in the adult brain throughout the lifespan of Drosophila. Spatio-temporally restricted caspase activation was observed in the antennal lobe and ellipsoid body, brain structures required for olfaction and visual place memory, respectively. We also found that caspase was activated in an age-dependent manner in specific subsets of Drosophila olfactory receptor neurons (ORNs), Or42b and Or92a neurons. These neurons are essential for mediating innate attraction to food-related odors. Furthermore, age-induced impairments of neural transmission and attraction behavior could be reversed by specific inhibition of caspase in these ORNs, indicating that caspase activation in Or42b and Or92a neurons is responsible for altering animal behavior during normal aging.

Synaptic genes are extensively downregulated across multiple brain regions in normal human aging and Alzheimer’s disease

PubMed Central

Berchtold, Nicole C.; Coleman, Paul D.; Cribbs, David H.; Rogers, Joseph; Gillen, Daniel L.; Cotman, Carl W.

2014-01-01

Synapses are essential for transmitting, processing, and storing information, all of which decline in aging and Alzheimer’s disease (AD). Because synapse loss only partially accounts for the cognitive declines seen in aging and AD, we hypothesized that existing synapses might undergo molecular changes that reduce their functional capacity. Microarrays were used to evaluate expression profiles of 340 synaptic genes in aging (20–99 years) and AD across 4 brain regions from 81 cases. The analysis revealed an unexpectedly large number of significant expression changes in synapse-related genes in aging, with many undergoing progressive downregulation across aging and AD. Functional classification of the genes showing altered expression revealed that multiple aspects of synaptic function are affected, notably synaptic vesicle trafficking and release, neurotransmitter receptors and receptor trafficking, postsynaptic density scaffolding, cell adhesion regulating synaptic stability, and neuromodulatory systems. The widespread declines in synaptic gene expression in normal aging suggests that function of existing synapses might be impaired, and that a common set of synaptic genes are vulnerable to change in aging and AD. PMID:23273601

ERP C250 shows the elderly (cognitively normal, Alzheimer's disease) store more stimuli in short-term memory than Young Adults do.

PubMed

Chapman, Robert M; Gardner, Margaret N; Mapstone, Mark; Klorman, Rafael; Porsteinsson, Anton P; Dupree, Haley M; Antonsdottir, Inga M; Kamalyan, Lily

2016-06-01

To determine how aging and dementia affect the brain's initial storing of task-relevant and irrelevant information in short-term memory. We used brain Event-Related Potentials (ERPs) to measure short-term memory storage (ERP component C250) in 36 Young Adults, 36 Normal Elderly, and 36 early-stage AD subjects. Participants performed the Number-Letter task, a cognitive paradigm requiring memory storage of a first relevant stimulus to compare it with a second stimulus. In Young Adults, C250 was more positive for the first task-relevant stimulus compared to all other stimuli. C250 in Normal Elderly and AD subjects was roughly the same to relevant and irrelevant stimuli in Intratrial Parts 1-3 but not 4. The AD group had lower C250 to relevant stimuli in part 1. Both normal aging and dementia cause less differentiation of relevant from irrelevant information in initial storage. There was a large aging effect involving differences in the pattern of C250 responses of the Young Adult versus the Normal Elderly/AD groups. Also, a potential dementia effect was obtained. C250 is a candidate tool for measuring short-term memory performance on a biological level, as well as a potential marker for memory changes due to normal aging and dementia. Copyright © 2016 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

The Aging of Iron Man

PubMed Central

Ashraf, Azhaar; Clark, Maryam; So, Po-Wah

2018-01-01

Brain iron is tightly regulated by a multitude of proteins to ensure homeostasis. Iron dyshomeostasis has become a molecular signature associated with aging which is accompanied by progressive decline in cognitive processes. A common theme in neurodegenerative diseases where age is the major risk factor, iron dyshomeostasis coincides with neuroinflammation, abnormal protein aggregation, neurodegeneration, and neurobehavioral deficits. There is a great need to determine the mechanisms governing perturbations in iron metabolism, in particular to distinguish between physiological and pathological aging to generate fruitful therapeutic targets for neurodegenerative diseases. The aim of the present review is to focus on the age-related alterations in brain iron metabolism from a cellular and molecular biology perspective, alongside genetics, and neuroimaging aspects in man and rodent models, with respect to normal aging and neurodegeneration. In particular, the relationship between iron dyshomeostasis and neuroinflammation will be evaluated, as well as the effects of systemic iron overload on the brain. Based on the evidence discussed here, we suggest a synergistic use of iron-chelators and anti-inflammatories as putative anti-brain aging therapies to counteract pathological aging in neurodegenerative diseases. PMID:29593525

Analysis of alternative splicing associated with aging and neurodegeneration in the human brain

PubMed Central

Tollervey, James R.; Wang, Zhen; Hortobágyi, Tibor; Witten, Joshua T.; Zarnack, Kathi; Kayikci, Melis; Clark, Tyson A.; Schweitzer, Anthony C.; Rot, Gregor; Curk, Tomaž; Zupan, Blaž; Rogelj, Boris; Shaw, Christopher E.; Ule, Jernej

2011-01-01

Age is the most important risk factor for neurodegeneration; however, the effects of aging and neurodegeneration on gene expression in the human brain have most often been studied separately. Here, we analyzed changes in transcript levels and alternative splicing in the temporal cortex of individuals of different ages who were cognitively normal, affected by frontotemporal lobar degeneration (FTLD), or affected by Alzheimer's disease (AD). We identified age-related splicing changes in cognitively normal individuals and found that these were present also in 95% of individuals with FTLD or AD, independent of their age. These changes were consistent with increased polypyrimidine tract binding protein (PTB)–dependent splicing activity. We also identified disease-specific splicing changes that were present in individuals with FTLD or AD, but not in cognitively normal individuals. These changes were consistent with the decreased neuro-oncological ventral antigen (NOVA)–dependent splicing regulation, and the decreased nuclear abundance of NOVA proteins. As expected, a dramatic down-regulation of neuronal genes was associated with disease, whereas a modest down-regulation of glial and neuronal genes was associated with aging. Whereas our data indicated that the age-related splicing changes are regulated independently of transcript-level changes, these two regulatory mechanisms affected expression of genes with similar functions, including metabolism and DNA repair. In conclusion, the alternative splicing changes identified in this study provide a new link between aging and neurodegeneration. PMID:21846794

Lower cognitive reserve in the aging human immunodeficiency virus-infected brain.

PubMed

Chang, Linda; Holt, John L; Yakupov, Renat; Jiang, Caroline S; Ernst, Thomas

2013-04-01

More HIV-infected individuals are living longer; however, how their brain function is affected by aging is not well understood. One hundred twenty-two men (56 seronegative control [SN] subjects, 37 HIV subjects with normal cognition [HIV+NC], 29 with HIV-associated neurocognitive disorder [HAND]) performed neuropsychological tests and had acceptable functional magnetic resonance imaging scans at 3 Tesla during tasks with increasing attentional load. With older age, SN and HIV+NC subjects showed increased activation in the left posterior (reserve, "bottom-up") attention network for low attentional-load tasks, and further increased activation in the left posterior and anterior ("top-down") attention network on intermediate (HIV+NC only) and high attentional-load tasks. HAND subjects had only age-dependent decreases in activation. Age-dependent changes in brain activation differed between the 3 groups, primarily in the left frontal regions (despite similar brain atrophy). HIV and aging act synergistically or interactively to exacerbate brain activation abnormalities in different brain regions, suggestive of a neuroadaptive mechanism in the attention network to compensate for declined neural efficiency. While the SN and HIV+NC subjects compensated for their declining attention with age by using reserve and "top-down" attentional networks, older HAND subjects were unable to compensate which resulted in cognitive decline. Copyright © 2013 Elsevier Inc. All rights reserved.

The Impact of Traumatic Brain Injury on Later Life: Effects on Normal Aging and Neurodegenerative Diseases.

PubMed

Griesbach, Grace S; Masel, Brent E; Helvie, Richard E; Ashley, Mark J

2018-01-01

The acute and chronic effects of traumatic brain injury (TBI) have been widely described; however, there is limited knowledge on how a TBI sustained during early adulthood or mid-adulthood will influence aging. Epidemiological studies have explored whether TBI poses a risk for dementia and other neurodegenerative diseases associated with aging. We will discuss the influence of TBI and resulting medical comorbidities such as endocrine, sleep, and inflammatory disturbances on age-related gray and white matter changes and cognitive decline. Post mortem studies examining amyloid, tau, and other proteins will be discussed within the context of neurodegenerative diseases and chronic traumatic encephalopathy. The data support the suggestion that pathological changes triggered by an earlier TBI will have an influence on normal aging processes and will interact with neurodegenerative disease processes rather than the development of a specific disease, such as Alzheimer's or Parkinson's. Chronic neurophysiologic change after TBI may have detrimental effects on neurodegenerative disease.

Age-specific MRI templates for pediatric neuroimaging

PubMed Central

Sanchez, Carmen E.; Richards, John E.; Almli, C. Robert

2012-01-01

This study created a database of pediatric age-specific MRI brain templates for normalization and segmentation. Participants included children from 4.5 through 19.5 years, totaling 823 scans from 494 subjects. Open-source processing programs (FSL, SPM, ANTS) constructed head, brain and segmentation templates in 6 month intervals. The tissue classification (WM, GM, CSF) showed changes over age similar to previous reports. A volumetric analysis of age-related changes in WM and GM based on these templates showed expected increase/decrease pattern in GM and an increase in WM over the sampled ages. This database is available for use for neuroimaging studies (blindedforreview). PMID:22799759

Role of Estrogen and Other Sex Hormones in Brain Aging. Neuroprotection and DNA Repair

PubMed Central

Zárate, Sandra; Stevnsner, Tinna; Gredilla, Ricardo

2017-01-01

Aging is an inevitable biological process characterized by a progressive decline in physiological function and increased susceptibility to disease. The detrimental effects of aging are observed in all tissues, the brain being the most important one due to its main role in the homeostasis of the organism. As our knowledge about the underlying mechanisms of brain aging increases, potential approaches to preserve brain function rise significantly. Accumulating evidence suggests that loss of genomic maintenance may contribute to aging, especially in the central nervous system (CNS) owing to its low DNA repair capacity. Sex hormones, particularly estrogens, possess potent antioxidant properties and play important roles in maintaining normal reproductive and non-reproductive functions. They exert neuroprotective actions and their loss during aging and natural or surgical menopause is associated with mitochondrial dysfunction, neuroinflammation, synaptic decline, cognitive impairment and increased risk of age-related disorders. Moreover, loss of sex hormones has been suggested to promote an accelerated aging phenotype eventually leading to the development of brain hypometabolism, a feature often observed in menopausal women and prodromal Alzheimer’s disease (AD). Although data on the relation between sex hormones and DNA repair mechanisms in the brain is still limited, various investigations have linked sex hormone levels with different DNA repair enzymes. Here, we review estrogen anti-aging and neuroprotective mechanisms, which are currently an area of intense study, together with the effect they may have on the DNA repair capacity in the brain. PMID:29311911

Microglia During Development and Aging

PubMed Central

Harry, G. Jean

2013-01-01

Microglia are critical nervous system-specific cells influencing brain development, maintenance of the neural environment, response to injury, and repair. They contribute to neuronal proliferation and differentiation, pruning of dying neurons, synaptic remodeling and clearance of debris and aberrant proteins. Colonization of the brain occurs during gestation with an expansion following birth with localization stimulated by programmed neuronal death, synaptic pruning, andaxonal degeneration. Changes inmicroglia phenotype relate to cellular processes including specific neurotransmitter, pattern recognition, or immune-related receptor activation. Upon activation, microglia cells have the capacity to release a number of substances, e.g., cytokines, chemokines, nitric oxide, and reactive oxygen species, which could be detrimental or beneficial to the surrounding cells. With aging, microglia shift their morphology and may display diminished capacity for normal functions related to migration, clearance, and the ability to shift from a pro-inflammatory to an anti-inflammatory state to regulate injury and repair. This shift in microgliapotentially contributes to increased susceptibility and neurodegeneration as a function of age. In the current review, information is provided on the colonization of the brain by microglia, the expression of various pattern recognition receptors to regulate migration and phagocytosis, and the shift in related functions that occur in normal aging. PMID:23644076

Gyrification brain abnormalities associated with adolescence and early-adulthood cannabis use.

PubMed

Mata, Ignacio; Perez-Iglesias, Rocio; Roiz-Santiañez, Roberto; Tordesillas-Gutierrez, Diana; Pazos, Angel; Gutierrez, Agustin; Vazquez-Barquero, Jose Luis; Crespo-Facorro, Benedicto

2010-03-04

Although cannabis is the most widely used illicit drug in the world, the long-term effect of its use in the brain remains controversial. In order to determine whether adolescence and early-adulthood cannabis use is associated with gross volumetric and gyrification abnormalities in the brain, we set up a cross-sectional study using structural magnetic resonance imaging in a sample of general population subjects. Thirty cannabis-using subjects (mean age, 25.7 years; mean duration of regular use, 8.4 years, range: 3-21) with no history of polydrug use or neurologic/mental disorder and 44 non-using control subjects (mean age, 25.8 years) were included. Cannabis users showed bilaterally decreased concavity of the sulci and thinner sulci in the right frontal lobe. Among non-users, age was significantly correlated with decreased gyrification (i.e., less concave sulci and more convexe gyri) and decreased cortical thickness, supporting the notion of age-related gyrification changes. However, among cannabis users gyrification indices did not show significant dependency on age, age of regular cannabis use initiation, or cumulative exposure to cannabis. These results suggest that cannabis use in adolescence and early-adulthood might involve a premature alteration in cortical gyrification similar to what is normally observed at a later age, probably through disruption of normal neurodevelopment. 2009 Elsevier B.V. All rights reserved.

Dopamine transporter availability in clinically normal aging is associated with individual differences in white matter integrity.

PubMed

Rieckmann, Anna; Hedden, Trey; Younger, Alayna P; Sperling, Reisa A; Johnson, Keith A; Buckner, Randy L

2016-02-01

Aging-related differences in white matter integrity, the presence of amyloid plaques, and density of biomarkers indicative of dopamine functions can be detected and quantified with in vivo human imaging. The primary aim of the present study was to investigate whether these imaging-based measures constitute independent imaging biomarkers in older adults, which would speak to the hypothesis that the aging brain is characterized by multiple independent neurobiological cascades. We assessed MRI-based markers of white matter integrity and PET-based marker of dopamine transporter density and amyloid deposition in the same set of 53 clinically normal individuals (age 65-87). A multiple regression analysis demonstrated that dopamine transporter availability is predicted by white matter integrity, which was detectable even after controlling for chronological age. Further post-hoc exploration revealed that dopamine transporter availability was further associated with systolic blood pressure, mirroring the established association between cardiovascular health and white matter integrity. Dopamine transporter availability was not associated with the presence of amyloid burden. Neurobiological correlates of dopamine transporter measures in aging are therefore likely unrelated to Alzheimer's disease but are aligned with white matter integrity and cardiovascular risk. More generally, these results suggest that two common imaging markers of the aging brain that are typically investigated separately do not reflect independent neurobiological processes. Hum Brain Mapp 37:621-631, 2016. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.

Age Related Changes in Metabolite Concentrations in the Normal Spinal Cord

PubMed Central

Abdel-Aziz, Khaled; Solanky, Bhavana S.; Yiannakas, Marios C.; Altmann, Daniel R.; Wheeler-Kingshott, Claudia A. M.; Thompson, Alan J.; Ciccarelli, Olga

2014-01-01

Magnetic resonance spectroscopy (MRS) studies have previously described metabolite changes associated with aging of the healthy brain and provided insights into normal brain aging that can assist us in differentiating age-related changes from those associated with neurological disease. The present study investigates whether age-related changes in metabolite concentrations occur in the healthy cervical spinal cord. 25 healthy volunteers, aged 23–65 years, underwent conventional imaging and single-voxel MRS of the upper cervical cord using an optimised point resolved spectroscopy sequence on a 3T Achieva system. Metabolite concentrations normalised to unsuppressed water were quantified using LCModel and associations between age and spinal cord metabolite concentrations were examined using multiple regressions. A linear decline in total N-Acetyl-aspartate concentration (0.049 mmol/L lower per additional year of age, p = 0.010) and Glutamate-Glutamine concentration (0.054 mmol/L lower per additional year of age, p = 0.002) was seen within our sample age range, starting in the early twenties. The findings suggest that neuroaxonal loss and/or metabolic neuronal dysfunction, and decline in glutamate-glutamine neurotransmitter pool progress with aging. PMID:25310093

Can physical exercise in old age improve memory and hippocampal function?

PubMed Central

van Praag, Henriette; Sendtner, Michael

2016-01-01

Abstract Physical exercise can convey a protective effect against cognitive decline in ageing and Alzheimer’s disease. While the long-term health-promoting and protective effects of exercise are encouraging, it’s potential to induce neuronal and vascular plasticity in the ageing brain is still poorly understood. It remains unclear whether exercise slows the trajectory of normal ageing by modifying vascular and metabolic risk factors and/or consistently boosts brain function by inducing structural and neurochemical changes in the hippocampus and related medial temporal lobe circuitry—brain areas that are important for learning and memory. Hence, it remains to be established to what extent exercise interventions in old age can improve brain plasticity above and beyond preservation of function. Existing data suggest that exercise trials aiming for improvement and preservation may require different outcome measures and that the balance between the two may depend on exercise intensity and duration, the presence of preclinical Alzheimer’s disease pathology, vascular and metabolic risk factors and genetic variability. PMID:26912638

Pharmacologic approaches to cerebral aging and neuroplasticity: insights from the stroke model.

PubMed

Chollet, François

2013-03-01

Brain plasticity is an intrinsic characteristic of the nervous system that allows continuous remodeling of brain functions in pathophysiological conditions. Although normal aging is associated with morphological modifications and decline of cerebral functions, brain plasticity is at least partially preserved in elderly individuals. A growing body of evidence supports the notion that cognitive enrichment and aerobic training induce a dynamic reorganization of higher cerebral functions, thereby helping to maintain operational skills in the elderly and reducing the incidence of dementia. The stroke model clearly shows that spontaneous brain plasticity exists after a lesion, even in old patients, and that it can be modulated through external factors like rehabilitation and drugs. Whether drugs can be used with the aim of modulating the effects of physical training or cognitive stimulation in healthy aged people has not been addressed until now. The risk:benefit ratio will be the key question with regard to the ethical aspect of this challenge. We review in this article the main aspects of human brain plasticity as shown in patients with stroke, the drug modulation of brain plasticity and its consequences on recovery, and finally we address the question of the influence of aging on brain plasticity.

Human brain networks in physiological aging: a graph theoretical analysis of cortical connectivity from EEG data.

PubMed

Vecchio, Fabrizio; Miraglia, Francesca; Bramanti, Placido; Rossini, Paolo Maria

2014-01-01

Modern analysis of electroencephalographic (EEG) rhythms provides information on dynamic brain connectivity. To test the hypothesis that aging processes modulate the brain connectivity network, EEG recording was conducted on 113 healthy volunteers. They were divided into three groups in accordance with their ages: 36 Young (15-45 years), 46 Adult (50-70 years), and 31 Elderly (>70 years). To evaluate the stability of the investigated parameters, a subgroup of 10 subjects underwent a second EEG recording two weeks later. Graph theory functions were applied to the undirected and weighted networks obtained by the lagged linear coherence evaluated by eLORETA on cortical sources. EEG frequency bands of interest were: delta (2-4 Hz), theta (4-8 Hz), alpha1 (8-10.5 Hz), alpha2 (10.5-13 Hz), beta1 (13-20 Hz), beta2 (20-30 Hz), and gamma (30-40 Hz). The spectral connectivity analysis of cortical sources showed that the normalized Characteristic Path Length (λ) presented the pattern Young > Adult>Elderly in the higher alpha band. Elderly also showed a greater increase in delta and theta bands than Young. The correlation between age and λ showed that higher ages corresponded to higher λ in delta and theta and lower in the alpha2 band; this pattern reflects the age-related modulation of higher (alpha) and decreased (delta) connectivity. The Normalized Clustering coefficient (γ) and small-world network modeling (σ) showed non-significant age-modulation. Evidence from the present study suggests that graph theory can aid in the analysis of connectivity patterns estimated from EEG and can facilitate the study of the physiological and pathological brain aging features of functional connectivity networks.

Neurodevelopmental Versus Neurodegenerative Model of Schizophrenia and Bipolar Disorder: Comparison with Physiological Brain Development and Aging.

PubMed

Buoli, Massimiliano; Serati, Marta; Caldiroli, Alice; Cremaschi, Laura; Altamura, Alfredo Carlo

2017-03-01

Available data support a contribution of both neurodevelopmental and neurodegenerative factors in the etiology of schizophrenia (SCH) and bipolar disorder (BD). Of note, one of the most important issue of the current psychiatric research is to identify the specific factors that contribute to impaired brain development and neurodegeneration in SCH and BD, and especially how these factors alter normal brain development and physiological aging process. Our hypothesis is that only specific damages, taking place in precise brain development stages, are associated with future SCH /BD onset and that neurodegeneration consists of an acceleration of brain aging after SCH /BD onset. In support of our hypothesis, the results of the present narrative mini-review shows as neurodevelopmental damages generally contribute to neuropsychiatric syndromes (e.g. hypothyroidism or treponema pallidum), but only some of them are specifically associated with adult SCH and BD (e.g. toxoplasma or substance abuse), particularly if they happen in specific stages of brain development. On the other hand, cognitive impairment and brain changes, associated with long duration of SCH /BD, look like what happens during aging: memory, executive domains and prefrontal cortex are implicated both in aging and in SCH /BD progression. Future research will explore possible validity of this etiological model for SCH and BD.

Glycemic extremes in youth with T1DM: the structural and functional integrity of the developing brain.

PubMed

Arbelaez, Ana Maria; Semenkovich, Katherine; Hershey, Tamara

2013-12-01

The adult brain accounts for a disproportionally large percentage of the body’s total energy consumption (1). However, during brain development,energy demand is even higher, reaching the adult rate by age 2 and increasing to nearly twice the adult rate by age 10, followed by gradual reduction toward adult levels in the next decade (1,2). The dramatic changes in brain metabolism occurring over the first two decades of life coincide with the initial proliferation and then pruning of synapses to adult levels.The brain derives its energy almost exclusively from glucose and is largely driven by neuronal signaling, biosynthesis, and neuroprotection (3–6).Glucose homeostasis in the body is tightly regulated by a series of hormones and physiologic responses. As a result, hypoglycemia and hyperglycemia are rare occurrences in normal individuals, but they occur commonly inpatients with type 1 diabetes mellitus (T1DM) due to a dysfunction of peripheral glucose-insulin-glucagon responses and non-physiologic doses of exogenous insulin, which imperfectly mimic normal physiology. These extremes can occur more frequently in children and adolescents with T1DM due to the inadequacies of insulin replacement therapy, events leading to the diagnosis [prolonged untreated hyperglycemia and diabetic ketoacidosis (DKA)], and to behavioral factors interfering with optimal treatment. When faced with fluctuations in glucose supply the metabolism of the body and brain change dramatically, largely to conserve resources and, at a cost to other organs, to preserve brain function (7). However,if the normal physiological mechanisms that prevent these severe glucose fluctuations and maintain homeostasis are impaired, neuronal function and potentially viability can be affected (8–11).

Abnormal brain aging as a radical-related disease: A new target for nuclear medicine

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fujibayashi, Y.; Yamamoto, S.; Waki, A.

DNA damages caused by endogenously produced radicals are closely correlated with aging. Among them, mitochondrial DNA (mtDNA) deletions have been reported as a memory of DNA damage by oxygen radicals. In fact, clinical as well as experimental studies indicated the accumulation of deleted mtDNA in the brain, myocardium and son on, in aged subjects. In our previous work, radioiodinated radical trapping agent, p-iodophenyl-N-t-butylnitrone, and hypoxia imaging agent, Cu-62 diacetyl-bis-N-4-methyl-thiosemicarbazone have been developed for the diagnosis of radical-related diseases, such as ischemic, inflammation, cancer or aging. The aim of the present work was to evaluate these agents for brain aging studies.more » In our university, an unique animal model, a senescence accelerated model mouse (SAM), has been established. Among the various substrains, SAMP8 showing memory deterioration in its young age ({approximately}3 month) was basically evaluated as an abnormal brain aging model with mtDNA deletion. As controls, SAMR1 showing normal aging and ddY mice were used. MtDNA deletion n the brain was analyzed with polymerase-chain reaction (PCR) method, and relationship between mtDNA deletion and brain uptake of IPBN or Cu-62-ATSM was studied. In 1-3 month old SAMP8 brain, multiple mtDNa deletions were already found and their content was significantly higher than that of SAMR1 or age-matched ddY control. Thus, it was cleared that SAMP8 brain has high tendency to be attacked by endogenously produced oxygen radicals, possibly from its birth. Both IPBN and Cu-ATSM showed significantly higher accumulation in the SAMP8 brain than in the SAMR1 brain, indicating that these agents have high possibility for the early detection of abnormal brain aging as a radical-related disease.« less

The myth of the normal, average human brain--the ICBM experience: (1) subject screening and eligibility.

PubMed

Mazziotta, John C; Woods, Roger; Iacoboni, Marco; Sicotte, Nancy; Yaden, Kami; Tran, Mary; Bean, Courtney; Kaplan, Jonas; Toga, Arthur W

2009-02-01

In the course of developing an atlas and reference system for the normal human brain throughout the human age span from structural and functional brain imaging data, the International Consortium for Brain Mapping (ICBM) developed a set of "normal" criteria for subject inclusion and the associated exclusion criteria. The approach was to minimize inclusion of subjects with any medical disorders that could affect brain structure or function. In the past two years, a group of 1685 potential subjects responded to solicitation advertisements at one of the consortium sites (UCLA). Subjects were screened by a detailed telephone interview and then had an in-person history and physical examination. Of those who responded to the advertisement and considered themselves to be normal, only 31.6% (532 subjects) passed the telephone screening process. Of the 348 individuals who submitted to in-person history and physical examinations, only 51.7% passed these screening procedures. Thus, only 10.7% of those individuals who responded to the original advertisement qualified for imaging. The most frequent cause for exclusion in the second phase of subject screening was high blood pressure followed by abnormal signs on neurological examination. It is concluded that the majority of individuals who consider themselves normal by self-report are found not to be so by detailed historical interviews about underlying medical conditions and by thorough medical and neurological examinations. Recommendations are made with regard to the inclusion of subjects in brain imaging studies and the criteria used to select them.

Proteomic profiling of mitochondria: what does it tell us about the ageing brain?

PubMed

Ingram, Thomas; Chakrabarti, Lisa

2016-12-13

Mitochondrial dysfunction is evident in numerous neurodegenerative and age-related disorders. It has also been linked to cellular ageing, however our current understanding of the mitochondrial changes that occur are unclear. Functional studies have made some progress reporting reduced respiration, dynamic structural modifications and loss of membrane potential, though there are conflicts within these findings. Proteomic analyses, together with functional studies, are required in order to profile the mitochondrial changes that occur with age and can contribute to unravelling the complexity of the ageing phenotype. The emergence of improved protein separation techniques, combined with mass spectrometry analyses has allowed the identification of age and cell-type specific mitochondrial changes in energy metabolism, antioxidants, fusion and fission machinery, chaperones, membrane proteins and biosynthesis pathways. Here, we identify and review recent data from the analyses of mitochondria from rodent brains. It is expected that knowledge gained from understanding age-related mitochondrial changes of the brain should lead to improved biomarkers of normal ageing and also age-related disease progression.

Quantitative Assessment of Normal Fetal Brain Myelination Using Fast Macromolecular Proton Fraction Mapping.

PubMed

Yarnykh, V L; Prihod'ko, I Y; Savelov, A A; Korostyshevskaya, A M

2018-05-10

Fast macromolecular proton fraction mapping is a recently emerged MRI method for quantitative myelin imaging. Our aim was to develop a clinically targeted technique for macromolecular proton fraction mapping of the fetal brain and test its capability to characterize normal prenatal myelination. This prospective study included 41 pregnant women (gestational age range, 18-38 weeks) without abnormal findings on fetal brain MR imaging performed for clinical indications. A fast fetal brain macromolecular proton fraction mapping protocol was implemented on a clinical 1.5T MR imaging scanner without software modifications and was performed after a clinical examination with an additional scan time of <5 minutes. 3D macromolecular proton fraction maps were reconstructed from magnetization transfer-weighted, T1-weighted, and proton density-weighted images by the single-point method. Mean macromolecular proton fraction in the brain stem, cerebellum, and thalamus and frontal, temporal, and occipital WM was compared between structures and pregnancy trimesters using analysis of variance. Gestational age dependence of the macromolecular proton fraction was assessed using the Pearson correlation coefficient ( r ). The mean macromolecular proton fraction in the fetal brain structures varied between 2.3% and 4.3%, being 5-fold lower than macromolecular proton fraction in adult WM. The macromolecular proton fraction in the third trimester was higher compared with the second trimester in the brain stem, cerebellum, and thalamus. The highest macromolecular proton fraction was observed in the brain stem, followed by the thalamus, cerebellum, and cerebral WM. The macromolecular proton fraction in the brain stem, cerebellum, and thalamus strongly correlated with gestational age ( r = 0.88, 0.80, and 0.73; P < .001). No significant correlations were found for cerebral WM regions. Myelin is the main factor determining macromolecular proton fraction in brain tissues. Macromolecular proton fraction mapping is sensitive to the earliest stages of the fetal brain myelination and can be implemented in a clinical setting. © 2018 by American Journal of Neuroradiology.

Towards a unified analysis of brain maturation and aging across the entire lifespan: A MRI analysis.

PubMed

Coupé, Pierrick; Catheline, Gwenaelle; Lanuza, Enrique; Manjón, José Vicente

2017-11-01

There is no consensus in literature about lifespan brain maturation and senescence, mainly because previous lifespan studies have been performed on restricted age periods and/or with a limited number of scans, making results instable and their comparison very difficult. Moreover, the use of nonharmonized tools and different volumetric measurements lead to a great discrepancy in reported results. Thanks to the new paradigm of BigData sharing in neuroimaging and the last advances in image processing enabling to process baby as well as elderly scans with the same tool, new insights on brain maturation and aging can be obtained. This study presents brain volume trajectory over the entire lifespan using the largest age range to date (from few months of life to elderly) and one of the largest number of subjects (N = 2,944). First, we found that white matter trajectory based on absolute and normalized volumes follows an inverted U-shape with a maturation peak around middle life. Second, we found that from 1 to 8-10 y there is an absolute gray matter (GM) increase related to body growth followed by a GM decrease. However, when normalized volumes were considered, GM continuously decreases all along the life. Finally, we found that this observation holds for almost all the considered subcortical structures except for amygdala which is rather stable and hippocampus which exhibits an inverted U-shape with a longer maturation period. By revealing the entire brain trajectory picture, a consensus can be drawn since most of the previously discussed discrepancies can be explained. Hum Brain Mapp 38:5501-5518, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Executive dysfunction, brain aging, and political leadership.

PubMed

Fisher, Mark; Franklin, David L; Post, Jerrold M

2014-01-01

Decision-making is an essential component of executive function, and a critical skill of political leadership. Neuroanatomic localization studies have established the prefrontal cortex as the critical brain site for executive function. In addition to the prefrontal cortex, white matter tracts as well as subcortical brain structures are crucial for optimal executive function. Executive function shows a significant decline beginning at age 60, and this is associated with age-related atrophy of prefrontal cortex, cerebral white matter disease, and cerebral microbleeds. Notably, age-related decline in executive function appears to be a relatively selective cognitive deterioration, generally sparing language and memory function. While an individual may appear to be functioning normally with regard to relatively obvious cognitive functions such as language and memory, that same individual may lack the capacity to integrate these cognitive functions to achieve normal decision-making. From a historical perspective, global decline in cognitive function of political leaders has been alternatively described as a catastrophic event, a slowly progressive deterioration, or a relatively episodic phenomenon. Selective loss of executive function in political leaders is less appreciated, but increased utilization of highly sensitive brain imaging techniques will likely bring greater appreciation to this phenomenon. Former Israeli Prime Minister Ariel Sharon was an example of a political leader with a well-described neurodegenerative condition (cerebral amyloid angiopathy) that creates a neuropathological substrate for executive dysfunction. Based on the known neuroanatomical and neuropathological changes that occur with aging, we should probably assume that a significant proportion of political leaders over the age of 65 have impairment of executive function.

Age-related changes in brain structural covariance networks.

PubMed

Li, Xinwei; Pu, Fang; Fan, Yubo; Niu, Haijun; Li, Shuyu; Li, Deyu

2013-01-01

Previous neuroimaging studies have suggested that cerebral changes over normal aging are not simply characterized by regional alterations, but rather by the reorganization of cortical connectivity patterns. The investigation of structural covariance networks (SCNs) using voxel-based morphometry is an advanced approach to examining the pattern of covariance in gray matter (GM) volumes among different regions of the human cortex. To date, how the organization of critical SCNs change during normal aging remains largely unknown. In this study, we used an SCN mapping approach to investigate eight large-scale networks in 240 healthy participants aged 18-89 years. These participants were subdivided into young (18-23 years), middle aged (30-58 years), and older (61-89 years) subjects. Eight seed regions were chosen from widely reported functional intrinsic connectivity networks. The voxels showing significant positive associations with these seed regions were used to describe the topological organization of an SCN. All of these networks exhibited non-linear patterns in their spatial extent that were associated with normal aging. These networks, except the primary motor network, had a distributed topology in young participants, a sharply localized topology in middle aged participants, and were relatively stable in older participants. The structural covariance derived using the primary motor cortex was limited to the ipsilateral motor regions in the young and older participants, but included contralateral homologous regions in the middle aged participants. In addition, there were significant between-group differences in the structural networks associated with language-related speech and semantics processing, executive control, and the default-mode network (DMN). Taken together, the results of this study demonstrate age-related changes in the topological organization of SCNs, and provide insights into normal aging of the human brain.

Age and disease related changes in the translocator protein (TSPO) system in the human brain: positron emission tomography measurements with [11C]vinpocetine.

PubMed

Gulyás, Balázs; Vas, Adám; Tóth, Miklós; Takano, Akihiro; Varrone, Andrea; Cselényi, Zsolt; Schain, Martin; Mattsson, Patrik; Halldin, Christer

2011-06-01

The main objectives of the present study were (i) to measure density changes of activated microglia and the peripheral benzodiazepine receptor/translocator protein (TSPO) system during normal ageing in the human brain with positron emission tomography (PET) using the TSPO molecular imaging biomarker [(11)C]vinpocetine and (ii) to compare the level and pattern of TSPO in Alzheimer (AD) patients with age matched healthy subjects, in order to assess the biomarker's usefulness as a diagnostic imaging marker in normal (ageing) and pathological (AD) up-regulation of microglia. PET measurements were made in healthy volunteers, aged between 25 and 78 years, and AD patients, aged between 67 and 82 years, using [(11)C]vinpocetine as the tracer. Global and regional quantitative parameters of tracer uptake and binding, including time activity curves (TAC) of standard uptake values (%SUV), binding affinity parameters, intensity spectrum and homogeneity of the uptake distribution were measured and analysed. Both %SUV and binding values increased with age linearly in the whole brain and in all brain regions. There were no significant differences between the %SUV values of the AD patients and age matched control subjects. There were, however, significant differences in %SUV values in a large number of brain regions between young subjects and old subjects, as well as young subjects and AD patients. The intensity spectrum analysis and homogeneity analysis of the voxel data show that the homogeneity of the %SUV values decreases with ageing and during the disease, whereas the centre of the intensity spectrum is shifted to higher %SUV values. These data indicate an inhomogeneous up-regulation of the TSPO system during ageing and AD. These changes were significant between the group of young subjects and old subjects, as well as young subjects and AD patients, but not between old subjects and AD patients. The present data indicate that [(11)C]vinpocetine may serve as a molecular imaging biomarker of the activity of the TSPO system and, consequently, of the up-regulation of microglia during ageing and in neuroinflammatory diseases. However, the global and regional brain %SUV values between AD patients and age matched controls are not different from each other. The disease specific changes, measured with [(11)C]vinpocetine in AD, are significantly different from those measured in age matched controls only if the inhomogeneities in the uptake pattern are explored with advanced mathematical techniques. For this reason, PET studies using [(11)C]vinpocetine, as molecular imaging biomarker, can efficiently visualise the activation of microglia and the up-regulation of TSPO during ageing and in diseased brains with the help of an appropriate inhomogeneity analysis of the radioligand's brain uptake pattern. Copyright © 2011 Elsevier Inc. All rights reserved.

Narrative discourse in children with early focal brain injury.

PubMed

Reilly, J S; Bates, E A; Marchman, V A

1998-02-15

Children with early brain damage, unlike adult stroke victims, often go on to develop nearly normal language. However, the route and extent of their linguistic development are still unclear, as is the relationship between lesion site and patterns of delay and recovery. Here we address these questions by examining narratives from children with early brain damage. Thirty children (ages 3:7-10:10) with pre- or perinatal unilateral focal brain damage and their matched controls participated in a storytelling task. Analyses focused on linguistic proficiency and narrative competence. Overall, children with brain damage scored significantly lower than their age-matched controls on both linguistic (morphological and syntactic) indices and those targeting broader narrative qualities. Rather than indicating that children with brain damage fully catch up, these data suggest that deficits in linguistic abilities reassert themselves as children face new linguistic challenges. Interestingly, after age 5, site of lesion does not appear to be a significant factor and the delays we have witnessed do not map onto the lesion profiles observed in adults with analogous brain injuries.

The road to LOAD: late-onset Alzheimer's disease and a possible way to block it.

PubMed

Whitfield, James F

2007-10-01

The ageing brain becomes increasingly less able to destroy or eject toxic amyloid (A) beta42 peptide byproducts of normal neuronal activity that consequently accumulate to induce Alzheimer's disease (AD). Therefore, the various components of the Abeta-clearing machinery are prime targets for AD therapeutics. In this connection, there are reports that taking statins to lower circulating cholesterol to prevent cardiovascular disease can also prevent late-onset AD (LOAD) the most common form of the disease. However, it seems unlikely that statins would prevent LOAD by lowering the very long-lived brain cholesterol that is controlled independently from the very much shorter-lived circulating cholesterol. In fact, reducing the ability of the brain astrocytes to make cholesterol for their closely associated neuron clients' synaptogenesis could damage the brain rather than protect it. However, a plausible way statins might prevent LOAD is to target a main component of the clearance machinery, low-density lipoprotein receptor-related protein 1 (LRP1), the brain's powerful Abeta-efflux driver. This is indicated by a reported ability of micromolar concentrations of lovastatin and simvastatin to strongly stimulate brain vascular endothelial cells to make this Abeta ejector. Therefore, if this holds up, taking a statin over the years would prevent the normal decline of LRP1 in the ageing brain and a LOAD-driving accumulation of Abeta.

Lifestyle-dependent brain change: a longitudinal cohort MRI study.

PubMed

Kim, Regina Ey; Yun, Chang-Ho; Thomas, Robert J; Oh, Jang-Hoon; Johnson, Hans J; Kim, Soriul; Lee, Seungku; Seo, Hyung Suk; Shin, Chol

2018-05-07

We investigated both independent and interconnected effects of 3 lifestyle factors on brain volume, measuring yearly changes using large-scale longitudinal magnetic resonance imaging, in middle-aged to older adults. We measured brain volumes in a cohort (n = 984, 49-79 years) from the Korean Genome and Epidemiology Study group, using baseline and follow-up estimates after 4 years. In our analysis, the accelerated brain atrophy in normal aging was observed across regions (e.g., brain tissue: -0.098 ± 0.01 mL/y, p < 0.001). An independent lifestyle-specific trend of brain atrophy across time was also evident in men, where smoking (p = 0.012) and physical activity (p = 0.014) showed the strongest association with the atrophy rate. Linear regression analysis of the interconnected effect revealed that brain atrophy is mitigated by intense physical activity in smoking males. Lifestyle factors did not show any significant effect on brain volume in women. These results provide important information regarding lifestyle factors that affect brain aging in mid-to-late adulthood. Our findings may aid in the identification of preventive measures against dementia. Copyright © 2018 Elsevier Inc. All rights reserved.

Progressive regional atrophy in normal adults with a maternal history of Alzheimer disease

PubMed Central

Swerdlow, Russell H.; Vidoni, Eric D.; Burns, Jeffrey M.

2011-01-01

Objective: Beyond age, having a family history is the most significant risk factor for Alzheimer disease (AD). This longitudinal brain imaging study examines whether there are differential patterns of regional gray matter atrophy in cognitively healthy elderly subjects with (FH+) and without (FH−) a family history of late-onset AD. Methods: As part of the KU Brain Aging Project, cognitively intact individuals with a maternal history (FHm, n = 11), paternal history (FHp, n = 10), or no parental history of AD (FH−, n = 32) similar in age, gender, education, and Mini-Mental State Examination (MMSE) score received MRI at baseline and 2-year follow-up. A custom voxel-based morphometry processing stream was used to examine regional differences in atrophy between FH groups, controlling for age, gender, and APOE ϵ4 (APOE4) status. We also analyzed APOE4-related atrophy. Results: Cognitively normal FH+ individuals had significantly increased whole-brain gray matter atrophy and CSF expansion compared to FH−. When FH+ groups were split, only FHm was associated with longitudinal measures of brain change. Moreover, our voxel-based analysis revealed that FHm subjects had significantly greater atrophy in the precuneus and parahippocampus/hippocampus regions compared to FH− and FHp subjects, independent of APOE4 status, gender, and age. Individuals with an ε4 allele had more regional atrophy in the frontal cortex compared to ε4 noncarriers. Conclusions: We conclude that FHm individuals without dementia have progressive gray matter volume reductions in select AD-vulnerable brain regions, specifically the precuneus and parahippocampal gyrus. These data complement and extend reports of regional cerebral metabolic differences and increases in amyloid-β burden in FHm subjects, which may be related to a higher risk for developing AD. PMID:21357834

Learning problems, delayed development, and puberty

PubMed Central

Wright, Beverly A.; Zecker, Steven G.

2004-01-01

Language-based learning disorders such as dyslexia affect millions of people, but there is little agreement as to their cause. New evidence from behavioral measures of the ability to hear tones in the presence of background noise indicates that the brains of affected individuals develop more slowly than those of their unaffected counterparts. In addition, it seems that brain changes occurring at ≈10 years of age, presumably associated with puberty, may prematurely halt this slower-than-normal development when improvements would normally continue into adolescence. The combination of these ideas can account for a wide range of previous results, suggesting that delayed brain development, and its interaction with puberty, may be key factors contributing to learning problems. PMID:15210987

Structural Imaging Measures of Brain Aging

PubMed Central

Lockhart, Samuel N.

2014-01-01

During the course of normal aging, biological changes occur in the brain that are associated with changes in cognitive ability. This review presents data from neuroimaging studies of primarily “normal” or healthy brain aging. As such, we focus on research in unimpaired or nondemented older adults, but also include findings from lifespan studies that include younger and middle aged individuals as well as from populations with prodromal or clinically symptomatic disease such as cerebrovascular or Alzheimer’s disease. This review predominantly addresses structural MRI biomarkers, such as volumetric or thickness measures from anatomical images, and measures of white matter injury and integrity respectively from FLAIR or DTI, and includes complementary data from PET and cognitive or clinical testing as appropriate. The findings reveal highly consistent age-related differences in brain structure, particularly frontal lobe and medial temporal regions that are also accompanied by age-related differences in frontal and medial temporal lobe mediated cognitive abilities. Newer findings also suggest that degeneration of specific white matter tracts such as those passing through the genu and splenium of the corpus callosum may also be related to age-related differences in cognitive performance. Interpretation of these findings, however, must be tempered by the fact that comorbid diseases such as cerebrovascular and Alzheimer’s disease also increase in prevalence with advancing age. As such, this review discusses challenges related to interpretation of current theories of cognitive aging in light of the common occurrence of these later-life diseases. Understanding the differences between “Normal” and “Healthy” brain aging and identifying potential modifiable risk factors for brain aging is critical to inform potential treatments to stall or reverse the effects of brain aging and possibly extend cognitive health for our aging society. PMID:25146995

Relationships between Head Circumference, Brain Volume and Cognition in Children with Prenatal Alcohol Exposure

PubMed Central

Treit, Sarah; Zhou, Dongming; Chudley, Albert E.; Andrew, Gail; Rasmussen, Carmen; Nikkel, Sarah M.; Samdup, Dawa; Hanlon-Dearman, Ana; Loock, Christine; Beaulieu, Christian

2016-01-01

Head circumference is used together with other measures as a proxy for central nervous system damage in the diagnosis of fetal alcohol spectrum disorders, yet the relationship between head circumference and brain volume has not been investigated in this population. The objective of this study is to characterize the relationship between head circumference, brain volume and cognitive performance in a large sample of children with prenatal alcohol exposure (n = 144) and healthy controls (n = 145), aged 5–19 years. All participants underwent magnetic resonance imaging to yield brain volumes and head circumference, normalized to control for age and sex. Mean head circumference, brain volume, and cognitive scores were significantly reduced in the prenatal alcohol exposure group relative to controls, albeit with considerable overlap between groups. Males with prenatal alcohol exposure had reductions in all three measures, whereas females with prenatal alcohol exposure had reduced brain volumes and cognitive scores, but no difference in head circumference relative to controls. Microcephaly (defined here as head circumference ≤ 3rd percentile) occurred more often in prenatal alcohol exposed participants than controls, but 90% of the exposed sample had head circumferences above this clinical cutoff indicating that head circumference is not a sensitive marker of prenatal alcohol exposure. Normalized head circumference and brain volume were positively correlated in both groups, and subjects with very low head circumference typically had below-average brain volumes. Conversely, over half of the subjects with very low brain volumes had normal head circumferences, which may stem from differential effects of alcohol on the skeletal and nervous systems. There were no significant correlations between head circumference and any cognitive score. These findings confirm group-level reductions in head circumference and increased rates of microcephaly in children with prenatal alcohol exposure, but raise concerns about the predictive value of this metric at an individual-subject level. PMID:26928125

Relationships between Head Circumference, Brain Volume and Cognition in Children with Prenatal Alcohol Exposure.

PubMed

Treit, Sarah; Zhou, Dongming; Chudley, Albert E; Andrew, Gail; Rasmussen, Carmen; Nikkel, Sarah M; Samdup, Dawa; Hanlon-Dearman, Ana; Loock, Christine; Beaulieu, Christian

2016-01-01

Head circumference is used together with other measures as a proxy for central nervous system damage in the diagnosis of fetal alcohol spectrum disorders, yet the relationship between head circumference and brain volume has not been investigated in this population. The objective of this study is to characterize the relationship between head circumference, brain volume and cognitive performance in a large sample of children with prenatal alcohol exposure (n = 144) and healthy controls (n = 145), aged 5-19 years. All participants underwent magnetic resonance imaging to yield brain volumes and head circumference, normalized to control for age and sex. Mean head circumference, brain volume, and cognitive scores were significantly reduced in the prenatal alcohol exposure group relative to controls, albeit with considerable overlap between groups. Males with prenatal alcohol exposure had reductions in all three measures, whereas females with prenatal alcohol exposure had reduced brain volumes and cognitive scores, but no difference in head circumference relative to controls. Microcephaly (defined here as head circumference ≤ 3rd percentile) occurred more often in prenatal alcohol exposed participants than controls, but 90% of the exposed sample had head circumferences above this clinical cutoff indicating that head circumference is not a sensitive marker of prenatal alcohol exposure. Normalized head circumference and brain volume were positively correlated in both groups, and subjects with very low head circumference typically had below-average brain volumes. Conversely, over half of the subjects with very low brain volumes had normal head circumferences, which may stem from differential effects of alcohol on the skeletal and nervous systems. There were no significant correlations between head circumference and any cognitive score. These findings confirm group-level reductions in head circumference and increased rates of microcephaly in children with prenatal alcohol exposure, but raise concerns about the predictive value of this metric at an individual-subject level.

Lesional perfusion abnormalities in Leigh disease demonstrated by arterial spin labeling correlate with disease activity.

PubMed

Whitehead, Matthew T; Lee, Bonmyong; Gropman, Andrea

2016-08-01

Leigh disease is a metabolic disorder of the mitochondrial respiratory chain culminating in symmetrical necrotizing lesions in the deep gray nuclei or brainstem. Apart from classic gliotic/necrotic lesions, small-vessel proliferation is also characteristic on histopathology. We have observed lesional hyperperfusion on arterial spin-labeling (ASL) sequence in children with Leigh disease. In this cross-sectional analysis, we evaluated lesional ASL perfusion characteristics in children with Leigh syndrome. We searched the imaging database from an academic children's hospital for "arterial spin labeling, perfusion, necrosis, lactate, and Leigh" to build a cohort of children for retrospective analysis. We reviewed each child's medical record to confirm a diagnosis of Leigh disease, excluding exams with artifact, technical limitations, and without ASL images. We evaluated the degree and extent of cerebral blood flow and relationship to brain lesions. Images were compared to normal exams from an aged-matche cohort. The database search yielded 45 exams; 30 were excluded. We evaluated 15 exams from 8 children with Leigh disease and 15 age-matched normal exams. In general, Leigh brain perfusion ranged from hyperintense (n=10) to hypointense (n=5). Necrotic lesions appeared hypointense/hypoperfused. Active lesions with associated restricted diffusion demonstrated hyperperfusion. ASL perfusion patterns differed significantly from those on age-matched normal studies (P=<.0001). Disease activity positively correlated with cerebral deep gray nuclei hyperperfusion (P=0.0037) and lesion grade (P=0.0256). Children with Leigh disease have abnormal perfusion of brain lesions. Hyperperfusion can be found in active brain lesions, possibly associated with small-vessel proliferation characteristic of the disease.

In vitro caloric restriction induces protective genes and functional rejuvenation in senescent SAMP8 astrocytes

PubMed Central

García-Matas, Silvia; Paul, Rajib K; Molina-Martínez, Patricia; Palacios, Hector; Gutierrez, Vincent M; Corpas, Rubén; Pallas, Mercè; Cristòfol, Rosa; de Cabo, Rafael; Sanfeliu, Coral

2015-01-01

Astrocytes are key cells in brain aging, helping neurons to undertake healthy aging or otherwise letting them enter into a spiral of neurodegeneration. We aimed to characterize astrocytes cultured from senescence-accelerated prone 8 (SAMP8) mice, a mouse model of brain pathological aging, along with the effects of caloric restriction, the most effective rejuvenating treatment known so far. Analysis of the transcriptomic profiles of SAMP8 astrocytes cultured in control conditions and treated with caloric restriction serum was performed using mRNA microarrays. A decrease in mitochondrial and ribosome mRNA, which was restored by caloric restriction, confirmed the age-related profile of SAMP8 astrocytes and the benefits of caloric restriction. An amelioration of antioxidant and neurodegeneration-related pathways confirmed the brain benefits of caloric restriction. Studies of oxidative stress and mitochondrial function demonstrated a reduction of oxidative damage and partial improvement of mitochondria after caloric restriction. In summary, caloric restriction showed a significant tendency to normalize pathologically aged astrocytes through the activation of pathways that are protective against the age-related deterioration of brain physiology. PMID:25711920

Accelerated Changes in Cortical Thickness Measurements with Age in Military Service Members with Traumatic Brain Injury.

PubMed

Savjani, Ricky R; Taylor, Brian A; Acion, Laura; Wilde, Elisabeth A; Jorge, Ricardo E

2017-11-15

Finding objective and quantifiable imaging markers of mild traumatic brain injury (TBI) has proven challenging, especially in the military population. Changes in cortical thickness after injury have been reported in animals and in humans, but it is unclear how these alterations manifest in the chronic phase, and it is difficult to characterize accurately with imaging. We used cortical thickness measures derived from Advanced Normalization Tools (ANTs) to predict a continuous demographic variable: age. We trained four different regression models (linear regression, support vector regression, Gaussian process regression, and random forests) to predict age from healthy control brains from publicly available datasets (n = 762). We then used these models to predict brain age in military Service Members with TBI (n = 92) and military Service Members without TBI (n = 34). Our results show that all four models overpredicted age in Service Members with TBI, and the predicted age difference was significantly greater compared with military controls. These data extend previous civilian findings and show that cortical thickness measures may reveal an association of accelerated changes over time with military TBI.

Auditory-evoked cortical activity: contribution of brain noise, phase locking, and spectral power

PubMed Central

Harris, Kelly C.; Vaden, Kenneth I.; Dubno, Judy R.

2017-01-01

Background The N1-P2 is an obligatory cortical response that can reflect the representation of spectral and temporal characteristics of an auditory stimulus. Traditionally, mean amplitudes and latencies of the prominent peaks in the averaged response are compared across experimental conditions. Analyses of the peaks in the averaged response only reflect a subset of the data contained within the electroencephalogram (EEG) signal. We used single-trial analyses techniques to identify the contribution of brain noise, neural synchrony, and spectral power to the generation of P2 amplitude and how these variables may change across age group. This information is important for appropriate interpretation of event-related potentials (ERPs) results and in understanding of age-related neural pathologies. Methods EEG was measured from 25 younger and 25 older normal hearing adults. Age-related and individual differences in P2 response amplitudes, and variability in brain noise, phase locking value (PLV), and spectral power (4–8 Hz) were assessed from electrode FCz. Model testing and linear regression were used to determine the extent to which brain noise, PLV, and spectral power uniquely predicted P2 amplitudes and varied by age group. Results Younger adults had significantly larger P2 amplitudes, PLV, and power compared to older adults. Brain noise did not differ between age groups. The results of regression testing revealed that brain noise and PLV, but not spectral power were unique predictors of P2 amplitudes. Model fit was significantly better in younger than in older adults. Conclusions ERP analyses are intended to provide a better understanding of the underlying neural mechanisms that contribute to individual and group differences in behavior. The current results support that age-related declines in neural synchrony contribute to smaller P2 amplitudes in older normal hearing adults. Based on our results, we discuss potential models in which differences in neural synchrony and brain noise can account for associations with P2 amplitudes and behavior and potentially provide a better explanation of the neural mechanisms that underlie declines in auditory processing and training benefits. PMID:25046314

Glutamate-glutamine and GABA in brain of normal aged and patients with cognitive impairment.

PubMed

Huang, Dandan; Liu, Dan; Yin, Jianzhong; Qian, Tianyi; Shrestha, Susan; Ni, Hongyan

2017-07-01

To explore the changes of glutamate-glutamine (Glx) and gamma-aminobutyric acid (GABA) in the brain in normal old age and cognitive impairment using magnetic resonance spectroscopy (MRS). Seventeen normal young controls (NYC), 15 normal elderly controls (NEC), 21 patients with mild cognitive impairment (MCI) and 17 with Alzheimer disease (AD) patients were included in this study. Glx and GABA+ levels in the anterior cingulate cortex (ACC) and right hippocampus (rHP) were measured by using a MEGA-PRESS sequence. Glx/Cr and GABA+/Cr ratios were compared between NYC and NEC and between the three elderly groups using analysis of covariance (ANCOVA); the tissue fractions of voxels were used as covariates. The relationships between metabolite ratios and cognitive performance were analysed using Spearman correlation coefficients. For NEC and NYC groups, Glx/Cr and GABA+/Cr ratios were lower in NEC in ACC and rHP. For the three elderly groups, Glx/Cr ratio was lower in AD in ACC compared to NEC and MCI; Glx/Cr ratio was lower in AD in rHP compared to NEC. There was no significant decrease for GABA+/Cr ratio. Glx and GABA levels may decrease simultaneously in normal aged, and Glx level decreased predominantly in AD, and it is helpful in the early diagnosis of AD. • Glx and GABA levels may decrease simultaneously in normal aged. • Glx level may decrease predominantly in Alzheimer disease. • The balance in excitatory-inhibitory systems may be broken in AD. • Decreased Glx level may be helpful in early diagnosis of AD.

Neuropathologic findings in an aged albino gorilla.

PubMed

Márquez, M; Serafin, A; Fernández-Bellon, H; Serrat, S; Ferrer-Admetlla, A; Bertranpetit, J; Ferrer, I; Pumarola, M

2008-07-01

Pallido-nigral spheroids associated with iron deposition have been observed in some aged clinically normal nonhuman primates. In humans, similar findings are observed in neurodegeneration with brain iron accumulation diseases, which, in some cases, show associated mutations in pantothenate kinase 2 gene (PANK2). Here we present an aged gorilla, 40 years old, suffering during the last 2 years of life from progressive tetraparesis, nystagmus, and dyskinesia of the arms, hands, and neck, with accompanying abnormal behavior. The postmortem neuropathologic examination revealed, in addition to aging-associated changes in the brain, numerous corpora amylacea in some brain areas, especially the substantia nigra, and large numbers of axonal spheroids associated with iron accumulation in the internal globus pallidus. Sequencing of the gorilla PANK2 gene failed to detect any mutation. The clinical, neuropathologic, and genetic findings in this gorilla point to an age-related pallido-nigral degeneration that presented PKAN-like neurologic deficits.

Can Ketones Help Rescue Brain Fuel Supply in Later Life? Implications for Cognitive Health during Aging and the Treatment of Alzheimer’s Disease

PubMed Central

Cunnane, Stephen C.; Courchesne-Loyer, Alexandre; Vandenberghe, Camille; St-Pierre, Valérie; Fortier, Mélanie; Hennebelle, Marie; Croteau, Etienne; Bocti, Christian; Fulop, Tamas; Castellano, Christian-Alexandre

2016-01-01

We propose that brain energy deficit is an important pre-symptomatic feature of Alzheimer’s disease (AD) that requires closer attention in the development of AD therapeutics. Our rationale is fourfold: (i) Glucose uptake is lower in the frontal cortex of people >65 years-old despite cognitive scores that are normal for age. (ii) The regional deficit in brain glucose uptake is present in adults <40 years-old who have genetic or lifestyle risk factors for AD but in whom cognitive decline has not yet started. Examples include young adult carriers of presenilin-1 or apolipoprotein E4, and young adults with mild insulin resistance or with a maternal family history of AD. (iii) Regional brain glucose uptake is impaired in AD and mild cognitive impairment (MCI), but brain uptake of ketones (beta-hydroxybutyrate and acetoacetate), remains the same in AD and MCI as in cognitively healthy age-matched controls. These observations point to a brain fuel deficit which appears to be specific to glucose, precedes cognitive decline associated with AD, and becomes more severe as MCI progresses toward AD. Since glucose is the brain’s main fuel, we suggest that gradual brain glucose exhaustion is contributing significantly to the onset or progression of AD. (iv) Interventions that raise ketone availability to the brain improve cognitive outcomes in both MCI and AD as well as in acute experimental hypoglycemia. Ketones are the brain’s main alternative fuel to glucose and brain ketone uptake is still normal in MCI and in early AD, which would help explain why ketogenic interventions improve some cognitive outcomes in MCI and AD. We suggest that the brain energy deficit needs to be overcome in order to successfully develop more effective therapeutics for AD. At present, oral ketogenic supplements are the most promising means of achieving this goal. PMID:27458340

Estimation of the brain stem volume by stereological method on magnetic resonance imaging.

PubMed

Erbagci, Hulya; Keser, Munevver; Kervancioglu, Selim; Kizilkan, Nese

2012-11-01

Neuron loss that occurs in some neurodegenerative diseases can lead to volume alterations by causing atrophy in the brain stem. The aim of this study was to determine the brain stem volume and the volume ratio of the brain stem to total brain volume related to gender and age using new Stereo Investigator system in normal subjects. For this purpose, MR images of 72 individuals who have no pathologic condition were evaluated. The total brain volumes of female and male were calculated as 966.81 ± 77.44 and 1,074.06 ± 111.75 cm3, respectively. Brain stem volumes of female and male were determined as 18.99 ± 2.36 and 22.05 ± 4.01 cm3, respectively. The ratios of brain stem volume to total brain volume were 1.96 ± 0.17 in female and 2.05 ± 0.29 in male. The total brain and brain stem volumes were observed smaller in female and it is statistically significant. Among the individuals whose ages are between 20 and 40, total brain and brain stem volume measurements with aging were not statistically significant. As a result, we believe that the measurement of brain stem volume with an objective and efficient calculation method will contribute to the early diagnosis of neurodegenerative diseases, as well as to determine the rate of disease progression, and the outcomes of treatment.

Brain aging and Aβ₁₋₄₂ neurotoxicity converge via deterioration in autophagy-lysosomal system: a conditional Drosophila model linking Alzheimer's neurodegeneration with aging.

PubMed

Ling, Daijun; Salvaterra, Paul M

2011-02-01

Aging is known to be the most prominent risk factor for Alzheimer's disease (AD); however, the underlying mechanism linking brain aging with AD pathogenesis remains unknown. The expression of human amyloid beta 42 peptide (Aβ₁₋₄₂), but not Aβ₁₋₄₀ in Drosophila brain induces an early onset and progressive autophagy-lysosomal neuropathology. Here we show that the natural process of brain aging also accompanies a chronic and late-onset deterioration of neuronal autophagy-lysosomal system. This process is characterized by accumulation of dysfunctional autophagy-lysosomal vesicles, a compromise of these vesicles leading to damage of intracellular membranes and organelles, necrotic-like intraneuronal destruction and neurodegeneration. In addition, conditional activation of neuronal autophagy in young animals is protective while late activation is deleterious for survival. Intriguingly, conditional Aβ₁₋₄₂ expression limited to young animals exacerbates the aging process to a greater extent than Aβ₁₋₄₂ expression in old animals. These data suggest that the neuronal autophagy-lysosomal system may shift from a functional and protective state to a pathological and deleterious state either during brain aging or via Aβ₁₋₄₂ neurotoxicity. A chronic deterioration of the neuronal autophagy-lysosomal system is likely to be a key event in transitioning from normal brain aging to pathological aging leading to Alzheimer's neurodegeneration.

MHC Class I Immune Proteins Are Critical for Hippocampus-Dependent Memory and Gate NMDAR-Dependent Hippocampal Long-Term Depression

ERIC Educational Resources Information Center

Nelson, P. Austin; Sage, Jennifer R.; Wood, Suzanne C.; Davenport, Christopher M.; Anagnostaras, Stephan G.; Boulanger, Lisa M.

2013-01-01

Memory impairment is a common feature of conditions that involve changes in inflammatory signaling in the brain, including traumatic brain injury, infection, neurodegenerative disorders, and normal aging. However, the causal importance of inflammatory mediators in cognitive impairments in these conditions remains unclear. Here we show that…

Consonant Accuracy after Severe Pediatric Traumatic Brain Injury: A Prospective Cohort Study

ERIC Educational Resources Information Center

Campbell, Thomas F.; Dollaghan, Christine; Janosky, Janine; Rusiewicz, Heather Leavy; Small, Steven L.; Dick, Frederic; Vick, Jennell; Adelson, P. David

2013-01-01

Purpose: The authors sought to describe longitudinal changes in Percentage of Consonants Correct--Revised (PCC-R) after severe pediatric traumatic brain injury (TBI), to compare the odds of normal-range PCC-R in children injured at older and younger ages, and to correlate predictor variables and PCC-R outcomes. Method: In 56 children injured…

Magnetization Transfer Ratio Relates to Cognitive Impairment in Normal Elderly

PubMed Central

Seiler, Stephan; Pirpamer, Lukas; Hofer, Edith; Duering, Marco; Jouvent, Eric; Fazekas, Franz; Mangin, Jean-Francois; Chabriat, Hugues; Dichgans, Martin; Ropele, Stefan; Schmidt, Reinhold

2014-01-01

Magnetization transfer imaging (MTI) can detect microstructural brain tissue changes and may be helpful in determining age-related cerebral damage. We investigated the association between the magnetization transfer ratio (MTR) in gray and white matter (WM) and cognitive functioning in 355 participants of the Austrian stroke prevention family study (ASPS-Fam) aged 38–86 years. MTR maps were generated for the neocortex, deep gray matter structures, WM hyperintensities, and normal appearing WM (NAWM). Adjusted mixed models determined whole brain and lobar cortical MTR to be directly and significantly related to performance on tests of memory, executive function, and motor skills. There existed an almost linear dose-effect relationship. MTR of deep gray matter structures and NAWM correlated to executive functioning. All associations were independent of demographics, vascular risk factors, focal brain lesions, and cortex volume. Further research is needed to understand the basis of this association at the tissue level, and to determine the role of MTR in predicting cognitive decline and dementia. PMID:25309438

Brain metabolism in autism. Resting cerebral glucose utilization rates as measured with positron emission tomography

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rumsey, J.M.; Duara, R.; Grady, C.

The cerebral metabolic rate for glucose was studied in ten men (mean age = 26 years) with well-documented histories of infantile autism and in 15 age-matched normal male controls using positron emission tomography and (F-18) 2-fluoro-2-deoxy-D-glucose. Positron emission tomography was completed during rest, with reduced visual and auditory stimulation. While the autistic group as a whole showed significantly elevated glucose utilization in widespread regions of the brain, there was considerable overlap between the two groups. No brain region showed a reduced metabolic rate in the autistic group. Significantly more autistic, as compared with control, subjects showed extreme relative metabolic ratesmore » (ratios of regional metabolic rates to whole brain rates and asymmetries) in one or more brain regions.« less

Disruptions of brain structural network in end-stage renal disease patients with long-term hemodialysis and normal-appearing brain tissues.

PubMed

Chou, Ming-Chung; Ko, Chih-Hung; Chang, Jer-Ming; Hsieh, Tsyh-Jyi

2018-05-04

End-stage renal disease (ESRD) patients on hemodialysis were demonstrated to exhibit silent and invisible white-matter alterations which would likely lead to disruptions of brain structural networks. Therefore, the purpose of this study was to investigate the disruptions of brain structural network in ESRD patients. Thiry-three ESRD patients with normal-appearing brain tissues and 29 age- and gender-matched healthy controls were enrolled in this study and underwent both cognitive ability screening instrument (CASI) assessment and diffusion tensor imaging (DTI) acquisition. Brain structural connectivity network was constructed using probabilistic tractography with automatic anatomical labeling template. Graph-theory analysis was performed to detect the alterations of node-strength, node-degree, node-local efficiency, and node-clustering coefficient in ESRD patients. Correlational analysis was performed to understand the relationship between network measures, CASI score, and dialysis duration. Structural connectivity, node-strength, node-degree, and node-local efficiency were significantly decreased, whereas node-clustering coefficient was significantly increased in ESRD patients as compared with healthy controls. The disrupted local structural networks were generally associated with common neurological complications of ESRD patients, but the correlational analysis did not reveal significant correlation between network measures, CASI score, and dialysis duration. Graph-theory analysis was helpful to investigate disruptions of brain structural network in ESRD patients with normal-appearing brain tissues. Copyright © 2018. Published by Elsevier Masson SAS.

Relationships between brain and body temperature, clinical and imaging outcomes after ischemic stroke

PubMed Central

Karaszewski, Bartosz; Carpenter, Trevor K; Thomas, Ralph G R; Armitage, Paul A; Lymer, Georgina Katherine S; Marshall, Ian; Dennis, Martin S; Wardlaw, Joanna M

2013-01-01

Pyrexia soon after stroke is associated with severe stroke and poor functional outcome. Few studies have assessed brain temperature after stroke in patients, so little is known of its associations with body temperature, stroke severity, or outcome. We measured temperatures in ischemic and normal-appearing brain using 1H-magnetic resonance spectroscopy and its correlations with body (tympanic) temperature measured four-hourly, infarct growth by 5 days, early neurologic (National Institute of Health Stroke Scale, NIHSS) and late functional outcome (death or dependency). Among 40 patients (mean age 73 years, median NIHSS 7, imaged at median 17 hours), temperature in ischemic brain was higher than in normal-appearing brain on admission (38.6°C-core, 37.9°C-contralateral hemisphere, P=0.03) but both were equally elevated by 5 days; both were higher than tympanic temperature. Ischemic lesion temperature was not associated with NIHSS or 3-month functional outcome; in contrast, higher contralateral normal-appearing brain temperature was associated with worse NIHSS, infarct expansion and poor functional outcome, similar to associations for tympanic temperature. We conclude that brain temperature is higher than body temperature; that elevated temperature in ischemic brain reflects a local tissue response to ischemia, whereas pyrexia reflects the systemic response to stroke, occurs later, and is associated with adverse outcomes. PMID:23571281

PET Imaging of Tau Deposition in the Aging Human Brain

PubMed Central

Schonhaut, Daniel R.; O’Neil, James P.; Janabi, Mustafa; Ossenkoppele, Rik; Baker, Suzanne L.; Vogel, Jacob W.; Faria, Jamie; Schwimmer, Henry D.; Rabinovici, Gil D.; Jagust, William J.

2016-01-01

SUMMARY Tau pathology is a hallmark of Alzheimer’s disease (AD) but also occurs in normal cognitive aging. Using the tau PET agent 18F-AV-1451, we examined retention patterns in cognitively normal older people in relation to young controls and AD patients. Age and β-amyloid (measured using PiB PET) were differentially associated with tau tracer retention in healthy aging. Older age was related to increased tracer retention in regions of the medial temporal lobe, which predicted worse episodic memory performance. PET detection of tau in other isocortical regions required the presence of cortical β-amyloid, and was associated with decline in global cognition. Furthermore, patterns of tracer retention corresponded well with Braak staging of neurofibrillary tau pathology. The present study defined patterns of tau tracer retention in normal aging in relation to age, cognition, and β-amyloid deposition. PMID:26938442

PET Imaging of Tau Deposition in the Aging Human Brain

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schöll, Michael; Lockhart, Samuel N.; Schonhaut, Daniel R.

Tau pathology is a hallmark of Alzheimer’s disease (AD) but also occurs in normal cognitive aging. In this study, using the tau PET agent 18F-AV-1451, we examined retention patterns in cognitively normal older people in relation to young controls and AD patients. Age and β-amyloid (measured using PiB PET) were differentially associated with tau tracer retention in healthy aging. Older age was related to increased tracer retention in regions of the medial temporal lobe, which predicted worse episodic memory performance. PET detection of tau in other isocortical regions required the presence of cortical β-amyloid and was associated with decline inmore » global cognition. Furthermore, patterns of tracer retention corresponded well with Braak staging of neurofibrillary tau pathology. In conclusion, the present study defined patterns of tau tracer retention in normal aging in relation to age, cognition, and β-amyloid deposition.« less

PET Imaging of Tau Deposition in the Aging Human Brain

DOE PAGES

Schöll, Michael; Lockhart, Samuel N.; Schonhaut, Daniel R.; ...

2016-03-02

Tau pathology is a hallmark of Alzheimer’s disease (AD) but also occurs in normal cognitive aging. In this study, using the tau PET agent 18F-AV-1451, we examined retention patterns in cognitively normal older people in relation to young controls and AD patients. Age and β-amyloid (measured using PiB PET) were differentially associated with tau tracer retention in healthy aging. Older age was related to increased tracer retention in regions of the medial temporal lobe, which predicted worse episodic memory performance. PET detection of tau in other isocortical regions required the presence of cortical β-amyloid and was associated with decline inmore » global cognition. Furthermore, patterns of tracer retention corresponded well with Braak staging of neurofibrillary tau pathology. In conclusion, the present study defined patterns of tau tracer retention in normal aging in relation to age, cognition, and β-amyloid deposition.« less

EEG Alpha and Beta Activity in Normal and Deaf Subjects.

ERIC Educational Resources Information Center

Waldron, Manjula; And Others

Electroencephalogram and task performance data were collected from three groups of young adult males: profoundly deaf Ss who signed from an early age, profoundly deaf Ss who only used oral (speech and speedreading) methods of communication, and normal hearing Ss. Alpha and Beta brain wave patterns over the Wernicke's area were compared across…

Sexually dimorphic subcortical brain volumes in emerging psychosis.

PubMed

Egloff, Laura; Lenz, Claudia; Studerus, Erich; Harrisberger, Fabienne; Smieskova, Renata; Schmidt, André; Huber, Christian; Simon, Andor; Lang, Undine E; Riecher-Rössler, Anita; Borgwardt, Stefan

2018-03-28

In schizophrenic psychoses, the normal sexual dimorphism of the brain has been shown to be disrupted or even reversed. Little is known, however, at what time point in emerging psychosis this occurs. We have therefore examined, if these alterations are already present in the at-risk mental state (ARMS) for psychosis and in first episode psychosis (FEP) patients. Data from 65 ARMS (48 (73.8%) male; age=25.1±6.32) and 50 FEP (37 (74%) male; age=27±6.56) patients were compared to those of 70 healthy controls (HC; 27 (38.6%) male; age=26±4.97). Structural T1-weighted images were acquired using a 3 Tesla magnetic resonance imaging (MRI) scanner. Linear mixed effects models were used to investigate whether subcortical brain volumes are dependent on sex. We found men to have larger total brain volumes (p<0.001), and smaller bilateral caudate (p=0.008) and hippocampus volume (p<0.001) than women across all three groups. Older subjects had more GM and WM volume than younger subjects. No significant sex×group interaction was found. In emerging psychosis there still seem to exist patterns of normal sexual dimorphism in total brain and caudate volume. The only structure affected by reversed sexual dimorphism was the hippocampus, with women showing larger volumes than men even in HC. Thus, we conclude that subcortical volumes may not be primarily affected by disrupted sexual dimorphism in emerging psychosis. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Regional brain glucose metabolism in patients with brain tumors before and after radiotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, G.J.; Volkow, N.D.; Lau, Y.H.

1994-05-01

This study was performed to measure regional glucose metabolism in nonaffected brain regions of patients with primary or metastatic brain tumors. Seven female and four male patients (mean age 51.5{plus_minus}14.0 years old) were compared with eleven age and sex matched normal subjects. None of the patients had hydrocephalus and/or increased intracranial pressure. Brain glucose metabolism was measured using FDG-PET scan. Five of the patients were reevaluated one week after receiving radiation treatment (RT) to the brain. Patients were on Decadron and/or Dilantin at the time of both scan. PET images were analyzed with a template of 115 nonoverlapping regions ofmore » interest and then grouped into eight gray matter regions on each hemisphere. Brain regions with tumors and edema shown in MR imaging were excluded. Z scores were used to compare individual patients` regional values with those of normal subjects. The number of regional values with Z scores of less than - 3.0 were considered abnormal and were quantified. The mean global glucose metabolic rate (mean of all regions) in nonaffected brain regions of patients was significantly lower than that of normal controls (32.1{plus_minus}9.0 versus 44.8{plus_minus}6.3 {mu}mol/100g/min, p<0.001). Analyses of individual subjects revealed that none of the controls and 8 of the 11 patients had at least one abnormal region. In these 8 patients the regions which were abnormal were most frequently localized in right (n=5) and left occipital (n=6) and right orbital frontal cortex (n=7) whereas the basal ganglia was not affected. Five of the patients who had repeated scans following RT showed decrements in tumor metabolism (41{plus_minus}20.5%) and a significant increase in whole brain metabolism (8.6{plus_minus}5.3%, p<0.001). The improvement in whole brain metabolism after RT suggests that the brain metabolic decrements in the patients were related to the presence of tumoral tissue and not just a medication effect.« less

Assessing age-related gray matter decline with voxel-based morphometry depends significantly on segmentation and normalization procedures

PubMed Central

Callaert, Dorothée V.; Ribbens, Annemie; Maes, Frederik; Swinnen, Stephan P.; Wenderoth, Nicole

2014-01-01

Healthy ageing coincides with a progressive decline of brain gray matter (GM) ultimately affecting the entire brain. For a long time, manual delineation-based volumetry within predefined regions of interest (ROI) has been the gold standard for assessing such degeneration. Voxel-Based Morphometry (VBM) offers an automated alternative approach that, however, relies critically on the segmentation and spatial normalization of a large collection of images from different subjects. This can be achieved via different algorithms, with SPM5/SPM8, DARTEL of SPM8 and FSL tools (FAST, FNIRT) being three of the most frequently used. We complemented these voxel based measurements with a ROI based approach, whereby the ROIs are defined by transforms of an atlas (containing different tissue probability maps as well as predefined anatomic labels) to the individual subject images in order to obtain volumetric information at the level of the whole brain or within separate ROIs. Comparing GM decline between 21 young subjects (mean age 23) and 18 elderly (mean age 66) revealed that volumetric measurements differed significantly between methods. The unified segmentation/normalization of SPM5/SPM8 revealed the largest age-related differences and DARTEL the smallest, with FSL being more similar to the DARTEL approach. Method specific differences were substantial after segmentation and most pronounced for the cortical structures in close vicinity to major sulci and fissures. Our findings suggest that algorithms that provide only limited degrees of freedom for local deformations (such as the unified segmentation and normalization of SPM5/SPM8) tend to overestimate between-group differences in VBM results when compared to methods providing more flexible warping. This difference seems to be most pronounced if the anatomy of one of the groups deviates from custom templates, a finding that is of particular importance when results are compared across studies using different VBM methods. PMID:25002845

Diffusion-weighted magnetic resonance imaging of the fetal brain in intrauterine growth restriction.

PubMed

Arthurs, O J; Rega, A; Guimiot, F; Belarbi, N; Rosenblatt, J; Biran, V; Elmaleh, M; Sebag, G; Alison, M

2017-07-01

Diffusion-weighted magnetic resonance imaging (DWI) is a sensitive method for assessing brain maturation and detecting brain lesions, providing apparent diffusion coefficient (ADC) values as a measure of water diffusion. Abnormal ADC values are seen in ischemic brain lesions, such as those associated with acute or chronic hypoxia. The aim of this study was to assess whether ADC values in the fetal brain were different in fetuses with severe intrauterine growth restriction (IUGR) compared with normal controls. Brain magnetic resonance imaging (MRI) with single-shot axial DWI (b = 0 and b = 700 s/mm 2 ) was performed in 30 fetuses with severe IUGR (estimated fetal weight < 3 rd centile with absent or reversed umbilical artery Doppler flow) and in 24 normal controls of similar gestational age. Brain morphology and biometry were analyzed. ADC values were measured in frontal and occipital white matter, centrum semiovale, thalami, cerebellar hemisphere and pons. Frontal-occipital and frontal-cerebellar ADC ratios were calculated, and values were compared between IUGR fetuses and controls. There was no difference in gestational age at MRI between IUGR and control fetuses (IUGR, 30.2 ± 1.6 weeks vs controls, 30.7 ± 1.4 weeks). Fetal brain morphology and signals were normal in all fetuses. Brain dimensions (supratentorial ± infratentorial) were decreased (Z-score, < -2) in 20 (66.7%) IUGR fetuses. Compared with controls, IUGR fetuses had significantly lower ADC values in frontal white matter (1.97 ± 0.23 vs 2.17 ± 0.22 × 10 -3 mm 2 /s; P < 0.0001), thalami (1.04 ± 0.15 vs 1.13 ± 0.10 ×10 -3 mm 2 /s; P = 0.0002), centrum semiovale (1.86 ± 0.22 vs 1.97 ± 0.23 ×10 -3 mm 2 /s; P = 0.01) and pons (0.85 ± 0.19 vs 0.94 ± 0.12 ×10 -3 mm 2 /s; P = 0.043). IUGR fetuses had a lower frontal-occipital ADC ratio than did normal fetuses (1.00 ± 0.11 vs 1.08 ± 0.05; P = 0.003). ADC values in IUGR fetuses were significantly lower than in normal controls in the frontal white matter, thalami, centrum semiovale and pons, suggesting abnormal maturation in these regions. However, the prognostic value of these ADC changes is still unknown. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Association between Dopamine D4 Receptor Polymorphism and Age Related Changes in Brain Glucose Metabolism

PubMed Central

Volkow, Nora D.; Tomasi, Dardo; Wang, Gene-Jack; Telang, Frank; Fowler, Joanna S.; Goldstein, Rita Z.; Klein, Nelly; Wong, Christopher; Swanson, James M.; Shumay, Elena

2013-01-01

Aging is associated with reductions in brain glucose metabolism in some cortical and subcortical regions, but the rate of decrease varies significantly between individuals, likely reflecting genetic and environmental factors and their interactions. Here we test the hypothesis that the variant of the dopamine receptor D4 (DRD4) gene (VNTR in exon 3), which has been associated with novelty seeking and sensitivity to environmental stimuli (negative and positive) including the beneficial effects of physical activity on longevity, influence the effects of aging on the human brain. We used positron emission tomography (PET) and [18F]fluoro-D-glucose (18FDG) to measure brain glucose metabolism (marker of brain function) under baseline conditions (no stimulation) in 82 healthy individuals (age range 22–55 years). We determined their DRD4 genotype and found an interaction with age: individuals who did not carry the 7-repeat allele (7R−, n = 53) had a significant (p<0.0001) negative association between age and relative glucose metabolism (normalized to whole brain glucose metabolism) in frontal (r = −0.52), temporal (r = −0.51) and striatal regions (r = −0.47, p<0.001); such that older individuals had lower metabolism than younger ones. In contrast, for carriers of the 7R allele (7R+ n = 29), these correlations with age were not significant and they only showed a positive association with cerebellar glucose metabolism (r = +0.55; p = 0.002). Regression slopes of regional brain glucose metabolism with age differed significantly between the 7R+ and 7R− groups in cerebellum, inferior temporal cortex and striatum. These results provide evidence that the DRD4 genotype might modulate the associations between regional brain glucose metabolism and age and that the carriers of the 7R allele appear to be less sensitive to the effects of age on brain glucose metabolism. PMID:23717434

Mitochondrial Complex 1 Activity Measured by Spectrophotometry Is Reduced across All Brain Regions in Ageing and More Specifically in Neurodegeneration.

PubMed

Pollard, Amelia Kate; Craig, Emma Louise; Chakrabarti, Lisa

2016-01-01

Mitochondrial function, in particular complex 1 of the electron transport chain (ETC), has been shown to decrease during normal ageing and in neurodegenerative disease. However, there is some debate concerning which area of the brain has the greatest complex 1 activity. It is important to identify the pattern of activity in order to be able to gauge the effect of age or disease related changes. We determined complex 1 activity spectrophotometrically in the cortex, brainstem and cerebellum of middle aged mice (70-71 weeks), a cerebellar ataxic neurodegeneration model (pcd5J) and young wild type controls. We share our updated protocol on the measurements of complex1 activity and find that mitochondrial fractions isolated from frozen tissues can be measured for robust activity. We show that complex 1 activity is clearly highest in the cortex when compared with brainstem and cerebellum (p<0.003). Cerebellum and brainstem mitochondria exhibit similar levels of complex 1 activity in wild type brains. In the aged brain we see similar levels of complex 1 activity in all three-brain regions. The specific activity of complex 1 measured in the aged cortex is significantly decreased when compared with controls (p<0.0001). Both the cerebellum and brainstem mitochondria also show significantly reduced activity with ageing (p<0.05). The mouse model of ataxia predictably has a lower complex 1 activity in the cerebellum, and although reductions are measured in the cortex and brain stem, the remaining activity is higher than in the aged brains. We present clear evidence that complex 1 activity decreases across the brain with age and much more specifically in the cerebellum of the pcd5j mouse. Mitochondrial impairment can be a region specific phenomenon in disease, but in ageing appears to affect the entire brain, abolishing the pattern of higher activity in cortical regions.

Evaluating Alzheimer's disease biomarkers as mediators of age-related cognitive decline.

PubMed

Hohman, Timothy J; Tommet, Doug; Marks, Shawn; Contreras, Joey; Jones, Rich; Mungas, Dan

2017-10-01

Age-related changes in cognition are partially mediated by the presence of neuropathology and neurodegeneration. This manuscript evaluates the degree to which biomarkers of Alzheimer's disease, (AD) neuropathology and longitudinal changes in brain structure, account for age-related differences in cognition. Data from the AD Neuroimaging Initiative (n = 1012) were analyzed, including individuals with normal cognition and mild cognitive impairment. Parallel process mixed effects regression models characterized longitudinal trajectories of cognitive variables and time-varying changes in brain volumes. Baseline age was associated with both memory and executive function at baseline (p's < 0.001) and change in memory and executive function performances over time (p's < 0.05). After adjusting for clinical diagnosis, baseline, and longitudinal changes in brain volume, and baseline levels of cerebrospinal fluid biomarkers, age effects on change in episodic memory and executive function were fully attenuated, age effects on baseline memory were substantially attenuated, but an association remained between age and baseline executive function. Results support previous studies that show that age effects on cognitive decline are fully mediated by disease and neurodegeneration variables but also show domain-specific age effects on baseline cognition, specifically an age pathway to executive function that is independent of brain and disease pathways. Copyright © 2017 Elsevier Inc. All rights reserved.

Age- and disease-dependent increase of the mitophagy marker phospho-ubiquitin in normal aging and Lewy body disease.

PubMed

Hou, Xu; Fiesel, Fabienne C; Truban, Dominika; Castanedes Casey, Monica; Lin, Wen-Lang; Soto, Alexandra I; Tacik, Pawel; Rousseau, Linda G; Diehl, Nancy N; Heckman, Michael G; Lorenzo-Betancor, Oswaldo; Ferrer, Isidre; Arbelo, José M; Steele, John C; Farrer, Matthew J; Cornejo-Olivas, Mario; Torres, Luis; Mata, Ignacio F; Graff-Radford, Neill R; Wszolek, Zbigniew K; Ross, Owen A; Murray, Melissa E; Dickson, Dennis W; Springer, Wolfdieter

2018-06-27

Although exact causes of Parkinson disease (PD) remain enigmatic, mitochondrial dysfunction is increasingly appreciated as a key determinant of dopaminergic neuron susceptibility in both familial and sporadic PD. Two genes associated with recessive, early-onset PD encode the ubiquitin (Ub) kinase PINK1 and the E3 Ub ligase PRKN/PARK2/Parkin, which together orchestrate a protective mitochondrial quality control (mitoQC) pathway. Upon stress, both enzymes cooperatively identify and decorate damaged mitochondria with phosphorylated poly-Ub (p-S65-Ub) chains. This specific label is subsequently recognized by autophagy receptors that further facilitate mitochondrial degradation in lysosomes (mitophagy). Here, we analyzed human post-mortem brain specimens and identified distinct pools of p-S65-Ub-positive structures that partially colocalized with markers of mitochondria, autophagy, lysosomes and/or granulovacuolar degeneration bodies. We further quantified levels and distribution of the 'mitophagy tag' in 2 large cohorts of brain samples from normal aging and Lewy body disease (LBD) cases using unbiased digital pathology. Somatic p-S65-Ub structures independently increased with age and disease in distinct brain regions and enhanced levels in LBD brain were age- and Braak tangle stage-dependent. Additionally, we observed significant correlations of p-S65-Ub with LBs and neurofibrillary tangle levels in disease. The degree of co-existing p-S65-Ub signals and pathological PD hallmarks increased in the pre-mature stage, but decreased in the late stage of LB or tangle aggregation. Altogether, our study provides further evidence for a potential pathogenic overlap among different forms of PD and suggests that p-S65-Ub can serve as a biomarker for mitochondrial damage in aging and disease.

Stable Microsaccades and Microsaccade-Induced Global Alpha Band Phase Reset Across the Life Span.

PubMed

Gao, Ying; Huber, Carl; Sabel, Bernhard A

2018-04-01

To understand the effect of aging on microsaccade functions and brain physiologic responses, we quantified microsaccades and their physiologic correlates (including their interaction with alpha band brain oscillation) in normal subjects of different ages. Twenty-two normally sighted young (18 to 29 years), 22 middle-aged (31 to 55 years), and 22 elderly subjects (56 to 77 years) participated in this cross-sectional study. Dense array EEG and high-resolution eye-tracking data were simultaneously recorded during a fixation task. We quantified microsaccade features, spike potential (SP), microsaccadic lambda response (MLR) and microsaccade-related spectral perturbation (ERSP), and intertrial coherence (ITC) in the alpha and beta frequency bands and compared them between three age groups. After microsaccade onset, (1) alpha band ERSP increased (100 to 150 ms) occipitally and ITC increased (150 to 220 ms) globally in the brain; (2) low beta ITC increased (150 to 220 ms) in occipital and central regions and peaked (0 to 50 ms) in frontal region; and (3) high beta ITC increased (0 to 50 ms) globally with no beta band ERSP changes. Microsaccade features, the latency and amplitude of SP and MLR, and microsaccade-related temporal-spectral power and synchronization dynamics were all stable across different age groups. Microsaccades are well preserved in aging and can be used as reference points for studying neurodegenerative or neuro-ophthalmologic diseases where the oculomotor system is affected. Microsaccade-induced alpha band activity is a potential biomarker to better understand and monitor these diseases, and we propose that microsaccades trigger "cortical refreshment" by resetting alpha band phase globally to prepare (sensitize) the brain for subsequent visual processing.

Late sequelae in children treated for brain tumors and leukemia.

PubMed

Jereb, B; Korenjak, R; Krzisnik, C; Petric-Grabnar, G; Zadravec-Zaletel, L; Anzic, J; Stare, J

1994-01-01

Forty-two survivors treated at an age of 2-16 years for brain tumors or leukemia were, 4-21 years after treatment, subjected to an extensive follow-up investigation, including physical examination and interview; 35 of them also had endocrinological and 33 psychological evaluation. Hormonal deficiencies were found in about two-thirds of patients and were most common in those treated for brain tumors. The great majority had verbal intelligence quotient (VIQ) within normal range. Also, the performance intelligence quotients (PIQ) were normal in most patients. However, the results suggested that the primary intellectual capacity in children treated for cancer was not being fully utilized, their PIQ being on the average higher than their VIQ; this tendency was especially pronounced in the leukemia patients.

Age-related changes of task-specific brain activity in normal aging.

PubMed

Ho, Ming-Chung; Chou, Chia-Yi; Huang, Chin-Fei; Lin, Yu-Te; Shih, Ching-Sen; Han, Shiang-Yi; Shen, Ming-Hsun; Chen, Tsung-Ching; Liang, Chi-lin; Lu, Ming-Chi; Liu, Chia-Ju

2012-01-17

An important question in healthcare for older patients is whether age-related changes in cortical reorganization can be measured with advancing age. This study investigated the factors behind such age-related changes, using time-frequency analysis of event-related potentials (ERPs). We hypothesized that brain rhythms was affected by age-related changes, which could be reflected in the ERP indices. An oddball task was conducted in two experimental groups, namely young participants (N=15; mean age 23.7±2.8 years) and older participants (N=15; mean age 70.1±7.9 years). Two types of stimuli were used: the target (1 kHz frequency) and standard (2 kHz frequency). We scrutinized three ERP indices: event-related spectral power (ERPSP), inter-trial phase-locking (ITPL), and event-related cross-phase coherence (ERPCOH). Both groups performed equally well for correct response rate. However, the results revealed a statistically significant age difference for inter-trial comparison. Compared with the young, the older participants showed the following age-related changes: (a) power activity decreased; however, an increase was found only in the late (P3, 280-450 ms) theta (4-7 Hz) component over the bilateral frontal and temporo-frontal areas; (b) low phase-locking in the early (N1, 80-140 ms) theta band over the parietal/frontal (right) regions appeared; (c) the functional connections decreased in the alpha (7-13 Hz) and beta (13-30 Hz) bands, but no difference emerged in the theta band between the two groups. These results indicate that age-related changes in task-specific brain activity for a normal aging population can be depicted using the three ERP indices. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Indestructible plastic: the neuroscience of the new aging brain

PubMed Central

Holman, Constance; de Villers-Sidani, Etienne

2014-01-01

In recent years, research on experience-dependent plasticity has provided valuable insight on adaptation to environmental input across the lifespan, and advances in understanding the minute cellular changes underlying the brain’s capacity for self-reorganization have opened exciting new possibilities for treating illness and injury. Ongoing work in this line of inquiry has also come to deeply influence another field: cognitive neuroscience of the normal aging. This complex process, once considered inevitable or beyond the reach of treatment, has been transformed into an arena of intense investigation and strategic intervention. However, important questions remain about this characterization of the aging brain, and the assumptions it makes about the social, cultural, and biological space occupied by cognition in the older individual and body. The following paper will provide a critical examination of the move from basic experiments on the neurophysiology of experience-dependent plasticity to the growing market for (and public conception of) cognitive aging as a medicalized space for intervention by neuroscience-backed technologies. Entangled with changing concepts of normality, pathology, and self-preservation, we will argue that this new understanding, led by personalized cognitive training strategies, is approaching a point where interdisciplinary research is crucial to provide a holistic and nuanced understanding of the aging process. This new outlook will allow us to move forward in a space where our knowledge, like our new conception of the brain, is never static. PMID:24782746

A study of the standard brain in Japanese children: morphological comparison with the MNI template.

PubMed

Uchiyama, Hitoshi T; Seki, Ayumi; Tanaka, Daisuke; Koeda, Tatsuya; Jcs Group

2013-03-01

Functional magnetic resonance imaging (MRI) studies involve normalization so that the brains of different subjects can be described using the same coordinate system. However, standard brain templates, including the Montreal Neurological Institute (MNI) template that is most frequently used at present, were created based on the brains of Western adults. Because morphological characteristics of the brain differ by race and ethnicity and between adults and children, errors are likely to occur when data from the brains of non-Western individuals are processed using these templates. Therefore, this study was conducted to collect basic data for the creation of a Japanese pediatric standard brain. Participants in this study were 45 healthy children (contributing 65 brain images) between the ages of 6 and 9 years, who had nothing notable in their perinatal and other histories and neurological findings, had normal physical findings and cognitive function, exhibited no behavioral abnormalities, and provided analyzable MR images. 3D-T1-weighted images were obtained using a 1.5-T MRI device, and images from each child were adjusted to the reference image by affine transformation using SPM8. The lengths were measured and compared with those of the MNI template. The Western adult standard brain and the Japanese pediatric standard brain obtained in this study differed greatly in size, particularly along the anteroposterior diameter and in height, suggesting that the correction rates are high, and that errors are likely to occur in the normalization of pediatric brain images. We propose that the use of the Japanese pediatric standard brain created in this study will improve the accuracy of identification of brain regions in functional brain imaging studies involving children. Copyright © 2012 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Neocortical Transplants in the Mammalian Brain Lack a Blood-Brain Barrier to Macromolecules

NASA Astrophysics Data System (ADS)

Rosenstein, Jeffrey M.

1987-02-01

In order to determine whether the blood-brain barrier was present in transplants of central nervous tissue, fetal neocortex, which already possesses blood-brain and blood-cerebrospinal fluid barriers to protein, was grafted into the undamaged fourth ventricle or directly into the neocortex of recipient rats. Horseradish peroxidase or a conjugated human immunoglobulin G-peroxidase molecule was systemically administered into the host. These proteins were detected within the cortical transplants within 2 minutes regardless of the age of the donor or postoperative time. At later times these compounds, which normally do not cross the blood-brain barrier, inundated the grafts and adjacent host brain and also entered the cerebrospinal fluid. Endogenous serum albumin detected immunocytochemically in untreated hosts had a comparable although less extensive distribution. Thus, transplants of fetal central nervous tissue have permanent barrier dysfunction, probably due to microvascular changes, and are not integrated physiologically within the host. Blood-borne compounds, either systemically administered or naturally occurring, which should never contact normal brain tissue, have direct access to these transplants and might affect neuronal function.

Relationship between brain R(2) and liver and serum iron concentrations in elderly men.

PubMed

House, Michael J; St Pierre, Timothy G; Milward, Elizabeth A; Bruce, David G; Olynyk, John K

2010-02-01

Studies of iron overload in humans and animals suggest that brain iron concentrations may be related in a regionally specific way to body iron status. However, few quantitative studies have investigated the associations between peripheral and regional brain iron in a normal elderly cohort. To examine these relationships, we used MRI to measure the proton transverse relaxation rate (R(2)) in 13 gray and white matter brain regions in 18 elderly men (average age, 75.5 years) with normal cognition. Brain R(2) values were compared with liver iron concentrations measured using the FerriScan MRI technique and serum iron indices. R(2) values in high-iron gray matter regions were significantly correlated (positively) with liver iron concentrations (globus pallidus, ventral pallidum) and serum transferrin saturation (caudate nucleus, globus pallidus, putamen) measured concurrently with brain R(2), and with serum iron concentrations (caudate nucleus, globus pallidus) measured three years before the current study. Our results suggest that iron levels in specific gray matter brain regions are influenced by systemic iron status in elderly men.

Cognitive Decline in Patients with Chronic Hydrocephalus and Normal Aging: ‘Growing into Deficits’

PubMed Central

de Beer, Marlijn H.; Scheltens, Philip

2016-01-01

Background/Aim To explore the theory of ‘growing into deficits’, a concept known from developmental neurology, in a series of cases with chronic hydrocephalus (CH). Methods Patients were selected from the Amsterdam Dementia Cohort and underwent extensive dementia screening. Results Twelve patients with CH were selected, in whom Alzheimer's disease was considered unlikely, based on biomarker information and follow-up. Mean Mini-Mental State Examination score was 24 (range 7-30). Most patients were functioning on a level of mild dementia [Clinical Dementia Rating score of 0.5 in 8/11 (66.7%) patients]. On neuropsychological examination, memory and executive functions, as well as processing speed were most frequently impaired. Conclusion In our opinion, the theory of ‘growing into deficits’ shows a parallel with the clinical course of CH and normal aging when Alzheimer's disease was considered very unlikely, because most of these patients were functioning well for a very large part of their lives. The altered cerebrospinal fluid dynamics might make the brain more vulnerable to aging-related changes, leading to a faster cognitive decline in CH patients compared to healthy subjects, especially in case of concomitant brain damage such as traumatic brain injury or meningitis. PMID:27920793

Neuropathology of White Matter Lesions, Blood-Brain Barrier Dysfunction, and Dementia.

PubMed

Hainsworth, Atticus H; Minett, Thais; Andoh, Joycelyn; Forster, Gillian; Bhide, Ishaan; Barrick, Thomas R; Elderfield, Kay; Jeevahan, Jamuna; Markus, Hugh S; Bridges, Leslie R

2017-10-01

We tested whether blood-brain barrier dysfunction in subcortical white matter is associated with white matter abnormalities or risk of clinical dementia in older people (n=126; mean age 86.4, SD: 7.7 years) in the MRC CFAS (Medical Research Council Cognitive Function and Ageing Study). Using digital pathology, we quantified blood-brain barrier dysfunction (defined by immunohistochemical labeling for the plasma marker fibrinogen). This was assessed within subcortical white matter tissue samples harvested from postmortem T 2 magnetic resonance imaging (MRI)-detected white matter hyperintensities, from normal-appearing white matter (distant from coexistent MRI-defined hyperintensities), and from equivalent areas in MRI normal brains. Histopathologic lesions were defined using a marker for phagocytic microglia (CD68, clone PGM1). Extent of fibrinogen labeling was not significantly associated with white matter abnormalities defined either by MRI (odds ratio, 0.90; 95% confidence interval, 0.79-1.03; P =0.130) or by histopathology (odds ratio, 0.93; 95% confidence interval, 0.77-1.12; P =0.452). Among participants with normal MRI (no detectable white matter hyperintensities), increased fibrinogen was significantly related to decreased risk of clinical dementia (odds ratio, 0.74; 95% confidence interval, 0.58-0.94; P =0.013). Among participants with histological lesions, increased fibrinogen was related to increased risk of dementia (odds ratio, 2.26; 95% confidence interval, 1.25-4.08; P =0.007). Our data suggest that some degree of blood-brain barrier dysfunction is common in older people and that this may be related to clinical dementia risk, additional to standard MRI biomarkers. © 2017 American Heart Association, Inc.

Daily supplementation with mushroom (Agaricus bisporus) improves balance and working memory in aged rats

USDA-ARS?s Scientific Manuscript database

Animals and humans show decrements in motor control, cognition, and brain function during normal aging, partly due to the long-term effects of oxidative stress and inflammation. Recent studies have identified a number of fruits and vegetables, whose phytochemical make-up contains potent antioxidant ...

Long-term influence of normal variation in neonatal characteristics on human brain development

PubMed Central

Walhovd, Kristine B.; Fjell, Anders M.; Brown, Timothy T.; Kuperman, Joshua M.; Chung, Yoonho; Hagler, Donald J.; Roddey, J. Cooper; Erhart, Matthew; McCabe, Connor; Akshoomoff, Natacha; Amaral, David G.; Bloss, Cinnamon S.; Libiger, Ondrej; Schork, Nicholas J.; Darst, Burcu F.; Casey, B. J.; Chang, Linda; Ernst, Thomas M.; Frazier, Jean; Gruen, Jeffrey R.; Kaufmann, Walter E.; Murray, Sarah S.; van Zijl, Peter; Mostofsky, Stewart; Dale, Anders M.; Jernigan, Terry L.; McCabe, Connor; Chang, Linda; Akshoomoff, Natacha; Newman, Erik; Dale, Anders M.; Ernst, Thomas; Dale, Anders M.; Van Zijl, Peter; Kuperman, Joshua; Murray, Sarah; Bloss, Cinnamon; Schork, Nicholas J.; Appelbaum, Mark; Gamst, Anthony; Thompson, Wesley; Bartsch, Hauke; Jernigan, Terry L.; Dale, Anders M.; Akshoomoff, Natacha; Chang, Linda; Ernst, Thomas; Keating, Brian; Amaral, David; Sowell, Elizabeth; Kaufmann, Walter; Van Zijl, Peter; Mostofsky, Stewart; Casey, B.J.; Ruberry, Erika J.; Powers, Alisa; Rosen, Bruce; Kenet, Tal; Frazier, Jean; Kennedy, David; Gruen, Jeffrey

2012-01-01

It is now recognized that a number of cognitive, behavioral, and mental health outcomes across the lifespan can be traced to fetal development. Although the direct mediation is unknown, the substantial variance in fetal growth, most commonly indexed by birth weight, may affect lifespan brain development. We investigated effects of normal variance in birth weight on MRI-derived measures of brain development in 628 healthy children, adolescents, and young adults in the large-scale multicenter Pediatric Imaging, Neurocognition, and Genetics study. This heterogeneous sample was recruited through geographically dispersed sites in the United States. The influence of birth weight on cortical thickness, surface area, and striatal and total brain volumes was investigated, controlling for variance in age, sex, household income, and genetic ancestry factors. Birth weight was found to exert robust positive effects on regional cortical surface area in multiple regions as well as total brain and caudate volumes. These effects were continuous across birth weight ranges and ages and were not confined to subsets of the sample. The findings show that (i) aspects of later child and adolescent brain development are influenced at birth and (ii) relatively small differences in birth weight across groups and conditions typically compared in neuropsychiatric research (e.g., Attention Deficit Hyperactivity Disorder, schizophrenia, and personality disorders) may influence group differences observed in brain parameters of interest at a later stage in life. These findings should serve to increase our attention to early influences. PMID:23169628

Long-term influence of normal variation in neonatal characteristics on human brain development.

PubMed

Walhovd, Kristine B; Fjell, Anders M; Brown, Timothy T; Kuperman, Joshua M; Chung, Yoonho; Hagler, Donald J; Roddey, J Cooper; Erhart, Matthew; McCabe, Connor; Akshoomoff, Natacha; Amaral, David G; Bloss, Cinnamon S; Libiger, Ondrej; Schork, Nicholas J; Darst, Burcu F; Casey, B J; Chang, Linda; Ernst, Thomas M; Frazier, Jean; Gruen, Jeffrey R; Kaufmann, Walter E; Murray, Sarah S; van Zijl, Peter; Mostofsky, Stewart; Dale, Anders M

2012-12-04

It is now recognized that a number of cognitive, behavioral, and mental health outcomes across the lifespan can be traced to fetal development. Although the direct mediation is unknown, the substantial variance in fetal growth, most commonly indexed by birth weight, may affect lifespan brain development. We investigated effects of normal variance in birth weight on MRI-derived measures of brain development in 628 healthy children, adolescents, and young adults in the large-scale multicenter Pediatric Imaging, Neurocognition, and Genetics study. This heterogeneous sample was recruited through geographically dispersed sites in the United States. The influence of birth weight on cortical thickness, surface area, and striatal and total brain volumes was investigated, controlling for variance in age, sex, household income, and genetic ancestry factors. Birth weight was found to exert robust positive effects on regional cortical surface area in multiple regions as well as total brain and caudate volumes. These effects were continuous across birth weight ranges and ages and were not confined to subsets of the sample. The findings show that (i) aspects of later child and adolescent brain development are influenced at birth and (ii) relatively small differences in birth weight across groups and conditions typically compared in neuropsychiatric research (e.g., Attention Deficit Hyperactivity Disorder, schizophrenia, and personality disorders) may influence group differences observed in brain parameters of interest at a later stage in life. These findings should serve to increase our attention to early influences.

High Resolution Topography of Age-Related Changes in Non-Rapid Eye Movement Sleep Electroencephalography

PubMed Central

Sprecher, Kate E.; Riedner, Brady A.; Smith, Richard F.; Tononi, Giulio; Davidson, Richard J.; Benca, Ruth M.

2016-01-01

Sleeping brain activity reflects brain anatomy and physiology. The aim of this study was to use high density (256 channel) electroencephalography (EEG) during sleep to characterize topographic changes in sleep EEG power across normal aging, with high spatial resolution. Sleep was evaluated in 92 healthy adults aged 18–65 years old using full polysomnography and high density EEG. After artifact removal, spectral power density was calculated for standard frequency bands for all channels, averaged across the NREM periods of the first 3 sleep cycles. To quantify topographic changes with age, maps were generated of the Pearson’s coefficient of the correlation between power and age at each electrode. Significant correlations were determined by statistical non-parametric mapping. Absolute slow wave power declined significantly with increasing age across the entire scalp, whereas declines in theta and sigma power were significant only in frontal regions. Power in fast spindle frequencies declined significantly with increasing age frontally, whereas absolute power of slow spindle frequencies showed no significant change with age. When EEG power was normalized across the scalp, a left centro-parietal region showed significantly less age-related decline in power than the rest of the scalp. This partial preservation was particularly significant in the slow wave and sigma bands. The effect of age on sleep EEG varies substantially by region and frequency band. This non-uniformity should inform the design of future investigations of aging and sleep. This study provides normative data on the effect of age on sleep EEG topography, and provides a basis from which to explore the mechanisms of normal aging as well as neurodegenerative disorders for which age is a risk factor. PMID:26901503

Aging and Gene Expression in the Primate Brain

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fraser, Hunter B.; Khaitovich, Philipp; Plotkin, Joshua B.

2005-02-18

It is well established that gene expression levels in many organisms change during the aging process, and the advent of DNA microarrays has allowed genome-wide patterns of transcriptional changes associated with aging to be studied in both model organisms and various human tissues. Understanding the effects of aging on gene expression in the human brain is of particular interest, because of its relation to both normal and pathological neurodegeneration. Here we show that human cerebral cortex, human cerebellum, and chimpanzee cortex each undergo different patterns of age-related gene expression alterations. In humans, many more genes undergo consistent expression changes inmore » the cortex than in the cerebellum; in chimpanzees, many genes change expression with age in cortex, but the pattern of changes in expression bears almost no resemblance to that of human cortex. These results demonstrate the diversity of aging patterns present within the human brain, as well as how rapidly genome-wide patterns of aging can evolve between species; they may also have implications for the oxidative free radical theory of aging, and help to improve our understanding of human neurodegenerative diseases.« less

Establishing age-associated normative ranges of the cerebral 18F-FDG uptake ratio in children.

PubMed

Hua, Chiaho; Merchant, Thomas E; Li, Xingyu; Li, Yimei; Shulkin, Barry L

2015-04-01

In this study, we reported age-associated ranges of the regional cerebral (18)F-FDG uptake ratio in pediatric patients as a surrogate to normative data from healthy children. (18)F-FDG PET scans of 132 children and adolescents (age, 1-20 y) with non-central nervous system-related diseases and normal-appearing tracer distributions in the brain were retrospectively analyzed. PET images of individual patients were warped to a 3-dimensional reference template. Uptake ratio was calculated for 63 anatomic regions by normalizing the regional count per voxel with the average count per voxel in all regions. Models of regional uptake ratio as a function of age and sex were developed to calculate the 95% prediction interval. The paracentral lobule and cuneus had the highest resting metabolic state among all gray matter regions, whereas the brain stem, uncus, and hippocampus had the lowest uptake. A large left-right asymmetry was present in the angular gyrus and inferior occipital gyrus. Quantitative data of the regression, 95% confidence interval, and 95% prediction interval for each age were summarized for the 63 regions. In 52 of 63 regions, the (18)F-FDG uptake ratio had a significant age effect. The linear model was optimal for 12 regions, whereas the spline model with 1 age knot was a better fit for 40 regions. In children younger than 5 y, frontal and temporal lobes had a lower uptake than parietal and occipital lobes in general. However, uptake in the frontal lobe continued to increase with age but it decreased in the parietal and occipital lobes. Anatomic regions of the brain in children and adolescents exhibited uniquely different (18)F-FDG uptake trends with age. Our results may be useful for studying childhood development and possibly regional metabolic defects in children with traumatic brain injury or central nervous system disorders or children receiving cancer treatment. © 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

Networks of myelin covariance.

PubMed

Melie-Garcia, Lester; Slater, David; Ruef, Anne; Sanabria-Diaz, Gretel; Preisig, Martin; Kherif, Ferath; Draganski, Bogdan; Lutti, Antoine

2018-04-01

Networks of anatomical covariance have been widely used to study connectivity patterns in both normal and pathological brains based on the concurrent changes of morphometric measures (i.e., cortical thickness) between brain structures across subjects (Evans, ). However, the existence of networks of microstructural changes within brain tissue has been largely unexplored so far. In this article, we studied in vivo the concurrent myelination processes among brain anatomical structures that gathered together emerge to form nonrandom networks. We name these "networks of myelin covariance" (Myelin-Nets). The Myelin-Nets were built from quantitative Magnetization Transfer data-an in-vivo magnetic resonance imaging (MRI) marker of myelin content. The synchronicity of the variations in myelin content between anatomical regions was measured by computing the Pearson's correlation coefficient. We were especially interested in elucidating the effect of age on the topological organization of the Myelin-Nets. We therefore selected two age groups: Young-Age (20-31 years old) and Old-Age (60-71 years old) and a pool of participants from 48 to 87 years old for a Myelin-Nets aging trajectory study. We found that the topological organization of the Myelin-Nets is strongly shaped by aging processes. The global myelin correlation strength, between homologous regions and locally in different brain lobes, showed a significant dependence on age. Interestingly, we also showed that the aging process modulates the resilience of the Myelin-Nets to damage of principal network structures. In summary, this work sheds light on the organizational principles driving myelination and myelin degeneration in brain gray matter and how such patterns are modulated by aging. © 2017 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.

Dysfunctional whole brain networks in mild cognitive impairment patients: an fMRI study

NASA Astrophysics Data System (ADS)

Liu, Zhenyu; Bai, Lijun; Dai, Ruwei; Zhong, Chongguang; Xue, Ting; You, Youbo; Tian, Jie

2012-03-01

Mild cognitive impairment (MCI) was recognized as the prodromal stage of Alzheimer's disease (AD). Recent researches have shown that cognitive and memory decline in AD patients is coupled with losses of small-world attributes. However, few studies pay attention to the characteristics of the whole brain networks in MCI patients. In the present study, we investigated the topological properties of the whole brain networks utilizing graph theoretical approaches in 16 MCI patients, compared with 18 age-matched healthy subjects as a control. Both MCI patients and normal controls showed small-world architectures, with large clustering coefficients and short characteristic path lengths. We detected significantly longer characteristic path length in MCI patients compared with normal controls at the low sparsity. The longer characteristic path lengths in MCI indicated disrupted information processing among distant brain regions. Compared with normal controls, MCI patients showed decreased nodal centrality in the brain areas of the angular gyrus, heschl gyrus, hippocampus and superior parietal gyrus, while increased nodal centrality in the calcarine, inferior occipital gyrus and superior frontal gyrus. These changes in nodal centrality suggested a widespread rewiring in MCI patients, which may be an integrated reflection of reorganization of the brain networks accompanied with the cognitive decline. Our findings may be helpful for further understanding the pathological mechanisms of MCI.

Congenital Amusia Persists in the Developing Brain after Daily Music Listening

PubMed Central

Mignault Goulet, Geneviève; Moreau, Patricia; Robitaille, Nicolas; Peretz, Isabelle

2012-01-01

Congenital amusia is a neurodevelopmental disorder that affects about 3% of the adult population. Adults experiencing this musical disorder in the absence of macroscopically visible brain injury are described as cases of congenital amusia under the assumption that the musical deficits have been present from birth. Here, we show that this disorder can be expressed in the developing brain. We found that (10–13 year-old) children exhibit a marked deficit in the detection of fine-grained pitch differences in both musical and acoustical context in comparison to their normally developing peers comparable in age and general intelligence. This behavioral deficit could be traced down to their abnormal P300 brain responses to the detection of subtle pitch changes. The altered pattern of electrical activity does not seem to arise from an anomalous functioning of the auditory cortex, because all early components of the brain potentials, the N100, the MMN, and the P200 appear normal. Rather, the brain and behavioral measures point to disrupted information propagation from the auditory cortex to other cortical regions. Furthermore, the behavioral and neural manifestations of the disorder remained unchanged after 4 weeks of daily musical listening. These results show that congenital amusia can be detected in childhood despite regular musical exposure and normal intellectual functioning. PMID:22606299

Quantitative susceptibility map analysis in preterm neonates with germinal matrix-intraventricular hemorrhage.

PubMed

Tortora, Domenico; Severino, Mariasavina; Sedlacik, Jan; Toselli, Benedetta; Malova, Mariya; Parodi, Alessandro; Morana, Giovanni; Fato, Marco Massimo; Ramenghi, Luca Antonio; Rossi, Andrea

2018-05-10

Germinal matrix-intraventricular hemorrhage (GMH-IVH) is a common form of intracranial hemorrhage occurring in preterm neonates that may affect normal brain development. Although the primary lesion is easily identified on MRI by the presence of blood products, its exact extent may not be recognizable with conventional sequences. Quantitative susceptibility mapping (QSM) quantify the spatial distribution of magnetic susceptibility within biological tissues, including blood degradation products. To evaluate magnetic susceptibility of normal-appearing white (WM) and gray matter regions in preterm neonates with and without GMH-IVH. Retrospective case-control. A total of 127 preterm neonates studied at term equivalent age: 20 had mild GMH-IVH (average gestational age 28.7 ± 2.1 weeks), 15 had severe GMH-IVH (average gestational age 29.3 ± 1.8 weeks), and 92 had normal brain MRI (average gestational age 29.8 ± 1.8 weeks). QSM at 1.5 Tesla. QSM analysis was performed for each brain hemisphere with a region of interest-based approach including five WM regions (centrum semiovale, frontal, parietal, temporal, and cerebellum), and a subcortical gray matter region (basal ganglia/thalami). Changes in magnetic susceptibility were explored using a one-way analysis of covariance, according to GMH-IVH severity (P < 0.05). In preterm neonates with normal brain MRI, all white and subcortical gray matter regions had negative magnetic susceptibility values (diamagnetic). Neonates with severe GMH-IVH showed higher positive magnetic susceptibility values (i.e. paramagnetic) in the centrum semiovale (0.0019 versus -0.0014 ppm; P < 0.001), temporal WM (0.0011 versus -0.0012 ppm; P = 0.037), and parietal WM (0.0005 versus -0.0001 ppm; P = 0.002) compared with controls. No differences in magnetic susceptibility were observed between neonates with mild GMH-IVH and controls (P = 0.236). Paramagnetic susceptibility changes occur in several normal-appearing WM regions of neonates with severe GMH-IVH, likely related to the accumulation of hemosiderin/ferritin iron secondary to diffusion of extracellular hemoglobin from the ventricle into the periventricular WM. 4 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2018. © 2018 International Society for Magnetic Resonance in Medicine.

Plasma levels of 24S-hydroxycholesterol reflect the balance between cerebral production and hepatic metabolism and are inversely related to body surface.

PubMed

Bretillon, L; Lütjohann, D; Ståhle, L; Widhe, T; Bindl, L; Eggertsen, G; Diczfalusy, U; Björkhem, I

2000-05-01

We have previously presented evidence that most of the 24S-hydroxycholesterol present in the circulation originates from the brain and that most of the elimination of this oxysterol occurs in the liver. Plasma 24S-hydroxycholesterol levels decline by a factor of about 5 during the first decades of life. The concentration of the enzyme cholesterol 24S-hydroxylase in the brain is, however, about constant from the first year of life, and reduced enzyme levels thus cannot explain the decreasing plasma levels during infancy. In the present work we tested the hypothesis that the plasma levels of 24S-hydroxycholesterol may reflect the size of the brain relative to the capacity of the liver to eliminate the substance. It is shown here that the age-dependent changes in absolute as well as cholesterol-related plasma level of 24S-hydroxycholesterol closely follow the changes in the ratio between estimated brain weight and estimated liver volume. The size of the brain is increased only about 50% whereas the size of the liver is increased by about 6-fold after the age of 1 year. Liver volume is known to be highly correlated to body surface, and in accordance with this the absolute as well as the cholesterol-related plasma level of 24S-hydroxycholesterol was found to be highly inversely correlated to body surface in 77 healthy subjects of varying ages (r(2) = 0.74). Two chondrodystrophic dwarves with normal size of the brain but with markedly reduced body area had increased levels of 24S-hydroxycholesterol when related to age but normal levels when related to body surface. It is concluded that the balance between cerebral production and hepatic metabolism is a critical determinant for plasma levels of 24S-hydroxycholesterol at different ages and that endocrinological factors are less important. The results are discussed in relation to the possibility to use 24S-hydroxycholesterol in the circulation as a marker for cholesterol homeostasis in the brain.

A Study of volumetric variations of basal nuclei in the normal human brain by magnetic resonance imaging.

PubMed

Elkattan, Amal; Mahdy, Amal; Eltomey, Mohamed; Ismail, Radwa

2017-03-01

Knowledge of the effects of healthy aging on brain structures is necessary to identify abnormal changes due to diseases. Many studies have demonstrated age-related volume changes in the brain using MRI. 60 healthy individuals who had normal MRI aged from 20 years to 80 years were examined and classified into three groups: Group I: 21 persons; nine males and 12 females aging between 20-39 years old. Group II: 22 persons; 11 males and 11 females aging between 40-59 years old. Group III: 17 persons; eight males and nine females aging between 60-80 years old. Volumetric analysis was done to evaluate the effect of age, gender and hemispheric difference in the caudate and putamen by the slicer 4.3.3.1 software using 3D T1-weighted images. Data were analyzed by student's unpaired t test, ANOVA and regression analysis. The volumes of the measured and corrected caudate nuclei and putamen significantly decreased with aging in males. There was a statistically insignificant relation between the age and the volume of the measured caudate nuclei and putamen in females but there was a statistically significant relation between the age and the corrected caudate nuclei and putamen. There was no significant difference on the caudate and putamen volumes between males and females. There was no significant difference between the right and left caudate nuclei volumes. There was a leftward asymmetry in the putamen volumes. The results can be considered as a base to track individual changes with time (aging and CNS diseases). Clin. Anat. 30:175-182, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Clinical utility of third-trimester uterine artery Doppler in the prediction of brain hemodynamic deterioration and adverse perinatal outcome in small-for-gestational-age fetuses.

PubMed

Cruz-Martinez, R; Savchev, S; Cruz-Lemini, M; Mendez, A; Gratacos, E; Figueras, F

2015-03-01

To assess the clinical value of third-trimester uterine artery (UtA) Doppler ultrasound in the prediction of hemodynamic deterioration and adverse perinatal outcome in term small-for-gestational-age (SGA) fetuses. UtA Doppler parameters, cerebroplacental ratio (CPR) and fetal middle cerebral artery (MCA) pulsatility index (PI) were evaluated weekly, starting from the time of SGA diagnosis until 24 h before induction of labor, in a cohort of 327 SGA fetuses with normal umbilical artery PI (< 95th centile), delivered at > 37 weeks' gestation. Differences in the sequence of CPR and MCA-PI changes < 5th centile, between the group with normal UtA Doppler indices at diagnosis and those with abnormal UtA indices, were analyzed by survival analysis. In addition, the use of UtA Doppler value, alone or in combination with a brain Doppler scan before delivery, to predict the risk of Cesarean section, Cesarean section for non-reassuring fetal status (NRFS), neonatal acidosis and neonatal hospitalization was evaluated by logistic regression analysis, adjusted for gestational age at birth and birth-weight percentile. Abnormal UtA Doppler at diagnosis of SGA was associated with a higher risk of developing abnormal brain Doppler indices before induction of labor than in those with a normal UtA at diagnosis (62.7% vs 34.6%, respectively; P < 0.01). Compared to those with normal UtA Doppler indices, those with abnormal UtA Doppler findings were associated with a higher risk of intrapartum Cesarean section (52.2% vs 37.3%, respectively; P = 0.03), Cesarean section for NRFS (35.8% vs 23.1%, respectively; P = 0.03), neonatal acidosis (10.4% vs 7.7%, respectively; P = 0.47) and neonatal hospitalization (23.9% vs 16.5%, respectively; P = 0.16). Logistic regression analysis indicated that UtA Doppler findings were not significantly associated with adverse perinatal outcome independent of brain Doppler findings. UtA Doppler indices predict adverse perinatal outcome, but do not help to improve the predictive value of brain Doppler indices. However, at the time of SGA diagnosis they identify the subgroup of fetuses at highest risk of progression to abnormal brain Doppler findings. Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.

Dynamic relationships between age, amyloid-β deposition, and glucose metabolism link to the regional vulnerability to Alzheimer’s disease

PubMed Central

Madison, Cindee; Baker, Suzanne; Rabinovici, Gil; Jagust, William

2016-01-01

Abstract See Hansson and Gouras (doi:10.1093/aww146) for a scientific commentary on this article. Although some brain regions such as precuneus and lateral temporo-parietal cortex have been shown to be more vulnerable to Alzheimer’s disease than other areas, a mechanism underlying the differential regional vulnerability to Alzheimer’s disease remains to be elucidated. Using fluorodeoxyglucose and Pittsburgh compound B positron emission tomography imaging glucose metabolism and amyloid-β deposition, we tested whether and how life-long changes in glucose metabolism relate to amyloid-β deposition and Alzheimer’s disease-related hypometabolism. Nine healthy young adults (age range: 20–30), 96 cognitively normal older adults (age range: 61–96), and 20 patients with Alzheimer’s disease (age range: 50–90) were scanned using fluorodeoxyglucose and Pittsburgh compound B positron emission tomography. Among cognitively normal older subjects, 32 were further classified as amyloid-positive, with 64 as amyloid-negative. To assess the contribution of glucose metabolism to the regional vulnerability to amyloid-β deposition, we defined the highest and lowest metabolic regions in young adults and examined differences in amyloid deposition between these regions across groups. Two-way analyses of variance were conducted to assess regional differences in age and amyloid-β-related changes in glucose metabolism. Multiple regressions were applied to examine the association between amyloid-β deposition and regional glucose metabolism. Both region of interest and whole-brain voxelwise analyses were conducted to complement and confirm the results derived from the other approach. Regional differences in glucose metabolism between the highest and lowest metabolism regions defined in young adults (T = 12.85, P < 0.001) were maintained both in Pittsburgh compound B-negative cognitively normal older subjects (T = 6.66, P < 0.001) and Pittsburgh compound B-positive cognitively normal older subjects (T = 10.62, P < 0.001), but, only the Pittsburgh compound B-positive cognitively normal older subjects group showed significantly higher Pittsburgh compound B retention in the highest compared to the lowest glucose metabolism regions defined in young adults (T = 2.05, P < 0.05). Regional differences in age and amyloid-β-dependent changes in glucose metabolism were found such that frontal glucose metabolism was reduced with age, while glucose metabolism in the precuneus was maintained across the lifespan (right hemisphere: F = 7.69, P < 0.001; left hemisphere: F = 8.69, P < 0.001). Greater Alzheimer’s disease-related hypometabolism was observed in brain regions that showed both age-invariance and amyloid-β-related increases in glucose metabolism. Our results indicate that although early and life-long regional variation in glucose metabolism relates to the regional vulnerability to amyloid-β accumulation, Alzheimer’s disease-related hypometabolism is more specific to brain regions showing age-invariant glucose metabolism and amyloid-β-related hypermetabolism. PMID:27190008

Age Drives Distortion of Brain Metabolic, Vascular and Cognitive Functions, and the Gut Microbiome

PubMed Central

Hoffman, Jared D.; Parikh, Ishita; Green, Stefan J.; Chlipala, George; Mohney, Robert P.; Keaton, Mignon; Bauer, Bjoern; Hartz, Anika M. S.; Lin, Ai-Ling

2017-01-01

Advancing age is the top risk factor for the development of neurodegenerative disorders, including Alzheimer’s disease (AD). However, the contribution of aging processes to AD etiology remains unclear. Emerging evidence shows that reduced brain metabolic and vascular functions occur decades before the onset of cognitive impairments, and these reductions are highly associated with low-grade, chronic inflammation developed in the brain over time. Interestingly, recent findings suggest that the gut microbiota may also play a critical role in modulating immune responses in the brain via the brain-gut axis. In this study, our goal was to identify associations between deleterious changes in brain metabolism, cerebral blood flow (CBF), gut microbiome and cognition in aging, and potential implications for AD development. We conducted our study with a group of young mice (5–6 months of age) and compared those to old mice (18–20 months of age) by utilizing metabolic profiling, neuroimaging, gut microbiome analysis, behavioral assessments and biochemical assays. We found that compared to young mice, old mice had significantly increased levels of numerous amino acids and fatty acids that are highly associated with inflammation and AD biomarkers. In the gut microbiome analyses, we found that old mice had increased Firmicutes/Bacteroidetes ratio and alpha diversity. We also found impaired blood-brain barrier (BBB) function and reduced CBF as well as compromised learning and memory and increased anxiety, clinical symptoms often seen in AD patients, in old mice. Our study suggests that the aging process involves deleterious changes in brain metabolic, vascular and cognitive functions, and gut microbiome structure and diversity, all which may lead to inflammation and thus increase the risk for AD. Future studies conducting comprehensive and integrative characterization of brain aging, including crosstalk with peripheral systems and factors, will be necessary to define the mechanisms underlying the shift from normal aging to pathological processes in the etiology of AD. PMID:28993728

DNA methylation age is not accelerated in brain or blood of subjects with schizophrenia.

PubMed

McKinney, Brandon C; Lin, Huang; Ding, Ying; Lewis, David A; Sweet, Robert A

2017-10-05

Individuals with schizophrenia (SZ) exhibit multiple premature age-related phenotypes and die ~20years prematurely. The accelerated aging hypothesis of SZ has been advanced to explain these observations, it posits that SZ-associated factors accelerate the progressive biological changes associated with normal aging. Testing the hypothesis has been limited by the absence of robust, meaningful, and multi-tissue measures of biological age. Recently, a method was described in which DNA methylation (DNAm) levels at 353 genomic sites are used to produce "DNAm age", an estimate of biological age with advantages over existing measures. We used this method and 3 publicly-available DNAm datasets, 1 from brain and 2 from blood, to test the hypothesis. The brain dataset was composed of data from the dorsolateral prefrontal cortex of 232 non-psychiatric control (NPC) and 195 SZ subjects. Blood dataset #1 was composed of data from whole blood of 304 NPC and 332 SZ subjects, and blood dataset #2 was composed of data from whole blood of 405 NPC and 260 SZ subjects. DNAm age and chronological age correlated strongly (r=0.92-0.95, p<0.0001) in both NPC and SZ subjects in all 3 datasets. DNAm age acceleration did not differ between NPC and SZ subjects in the brain dataset (t=0.52, p=0.60), blood dataset #1 (t=1.51, p=0.13), or blood dataset #2 (t=0.93, p=0.35). Consistent with our previous findings from a smaller study of postmortem brains, our findings suggest there is no acceleration of brain or blood aging in SZ and, thus, do not support the accelerated aging hypothesis of SZ. Copyright © 2017 Elsevier B.V. All rights reserved.

Socialization of prosocial behavior: Gender differences in the mediating role of child brain volume.

PubMed

Kok, Rianne; Prinzie, Peter; Bakermans-Kranenburg, Marian J; Verhulst, Frank C; White, Tonya; Tiemeier, Henning; van IJzendoorn, Marinus H

2018-08-01

Evidence has been accumulating for the impact of normal variation in caregiving quality on brain morphology in children, but the question remains whether differences in brain volume related to early caregiving translate to behavioral implications. In this longitudinal population-based study (N = 162), moderated mediation was tested for the relation between parental sensitivity and child prosocial behavior via brain volume, in boys and girls. Both maternal and paternal sensitivity were repeatedly observed between 1 and 4 years of age. Brain volume was assessed using magnetic resonance imaging measurements at age 8, and self-reported prosocial behavior of children was assessed at 9 years of age. Parental sensitivity was positively related to child brain volume, and to child prosocial behavior at trend level. Child brain volume was negatively related to child prosocial behavior. A significant gender-by-brain interaction was found, illustrating that daughters of sensitive parents were more prosocial and that less prosocial behavior was reported for girls with a larger total brain volume. Child gender significantly moderated the indirect effect of parental sensitivity on prosocial behavior via total brain volume. A significant indirect pathway was found only in girls. The results warrant replication but indicate the importance of considering gender when studying the behavioral implications of differences in brain volume related to early caregiving experiences.

Is NAA reduction in normal contralateral cerebral tissue in stroke patients dependent on underlying risk factors?

PubMed

Walker, P M; Ben Salem, D; Giroud, M; Brunotte, F

2006-05-01

This retrospective study investigated the dependence of N-acetyl aspartate (NAA) ratios on risk factors for cerebral vasculopathy such as sex, age, hypertension, diabetes mellitus, carotid stenosis, and dyslipidaemia, which may have affected brain vessels and induced metabolic brain abnormalities prior to stroke. We hypothesise that in stroke patients metabolic alterations in the apparently normal contralateral brain are dependent on the presence or not of such risk factors. Fifty nine patients (31 male, 28 female: 58.8+/-16.1 years old) with cortical middle cerebral artery (MCA) territory infarction were included. Long echo time chemical shift imaging spectroscopy was carried out on a Siemens 1.5 T Magnetom Vision scanner using a multi-voxel PRESS technique. Metabolite ratios (NAA/choline, NAA/creatine, lactate/choline, etc) were studied using uni- and multivariate analyses with respect to common risk factors. The influence of age, stroke lesion size, and time since stroke was studied using a linear regression approach. Age, sex, and hypertension all appeared to individually influence metabolite ratios, although only hypertension was significant after multivariate analysis. In both basal ganglia and periventricular white matter regions in apparently normal contralateral brain, the NAA/choline ratio was significantly lower in hypertensive (1.37+/-0.16 and 1.50+/-0.19, respectively) than in normotensive patients (1.72+/-0.19 and 1.85+/-0.15, respectively). Regarding MCA infarction, contralateral tissue remote from the lesion behaves abnormally in the presence of hypertension, the NAA ratios in hypertensive patients being significantly lower. These data suggest that hypertension may compromise the use of contralateral tissue data as a reference for comparison with ischaemic tissue.

Factors Influencing Neurocognitive Outcomes in Young Patients With Benign and Low-Grade Brain Tumors Treated With Stereotactic Conformal Radiotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jalali, Rakesh, E-mail: rjalali@tmc.gov.i; Mallick, Indranil; Dutta, Debnarayan

2010-07-15

Purpose: To present the effect of radiotherapy doses to different volumes of normal structures on neurocognitive outcomes in young patients with benign and low-grade brain tumors treated prospectively with stereotactic conformal radiotherapy (SCRT). Methods and Materials: Twenty-eight patients (median age, 13 years) with residual/progressive brain tumors (10 craniopharyngioma, 8 cerebellar astrocytoma, 6 optic pathway glioma and 4 cerebral low-grade glioma) were treated with SCRT to a dose of 54 Gy in 30 fractions over 6 weeks. Prospective neuropsychological assessments were done at baseline before RT and at subsequent follow-up examinations. The change in intelligence quotient (IQ) scores was correlated withmore » various factors, including dose-volume to normal structures. Results: Although the overall mean full-scale IQ (FSIQ) at baseline before RT remained unchanged at 2-year follow-up after SCRT, one third of patients did show a >10% decline in FSIQ as compared with baseline. Logistic regression analysis demonstrated that patients aged <15 years had a significantly higher chance of developing a >10% drop in FSIQ than older patients (53% vs. 10%, p = 0.03). Dosimetric comparison in patients showing a >10% decline vs. patients showing a <10% decline in IQ revealed that patients receiving >43.2 Gy to >13% of volume of the left temporal lobe were the ones to show a significant drop in FSIQ (p = 0.048). Radiotherapy doses to other normal structures, including supratentorial brain, right temporal lobe, and frontal lobes, did not reveal any significant correlation. Conclusion: Our prospectively collected dosimetric data show younger age and radiotherapy doses to left temporal lobe to be predictors of neurocognitive decline, and may well be used as possible dose constraints for high-precision radiotherapy planning.« less

Networks of myelin covariance

PubMed Central

Slater, David; Ruef, Anne; Sanabria‐Diaz, Gretel; Preisig, Martin; Kherif, Ferath; Draganski, Bogdan; Lutti, Antoine

2017-01-01

Abstract Networks of anatomical covariance have been widely used to study connectivity patterns in both normal and pathological brains based on the concurrent changes of morphometric measures (i.e., cortical thickness) between brain structures across subjects (Evans, 2013). However, the existence of networks of microstructural changes within brain tissue has been largely unexplored so far. In this article, we studied in vivo the concurrent myelination processes among brain anatomical structures that gathered together emerge to form nonrandom networks. We name these “networks of myelin covariance” (Myelin‐Nets). The Myelin‐Nets were built from quantitative Magnetization Transfer data—an in‐vivo magnetic resonance imaging (MRI) marker of myelin content. The synchronicity of the variations in myelin content between anatomical regions was measured by computing the Pearson's correlation coefficient. We were especially interested in elucidating the effect of age on the topological organization of the Myelin‐Nets. We therefore selected two age groups: Young‐Age (20–31 years old) and Old‐Age (60–71 years old) and a pool of participants from 48 to 87 years old for a Myelin‐Nets aging trajectory study. We found that the topological organization of the Myelin‐Nets is strongly shaped by aging processes. The global myelin correlation strength, between homologous regions and locally in different brain lobes, showed a significant dependence on age. Interestingly, we also showed that the aging process modulates the resilience of the Myelin‐Nets to damage of principal network structures. In summary, this work sheds light on the organizational principles driving myelination and myelin degeneration in brain gray matter and how such patterns are modulated by aging. PMID:29271053

Brain-derived neurotrophic factor transgenic mice exhibit passive avoidance deficits, increased seizure severity and in vitro hyperexcitability in the hippocampus and entorhinal cortex.

PubMed

Croll, S D; Suri, C; Compton, D L; Simmons, M V; Yancopoulos, G D; Lindsay, R M; Wiegand, S J; Rudge, J S; Scharfman, H E

1999-01-01

Transgenic mice overexpressing brain-derived neurotrophic factor from the beta-actin promoter were tested for behavioral, gross anatomical and physiological abnormalities. Brain-derived neurotrophic factor messenger RNA overexpression was widespread throughout brain. Overexpression declined with age, such that levels of overexpression decreased sharply by nine months. Brain-derived neurotrophic factor transgenic mice had no gross deformities or behavioral abnormalities. However, they showed a significant passive avoidance deficit. This deficit was dependent on continued overexpression, and resolved with age as brain-derived neurotrophic factor transcripts decreased. In addition, the brain-derived neurotrophic factor transgenic mice showed increased seizure severity in response to kainic acid. Hippocampal slices from brain-derived neurotrophic factor transgenic mice showed hyperexcitability in area CA3 and entorhinal cortex, but not in dentate gyrus. Finally, area CA1 long-term potentiation was disrupted, indicating abnormal plasticity. Our data suggest that overexpression of brain-derived neurotrophic factor in the brain can interfere with normal brain function by causing learning impairments and increased excitability. The results also support the hypothesis that excess brain-derived neurotrophic factor could be pro-convulsant in the limbic system.

Structural MRI markers of brain aging early after ischemic stroke.

PubMed

Werden, Emilio; Cumming, Toby; Li, Qi; Bird, Laura; Veldsman, Michele; Pardoe, Heath R; Jackson, Graeme; Donnan, Geoffrey A; Brodtmann, Amy

2017-07-11

To examine associations between ischemic stroke, vascular risk factors, and MRI markers of brain aging. Eighty-one patients (mean age 67.5 ± 13.1 years, 31 left-sided, 61 men) with confirmed first-ever (n = 66) or recurrent (n = 15) ischemic stroke underwent 3T MRI scanning within 6 weeks of symptom onset (mean 26 ± 9 days). Age-matched controls (n = 40) completed identical testing. Multivariate regression analyses examined associations between group membership and MRI markers of brain aging (cortical thickness, total brain volume, white matter hyperintensity [WMH] volume, hippocampal volume), normalized against intracranial volume, and the effects of vascular risk factors on these relationships. First-ever stroke was associated with smaller hippocampal volume ( p = 0.025) and greater WMH volume ( p = 0.004) relative to controls. Recurrent stroke was in turn associated with smaller hippocampal volume relative to both first-ever stroke ( p = 0.017) and controls ( p = 0.001). These associations remained significant after adjustment for age, sex, education, and, in stroke patients, infarct volume. Total brain volume was not significantly smaller in first-ever stroke patients than in controls ( p = 0.056), but the association became significant after further adjustment for atrial fibrillation ( p = 0.036). Cortical thickness and brain volumes did not differ as a function of stroke type, infarct volume, or etiology. Brain structure is likely to be compromised before ischemic stroke by vascular risk factors. Smaller hippocampal and total brain volumes and increased WMH load represent proxies for underlying vascular brain injury. Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

The developing human brain: age-related changes in cortical, subcortical, and cerebellar anatomy.

PubMed

Sussman, Dafna; Leung, Rachel C; Chakravarty, M Mallar; Lerch, Jason P; Taylor, Margot J

2016-04-01

This study is the first to characterize normal development and sex differences across neuroanatomical structures in cortical, subcortical, and cerebellar brain regions in a single large cohort. One hundred and ninety-two magnetic resonance images were examined from 96 typically developing females and 96 age-matched typically developing males from 4 to 18 years of age. Image segmentation of the cortex was conducted with CIVET, while that of the cerebellum, hippocampi, thalamus, and basal ganglia were conducted using the MAGeT algorithm. Cortical thickness analysis revealed that most cortical regions decrease linearly, while surface area increases linearly with age. Volume relative to total cerebrum followed a quadratic trend with age, with only the left supramarginal gyrus showing sexual dimorphism. Hippocampal relative volume increased linearly, while the thalamus, caudate, and putamen decreased linearly, and the cerebellum did not change with age. The relative volumes of several subcortical subregions followed inverted U-shaped trends that peaked at ~12 years of age. Many subcortical structures were found to be larger in females than in males, independently of age, while others showed a sex-by-age interaction. This study provides a comprehensive assessment of cortical, subcortical, and cerebellar growth patterns during normal development, and draws attention to the role of sex on neuroanatomical maturation throughout childhood and adolescence.

Brain ultrasound findings in neonates treated with intrauterine transfusion for fetal anaemia.

PubMed

Leijser, Lara M; Vos, Nikki; Walther, Frans J; van Wezel-Meijler, Gerda

2012-09-01

The main causes of severe fetal anaemia are red-cell allo-immunization, parvo B19 virus infection and feto-maternal haemorrhage. Treatment consists of intrauterine transfusion (IUT). Neuro-imaging studies in surviving neonates treated with IUT are scarce. To assess if neonates treated with IUT for fetal anaemia are at risk for cerebral injury, report the incidence and severity of brain ultrasound (US) abnormalities and explore the relation between brain US findings and perinatal parameters and neurological outcome. Brain US scans of neonates born alive between 2001 and 2008 with at least one IUT were retrospectively reviewed and classified as normal, mildly or moderately/severely abnormal. Incidences of abnormalities were calculated for full-term and preterm neonates. Presence and severity of abnormalities were related to clinical and IUT related parameters and to neurological outcome around 2 years of age (adverse: moderate or severe disability; favourable: normal or mild disability). A total of 127 neonates (82 born preterm) were included. Median number of IUTs was 3 (range 1-6) and of brain US 2 (1-6). Median gestational age and weight at birth were 36.6 (26.0-41.1) weeks and 2870 (1040-3950)g. In 72/127 (57%) neonates ≥1 abnormality was seen on brain US, classified as moderate/severe in 30/127 (24%). Neurological outcome was adverse in 5 infants. Presence of brain US abnormalities was not significantly related to any of the perinatal parameters or to neurological outcome. Neonates undergoing IUT for fetal anaemia are at high risk of brain injury. Copyright © 2012 Elsevier Ltd. All rights reserved.

Modifiable Risk Factors and Brain PET Measures of Amyloid and Tau in Non-Demented Adults with Memory Complaints

PubMed Central

Merrill, David A.; Siddarth, Prabha; Raji, Cyrus A.; Emerson, Natacha D.; Rueda, Florangel; Ercoli, Linda M.; Miller, Karen J.; Lavretsky, Helen; Harris, Laurel M.; Burggren, Alison C.; Bookheimer, Susan Y.; Barrio, Jorge R.; Small, Gary W.

2016-01-01

Objective Exercise and diet impact body composition, but their age-related brain effects are unclear at the molecular imaging level. To address these issues, we determined whether body mass index (BMI), physical activity, and diet relate to brain positron emission tomography (PET) of amyloid plaques and tau tangles using 2-(1-(6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl)ethylidene)malononitrile (FDDNP). Methods Volunteers (n = 44, mean age = 62.6 ± 10.7 years) with subjective memory impairment (n = 24) or mild cognitive impairment (MCI; n = 20) were recruited by soliciting for memory complaints. Levels of physical activity and extent of following a Mediterranean-type diet were self-reported. FDDNP-PET scans assessed plaque/tangle binding in Alzheimer’s disease (AD)-associated regions (frontal, parietal, medial and lateral temporal, posterior cingulate). Mixed models controlling for known covariates examined BMI, physical activity, and diet in relation to FDDNP-PET. Results MCI subjects with above normal BMI (>25) had higher FDDNP-PET binding compared to those with normal BMI (1.11(.03) vs 1.08(.03), ES=1.04, t(35)=3.3, p=.002). Greater physical activity was associated with lower FDDNP-PET binding in MCI subjects (1.07(.03) vs 1.11(.03), ES=1.13, t(35) =−3.1, p=.004) but not in subjects with subjective memory impairment (1.07 (.03) vs 1.07(.03), ES=.02, t(35)=−0.1, p=.9). Healthier diet related to lower FDDNP-PET binding, regardless of cognitive status (1.07(.03) vs 1.09(.02), ES=0.72, t(35)=−2.1, p = .04). Conclusion and Relevance These preliminary findings are consistent with a relationship between risk modifiers and brain plaque/tangle deposition in non-demented individuals and supports maintenance of normal body weight, regular physical activity, and healthy diet adherence to protect the brain during aging. PMID:27421618

[The Prevalence and Risk Factors of Dementia in Centenarians].

PubMed

Arai, Yasumichi

2017-07-01

Centenarians are less susceptible to the diseases, functional losses and dependencies related to old age than the general public, and are therefore regarded as model cases of successful aging. For this reason, an important focus of the study of centenarians is their relative resilience to age-related cognitive decline or dementia. In the Tokyo Centenarian Study, we found approximately 60% of centenarians to have dementia; however, supercentenarians (those people living at least 110 years) maintained normal cognitive function at 100 years of age. Our preliminary data also demonstrated extremely low frequencies of the apolipoprotein E4 allele in supercentenarians. Moreover, postmortem brain samples from supercentenarians demonstrated relatively mild age-related neuropathological findings. Therefore, a more extensive investigation of supercentenarian populations might provide insight into successful brain aging.

Linear and curvilinear correlations of brain gray matter volume and density with age using voxel-based morphometry with the Akaike information criterion in 291 healthy children.

PubMed

Taki, Yasuyuki; Hashizume, Hiroshi; Thyreau, Benjamin; Sassa, Yuko; Takeuchi, Hikaru; Wu, Kai; Kotozaki, Yuka; Nouchi, Rui; Asano, Michiko; Asano, Kohei; Fukuda, Hiroshi; Kawashima, Ryuta

2013-08-01

We examined linear and curvilinear correlations of gray matter volume and density in cortical and subcortical gray matter with age using magnetic resonance images (MRI) in a large number of healthy children. We applied voxel-based morphometry (VBM) and region-of-interest (ROI) analyses with the Akaike information criterion (AIC), which was used to determine the best-fit model by selecting which predictor terms should be included. We collected data on brain structural MRI in 291 healthy children aged 5-18 years. Structural MRI data were segmented and normalized using a custom template by applying the diffeomorphic anatomical registration using exponentiated lie algebra (DARTEL) procedure. Next, we analyzed the correlations of gray matter volume and density with age in VBM with AIC by estimating linear, quadratic, and cubic polynomial functions. Several regions such as the prefrontal cortex, the precentral gyrus, and cerebellum showed significant linear or curvilinear correlations between gray matter volume and age on an increasing trajectory, and between gray matter density and age on a decreasing trajectory in VBM and ROI analyses with AIC. Because the trajectory of gray matter volume and density with age suggests the progress of brain maturation, our results may contribute to clarifying brain maturation in healthy children from the viewpoint of brain structure. Copyright © 2012 Wiley Periodicals, Inc.

Spatial working memory deficits in children at ages 3-4 who were low birth weight, preterm infants.

PubMed

Vicari, Stefano; Caravale, Barbara; Carlesimo, Giovanni Augusto; Casadei, Anna Maria; Allemand, Federico

2004-10-01

The aim of this study was to investigate attention and perceptual and spatial working memory abilities in preterm, low birth weight preschool children without evident brain disorders as determined by normal cerebral ultrasound findings and normal motor development. The authors evaluated 19 preterm and 19 typically developing children who were matched for IQ and chronological age. Results indicated that children born prematurely without major neurological deficits and with a normal cognitive level may have specific difficulty in sustained attention, visuospatial processing, and spatial working memory when evaluated at ages 3-4. This finding is relevant for understanding the qualitative aspects of cognitive development in preterm children and the neurobiological substrate underlying this development.

Cardiac index is associated with brain aging: the Framingham Heart Study.

PubMed

Jefferson, Angela L; Himali, Jayandra J; Beiser, Alexa S; Au, Rhoda; Massaro, Joseph M; Seshadri, Sudha; Gona, Philimon; Salton, Carol J; DeCarli, Charles; O'Donnell, Christopher J; Benjamin, Emelia J; Wolf, Philip A; Manning, Warren J

2010-08-17

Cardiac dysfunction is associated with neuroanatomic and neuropsychological changes in aging adults with prevalent cardiovascular disease, theoretically because systemic hypoperfusion disrupts cerebral perfusion, contributing to subclinical brain injury. We hypothesized that cardiac function, as measured by cardiac index, would be associated with preclinical brain magnetic resonance imaging (MRI) and neuropsychological markers of ischemia and Alzheimer disease in the community. Brain MRI, cardiac MRI, neuropsychological, and laboratory data were collected on 1504 Framingham Offspring Cohort participants free of clinical stroke, transient ischemic attack, or dementia (age, 61+/-9 years; 54% women). Neuropsychological and brain MRI variables were related to cardiac MRI-assessed cardiac index (cardiac output/body surface area). In multivariable-adjusted models, cardiac index was positively related to total brain volume (P=0.03) and information processing speed (P=0.02) and inversely related to lateral ventricular volume (P=0.048). When participants with clinically prevalent cardiovascular disease were excluded, the relation between cardiac index and total brain volume remained (P=0.02). Post hoc comparisons revealed that participants in the bottom cardiac index tertile (values <2.54) and middle cardiac index tertile (values between 2.54 and 2.92) had significantly lower brain volumes (P=0.04) than participants in the top cardiac index tertile (values >2.92). Although observational data cannot establish causality, our findings are consistent with the hypothesis that decreasing cardiac function, even at normal cardiac index levels, is associated with accelerated brain aging.

Intrinsic Brain Activity of Cognitively Normal Older Persons Resembles More That of Patients Both with and at Risk for Alzheimer's Disease Than That of Healthy Younger Persons

PubMed Central

Pasquini, Lorenzo; Tonch, Annika; Plant, Claudia; Zherdin, Andrew; Ortner, Marion; Kurz, Alexander; Förstl, Hans; Zimmer, Claus; Grimmer, Timo; Wohlschäger, Afra; Riedl, Valentin

2014-01-01

Abstract In Alzheimer's disease (AD), recent findings suggest that amyloid-β (Aβ)-pathology might start 20–30 years before first cognitive symptoms arise. To account for age as most relevant risk factor for sporadic AD, it has been hypothesized that lifespan intrinsic (i.e., ongoing) activity of hetero-modal brain areas with highest levels of functional connectivity triggers Aβ-pathology. This model induces the simple question whether in older persons without any cognitive symptoms intrinsic activity of hetero-modal areas is more similar to that of symptomatic patients with AD or to that of younger healthy persons. We hypothesize that due to advanced age and therefore potential impact of pre-clinical AD, intrinsic activity of older persons resembles more that of patients than that of younger controls. We tested this hypothesis in younger (ca. 25 years) and older healthy persons (ca. 70 years) and patients with mild cognitive impairment and AD-dementia (ca. 70 years) by the use of resting-state functional magnetic resonance imaging, distinct measures of intrinsic brain activity, and different hierarchical clustering approaches. Independently of applied methods and involved areas, healthy older persons' intrinsic brain activity was consistently more alike that of patients than that of younger controls. Our result provides evidence for larger similarity in intrinsic brain activity between healthy older persons and patients with or at-risk for AD than between older and younger ones, suggesting a significant proportion of pre-clinical AD cases in the group of cognitively normal older people. The observed link of aging and AD with intrinsic brain activity supports the view that lifespan intrinsic activity may contribute critically to the pathogenesis of AD. PMID:24689864

DNA damage in the oligodendrocyte lineage and its role in brain aging.

PubMed

Tse, Kai-Hei; Herrup, Karl

2017-01-01

Myelination is a recent evolutionary addition that significantly enhances the speed of transmission in the neural network. Even slight defects in myelin integrity impair performance and enhance the risk of neurological disorders. Indeed, myelin degeneration is an early and well-recognized neuropathology that is age associated, but appears before cognitive decline. Myelin is only formed by fully differentiated oligodendrocytes, but the entire oligodendrocyte lineage are clear targets of the altered chemistry of the aging brain. As in neurons, unrepaired DNA damage accumulates in the postmitotic oligodendrocyte genome during normal aging, and indeed may be one of the upstream causes of cellular aging - a fact well illustrated by myelin co-morbidity in premature aging syndromes arising from deficits in DNA repair enzymes. The clinical and experimental evidence from Alzheimer's disease, progeroid syndromes, ataxia-telangiectasia and other conditions strongly suggest that oligodendrocytes may in fact be uniquely vulnerable to oxidative DNA damage. If this damage remains unrepaired, as is increasingly true in the aging brain, myelin gene transcription and oligodendrocyte differentiation is impaired. Delineating the relationships between early myelin loss and DNA damage in brain aging will offer an additional dimension outside the neurocentric view of neurodegenerative disease. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Widespread age-related differences in the human brain microstructure revealed by quantitative magnetic resonance imaging.

PubMed

Callaghan, Martina F; Freund, Patrick; Draganski, Bogdan; Anderson, Elaine; Cappelletti, Marinella; Chowdhury, Rumana; Diedrichsen, Joern; Fitzgerald, Thomas H B; Smittenaar, Peter; Helms, Gunther; Lutti, Antoine; Weiskopf, Nikolaus

2014-08-01

A pressing need exists to disentangle age-related changes from pathologic neurodegeneration. This study aims to characterize the spatial pattern and age-related differences of biologically relevant measures in vivo over the course of normal aging. Quantitative multiparameter maps that provide neuroimaging biomarkers for myelination and iron levels, parameters sensitive to aging, were acquired from 138 healthy volunteers (age range: 19-75 years). Whole-brain voxel-wise analysis revealed a global pattern of age-related degeneration. Significant demyelination occurred principally in the white matter. The observed age-related differences in myelination were anatomically specific. In line with invasive histologic reports, higher age-related differences were seen in the genu of the corpus callosum than the splenium. Iron levels were significantly increased in the basal ganglia, red nucleus, and extensive cortical regions but decreased along the superior occipitofrontal fascicle and optic radiation. This whole-brain pattern of age-associated microstructural differences in the asymptomatic population provides insight into the neurobiology of aging. The results help build a quantitative baseline from which to examine and draw a dividing line between healthy aging and pathologic neurodegeneration. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Widespread age-related differences in the human brain microstructure revealed by quantitative magnetic resonance imaging☆

PubMed Central

Callaghan, Martina F.; Freund, Patrick; Draganski, Bogdan; Anderson, Elaine; Cappelletti, Marinella; Chowdhury, Rumana; Diedrichsen, Joern; FitzGerald, Thomas H.B.; Smittenaar, Peter; Helms, Gunther; Lutti, Antoine; Weiskopf, Nikolaus

2014-01-01

A pressing need exists to disentangle age-related changes from pathologic neurodegeneration. This study aims to characterize the spatial pattern and age-related differences of biologically relevant measures in vivo over the course of normal aging. Quantitative multiparameter maps that provide neuroimaging biomarkers for myelination and iron levels, parameters sensitive to aging, were acquired from 138 healthy volunteers (age range: 19–75 years). Whole-brain voxel-wise analysis revealed a global pattern of age-related degeneration. Significant demyelination occurred principally in the white matter. The observed age-related differences in myelination were anatomically specific. In line with invasive histologic reports, higher age-related differences were seen in the genu of the corpus callosum than the splenium. Iron levels were significantly increased in the basal ganglia, red nucleus, and extensive cortical regions but decreased along the superior occipitofrontal fascicle and optic radiation. This whole-brain pattern of age-associated microstructural differences in the asymptomatic population provides insight into the neurobiology of aging. The results help build a quantitative baseline from which to examine and draw a dividing line between healthy aging and pathologic neurodegeneration. PMID:24656835

Primary cortical folding in the human newborn: an early marker of later functional development.

PubMed

Dubois, J; Benders, M; Borradori-Tolsa, C; Cachia, A; Lazeyras, F; Ha-Vinh Leuchter, R; Sizonenko, S V; Warfield, S K; Mangin, J F; Hüppi, P S

2008-08-01

In the human brain, the morphology of cortical gyri and sulci is complex and variable among individuals, and it may reflect pathological functioning with specific abnormalities observed in certain developmental and neuropsychiatric disorders. Since cortical folding occurs early during brain development, these structural abnormalities might be present long before the appearance of functional symptoms. So far, the precise mechanisms responsible for such alteration in the convolution pattern during intra-uterine or post-natal development are still poorly understood. Here we compared anatomical and functional brain development in vivo among 45 premature newborns who experienced different intra-uterine environments: 22 normal singletons, 12 twins and 11 newborns with intrauterine growth restriction (IUGR). Using magnetic resonance imaging (MRI) and dedicated post-processing tools, we investigated early disturbances in cortical formation at birth, over the developmental period critical for the emergence of convolutions (26-36 weeks of gestational age), and defined early 'endophenotypes' of sulcal development. We demonstrated that twins have a delayed but harmonious maturation, with reduced surface and sulcation index compared to singletons, whereas the gyrification of IUGR newborns is discordant to the normal developmental trajectory, with a more pronounced reduction of surface in relation to the sulcation index compared to normal newborns. Furthermore, we showed that these structural measurements of the brain at birth are predictors of infants' outcome at term equivalent age, for MRI-based cerebral volumes and neurobehavioural development evaluated with the assessment of preterm infant's behaviour (APIB).

DOE Office of Scientific and Technical Information (OSTI.GOV)

Khatoon, S.; Slevin, J.T.; Haley, B.E.

A decrease occurs (80-100%) in the (/sup 32/P)8N/sub 3/GTP photoinsertion into a cytosolic protein (55K M/sub r/) of Alzheimer's (AD) brain, tentatively identified as the ..beta..-subunit of tubulin (co-migration with purified tubulin, concentration dependence of interaction with GTP, ATP and their 8-azido photoprobes, and similar effects of Ca/sup 2 +/ and EDTA on photoinsertion). This agrees with prior observations of (/sup 32/P)8N/sub 3/GTP interactions with brain tubulin and a recent report on faulty microtubular assembly in AD brain. The decrease in (/sup 32/P)8N/sub 3/GTP photoinsertion into the 55K M/sub r/ protein of AD brain was in contrast with other photolabeledmore » proteins, which remained at equal levels in AD and age-matched normal brain tissues. The 55K and 45K M/sub r/ were the two major (/sup 32/P)8N/sub 3/GTP photoinsertion species in non-AD brain. Of 5 AD brains, the photoinsertion of (/sup 32/P)8N/sub 3/GTP into the 55K M/sub r/ region was low or absent in 4 (55K/45K=0.1); one was 75% below normals (55K/45K=0.24). Total protein migrating at 55K M/sub r/ was similar in AD and controls. AD brain tubulin, while present, has its exchangeable GTP binding site on ..beta..-tubulin blocked/modified such that (/sup 32/P)8N/sub 3/GTP cannot interact normally with this site.« less

Cortical venous disease severity in MELAS syndrome correlates with brain lesion development.

PubMed

Whitehead, M T; Wien, M; Lee, B; Bass, N; Gropman, A

2017-08-01

MELAS syndrome is a mitochondrial disorder typified by recurrent stroke-like episodes, seizures, and progressive brain injury. Abnormal mitochondria have been found in arterial walls implicating a vasculogenic etiology. We have observed abnormal cortical vein T2/FLAIR signal in MELAS patients, potentially representing wall thickening and sluggish flow. We sought to examine the relationship of hyperintense veins and brain lesions in MELAS. Imaging databases at two children's hospitals were searched for brain MRIs from MELAS patients. Artifact, sedated exams, and lack of 2D-T2/FLAIR sequences were exclusion criteria. Each exam was assigned a venous score based on number of T2/FLAIR hyperintense veins: 1 = <10, 2 = 10 to 20, 3 = >20. Cumulative brain lesions and venous score in MELAS and aged-matched normal exams were compared by Mann-Whitney test. A total of 106 exams from 14 unique MELAS patients (mean 16 ± 3 years) and 30 exams from normal aged-matched patients (mean 15 ± 3 years) were evaluated. Median venous score between MELAS and control patients significantly differed (3 versus 1; p < 0.001). In the MELAS group, venous score correlated with presence (median = 3) or absence (median = 1) of cumulative brain lesions. In all 8 MELAS patients who developed lesions, venous hyperintensity was present prior to, during, and after lesion onset. Venous score did not correlate with brain lesion acuity. Abnormal venous signal correlates with cumulative brain lesion severity in MELAS syndrome. Cortical venous stenosis, congestion, and venous ischemia may be mechanisms of brain injury. Identification of cortical venous pathology may aid in diagnosis and could be predictive of lesion development.

Is early adulthood a critical developmental stage for psychosis proneness? A survey of delusional ideation in normal subjects.

PubMed

Verdoux, H; van Os, J; Maurice-Tison, S; Gay, B; Salamon, R; Bourgeois, M

1998-02-09

It has been hypothesized that late adolescence and early adulthood might be a brain developmental stage favoring the clinical expression of psychotic symptoms in psychiatric or neurological diseases. The aim of the present survey was to examine the relationship between age and delusional ideation in a sample of subjects with no psychiatric disorder. The survey was carried out with the Aquitaine Sentinel Network of general practitioners. Consecutive practice attenders were invited to complete the PDI-21 (Peters Delusional Inventory 21 items), a self-report questionnaire designed to measure delusional ideation in the normal population. The study concerned 444 patients who had no lifetime history of psychiatric disorder and who completed the PDI-21. A principal component analysis of the PDI-21 items was performed in order to identify delusional dimensions. An age-related decrease in the likelihood to report delusional ideas was found, younger subjects scoring higher on most dimensions of delusional ideation, such as 'persecution', 'thought disturbance', 'grandiosity' and 'paranormal beliefs'. 'Religiosity' was the only dimension positively associated with age. The results suggest that there may be a physiological neurodevelopmental stage favouring the expression of psychosis proneness in normal subjects, and support the hypothesis that the association between age and positive psychotic symptoms in functional and organic psychoses may be linked to the interaction between normal brain maturational processes and cerebral abnormalities involved in the aetiology of functional and organic psychoses.

Fractal dimension as an index of brain cortical changes throughout life.

PubMed

Kalmanti, Elina; Maris, Thomas G

2007-01-01

The fractal dimension (FD) of the cerebral cortex was measured in 93 individuals, aged from 3 months to 78 years, with normal brain MRI's in order to compare the convolutions of the cerebral cortex between genders and age groups. Image J, an image processing program, was used to skeletonize cerebral cortex and the box counting method applied. FDs on slices taken from left and right hemispheres were calculated. Our results showed a significant degree of lateralization in the left hemisphere. It appears that basal ganglia development, mainly in the left hemisphere, is heavily dependent upon age until puberty. In addition, both left and right cortex development equally depends on age until puberty, while the corresponding right hemisphere convolutions continue to develop until a later stage. An increased developmental activity appears between the ages of 1 and 15 years, indicating a significant brain remodelling during childhood and adolescence. In infancy, only changes in basal ganglia are observed, while the right hemisphere continues to remodel in adulthood.

Sex differences in Alzheimer risk: Brain imaging of endocrine vs chronologic aging.

PubMed

Mosconi, Lisa; Berti, Valentina; Quinn, Crystal; McHugh, Pauline; Petrongolo, Gabriella; Varsavsky, Isabella; Osorio, Ricardo S; Pupi, Alberto; Vallabhajosula, Shankar; Isaacson, Richard S; de Leon, Mony J; Brinton, Roberta Diaz

2017-09-26

This observational multimodality brain imaging study investigates emergence of endophenotypes of late-onset Alzheimer disease (AD) risk during endocrine transition states in a cohort of clinically and cognitively normal women and age-matched men. Forty-two 40- to 60-year-old cognitively normal women (15 asymptomatic perimenopausal by age [CNT], 13 perimenopausal [PERI], and 14 postmenopausal [MENO]) and 18 age- and education-matched men were examined. All patients had volumetric MRI, 18 F-fluoro-2-deoxyglucose (FDG)-PET (glucose metabolism), and Pittsburgh compound B-PET scans (β-amyloid [Aβ] deposition, a hallmark of AD pathology). As expected, the MENO group was older than the PERI and CNT groups. Otherwise, groups were comparable on clinical and neuropsychological measures and APOE4 distribution. Compared to CNT women and to men, and controlling for age, PERI and MENO groups exhibited increased indicators of AD endophenotype, including hypometabolism, increased Aβ deposition, and reduced gray and white matter volumes in AD-vulnerable regions ( p < 0.001). AD biomarker abnormalities were greatest in MENO, intermediate in PERI, and lowest in CNT women ( p < 0.001). Aβ deposition was exacerbated in APOE4 -positive MENO women relative to the other groups ( p < 0.001). Multimodality brain imaging indicates sex differences in development of the AD endophenotype, suggesting that the preclinical AD phase is early in the female aging process and coincides with the endocrine transition of perimenopause. These data indicate that the optimal window of opportunity for therapeutic intervention in women is early in the endocrine aging process. © 2017 American Academy of Neurology.

Involvement of brain oxidation in the cognitive impairment in a triple transgenic mouse model of Alzheimer's disease: noninvasive measurement of the brain redox state by magnetic resonance imaging.

PubMed

Ishihara, Y; Itoh, K; Mitsuda, Y; Shimada, T; Kubota, T; Kato, C; Song, S Y; Kobayashi, Y; Mori-Yasumoto, K; Sekita, S; Kirino, Y; Yamazaki, T; Shimamoto, N

2013-09-01

Oxidative stress is considered to be related to the onset and/or progression of Alzheimer's disease (AD), but there is insufficient evidence of its role(s). In this study, we evaluated the relationships between the brain redox state and cognitive function using a triple transgenic mouse model of AD (3 × Tg-AD mouse). One group of 3 × Tg-AD mice started to receive an α-tocopherol-supplemented diet at 2 months of age and another group of 3 × Tg-AD mice was fed a normal diet. The levels of α-tocopherol, reduced glutathione, oxidized glutathione, and lipid peroxidation were decreased in the cerebral cortex and hippocampus at 4 months of age in the 3 × Tg-AD mice fed a normal diet. These reductions were abrogated by the supplementation of α-tocopherol in the diet. During Morris water maze testing, the 3 × Tg-AD mice did not exhibit cognitive impairment at 4 months of age, but started to show cognitive dysfunction at 6 months of age, and α-tocopherol supplementation suppressed this dysfunction. Magnetic resonance imaging (MRI) using 3-hydroxymethyl-proxyl as a probe showed decreases in the signal intensity in the brains of 3 × Tg-AD mice at 4 months of age, and this reduction was clearly attenuated by α-tocopherol supplementation. Taken together, these findings suggest that oxidative stress can be associated with the cognitive impairment in 3 × Tg-AD mice. Furthermore, MRI might be a powerful tool to noninvasively evaluate the increases in reactive radicals, especially those occurring during the early stages of AD.

The Effect of Age on a Visual Learning Task in the American Cockroach

ERIC Educational Resources Information Center

Brown, Sheena; Strausfeld, Nicholas

2009-01-01

Neuronal modifications that accompany normal aging occur in brain neuropils and might share commonalties across phyla including the most successful group, the Insecta. This study addresses the kinds of neuronal modifications associated with loss of memory that occur in the hemimetabolous insect "Periplaneta americana." Among insects that display…

Auditory Temporal Processing Deficits in Chronic Stroke: A Comparison of Brain Damage Lateralization Effect.

PubMed

Jafari, Zahra; Esmaili, Mahdiye; Delbari, Ahmad; Mehrpour, Masoud; Mohajerani, Majid H

2016-06-01

There have been a few reports about the effects of chronic stroke on auditory temporal processing abilities and no reports regarding the effects of brain damage lateralization on these abilities. Our study was performed on 2 groups of chronic stroke patients to compare the effects of hemispheric lateralization of brain damage and of age on auditory temporal processing. Seventy persons with normal hearing, including 25 normal controls, 25 stroke patients with damage to the right brain, and 20 stroke patients with damage to the left brain, without aphasia and with an age range of 31-71 years were studied. A gap-in-noise (GIN) test and a duration pattern test (DPT) were conducted for each participant. Significant differences were found between the 3 groups for GIN threshold, overall GIN percent score, and DPT percent score in both ears (P ≤ .001). For all stroke patients, performance in both GIN and DPT was poorer in the ear contralateral to the damaged hemisphere, which was significant in DPT and in 2 measures of GIN (P ≤ .046). Advanced age had a negative relationship with temporal processing abilities for all 3 groups. In cases of confirmed left- or right-side stroke involving auditory cerebrum damage, poorer auditory temporal processing is associated with the ear contralateral to the damaged cerebral hemisphere. Replication of our results and the use of GIN and DPT tests for the early diagnosis of auditory processing deficits and for monitoring the effects of aural rehabilitation interventions are recommended. Copyright © 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Construction and comparative evaluation of different activity detection methods in brain FDG-PET.

PubMed

Buchholz, Hans-Georg; Wenzel, Fabian; Gartenschläger, Martin; Thiele, Frank; Young, Stewart; Reuss, Stefan; Schreckenberger, Mathias

2015-08-18

We constructed and evaluated reference brain FDG-PET databases for usage by three software programs (Computer-aided diagnosis for dementia (CAD4D), Statistical Parametric Mapping (SPM) and NEUROSTAT), which allow a user-independent detection of dementia-related hypometabolism in patients' brain FDG-PET. Thirty-seven healthy volunteers were scanned in order to construct brain FDG reference databases, which reflect the normal, age-dependent glucose consumption in human brain, using either software. Databases were compared to each other to assess the impact of different stereotactic normalization algorithms used by either software package. In addition, performance of the new reference databases in the detection of altered glucose consumption in the brains of patients was evaluated by calculating statistical maps of regional hypometabolism in FDG-PET of 20 patients with confirmed Alzheimer's dementia (AD) and of 10 non-AD patients. Extent (hypometabolic volume referred to as cluster size) and magnitude (peak z-score) of detected hypometabolism was statistically analyzed. Differences between the reference databases built by CAD4D, SPM or NEUROSTAT were observed. Due to the different normalization methods, altered spatial FDG patterns were found. When analyzing patient data with the reference databases created using CAD4D, SPM or NEUROSTAT, similar characteristic clusters of hypometabolism in the same brain regions were found in the AD group with either software. However, larger z-scores were observed with CAD4D and NEUROSTAT than those reported by SPM. Better concordance with CAD4D and NEUROSTAT was achieved using the spatially normalized images of SPM and an independent z-score calculation. The three software packages identified the peak z-scores in the same brain region in 11 of 20 AD cases, and there was concordance between CAD4D and SPM in 16 AD subjects. The clinical evaluation of brain FDG-PET of 20 AD patients with either CAD4D-, SPM- or NEUROSTAT-generated databases from an identical reference dataset showed similar patterns of hypometabolism in the brain regions known to be involved in AD. The extent of hypometabolism and peak z-score appeared to be influenced by the calculation method used in each software package rather than by different spatial normalization parameters.

Combined Diffusion Tensor and Magnetic Resonance Spectroscopic Imaging Methodology for Automated Regional Brain Analysis: Application in a Normal Pediatric Population.

PubMed

Ghosh, Nirmalya; Holshouser, Barbara; Oyoyo, Udo; Barnes, Stanley; Tong, Karen; Ashwal, Stephen

2017-01-01

During human brain development, anatomic regions mature at different rates. Quantitative anatomy-specific analysis of longitudinal diffusion tensor imaging (DTI) and magnetic resonance spectroscopic imaging (MRSI) data may improve our ability to quantify and categorize these maturational changes. Computational tools designed to quickly fuse and analyze imaging information from multiple, technically different datasets would facilitate research on changes during normal brain maturation and for comparison to disease states. In the current study, we developed a complete battery of computational tools to execute such data analyses that include data preprocessing, tract-based statistical analysis from DTI data, automated brain anatomy parsing from T1-weighted MR images, assignment of metabolite information from MRSI data, and co-alignment of these multimodality data streams for reporting of region-specific indices. We present statistical analyses of regional DTI and MRSI data in a cohort of normal pediatric subjects (n = 72; age range: 5-18 years; mean 12.7 ± 3.3 years) to establish normative data and evaluate maturational trends. Several regions showed significant maturational changes for several DTI parameters and MRSI ratios, but the percent change over the age range tended to be small. In the subcortical region (combined basal ganglia [BG], thalami [TH], and corpus callosum [CC]), the largest combined percent change was a 10% increase in fractional anisotropy (FA) primarily due to increases in the BG (12.7%) and TH (9%). The largest significant percent increase in N-acetylaspartate (NAA)/creatine (Cr) ratio was seen in the brain stem (BS) (18.8%) followed by the subcortical regions in the BG (11.9%), CC (8.9%), and TH (6.0%). We found consistent, significant (p < 0.01), but weakly positive correlations (r = 0.228-0.329) between NAA/Cr ratios and mean FA in the BS, BG, and CC regions. Age- and region-specific normative MR diffusion and spectroscopic metabolite ranges show brain maturation changes and are requisite for detecting abnormalities in an injured or diseased population. © 2017 S. Karger AG, Basel.

Proteomic analysis of specific brain proteins in aged SAMP8 mice treated with alpha-lipoic acid: implications for aging and age-related neurodegenerative disorders.

PubMed

Poon, H Fai; Farr, Susan A; Thongboonkerd, Visith; Lynn, Bert C; Banks, William A; Morley, John E; Klein, Jon B; Butterfield, D Allan

2005-01-01

Free radical-mediated damage to neuronal membrane components has been implicated in the etiology of Alzheimer's disease (AD) and aging. The senescence accelerated prone mouse strain 8 (SAMP8) exhibits age-related deterioration in memory and learning along with increased oxidative markers. Therefore, SAMP8 is a suitable model to study brain aging and, since aging is the major risk factor for AD and SAMP8 exhibits many of the biochemical findings of AD, perhaps as a model for and the early phase of AD. Our previous studies reported higher oxidative stress markers in brains of 12-month-old SAMP8 mice when compared to that of 4-month-old SAMP8 mice. Further, we have previously shown that injecting the mice with alpha-lipoic acid (LA) reversed brain lipid peroxidation, protein oxidation, as well as the learning and memory impairments in SAMP8 mice. Recently, we reported the use of proteomics to identify proteins that are expressed differently and/or modified oxidatively in aged SAMP8 brains. In order to understand how LA reverses the learning and memory deficits of aged SAMP8 mice, in the current study, we used proteomics to compare the expression levels and specific carbonyl levels of proteins in brains from 12-month-old SAMP8 mice treated or not treated with LA. We found that the expressions of the three brain proteins (neurofilament triplet L protein, alpha-enolase, and ubiquitous mitochondrial creatine kinase) were increased significantly and that the specific carbonyl levels of the three brain proteins (lactate dehydrogenase B, dihydropyrimidinase-like protein 2, and alpha-enolase) were significantly decreased in the aged SAMP8 mice treated with LA. These findings suggest that the improved learning and memory observed in LA-injected SAMP8 mice may be related to the restoration of the normal condition of specific proteins in aged SAMP8 mouse brain. Moreover, our current study implicates neurofilament triplet L protein, alpha-enolase, ubiquitous mitochondrial creatine kinase, lactate dehydrogenase B, and dihydropyrimidinase-like protein 2 in process associated with learning and memory of SAMP8 mice.

Neural correlates of free recall of "famous events" in a "hypermnestic" individual as compared to an age- and education-matched reference group.

PubMed

Fehr, Thorsten; Staniloiu, Angelica; Markowitsch, Hans J; Erhard, Peter; Herrmann, Manfred

2018-06-19

Memory performance of an individual (within the age range: 50-55 years old) showing superior memory abilities (protagonist PR) was compared to an age- and education-matched reference group in a historical facts ("famous events") retrieval task. Contrasting task versus baseline performance both PR and the reference group showed fMRI activation patterns in parietal and occipital brain regions. The reference group additionally demonstrated activation patterns in cingulate gyrus, whereas PR showed additional widespread activation patterns comprising frontal and cerebellar brain regions. The direct comparison between PR and the reference group revealed larger fMRI contrasts for PR in right frontal, superior temporal and cerebellar brain regions. It was concluded that PR generally recruits brain regions as normal memory performers do, but in a more elaborate way, and furthermore, that he applied a memory-strategy that potentially includes executively driven multi-modal transcoding of information and recruitment of implicit memory resources.

Comparative proteomic analysis of brains of naturally aging mice.

PubMed

Yang, S; Liu, T; Li, S; Zhang, X; Ding, Q; Que, H; Yan, X; Wei, K; Liu, S

2008-06-26

We used comparative proteomic techniques to identify aging-related brain proteins in normal mice from neonate to old age. By 2-dimensional electrophoresis (2-DE), matrix assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry (MS) and peptide mass fingerprint (PMF) analysis, 39 proteins were identified, among which 6 stayed unchanged since 3 months, 6 increased and 27 decreased in various manners during aging. They are mainly involved in processes usually with destructive changes during aging, such as metabolism, transport, signaling, stress response and apoptosis. The 27 proteins' decrease may be responsible for brain aging. In particular, decrease of proteasome alpha subunits 3/6, ubiquitin carboxyl-terminal esterase L3, valosin-containing protein and calreticulin may be responsible for the declination of protein quality control; glutamate dehydrogenase 1, isocitrate dehydrogenase 1 and ubiquinol cytochrome c reductase core protein 2 for the shortage of energy and reducing agent; ubiquitin-conjugating enzyme E2N and heterogeneous nuclear ribonucleoprotein A2/B1 for the increase of DNA damage and transcription detuning; calbindin 1 and amphiphysin for the disturbance of synaptic transport and ion signals. The six proteins' increase may be involved in anti-aging processes. In particular, transketolase, mitochondrial creatine kinase 1 and ribosomal protein L37 may help to enhance energy metabolism; triosephosphate isomerase 1 may help to resist oxidative stress. Moreover, most of these proteins were found for the first time to be involved in the natural senescence of brain, which would provide new clues about the mechanism of brain aging.

Brain Ultrasonography Findings in Neonatal Seizure; a Cross-sectional Study.

PubMed

Nabavi, Seyed Saeed; Partovi, Parinaz

2017-01-01

Screening of newborns with seizure, who have curable pathologic brain findings, might be able to improve their final outcome by accelerating treatment intervention. The present study aimed to evaluate the brain ultrasonography findings of newborns hospitalized with complaint of seizure. The present cross-sectional study designed to evaluate brain ultrasonography findings of hospitalized newborns complaining seizure. Neonatal seizure was defined as presence of tonic, clonic, myoclonic, and subtle attacks in 1 - 28 day old newborns. 100 newborns with the mean age of 5.82 ± 6.29 days were evaluated (58% male). Most newborns were in the < 10 days age range (76%), term (83%) and with normal birth weight (81%). 22 (22%) of the ultrasonography examinations showed a pathologic finding. A correlation was only found between birth age and probability of the presence of a pathologic problem in the brain as the frequency of these problems was significantly higher in pre-term newborns (p = 0.023). Based on the findings of the present study, frequency of pathologic findings in neonatal brain ultrasonography was 22%. Hemorrhage (12%) and hydrocephaly (7%) were the most common findings. The only factor correlating with increased probability of positive findings was the newborns being pre-term.

Cellular senescence in honey bee brain is largely independent of chronological age

PubMed Central

Seehuus, Siri-Christine; Krekling, Trygve; Amdam, Gro V.

2008-01-01

Accumulation of oxidative stress-induced damage in brain tissue plays an important role in the pathogenesis of normal aging and neurodegenerative diseases. Neuronal oxidative damage typically increases with age in humans, and also in the invertebrate and vertebrate model species most commonly used in aging research. By use of quantitative immunohistochemistry and Western blot, we show that this aspect of brain senescence is largely decoupled from chronological age in the honey bee (Apis mellifera). The bee is a eusocial insect characterized by the presence of a reproductive queen caste and a caste of functionally sterile female workers that performs various alloparental tasks such as nursing and foraging. We studied patterns of oxidative nitration and carbonylation damage in the brain of worker bees that performed nurse tasks as 8- and 200-day-olds and foraging tasks as 20- and 200-day-olds. In addition, we examined 180-day-old diutinus bees, a stress-resistant temporal worker form that survives unfavorable periods. Our results indicate that nitration damage occurs only at low levels in vivo, but that a 60-kDa protein from honey bee brain is selectively nitrated by peroxynitrite in vitro. Oxidative carbonylation is present at varying levels in the visual and chemosensory neuropiles of worker bees, and this inter-individual variation is better explained by social role than by chronological age. PMID:17052880

Aging Effects on Whole-Brain Functional Connectivity in Adults Free of Cognitive and Psychiatric Disorders.

PubMed

Ferreira, Luiz Kobuti; Regina, Ana Carolina Brocanello; Kovacevic, Natasa; Martin, Maria da Graça Morais; Santos, Pedro Paim; Carneiro, Camila de Godoi; Kerr, Daniel Shikanai; Amaro, Edson; McIntosh, Anthony Randal; Busatto, Geraldo F

2016-09-01

Aging is associated with decreased resting-state functional connectivity (RSFC) within the default mode network (DMN), but most functional imaging studies have restricted the analysis to specific brain regions or networks, a strategy not appropriate to describe system-wide changes. Moreover, few investigations have employed operational psychiatric interviewing procedures to select participants; this is an important limitation since mental disorders are prevalent and underdiagnosed and can be associated with RSFC abnormalities. In this study, resting-state fMRI was acquired from 59 adults free of cognitive and psychiatric disorders according to standardized criteria and based on extensive neuropsychological and clinical assessments. We tested for associations between age and whole-brain RSFC using Partial Least Squares, a multivariate technique. We found that normal aging is not only characterized by decreased RSFC within the DMN but also by ubiquitous increases in internetwork positive correlations and focal internetwork losses of anticorrelations (involving mainly connections between the DMN and the attentional networks). Our results reinforce the notion that the aging brain undergoes a dedifferentiation processes with loss of functional diversity. These findings advance the characterization of healthy aging effects on RSFC and highlight the importance of adopting a broad, system-wide perspective to analyze brain connectivity. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Area, age and gender dependence of the nucleoside system in the brain: a review of current literature.

PubMed

Kovács, Zsolt; Juhász, Gábor; Palkovits, Miklós; Dobolyi, Arpád; Kékesi, Katalin A

2011-01-01

Nucleosides, such as uridine, inosine, guanosine and adenosine, may participate in the regulation of sleep, cognition, memory and nociception, the suppression of seizures, and have also been suggested to play a role in the pathophysiology of some neurodegenerative and neuropsychiatric diseases. Under pathological conditions, levels of nucleosides change extremely in the brain, indicating their participation in the pathophysiology of disorders like Alzheimer's disease, Parkinson's disease and schizophrenia. These findings have resulted in an increasing attention to the roles of nucleosides in the central nervous system. The specific effects of nucleosides depend on the expression of their receptors and transporters in neuronal and glial cells, as well as their extracellular concentrations in the brain. A complex interlinked metabolic network and transporters of nucleosides may balance nucleoside levels in the brain tissue under normal conditions and enable the fine modulation of neuronal and glial processes via nucleoside receptor signaling mechanisms. Brain levels of nucleosides were found to vary when measured in a variety of different brain regions. In addition, nucleoside levels also depend on age and gender. Furthermore, distributions of nucleoside transporters and receptors as well as nucleoside metabolic enzyme activities demonstrate the area, age and gender dependence of the nucleoside system, suggesting different roles of nucleosides in functionally different brain areas. The aim of this review article is to summarize our present knowledge of the area-, age- and gender-dependent distribution of nucleoside levels, nucleoside metabolic enzyme activity, nucleoside receptors and nucleoside transporters in the brain.

Brain enlargement is associated with regression in preschool-age boys with autism spectrum disorders

PubMed Central

Nordahl, Christine Wu; Lange, Nicholas; Li, Deana D.; Barnett, Lou Ann; Lee, Aaron; Buonocore, Michael H.; Simon, Tony J.; Rogers, Sally; Ozonoff, Sally; Amaral, David G.

2011-01-01

Autism is a heterogeneous disorder with multiple behavioral and biological phenotypes. Accelerated brain growth during early childhood is a well-established biological feature of autism. Onset pattern, i.e., early onset or regressive, is an intensely studied behavioral phenotype of autism. There is currently little known, however, about whether, or how, onset status maps onto the abnormal brain growth. We examined the relationship between total brain volume and onset status in a large sample of 2- to 4-y-old boys and girls with autism spectrum disorder (ASD) [n = 53, no regression (nREG); n = 61, regression (REG)] and a comparison group of age-matched typically developing controls (n = 66). We also examined retrospective head circumference measurements from birth through 18 mo of age. We found that abnormal brain enlargement was most commonly found in boys with regressive autism. Brain size in boys without regression did not differ from controls. Retrospective head circumference measurements indicate that head circumference in boys with regressive autism is normal at birth but diverges from the other groups around 4–6 mo of age. There were no differences in brain size in girls with autism (n = 22, ASD; n = 24, controls). These results suggest that there may be distinct neural phenotypes associated with different onsets of autism. For boys with regressive autism, divergence in brain size occurs well before loss of skills is commonly reported. Thus, rapid head growth may be a risk factor for regressive autism. PMID:22123952

The Aging Brain and Cognition

PubMed Central

Marchant, Natalie L.; Reed, Bruce R.; Sanossian, Nerses; Madison, Cindee M.; Kriger, Stephen; Dhada, Roxana; Mack, Wendy J.; DeCarli, Charles; Weiner, Michael W.; Mungas, Dan M.; Chui, Helena C.; Jagust, William J.

2013-01-01

Importance β-Amyloid (Aβ) deposition and vascular brain injury (VBI) frequently co-occur and are both associated with cognitive decline in aging. Determining whether a direct relationship exists between them has been challenging. We sought to understand VBI’s influence on cognition and clinical impairment, separate from and in conjunction with pathologic changes associated with Alzheimer disease (AD). Objective To examine the relationship between neuroimaging measures of VBI and brain Aβ deposition and their associations with cognition. Design and Setting A cross-sectional study in a community- and clinic-based sample recruited for elevated vascular disease risk factors. Participants Clinically normal (mean age, 77.1 years [N=30]), cognitively impaired (mean age, 78.0 years [N=24]), and mildly demented (mean age, 79.8 years [N=7]) participants. Interventions Magnetic resonance imaging, Aβ (Pitts-burgh Compound B–positron emission tomographic [PiB-PET]) imaging, and cognitive testing. Main Outcome Measures Magnetic resonance images were rated for the presence and location of infarct (34 infarct-positive participants, 27 infarct-negative participants) and were used to quantify white matter lesion volume. The PiB-PET uptake ratios were used to create a PiB index by averaging uptake across regions vulnerable to early Aβ deposition; PiB positivity (29 PiB-positive participants, 32 PiB-negative participants) was determined from a data-derived threshold. Standardized composite cognitive measures included executive function and verbal and nonverbal memory. Results Vascular brain injury and Aβ were independent in both cognitively normal and impaired participants. Infarction, particularly in cortical and subcortical gray matter, was associated with lower cognitive performance in all domains (P<.05 for all comparisons). Pittsburgh Compound B positivity was neither a significant predictor of cognition nor interacted with VBI. Conclusions and Relevance In this elderly sample with normal cognition to mild dementia, enriched for vascular disease, VBI was more influential than Aβ in contemporaneous cognitive function and remained predictive after including the possible influence of Aβ. There was no evidence that VBI increases the likelihood of Aβ deposition. This finding highlights the importance of VBI in mild cognitive impairment and suggests that the impact of cerebrovascular disease should be considered with respect to defining the etiology of mild cognitive impairment. PMID:23400560

REST and stress resistance in ageing and Alzheimer's disease

NASA Astrophysics Data System (ADS)

Lu, Tao; Aron, Liviu; Zullo, Joseph; Pan, Ying; Kim, Haeyoung; Chen, Yiwen; Yang, Tun-Hsiang; Kim, Hyun-Min; Drake, Derek; Liu, X. Shirley; Bennett, David A.; Colaiácovo, Monica P.; Yankner, Bruce A.

2014-03-01

Human neurons are functional over an entire lifetime, yet the mechanisms that preserve function and protect against neurodegeneration during ageing are unknown. Here we show that induction of the repressor element 1-silencing transcription factor (REST; also known as neuron-restrictive silencer factor, NRSF) is a universal feature of normal ageing in human cortical and hippocampal neurons. REST is lost, however, in mild cognitive impairment and Alzheimer's disease. Chromatin immunoprecipitation with deep sequencing and expression analysis show that REST represses genes that promote cell death and Alzheimer's disease pathology, and induces the expression of stress response genes. Moreover, REST potently protects neurons from oxidative stress and amyloid β-protein toxicity, and conditional deletion of REST in the mouse brain leads to age-related neurodegeneration. A functional orthologue of REST, Caenorhabditis elegans SPR-4, also protects against oxidative stress and amyloid β-protein toxicity. During normal ageing, REST is induced in part by cell non-autonomous Wnt signalling. However, in Alzheimer's disease, frontotemporal dementia and dementia with Lewy bodies, REST is lost from the nucleus and appears in autophagosomes together with pathological misfolded proteins. Finally, REST levels during ageing are closely correlated with cognitive preservation and longevity. Thus, the activation state of REST may distinguish neuroprotection from neurodegeneration in the ageing brain.

Accelerated protein damage in brains of PIMT+/- mice; a possible model for the variability of cognitive decline in human aging.

PubMed

Qin, Zhenxia; Dimitrijevic, Aleksandra; Aswad, Dana W

2015-02-01

Isoaspartate formation is a common type of protein damage normally kept in check by the repair enzyme protein-L-isoaspartyl methyltransferase (PIMT). Mice with a knockout of the gene (Pcmt1) for this enzyme (KO, -/-) exhibit a pronounced neuropathology with fatal epileptic seizures at 30-60 days. Heterozygous (HZ, +/-) mice have 50% of the PIMT activity found in wild-type (WT, +/+) mice, but appear normal. To see if HZ mice exhibit accelerated aging at the molecular level, we compared brain extracts from HZ and WT mice at 8 months and 2 years with regard to PIMT activity, isoaspartate levels, and activity of an endogenous PIMT substrate, creatine kinase B. PIMT activity declined modestly with age in both genotypes. Isoaspartate was significantly higher in HZ than WT mice at 8 months and more so at 2 years, rising 5× faster in HZ males and 3× faster in females. Creatine kinase activity decreased with age and was always lower in the HZ mice. These findings suggest the individual variation of human PIMT levels may significantly influence the course of age-related central nervous system dysfunction. Copyright © 2015 Elsevier Inc. All rights reserved.

Visual feature integration with an attention deficit.

PubMed

Arguin, M; Cavanagh, P; Joanette, Y

1994-01-01

Treisman's feature integration theory proposes that the perception of illusory conjunctions of correctly encoded visual features is due to the failure of an attentional process. This hypothesis was examined by studying brain-damaged subjects who had previously been shown to have difficulty in attending to contralesional stimulation. These subjects exhibited a massive feature integration deficit for contralesional stimulation relative to ipsilesional displays. In contrast, both normal age-matched controls and brain-damaged subjects who did not exhibit any evidence of an attention deficit showed comparable feature integration performance with left- and right-hemifield stimulation. These observations indicate the crucial function of attention for visual feature integration in normal perception.

Music for the ageing brain: Cognitive, emotional, social, and neural benefits of musical leisure activities in stroke and dementia.

PubMed

Särkämö, Teppo

2017-01-01

Music engages an extensive network of auditory, cognitive, motor, and emotional processing regions in the brain. Coupled with the fact that the emotional and cognitive impact of music is often well preserved in ageing and dementia, music is a powerful tool in the care and rehabilitation of many ageing-related neurological diseases. In addition to formal music therapy, there has been a growing interest in self- or caregiver-implemented musical leisure activities or hobbies as a widely applicable means to support psychological wellbeing in ageing and in neurological rehabilitation. This article reviews the currently existing evidence on the cognitive, emotional, and neural benefits of musical leisure activities in normal ageing as well as in the rehabilitation and care of two of the most common and ageing-related neurological diseases: stroke and dementia.

Brain white matter structure and information processing speed in healthy older age.

PubMed

Kuznetsova, Ksenia A; Maniega, Susana Muñoz; Ritchie, Stuart J; Cox, Simon R; Storkey, Amos J; Starr, John M; Wardlaw, Joanna M; Deary, Ian J; Bastin, Mark E

2016-07-01

Cognitive decline, especially the slowing of information processing speed, is associated with normal ageing. This decline may be due to brain cortico-cortical disconnection caused by age-related white matter deterioration. We present results from a large, narrow age range cohort of generally healthy, community-dwelling subjects in their seventies who also had their cognitive ability tested in youth (age 11 years). We investigate associations between older age brain white matter structure, several measures of information processing speed and childhood cognitive ability in 581 subjects. Analysis of diffusion tensor MRI data using Tract-based Spatial Statistics (TBSS) showed that all measures of information processing speed, as well as a general speed factor composed from these tests (g speed), were significantly associated with fractional anisotropy (FA) across the white matter skeleton rather than in specific tracts. Cognitive ability measured at age 11 years was not associated with older age white matter FA, except for the g speed-independent components of several individual processing speed tests. These results indicate that quicker and more efficient information processing requires global connectivity in older age, and that associations between white matter FA and information processing speed (both individual test scores and g speed), unlike some other aspects of later life brain structure, are generally not accounted for by cognitive ability measured in youth.

Involvement of insulin resistance in D-galactose-induced age-related dementia in rats: Protective role of metformin and saxagliptin

PubMed Central

Kenawy, Sara; Hassan, Azza; El-Shenawy, Siham; Gomaa, Nawal; Zaki, Hala; Attia, Amina

2017-01-01

Age-related dementia is one of the most devastating disorders affecting the elderly. Recently, emerging data suggest that impaired insulin signaling is the major contributor in the development of Alzheimer’s dementia (AD), which is the most common type of senile dementia. In the present study, we investigated the potential therapeutic effects of metformin (Met) and saxagliptin (Saxa), as insulin sensitizing agents, in a rat model of brain aging and AD using D-galactose (D-gal, 150 mg/kg/day, s.c. for 90 successive days). Six groups of adult male Wistar rats were used: normal, D-gal, Met (500 mg/kg/day, p.o), and Saxa (1 mg/kg/day, p.o) control groups, as well as D-gal/Met and D-gal/Sax treated groups. Impaired learning and memory function was observed in rats treated with D-gal using Morris water maze test. Biochemical and histopathological findings also revealed some characteristic changes of AD in the brain that include the increased content of acetylcholine, glutamate, and phosphorelated tau, as well as deposition of amyloid plaques and neurofibrillary tangles. Induction of insulin resistance in experimentally aged rats was evidenced by increased blood glycated hemoglobin, brain contents of insulin and receptors for advanced glycated end-products, as well as decreased brain insulin receptor level. Elevation of oxidative stress markers and TNF-α brain content was also demonstrated. Met and Saxa, with a preference to Met, restored the normal memory and learning functions in rats, improved D-gal-induced state of insulin resistance, oxidative stress and inflammation, and ameliorated the AD biochemical and histopathological alterations in brain tissues. Our findings suggest that D-gal model of aging results in a diminishing of learning and memory function by producing a state of impaired insulin signaling that causes a cascade of deleterious events like oxidative stress, inflammation, and tau hyper-phosphorylation. Reversing of these harmful effects by the use of insulin-sensitizing drugs like Met and Saxa suggests their involvement in alleviation insulin resistance as the underlying pathology of AD and hence their potential use as anti-dementia drugs. PMID:28832656

Bioimaging of metals in brain tissue by laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) and metallomics.

PubMed

Becker, J Sabine; Matusch, Andreas; Palm, Christoph; Salber, Dagmar; Morton, Kathryn A; Becker, J Susanne

2010-02-01

Laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) has been developed and established as an emerging technique in the generation of quantitative images of metal distributions in thin tissue sections of brain samples (such as human, rat and mouse brain), with applications in research related to neurodegenerative disorders. A new analytical protocol is described which includes sample preparation by cryo-cutting of thin tissue sections and matrix-matched laboratory standards, mass spectrometric measurements, data acquisition, and quantitative analysis. Specific examples of the bioimaging of metal distributions in normal rodent brains are provided. Differences to the normal were assessed in a Parkinson's disease and a stroke brain model. Furthermore, changes during normal aging were studied. Powerful analytical techniques are also required for the determination and characterization of metal-containing proteins within a large pool of proteins, e.g., after denaturing or non-denaturing electrophoretic separation of proteins in one-dimensional and two-dimensional gels. LA-ICP-MS can be employed to detect metalloproteins in protein bands or spots separated after gel electrophoresis. MALDI-MS can then be used to identify specific metal-containing proteins in these bands or spots. The combination of these techniques is described in the second section.

Agrin in Alzheimer's Disease: Altered Solubility and Abnormal Distribution within Microvasculature and Brain Parenchyma

NASA Astrophysics Data System (ADS)

Donahue, John E.; Berzin, Tyler M.; Rafii, Michael S.; Glass, David J.; Yancopoulos, George D.; Fallon, Justin R.; Stopa, Edward G.

1999-05-01

Agrin is a heparan sulfate proteoglycan that is widely expressed in neurons and microvascular basal lamina in the rodent and avian central nervous system. Agrin induces the differentiation of nerve-muscle synapses, but its function in either normal or diseased brains is not known. Alzheimer's disease (AD) is characterized by loss of synapses, changes in microvascular architecture, and formation of neurofibrillary tangles and senile plaques. Here we have asked whether AD causes changes in the distribution and biochemical properties of agrin. Immunostaining of normal, aged human central nervous system revealed that agrin is expressed in neurons in multiple brain areas. Robust agrin immunoreactivity was observed uniformly in the microvascular basal lamina. In AD brains, agrin is highly concentrated in both diffuse and neuritic plaques as well as neurofibrillary tangles; neuronal expression of agrin also was observed. Furthermore, patients with AD had microvascular alterations characterized by thinning and fragmentation of the basal lamina. Detergent extraction and Western blotting showed that virtually all the agrin in normal brain is soluble in 1% SDS. In contrast, a large fraction of the agrin in AD brains is insoluble under these conditions, suggesting that it is tightly associated with β -amyloid. Together, these data indicate that the agrin abnormalities observed in AD are closely linked to β -amyloid deposition. These observations suggest that altered agrin expression in the microvasculature and the brain parenchyma contribute to the pathogenesis of AD.

NF-κB Immunity in the Brain Determines Fly Lifespan in Healthy Aging and Age-Related Neurodegeneration.

PubMed

Kounatidis, Ilias; Chtarbanova, Stanislava; Cao, Yang; Hayne, Margaret; Jayanth, Dhruv; Ganetzky, Barry; Ligoxygakis, Petros

2017-04-25

During aging, innate immunity progresses to a chronically active state. However, what distinguishes those that "age well" from those developing age-related neurological conditions is unclear. We used Drosophila to explore the cost of immunity in the aging brain. We show that mutations in intracellular negative regulators of the IMD/NF-κB pathway predisposed flies to toxic levels of antimicrobial peptides, resulting in early locomotor defects, extensive neurodegeneration, and reduced lifespan. These phenotypes were rescued when immunity was suppressed in glia. In healthy flies, suppressing immunity in glial cells resulted in increased adipokinetic hormonal signaling with high nutrient levels in later life and an extension of active lifespan. Thus, when levels of IMD/NF-κB deviate from normal, two mechanisms are at play: lower levels derepress an immune-endocrine axis, which mobilizes nutrients, leading to lifespan extension, whereas higher levels increase antimicrobial peptides, causing neurodegeneration. Immunity in the fly brain is therefore a key lifespan determinant. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

The independent influences of age and education on functional brain networks and cognition in healthy older adults.

PubMed

Perry, Alistair; Wen, Wei; Kochan, Nicole A; Thalamuthu, Anbupalam; Sachdev, Perminder S; Breakspear, Michael

2017-10-01

Healthy aging is accompanied by a constellation of changes in cognitive processes and alterations in functional brain networks. The relationships between brain networks and cognition during aging in later life are moderated by demographic and environmental factors, such as prior education, in a poorly understood manner. Using multivariate analyses, we identified three latent patterns (or modes) linking resting-state functional connectivity to demographic and cognitive measures in 101 cognitively normal elders. The first mode (P = 0.00043) captures an opposing association between age and core cognitive processes such as attention and processing speed on functional connectivity patterns. The functional subnetwork expressed by this mode links bilateral sensorimotor and visual regions through key areas such as the parietal operculum. A strong, independent association between years of education and functional connectivity loads onto a second mode (P = 0.012), characterized by the involvement of key hub regions. A third mode (P = 0.041) captures weak, residual brain-behavior relations. Our findings suggest that circuits supporting lower level cognitive processes are most sensitive to the influence of age in healthy older adults. Education, and to a lesser extent, executive functions, load independently onto functional networks-suggesting that the moderating effect of education acts upon networks distinct from those vulnerable with aging. This has important implications in understanding the contribution of education to cognitive reserve during healthy aging. Hum Brain Mapp 38:5094-5114, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Late-onset dietary restriction compensates for age-related increase in oxidative stress and alterations of HSP 70 and synapsin 1 protein levels in male Wistar rats.

PubMed

Sharma, Sandeep; Singh, Rumani; Kaur, Manpreet; Kaur, Gurcharan

2010-04-01

Numerous reports implicate increased oxidative stress in the functional and structural changes occurring in the brain and other organs as a part of the normal aging process. Dietary restriction (DR) has long been shown to be life-prolonging intervention in several species. This study was aimed to assess the potential efficacy of late-onset short term DR when initiated in 21 months old male wistar rats for 3 months on the antioxidant defense system and lipid peroxidation, cellular stress response protein HSP 70 and synaptic marker protein synapsin 1 in discrete brain regions such as cortex, hypothalamus, and hippocampus as well as liver, kidney and heart from 24 month old rats. Age-associated decline in activities of superoxide dismutase, catalase, glutathione peroxidase, glutathione, and elevated levels of lipid peroxidation was observed in brain and peripheral organ as well as increased expression of HSP 70 and reduction in synapsin 1 was observed in brain studied. Late-onset short term DR was effective in partially restoring the antioxidant status and in decreasing lipid peroxidation level as well as enhancing the expression of HSP 70 and synapsin 1 in aged rats. Late onset short term DR also prevented age-related neurodegeneration as revealed by Fluoro-Jade B staining in hippocampus and cortex regions of rat brain. Thus our current results suggest that DR initiated even in old age has the potential to improve age related decline in body functions.

Use of the Progressive Figures Test in evaluating brain-damaged children, children with academic problems, and normal controls.

PubMed

Reitan, Ralph M; Wolfson, Deborah

2004-03-01

This study explores the use of the Progressive Figures Test as an instrument for broad initial screening of children in the 6- through 8-year age range with respect to the possible need for more definitive neuropsychological evaluation. Considering earlier results obtained in comparison of brain-damaged and control children [Clinical Neuropsychology: Current Applications, Hemisphere Publishing Corp., Washington, DC, 1974, p. 53; Proceedings of the Conference on Minimal Brain Dysfunction, New York Academy of Sciences, New York, 1973, p. 65], the Progressive Figures Test seemed potentially useful as a first step in determining whether a comprehensive neuropsychological evaluation is indicated. In this investigation, three groups were studied: (1) children with definitive evidence of brain damage or disease who, when compared with normal controls, help to establish the limits of neuropsychological functioning, (2) a group of children who had normal neurological examinations but also had academic problems of significant concern to both parents and teachers, and (3) a normal control group. Statistically significant differences were present in comparing each pair of groups, with the brain-damaged children performing most poorly and the controls performing best. Score distributions for the three groups make it possible to identify a score-range that represented a borderline or "gray" area and to suggest a cutting score that identified children whose academic problems might have a neurological basis and for whom additional neuropsychological evaluation appeared to be indicated.

Reversible brain atrophy in glutaric aciduria type 1.

PubMed

Numata-Uematsu, Yurika; Sakamoto, Osamu; Kakisaka, Yosuke; Okubo, Yukimune; Oikawa, Yoshitsugu; Arai-Ichinoi, Natsuko; Kure, Shigeo; Uematsu, Mitsugu

2017-06-01

Glutaric aciduria type 1 (GA1) is a rare metabolic disorder caused by a deficiency of glutaryl-CoA dehydrogenase. The typical clinical onset features an acute encephalopathic crisis developed in early childhood, causing irreversible striatal injury. Recently, tandem mass spectrometry of spots of dried blood has allowed pre-symptomatic detection of GA1 in newborns. Early treatment can prevent irreversible neurological injury. We report the case of a girl with GA1 who exhibited a characteristic reversible change upon brain magnetic resonance imaging (MRI). She was diagnosed with GA1 as a newborn. She commenced dietary carnitine and her intake of lysine and tryptophan were reduced at the age of 4weeks. After treatment commenced, her mean glutarylcarnitine level was lower than that in the previous reports. The plasma lysine and tryptophan levels were maintained below the normal ranges. At 4months, brain MRI revealed a widened operculum with dilatation of the subarachnoid spaces surrounding the atrophic bilateral frontotemporal lobes; this is typical of GA1 patients. However, at 17months, MRI revealed that the atrophic lesion had disappeared and she subsequently underwent normal maturation. She has never suffered a metabolic decompensation episode. At 26months, her development and brain MRI were normal. The present reversible brain atrophy in a patient with GA1 indicates that early dietary modifications with a lower level of glutarylcarnitine and administration of carnitine can lead to normal development. Copyright © 2017 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Prevalence of lateral ventricle asymmetry in brain MRI studies of neurologically normal dogs and dogs with idiopathic epilepsy.

PubMed

Pivetta, Mauro; De Risio, Luisa; Newton, Richard; Dennis, Ruth

2013-01-01

Asymmetry of the cerebral lateral ventricles is a common finding in cross-sectional imaging of otherwise normal canine brains and has been assumed to be incidental. The purpose of this retrospective study was to compare the prevalence of ventricular asymmetry in brain MRI studies of normal dogs and dogs with idiopathic epilepsy. Brain MRI archives were searched for 100 neurologically normal dogs (Group 1) and 100 dogs with idiopathic epilepsy (Group 2). For each dog, asymmetry of the lateral ventricles was subjectively classified as absent, mild, moderate, and severe based on a consensus of two observers who were unaware of group status. Ventricular areas were measured from transverse T1W images at the level of the interthalamic adhesion. An asymmetry ratio was calculated as the ratio of the larger to smaller ventricular transverse area. There was excellent agreement between subjective assessments of ventricular asymmetry and quantitative assessments using asymmetry ratios (k = 0.995). The prevalence of asymmetry was 38% in Group 1 dogs and 44% in Group 2 dogs. Assymmetry was scored as mild in the majority of Group 2 dogs. There was no significant association between presence/absence and degree of ventricular asymmetry vs. dog group, age, gender, or skull conformation. Findings from the current study supported previously published assumptions that asymmetry of the lateral cerebral ventricles is an incidental finding in MRI studies of the canine brain. © 2013 Veterinary Radiology & Ultrasound.

Age and sex effects levels of choline compounds in the anterior cingulate cortex of adolescent methamphetamine users.

PubMed

Cloak, Christine C; Alicata, Daniel; Chang, Linda; Andrews-Shigaki, Brian; Ernst, Thomas

2011-12-15

Methamphetamine can be neurotoxic to the adult brain; however, many individuals first use methamphetamine during adolescence, and the drug's impact on this period of brain development is unknown. Therefore, we evaluated young methamphetamine users for possible abnormalities in brain metabolite concentrations. Anterior cingulate cortex (ACC), frontal white matter (FWM), basal ganglia, and thalamus were studied with localized proton magnetic resonance spectroscopy in 54 periadolescent (ages 13-23 years) methamphetamine users and 53 comparison subjects. The concentrations of major brain metabolites and their associations with age, sex and cognition were assessed. FWM total-creatine correlated with age in methamphetamine-using males and comparison females, but not comparison males or methamphetamine-using females, leading to a drug by sex by age interaction (p=0.003) and ACC choline-containing compounds (CHO) correlated with age only in comparison males leading to a drug by sex by age interaction (p=0.03). Higher ACC CHO was associated with faster performance on the Stroop Interference task in the control males. Male methamphetamine users had slowest performance on the Stroop Interference task and did not show age-appropriate levels of ACC CHO. The altered age-appropriate levels of ACC CHO and poorer executive function in male methamphetamine users suggest methamphetamine abuse may interfere with brain maturation. These periadolescents did not have the abnormal neuronal markers previously reported in adult methamphetamine users, suggesting that neuronal abnormalities may be the result of long-term use or interference in normal cortical maturation, emphasizing the need for early intervention for young methamphetamine users. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Age and sex effects levels of choline compounds in the anterior cingulate cortex of adolescent methamphetamine users

PubMed Central

Cloak, Christine C.; Alicata, Daniel; Chang, Linda; Andrews-Shigaki, Brian; Ernst, Thomas

2011-01-01

Background Methamphetamine can be neurotoxic to the adult brain; however, many individuals first use methamphetamine during adolescence, and the drug’s impact on this period of brain development is unknown. Therefore, we evaluated young methamphetamine users for possible abnormalities in brain metabolite concentrations. Methods Anterior cingulate cortex (ACC), frontal white matter (FWM), basal ganglia, and thalamus were studied with localized proton magnetic resonance spectroscopy in 54 periadolescent (ages 13–23 years) methamphetamine users and 53 comparison subjects. The concentrations of major brain metabolites and their associations with age, sex and cognition were assessed. Results FWM total-creatine correlated with age in methamphetamine-using males and comparison females, but not comparison males or methamphetamine-using females, leading to a drug by sex by age interaction (p=0.003) and ACC choline-containing compounds (CHO) correlated with age only in comparison males leading to a drug by sex by age interaction (p=0.03). Higher ACC CHO was associated with faster performance on the Stroop Interference task in the control males. Male methamphetamine users had slowest performance on the Stroop Interference task and did not show showed age-appropriate levels of ACC CHO. Conclusions The altered age-appropriate levels of ACC CHO and poorer executive function in male methamphetamine users suggest methamphetamine abuse may interfere with brain maturation. These periadolescents did not have the abnormal neuronal markers previously reported in adult methamphetamine users, suggesting that neuronal abnormalities may be the result of long-term use or interference in normal cortical maturation, emphasizing the need for early intervention for young methamphetamine users. PMID:21775074

Stability of auditory discrimination and novelty processing in physiological aging.

PubMed

Raggi, Alberto; Tasca, Domenica; Rundo, Francesco; Ferri, Raffaele

2013-01-01

Complex higher-order cognitive functions and their possible changes with aging are mandatory objectives of cognitive neuroscience. Event-related potentials (ERPs) allow investigators to probe the earliest stages of information processing. N100, Mismatch negativity (MMN) and P3a are auditory ERP components that reflect automatic sensory discrimination. The aim of the present study was to determine if N100, MMN and P3a parameters are stable in healthy aged subjects, compared to those of normal young adults. Normal young adults and older participants were assessed using standardized cognitive functional instruments and their ERPs were obtained with an auditory stimulation at two different interstimulus intervals, during a passive paradigm. All individuals were within the normal range on cognitive tests. No significant differences were found for any ERP parameters obtained from the two age groups. This study shows that aging is characterized by a stability of the auditory discrimination and novelty processing. This is important for the arrangement of normative for the detection of subtle preclinical changes due to abnormal brain aging.

Brain activation by visual erotic stimuli in healthy middle aged males.

PubMed

Kim, S W; Sohn, D W; Cho, Y-H; Yang, W S; Lee, K-U; Juh, R; Ahn, K-J; Chung, Y-A; Han, S-I; Lee, K H; Lee, C U; Chae, J-H

2006-01-01

The objective of the present study was to identify brain centers, whose activity changes are related to erotic visual stimuli in healthy, heterosexual, middle aged males. Ten heterosexual, right-handed males with normal sexual function were entered into the present study (mean age 52 years, range 46-55). All potential subjects were screened over 1 h interview, and were encouraged to fill out questionnaires including the Brief Male Sexual Function Inventory. All subjects with a history of sexual arousal disorder or erectile dysfunction were excluded. We performed functional brain magnetic resonance imaging (fMRI) in male volunteers when an alternatively combined erotic and nonerotic film was played for 14 min and 9 s. The major areas of activation associated with sexual arousal to visual stimuli were occipitotemporal area, anterior cingulate gyrus, insula, orbitofrontal cortex, caudate nucleus. However, hypothalamus and thalamus were not activated. We suggest that the nonactivation of hypothalamus and thalamus in middle aged males may be responsible for the lesser physiological arousal in response to the erotic visual stimuli.

Age differences in arterial and venous extra-cerebral blood flow in healthy adults: contributions of vascular risk factors and genetic variants.

PubMed

Raz, Naftali; Daugherty, Ana M; Sethi, Sean K; Arshad, Muzamil; Haacke, E Mark

2017-08-01

Sufficient cerebral blood flow (CBF) and venous drainage are critical for normal brain function, and their alterations can affect brain aging. However, to date, most studies focused on arterial CBF (inflow) with little attention paid to the age differences in venous outflow. We measured extra-cerebral arterial and venous blood flow rates with phase-contrast MRI and assessed the influence of vascular risk factors and genetic polymorphisms (ACE insertion/deletion, COMT val158met, and APOEε4) in 73 adults (age 18-74 years). Advanced age, elevated vascular risk, ACE Deletion, and COMT met alleles were linked to lower in- and outflow, with no effects of APOE ε4 noted. Lower age-related CBF rate was unrelated to brain volume and was observed only in val homozygotes of COMTval158met. Thus, in a disease-free population, age differences in CBF may be notable only in persons with high vascular risk and carriers of genetic variants associated with vasoconstriction and lower dopamine availability. It remains to be established if treatments targeting alleviation of the mutable factors can improve the course of cerebrovascular aging in spite of the immutable genetic influence.

Long-term follow-up of endocrine function among young children with newly diagnosed malignant central nervous system tumors treated with irradiation-avoiding regimens.

PubMed

Cochrane, Anne M; Cheung, Clement; Rangan, Kasey; Freyer, David; Nahata, Leena; Dhall, Girish; Finlay, Jonathan L

2017-11-01

The adverse effects of irradiation on endocrine function among patients with pediatric brain tumor are well documented. Intensive induction chemotherapy followed by marrow-ablative chemotherapy with autologous hematopoietic cell rescue (AuHCR) without central nervous system (CNS) irradiation has demonstrated efficacy in a proportion of very young children with some malignant CNS tumors. This study assessed the long-term endocrine function of young children following chemotherapy-only treatment regimens. A retrospective chart review was performed on 99 patients under 6 years of age with malignant brain tumors newly diagnosed between May 1991 and October 2010 treated with irradiation-avoiding strategies. Thirty patients survived post-AuHCR without cranial irradiation for a mean of 8.1 years (range 3.0-22.25 years). The patient cohort included 18 males and 12 females (mean age at AuHCR of 2.5 years, range 0.8-5.1 years). All 30 surviving patients had documented normal age-related thyroid function, insulin-like growth factor binding protein 3 (IGF-BP3), prolactin, testosterone, and estradiol levels. Insulin-like growth factor 1 age-related levels were abnormal in one child with normal height. Ninety-seven percent of patients had normal cortisol levels, while follicle-stimulating hormone and LH levels among females were normal in 83% and 92%, respectively, and in 100% of males. Growth charts demonstrated age-associated growth within 2 standard deviations of the mean in 67% of patients. Of 10 patients (33%) with short stature, 6 had proportional diminutions in both height and weight. These findings demonstrate that the use of relatively brief, intensive chemotherapy regimens including marrow-ablative chemotherapy with AuHCR results in fewer endocrine sequelae than treatment schemes utilizing CNS irradiation. © 2017 Wiley Periodicals, Inc.

Age-Related Changes in Axonal and Mitochondrial Ultrastructure and Function in White Matter

PubMed Central

Stahon, Katharine E.; Bastian, Chinthasagar; Griffith, Shelby; Kidd, Grahame J.; Brunet, Sylvain

2016-01-01

The impact of aging on CNS white matter (WM) is of general interest because the global effects of aging on myelinated nerve fibers are more complex and profound than those in cortical gray matter. It is important to distinguish between axonal changes created by normal aging and those caused by neurodegenerative diseases, including multiple sclerosis, stroke, glaucoma, Alzheimer's disease, and traumatic brain injury. Using three-dimensional electron microscopy, we show that in mouse optic nerve, which is a pure and fully myelinated WM tract, aging axons are larger, have thicker myelin, and are characterized by longer and thicker mitochondria, which are associated with altered levels of mitochondrial shaping proteins. These structural alterations in aging mitochondria correlate with lower ATP levels and increased generation of nitric oxide, protein nitration, and lipid peroxidation. Moreover, mitochondria–smooth endoplasmic reticulum interactions are compromised due to decreased associations and decreased levels of calnexin and calreticulin, suggesting a disruption in Ca2+ homeostasis and defective unfolded protein responses in aging axons. Despite these age-related modifications, axon function is sustained in aging WM, which suggests that age-dependent changes do not lead to irreversible functional decline under normal conditions, as is observed in neurodegenerative diseases. SIGNIFICANCE STATEMENT Aging is a common risk factor for a number of neurodegenerative diseases, including stroke. Mitochondrial dysfunction and oxidative damage with age are hypothesized to increase risk for stroke. We compared axon–myelin–node–mitochondrion–smooth endoplasmic reticulum (SER) interactions in white matter obtained at 1 and 12 months. We show that aging axons have enlarged volume, thicker myelin, and elongated and thicker mitochondria. Furthermore, there are reduced SER connections to mitochondria that correlate with lower calnexin and calreticulin levels. Despite a prominent decrease in number, elongated aging mitochondria produce excessive stress markers with reduced ATP production. Because axons maintain function under these conditions, our study suggests that it is important to understand the process of normal brain aging to identify neurodegenerative changes. PMID:27683897

Dementia

MedlinePlus

... elderly people, it is not part of normal aging. Many different diseases can cause dementia, including Alzheimer's disease and stroke. Drugs are available to treat some of these diseases. While these drugs cannot cure dementia or repair brain damage, they may improve symptoms or slow down ...

Fluid Mechanics of the Vascular Basement Membrane in the Brain

NASA Astrophysics Data System (ADS)

Coloma, Mikhail; Hui, Jonathan; Chiarot, Paul; Huang, Peter; Carare, Roxana; McLeod, Kenneth; Schaffer, David

2013-11-01

Beta-amyloid is a normal product of brain metabolic function and is found within the interstitial fluid of the brain. Failure of the clearance of beta-amyloid from the aging brain leads to its accumulation within the walls of arteries and to Alzheimer's disease. The vascular basement membrane (VBM) within the walls of cerebral arteries surrounds the spirally arranged smooth muscle cells and represents an essential pathway for removal of beta-amyloid from the brain. This process fails with the stiffening of arterial walls associated with aging. In this study we hypothesize that the deformation of the VBM associated with arterial pulsations drives the interstitial fluid to drain in the direction opposite of the arterial blood flow. This hypothesis is theoretically investigated by modeling the VBM as a thin, coaxial, fluid-filled porous medium surrounding a periodically deforming cylindrical tube. Flow and boundary conditions required to achieve such a backward clearance are derived through a control volume analysis of mass, momentum, and energy.

Regional Brain Glucose Hypometabolism in Young Women with Polycystic Ovary Syndrome: Possible Link to Mild Insulin Resistance

PubMed Central

Castellano, Christian-Alexandre; Baillargeon, Jean-Patrice; Nugent, Scott; Tremblay, Sébastien; Fortier, Mélanie; Imbeault, Hélène; Duval, Julie; Cunnane, Stephen C.

2015-01-01

Objective To investigate whether cerebral metabolic rate of glucose (CMRglu) is altered in normal weight young women with polycystic ovary syndrome (PCOS) who exhibit mild insulin resistance. Materials and methods Seven women with PCOS were compared to eleven healthy female controls of similar age, education and body mass index. Regional brain glucose uptake was quantified using FDG with dynamic positron emission tomography and magnetic resonance imaging, and its potential relationship with insulin resistance assessed using the updated homeostasis model assessment (HOMA2-IR). A battery of cognitive tests was administered to evaluate working memory, attention and executive function. Results The PCOS group had 10% higher fasting glucose and 40% higher HOMA2-IR (p ≤ 0.035) compared to the Controls. The PCOS group had 9–14% lower CMRglu in specific regions of the frontal, parietal and temporal cortices (p ≤ 0.018). A significant negative relation was found between the CMRglu and HOMA2-IR mainly in the frontal, parietal and temporal cortices as well as in the hippocampus and the amygdala (p ≤ 0.05). Globally, cognitive performance was normal in both groups but scores on the PASAT test of working memory tended to be low in the PCOS group. Conclusions The PCOS group exhibited a pattern of low regional CMRglu that correlated inversely with HOMA2-IR in several brain regions and which resembled the pattern seen in aging and early Alzheimer’s disease. These results suggest that a direct association between mild insulin resistance and brain glucose hypometabolism independent of overweight or obesity can exist in young adults in their 20s. Further investigation of the influence of insulin resistance on brain glucose metabolism and cognition in younger and middle-aged adults is warranted. PMID:26650926

Regional Brain Glucose Hypometabolism in Young Women with Polycystic Ovary Syndrome: Possible Link to Mild Insulin Resistance.

PubMed

Castellano, Christian-Alexandre; Baillargeon, Jean-Patrice; Nugent, Scott; Tremblay, Sébastien; Fortier, Mélanie; Imbeault, Hélène; Duval, Julie; Cunnane, Stephen C

2015-01-01

To investigate whether cerebral metabolic rate of glucose (CMRglu) is altered in normal weight young women with polycystic ovary syndrome (PCOS) who exhibit mild insulin resistance. Seven women with PCOS were compared to eleven healthy female controls of similar age, education and body mass index. Regional brain glucose uptake was quantified using FDG with dynamic positron emission tomography and magnetic resonance imaging, and its potential relationship with insulin resistance assessed using the updated homeostasis model assessment (HOMA2-IR). A battery of cognitive tests was administered to evaluate working memory, attention and executive function. The PCOS group had 10% higher fasting glucose and 40% higher HOMA2-IR (p ≤ 0.035) compared to the Controls. The PCOS group had 9-14% lower CMRglu in specific regions of the frontal, parietal and temporal cortices (p ≤ 0.018). A significant negative relation was found between the CMRglu and HOMA2-IR mainly in the frontal, parietal and temporal cortices as well as in the hippocampus and the amygdala (p ≤ 0.05). Globally, cognitive performance was normal in both groups but scores on the PASAT test of working memory tended to be low in the PCOS group. The PCOS group exhibited a pattern of low regional CMRglu that correlated inversely with HOMA2-IR in several brain regions and which resembled the pattern seen in aging and early Alzheimer's disease. These results suggest that a direct association between mild insulin resistance and brain glucose hypometabolism independent of overweight or obesity can exist in young adults in their 20s. Further investigation of the influence of insulin resistance on brain glucose metabolism and cognition in younger and middle-aged adults is warranted.

Brain plasticity, memory, and aging: a discussion

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bennett, E.L.; Rosenzweig, M.R.

1977-12-01

It is generally assumed that memory faculties decline with age. A discussion of the relationship of memory and aging and the possibility of retarding the potential decline is hampered by the fact that no satisfactory explanation of memory is available in either molecular or anatomical terms. However, this lack of description of memory does not mean that there is a lack of suggested mechanisms for long-term memory storage. Present theories of memory usually include first, neurophysiological or electrical events, followed by a series of chemical events which ultimately lead to long-lasting anatomical changes in the brain. Evidence is increasing formore » the biochemical and anatomical plasticity of the nervous system and its importance in the normal functioning of the brain. Modification of this plasticity may be an important factor in senescence. This discussion reports experiments which indicate that protein synthesis and anatomical changes may be involved in long-term memory storage. Environmental influences can produce quantitative differences in brain anatomy and in behavior. In experimental animals, enriched environments lead to more complex anatomical patterns than do colony or impoverished environments. This raises fundamental questions about the adequacy of the isolated animal which is frequently being used as a model for aging research. A more important applied question is the role of social and intellectual stimulation in influencing aging of the human brain.« less

Altered Brain Functional Activity in Infants with Congenital Bilateral Severe Sensorineural Hearing Loss: A Resting-State Functional MRI Study under Sedation.

PubMed

Xia, Shuang; Song, TianBin; Che, Jing; Li, Qiang; Chai, Chao; Zheng, Meizhu; Shen, Wen

2017-01-01

Early hearing deprivation could affect the development of auditory, language, and vision ability. Insufficient or no stimulation of the auditory cortex during the sensitive periods of plasticity could affect the function of hearing, language, and vision development. Twenty-three infants with congenital severe sensorineural hearing loss (CSSHL) and 17 age and sex matched normal hearing subjects were recruited. The amplitude of low frequency fluctuations (ALFF) and regional homogeneity (ReHo) of the auditory, language, and vision related brain areas were compared between deaf infants and normal subjects. Compared with normal hearing subjects, decreased ALFF and ReHo were observed in auditory and language-related cortex. Increased ALFF and ReHo were observed in vision related cortex, which suggest that hearing and language function were impaired and vision function was enhanced due to the loss of hearing. ALFF of left Brodmann area 45 (BA45) was negatively correlated with deaf duration in infants with CSSHL. ALFF of right BA39 was positively correlated with deaf duration in infants with CSSHL. In conclusion, ALFF and ReHo can reflect the abnormal brain function in language, auditory, and visual information processing in infants with CSSHL. This demonstrates that the development of auditory, language, and vision processing function has been affected by congenital severe sensorineural hearing loss before 4 years of age.

MHC class I immune proteins are critical for hippocampus-dependent memory and gate NMDAR-dependent hippocampal long-term depression

PubMed Central

Nelson, P. Austin; Sage, Jennifer R.; Wood, Suzanne C.; Davenport, Christopher M.; Anagnostaras, Stephan G.; Boulanger, Lisa M.

2013-01-01

Memory impairment is a common feature of conditions that involve changes in inflammatory signaling in the brain, including traumatic brain injury, infection, neurodegenerative disorders, and normal aging. However, the causal importance of inflammatory mediators in cognitive impairments in these conditions remains unclear. Here we show that specific immune proteins, members of the major histocompatibility complex class I (MHC class I), are essential for normal hippocampus-dependent memory, and are specifically required for NMDAR-dependent forms of long-term depression (LTD) in the healthy adult hippocampus. In β2m−/−TAP−/−mice, which lack stable cell-surface expression of most MHC class I proteins, NMDAR-dependent LTD in area CA1 of adult hippocampus is abolished, while NMDAR-independent forms of potentiation, facilitation, and depression are unaffected. Altered NMDAR-dependent synaptic plasticity in the hippocampus of β2m−/−TAP−/−mice is accompanied by pervasive deficits in hippocampus-dependent memory, including contextual fear memory, object recognition memory, and social recognition memory. Thus normal MHC class I expression is essential for NMDAR-dependent hippocampal synaptic depression and hippocampus-dependent memory. These results suggest that changes in MHC class I expression could be an unexpected cause of disrupted synaptic plasticity and cognitive deficits in the aging, damaged, and diseased brain. PMID:23959708

Brain imaging in normal kids: a community-based MRI study in Malawian children.

PubMed

Potchen, M J; Kampondeni, S D; Mallewa, M; Taylor, T E; Birbeck, G L

2013-04-01

To collect normative MRI data for effective clinical and research applications. Such data may also offer insights into common neurological insults. We identified a representative, community-based sample of children aged 9-14 years. Children were screened for neurodevelopmental problems. Demographic data, medical history and environmental exposures were ascertained. Eligible children underwent the Neurologic Examination for Subtle Signs (NESS) and a brain MRI. Descriptive findings and analyses to identify risk factors for MRI abnormalities are detailed. One hundred and two of 170 households screened had age-appropriate children. Two of 102 children had neurological problems - one each with cerebral palsy and epilepsy. Ninety-six of 100 eligible children were enrolled. Mean age was 11.9 years (SD 1.5), and 43 (45%) were boys. No acute MRI abnormalities were seen. NESS abnormalities were identified in 6 of 96 children (6%). Radiographic evidence of sinusitis in 29 children (30%) was the most common MRI finding. Brain abnormalities were found in 16 (23%): mild diffuse atrophy in 4 (4%), periventricular white matter changes/gliosis in 6 (6%), multifocal punctuate subcortical white matter changes in 2 (2%), vermian atrophy in 1 (1%), empty sella in 3 (3%) and multifocal granulomas with surrounding gliosis in 1 (1%). Having an abnormal MRI was not associated with age, sex, antenatal problems, early malnutrition, febrile seizures, an abnormal neurological examination or housing quality (all P values >0.05). No predictors of radiographic sinusitis were identified. Incidental brain MRI abnormalities are common in normal Malawian children. The incidental atrophy and white matter abnormalities seen in this African population have not been reported among incidental findings from US populations, suggesting Malawi-specific exposures may be the cause. © 2013 Blackwell Publishing Ltd.

Classic infantile Pompe patients approaching adulthood: a cohort study on consequences for the brain.

PubMed

Ebbink, Berendine J; Poelman, Esther; Aarsen, Femke K; Plug, Iris; Régal, Luc; Muentjes, Carsten; van der Beek, Nadine A M E; Lequin, Maarten H; van der Ploeg, Ans T; van den Hout, Johanna M P

2018-06-01

To examine the long-term consequences of glycogen storage in the central nervous system (CNS) for classic infantile Pompe disease using enzyme replacement therapy. Using neuropsychological tests and brain magnetic resonance imaging (MRI), we prospectively assessed a cohort of 11 classic infantile Pompe patients aged up to 17 years. From approximately age 2 years onwards, brain MRI showed involvement of the periventricular white matter and centrum semiovale. After 8 years of age, additional white-matter abnormalities occurred in the corpus callosum, internal and external capsule, and subcortical areas. From 11 years of age, white-matter abnormalities were also found in the brainstem. Although there seemed to be a characteristic pattern of involvement over time, there were considerable variations between patients, reflected by variations in neuropsychological development. Cognitive development ranged from stable and normal to declines that lead to intellectual disabilities. As treatment enables patients with classic infantile Pompe disease to reach adulthood, white-matter abnormalities are becoming increasingly evident, affecting the neuropsychological development. Therefore, we advise follow-up programs are expanded to capture CNS involvement in larger, international patient cohorts, to incorporate our findings in the counselling of parents before the start of treatment, and to include the brain as an additional target in the development of next-generation therapeutic strategies for classic infantile Pompe disease. In our long-term survivors treated intravenously with enzyme replacement therapy, we found slowly progressive symmetric white-matter abnormalities. Cognitive development varied from stable and normal to declines towards intellectual disabilities. © 2018 The Authors. Developmental Medicine & Child Neurology published by John Wiley & Sons Ltd on behalf of Mac Keith Press.

Posterior cingulate glucose metabolism, hippocampal glucose metabolism, and hippocampal volume in cognitively normal, late-middle-aged persons at 3 levels of genetic risk for Alzheimer disease.

PubMed

Protas, Hillary D; Chen, Kewei; Langbaum, Jessica B S; Fleisher, Adam S; Alexander, Gene E; Lee, Wendy; Bandy, Daniel; de Leon, Mony J; Mosconi, Lisa; Buckley, Shannon; Truran-Sacrey, Diana; Schuff, Norbert; Weiner, Michael W; Caselli, Richard J; Reiman, Eric M

2013-03-01

To characterize and compare measurements of the posterior cingulate glucose metabolism, the hippocampal glucose metabolism, and hippocampal volume so as to distinguish cognitively normal, late-middle-aged persons with 2, 1, or 0 copies of the apolipoprotein E (APOE) ε4 allele, reflecting 3 levels of risk for late-onset Alzheimer disease. Cross-sectional comparison of measurements of cerebral glucose metabolism using 18F-fluorodeoxyglucose positron emission tomography and measurements of brain volume using magnetic resonance imaging in cognitively normal ε4 homozygotes, ε4 heterozygotes, and noncarriers. Academic medical center. A total of 31 ε4 homozygotes, 42 ε4 heterozygotes, and 76 noncarriers, 49 to 67 years old, matched for sex, age, and educational level. The measurements of posterior cingulate and hippocampal glucose metabolism were characterized using automated region-of-interest algorithms and normalized for whole-brain measurements. The hippocampal volume measurements were characterized using a semiautomated algorithm and normalized for total intracranial volume. Although there were no significant differences among the 3 groups of participants in their clinical ratings, neuropsychological test scores, hippocampal volumes (P = .60), or hippocampal glucose metabolism measurements (P = .12), there were significant group differences in their posterior cingulate glucose metabolism measurements (P = .001). The APOE ε4 gene dose was significantly associated with posterior cingulate glucose metabolism (r = 0.29, P = .0003), and this association was significantly greater than those with hippocampal volume or hippocampal glucose metabolism (P < .05, determined by use of pairwise Fisher z tests). Although our findings may depend in part on the analysis algorithms used, they suggest that a reduction in posterior cingulate glucose metabolism precedes a reduction in hippocampal volume or metabolism in cognitively normal persons at increased genetic risk for Alzheimer disease.

Flight restriction prevents associative learning deficits but not changes in brain protein-adduct formation during honeybee ageing.

PubMed

Tolfsen, Christina C; Baker, Nicholas; Kreibich, Claus; Amdam, Gro V

2011-04-15

Honeybees (Apis mellifera) senesce within 2 weeks after they discontinue nest tasks in favour of foraging. Foraging involves metabolically demanding flight, which in houseflies (Musca domestica) and fruit flies (Drosophila melanogaster) is associated with markers of ageing such as increased mortality and accumulation of oxidative damage. The role of flight in honeybee ageing is incompletely understood. We assessed relationships between honeybee flight activity and ageing by simulating rain that confined foragers to their colonies most of the day. After 15 days on average, flight-restricted foragers were compared with bees with normal (free) flight: one group that foraged for ∼15 days and two additional control groups, for flight duration and chronological age, that foraged for ∼5 days. Free flight over 15 days on average resulted in impaired associative learning ability. In contrast, flight-restricted foragers did as well in learning as bees that foraged for 5 days on average. This negative effect of flight activity was not influenced by chronological age or gustatory responsiveness, a measure of the bees' motivation to learn. Contrasting their intact learning ability, flight-restricted bees accrued the most oxidative brain damage as indicated by malondialdehyde protein adduct levels in crude cytosolic fractions. Concentrations of mono- and poly-ubiquitinated brain proteins were equal between the groups, whereas differences in total protein amounts suggested changes in brain protein metabolism connected to forager age, but not flight. We propose that intense flight is causal to brain deficits in aged bees, and that oxidative protein damage is unlikely to be the underlying mechanism.

Obesity and Aging: Consequences for Cognition, Brain Structure, and Brain Function.

PubMed

Bischof, Gérard N; Park, Denise C

2015-01-01

This review focuses on the relationship between obesity and aging and how these interact to affect cognitive function. The topics covered are guided by the Scaffolding Theory of Aging and Cognition (STAC [Park and Reuter-Lorenz. Annu Rev Psychol 2009;60:173-96]-a conceptual model designed to relate brain structure and function to one's level of cognitive ability. The initial literature search was focused on normal aging and was guided by the key words, "aging, cognition, and obesity" in PubMed. In a second search, we added key words related to neuropathology including words "Alzheimer's disease," "vascular dementia," and "mild cognitive impairment." The data suggest that being overweight or obese in midlife may be more detrimental to subsequent age-related cognitive decline than being overweight or obese at later stages of the life span. These effects are likely mediated by the accelerated effects obesity has on the integrity of neural structures, including both gray and white matter. Further epidemiological studies have provided evidence that obesity in midlife is linked to an increased risk for Alzheimer's disease and vascular dementia, most likely via an increased accumulation of Alzheimer's disease pathology. Although it is clear that obesity negatively affects cognition, more work is needed to better understand how aging plays a role and how brain structure and brain function might mediate the relationship of obesity and age on cognition. Guided by the STAC and the STAC-R models, we provide a roadmap for future investigations of the role of obesity on cognition across the life span.

Obesity and Aging: Consequences for Cognition, Brain Structure and Brain Function

PubMed Central

Bischof, Gérard N.; Park, Denise C.

2017-01-01

Objective This review focuses on the relationship between obesity and aging and how these interact together to affect cognitive function. The topics covered are guided by the Scaffolding Theory of Aging and Cognition (STAC; Park & Reuter-Lorenz, 2009—a conceptual model designed to relate brain structure and function to one’s level of cognitive ability. Methods The initial literature search was focused on normal aging and was guided by the key words, “aging, cognition, and obesity” in “PUBMED”. In a second search we added key words related to neuropathology including words “Alzheimer’s Disease”, “Vascular dementia” (VaD) and “Mild Cognitive Impairment” (MCI). Results The data suggest that being overweight or obese in midlife may be more detrimental to subsequent age-related cognitive decline than being overweight or obese at later stages of the lifespan. These effects are likely mediated by the accelerated effects obesity has on the integrity of neural structures, including both gray and white matter. Further epidemiological studies have provided evidence that obesity in mid-life is linked to an increased risk for AD and VaD, most likely via an increased accumulation of AD pathology. Conclusion While it is clear that obesity negatively affects cognition, more work is needed to better understand how aging plays a role and how brain structure and brain function might mediate the relationship of obesity and age on cognition. Guided by the STAC and the STAC-R models, we provide a roadmap for future investigations of the role of obesity on cognition across the lifespan. PMID:26107577

Flight restriction prevents associative learning deficits but not changes in brain protein-adduct formation during honeybee ageing

PubMed Central

Tolfsen, Christina C.; Baker, Nicholas; Kreibich, Claus; Amdam, Gro V.

2011-01-01

SUMMARY Honeybees (Apis mellifera) senesce within 2 weeks after they discontinue nest tasks in favour of foraging. Foraging involves metabolically demanding flight, which in houseflies (Musca domestica) and fruit flies (Drosophila melanogaster) is associated with markers of ageing such as increased mortality and accumulation of oxidative damage. The role of flight in honeybee ageing is incompletely understood. We assessed relationships between honeybee flight activity and ageing by simulating rain that confined foragers to their colonies most of the day. After 15 days on average, flight-restricted foragers were compared with bees with normal (free) flight: one group that foraged for ∼15 days and two additional control groups, for flight duration and chronological age, that foraged for ∼5 days. Free flight over 15 days on average resulted in impaired associative learning ability. In contrast, flight-restricted foragers did as well in learning as bees that foraged for 5 days on average. This negative effect of flight activity was not influenced by chronological age or gustatory responsiveness, a measure of the bees' motivation to learn. Contrasting their intact learning ability, flight-restricted bees accrued the most oxidative brain damage as indicated by malondialdehyde protein adduct levels in crude cytosolic fractions. Concentrations of mono- and poly-ubiquitinated brain proteins were equal between the groups, whereas differences in total protein amounts suggested changes in brain protein metabolism connected to forager age, but not flight. We propose that intense flight is causal to brain deficits in aged bees, and that oxidative protein damage is unlikely to be the underlying mechanism. PMID:21430210

Genome-wide expression and methylation profiling in the aged rodent brain due to early-life Pb exposure and its relevance to aging.

PubMed

Dosunmu, Remi; Alashwal, Hany; Zawia, Nasser H

2012-06-01

In this study, we assessed global gene expression patterns in adolescent mice exposed to lead (Pb) as infants and their aged siblings to identify reprogrammed genes. Global expression on postnatal day 20 and 700 was analyzed and genes that were down- and up-regulated (≥2 fold) were identified, clustered and analyzed for their relationship to DNA methylation. About 150 genes were differentially expressed in old age. In normal aging, we observed an up-regulation of genes related to the immune response, metal-binding, metabolism and transcription/transduction coupling. Prior exposure to Pb revealed a repression in these genes suggesting that disturbances in developmental stages of the brain compromise the ability to defend against age-related stressors, thus promoting the neurodegenerative process. Overexpression and repression of genes corresponded with their DNA methylation profile. Published by Elsevier Ireland Ltd.

Appraising the Role of Iron in Brain Aging and Cognition: Promises and Limitations of MRI Methods

PubMed Central

Daugherty, Ana M; Raz, Naftali

2015-01-01

Age-related increase in frailty is accompanied by a fundamental shift in cellular iron homeostasis. By promoting oxidative stress, the intracellular accumulation of non-heme iron outside of binding complexes contributes to chronic inflammation and interferes with normal brain metabolism. In the absence of direct non-invasive biomarkers of brain oxidative stress, iron accumulation estimated in vivo may serve as its proxy indicator. Hence, developing reliable in vivo measurements of brain iron content via magnetic resonance imaging (MRI) is of significant interest in human neuroscience. To date, by estimating brain iron content through various MRI methods, significant age differences and age-related increases in iron content of the basal ganglia have been revealed across multiple samples. Less consistent are the findings that pertain to the relationship between elevated brain iron content and systemic indices of vascular and metabolic dysfunction. Only a handful of cross-sectional investigations have linked high iron content in various brain regions and poor performance on assorted cognitive tests. The even fewer longitudinal studies indicate that iron accumulation may precede shrinkage of the basal ganglia and thus predict poor maintenance of cognitive functions. This rapidly developing field will benefit from introduction of higher-field MRI scanners, improvement in iron-sensitive and -specific acquisition sequences and post-processing analytic and computational methods, as well as accumulation of data from long-term longitudinal investigations. This review describes the potential advantages and promises of MRI-based assessment of brain iron, summarizes recent findings and highlights the limitations of the current methodology. PMID:26248580

Structural brain abnormalities in adolescent anorexia nervosa before and after weight recovery and associated hormonal changes.

PubMed

Mainz, Verena; Schulte-Rüther, Martin; Fink, Gereon R; Herpertz-Dahlmann, Beate; Konrad, Kerstin

2012-01-01

The neurobiological mechanisms of structural brain abnormalities in patients with anorexia nervosa (AN) remain poorly understood. In particular, little is known about the changes in and the recovery of gray matter (GM) volumes after weight gain and the relation to hormonal normalization in adolescent patients with AN. Nineteen female patients aged 12 to 17 years were assessed using magnetic resonance imaging at the time of admission to the hospital (T1) and after weight recovery (T2). Patients were compared with typically developing girls matched for age and intelligence quotient. Structural brain images were analyzed using a voxel-based morphometric approach. Circulating levels of cortisol and gonadotropins were assessed in blood samples. Compared with controls, patients with AN showed reduced GM in several brain regions along the cortical midline, reaching from the occipital cortex to the medial frontal areas. These GM reductions were mostly reversible at T1. Patients showed a GM increase from T1 to T2 along the cortical midline and in the occipital, temporal, parietal, and frontal lobes. GM increases at T2 correlated inversely with cortisol levels at T1 and positively with weight gain at T2. The strongest associations between regional GM increase and weight gain were found in the cerebellum. In addition, increases in GM volumes at T2 in the thalamus, hippocampus, and amygdala were associated with increases in follicle-stimulating hormone. Our data suggest that brain alterations in adolescents with acute AN are mostly reversible at T1 and that GM recovery in specific brain regions is associated with weight and hormonal normalization.

Region-specific changes in presynaptic agmatine and glutamate levels in the aged rat brain.

PubMed

Jing, Y; Liu, P; Leitch, B

2016-01-15

During the normal aging process, the brain undergoes a range of biochemical and structural alterations, which may contribute to deterioration of sensory and cognitive functions. Age-related deficits are associated with altered efficacy of synaptic neurotransmission. Emerging evidence indicates that levels of agmatine, a putative neurotransmitter in the mammalian brain, are altered in a region-specific manner during the aging process. The gross tissue content of agmatine in the prefrontal cortex (PFC) of aged rat brains is decreased whereas levels in the temporal cortex (TE) are increased. However, it is not known whether these changes in gross tissue levels are also mirrored by changes in agmatine levels at synapses and thus could potentially contribute to altered synaptic function with age. In the present study, agmatine levels in presynaptic terminals in the PFC and TE regions (300 terminals/region) of young (3month; n=3) and aged (24month; n=3) brains of male Sprague-Dawley rats were compared using quantitative post-embedding immunogold electron-microscopy. Presynaptic levels of agmatine were significantly increased in the TE region (60%; p<0.001) of aged rats compared to young rats, however no significant differences were detected in synaptic levels in the PFC region. Double immunogold labeling indicated that agmatine and glutamate were co-localized in the same synaptic terminals, and quantitative analyses revealed significantly reduced glutamate levels in agmatine-immunopositive synaptic terminals in both regions in aged rats compared to young animals. This study, for the first time, demonstrates differential effects of aging on agmatine and glutamate in the presynaptic terminals of PFC and TE. Future research is required to understand the functional significance of these changes and the underlying mechanisms. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

[Immune dysfunction and cognitive deficit in stress and physiological aging (Part I): Pathogenesis and risk factors].

PubMed

Pukhal'skiĭ, A L; Shmarina, G V; Aleshkin, V A

2014-01-01

The concept of stressful cognitive dysfunction, which is under consideration in this review, allows picking out several therapeutic targets. The brain, immune and endocrine systems being the principal adaptive systems in the body permanently share information both in the form of neural impulses and soluble mediators. The CNS differs from other organs due to several peculiarities that affect local immune surveillance. The brain cells secluded from the blood flow by a specialized blood-brain-barrier (BBB) can endogenously express pro- and anti-inflammatory cytokines without the intervention of the immune system. In normal brain the cytokine signaling rather contributes to exclusive brain function (e.g. long-term potentiation, synaptic plasticity, adult neurogenesis) than serves as immune communicator. The stress of different origin increases the serum cytokine levels and disrupts BBB. As a result peripheral cytokines penetrate into the brain where they begin to perform new functions. Mass intrusion of biologically active peptides having a lot of specific targets alters the brain work that we can observe both in humans and in animal experiments. In addition owing to BBB disruption dendritic cells and T cells also penetrate into the brain where they take up a perivascular position. The changes observed in stressed subject may accumulate during repeated episodes of stress forming a picture typical of the aging brain. Moreover long-term stress as well as physiological aging result in hormonal and immunological disturbances including hypothalamic-pituitary-adrenal axis depletion, regulatory T-cell accumulation and dehydroepiandrosterone decrease.

Cardiac index is associated with brain aging: The Framingham Heart Study

PubMed Central

Jefferson, Angela L.; Himali, Jayandra J.; Beiser, Alexa S.; Au, Rhoda; Massaro, Joseph M.; Seshadri, Sudha; Gona, Philimon; Salton, Carol J.; DeCarli, Charles; O’Donnell, Christopher J.; Benjamin, Emelia J.; Wolf, Philip A.; Manning, Warren J.

2010-01-01

Background Cardiac dysfunction is associated with neuroanatomic and neuropsychological changes in aging adults with prevalent cardiovascular disease (CVD), theoretically because systemic hypoperfusion disrupts cerebral perfusion, contributing to subclinical brain injury. We hypothesized that cardiac function, as measured by cardiac index, would be associated with pre-clinical brain magnetic resonance imaging (MRI) and neuropsychological markers of ischemia and Alzheimer’s disease in the community. Methods and Results Brain MRI, cardiac MRI, neuropsychological, and laboratory data were collected on 1504 Framingham Offspring Cohort participants free from clinical stroke, transient ischemic attack, or dementia (61±9 years; 54% women). Neuropsychological and brain MRI variables were related to cardiac MRI-assessed cardiac index (cardiac output/body surface area). In multivariable-adjusted models, cardiac index was positively related to total brain volume (P=0.03) and information processing speed (P=0.02) and inversely related to lateral ventricular volume (P=0.048). When participants with clinically prevalent CVD were excluded, the relation between cardiac index and total brain volume remained (P=0.02). Post-hoc comparisons revealed that participants in the bottom cardiac index tertile (values<2.54) and middle cardiac index tertile (values between 2.54 and 2.92) had significantly lower brain volumes (P=0.04) than participants in the top cardiac index tertile (values>2.92). Conclusions Although observational data cannot establish causality, our findings are consistent with the hypothesis that decreasing cardiac function, even at normal cardiac index levels, is associated with accelerated brain aging. PMID:20679552

A spline-based regression parameter set for creating customized DARTEL MRI brain templates from infancy to old age.

PubMed

Wilke, Marko

2018-02-01

This dataset contains the regression parameters derived by analyzing segmented brain MRI images (gray matter and white matter) from a large population of healthy subjects, using a multivariate adaptive regression splines approach. A total of 1919 MRI datasets ranging in age from 1-75 years from four publicly available datasets (NIH, C-MIND, fCONN, and IXI) were segmented using the CAT12 segmentation framework, writing out gray matter and white matter images normalized using an affine-only spatial normalization approach. These images were then subjected to a six-step DARTEL procedure, employing an iterative non-linear registration approach and yielding increasingly crisp intermediate images. The resulting six datasets per tissue class were then analyzed using multivariate adaptive regression splines, using the CerebroMatic toolbox. This approach allows for flexibly modelling smoothly varying trajectories while taking into account demographic (age, gender) as well as technical (field strength, data quality) predictors. The resulting regression parameters described here can be used to generate matched DARTEL or SHOOT templates for a given population under study, from infancy to old age. The dataset and the algorithm used to generate it are publicly available at https://irc.cchmc.org/software/cerebromatic.php.

Life-long stability of neurons: a century of research on neurogenesis, neuronal death and neuron quantification in adult CNS.

PubMed

Turlejski, Kris; Djavadian, Ruzanna

2002-01-01

In this chapter we provide an extensive review of 100 years of research on the stability of neurons in the mammalian brain, with special emphasis on humans. Although Cajal formulated the Neuronal Doctrine, he was wrong in his beliefs that adult neurogenesis did not occur and adult neurons are dying throughout life. These two beliefs became accepted "common knowledge" and have shaped much of neuroscience research and provided much of the basis for clinical treatment of age-related brain diseases. In this review, we consider adult neurogenesis from a historical and evolutionary perspective. It is concluded, that while adult neurogenesis is a factor in the dynamics of the dentate gyrus and olfactory bulb, it is probably not a major factor during the life-span in most brain areas. Likewise, the acceptance of neuronal death as an explanation for normal age-related senility is challenged with evidence collected over the last fifty years. Much of the problem in changing this common belief of dying neurons was the inadequacies of neuronal counting methods. In this review we discuss in detail implications of recent improvements in neuronal quantification. We conclude: First, age-related neuronal atrophy is the major factor in functional deterioration of existing neurons and could be slowed down, or even reversed by various pharmacological interventions. Second, in most cases neuronal degeneration during aging is a pathology that in principle may be avoided. Third, loss of myelin and of the white matter is more frequent and important than the limited neuronal death in normal aging.

Modifiable Risk Factors and Brain Positron Emission Tomography Measures of Amyloid and Tau in Nondemented Adults with Memory Complaints.

PubMed

Merrill, David A; Siddarth, Prabha; Raji, Cyrus A; Emerson, Natacha D; Rueda, Florangel; Ercoli, Linda M; Miller, Karen J; Lavretsky, Helen; Harris, Laurel M; Burggren, Alison C; Bookheimer, Susan Y; Barrio, Jorge R; Small, Gary W

2016-09-01

Exercise and diet impact body composition, but their age-related brain effects are unclear at the molecular imaging level. To address these issues, the authors determined whether body mass index (BMI), physical activity, and diet relate to brain positron emission tomography (PET) of amyloid plaques and tau tangles using 2-(1-(6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl)ethylidene)malononitrile (FDDNP). Volunteers (N = 44; mean age: 62.6 ± 10.7 years) with subjective memory impairment (N = 24) or mild cognitive impairment (MCI; N = 20) were recruited by soliciting for memory complaints. Levels of physical activity and extent of following a Mediterranean-type diet were self-reported. FDDNP-PET scans assessed plaque/tangle binding in Alzheimer disease-associated regions (frontal, parietal, medial and lateral temporal, posterior cingulate). Mixed models controlling for known covariates examined BMI, physical activity, and diet in relation to FDDNP-PET. MCI subjects with above normal BMI (>25) had higher FDDNP-PET binding compared with those with normal BMI (1.11(0.03) versus 1.08(0.03), ES = 1.04, t(35) = 3.3, p = 0.002). Greater physical activity was associated with lower FDDNP-PET binding in MCI subjects (1.07(0.03) versus 1.11(0.03), ES = 1.13, t(35) = -3.1, p = 0.004) but not in subjects with subjective memory impairment (1.07(0.03) versus 1.07(0.03), ES = 0.02, t(35) = -0.1, p = 0.9). Healthier diet related to lower FDDNP-PET binding, regardless of cognitive status (1.07(0.03) versus 1.09(0.02), ES = 0.72, t(35) = -2.1, p = 0.04). These preliminary findings are consistent with a relationship between risk modifiersand brain plaque/tangle deposition in nondemented individuals and supports maintenance of normal body weight, regular physical activity, and healthy diet to protect the brain during aging. (clinicaltrials.gov; NCT00355498). Copyright © 2016 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.

The different maturation of the corticospinal tract and corticoreticular pathway in normal brain development: diffusion tensor imaging study

PubMed Central

Yeo, Sang Seok; Jang, Sung Ho; Son, Su Min

2014-01-01

Background and Purpose: The corticospinal tract (CST) and corticoreticular pathway (CRP) are known to be important neural tracts for motor development. However, little is known about the difference in maturation of the CST and CRP. In this study, using diffusion tensor imaging (DTI), we investigated maturation of the CST and CRP in typically developed children and normal healthy adults. Methods: We recruited 75 normal healthy subjects for this study. DTI was performed using 1.5-T, and the CST and CRP were reconstructed using DTI-Studio software. Values of fractional anisotropy (FA) and fiber volume (FV) of the CST and CRP were measured. Results: In the current study, the threshold points for CST and CRP maturation were different in normal brain development. Change in FA value of the CST showed a steep increase until 7 years of age and then a gradual increase until adulthood, however, the CRP showed a steep increase only until 2 years of age and then a very gradual increase or plateau until adulthood. In terms of FV, the CST showed a steep increase until 12 years and then a gradual increase until adulthood, in contrast, the CRP showed gradual increase of FV across whole age range (0–25 years). Conclusion: The difference in maturation process between CST and CRP appears to be related to different periods of fine and gross motor development. This radiologic information can provide a scientific basis for understanding development in motor function. PMID:25309378

I've Got the Music in Me: A Study of Peak Musical Memory Age and the Implications for Future Advertising

ERIC Educational Resources Information Center

Gerlich, R. Nicholas; Browning, Leigh; Westermann, Lori

2010-01-01

Neuropsychologists have demonstrated the effect music has on the human brain, and that a peak "musical memory age" occurs around 14, when normal bodily maturation is in progress. A group of 114 college students between the ages of 19 and 25 was exposed to short clips of the top 20 songs from each of the 11 years during their youth;…

Toward a multifactorial model of Alzheimer disease

PubMed Central

Storandt, Martha; Head, Denise; Fagan, Anne M.; Holtzman, David M.; Morris, John C.

2011-01-01

Relations among antecedant biomarkers of AD were evaluated using causal modeling; although correlation cannot be equated to causation, causation does require correlation. Individuals aged 43 to 89 years (N = 220) enrolled as cognitively normal controls in longitudinal studies had clinical and psychometric assessment, structural magnetic resonance imaging (MRI), cerebrospinal fluid (CSF) biomarkers, and brain amyloid imaging via positron emission tomography with Pittsburgh Compound B (PIB) obtained within 1 year. CSF levels of Aβ42 and tau were minimally correlated, indicating they represent independent processes. Aβ42, tau, and their interaction explained 60% of the variance in PIB. Effects of APOE genotype and age on PIB were indirect, operating through CSF markers. Only spurious relations via their common relation with age were found between the biomarkers and regional brain volumes or cognition. Hence, at least two independent hypothesized processes, one reflected by CSF Aβ42 and one by CSF tau, contribute to the development of fibrillar amyloid plaques preclinically. The lack of correlation between these two processes and brain volume in the regions most often affected in AD suggests the operation of a third process related to brain atrophy. PMID:22261556

Functional and Structural Benefits Induced by Omega-3 Polyunsaturated Fatty Acids During Aging

PubMed Central

Cutuli, Debora

2017-01-01

Background Omega-3 polyunsaturated fatty acids (n-3 PUFA) are structural components of the brain and are indispensable for neuronal membrane synthesis. Along with decline in cognition, decreased synaptic density and neuronal loss, normal aging is accompanied by a reduction in n-3 PUFA concentration in the brain in both humans and rodents. Recently, many clinical and experimental studies have demonstrated the importance of n-3 PUFA in counteracting neurodegeneration and age-related dysfunctions. Methods Methods: This review will focus on the neuroprotective effects of n-3 PUFA on cognitive impairment, neuroinflammation and neurodegeneration during normal aging. Multiple pathways of n-3 PUFA preventive action will be examined. Results Namely, n-3 PUFA have been shown to increase the levels of several signaling factors involved in synaptic plasticity, thus leading to the increase of dendritic spines and synapses as well as the enhancement of hippocampal neurogenesis even at old age. In elderly subjects n-3 PUFA exert anti-inflammatory effects associated with improved cognitive functions. Interestingly, growing evidence highlights n-3 PUFA efficacy in preventing the loss of both gray and white matter volume and integrity. Conclusion This review shows that n-3 PUFA are essential for a successful aging and appear as ideal cognitive enhancers to be implemented in nutritional interventions for the promotion of healthy aging. PMID:27306037

Measuring the effects of aging and sex on regional brain stiffness with MR elastography in healthy older adults

PubMed Central

Arani, Arvin; Murphy, Matthew C; Glaser, Kevin J; Manduca, Armando; Lake, David S; Kruse, Scott; Jack, Clifford R; Ehman, Richard; Huston, John

2015-01-01

Changes in tissue composition and cellular architecture have been associated with neurological disease, and these in turn can affect biomechanical properties. Natural biological factors such as aging and an individual’s sex also affect underlying tissue biomechanics in different brain regions. Understanding the normal changes is necessary before determining the efficacy of stiffness imaging for neurological disease diagnosis and therapy monitoring. The objective of this study was to evaluate global and regional changes in brain stiffness as a function of age and sex, using improved MRE acquisition and processing that has been shown to provide median stiffness values that are typically reproducible to within 1% in global measurements and within 2% for regional measurements. Furthermore, this is the first study to report the effects of age and sex over the entire cerebrum volume and over the full frontal, occipital, parietal, temporal, deep gray matter/white matter (insula, deep gray nuclei and white matter tracts), and cerebellum volumes. In 45 volunteers, we observed a significant linear correlation between age and brain stiffness in the cerebrum (P<.0001), frontal lobes (P<.0001), occipital lobes (P=.0005), parietal lobes (P=.0002), and the temporal lobes (P<.0001) of the brain. No significant linear correlation between brain stiffness and age was observed in the cerebellum (P=.74), and the sensory-motor regions (P=.32) of the brain, and a weak linear trend was observed in the deep gray matter/white matter (P=.075). A multiple linear regression model predicted an annual decline of 0.011±0.002 kPa in cerebrum stiffness with a theoretical median age value (76 years old) of 2.56±0.08 kPa. Sexual dimorphism was observed in the temporal (P=.03) and occipital (P=.001) lobes of the brain, but no significant difference was observed in any of the other brain regions (P>.20 for all other regions). The model predicted female occipital and temporal lobes to be 0.23 kPa and 0.09 kPa stiffer than males of the same age, respectively. This study confirms that as the brain ages, there is softening; however, the changes are dependent on region. In addition, stiffness effects due to sex exist in the occipital and temporal lobes. PMID:25698157

Evaluation of AAV-mediated Gene Therapy for Central Nervous System Disease in Canine Mucopolysaccharidosis VII

PubMed Central

Gurda, Brittney L; De Guilhem De Lataillade, Adrien; Bell, Peter; Zhu, Yanqing; Yu, Hongwei; Wang, Ping; Bagel, Jessica; Vite, Charles H; Sikora, Tracey; Hinderer, Christian; Calcedo, Roberto; Yox, Alexander D; Steet, Richard A; Ruane, Therese; O'Donnell, Patricia; Gao, Guangping; Wilson, James M; Casal, Margret; Ponder, Katherine P; Haskins, Mark E

2016-01-01

Mucopolysaccharidosis VII (MPS VII) is a lysosomal storage disease arising from mutations in β-d-glucuronidase (GUSB), which results in glycosaminoglycan (GAG) accumulation and a variety of clinical manifestations including neurological disease. Herein, MPS VII dogs were injected intravenously (i.v.) and/or intrathecally (i.t.) via the cisterna magna with AAV9 or AAVrh10 vectors carrying the canine GUSB cDNA. Although i.v. injection alone at 3 days of age resulted in normal cerebrospinal fluid (CSF) GUSB activity, brain tissue homogenates had only ~1 to 6% normal GUSB activity and continued to have elevated GAG storage. In contrast, i.t. injection at 3 weeks of age resulted in CSF GUSB activity 44-fold normal while brain tissue homogenates had >100% normal GUSB activity and reduced GAGs compared with untreated dogs. Markers for secondary storage and inflammation were eliminated in i.t.-treated dogs and reduced in i.v.-treated dogs compared with untreated dogs. Given that i.t.-treated dogs expressed higher levels of GUSB in the CNS tissues compared to those treated i.v., we conclude that i.t. injection of AAV9 or AAVrh10 vectors is more effective than i.v. injection alone in the large animal model of MPS VII. PMID:26447927

Evaluation of AAV-mediated Gene Therapy for Central Nervous System Disease in Canine Mucopolysaccharidosis VII.

PubMed

Gurda, Brittney L; De Guilhem De Lataillade, Adrien; Bell, Peter; Zhu, Yanqing; Yu, Hongwei; Wang, Ping; Bagel, Jessica; Vite, Charles H; Sikora, Tracey; Hinderer, Christian; Calcedo, Roberto; Yox, Alexander D; Steet, Richard A; Ruane, Therese; O'Donnell, Patricia; Gao, Guangping; Wilson, James M; Casal, Margret; Ponder, Katherine P; Haskins, Mark E

2016-02-01

Mucopolysaccharidosis VII (MPS VII) is a lysosomal storage disease arising from mutations in β-d-glucuronidase (GUSB), which results in glycosaminoglycan (GAG) accumulation and a variety of clinical manifestations including neurological disease. Herein, MPS VII dogs were injected intravenously (i.v.) and/or intrathecally (i.t.) via the cisterna magna with AAV9 or AAVrh10 vectors carrying the canine GUSB cDNA. Although i.v. injection alone at 3 days of age resulted in normal cerebrospinal fluid (CSF) GUSB activity, brain tissue homogenates had only ~1 to 6% normal GUSB activity and continued to have elevated GAG storage. In contrast, i.t. injection at 3 weeks of age resulted in CSF GUSB activity 44-fold normal while brain tissue homogenates had >100% normal GUSB activity and reduced GAGs compared with untreated dogs. Markers for secondary storage and inflammation were eliminated in i.t.-treated dogs and reduced in i.v.-treated dogs compared with untreated dogs. Given that i.t.-treated dogs expressed higher levels of GUSB in the CNS tissues compared to those treated i.v., we conclude that i.t. injection of AAV9 or AAVrh10 vectors is more effective than i.v. injection alone in the large animal model of MPS VII.

Neuronal Function in Male Sprague Dawley Rats During Normal Ageing.

PubMed

Idowu, A J; Olatunji-Bello, I I; Olagunju, J A

2017-03-06

During normal ageing, there are physiological changes especially in high energy demanding tissues including the brain and skeletal muscles. Ageing may disrupt homeostasis and allow tissue vulnerability to disease. To establish an appropriate animal model which is readily available and will be useful to test therapeutic strategies during normal ageing, we applied behavioral approaches to study age-related changes in memory and motor function as a basis for neuronal function in ageing in male Sprague Dawley rats. 3 months, n=5; 6 months, n=5 and 18 months, n=5 male Sprague Dawley Rats were tested using the Novel Object Recognition Task (NORT) and the Elevated plus Maze (EPM) Test. Data was analyzed by ANOVA and the Newman-Keuls post hoc test. The results showed an age-related gradual decline in exploratory behavior and locomotor activity with increasing age in 3 months, 6 months and 18 months old rats, although the values were not statistically significant, but grooming activity significantly increased with increasing age. Importantly, we established a novel finding that the minimum distance from the novel object was statistically significant between 3 months and 18 months old rats and this may be an index for age-related memory impairment in the NORT. Altogether, we conclude that the male Sprague Dawley rat show age-related changes in neuronal function and may be a useful model for carrying out investigations into the mechanisms involved in normal ageing.

Lack of serotonin1B receptor expression leads to age-related motor dysfunction, early onset of brain molecular aging and reduced longevity.

PubMed

Sibille, E; Su, J; Leman, S; Le Guisquet, A M; Ibarguen-Vargas, Y; Joeyen-Waldorf, J; Glorioso, C; Tseng, G C; Pezzone, M; Hen, R; Belzung, C

2007-11-01

Normal aging of the brain differs from pathological conditions and is associated with increased risk for psychiatric and neurological disorders. In addition to its role in the etiology and treatment of mood disorders, altered serotonin (5-HT) signaling is considered a contributing factor to aging; however, no causative role has been identified in aging. We hypothesized that a deregulation of the 5-HT system would reveal its contribution to age-related processes and investigated behavioral and molecular changes throughout adult life in mice lacking the regulatory presynaptic 5-HT(1B) receptor (5-HT(1B)R), a candidate gene for 5-HT-mediated age-related functions. We show that the lack of 5-HT(1B)R (Htr1b(KO) mice) induced an early age-related motor decline and resulted in decreased longevity. Analysis of life-long transcriptome changes revealed an early and global shift of the gene expression signature of aging in the brain of Htr1b(KO) mice. Moreover, molecular changes reached an apparent maximum effect at 18-months in Htr1b(KO) mice, corresponding to the onset of early death in that group. A comparative analysis with our previous characterization of aging in the human brain revealed a phylogenetic conservation of age-effect from mice to humans, and confirmed the early onset of molecular aging in Htr1b(KO) mice. Potential mechanisms appear independent of known central mechanisms (Bdnf, inflammation), but may include interactions with previously identified age-related systems (IGF-1, sirtuins). In summary, our findings suggest that the onset of age-related events can be influenced by altered 5-HT function, thus identifying 5-HT as a modulator of brain aging, and suggesting age-related consequences to chronic manipulation of 5-HT.

Brain Biochemistry and Personality: A Magnetic Resonance Spectroscopy Study

PubMed Central

Ryman, Sephira G.; Gasparovic, Chuck; Bedrick, Edward J.; Flores, Ranee A.; Marshall, Alison N.; Jung, Rex E.

2011-01-01

To investigate the biochemical correlates of normal personality we utilized proton magnetic resonance spectroscopy (1H-MRS). Our sample consisted of 60 subjects ranging in age from 18 to 32 (27 females). Personality was assessed with the NEO Five-Factor Inventory (NEO-FFI). We measured brain biochemistry within the precuneus, the cingulate cortex, and underlying white matter. We hypothesized that brain biochemistry within these regions would predict individual differences across major domains of personality functioning. Biochemical models were fit for all personality domains including Neuroticism, Extraversion, Openness, Agreeableness, and Conscientiousness. Our findings involved differing concentrations of Choline (Cho), Creatine (Cre), and N-acetylaspartate (NAA) in regions both within (i.e., posterior cingulate cortex) and white matter underlying (i.e., precuneus) the Default Mode Network (DMN). These results add to an emerging literature regarding personality neuroscience, and implicate biochemical integrity within the default mode network as constraining major personality domains within normal human subjects. PMID:22073190

Low cortical iron and high entorhinal cortex volume promote cognitive functioning in the oldest-old.

PubMed

van Bergen, Jiri M G; Li, Xu; Quevenco, Frances C; Gietl, Anton F; Treyer, Valerie; Leh, Sandra E; Meyer, Rafael; Buck, Alfred; Kaufmann, Philipp A; Nitsch, Roger M; van Zijl, Peter C M; Hock, Christoph; Unschuld, Paul G

2018-04-01

The aging brain is characterized by an increased presence of neurodegenerative and vascular pathologies. However, there is substantial variation regarding the relationship between an individual's pathological burden and resulting cognitive impairment. To identify correlates of preserved cognitive functioning at highest age, the relationship between β-amyloid plaque load, presence of small vessel cerebrovascular disease (SVCD), iron-burden, and brain atrophy was investigated. Eighty cognitively unimpaired participants (44 oldest-old, aged 85-96 years; 36 younger-old, aged 55-80 years) were scanned by integrated positron emission tomography-magnetic resonance imaging for assessing beta regional amyloid plaque load (18F-flutemetamol), white matter hyperintensities as an indicator of SVCD (fluid-attenuated inversion recovery-magnetic resonance imaging), and iron load (quantitative susceptibility mapping). For the oldest-old group, lower cortical volume, increased β-amyloid plaque load, prevalence of SVCD, and lower cognitive performance in the normal range were found. However, compared to normal-old, cortical iron burden was lower in the oldest-old. Moreover, only in the oldest-old, entorhinal cortex volume positively correlated with β-amyloid plaque load. Our data thus indicate that the co-occurrence of aging-associated neuropathologies with reduced quantitative susceptibility mapping measures of cortical iron load constitutes a lower vulnerability to cognitive loss. Copyright © 2017 Elsevier Inc. All rights reserved.

Oxidative Glial Cell Damage Associated with White Matter Lesions in the Aging Human Brain.

PubMed

Al-Mashhadi, Sufana; Simpson, Julie E; Heath, Paul R; Dickman, Mark; Forster, Gillian; Matthews, Fiona E; Brayne, Carol; Ince, Paul G; Wharton, Stephen B

2015-09-01

White matter lesions (WML) are common in brain aging and are associated with dementia. We aimed to investigate whether oxidative DNA damage and occur in WML and in apparently normal white matter in cases with lesions. Tissue from WML and control white matter from brains with lesions (controls lesional) and without lesions (controls non-lesional) were obtained, using post-mortem magnetic resonance imaging-guided sampling, from the Medical Research Council Cognitive Function and Ageing Study. Oxidative damage was assessed by immunohistochemistry to 8-hydroxy-2'-deoxoguanosine (8-OHdG) and Western blotting for malondialdehyde. DNA response was assessed by phosphorylated histone H2AX (γH2AX), p53, senescence markers and by quantitative Reverse transcription polymerase chain reaction (RT-PCR) panel for candidate DNA damage-associated genes. 8-OHdG was expressed in glia and endothelium, with increased expression in both WML and controls lesional compared with controls non-lesional (P < 0.001). γH2Ax showed a similar, although attenuated difference among groups (P = 0.03). Expression of senescence-associated β-galactosidase and p16 suggested induction of senescence mechanisms in glia. Oxidative DNA damage and a DNA damage response are features of WML pathogenesis and suggest candidate mechanisms for glial dysfunction. Their expression in apparently normal white matter in cases with WML suggests that white matter dysfunction is not restricted to lesions. The role of this field-effect lesion pathogenesis and cognitive impairment are areas to be defined. © 2014 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology.

Retinoid receptors, transporters, and metabolizers as therapeutic targets in late onset Alzheimer disease.

PubMed

Goodman, Ann B

2006-12-01

Vitamin A (retinoid) is required in the adult brain to enable cognition, learning, and memory. While brain levels of retinoid diminish over the course of normal ageing, retinoid deficit is greater in late onset Alzheimer disease (LOAD) brains than in normal-aged controls. This paper reviews recent evidence supporting these statements and further suggests that genes necessary for the synthesis, transport and function of retinoid to and within the ageing brain are appropriate targets for treatment of LOAD. These genes tend to be clustered with genes that have been proposed as candidates in LOAD, are found at chromosomal regions linked to LOAD, and suggest the possibility of an overall coordinated regulation. This phenomenon is termed Chromeron and is analogous to the operon mechanism observed in prokaryotes. Suggested treatment targets are the retinoic-acid inactivating enzymes (CYP26)s, the retinol binding and transport proteins, retinol-binding protein (RBP)4 and transthyretin (TTR), and the retinoid receptors. TTR as a LOAD target is the subject of active investigation. The retinoid receptors and the retinoid-inactivating enzymes have previously been proposed as targets. This is the first report to suggest that RBP4 is an amenable treatment target in LOAD. RBP4 is elevated in type-2 diabetes and obesity, conditions associated with increased risk for LOAD. Fenretinide, a novel synthetic retinoic acid (RA) analog lowers RBP4 in glucose intolerant obese mice. The feasibility of using fenretinide either as an adjunct to present LOAD therapies, or on its own as an early prevention strategy should be determined. (c) 2006 Wiley-Liss, Inc.

Glucose hypometabolism is highly localized, but lower cortical thickness and brain atrophy are widespread in cognitively normal older adults.

PubMed

Nugent, Scott; Castellano, Christian-Alexandre; Goffaux, Philippe; Whittingstall, Kevin; Lepage, Martin; Paquet, Nancy; Bocti, Christian; Fulop, Tamas; Cunnane, Stephen C

2014-06-01

Several studies have suggested that glucose hypometabolism may be present in specific brain regions in cognitively normal older adults and could contribute to the risk of subsequent cognitive decline. However, certain methodological shortcomings, including a lack of partial volume effect (PVE) correction or insufficient cognitive testing, confound the interpretation of most studies on this topic. We combined [(18)F]fluorodeoxyglucose ([(18)F]FDG) positron emission tomography (PET) and magnetic resonance (MR) imaging to quantify cerebral metabolic rate of glucose (CMRg) as well as cortical volume and thickness in 43 anatomically defined brain regions from a group of cognitively normal younger (25 ± 3 yr old; n = 25) and older adults (71 ± 9 yr old; n = 31). After correcting for PVE, we observed 11-17% lower CMRg in three specific brain regions of the older group: the superior frontal cortex, the caudal middle frontal cortex, and the caudate (P ≤ 0.01 false discovery rate-corrected). In the older group, cortical volumes and cortical thickness were 13-33 and 7-18% lower, respectively, in multiple brain regions (P ≤ 0.01 FDR correction). There were no differences in CMRg between individuals who were or were not prescribed antihypertensive medication. There were no significant correlations between CMRg and cognitive performance or metabolic parameters measured in fasting plasma. We conclude that highly localized glucose hypometabolism and widespread cortical thinning and atrophy can be present in older adults who are cognitively normal, as assessed using age-normed neuropsychological testing measures. Copyright © 2014 the American Physiological Society.

The Myth of the Normal, Average Human Brain—The ICBM Experience: (1) Subject Screening and Eligibility

PubMed Central

Mazziotta, John C.; Woods, Roger; Iacoboni, Marco; Sicotte, Nancy; Yaden, Kami; Tran, Mary; Bean, Courtney; Kaplan, Jonas; Toga, Arthur W.

2009-01-01

In the course of developing an atlas and reference system for the normal human brain throughout the human age span from structural and functional brain imaging data, the International Consortium for Brain Mapping (ICBM) developed a set of “normal” criteria for subject inclusion and the associated exclusion criteria. The approach was to minimize inclusion of subjects with any medical disorders that could affect brain structure or function. In the past two years, a group of 1,685 potential subjects responded to solicitation advertisements at one of the consortium sites (UCLA). Subjects were screened by a detailed telephone interview and then had an in-person history and physical examination. Of those who responded to the advertisement and considered themselves to be normal, only 31.6% (532 subjects) passed the telephone screening process. Of the 348 individuals who submitted to in-person history and physical examinations, only 51.7% passed these screening procedures. Thus, only 10.7% of those individuals who responded to the original advertisement qualified for imaging. The most frequent cause for exclusion in the second phase of subject screening was high blood pressure followed by abnormal signs on neurological examination. It is concluded that the majority of individuals who consider themselves normal by self-report are found not to be so by detailed historical interviews about underlying medical conditions and by thorough medical and neurological examinations. Recommendations are made with regard to the inclusion of subjects in brain imaging studies and the criteria used to select them. PMID:18775497

Regional CBF in chronic stable TBI treated with hyperbaric oxygen.

PubMed

Barrett, K F; Masel, B; Patterson, J; Scheibel, R S; Corson, K P; Mader, J T

2004-01-01

To investigate whether Hyperbaric Oxygen Therapy (HBO2) could improve neurologic deficits and regional cerebral blood flow (rCBF) in chronic traumatic brain injuries (TBI), the authors employed a nonrandomized control pilot trial. Five subjects, at least three years post head injury, received HBO2. Five head injured controls (HIC) were matched for age, sex, and type of injury. Five healthy subjects served as normal controls. Sixty-eight normal volunteers comprised a reference data bank against which to compare SPECT brain scans. HBO2 subjects received 120 HBO2 in blocks of 80 and 40 treatments with an interval five-month break. Normal controls underwent a single SPECT brain scan, HBO2, and repeat SPECT battery. TBI subjects were evaluated by neurologic, neuropsychometric, exercise testing, and pre and post study MRIs, or CT scans if MRI was contraindicated. Statistical Parametric Mapping was applied to SPECT scans for rCBF analysis. There were no significant objective changes in neurologic, neuropsychometric, exercise testing, MRIs, or rCBF. In this small pilot study, HBO2 did not effect clinical or regional cerebral blood flow improvement in TBI subjects.

Higher fasting plasma glucose is associated with smaller striatal volume and poorer fine motor skills in a longitudinal cohort.

PubMed

Zhang, Tianqi; Shaw, Marnie E; Walsh, Erin I; Sachdev, Perminder S; Anstey, Kaarin J; Cherbuin, Nicolas

2018-06-07

Previous studies have demonstrated associations between higher blood glucose and brain atrophy and functional deficits, however, little is known about the association between blood glucose, striatal volume and striatal function despite sensori-motor deficits being reported in diabetes. This study investigated the relationship between blood glucose levels, striatal volume and fine motor skills in a longitudinal cohort of cognitively healthy individuals living in the community with normal or impaired fasting glucose or type 2 diabetes. Participants were 271 cognitively healthy individuals (mean age 63 years at inclusion) with normal fasting glucose levels (<5.6 mmol/L) (n=173), impaired fasting glucose (5.6-6.9 mmol/L) (n=57), or with type 2 diabetes (≥7.0 mmol/L) (n=41). Fasting glucose, Purdue Pegboard scores as measurement of fine motor skills, and brain scans were collected at wave 1, 2 and 4, over a total follow-up of twelve years. Striatal volumes were measured using FreeSurfer after controlling for age, sex and intracranial volume. Results showed that type 2 diabetes was associated with smaller right putamen volume and lower Purdue Pegboard scores after controlling for age, sex and intracranial volume. These findings add to the evidence suggesting that higher blood glucose levels, especially type 2 diabetes, may impair brain structure and function. Copyright © 2018. Published by Elsevier B.V.

Age-associated evolution of plasmatic amyloid in mouse lemur primates: Relationship with intracellular amyloid deposition

PubMed Central

Roy, Maggie; Cardoso, Cécile; Dorieux, Olène; Malgorn, Carole; Epelbaum, Stephane; Petit, Fanny; Kraska, Audrey; Brouillet, Emmanuel; Delatour, Benoît; Perret, Martine; Aujard, Fabienne; Dhenain, Marc

2014-01-01

Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder. Amyloid-β peptide (Aβ) deposition in the brain is one of its hallmarks and the measure of plasma Aβ is considered to be a biomarker for anti-amyloid drug efficacy in animal models of AD. However, age-associated plasmatic Aβ modulation in animal models is practically never addressed in the literature. Mouse lemur primates are used as a model of normal and AD-like cerebral aging. Here, we studied the effect of age on plasmatic Aβ in 58 mouse lemurs aged from 1 to 10 years. A subset of animals presented high plasmatic Aβ and the proportion of animals with high plasmatic Aβ was higher in aged animals as compared to young ones. Histological evaluation of the brain of some of these animals was carried out to assess extracellular and intracellular amyloid load. In aged lemurs, plasmatic Aβ was negatively correlated with the density of neurons accumulating deposits of Aβ. PMID:25131002

Brain atrophy can introduce age-related differences in BOLD response.

PubMed

Liu, Xueqing; Gerraty, Raphael T; Grinband, Jack; Parker, David; Razlighi, Qolamreza R

2017-04-11

Use of functional magnetic resonance imaging (fMRI) in studies of aging is often hampered by uncertainty about age-related differences in the amplitude and timing of the blood oxygenation level dependent (BOLD) response (i.e., hemodynamic impulse response function (HRF)). Such uncertainty introduces a significant challenge in the interpretation of the fMRI results. Even though this issue has been extensively investigated in the field of neuroimaging, there is currently no consensus about the existence and potential sources of age-related hemodynamic alterations. Using an event-related fMRI experiment with two robust and well-studied stimuli (visual and auditory), we detected a significant age-related difference in the amplitude of response to auditory stimulus. Accounting for brain atrophy by circumventing spatial normalization and processing the data in subjects' native space eliminated these observed differences. In addition, we simulated fMRI data using age differences in brain morphology while controlling HRF shape. Analyzing these simulated fMRI data using standard image processing resulted in differences in HRF amplitude, which were eliminated when the data were analyzed in subjects' native space. Our results indicate that age-related atrophy introduces inaccuracy in co-registration to standard space, which subsequently appears as attenuation in BOLD response amplitude. Our finding could explain some of the existing contradictory reports regarding age-related differences in the fMRI BOLD responses. Hum Brain Mapp, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Microglial pathology.

PubMed

Streit, Wolfgang J; Xue, Qing-Shan; Tischer, Jasmin; Bechmann, Ingo

2014-09-26

This paper summarizes pathological changes that affect microglial cells in the human brain during aging and in aging-related neurodegenerative diseases, primarily Alzheimer's disease (AD). It also provides examples of microglial changes that have been observed in laboratory animals during aging and in some experimentally induced lesions and disease models. Dissimilarities and similarities between humans and rodents are discussed in an attempt to generate a current understanding of microglial pathology and its significance during aging and in the pathogenesis of Alzheimer dementia (AD). The identification of dystrophic (senescent) microglia has created an ostensible conflict with prior work claiming a role for activated microglia and neuroinflammation during normal aging and in AD, and this has raised a basic question: does the brain's immune system become hyperactive (inflamed) or does it become weakened (senescent) in elderly and demented people, and what is the impact on neuronal function and cognition? Here we strive to reconcile these seemingly contradictory notions by arguing that both low-grade neuroinflammation and microglial senescence are the result of aging-associated free radical injury. Both processes are damaging for microglia as they synergistically exhaust this essential cell population to the point where the brain's immune system is effete and unable to support neuronal function.

Age-related differences in the neural bases of phonological and semantic processes

PubMed Central

Diaz, Michele T.; Johnson, Micah A.; Burke, Deborah M.; Madden, David J.

2014-01-01

Changes in language functions during normal aging are greater for phonological compared to semantic processes. To investigate the behavioral and neural basis for these age-related differences, we used functional magnetic resonance imaging (fMRI) to examine younger and older adults who made semantic and phonological decisions about pictures. The behavioral performance of older adults was less accurate and less efficient than younger adults’ in the phonological task, but did not differ in the semantic task. In the fMRI analyses, the semantic task activated left-hemisphere language regions, while the phonological task activated bilateral cingulate and ventral precuneus. Age-related effects were widespread throughout the brain, and most often expressed as greater activation for older adults. Activation was greater for younger compared to older adults in ventral brain regions involved in visual and object processing. Although there was not a significant Age x Condition interaction in the whole-brain fMRI results, correlations examining the relationship between behavior and fMRI activation were stronger for younger compared to older adults. Our results suggest that the relationship between behavior and neural activation declines with age and this may underlie some of the observed declines in performance. PMID:24893737

Early brain response to low-dose radiation exposure involves molecular networks and pathways associated with cognitive functions, advanced aging and Alzheimer's disease.

PubMed

Lowe, Xiu R; Bhattacharya, Sanchita; Marchetti, Francesco; Wyrobek, Andrew J

2009-01-01

Understanding the cognitive and behavioral consequences of brain exposures to low-dose ionizing radiation has broad relevance for health risks from medical radiation diagnostic procedures, radiotherapy and environmental nuclear contamination as well as for Earth-orbit and space missions. Analyses of transcriptome profiles of mouse brain tissue after whole-body irradiation showed that low-dose exposures (10 cGy) induced genes not affected by high-dose radiation (2 Gy) and that low-dose genes were associated with unique pathways and functions. The low-dose response had two major components: pathways that are consistently seen across tissues and pathways that were specific for brain tissue. Low-dose genes clustered into a saturated network (P < 10(-53)) containing mostly down-regulated genes involving ion channels, long-term potentiation and depression, vascular damage, etc. We identified nine neural signaling pathways that showed a high degree of concordance in their transcriptional response in mouse brain tissue after low-dose irradiation, in the aging human brain (unirradiated), and in brain tissue from patients with Alzheimer's disease. Mice exposed to high-dose radiation did not show these effects and associations. Our findings indicate that the molecular response of the mouse brain within a few hours after low-dose irradiation involves the down-regulation of neural pathways associated with cognitive dysfunctions that are also down-regulated in normal human aging and Alzheimer's disease.

Creatine, Glutamine plus Glutamate, and Macromolecules Are Decreased in the Central White Matter of Premature Neonates around Term

PubMed Central

Le Fur, Yann; Viout, Patrick; Ratiney, Hélène; Confort-Gouny, Sylviane; Cozzone, Patrick J.; Girard, Nadine

2016-01-01

Preterm birth represents a high risk of neurodevelopmental disabilities when associated with white-matter damage. Recent studies have reported cognitive deficits in children born preterm without brain injury on MRI at term-equivalent age. Understanding the microstructural and metabolic underpinnings of these deficits is essential for their early detection. Here, we used diffusion-weighted imaging and single-voxel 1H magnetic resonance spectroscopy (MRS) to compare brain maturation at term-equivalent age in premature neonates with no evidence of white matter injury on conventional MRI except diffuse excessive high-signal intensity, and normal term neonates. Thirty-two infants, 16 term neonates (mean post-conceptional age at scan: 39.8±1 weeks) and 16 premature neonates (mean gestational age at birth: 29.1±2 weeks, mean post-conceptional age at scan: 39.2±1 weeks) were investigated. The MRI/MRS protocol performed at 1.5T involved diffusion-weighted MRI and localized 1H-MRS with the Point RESolved Spectroscopy (PRESS) sequence. Preterm neonates showed significantly higher ADC values in the temporal white matter (P<0.05), the occipital white matter (P<0.005) and the thalamus (P<0.05). The proton spectrum of the centrum semiovale was characterized by significantly lower taurine/H2O and macromolecules/H2O ratios (P<0.05) at a TE of 30 ms, and reduced (creatine+phosphocreatine)/H2O and (glutamine+glutamate)/H2O ratios (P<0.05) at a TE of 135 ms in the preterm neonates than in full-term neonates. Our findings indicate that premature neonates with normal conventional MRI present a delay in brain maturation affecting the white matter and the thalamus. Their brain metabolic profile is characterized by lower levels of creatine, glutamine plus glutamate, and macromolecules in the centrum semiovale, a finding suggesting altered energy metabolism and protein synthesis. PMID:27547969

Amphetamine modulates brain signal variability and working memory in younger and older adults.

PubMed

Garrett, Douglas D; Nagel, Irene E; Preuschhof, Claudia; Burzynska, Agnieszka Z; Marchner, Janina; Wiegert, Steffen; Jungehülsing, Gerhard J; Nyberg, Lars; Villringer, Arno; Li, Shu-Chen; Heekeren, Hauke R; Bäckman, Lars; Lindenberger, Ulman

2015-06-16

Better-performing younger adults typically express greater brain signal variability relative to older, poorer performers. Mechanisms for age and performance-graded differences in brain dynamics have, however, not yet been uncovered. Given the age-related decline of the dopamine (DA) system in normal cognitive aging, DA neuromodulation is one plausible mechanism. Hence, agents that boost systemic DA [such as d-amphetamine (AMPH)] may help to restore deficient signal variability levels. Furthermore, despite the standard practice of counterbalancing drug session order (AMPH first vs. placebo first), it remains understudied how AMPH may interact with practice effects, possibly influencing whether DA up-regulation is functional. We examined the effects of AMPH on functional-MRI-based blood oxygen level-dependent (BOLD) signal variability (SD(BOLD)) in younger and older adults during a working memory task (letter n-back). Older adults expressed lower brain signal variability at placebo, but met or exceeded young adult SD(BOLD) levels in the presence of AMPH. Drug session order greatly moderated change-change relations between AMPH-driven SD(BOLD) and reaction time means (RT(mean)) and SDs (RT(SD)). Older adults who received AMPH in the first session tended to improve in RT(mean) and RT(SD) when SD(BOLD) was boosted on AMPH, whereas younger and older adults who received AMPH in the second session showed either a performance improvement when SD(BOLD) decreased (for RT(mean)) or no effect at all (for RT(SD)). The present findings support the hypothesis that age differences in brain signal variability reflect aging-induced changes in dopaminergic neuromodulation. The observed interactions among AMPH, age, and session order highlight the state- and practice-dependent neurochemical basis of human brain dynamics.

Amphetamine modulates brain signal variability and working memory in younger and older adults

PubMed Central

Garrett, Douglas D.; Nagel, Irene E.; Preuschhof, Claudia; Burzynska, Agnieszka Z.; Marchner, Janina; Wiegert, Steffen; Jungehülsing, Gerhard J.; Nyberg, Lars; Villringer, Arno; Li, Shu-Chen; Heekeren, Hauke R.; Bäckman, Lars; Lindenberger, Ulman

2015-01-01

Better-performing younger adults typically express greater brain signal variability relative to older, poorer performers. Mechanisms for age and performance-graded differences in brain dynamics have, however, not yet been uncovered. Given the age-related decline of the dopamine (DA) system in normal cognitive aging, DA neuromodulation is one plausible mechanism. Hence, agents that boost systemic DA [such as d-amphetamine (AMPH)] may help to restore deficient signal variability levels. Furthermore, despite the standard practice of counterbalancing drug session order (AMPH first vs. placebo first), it remains understudied how AMPH may interact with practice effects, possibly influencing whether DA up-regulation is functional. We examined the effects of AMPH on functional-MRI–based blood oxygen level-dependent (BOLD) signal variability (SDBOLD) in younger and older adults during a working memory task (letter n-back). Older adults expressed lower brain signal variability at placebo, but met or exceeded young adult SDBOLD levels in the presence of AMPH. Drug session order greatly moderated change–change relations between AMPH-driven SDBOLD and reaction time means (RTmean) and SDs (RTSD). Older adults who received AMPH in the first session tended to improve in RTmean and RTSD when SDBOLD was boosted on AMPH, whereas younger and older adults who received AMPH in the second session showed either a performance improvement when SDBOLD decreased (for RTmean) or no effect at all (for RTSD). The present findings support the hypothesis that age differences in brain signal variability reflect aging-induced changes in dopaminergic neuromodulation. The observed interactions among AMPH, age, and session order highlight the state- and practice-dependent neurochemical basis of human brain dynamics. PMID:26034283

Growth without growth hormone in combined pituitary hormone deficiency caused by pituitary stalk interruption syndrome

PubMed Central

Lee, Sang Soo; Han, A-Leum; Ahn, Moon Bae; Kim, Shin Hee; Cho, Kyoung Soon; Park, So Hyun; Jung, Min Ho; Suh, Byung-Kyu

2017-01-01

Growth hormone (GH) is an essential element for normal growth. However, reports of normal growth without GH have been made in patients who have undergone brain surgery for craniopharyngioma. Normal growth without GH can be explained by hyperinsulinemia, hyperprolactinemia, elevated leptin levels, and GH variants; however, its exact mechanism has not been elucidated yet. We diagnosed a female patient aged 13 with combined pituitary hormone deficiency (CPHD) caused by pituitary stalk interruption syndrome (PSIS). The patient has experienced recurrent hypoglycemic seizures since birth, but reached the height of 160 cm at the age of 13, showing normal growth. She grew another 8 cm for 3 years after the diagnosis, and she reached her final adult height of 168 cm which was greater than the midparental height, at the age of 16. The patient's blood GH and insulin-like growth factor-I levels were consistently subnormal, although her insulin levels were normal. Her physical examination conducted at the age of 15 showed truncal obesity, dyslipidemia, and osteoporosis, which are metabolic features of GH deficiency (GHD). Herein, we report a case in which a PSIS-induced CPHD patient attained her final height above mid parental height despite a severe GHD. PMID:28443260

Growth without growth hormone in combined pituitary hormone deficiency caused by pituitary stalk interruption syndrome.

PubMed

Lee, Sang Soo; Han, A-Leum; Ahn, Moon Bae; Kim, Shin Hee; Cho, Won Kyoung; Cho, Kyoung Soon; Park, So Hyun; Jung, Min Ho; Suh, Byung-Kyu

2017-03-01

Growth hormone (GH) is an essential element for normal growth. However, reports of normal growth without GH have been made in patients who have undergone brain surgery for craniopharyngioma. Normal growth without GH can be explained by hyperinsulinemia, hyperprolactinemia, elevated leptin levels, and GH variants; however, its exact mechanism has not been elucidated yet. We diagnosed a female patient aged 13 with combined pituitary hormone deficiency (CPHD) caused by pituitary stalk interruption syndrome (PSIS). The patient has experienced recurrent hypoglycemic seizures since birth, but reached the height of 160 cm at the age of 13, showing normal growth. She grew another 8 cm for 3 years after the diagnosis, and she reached her final adult height of 168 cm which was greater than the midparental height, at the age of 16. The patient's blood GH and insulin-like growth factor-I levels were consistently subnormal, although her insulin levels were normal. Her physical examination conducted at the age of 15 showed truncal obesity, dyslipidemia, and osteoporosis, which are metabolic features of GH deficiency (GHD). Herein, we report a case in which a PSIS-induced CPHD patient attained her final height above mid parental height despite a severe GHD.

Longitudinal study of children with perinatal brain damage in whom early neurohabilitation was applied: Preliminary report.

PubMed

Harmony, Thalía; Barrera-Reséndiz, Jesús; Juárez-Colín, María Elena; Carrillo-Prado, Cristina; Pedraza-Aguilar, M del Consuelo; Asprón Ramírez, Aurora; Hinojosa-Rodríguez, Manuel; Fernández, Thalía; Ricardo-Garcell, Josefina

2016-01-12

The neurohabilitation treatment has been shown to be a successful method for decreasing the sequelae of perinatal brain damage (PBD) in Hungarian population. The goal of this pilot trial was to introduce this procedure by describing the results of its application in infants with PBD as demonstrated by clinical, developmental and MRI studies. As this procedure has proved to be useful, according the declaration of Helsinki, no control clinical trial was permitted. Infants younger than 2 months of corrected age (CA) with prenatal and/or perinatal risk factors for brain damage. Two groups were considered. One group was treated using the "neurohabilitation" method (n=20), and the other was not treated (n=13) because treatment was voluntarily discontinued after the initial evaluation. Evaluations were carried out prior to 2 months of CA and at 6-8 years of age. All children showed abnormal clinical and MRI characteristics in the first study. The treated group had a higher percentage (90%) of children with normal outcome than did the non-treated group (38%; OR=2.37, CI 95%=1.2-4.7; p<0.005). In this latter group, only one out of five (20%) children born at or before 34 weeks of gestational age had a normal outcome. In contrast, eight out of nine treated preterm infants had normal outcomes (8/9=89%, OR=4.45, CI 95%=0.7-26; p=0.017). This pilot trial confirms previous studies suggesting that Neurohabilitation decreases the neurological and cognitive sequelae of preterm and at-term infants with PBD. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Absence of age-related dopamine transporter loss in current cocaine abusers

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, G.J.; Volkow, N.D.; Fischman, M.

The brain dopamine (DA) system appears to play a crucial role in the reinforcing properties of cocaine. Using PET we had previously shown significant decreases in DA D2 receptors but no changes in DA transporters (DAT) in detoxified cocaine abusers (>1 month after last cocaine use). This study evaluates DAT availability in current cocaine abusers (15 male and 5 female; age = 36.2{+-}5.3 years old) using PET and [C-11]cocaine, as a DAT ligand, and compares it to that in 18 male and 2 female age matched normal controls. Cocaine abusers had a history of abusing 4.2{+-}2.8 gm /week of cocainemore » for an average of 11.0{+-}4.9 years and their last use of cocaine was 5.4{+-}8 days prior to PET study. DAT availability was obtained using the ratio of the distribution volume in the region of interest (caudate, pulamen) to that in cerebellum which is a function of Bmax./Kd.+1. DAT availability in cocaine abusers did not differ to that in normals (N) (C= 1.78{+-}0.14, N= 1.77{+-}0.13). In addition, there were no differences between the groups in the distribution volume or the Kl (plasma to brain transfer constant) measures for [C-11]cocaine. However, in the normals but not in the abusers striatal DAT availability decreased with age (C: r = -0.07, p = 0.76; N: r = -0.55, p < 0.01). Though this study fails to show group differences in DAT availability between normals and current cocaine abusers it indicates a blunting of the age-related decline in DAT availability in the cocaine abusers. Future studies in older cocaine abusers at different time after detoxification arc required in order to assess if cocaine slows the loss of DAT with age or whether these changes reflect compensation to increased DAT blockade and recover with detoxification.« less

Body growth and brain development in premature babies: an MRI study.

PubMed

Tzarouchi, Loukia C; Drougia, Aikaterini; Zikou, Anastasia; Kosta, Paraskevi; Astrakas, Loukas G; Andronikou, Styliani; Argyropoulou, Maria I

2014-03-01

Prematurity and intrauterine growth restriction are associated with neurodevelopmental disabilities. To assess the relationship between growth status and regional brain volume (rBV) and white matter microstructure in premature babies at around term-equivalent age. Premature infants (n= 27) of gestational age (GA): 29.8 ± 2.1 weeks, with normal brain MRI scans were studied at corrected age: 41.2 ± 1.4 weeks. The infants were divided into three groups: 1) appropriate for GA at birth and at the time of MRI (AGA), 2) small for GA at birth with catch-up growth at the time of MRI (SGAa) and 3) small for GA at birth with failure of catch-up growth at the time of MRI (SGAb). The T1-weighted images were segmented into 90 rBVs using the SPM8/IBASPM and differences among groups were assessed. Fractional anisotropy (FA) was measured bilaterally in 15 fiber tracts and its relationship to GA and somatometric measurements was explored. Lower rBV was observed in SGAb in superior and anterior brain areas. A positive correlation was demonstrated between FA and head circumference and body weight. Body weight was the only significant predictor for FA (P< 0.05). In premature babies, catch-up growth is associated with regional brain volume catch-up at around term-equivalent age, starting from the brain areas maturing first. Body weight seems to be a strong predictor associated with WM microstructure in brain areas related to attention, language, cognition, memory and executing functioning.

Effect of Sex Differences on Brain Mitochondrial Function and Its Suppression by Ovariectomy and in Aged Mice.

PubMed

Gaignard, Pauline; Savouroux, Stéphane; Liere, Philippe; Pianos, Antoine; Thérond, Patrice; Schumacher, Michael; Slama, Abdelhamid; Guennoun, Rachida

2015-08-01

Sex steroids regulate brain function in both normal and pathological states. Mitochondria are an essential target of steroids, as demonstrated by the experimental administration of 17β-estradiol or progesterone (PROG) to ovariectomized female rodents, but the influence of endogenous sex steroids remains understudied. To address this issue, mitochondrial oxidative stress, the oxidative phosphorylation system, and brain steroid levels were analyzed under 3 different experimental sets of endocrine conditions. The first set was designed to study steroid-mediated sex differences in young male and female mice, intact and after gonadectomy. The second set concerned young female mice at 3 time points of the estrous cycle in order to analyze the influence of transient variations in steroid levels. The third set involved the evaluation of the effects of a permanent decrease in gonadal steroids in aged male and female mice. Our results show that young adult females have lower oxidative stress and a higher reduced nicotinamide adenine dinucleotide (NADH)-linked respiration rate, which is related to a higher pyruvate dehydrogenase complex activity as compared with young adult males. This sex difference did not depend on phases of the estrous cycle, was suppressed by ovariectomy but not by orchidectomy, and no longer existed in aged mice. Concomitant analysis of brain steroids showed that pregnenolone and PROG brain levels were higher in females during the reproductive period than in males and decreased with aging in females. These findings suggest that the major male/female differences in brain pregnenolone and PROG levels may contribute to the sex differences observed in brain mitochondrial function.

Short and long-term outcomes in children with suspected acute encephalopathy.

PubMed

Nishiyama, Masahiro; Nagase, Hiroaki; Tanaka, Tsukasa; Fujita, Kyoko; Kusumoto, Mayumi; Kajihara, Shinsuke; Yamaguchi, Yoshimichi; Maruyama, Azusa; Takeda, Hiroki; Uetani, Yoshiyuki; Tomioka, Kazumi; Toyoshima, Daisaku; Taniguchi-Ikeda, Mariko; Morioka, Ichiro; Takada, Satoshi; Iijima, Kazumoto

2016-09-01

The time-dependent changes that occur in children after acute encephalopathy are not clearly understood. Therefore, we assessed changes in brain function after suspected acute encephalopathy over time. We created a database of children admitted to the pediatric intensive care unit at Kobe Children's Hospital because of convulsions or impaired consciousness with fever between 2002 and 2013. Clinical courses and outcomes were reviewed and patients who met the following criteria were included in the study: (1) 6months to 15years of age, (2) no neurological abnormality before onset, (3) treated for suspected acute encephalopathy, and (4) followed after 1 (0-2) month and 12 (10-17) months of onset. Outcomes were assessed using the Pediatric Cerebral Performance Category (PCPC) scale, with a score of 1 representing normal performance; 2, mild disability; 3, moderate disability; 4, severe disability; 5, vegetative state; and 6, brain death. A total of 78 children (32 male) with a median (range) age at onset of 20 (6-172) months were enrolled. Fifty-one cases scored 1 on the PCPC, 13 scored 2, three scored 3, five scored 4, one scored 5, and five cases scored 6 at discharge. Whereas seven of the 13 cases that scored a 2 on the PCPC recovered normal brain function after 12months, none of the nine cases that scored a 3-5 on the PCPC recovered normal function. Our findings suggest moderate to severe disability caused by acute encephalopathy had lasting consequences on brain function, whereas mild disability might result in improved function. Copyright © 2016 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Effects of experimental suppression of active (REM) sleep during early development upon adult brain and behavior in the rat.

PubMed

Mirmiran, M; Scholtens, J; van de Poll, N E; Uylings, H B; van der Gugten, J; Boer, G J

1983-04-01

In order to test the hypothesis that active sleep (AS) is important for the normal development of the central nervous system, 3 different deprivation methods were applied to male Wistar rat pups during the first month of life. Daily injection of clomipramine from 8 to 21 days of age reduced the high level of AS to less than the adult value throughout most of the experimental period. Administration of clonidine from 8 to 21 days of life induced an almost total suppression of AS. Instrumental deprivation, using the 'pendulum' method, led to a significant (but less severe) AS reduction during 2-4 weeks of postnatal age. Open-field behavior testing in adulthood revealed a higher than normal level of ambulation in all 3 experimental groups. Masculine sexual responses were deficient, due to a low level of both mounts and ejaculations, in both clomipramine- and clonidine-treated animals. Neither passive avoidance learning nor dark preference tests revealed any differences between the experimental and control rats. Sleep observations showed that there was an abnormally high incidence of large myoclonic jerks during AS in both clomipramine- and clonidine-treated rats. Subsequent measurement of regional brain weights showed a significant reduction in the cerebral cortex and medulla oblongata, as compared with the respective control groups, in both the clomipramine- and the clonidine-treated rats. In addition, DNA and protein determination in the affected brain areas showed a proportional reduction in the cortex and in the medulla. These results demonstrate that interference with normal functioning either of AS per se or of specific monoaminergic transmitter systems during early development can produce long-lasting behavioral as well as brain morphological and biochemical abnormalities in later life.

Thyroid function and the risk of dementia: The Rotterdam Study.

PubMed

Chaker, Layal; Wolters, Frank J; Bos, Daniel; Korevaar, Tim I M; Hofman, Albert; van der Lugt, Aad; Koudstaal, Peter J; Franco, Oscar H; Dehghan, Abbas; Vernooij, Meike W; Peeters, Robin P; Ikram, M Arfan

2016-10-18

To study the role of thyroid function in dementia, cognitive function, and subclinical vascular brain disease with MRI. Analyses were performed within the Rotterdam Study (baseline 1997), a prospective, population-based cohort. We evaluated the association of thyroid-stimulating hormone (TSH) and free thyroxine with incident dementia using Cox models adjusted for age, sex, cardiovascular risk factors, and education. Absolute risks were calculated accounting for death as a competing risk factor. Associations of thyroid function with cognitive test scores and subclinical vascular brain disease (white matter lesions, lacunes, and microbleeds) were assessed with linear or logistic regression. Additionally, we stratified by sex and restricted analyses to normal thyroid function. We included 9,446 participants with a mean age of 65 years. During follow-up (mean 8.0 years), 601 participants had developed dementia. Higher TSH was associated with lower dementia risk in both the full and normal ranges of thyroid function (hazard ratio [HR] 0.90, 95% confidence interval [CI] 0.83-0.98; and HR 0.76, 95% CI 0.64-0.91, respectively). This association was independent of cardiovascular risk factors. Dementia risk was higher in individuals with higher free thyroxine (HR 1.04, 95% CI 1.01-1.07). Absolute 10-year dementia risk decreased from 15% to 10% with higher TSH in older women. Higher TSH was associated with better global cognitive scores (p = 0.021). Thyroid function was not related to subclinical vascular brain disease as indicated by MRI. High and high-normal thyroid function is associated with increased dementia risk. Thyroid function is not related to vascular brain disease as assessed by MRI, suggesting a role for thyroid hormone in nonvascular pathways leading to dementia. © 2016 American Academy of Neurology.

Cortisol Excess and the Brain.

PubMed

Resmini, Eugenia; Santos, Alicia; Webb, Susan M

2016-01-01

Until the last decade, little was known about the effects of chronic hypercortisolism on the brain. In the last few years, new data have arisen thanks to advances in imaging techniques; therefore, it is now possible to investigate brain activity in vivo. Memory impairments are present in patients with Cushing's syndrome (CS) and are related to hippocampal damage; functional dysfunctions would precede structural abnormalities as detected by brain imaging. Earlier diagnosis and rapid normalization of hypercortisolism could stop the progression of hippocampal damage and memory impairments. Impairments of executive functions (including decision-making) and other functions such as visuoconstructive skills, language, motor functions and information processing speed are also present in CS patients. There is controversy concerning the reversibility of brain impairment. It seems that longer disease duration and older age are associated with less recovery of brain functioning. Conversely, earlier diagnosis and rapid normalization of hypercortisolism appear to stop progression of brain damage and functional impairments. Moreover, brain tissue functioning and neuroplasticity can be influenced by many factors. Currently available studies appear to be complementary, evaluating the same phenomenon from different points of view, but are often not directly comparable. Finally, CS patients have a high prevalence of psychopathology, such as depression and anxiety which do not completely revert after cure. Thus, psychological or psychiatric evaluation could be recommended in CS patients, so that treatment may be prescribed if required. © 2016 S. Karger AG, Basel.

Tau and β-Amyloid Are Associated with Medial Temporal Lobe Structure, Function, and Memory Encoding in Normal Aging

PubMed Central

2017-01-01

Normal aging is associated with a decline in episodic memory and also with aggregation of the β-amyloid (Aβ) and tau proteins and atrophy of medial temporal lobe (MTL) structures crucial to memory formation. Although some evidence suggests that Aβ is associated with aberrant neural activity, the relationships among these two aggregated proteins, neural function, and brain structure are poorly understood. Using in vivo human Aβ and tau imaging, we demonstrate that increased Aβ and tau are both associated with aberrant fMRI activity in the MTL during memory encoding in cognitively normal older adults. This pathological neural activity was in turn associated with worse memory performance and atrophy within the MTL. A mediation analysis revealed that the relationship with regional atrophy was explained by MTL tau. These findings broaden the concept of cognitive aging to include evidence of Alzheimer's disease-related protein aggregation as an underlying mechanism of age-related memory impairment. SIGNIFICANCE STATEMENT Alterations in episodic memory and the accumulation of Alzheimer's pathology are common in cognitively normal older adults. However, evidence of pathological effects on episodic memory has largely been limited to β-amyloid (Aβ). Because Aβ and tau often cooccur in older adults, previous research offers an incomplete understanding of the relationship between pathology and episodic memory. With the recent development of in vivo tau PET radiotracers, we show that Aβ and tau are associated with different aspects of memory encoding, leading to aberrant neural activity that is behaviorally detrimental. In addition, our results provide evidence linking Aβ- and tau-associated neural dysfunction to brain atrophy. PMID:28213439

Are Anxiety Disorders Associated with Accelerated Aging? A Focus on Neuroprogression

PubMed Central

Perna, Giampaolo; Iannone, Giuseppe; Alciati, Alessandra; Caldirola, Daniela

2016-01-01

Anxiety disorders (AnxDs) are highly prevalent throughout the lifespan, with detrimental effects on daily-life functioning, somatic health, and quality of life. An emerging perspective suggested that AnxDs may be associated with accelerated aging. In this paper, we explored the association between AnxDs and hallmarks of accelerated aging, with a specific focus on neuroprogression. We reviewed animal and human findings that suggest an overlap between processes of impaired neurogenesis, neurodegeneration, structural, functional, molecular, and cellular modifications in AnxDs, and aging. Although this research is at an early stage, our review suggests a link between anxiety and accelerated aging across multiple processes involved in neuroprogression. Brain structural and functional changes that accompany normal aging were more pronounced in subjects with AnxDs than in coevals without AnxDs, including reduced grey matter density, white matter alterations, impaired functional connectivity of large-scale brain networks, and poorer cognitive performance. Similarly, molecular correlates of brain aging, including telomere shortening, Aβ accumulation, and immune-inflammatory and oxidative/nitrosative stress, were overrepresented in anxious subjects. No conclusions about causality or directionality between anxiety and accelerated aging can be drawn. Potential mechanisms of this association, limitations of the current research, and implications for treatments and future studies are discussed. PMID:26881136

Personality and complex brain networks: The role of openness to experience in default network efficiency

PubMed Central

Kaufman, Scott Barry; Benedek, Mathias; Jung, Rex E.; Kenett, Yoed N.; Jauk, Emanuel; Neubauer, Aljoscha C.; Silvia, Paul J.

2015-01-01

Abstract The brain's default network (DN) has been a topic of considerable empirical interest. In fMRI research, DN activity is associated with spontaneous and self‐generated cognition, such as mind‐wandering, episodic memory retrieval, future thinking, mental simulation, theory of mind reasoning, and creative cognition. Despite large literatures on developmental and disease‐related influences on the DN, surprisingly little is known about the factors that impact normal variation in DN functioning. Using structural equation modeling and graph theoretical analysis of resting‐state fMRI data, we provide evidence that Openness to Experience—a normally distributed personality trait reflecting a tendency to engage in imaginative, creative, and abstract cognitive processes—underlies efficiency of information processing within the DN. Across two studies, Openness predicted the global efficiency of a functional network comprised of DN nodes and corresponding edges. In Study 2, Openness remained a robust predictor—even after controlling for intelligence, age, gender, and other personality variables—explaining 18% of the variance in DN functioning. These findings point to a biological basis of Openness to Experience, and suggest that normally distributed personality traits affect the intrinsic architecture of large‐scale brain systems. Hum Brain Mapp 37:773–779, 2016. © 2015 Wiley Periodicals, Inc. PMID:26610181

Factors associated with resistance to dementia despite high Alzheimer disease pathology.

PubMed

Erten-Lyons, D; Woltjer, R L; Dodge, H; Nixon, R; Vorobik, R; Calvert, J F; Leahy, M; Montine, T; Kaye, J

2009-01-27

Autopsy series have shown that some elderly people remain with normal cognitive function during life despite having high burdens of pathologic lesions associated with Alzheimer disease (AD) at death. Understanding why these individuals show no cognitive decline, despite high AD pathologic burdens, may be key to discovery of neuroprotective mechanisms. A total of 36 subjects who on autopsy had Braak stage V or VI and moderate or frequent neuritic plaque scores based on Consortium to Establish a Registry for Alzheimer's Disease (CERAD) standards were included. Twelve had normal cognitive function and 24 a diagnosis of AD before death. Demographic characteristics, clinical and pathologic data, as well as antemortem brain volumes were compared between the groups. In multiple regression analysis, antemortem hippocampal and total brain volumes were significantly larger in the group with normal cognitive function after adjusting for gender, age at MRI, time from MRI to death, Braak stage, CERAD neuritic plaque score, and overall presence of vascular disease. Larger brain and hippocampal volumes were associated with preserved cognitive function during life despite a high burden of Alzheimer disease (AD) pathologic lesions at death. A better understanding of processes that lead to preservation of brain volume may provide important clues for the discovery of mechanisms that protect the elderly from AD.

Increased determinism in brain electrical activity occurs in association with multiple sclerosis.

PubMed

Carrubba, Simona; Minagar, Alireza; Chesson, Andrew L; Frilot, Clifton; Marino, Andrew A

2012-04-01

Increased determinism (decreased complexity) of brain electrical activity has been associated with some brain diseases. Our objective was to determine whether a similar association occurred for multiple sclerosis (MS). Ten subjects with a relapsing-remitting course of MS who were in remission were studied; the controls were age- and gender-matched clinically normal subjects. Recurrence plots were calculated using representative electroencephalogram (EEG) epochs (1-7 seconds) from six derivations; the plots were quantified using the nonlinear variables percent recurrence (%R) and percent determinism (%D). The results were averaged over all derivations for each participant, and the means were compared between the groups. As a linear control procedure the groups were also compared using spectral analysis. The mean±SD of %R for the MS subjects was 6·6±1·3%, compared with 5·1±1·3% in the normal group (P = 0·017), indicating that brain activity in the subjects with MS was less complex, as hypothesized. The groups were not distinguishable using %D or spectral analysis. Taken together with our earlier report that %R could be used to discriminate between MS and normal subjects based on the ability to exhibit evoked potentials, the evidence suggests that complexity analysis of the EEG has potential for development as a diagnostic test for MS.

Microglia of the Aged Brain: Primed to be Activated and Resistant to Regulation

PubMed Central

Norden, Diana M.; Godbout, Jonathan P.

2012-01-01

Innate immunity within the central nervous system (CNS) is primarily provided by resident microglia. Microglia are pivotal in immune surveillance and also facilitate the coordinated responses between the immune system and the brain. For example, microglia interpret and propagate inflammatory signals that are initiated in the periphery. This transient microglial activation helps mount the appropriate physiological and behavioral response following peripheral infection. With normal aging, however, microglia develop a more inflammatory phenotype. For instance, in several models of aging there are increased pro-inflammatory cytokines in the brain and increased expression of inflammatory receptors on microglia. This increased inflammatory status of microglia with aging is referred to as primed, reactive, or sensitized. A modest increase in the inflammatory profile of the CNS and altered microglial function in aging has behavioral and cognitive consequences. Nonetheless, there are major differences in microglial biology between young and old age when the immune system is challenged and microglia are activated. In this context, microglial activation is amplified and prolonged in the aged brain compared to adults. The cause of this amplified microglial activation may be related to impairments in several key regulatory systems with age that make it more difficult to resolve microglial activation. The consequences of impaired regulation and microglial hyper-activation following immune challenge are exaggerated neuroinflammation, sickness behavior, depressive-like behavior and cognitive deficits. Therefore the purpose of this review is to discuss the current understanding of age-associated microglial priming, consequences of priming and reactivity, and the impairments in regulatory systems that may underlie these age-related deficits. PMID:23039106

Freesurfer-initialized large deformation diffeomorphic metric mapping with application to Parkinson's disease

NASA Astrophysics Data System (ADS)

Chen, Jingyun; Palmer, Samantha J.; Khan, Ali R.; Mckeown, Martin J.; Beg, Mirza Faial

2009-02-01

We apply a recently developed automated brain segmentation method, FS+LDDMM, to brain MRI scans from Parkinson's Disease (PD) subjects, and normal age-matched controls and compare the results to manual segmentation done by trained neuroscientists. The data set consisted of 14 PD subjects and 12 age-matched control subjects without neurologic disease and comparison was done on six subcortical brain structures (left and right caudate, putamen and thalamus). Comparison between automatic and manual segmentation was based on Dice Similarity Coefficient (Overlap Percentage), L1 Error, Symmetrized Hausdorff Distance and Symmetrized Mean Surface Distance. Results suggest that FS+LDDMM is well-suited for subcortical structure segmentation and further shape analysis in Parkinson's Disease. The asymmetry of the Dice Similarity Coefficient over shape change is also discussed based on the observation and measurement of FS+LDDMM segmentation results.

Astrocytes require insulin-like growth factor I to protect neurons against oxidative injury

PubMed Central

Genis, Laura; Dávila, David; Fernandez, Silvia; Pozo-Rodrigálvarez, Andrea; Martínez-Murillo, Ricardo; Torres-Aleman, Ignacio

2014-01-01

Oxidative stress is a proposed mechanism in brain aging, making the study of its regulatory processes an important aspect of current neurobiological research. In this regard, the role of the aging regulator insulin-like growth factor I (IGF-I) in brain responses to oxidative stress remains elusive as both beneficial and detrimental actions have been ascribed to this growth factor. Because astrocytes protect neurons against oxidative injury, we explored whether IGF-I participates in astrocyte neuroprotection and found that blockade of the IGF-I receptor in astrocytes abrogated their rescuing effect on neurons. We found that IGF-I directly protects astrocytes against oxidative stress (H 2O 2). Indeed, in astrocytes but not in neurons, IGF-I decreases the pro-oxidant protein thioredoxin-interacting protein 1 and normalizes the levels of reactive oxygen species. Furthermore, IGF-I cooperates with trophic signals produced by astrocytes in response to H 2O 2 such as stem cell factor (SCF) to protect neurons against oxidative insult. After stroke, a condition associated with brain aging where oxidative injury affects peri-infarcted regions, a simultaneous increase in SCF and IGF-I expression was found in the cortex, suggesting that a similar cooperative response takes place in vivo. Cell-specific modulation by IGF-I of brain responses to oxidative stress may contribute in clarifying the role of IGF-I in brain aging. PMID:24715976

Functional and Structural Benefits Induced by Omega-3 Polyunsaturated Fatty Acids During Aging.

PubMed

Cutuli, Debora

2017-01-01

Omega-3 polyunsaturated fatty acids (n-3 PUFA) are structural components of the brain and are indispensable for neuronal membrane synthesis. Along with decline in cognition, decreased synaptic density and neuronal loss, normal aging is accompanied by a reduction in n-3 PUFA concentration in the brain in both humans and rodents. Recently, many clinical and experimental studies have demonstrated the importance of n-3 PUFA in counteracting neurodegeneration and agerelated dysfunctions. This review will focus on the neuroprotective effects of n-3 PUFA on cognitive impairment, neuroinflammation and neurodegeneration during normal aging. Multiple pathways of n-3 PUFA preventive action will be examined. Namely, n-3 PUFA have been shown to increase the levels of several signaling factors involved in synaptic plasticity, thus leading to the increase of dendritic spines and synapses as well as the enhancement of hippocampal neurogenesis even at old age. In elderly subjects n-3 PUFA exert anti-inflammatory effects associated with improved cognitive functions. Interestingly, growing evidence highlights n-3 PUFA efficacy in preventing the loss of both gray and white matter volume and integrity. This review shows that n-3 PUFA are essential for a successful aging and appear as ideal cognitive enhancers to be implemented in nutritional interventions for the promotion of healthy aging. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

The Longitudinal Trajectory of Default Mode Network Connectivity in Healthy Older Adults Varies As a Function of Age and Is Associated with Changes in Episodic Memory and Processing Speed.

PubMed

Staffaroni, Adam M; Brown, Jesse A; Casaletto, Kaitlin B; Elahi, Fanny M; Deng, Jersey; Neuhaus, John; Cobigo, Yann; Mumford, Paige S; Walters, Samantha; Saloner, Rowan; Karydas, Anna; Coppola, Giovanni; Rosen, Howie J; Miller, Bruce L; Seeley, William W; Kramer, Joel H

2018-03-14

The default mode network (DMN) supports memory functioning and may be sensitive to preclinical Alzheimer's pathology. Little is known, however, about the longitudinal trajectory of this network's intrinsic functional connectivity (FC). In this study, we evaluated longitudinal FC in 111 cognitively normal older human adults (ages 49-87, 46 women/65 men), 92 of whom had at least three task-free fMRI scans ( n = 353 total scans). Whole-brain FC and three DMN subnetworks were assessed: (1) within-DMN, (2) between anterior and posterior DMN, and (3) between medial temporal lobe network and posterior DMN. Linear mixed-effects models demonstrated significant baseline age × time interactions, indicating a nonlinear trajectory. There was a trend toward increasing FC between ages 50-66 and significantly accelerating declines after age 74. A similar interaction was observed for whole-brain FC. APOE status did not predict baseline connectivity or change in connectivity. After adjusting for network volume, changes in within-DMN connectivity were specifically associated with changes in episodic memory and processing speed but not working memory or executive functions. The relationship with processing speed was attenuated after covarying for white matter hyperintensities (WMH) and whole-brain FC, whereas within-DMN connectivity remained associated with memory above and beyond WMH and whole-brain FC. Whole-brain and DMN FC exhibit a nonlinear trajectory, with more rapid declines in older age and possibly increases in connectivity early in the aging process. Within-DMN connectivity is a marker of episodic memory performance even among cognitively healthy older adults. SIGNIFICANCE STATEMENT Default mode network and whole-brain connectivity, measured using task-free fMRI, changed nonlinearly as a function of age, with some suggestion of early increases in connectivity. For the first time, longitudinal changes in DMN connectivity were shown to correlate with changes in episodic memory, whereas volume changes in relevant brain regions did not. This relationship was not accounted for by white matter hyperintensities or mean whole-brain connectivity. Functional connectivity may be an early biomarker of changes in aging but should be used with caution given its nonmonotonic nature, which could complicate interpretation. Future studies investigating longitudinal network changes should consider whole-brain changes in connectivity. Copyright © 2018 the authors 0270-6474/18/382810-09$15.00/0.

Impact of brain injury on functional measures of amplitude-integrated EEG at term equivalent age in premature infants.

PubMed

El Ters, N M; Vesoulis, Z A; Liao, S M; Smyser, C D; Mathur, A M

2017-08-01

To evaluate the association between qualitative and quantitative amplitude-integrated EEG (aEEG) measures at term equivalent age (TEA) and brain injury on magnetic resonance imaging (MRI) in preterm infants. A cohort of premature infants born at <30 weeks of gestation and with moderate-to-severe MRI injury on a TEA MRI scan was identified. A contemporaneous group of gestational age-matched control infants also born at <30 weeks of gestation with none/mild injury on MRI was also recruited. Quantitative aEEG measures, including maximum and minimum amplitudes, bandwidth span and spectral edge frequency (SEF 90 ), were calculated using an offline software package. The aEEG recordings were qualitatively scored using the Burdjalov system. MRI scans, performed on the same day as aEEG, occurred at a mean postmenstrual age of 38.0 (range 37 to 42) weeks and were scored for abnormality in a blinded manner using an established MRI scoring system. Twenty-eight (46.7%) infants had a normal MRI or mild brain abnormality, while 32 (53.3%) infants had moderate-to-severe brain abnormality. Univariate regression analysis demonstrated an association between severity of brain abnormality and quantitative measures of left and right SEF 90 and bandwidth span (β=-0.38, -0.40 and 0.30, respectively) and qualitative measures of cyclicity, continuity and total Burdjalov score (β=-0.10, -0.14 and -0.12, respectively). After correcting for confounding variables, the relationship between MRI abnormality score and aEEG measures of SEF 90 , bandwidth span and Burdjalov score remained significant. Brain abnormalities on MRI at TEA in premature infants are associated with abnormalities on term aEEG measures, suggesting that anatomical brain injury may contribute to delay in functional brain maturation as assessed using aEEG.

Tau and spectraplakins promote synapse formation and maintenance through Jun kinase and neuronal trafficking

PubMed Central

Voelzmann, Andre; Okenve-Ramos, Pilar; Qu, Yue; Chojnowska-Monga, Monika; del Caño-Espinel, Manuela; Prokop, Andreas; Sanchez-Soriano, Natalia

2016-01-01

The mechanisms regulating synapse numbers during development and ageing are essential for normal brain function and closely linked to brain disorders including dementias. Using Drosophila, we demonstrate roles of the microtubule-associated protein Tau in regulating synapse numbers, thus unravelling an important cellular requirement of normal Tau. In this context, we find that Tau displays a strong functional overlap with microtubule-binding spectraplakins, establishing new links between two different neurodegenerative factors. Tau and the spectraplakin Short Stop act upstream of a three-step regulatory cascade ensuring adequate delivery of synaptic proteins. This cascade involves microtubule stability as the initial trigger, JNK signalling as the central mediator, and kinesin-3 mediated axonal transport as the key effector. This cascade acts during development (synapse formation) and ageing (synapse maintenance) alike. Therefore, our findings suggest novel explanations for intellectual disability in Tau deficient individuals, as well as early synapse loss in dementias including Alzheimer’s disease. DOI: http://dx.doi.org/10.7554/eLife.14694.001 PMID:27501441

Déjà-vu in temporal lobe epilepsy: metabolic pattern of cortical involvement in patients with normal brain MRI.

PubMed

Guedj, Eric; Aubert, Sandrine; McGonigal, Aileen; Mundler, Olivier; Bartolomei, Fabrice

2010-06-01

To contribute to the identification of brain regions involved in déjà-vu, we studied the metabolic pattern of cortical involvement in patients with seizures of temporal lobe origin presenting with or without déjà-vu. Using voxel-based analysis of 18FDG-PET brain scans, we compared glucose metabolic rate of 8 patients with déjà-vu, 8 patients without déjà-vu, and 20 age-matched healthy subjects. Patients were selected after comprehensive non-invasive presurgical evaluation, including normal brain MRI and surface electroclinical features compatible with unilateral temporal lobe epilepsy (TLE). Patients with and without déjà-vu did not differ in terms of age, gender, epilepsy lateralization, epilepsy onset, epilepsy duration, and other subjective ictal manifestations. TLE patients with déjà-vu exhibited ipsilateral hypometabolism of superior temporal gyrus and of parahippocampal region, in the vicinity of perirhinal/entorhinal cortex, in comparison either to healthy subjects or to TLE patients without déjà-vu (p<0.05 FDR-corrected). By contrast, no difference was found between patient subgroups for hypometabolism of hippocampus and amygdala. At an individual-level, in comparison to healthy subjects, hypometabolism of both parahippocampal region and superior temporal gyrus was present in 7/8 patients with déjà-vu. Hippocampal metabolism was spared in 3 of these 7 patients. These findings argue for metabolic dysfunction of a medial-lateral temporal network in patients with déjà-vu and normal brain MRI. Within the medial temporal lobe, specific involvement of the parahippocampal region, often in the absence of hippocampal impairment, suggests that the feeling of familiarity during seizures greatly depends on alteration of the recognition memory system. Copyright 2010 Elsevier Ltd. All rights reserved.

Effect of growth hormone deficiency on brain MRI findings among children with growth restrictions.

PubMed

Naderi, Fariba; Eslami, Samira Rajabi; Mirak, Sohrab Afshari; Khak, Mohammad; Amiri, Jalaladin; Beyrami, Bahram; Shekarchi, Babak; Poureisa, Masoud

2015-01-01

Growth hormone deficiency (GHD) is a major problem among children with short stature. In this study, the role of brain magnetic resonance imaging (MRI) in defining the underlying defects among short children with GHD is evaluated. In a cross-sectional study, data of 158 children were evaluated. Growth hormone (GH) levels were measured using stimulating tests and brain MRI with gadolinium contrast was applied, as well. Some 25.3% of patients had GHD with a mean age of 8.01±3.40 years. MRI results showed 35 as normal, four with pituitary hypoplasia, and one with microadenoma. The MRI results were significantly associated with GH levels and presence of other endocrine disorders. There was a significant association between prenatal disorders and patients' bone age delay. In patients with severe GHD and patients with multiple pituitary hormone deficiencies, MRI is more likely to be abnormal, and bone age is much delayed in patients with history of prenatal disorders.

Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer's Disease: Methodology and Baseline Sample Characteristics.

PubMed

Byun, Min Soo; Yi, Dahyun; Lee, Jun Ho; Choe, Young Min; Sohn, Bo Kyung; Lee, Jun-Young; Choi, Hyo Jung; Baek, Hyewon; Kim, Yu Kyeong; Lee, Yun-Sang; Sohn, Chul-Ho; Mook-Jung, Inhee; Choi, Murim; Lee, Yu Jin; Lee, Dong Woo; Ryu, Seung-Ho; Kim, Shin Gyeom; Kim, Jee Wook; Woo, Jong Inn; Lee, Dong Young

2017-11-01

The Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer's disease (KBASE) aimed to recruit 650 individuals, aged from 20 to 90 years, to search for new biomarkers of Alzheimer's disease (AD) and to investigate how multi-faceted lifetime experiences and bodily changes contribute to the brain changes or brain pathologies related to the AD process. All participants received comprehensive clinical and neuropsychological evaluations, multi-modal brain imaging, including magnetic resonance imaging, magnetic resonance angiography, [ 11 C]Pittsburgh compound B-positron emission tomography (PET), and [ 18 F]fluorodeoxyglucose-PET, blood and genetic marker analyses at baseline, and a subset of participants underwent actigraph monitoring and completed a sleep diary. Participants are to be followed annually with clinical and neuropsychological assessments, and biannually with the full KBASE assessment, including neuroimaging and laboratory tests. As of March 2017, in total, 758 individuals had volunteered for this study. Among them, in total, 591 participants-291 cognitively normal (CN) old-aged individuals, 74 CN young- and middle-aged individuals, 139 individuals with mild cognitive impairment (MCI), and 87 individuals with AD dementia (ADD)-were enrolled at baseline, after excluding 162 individuals. A subset of participants (n=275) underwent actigraph monitoring. The KBASE cohort is a prospective, longitudinal cohort study that recruited participants with a wide age range and a wide distribution of cognitive status (CN, MCI, and ADD) and it has several strengths in its design and methodologies. Details of the recruitment, study methodology, and baseline sample characteristics are described in this paper.

Herpesviruses in brain and Alzheimer's disease.

PubMed

Lin, Woan-Ru; Wozniak, Matthew A; Cooper, Robert J; Wilcock, Gordon K; Itzhaki, Ruth F

2002-07-01

It has been established, using polymerase chain reaction (PCR), that herpes simplex virus type 1 (HSV1) is present in a high proportion of brains of elderly normal subjects and Alzheimer's disease (AD) patients. It was subsequently discovered that the virus confers a strong risk of AD when in brain of carriers of the type 4 allele of the apolipoprotein E gene (apoE-epsilon4). This study has now sought, using PCR, the presence of three other herpesviruses in brain: human herpesvirus 6 (HHV6)-types A and B, herpes simplex virus type 2 (HSV2) and cytomegalovirus (CMV). HHV6 is present in a much higher proportion of the AD than of age-matched normal brains (70% vs. 40%, p=0.003) and there is extensive overlap with the presence of HSV1 in AD brains, but HHV6, unlike HSV1, is not directly associated in AD with apoE-epsilon4. In 59% of the AD patients' brains harbouring HHV6, type B is present while 38% harbour both type A and type B, and 3% type A. HSV2 is present at relatively low frequency in brains of both AD patients and normals (13% and 20%), and CMV at rather higher frequencies in the two groups (36% and 35%); in neither case is the difference between the groups statistically significant. It is suggested that the striking difference in the proportion of elderly brains harbouring HSV1 and HSV2 might reflect the lower proportion of people infected with the latter, or the difference in susceptibility of the frontotemporal regions to the two viruses. In the case of HHV6, it is not possible to exclude its presence as an opportunist, but alternatively, it might enhance the damage caused by HSV1 and apoE-epsilon4 in AD; in some viral diseases it is associated with characteristic brain lesions and it also augments the damage caused by certain viruses in cell culture and in animals. Copyright 2002 John Wiley & Sons, Ltd.

A novel POMT2 mutation causes mild congenital muscular dystrophy with normal brain MRI

PubMed Central

MURAKAMI, Terumi; HAYASHI, Yukiko K.; OGAWA, Megumu; NOGUCHI, Satoru; CAMPBELL, Kevin P.; TOGAWA, Masami; INOUE, Takehiko; OKA, Akira; OHNO, Kousaku; NONAKA, Ikuya; NISHINO, Ichizo

2009-01-01

We report a patient harboring a novel homozygous mutation of c.604T>G (p.F202V) in POMT2. He showed delayed psychomotor development but acquired the ability to walk at the age of 3 years and 10 months. His brain MRI was normal. No ocular abnormalities were seen. Biopsied skeletal muscle revealed markedly decreased but still detectable glycosylated forms of alpha-dystroglycan (α-DG). Our results indicate that mutations in POMT2 can cause a wide spectrum of clinical phenotypes as observed in other genes associated with alpha-dystroglycanopathy. Presence of small amounts of partly glycosylated α-DG may have a role in reducing the clinical symptoms of alpha-dystroglycanopathy. PMID:18804929

Delayed visual maturation in infants: a disorder of figure-ground separation?

PubMed

Harris, C M; Kriss, A; Shawkat, F; Taylor, D; Russell-Eggitt, I

1996-01-01

Delayed visual maturation (DVM) is characterised by visual unresponsiveness in early infancy, which subsequently improves spontaneously to normal levels. We studied the optokinetic response and recorded pattern reversal VEPs in six infants with DVM (aged 2-4 months) when they were at the stage of complete visual unresponsiveness. Although no saccades or visual tracking with the eyes or head could be elicited to visual objects, a normal full-field rapid buildup OKN response occurred when viewing biocularly or during monocular stimulation in the temporo-nasal direction of the viewing eye. Almost no monocular OKN could be elicited in the naso-temporal direction, which was significantly poorer than normal age-matched infants. No OKN quick phases were missed, and there were no other signs of "ocular motor apraxia." VEPs were normal in amplitude and latency for age. It appears, therefore, that infants with DVM are delayed in orienting to local regions of the visual field, but can respond to full-field motion. The presence of normal OKN quick-phases and slow-phases suggests normal brain stem function, and the presence of normal pattern VEPs suggests a normal retino-geniculo-striate pathway. These oculomotor and electrophysiological findings suggest delayed development of extra-striate cortical structures, possibly involving either an abnormality in figure-ground segregation or in attentional pathways.

Tau and β-Amyloid Are Associated with Medial Temporal Lobe Structure, Function, and Memory Encoding in Normal Aging

DOE Office of Scientific and Technical Information (OSTI.GOV)

Marks, Shawn M.; Lockhart, Samuel N.; Baker, Suzanne L.

Normal aging is associated with a decline in episodic memory and also with aggregation of the β-amyloid (Aβ) and tau proteins and atrophy of medial temporal lobe (MTL) structures crucial to memory formation. Although some evidence suggests that Aβ is associated with aberrant neural activity, the relationships among these two aggregated proteins, neural function, and brain structure are poorly understood. Using in vivo human Aβ and tau imaging, we demonstrate that increased Aβ and tau are both associated with aberrant fMRI activity in the MTL during memory encoding in cognitively normal older adults. This pathological neural activity was in turnmore » associated with worse memory performance and atrophy within the MTL. A mediation analysis revealed that the relationship with regional atrophy was explained by MTL tau. These findings broaden the concept of cognitive aging to include evidence of Alzheimer’s disease-related protein aggregation as an underlying mechanism of age-related memory impairment.« less

Neonatal Magnetic Resonance Imaging Pattern of Brain Injury as a Biomarker of Childhood Outcomes following a Trial of Hypothermia for Neonatal Hypoxic-Ischemic Encephalopathy.

PubMed

Shankaran, Seetha; McDonald, Scott A; Laptook, Abbot R; Hintz, Susan R; Barnes, Patrick D; Das, Abhik; Pappas, Athina; Higgins, Rosemary D

2015-11-01

To examine the ability of magnetic resonance imaging (MRI) patterns of neonatal brain injury defined by the National Institute of Child Health and Human Development Neonatal Research Network to predict death or IQ at 6-7 years of age following hypothermia for neonatal encephalopathy. Out of 208 participants, 124 had MRI and primary outcome (death or IQ <70) data. The relationship between injury pattern and outcome was assessed. Death or IQ <70 occurred in 4 of 50 (8%) of children with pattern 0 (normal MRI), 1 of 6 (17%) with 1A (minimal cerebral lesions), 1 of 4 (25%) with 1B (extensive cerebral lesions), 3 of 8 (38%) with 2A (basal ganglia thalamic, anterior or posterior limb of internal capsule, or watershed infarction), 32 of 49 (65%) with 2B (2A with cerebral lesions), and 7 of 7 (100%) with pattern 3 (hemispheric devastation), P < .001; this association was also seen within hypothermia and control subgroups. IQ was 90 ± 13 among the 46 children with a normal MRI and 69 ± 25 among the 50 children with an abnormal MRI. In childhood, for a normal outcome, a normal neonatal MRI had a sensitivity of 61%, specificity of 92%, a positive predictive value of 92%, and a negative predictive value of 59%; for death or IQ <70, the 2B and 3 pattern combined had a sensitivity of 81%, specificity of 78%, positive predictive value of 70%, and a negative predictive value of 87%. The Neonatal Research Network MRI pattern of neonatal brain injury is a biomarker of neurodevelopmental outcome at 6-7 years of age. ClinicalTrials.gov: NCT00005772. Copyright © 2015. Published by Elsevier Inc.

A Four-Dimensional Probabilistic Atlas of the Human Brain

PubMed Central

Mazziotta, John; Toga, Arthur; Evans, Alan; Fox, Peter; Lancaster, Jack; Zilles, Karl; Woods, Roger; Paus, Tomas; Simpson, Gregory; Pike, Bruce; Holmes, Colin; Collins, Louis; Thompson, Paul; MacDonald, David; Iacoboni, Marco; Schormann, Thorsten; Amunts, Katrin; Palomero-Gallagher, Nicola; Geyer, Stefan; Parsons, Larry; Narr, Katherine; Kabani, Noor; Le Goualher, Georges; Feidler, Jordan; Smith, Kenneth; Boomsma, Dorret; Pol, Hilleke Hulshoff; Cannon, Tyrone; Kawashima, Ryuta; Mazoyer, Bernard

2001-01-01

The authors describe the development of a four-dimensional atlas and reference system that includes both macroscopic and microscopic information on structure and function of the human brain in persons between the ages of 18 and 90 years. Given the presumed large but previously unquantified degree of structural and functional variance among normal persons in the human population, the basis for this atlas and reference system is probabilistic. Through the efforts of the International Consortium for Brain Mapping (ICBM), 7,000 subjects will be included in the initial phase of database and atlas development. For each subject, detailed demographic, clinical, behavioral, and imaging information is being collected. In addition, 5,800 subjects will contribute DNA for the purpose of determining genotype– phenotype–behavioral correlations. The process of developing the strategies, algorithms, data collection methods, validation approaches, database structures, and distribution of results is described in this report. Examples of applications of the approach are described for the normal brain in both adults and children as well as in patients with schizophrenia. This project should provide new insights into the relationship between microscopic and macroscopic structure and function in the human brain and should have important implications in basic neuroscience, clinical diagnostics, and cerebral disorders. PMID:11522763

What is special about the adolescent (JME) brain?

PubMed

Craiu, Dana

2013-07-01

Juvenile myoclonic epilepsy (JME) involves cortico-thalamo-cortical networks. Thalamic, frontal gray matter, connectivity, and neurotransmitter disturbances have been demonstrated by structural/functional imaging studies. Few patients with JME show mutations in genes coding ion channels or GABAA (gamma-aminobutyric acid) receptor subunits. Recent research points to EFHC1 gene mutations leading to microdysgenesis and possible aberrant circuitry. Imaging studies have shown massive structural/functional changes of normally developing adolescent brain structures maturing at strikingly different rates and times. Gray matter (GM) volume diminishes in cortical areas (frontal and parietal) and deep structures (anterior thalamus, putamen, and caudate). Diffusion tensor imaging (DTI) findings support continued microstructural change in WM (white matter) during late adolescence with robust developmental changes in thalamocortical connectivity. The GABAA receptor distribution and specific receptor subunits' expression patterns change with age from neonate to adolescent/adult, contributing to age-related changes in brain excitability. Hormonal influence on brain structure development during adolescence is presented. Possible implications of brain changes during adolescence on the course of JME are discussed. Copyright © 2012 Elsevier Inc. All rights reserved.

Detection and mapping of delays in early cortical folding derived from in utero MRI

NASA Astrophysics Data System (ADS)

Habas, Piotr A.; Rajagopalan, Vidya; Scott, Julia A.; Kim, Kio; Roosta, Ahmad; Rousseau, Francois; Barkovich, A. James; Glenn, Orit A.; Studholme, Colin

2011-03-01

Understanding human brain development in utero and detecting cortical abnormalities related to specific clinical conditions is an important area of research. In this paper, we describe and evaluate methodology for detection and mapping of delays in early cortical folding from population-based studies of fetal brain anatomies imaged in utero. We use a general linear modeling framework to describe spatiotemporal changes in curvature of the developing brain and explore the ability to detect and localize delays in cortical folding in the presence of uncertainty in estimation of the fetal age. We apply permutation testing to examine which regions of the brain surface provide the most statistical power to detect a given folding delay at a given developmental stage. The presented methodology is evaluated using MR scans of fetuses with normal brain development and gestational ages ranging from 20.57 to 27.86 weeks. This period is critical in early cortical folding and the formation of the primary and secondary sulci. Finally, we demonstrate a clinical application of the framework for detection and localization of folding delays in fetuses with isolated mild ventriculomegaly.

Cortical Thickness and Anxiety Symptoms Among Cognitively Normal Elderly Persons: The Mayo Clinic Study of Aging.

PubMed

Pink, Anna; Przybelski, Scott A; Krell-Roesch, Janina; Stokin, Gorazd B; Roberts, Rosebud O; Mielke, Michelle M; Spangehl, Kathleen A; Knopman, David S; Jack, Clifford R; Petersen, Ronald C; Geda, Yonas E

2017-01-01

The authors conducted a cross-sectional study to investigate the association between anxiety symptoms and cortical thickness, as well as amygdalar volume. A total of 1,505 cognitively normal participants, aged ≥70 years, were recruited from the Mayo Clinic Study of Aging in Olmsted County, Minnesota, on whom Beck Anxiety Inventory and 3T brain MRI data were available. Even though the effect sizes were small in this community-dwelling group of participants, anxiety symptoms were associated with reduced global cortical thickness and reduced thickness within the frontal and temporal cortex. However, after additionally adjusting for comorbid depressive symptoms, only the association between anxiety symptoms and reduced insular thickness remained significant.

Brain plasticity and functional losses in the aged: scientific bases for a novel intervention.

PubMed

Mahncke, Henry W; Bronstone, Amy; Merzenich, Michael M

2006-01-01

Aging is associated with progressive losses in function across multiple systems, including sensation, cognition, memory, motor control, and affect. The traditional view has been that functional decline in aging is unavoidable because it is a direct consequence of brain machinery wearing down over time. In recent years, an alternative perspective has emerged, which elaborates on this traditional view of age-related functional decline. This new viewpoint--based upon decades of research in neuroscience, experimental psychology, and other related fields--argues that as people age, brain plasticity processes with negative consequences begin to dominate brain functioning. Four core factors--reduced schedules of brain activity, noisy processing, weakened neuromodulatory control, and negative learning--interact to create a self-reinforcing downward spiral of degraded brain function in older adults. This downward spiral might begin from reduced brain activity due to behavioral change, from a loss in brain function driven by aging brain machinery, or more likely from both. In aggregate, these interrelated factors promote plastic changes in the brain that result in age-related functional decline. This new viewpoint on the root causes of functional decline immediately suggests a remedial approach. Studies of adult brain plasticity have shown that substantial improvement in function and/or recovery from losses in sensation, cognition, memory, motor control, and affect should be possible, using appropriately designed behavioral training paradigms. Driving brain plasticity with positive outcomes requires engaging older adults in demanding sensory, cognitive, and motor activities on an intensive basis, in a behavioral context designed to re-engage and strengthen the neuromodulatory systems that control learning in adults, with the goal of increasing the fidelity, reliability, and power of cortical representations. Such a training program would serve a substantial unmet need in aging adults. Current treatments directed at age-related functional losses are limited in important ways. Pharmacological therapies can target only a limited number of the many changes believed to underlie functional decline. Behavioral approaches focus on teaching specific strategies to aid higher order cognitive functions, and do not usually aspire to fundamentally change brain function. A brain-plasticity-based training program would potentially be applicable to all aging adults with the promise of improving their operational capabilities. We have constructed such a brain-plasticity-based training program and conducted an initial randomized controlled pilot study to evaluate the feasibility of its use by older adults. A main objective of this initial study was to estimate the effect size on standardized neuropsychological measures of memory. We found that older adults could learn the training program quickly, and could use it entirely unsupervised for the majority of the time required. Pre- and posttesting documented a significant improvement in memory within the training group (effect size 0.41, p<0.0005), with no significant within-group changes in a time-matched computer using active control group, or in a no-contact control group. Thus, a brain-plasticity-based intervention targeting normal age-related cognitive decline may potentially offer benefit to a broad population of older adults.

The effects of HIV and aging on brain functions: proposing a research framework and update on last 3 years' findings.

PubMed

Cysique, Lucette A; Brew, Bruce J

2014-07-01

The effect of HIV and aging on brain functions is an increasingly important topic of research: HIV-infected (HIV+) persons aged ≥50 represent a growing part of the HIV epidemic. Research is embracing this new axis, but there has been a lack of conceptualization of the factors that are at stake in both aging and HIV. To start to remedy this theoretical limitation, we are proposing a research framework in the hope that it will optimize how research questions and findings are formulated. Moreover, in the light of this proposed research framework, we review the last 3  years' research findings. Our review highlights that as HIV+ persons are aging, there is some signal for acceleration of normal aging processes and facilitated expression of age-associated diseases. Evidence for dramatic neurodegeneration in aging HIV+ persons remains limited and may be different in nature to typical neurodegenerative processes. Also, it should be kept in mind that most HIV+ persons are still below age 60. The vast majority of studies are still cross-sectional thereby underlining the critical importance of longitudinal studies to fully assess the effect of comorbidities. The complex effects of aging and nonaging comorbidities and key HIV effects (as opposed to only HIV status) need to be taken into account in future research by increasing sample size and selecting the most appropriate control group(s). Ideally, life-span studies should be established using neuropsychological and neuroimaging outcomes that have a proven track record in both HIV-related brain injury and brain aging. These would be similar to those that exist in non-HIV aging research and would optimally account for comorbidity effects and survivor bias.

Age-related white matter microstructural differences partly mediate age-related decline in processing speed but not cognition.

PubMed

Salami, Alireza; Eriksson, Johan; Nilsson, Lars-Göran; Nyberg, Lars

2012-03-01

Aging is associated with declining cognitive performance as well as structural changes in brain gray and white matter (WM). The WM deterioration contributes to a disconnection among distributed brain networks and may thus mediate age-related cognitive decline. The present diffusion tensor imaging (DTI) study investigated age-related differences in WM microstructure and their relation to cognition (episodic memory, visuospatial processing, fluency, and speed) in a large group of healthy subjects (n=287) covering 6 decades of the human life span. Age related decreases in fractional anisotropy (FA) and increases in mean diffusivity (MD) were observed across the entire WM skeleton as well as in specific WM tracts, supporting the WM degeneration hypothesis. The anterior section of the corpus callosum was more susceptible to aging compared to the posterior section, lending support to the anterior-posterior gradient of WM integrity in the corpus callosum. Finally, and of critical interest, WM integrity differences were found to mediate age-related reductions in processing speed but no significant mediation was found for episodic memory, visuospatial ability, or fluency. These findings suggest that compromised WM integrity is not a major contributing factor to declining cognitive performance in normal aging. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease. Copyright © 2011 Elsevier B.V. All rights reserved.

Change of Brain Functional Connectivity in Patients With Spinal Cord Injury: Graph Theory Based Approach.

PubMed

Min, Yu-Sun; Chang, Yongmin; Park, Jang Woo; Lee, Jong-Min; Cha, Jungho; Yang, Jin-Ju; Kim, Chul-Hyun; Hwang, Jong-Moon; Yoo, Ji-Na; Jung, Tae-Du

2015-06-01

To investigate the global functional reorganization of the brain following spinal cord injury with graph theory based approach by creating whole brain functional connectivity networks from resting state-functional magnetic resonance imaging (rs-fMRI), characterizing the reorganization of these networks using graph theoretical metrics and to compare these metrics between patients with spinal cord injury (SCI) and age-matched controls. Twenty patients with incomplete cervical SCI (14 males, 6 females; age, 55±14.1 years) and 20 healthy subjects (10 males, 10 females; age, 52.9±13.6 years) participated in this study. To analyze the characteristics of the whole brain network constructed with functional connectivity using rs-fMRI, graph theoretical measures were calculated including clustering coefficient, characteristic path length, global efficiency and small-worldness. Clustering coefficient, global efficiency and small-worldness did not show any difference between controls and SCIs in all density ranges. The normalized characteristic path length to random network was higher in SCI patients than in controls and reached statistical significance at 12%-13% of density (p<0.05, uncorrected). The graph theoretical approach in brain functional connectivity might be helpful to reveal the information processing after SCI. These findings imply that patients with SCI can build on preserved competent brain control. Further analyses, such as topological rearrangement and hub region identification, will be needed for better understanding of neuroplasticity in patients with SCI.

The neuropathological study of myelin oligodendrocyte glycoprotein in the temporal lobe of schizophrenia patients.

PubMed

Marui, Tomoyasu; Torii, Youta; Iritani, Shuji; Sekiguchi, Hirotaka; Habuchi, Chikako; Fujishiro, Hiroshige; Oshima, Kenichi; Niizato, Kazuhiro; Hayashida, Shotaro; Masaki, Katsuhisa; Kira, Junichi; Ozaki, Norio

2018-03-22

Recent studies based on the neuroimaging analysis, genomic analysis and transcriptome analysis of the postmortem brain suggest that the pathogenesis of schizophrenia is related to myelin-oligodendrocyte abnormalities. However, no serious neuropathological investigation of this protein in the schizophrenic brain has yet been performed. In this study, to confirm the change in neuropathological findings due to the pathogenesis of this disease, we observed the expression of myelin-oligodendrocyte directly in the brain tissue of schizophrenia patients. Myelin oligodendrocyte glycoprotein (MOG) was evaluated in the cortex of the superior temporal gyrus (STG) and the hippocampus in 10 schizophrenic and nine age- and sex-matched normal control postmortem brains. The expression of MOG was significantly lower in the middle layer of the neocortex of the STG and stratum lucidum of CA3 in the hippocampus in the long-term schizophrenic brains (patients with ≥30 years of illness duration) than in the age-matched controls. Furthermore, the thickness of MOG-positive fibre-like structures was significantly lower in both regions of the long-term schizophrenic brains than in the age-matched controls. These findings suggest that a long duration of illness has a marked effect on the expression of MOG in these regions, and that myelin-oligodendrocyte abnormalities in these regions may be related to the progressive pathophysiology of schizophrenia.

Mid-sagittal plane and mid-sagittal surface optimization in brain MRI using a local symmetry measure

NASA Astrophysics Data System (ADS)

Stegmann, Mikkel B.; Skoglund, Karl; Ryberg, Charlotte

2005-04-01

This paper describes methods for automatic localization of the mid-sagittal plane (MSP) and mid-sagittal surface (MSS). The data used is a subset of the Leukoaraiosis And DISability (LADIS) study consisting of three-dimensional magnetic resonance brain data from 62 elderly subjects (age 66 to 84 years). Traditionally, the mid-sagittal plane is localized by global measures. However, this approach fails when the partitioning plane between the brain hemispheres does not coincide with the symmetry plane of the head. We instead propose to use a sparse set of profiles in the plane normal direction and maximize the local symmetry around these using a general-purpose optimizer. The plane is parameterized by azimuth and elevation angles along with the distance to the origin in the normal direction. This approach leads to solutions confirmed as the optimal MSP in 98 percent of the subjects. Despite the name, the mid-sagittal plane is not always planar, but a curved surface resulting in poor partitioning of the brain hemispheres. To account for this, this paper also investigates an optimization strategy which fits a thin-plate spline surface to the brain data using a robust least median of squares estimator. Albeit computationally more expensive, mid-sagittal surface fitting demonstrated convincingly better partitioning of curved brains into cerebral hemispheres.

Brain connectivity study of joint attention using frequency-domain optical imaging technique

NASA Astrophysics Data System (ADS)

Chaudhary, Ujwal; Zhu, Banghe; Godavarty, Anuradha

2010-02-01

Autism is a socio-communication brain development disorder. It is marked by degeneration in the ability to respond to joint attention skill task, from as early as 12 to 18 months of age. This trait is used to distinguish autistic from nonautistic populations. In this study, diffuse optical imaging is being used to study brain connectivity for the first time in response to joint attention experience in normal adults. The prefrontal region of the brain was non-invasively imaged using a frequency-domain based optical imager. The imaging studies were performed on 11 normal right-handed adults and optical measurements were acquired in response to joint-attention based video clips. While the intensity-based optical data provides information about the hemodynamic response of the underlying neural process, the time-dependent phase-based optical data has the potential to explicate the directional information on the activation of the brain. Thus brain connectivity studies are performed by computing covariance/correlations between spatial units using this frequency-domain based optical measurements. The preliminary results indicate that the extent of synchrony and directional variation in the pattern of activation varies in the left and right frontal cortex. The results have significant implication for research in neural pathways associated with autism that can be mapped using diffuse optical imaging tools in the future.

Patterns of brain structural connectivity differentiate normal weight from overweight subjects

PubMed Central

Gupta, Arpana; Mayer, Emeran A.; Sanmiguel, Claudia P.; Van Horn, John D.; Woodworth, Davis; Ellingson, Benjamin M.; Fling, Connor; Love, Aubrey; Tillisch, Kirsten; Labus, Jennifer S.

2015-01-01

Background Alterations in the hedonic component of ingestive behaviors have been implicated as a possible risk factor in the pathophysiology of overweight and obese individuals. Neuroimaging evidence from individuals with increasing body mass index suggests structural, functional, and neurochemical alterations in the extended reward network and associated networks. Aim To apply a multivariate pattern analysis to distinguish normal weight and overweight subjects based on gray and white-matter measurements. Methods Structural images (N = 120, overweight N = 63) and diffusion tensor images (DTI) (N = 60, overweight N = 30) were obtained from healthy control subjects. For the total sample the mean age for the overweight group (females = 32, males = 31) was 28.77 years (SD = 9.76) and for the normal weight group (females = 32, males = 25) was 27.13 years (SD = 9.62). Regional segmentation and parcellation of the brain images was performed using Freesurfer. Deterministic tractography was performed to measure the normalized fiber density between regions. A multivariate pattern analysis approach was used to examine whether brain measures can distinguish overweight from normal weight individuals. Results 1. White-matter classification: The classification algorithm, based on 2 signatures with 17 regional connections, achieved 97% accuracy in discriminating overweight individuals from normal weight individuals. For both brain signatures, greater connectivity as indexed by increased fiber density was observed in overweight compared to normal weight between the reward network regions and regions of the executive control, emotional arousal, and somatosensory networks. In contrast, the opposite pattern (decreased fiber density) was found between ventromedial prefrontal cortex and the anterior insula, and between thalamus and executive control network regions. 2. Gray-matter classification: The classification algorithm, based on 2 signatures with 42 morphological features, achieved 69% accuracy in discriminating overweight from normal weight. In both brain signatures regions of the reward, salience, executive control and emotional arousal networks were associated with lower morphological values in overweight individuals compared to normal weight individuals, while the opposite pattern was seen for regions of the somatosensory network. Conclusions 1. An increased BMI (i.e., overweight subjects) is associated with distinct changes in gray-matter and fiber density of the brain. 2. Classification algorithms based on white-matter connectivity involving regions of the reward and associated networks can identify specific targets for mechanistic studies and future drug development aimed at abnormal ingestive behavior and in overweight/obesity. PMID:25737959

Cerebral glucose uptake in patients with chronic mental and cognitive sequelae following a single blunt mild TBI without visible brain lesions.

PubMed

Komura, Akifumi; Kawasaki, Tomohiro; Yamada, Yuichi; Uzuyama, Shiho; Asano, Yoshitaka; Shinoda, Jun

2018-06-19

The aim of this study is to investigate glucose uptake on FDG-PET in patients with chronic mental and cognitive symptoms following a single blunt mild traumatic brain injury (TBI) and without visible brain lesions on CT/MRI. Eighty-nine consecutive patients (mean age 43.8±10.75) who had a single blunt mild TBI from a traffic accident and suffering from chronic mental and cognitive symptoms without visible brain lesions on CT/MRI were enrolled in the study. Patients underwent FDG-PET imaging, and the mean interval between the TBI and FDG-PET was 50.0 months. The Wechsler Adult Intelligence Scale version III testing was performed within one month of the FDG-PET. A control group consisting of 93 healthy adult volunteers (mean age 42.2±14.3 years) also underwent FDG-PET. The glucose uptake pattern from FDG-PET in the patient group was compared to that from normal controls using statistical parametric mapping. Glucose uptake was significantly decreased in the bilateral prefrontal area and significantly increased around the limbic system in the patient group compared to normal controls. This topographical pattern of glucose uptake is different from that reported previously in patients with diffuse axonal injury (DAI), but may be similar to that seen in patients with major depression disorder. These results suggest that the pathological mechanism causing chronic mental and cognitive symptoms in patients with a single blunt mild TBI and without visible brain lesions might be different from that due to primary axonopathy in patients with DAI.

Curcumin prevents mitochondrial dysfunction in the brain of the senescence-accelerated mouse-prone 8.

PubMed

Eckert, Gunter P; Schiborr, Christina; Hagl, Stephanie; Abdel-Kader, Reham; Müller, Walter E; Rimbach, Gerald; Frank, Jan

2013-04-01

The aging brain suffers mitochondrial dysfunction and a reduced availability of energy in the form of ATP, which in turn may cause or promote the decline in cognitive, sensory, and motor function observed with advancing age. There is a need for animal models that display some of the pathological features of human brain aging in order to study their prevention by e.g. dietary factors. We thus investigated the suitability of the fast-aging senescence-accelerated mouse-prone 8 (SAMP8) strain and its normally aging control senescence-accelerated mouse-resistant 1 (SAMR1) as a model for the age-dependent changes in mitochondrial function in the brain. To this end, 2-months old male SAMR1 (n=10) and SAMP8 mice (n=7) were fed a Western type diet (control groups) for 5months and one group of SAMP8 mice (n=6) was fed an identical diet fortified with 500mg curcumin per kg. Dissociated brain cells and brain tissue homogenates were analyzed for malondialdehyde, heme oxygenase-1 mRNA, mitochondrial membrane potential (MMP), ATP concentrations, protein levels of mitochondrial marker proteins for mitochondrial membranes (TIMM, TOMM), the mitochondrial permeability transition pore (ANT1, VDAC1, TSPO), respiration complexes, and fission and fusion (Fis, Opa1, Mfn1, Drp1). Dissociated brain cells isolated from SAMP8 mice showed significantly reduced MMP and ATP levels, probably due to significantly diminished complex V protein expression, and increased expression of TSPO. Fission and fusion marker proteins indicate enhanced mitochondrial fission in brains of SAMP8 mice. Treatment of SAMP8 mice with curcumin improved MMP and ATP and restored mitochondrial fusion, probably by up-regulating nuclear factor PGC1α protein expression. In conclusion, SAMP8 compared to SAMR1 mice are a suitable model to study age-dependent changes in mitochondrial function and curcumin emerges as a promising nutraceutical for the prevention of neurodegenerative diseases that are accompanied or caused by mitochondrial dysfunction. Copyright © 2013 Elsevier Ltd. All rights reserved.

Age-Related Effects and Sex Differences in Gray Matter Density, Volume, Mass, and Cortical Thickness from Childhood to Young Adulthood.

PubMed

Gennatas, Efstathios D; Avants, Brian B; Wolf, Daniel H; Satterthwaite, Theodore D; Ruparel, Kosha; Ciric, Rastko; Hakonarson, Hakon; Gur, Raquel E; Gur, Ruben C

2017-05-17

Developmental structural neuroimaging studies in humans have long described decreases in gray matter volume (GMV) and cortical thickness (CT) during adolescence. Gray matter density (GMD), a measure often assumed to be highly related to volume, has not been systematically investigated in development. We used T1 imaging data collected on the Philadelphia Neurodevelopmental Cohort to study age-related effects and sex differences in four regional gray matter measures in 1189 youths ranging in age from 8 to 23 years. Custom T1 segmentation and a novel high-resolution gray matter parcellation were used to extract GMD, GMV, gray matter mass (GMM; defined as GMD × GMV), and CT from 1625 brain regions. Nonlinear models revealed that each modality exhibits unique age-related effects and sex differences. While GMV and CT generally decrease with age, GMD increases and shows the strongest age-related effects, while GMM shows a slight decline overall. Females have lower GMV but higher GMD than males throughout the brain. Our findings suggest that GMD is a prime phenotype for the assessment of brain development and likely cognition and that periadolescent gray matter loss may be less pronounced than previously thought. This work highlights the need for combined quantitative histological MRI studies. SIGNIFICANCE STATEMENT This study demonstrates that different MRI-derived gray matter measures show distinct age and sex effects and should not be considered equivalent but complementary. It is shown for the first time that gray matter density increases from childhood to young adulthood, in contrast with gray matter volume and cortical thickness, and that females, who are known to have lower gray matter volume than males, have higher density throughout the brain. A custom preprocessing pipeline and a novel high-resolution parcellation were created to analyze brain scans of 1189 youths collected as part of the Philadelphia Neurodevelopmental Cohort. A clear understanding of normal structural brain development is essential for the examination of brain-behavior relationships, the study of brain disease, and, ultimately, clinical applications of neuroimaging. Copyright © 2017 the authors 0270-6474/17/375065-09$15.00/0.

Old Maids: Aging and Its Impact on Microglia Function

PubMed Central

Koellhoffer, Edward C.; McCullough, Louise D.; Ritzel, Rodney M.

2017-01-01

Microglia are highly active and vigilant housekeepers of the central nervous system that function to promote neuronal growth and activity. With advanced age, however, dysregulated inflammatory signaling and defects in phagocytosis impede their ability to perform the most essential of homeostatic functions, including immune surveillance and debris clearance. Microglial activation is one of the hallmarks of the aging brain and coincides with age-related neurodegeneration and cognitive decline. Age-associated microglial dysfunction leads to cellular senescence and can profoundly alter the response to sterile injuries and immune diseases, often resulting in maladaptive responses, chronic inflammation, and worsened outcomes after injury. Our knowledge of microglia aging and the factors that regulate age-related microglial dysfunction remain limited, as the majority of pre-clinical studies are performed in young animals, and human brain samples are difficult to obtain quickly post-mortem or in large numbers. This review outlines the impact of normal aging on microglial function, highlights the potential mechanisms underlying age-related changes in microglia, and discusses how aging can shape the recovery process following injury. PMID:28379162

Brain metabolism in health, aging, and neurodegeneration.

PubMed

Camandola, Simonetta; Mattson, Mark P

2017-06-01

Brain cells normally respond adaptively to bioenergetic challenges resulting from ongoing activity in neuronal circuits, and from environmental energetic stressors such as food deprivation and physical exertion. At the cellular level, such adaptive responses include the "strengthening" of existing synapses, the formation of new synapses, and the production of new neurons from stem cells. At the molecular level, bioenergetic challenges result in the activation of transcription factors that induce the expression of proteins that bolster the resistance of neurons to the kinds of metabolic, oxidative, excitotoxic, and proteotoxic stresses involved in the pathogenesis of brain disorders including stroke, and Alzheimer's and Parkinson's diseases. Emerging findings suggest that lifestyles that include intermittent bioenergetic challenges, most notably exercise and dietary energy restriction, can increase the likelihood that the brain will function optimally and in the absence of disease throughout life. Here, we provide an overview of cellular and molecular mechanisms that regulate brain energy metabolism, how such mechanisms are altered during aging and in neurodegenerative disorders, and the potential applications to brain health and disease of interventions that engage pathways involved in neuronal adaptations to metabolic stress. Published 2017. This article is a U.S. Government work and is in the public domain in the USA.

An automated normative-based fluorodeoxyglucose positron emission tomography image-analysis procedure to aid Alzheimer disease diagnosis using statistical parametric mapping and interactive image display

NASA Astrophysics Data System (ADS)

Chen, Kewei; Ge, Xiaolin; Yao, Li; Bandy, Dan; Alexander, Gene E.; Prouty, Anita; Burns, Christine; Zhao, Xiaojie; Wen, Xiaotong; Korn, Ronald; Lawson, Michael; Reiman, Eric M.

2006-03-01

Having approved fluorodeoxyglucose positron emission tomography (FDG PET) for the diagnosis of Alzheimer's disease (AD) in some patients, the Centers for Medicare and Medicaid Services suggested the need to develop and test analysis techniques to optimize diagnostic accuracy. We developed an automated computer package comparing an individual's FDG PET image to those of a group of normal volunteers. The normal control group includes FDG-PET images from 82 cognitively normal subjects, 61.89+/-5.67 years of age, who were characterized demographically, clinically, neuropsychologically, and by their apolipoprotein E genotype (known to be associated with a differential risk for AD). In addition, AD-affected brain regions functionally defined as based on a previous study (Alexander, et al, Am J Psychiatr, 2002) were also incorporated. Our computer package permits the user to optionally select control subjects, matching the individual patient for gender, age, and educational level. It is fully streamlined to require minimal user intervention. With one mouse click, the program runs automatically, normalizing the individual patient image, setting up a design matrix for comparing the single subject to a group of normal controls, performing the statistics, calculating the glucose reduction overlap index of the patient with the AD-affected brain regions, and displaying the findings in reference to the AD regions. In conclusion, the package automatically contrasts a single patient to a normal subject database using sound statistical procedures. With further validation, this computer package could be a valuable tool to assist physicians in decision making and communicating findings with patients and patient families.

Brain activation changes during locomotion in middle-aged to older adults with multiple sclerosis.

PubMed

Hernandez, Manuel E; Holtzer, Roee; Chaparro, Gioella; Jean, Kharine; Balto, Julia M; Sandroff, Brian M; Izzetoglu, Meltem; Motl, Robert W

2016-11-15

Mobility and cognitive impairments are common in persons with multiple sclerosis (MS), and are expected to worsen with increasing age. However, no studies, to date, in part due to limitations of conventional neuroimaging methods, have examined changes in brain activation patterns during active locomotion in older patients with MS. This study used functional Near Infrared Spectroscopy (fNIRS) to evaluate real-time neural activation differences in the pre-frontal cortex (PFC) between middle-aged to older adults with MS and healthy controls during single (Normal Walk; NW) and dual-task (Walking While Talking; WWT) locomotion tasks. Eight middle-aged to older adults with MS and eight healthy controls underwent fNIRS recording while performing the NW and WWT tasks with an fNIRS cap consisting of 16 optodes positioned over the forehead. The MS group had greater elevations in PFC oxygenation levels during WWT compared to NW than healthy controls. There was no walking performance difference between groups during locomotion. These findings suggest that middle-aged to older individuals with MS might be able to achieve similar levels of performance through the use of increased brain activation. This study is the first to investigate brain activation changes during the performance of simple and divided-attention locomotion tasks in MS using fNIRS. Copyright © 2016 Elsevier B.V. All rights reserved.

Sex and the development of Alzheimer’s disease

PubMed Central

Pike, Christian J.

2016-01-01

Men and women exhibit differences in the development and progression of Alzheimer’s disease (AD). The factors underlying the sex differences in AD are not well understood. This review emphasizes the contributions of sex steroid hormones to the relationship between sex and AD. In women, events that decrease lifetime exposure to estrogens are generally associated with increased AD risk, whereas estrogen-based hormone therapy administered near the time of menopause may reduce AD risk. In men, estrogens do not exhibit age-related reduction and are not significantly associated with AD risk. Rather, normal age-related depletions of testosterone in plasma and brain predict enhanced vulnerability to AD. Both estrogens and androgens exert numerous protective actions in the adult brain that increase neural functioning and resilience as well as specifically attenuate multiple aspects of AD-related neuropathology. Aging diminishes the activational effects of sex hormones in sex-specific manners, which is hypothesized to contribute to the relationship between aging and AD. Sex steroid hormones may also drive sex differences in AD through their organizational effects during developmental sexual differentiation of the brain. Specifically, sex hormone actions during early development may confer inherent vulnerability of the female brain to development of AD in advanced age. The combined effects of organizational and activational effects of sex steroids yield distinct sex differences in AD pathogenesis, a significant variable that must be more rigorously considered in future research. PMID:27870425

Language comprehension and brain function in individuals with an optimal outcome from autism.

PubMed

Eigsti, Inge-Marie; Stevens, Michael C; Schultz, Robert T; Barton, Marianne; Kelley, Elizabeth; Naigles, Letitia; Orinstein, Alyssa; Troyb, Eva; Fein, Deborah A

2016-01-01

Although Autism Spectrum Disorder (ASD) is generally a lifelong disability, a minority of individuals with ASD overcome their symptoms to such a degree that they are generally indistinguishable from their typically-developing peers. That is, they have achieved an Optimal Outcome (OO). The question addressed by the current study is whether this normalized behavior reflects normalized brain functioning, or alternatively, the action of compensatory systems. Either possibility is plausible, as most participants with OO received years of intensive therapy that could alter brain networks to align with typical function or work around ASD-related neural dysfunction. Individuals ages 8 to 21 years with high-functioning ASD (n = 23), OO (n = 16), or typical development (TD; n = 20) completed a functional MRI scan while performing a sentence comprehension task. Results indicated similar activations in frontal and temporal regions (left middle frontal, left supramarginal, and right superior temporal gyri) and posterior cingulate in OO and ASD groups, where both differed from the TD group. Furthermore, the OO group showed heightened "compensatory" activation in numerous left- and right-lateralized regions (left precentral/postcentral gyri, right precentral gyrus, left inferior parietal lobule, right supramarginal gyrus, left superior temporal/parahippocampal gyrus, left middle occipital gyrus) and cerebellum, relative to both ASD and TD groups. Behaviorally normalized language abilities in OO individuals appear to utilize atypical brain networks, with increased recruitment of language-specific as well as right homologue and other systems. Early intensive learning and experience may normalize behavioral language performance in OO, but some brain regions involved in language processing may continue to display characteristics that are more similar to ASD than typical development, while others show characteristics not like ASD or typical development.

Lymphatic drainage system of the brain: A novel target for intervention of neurological diseases.

PubMed

Sun, Bao-Liang; Wang, Li-Hua; Yang, Tuo; Sun, Jing-Yi; Mao, Lei-Lei; Yang, Ming-Feng; Yuan, Hui; Colvin, Robert A; Yang, Xiao-Yi

2017-09-10

The belief that the vertebrate brain functions normally without classical lymphatic drainage vessels has been held for many decades. On the contrary, new findings show that functional lymphatic drainage does exist in the brain. The brain lymphatic drainage system is composed of basement membrane-based perivascular pathway, a brain-wide glymphatic pathway, and cerebrospinal fluid (CSF) drainage routes including sinus-associated meningeal lymphatic vessels and olfactory/cervical lymphatic routes. The brain lymphatic systems function physiological as a route of drainage for interstitial fluid (ISF) from brain parenchyma to nearby lymph nodes. Brain lymphatic drainage helps maintain water and ion balance of the ISF, waste clearance, and reabsorption of macromolecular solutes. A second physiological function includes communication with the immune system modulating immune surveillance and responses of the brain. These physiological functions are influenced by aging, genetic phenotypes, sleep-wake cycle, and body posture. The impairment and dysfunction of the brain lymphatic system has crucial roles in age-related changes of brain function and the pathogenesis of neurovascular, neurodegenerative, and neuroinflammatory diseases, as well as brain injury and tumors. In this review, we summarize the key component elements (regions, cells, and water transporters) of the brain lymphatic system and their regulators as potential therapeutic targets in the treatment of neurologic diseases and their resulting complications. Finally, we highlight the clinical importance of ependymal route-based targeted gene therapy and intranasal drug administration in the brain by taking advantage of the unique role played by brain lymphatic pathways in the regulation of CSF flow and ISF/CSF exchange. Copyright © 2017. Published by Elsevier Ltd.

Suppression of brain cholesterol synthesis in male Mecp2-deficient mice is age dependent and not accompanied by a concurrent change in the rate of fatty acid synthesis.

PubMed

Lopez, Adam M; Chuang, Jen-Chieh; Posey, Kenneth S; Turley, Stephen D

2017-01-01

Mutations in the X-linked gene methyl-CpG-binding protein 2 (MECP2) are the principal cause of Rett syndrome, a progressive neurodevelopmental disorder afflicting 1 in 10,000 to 15,000 females. Studies using hemizygous Mecp2 mouse models have revealed disruptions to some aspects of their lipid metabolism including a partial suppression of cholesterol synthesis in the brains of mature Mecp2 mutants. The present studies investigated whether this suppression is evident from early neonatal life, or becomes manifest at a later stage of development. We measured the rate of cholesterol synthesis, in vivo, in the brains of male Mecp2 - /y and their Mecp2 +/y littermates at 7, 14, 21, 28, 42 and 56 days of age. Brain weight was consistently lower in the Mecp2 -/y mice than in their Mecp2 +/y controls except at 7 days of age. In the 7- and 14-day-old mice there was no genotypic difference in the rate of brain cholesterol synthesis but, from 21 days and later, it was always marginally lower in the Mecp2 -/y mice than in age-matched Mecp2 +/y littermates. At no age was a genotypic difference detected in either the rate of fatty acid synthesis or cholesterol concentration in the brain. Cholesterol synthesis rates in the liver and lungs of 56-day-old Mecp2 -/y mice were normal. The onset of lower rates of brain cholesterol synthesis at about the time closure of the blood brain barrier purportedly occurs might signify a disruption to mechanism(s) that dictate intracellular levels of cholesterol metabolites including oxysterols known to exert a regulatory influence on the cholesterol biosynthetic pathway. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Support vector machine classification and characterization of age-related reorganization of functional brain networks

PubMed Central

Meier, Timothy B.; Desphande, Alok S.; Vergun, Svyatoslav; Nair, Veena A.; Song, Jie; Biswal, Bharat B.; Meyerand, Mary E.; Birn, Rasmus M.; Prabhakaran, Vivek

2012-01-01

Most of what is known about the reorganization of functional brain networks that accompanies normal aging is based on neuroimaging studies in which participants perform specific tasks. In these studies, reorganization is defined by the differences in task activation between young and old adults. However, task activation differences could be the result of differences in task performance, strategy, or motivation, and not necessarily reflect reorganization. Resting-state fMRI provides a method of investigating functional brain networks without such confounds. Here, a support vector machine (SVM) classifier was used in an attempt to differentiate older adults from younger adults based on their resting-state functional connectivity. In addition, the information used by the SVM was investigated to see what functional connections best differentiated younger adult brains from older adult brains. Three separate resting-state scans from 26 younger adults (18-35 yrs) and 26 older adults (55-85) were obtained from the International Consortium for Brain Mapping (ICBM) dataset made publically available in the 1000 Functional Connectomes project www.nitrc.org/projects/fcon_1000. 100 seed-regions from four functional networks with 5 mm3 radius were defined based on a recent study using machine learning classifiers on adolescent brains. Time-series for every seed-region were averaged and three matrices of z-transformed correlation coefficients were created for each subject corresponding to each individual’s three resting-state scans. SVM was then applied using leave-one-out cross-validation. The SVM classifier was 84% accurate in classifying older and younger adult brains. The majority of the connections used by the classifier to distinguish subjects by age came from seed-regions belonging to the sensorimotor and cingulo-opercular networks. These results suggest that age-related decreases in positive correlations within the cingulo-opercular and default networks, and decreases in negative correlations between the default and sensorimotor networks, are the distinguishing characteristics of age-related reorganization. PMID:22227886

Support vector machine classification and characterization of age-related reorganization of functional brain networks.

PubMed

Meier, Timothy B; Desphande, Alok S; Vergun, Svyatoslav; Nair, Veena A; Song, Jie; Biswal, Bharat B; Meyerand, Mary E; Birn, Rasmus M; Prabhakaran, Vivek

2012-03-01

Most of what is known about the reorganization of functional brain networks that accompanies normal aging is based on neuroimaging studies in which participants perform specific tasks. In these studies, reorganization is defined by the differences in task activation between young and old adults. However, task activation differences could be the result of differences in task performance, strategy, or motivation, and not necessarily reflect reorganization. Resting-state fMRI provides a method of investigating functional brain networks without such confounds. Here, a support vector machine (SVM) classifier was used in an attempt to differentiate older adults from younger adults based on their resting-state functional connectivity. In addition, the information used by the SVM was investigated to see what functional connections best differentiated younger adult brains from older adult brains. Three separate resting-state scans from 26 younger adults (18-35 yrs) and 26 older adults (55-85) were obtained from the International Consortium for Brain Mapping (ICBM) dataset made publically available in the 1000 Functional Connectomes project www.nitrc.org/projects/fcon_1000. 100 seed-regions from four functional networks with 5mm(3) radius were defined based on a recent study using machine learning classifiers on adolescent brains. Time-series for every seed-region were averaged and three matrices of z-transformed correlation coefficients were created for each subject corresponding to each individual's three resting-state scans. SVM was then applied using leave-one-out cross-validation. The SVM classifier was 84% accurate in classifying older and younger adult brains. The majority of the connections used by the classifier to distinguish subjects by age came from seed-regions belonging to the sensorimotor and cingulo-opercular networks. These results suggest that age-related decreases in positive correlations within the cingulo-opercular and default networks, and decreases in negative correlations between the default and sensorimotor networks, are the distinguishing characteristics of age-related reorganization. Copyright © 2011 Elsevier Inc. All rights reserved.

Germline mitochondrial DNA mutations aggravate ageing and can impair brain development.

PubMed

Ross, Jaime M; Stewart, James B; Hagström, Erik; Brené, Stefan; Mourier, Arnaud; Coppotelli, Giuseppe; Freyer, Christoph; Lagouge, Marie; Hoffer, Barry J; Olson, Lars; Larsson, Nils-Göran

2013-09-19

Ageing is due to an accumulation of various types of damage, and mitochondrial dysfunction has long been considered to be important in this process. There is substantial sequence variation in mammalian mitochondrial DNA (mtDNA), and the high mutation rate is counteracted by different mechanisms that decrease maternal transmission of mutated mtDNA. Despite these protective mechanisms, it is becoming increasingly clear that low-level mtDNA heteroplasmy is quite common and often inherited in humans. We designed a series of mouse mutants to investigate the extent to which inherited mtDNA mutations can contribute to ageing. Here we report that maternally transmitted mtDNA mutations can induce mild ageing phenotypes in mice with a wild-type nuclear genome. Furthermore, maternally transmitted mtDNA mutations lead to anticipation of reduced fertility in mice that are heterozygous for the mtDNA mutator allele (PolgA(wt/mut)) and aggravate premature ageing phenotypes in mtDNA mutator mice (PolgA(mut/mut)). Unexpectedly, a combination of maternally transmitted and somatic mtDNA mutations also leads to stochastic brain malformations. Our findings show that a pre-existing mutation load will not only allow somatic mutagenesis to create a critically high total mtDNA mutation load sooner but will also increase clonal expansion of mtDNA mutations to enhance the normally occurring mosaic respiratory chain deficiency in ageing tissues. Our findings suggest that maternally transmitted mtDNA mutations may have a similar role in aggravating aspects of normal human ageing.

Differences in interregional brain connectivity in children with unilateral hearing loss.

PubMed

Jung, Matthew E; Colletta, Miranda; Coalson, Rebecca; Schlaggar, Bradley L; Lieu, Judith E C

2017-11-01

To identify functional network architecture differences in the brains of children with unilateral hearing loss (UHL) using resting-state functional-connectivity magnetic resonance imaging (rs-fcMRI). Prospective observational study. Children (7 to 17 years of age) with severe to profound hearing loss in one ear, along with their normal hearing (NH) siblings, were recruited and imaged using rs-fcMRI. Eleven children had right UHL; nine had left UHL; and 13 had normal hearing. Forty-one brain regions of interest culled from established brain networks such as the default mode (DMN); cingulo-opercular (CON); and frontoparietal networks (FPN); as well as regions for language, phonological, and visual processing, were analyzed using regionwise correlations and conjunction analysis to determine differences in functional connectivity between the UHL and normal hearing children. When compared to the NH group, children with UHL showed increased connectivity patterns between multiple networks, such as between the CON and visual processing centers. However, there were decreased, as well as aberrant connectivity patterns with the coactivation of the DMN and FPN, a relationship that usually is negatively correlated. Children with UHL demonstrate multiple functional connectivity differences between brain networks involved with executive function, cognition, and language comprehension that may represent adaptive as well as maladaptive changes. These findings suggest that possible interventions or habilitation, beyond amplification, might be able to affect some children's requirement for additional help at school. 3b. Laryngoscope, 127:2636-2645, 2017. © 2017 The American Laryngological, Rhinological and Otological Society, Inc.

C145 as a short-latency electrophysiological index of cognitive compensation in Alzheimer's disease

PubMed Central

Chapman, Robert M.; Porsteinsson, Anton P.; Gardner, Margaret N.; Mapstone, Mark; McCrary, John W.; Sandoval, Tiffany C.; Guillily, Maria D.; DeGrush, Elizabeth; Reilly, Lindsey A.

2012-01-01

Brain plasticity and cognitive compensation in the elderly are of increasing interest, and Alzheimer's disease (AD) offers an opportunity to elucidate how the brain may overcome damage. We provide neurophysiological evidence of a short-latency ERP component (C145) linked to stimulus relevancy that may reflect cognitive compensation in early-stage Alzheimer's disease (AD). Thirty-six subjects with early-stage, mild AD and 36 like-aged normal elderly (Controls) had their EEG recorded while performing our Number-Letter task, a cognitive/perceptual paradigm that manipulates stimulus relevancies. ERP components, including C145, were extracted from ERPs using Principal Components Analysis. C145 amplitudes and spatial distributions were compared among Controls, AD subjects with high performance on the Number-Letter task, and AD subjects with low performance. Compared to AD subjects, Control subjects showed enhanced C145 processing of visual stimuli in the occipital region where differential processing of relevant stimuli occurred. AD high performers recruited central brain areas in processing task relevancy. Controls and AD low performers did not show a significant task relevancy effect in these areas. We conclude that short-latency ERP components can detect electrophysiological differences in early-stage AD that reflect altered cognition. Differences in C145 amplitudes between AD and normal elderly groups regarding brain locations and types of task effects suggest compensatory mechanisms can occur in the AD brain to overcome loss of normal functionality, and this early compensation may have a profound effect on the cognitive efficiency of AD individuals. PMID:22886016

Accelerated cognitive aging following severe traumatic brain injury: A review.

PubMed

Wood, Rodger Ll

2017-01-01

The primary objective of this review was to examine relevant clinical and experimental literatures for information on the long-term cognitive impact of serious traumatic brain injury (TBI) with regard to the process of cognitive aging. Online journal databases were queried for studies pertaining to cognitive aging in neurologically healthy populations, as well as the late cognitive effects of serious TBI. Additional studies were identified through searching bibliographies of related publications and using Google search engine. Problems of cognition exhibited by young adults after TBI resemble many cognitive weaknesses of attention deficit and poor working memory that are usually seen in an elderly population who have no neurological history. The current state of the literature provides support for the argument that TBI can result in diminished cognitive reserve which may accelerate the normal process of cognitive decline, leading to premature aging, potentially increasing the risk of dementia.

Brain MRI lesions and atrophy are associated with employment status in patients with multiple sclerosis.

PubMed

Tauhid, Shahamat; Chu, Renxin; Sasane, Rahul; Glanz, Bonnie I; Neema, Mohit; Miller, Jennifer R; Kim, Gloria; Signorovitch, James E; Healy, Brian C; Chitnis, Tanuja; Weiner, Howard L; Bakshi, Rohit

2015-11-01

Multiple sclerosis (MS) commonly affects occupational function. We investigated the link between brain MRI and employment status. Patients with MS (n = 100) completed a Work Productivity and Activity Impairment (WPAI) (general health version) survey measuring employment status, absenteeism, presenteeism, and overall work and daily activity impairment. Patients "working for pay" were considered employed; "temporarily not working but looking for work," "not working or looking for work due to age," and "not working or looking for work due to disability" were considered not employed. Brain MRI T1 hypointense (T1LV) and T2 hyperintense (T2LV) lesion volumes were quantified. To assess lesional destructive capability, we calculated each subject's ratio of T1LV to T2LV (T1/T2). Normalized brain parenchymal volume (BPV) assessed brain atrophy. The mean (SD) age was 45.5 (9.7) years; disease duration was 12.1 (8.1) years; 75 % were women, 76 % were relapsing-remitting, and 76 % were employed. T1LV, T1/T2, Expanded Disability Status Scale (EDSS) scores, and activity impairment were lower and BPV was higher in the employed vs. not employed group (Wilcoxon tests, p < 0.05). Age, disease duration, MS clinical subtype, and T2LV did not differ between groups (p > 0.05). In multivariable logistic regression modeling, adjusting for age, sex, and disease duration, higher T1LV predicted a lower chance of employment (p < 0.05). Pearson correlations showed that EDSS was associated with activity impairment (p < 0.05). Disease duration, age, and MRI measures were not correlated with activity impairment or other WPAI outcomes (p > 0.05). We report a link between brain atrophy and lesions, particularly lesions with destructive potential, to MS employment status.

An architecture for a brain-image database

NASA Technical Reports Server (NTRS)

Herskovits, E. H.

2000-01-01

The widespread availability of methods for noninvasive assessment of brain structure has enabled researchers to investigate neuroimaging correlates of normal aging, cerebrovascular disease, and other processes; we designate such studies as image-based clinical trials (IBCTs). We propose an architecture for a brain-image database, which integrates image processing and statistical operators, and thus supports the implementation and analysis of IBCTs. The implementation of this architecture is described and results from the analysis of image and clinical data from two IBCTs are presented. We expect that systems such as this will play a central role in the management and analysis of complex research data sets.

Quantitative Susceptibility Mapping by Inversion of a Perturbation Field Model: Correlation with Brain Iron in Normal Aging

PubMed Central

Poynton, Clare; Jenkinson, Mark; Adalsteinsson, Elfar; Sullivan, Edith V.; Pfefferbaum, Adolf; Wells, William

2015-01-01

There is increasing evidence that iron deposition occurs in specific regions of the brain in normal aging and neurodegenerative disorders such as Parkinson's, Huntington's, and Alzheimer's disease. Iron deposition changes the magnetic susceptibility of tissue, which alters the MR signal phase, and allows estimation of susceptibility differences using quantitative susceptibility mapping (QSM). We present a method for quantifying susceptibility by inversion of a perturbation model, or ‘QSIP’. The perturbation model relates phase to susceptibility using a kernel calculated in the spatial domain, in contrast to previous Fourier-based techniques. A tissue/air susceptibility atlas is used to estimate B0 inhomogeneity. QSIP estimates in young and elderly subjects are compared to postmortem iron estimates, maps of the Field-Dependent Relaxation Rate Increase (FDRI), and the L1-QSM method. Results for both groups showed excellent agreement with published postmortem data and in-vivo FDRI: statistically significant Spearman correlations ranging from Rho = 0.905 to Rho = 1.00 were obtained. QSIP also showed improvement over FDRI and L1-QSM: reduced variance in susceptibility estimates and statistically significant group differences were detected in striatal and brainstem nuclei, consistent with age-dependent iron accumulation in these regions. PMID:25248179

Patterns of brain activity during a semantic task differentiate normal aging from early Alzheimer's disease.

PubMed

McGeown, William Jonathan; Shanks, Michael Fraser; Forbes-McKay, Katrina Elaine; Venneri, Annalena

2009-09-30

In a study of the effects of normal and pathological aging on semantic-related brain activity, 29 patients with Alzheimer's disease (AD) and 19 controls subjects (10 young and 9 older controls) performed a version of the Pyramids and Palm Trees Test that had been adapted for use during functional magnetic resonance imaging (fMRI). Young and older controls activated the left inferior and middle frontal gyri, precuneus and superior parietal lobule. Right frontal and left temporal cortices were activated only in the young. The AD group activated only the left prefrontal and cingulate cortex. Separate analyses of high- and low-performing AD subgroups showed a similar pattern of activation in the left frontal lobe, although activiation was more widespread in low performers. High performers significantly deactivated anterior midline frontal structures, however, while low performers did not. When the older adult and AD groups were combined, there was a significant positive correlation between left frontal and parietal activation and Mini-Mental State Examination (MMSE) score (covarying for age), suggesting a disease effect. A significant negative correlation between activation in the left temporal cortex and age (covarying for MMSE score) reflected a possible age effect. These differential effects suggest that semantic activation paradigms might aid diagnosis in those cases for whom conventional assessments lack the necessary sensitivity to detect subtle changes.

Cross-sectional and longitudinal relationships between cerebrospinal fluid biomarkers and cognitive function in people without cognitive impairment from across the adult life span.

PubMed

Li, Ge; Millard, Steven P; Peskind, Elaine R; Zhang, Jing; Yu, Chang-En; Leverenz, James B; Mayer, Cynthia; Shofer, Jane S; Raskind, Murray A; Quinn, Joseph F; Galasko, Douglas R; Montine, Thomas J

2014-06-01

Age-related cognitive decline among older individuals with normal cognition is a complex trait that potentially derives from processes of aging, inherited vulnerabilities, environmental factors, and common latent diseases that can progress to cause dementia, such as Alzheimer disease and vascular brain injury. To use cerebrospinal fluid (CSF) biomarkers to gain insight into this complex trait. Secondary analyses of an academic multicenter cross-sectional (n = 315) and longitudinal (n = 158) study of 5 neuropsychological tests (Immediate Recall, Delayed Recall, Trail Making Test Parts A and B, and Category Fluency) in cognitively normal individuals aged 21 to 100 years. To investigate the association of these cognitive function test results with age, sex, educational level, inheritance of the ε4 allele of the apolipoprotein E gene, and CSF concentrations of β-amyloid 42 (Aβ42) and tau (biomarkers of Alzheimer disease) as well as F2-isoprostanes (measures of free radical injury). Age and educational level were broadly predictive of cross-sectional cognitive performance; of the genetic and CSF measures, only greater CSF F2-isoprostane concentration was significantly associated with poorer executive function (adjusted R2 ≤0.31). Longitudinal measures of cognitive abilities, except Category Fluency, also were associated broadly with age; of the genetic and CSF measures, only lower baseline CSF Aβ42 concentration was associated with longitudinal measures of immediate and delayed recall (marginal R2 ≤0.31). Our results suggest that age and educational level accounted for a substantial minority of variance in cross-sectional or longitudinal cognitive test performance in this large group of cognitively normal adults. Latent Alzheimer disease and other diseases that produce free radical injury, such as vascular brain injury, accounted for a small amount of variation in cognitive test performance across the adult human life span. Additional genetic and environmental factors likely contribute substantially to age-related cognitive decline.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lowe, Xiu R; Bhattacharya, Sanchita; Marchetti, Francesco

Understanding the cognitive and behavioral consequences of brain exposures to low-dose ionizing radiation has broad relevance for health risks from medical radiation diagnostic procedures, radiotherapy, environmental nuclear contamination, as well as earth orbit and space missions. Analyses of transcriptome profiles of murine brain tissue after whole-body radiation showed that low-dose exposures (10 cGy) induced genes not affected by high dose (2 Gy), and low-dose genes were associated with unique pathways and functions. The low-dose response had two major components: pathways that are consistently seen across tissues, and pathways that were brain tissue specific. Low-dose genes clustered into a saturated networkmore » (p < 10{sup -53}) containing mostly down-regulated genes involving ion channels, long-term potentiation and depression, vascular damage, etc. We identified 9 neural signaling pathways that showed a high degree of concordance in their transcriptional response in mouse brain tissue after low-dose radiation, in the aging human brain (unirradiated), and in brain tissue from patients with Alzheimer's disease. Mice exposed to high-dose radiation did not show these effects and associations. Our findings indicate that the molecular response of the mouse brain within a few hours after low-dose irradiation involves the down-regulation of neural pathways associated with cognitive dysfunctions that are also down regulated in normal human aging and Alzheimer's disease.« less

Longitudinal atlas for normative human brain development and aging over the lifespan using quantitative susceptibility mapping.

PubMed

Zhang, Yuyao; Wei, Hongjiang; Cronin, Matthew J; He, Naying; Yan, Fuhua; Liu, Chunlei

2018-05-01

Longitudinal brain atlases play an important role in the study of human brain development and cognition. Existing atlases are mainly based on anatomical features derived from T1-and T2-weighted MRI. A 4D developmental quantitative susceptibility mapping (QSM) atlas may facilitate the estimation of age-related iron changes in deep gray matter nuclei and myelin changes in white matter. To this end, group-wise co-registered QSM templates were generated over various age intervals from age 1-83 years old. Registration was achieved by combining both T1-weighted and QSM images. Based on the proposed template, we created an accurate deep gray matter nuclei parcellation map (DGM map). Notably, we segmented thalamus into 5 sub-regions, i.e. the anterior nuclei, the median nuclei, the lateral nuclei, the pulvinar and the internal medullary lamina. Furthermore, we built a "whole brain QSM parcellation map" by combining existing cortical parcellation and white-matter atlases with the proposed DGM map. Based on the proposed QSM atlas, the segmentation accuracy of iron-rich nuclei using QSM is significantly improved, especially for children and adolescent subjects. The age-related progression of magnetic susceptibility in each of the deep gray matter nuclei, the hippocampus, and the amygdala was estimated. Our automated atlas-based analysis provided a systematic confirmation of previous findings on susceptibility progression with age resulting from manual ROI drawings in deep gray matter nuclei. The susceptibility development in the hippocampus and the amygdala follow an iron accumulation model; while in the thalamus sub-regions, the susceptibility development exhibits a variety of trends. It is envisioned that the newly developed 4D QSM atlas will serve as a template for studying brain iron deposition and myelination/demyelination in both normal aging and various brain diseases. Copyright © 2018 Elsevier Inc. All rights reserved.

Individual Patient Diagnosis of AD and FTD via High-Dimensional Pattern Classification of MRI

PubMed Central

Davatzikos, C.; Resnick, S. M.; Wu, X.; Parmpi, P.; Clark, C. M.

2008-01-01

The purpose of this study is to determine the diagnostic accuracy of MRI-based high-dimensional pattern classification in differentiating between patients with Alzheimer’s Disease (AD), Frontotemporal Dementia (FTD), and healthy controls, on an individual patient basis. MRI scans of 37 patients with AD and 37 age-matched cognitively normal elderly individuals, as well as 12 patients with FTD and 12 age-matched cognitively normal elderly individuals, were analyzed using voxel-based analysis and high-dimensional pattern classification. Diagnostic sensitivity and specificity of spatial patterns of regional brain atrophy found to be characteristic of AD and FTD were determined via cross-validation and via split-sample methods. Complex spatial patterns of relatively reduced brain volumes were identified, including temporal, orbitofrontal, parietal and cingulate regions, which were predominantly characteristic of either AD or FTD. These patterns provided 100% diagnostic accuracy, when used to separate AD or FTD from healthy controls. The ability to correctly distinguish AD from FTD averaged 84.3%. All estimates of diagnostic accuracy were determined via cross-validation. In conclusion, AD- and FTD-specific patterns of brain atrophy can be detected with high accuracy using high-dimensional pattern classification of MRI scans obtained in a typical clinical setting. PMID:18474436

Oxidative Glial Cell Damage Associated with White Matter Lesions in the Aging Human Brain

PubMed Central

Al-Mashhadi, Sufana; Simpson, Julie E.; Heath, Paul R.; Dickman, Mark; Forster, Gillian; Matthews, Fiona E.; Brayne, Carol; Ince, Paul G.; Wharton, Stephen B.

2016-01-01

White matter lesions (WML) are common in brain aging and are associated with dementia. We aimed to investigate whether oxidative DNA damage and occur in WML and in apparently normal white matter in cases with lesions. Tissue from WML and control white matter from brains with lesions (controls lesional) and without lesions (controls non-lesional) were obtained, using post-mortem magnetic resonance imaging-guided sampling, from the Medical Research Council Cognitive Function and Ageing Study. Oxidative damage was assessed by immunohistochemistry to 8-hydroxy-2′-deoxoguanosine (8-OHdG) and Western blotting for malondialdehyde. DNA response was assessed by phosphorylated histone H2AX (γH2AX), p53, senescence markers and by quantitative Reverse transcription polymerase chain reaction (RT-PCR) panel for candidate DNA damage-associated genes. 8-OHdG was expressed in glia and endothelium, with increased expression in both WML and controls lesional compared with controls non-lesional (P < 0.001). γH2Ax showed a similar, although attenuated difference among groups (P = 0.03). Expression of senescence-associated β-galactosidase and p16 suggested induction of senescence mechanisms in glia. Oxidative DNA damage and a DNA damage response are features of WML pathogenesis and suggest candidate mechanisms for glial dysfunction. Their expression in apparently normal white matter in cases with WML suggests that white matter dysfunction is not restricted to lesions. The role of this field-effect lesion pathogenesis and cognitive impairment are areas to be defined. PMID:25311358

Corpus Callosum Morphology in Children Who Stutter

ERIC Educational Resources Information Center

Choo, Ai Leen; Chang, Soo-Eun; Zengin-Bolatkale, Hatun; Ambrose, Nicoline G.; Loucks, Torrey M.

2012-01-01

Multiple studies have reported both functional and neuroanatomical differences between adults who stutter and their normally fluent peers. However, the reasons for these differences remain unclear although some developmental data suggest that structural brain differences may be present in school-age children who stutter. In the present study, the…

Delayed White Matter Growth Trajectory in Young Nonpsychotic Siblings of Patients With Childhood-Onset Schizophrenia

PubMed Central

Gogtay, Nitin; Hua, Xue; Stidd, Reva; Boyle, Christina P.; Lee, Suh; Weisinger, Brian; Chavez, Alex; Giedd, Jay N.; Clasen, Liv; Toga, Arthur W.; Rapoport, Judith L.; Thompson, Paul M.

2013-01-01

Context Nonpsychotic siblings of patients with childhood-onset schizophrenia (COS) share cortical gray matter abnormalities with their probands at an early age; these normalize by the time the siblings are aged 18 years, suggesting that the gray matter abnormalities in schizophrenia could be an age-specific endophenotype. Patients with COS also show significant white matter (WM) growth deficits, which have not yet been explored in nonpsychotic siblings. Objective To study WM growth differences in non-psychotic siblings of patients with COS. Design Longitudinal (5-year) anatomic magnetic resonance imaging study mapping WM growth using a novel tensor-based morphometry analysis. Setting National Institutes of Health Clinical Center, Bethesda, Maryland. Participants Forty-nine healthy siblings of patients with COS (mean [SD] age, 16.1[5.3] years; 19 male, 30 female) and 57 healthy persons serving as controls (age, 16.9[5.3] years; 29 male, 28 female). Intervention Magnetic resonance imaging. Main Outcome Measure White matter growth rates. Results We compared the WM growth rates in 3 age ranges. In the youngest age group (7 to <14 years), we found a significant difference in growth rates, with siblings of patients with COS showing slower WM growth rates in the parietal lobes of the brain than age-matched healthy controls (false discovery rate, q = 0.05; critical P = .001 in the bilateral parietal WM; a post hoc analysis identified growth rate differences only on the left side, critical P =.004). A growth rate difference was not detectable at older ages. In 3-dimensional maps, growth rates in the siblings even appeared to surpass those of healthy individuals at later ages, at least locally in the brain, but this effect did not survive a multiple comparisons correction. Conclusions In this first longitudinal study of nonpsychotic siblings of patients with COS, the siblings showed early WM growth deficits, which normalized with age. As reported before for gray matter, WM growth may also be an age-specific endophenotype that shows compensatory normalization with age. PMID:22945617

Disconnected aging: cerebral white matter integrity and age-related differences in cognition.

PubMed

Bennett, I J; Madden, D J

2014-09-12

Cognition arises as a result of coordinated processing among distributed brain regions and disruptions to communication within these neural networks can result in cognitive dysfunction. Cortical disconnection may thus contribute to the declines in some aspects of cognitive functioning observed in healthy aging. Diffusion tensor imaging (DTI) is ideally suited for the study of cortical disconnection as it provides indices of structural integrity within interconnected neural networks. The current review summarizes results of previous DTI aging research with the aim of identifying consistent patterns of age-related differences in white matter integrity, and of relationships between measures of white matter integrity and behavioral performance as a function of adult age. We outline a number of future directions that will broaden our current understanding of these brain-behavior relationships in aging. Specifically, future research should aim to (1) investigate multiple models of age-brain-behavior relationships; (2) determine the tract-specificity versus global effect of aging on white matter integrity; (3) assess the relative contribution of normal variation in white matter integrity versus white matter lesions to age-related differences in cognition; (4) improve the definition of specific aspects of cognitive functioning related to age-related differences in white matter integrity using information processing tasks; and (5) combine multiple imaging modalities (e.g., resting-state and task-related functional magnetic resonance imaging; fMRI) with DTI to clarify the role of cerebral white matter integrity in cognitive aging. Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.

Disconnected Aging: Cerebral White Matter Integrity and Age-Related Differences in Cognition

PubMed Central

Bennett, Ilana J.; Madden, David J.

2013-01-01

Cognition arises as a result of coordinated processing among distributed brain regions and disruptions to communication within these neural networks can result in cognitive dysfunction. Cortical disconnection may thus contribute to the declines in some aspects of cognitive functioning observed in healthy aging. Diffusion tensor imaging (DTI) is ideally suited for the study of cortical disconnection as it provides indices of structural integrity within interconnected neural networks. The current review summarizes results of previous DTI aging research with the aim of identifying consistent patterns of age-related differences in white matter integrity, and of relationships between measures of white matter integrity and behavioral performance as a function of adult age. We outline a number of future directions that will broaden our current understanding of these brain-behavior relationships in aging. Specifically, future research should aim to (1) investigate multiple models of age-brain-behavior relationships; (2) determine the tract-specificity versus global effect of aging on white matter integrity; (3) assess the relative contribution of normal variation in white matter integrity versus white matter lesions to age-related differences in cognition; (4) improve the definition of specific aspects of cognitive functioning related to age-related differences in white matter integrity using information processing tasks; and (5) combine multiple imaging modalities (e.g., resting-state and task-related functional magnetic resonance imaging; fMRI) with DTI to clarify the role of cerebral white matter integrity in cognitive aging. PMID:24280637

Higher serum glucose levels are associated with cerebral hypometabolism in Alzheimer regions.

PubMed

Burns, Christine M; Chen, Kewei; Kaszniak, Alfred W; Lee, Wendy; Alexander, Gene E; Bandy, Daniel; Fleisher, Adam S; Caselli, Richard J; Reiman, Eric M

2013-04-23

To investigate whether higher fasting serum glucose levels in cognitively normal, nondiabetic adults were associated with lower regional cerebral metabolic rate for glucose (rCMRgl) in brain regions preferentially affected by Alzheimer disease (AD). This is a cross-sectional study of 124 cognitively normal persons aged 64 ± 6 years with a first-degree family history of AD, including 61 APOEε4 noncarriers and 63 carriers. An automated brain mapping algorithm characterized and compared correlations between higher fasting serum glucose levels and lower [(18)F]-fluorodeoxyglucose-PET rCMRgl measurements. As predicted, higher fasting serum glucose levels were significantly correlated with lower rCMRgl and were confined to the vicinity of brain regions preferentially affected by AD. A similar pattern of regional correlations occurred in the APOEε4 noncarriers and carriers. Higher fasting serum glucose levels in cognitively normal, nondiabetic adults may be associated with AD pathophysiology. Findings suggest that the risk imparted by higher serum glucose levels may be independent of APOEε4 status. This study raises additional questions about the role of the metabolic process in the predisposition to AD and supports the possibility of targeting these processes in presymptomatic AD trials.

Posterior Cingulate Glucose Metabolism, Hippocampal Glucose Metabolism, and Hippocampal Volume in Cognitively Normal, Late-Middle-Aged Persons at 3 Levels of Genetic Risk for Alzheimer Disease

PubMed Central

Protas, Hillary D.; Chen, Kewei; Langbaum, Jessica B. S.; Fleisher, Adam S.; Alexander, Gene E.; Lee, Wendy; Bandy, Daniel; de Leon, Mony J.; Mosconi, Lisa; Buckley, Shannon; Truran-Sacrey, Diana; Schuff, Norbert; Weiner, Michael W.; Caselli, Richard J.; Reiman, Eric M.

2013-01-01

Objective To characterize and compare measurements of the posterior cingulate glucose metabolism, the hippocampal glucose metabolism, and hippocampal volume so as to distinguish cognitively normal, late-middle-aged persons with 2, 1, or 0 copies of the apolipoprotein E (APOE) ε4 allele, reflecting 3 levels of risk for late-onset Alzheimer disease. Design Cross-sectional comparison of measurements of cerebral glucose metabolism using 18F-fluorodeoxy-glucose positron emission tomography and measurements of brain volume using magnetic resonance imaging in cognitively normal ε4 homozygotes, ε4 heterozygotes, and noncarriers. Setting Academic medical center. Participants A total of 31 ε4 homozygotes, 42 ε4 heterozygotes, and 76 noncarriers, 49 to 67 years old, matched for sex, age, and educational level. Main Outcome Measures The measurements of posterior cingulate and hippocampal glucose metabolism were characterized using automated region-of-interest algorithms and normalized for whole-brain measurements. The hippocampal volume measurements were characterized using a semiautomated algorithm and normalized for total intracranial volume. Results Although there were no significant differences among the 3 groups of participants in their clinical ratings, neuropsychological test scores, hippocampal volumes (P=.60), or hippocampal glucose metabolism measurements (P = .12), there were significant group differences in their posterior cingulate glucose metabolism measurements (P=.001). The APOE ε4 gene dose was significantly associated with posterior cingulate glucose metabolism (r=0.29, P=.0003), and this association was significantly greater than those with hippocampal volume or hippocampal glucose metabolism (P<.05, determined by use of pairwise Fisher z tests). Conclusions Although our findings may depend in part on the analysis algorithms used, they suggest that a reduction in posterior cingulate glucose metabolism precedes a reduction in hippocampal volume or metabolism in cognitively normal persons at increased genetic risk for Alzheimer disease. PMID:23599929

Use of near-infrared spectroscopy in the investigation of brain activation during cognitive aging: A systematic review of an emerging area of research.

PubMed

Agbangla, Nounagnon F; Audiffren, Michel; Albinet, Cédric T

2017-09-01

The cognitive neuroscience of aging is a growing and stimulating research area. The development of neuroimaging techniques in the past two decades has considerably increased our understanding of the brain mechanisms that might underlie cognitive performance and resulting changes due to normal aging. Beside traditional metabolic neuroimaging techniques, such as Positron Emission Tomography and functional Magnetic Resonance Imaging, near infrared spectroscopy (NIRS), an optical imaging technique allowing to monitor real-time cerebral blood oxygenation, has gained recent interest in this field. The aim of the present review paper, after briefly presenting the NIRS technique, is to review and to summarize the recent results of neuroimaging studies using this technique in the field of cognitive aging. The reviewed literature shows that, despite low spatial resolution and cerebral depth penetration, this technique provides consistent findings on the reduced hemodynamic activity as a function of chronological age, mainly in the prefrontal cortex. Important moderators of brain hemodynamics, such as cognitive load, subjects' characteristics and experimental conditions, for which the NIRS technique is sensitive, are discussed. Strengths and weaknesses of functional NIRS in the field of cognitive aging are presented and finally, novel perspectives of research are proposed. Copyright © 2017 Elsevier B.V. All rights reserved.

Application of machine learning methods to describe the effects of conjugated equine estrogens therapy on region-specific brain volumes.

PubMed

Casanova, Ramon; Espeland, Mark A; Goveas, Joseph S; Davatzikos, Christos; Gaussoin, Sarah A; Maldjian, Joseph A; Brunner, Robert L; Kuller, Lewis H; Johnson, Karen C; Mysiw, W Jerry; Wagner, Benjamin; Resnick, Susan M

2011-05-01

Use of conjugated equine estrogens (CEE) has been linked to smaller regional brain volumes in women aged ≥65 years; however, it is unknown whether this results in a broad-based characteristic pattern of effects. Structural magnetic resonance imaging was used to assess regional volumes of normal tissue and ischemic lesions among 513 women who had been enrolled in a randomized clinical trial of CEE therapy for an average of 6.6 years, beginning at ages 65-80 years. A multivariate pattern analysis, based on a machine learning technique that combined Random Forest and logistic regression with L(1) penalty, was applied to identify patterns among regional volumes associated with therapy and whether patterns discriminate between treatment groups. The multivariate pattern analysis detected smaller regional volumes of normal tissue within the limbic and temporal lobes among women that had been assigned to CEE therapy. Mean decrements ranged as high as 7% in the left entorhinal cortex and 5% in the left perirhinal cortex, which exceeded the effect sizes reported previously in frontal lobe and hippocampus. Overall accuracy of classification based on these patterns, however, was projected to be only 54.5%. Prescription of CEE therapy for an average of 6.6 years is associated with lower regional brain volumes, but it does not induce a characteristic spatial pattern of changes in brain volumes of sufficient magnitude to discriminate users and nonusers. Copyright © 2011 Elsevier Inc. All rights reserved.

Application of machine learning methods to describe the effects of conjugated equine estrogens therapy on region-specific brain volumes

PubMed Central

Casanova, Ramon; Espeland, Mark A.; Goveas, Joseph S.; Davatzikos, Christos; Gaussoin, Sarah A.; Maldjian, Joseph A.; Brunner, Robert L.; Kuller, Lewis H.; Johnson, Karen C.; Mysiw, W. Jerry; Wagner, Benjamin; Resnick, Susan M.

2011-01-01

Use of conjugated equine estrogens (CEE) has been linked to smaller regional brain volumes in women aged ≥65 years, however it is unknown whether this results in a broad-based characteristic pattern of effects. Structural MRI was used to assess regional volumes of normal tissue and ischemic lesions among 513 women who had been enrolled in a randomized clinical trial of CEE therapy for an average of 6.6 years, beginning at ages 65-80 years. A multivariate pattern analysis, based on a machine learning technique that combined Random Forest and logistic regression with L1 penalty, was applied to identify patterns among regional volumes associated with therapy and whether patterns discriminate between treatment groups. The multivariate pattern analysis detected smaller regional volumes of normal tissue within the limbic and temporal lobes among women that had been assigned to CEE therapy. Mean decrements ranged as high as 7% in the left entorhinal cortex and 5% in the left perirhinal cortex, which exceeded the effect sizes reported previously in frontal lobe and hippocampus. Overall accuracy of classification based on these patterns, however, was projected to be only 54.5%. Prescription of CEE therapy for an average of 6.6 years is associated with lower regional brain volumes, but it does not induce a characteristic spatial pattern of changes in brain volumes of sufficient magnitude to discriminate users and non-users. PMID:21292420

Compensatory brain activation in children with attention deficit/hyperactivity disorder during a simplified Go/No-go task.

PubMed

Ma, Jun; Lei, Du; Jin, Xingming; Du, Xiaoxia; Jiang, Fan; Li, Fei; Zhang, Yiwen; Shen, Xiaoming

2012-05-01

Given that a number of recent studies have shown attenuated brain activation in prefrontal regions in children with ADHD, it has been recognized as a disorder in executive function. However, fewer studies have focused exclusively on the compensatory brain activation in ADHD. The present study objective was to investigate the compensatory brain activation patterns during response inhibition (RI) processing in ADHD children. In this study, 15 ADHD children and 15 sex-, age-, and IQ-matched control children were scanned with a 3-T MRI equipment while performing a simplified letter Go/No-go task. The results showed more brain activation in the ADHD group compared with the control group, whereas the accuracy and reaction time of behavioral performance were the same. Children with ADHD did not activate the normal RI brain circuits, which are thought to be predominantly located in the right middle/inferior frontal gyrus (BA46/44), right inferior parietal regions (BA40), and pre-SMA(BA6), but instead, activated brain regions, such as the left inferior frontal cortex, the right inferior temporal cortex, the right precentral gyrus, the left postcentral gyrus, the inferior occipital cortex, the middle occipital cortex, the right calcarine, the right hippocampus, the right midbrain, and the cerebellum. Our conclusion is that children with ADHD tend to compensatorily use more posterior and diffusive brain regions to sustain normal RI function. © Springer-Verlag 2011

Brain behavior relationships among African Americans, whites, and Hispanics.

PubMed

DeCarli, Charles; Reed, Bruce R; Jagust, William; Martinez, Oliver; Ortega, Mario; Mungas, Dan

2008-01-01

There is an increasing racial and ethnic diversity within the elderly population of the United States. Although increased diversity offers unique opportunities to study novel influences on aging and dementia, some aspects of racial and ethnic research have been hampered by the lack of culturally and linguistically consistent testing protocols. Structural brain imaging is commonly used to study the biology of normal aging and cognitive impairment and may therefore serve to explore potential biologic differences of cognitive impairment among racially and ethnically diverse individuals. To test this hypothesis, we recruited a cohort of approximately 400 African American, white, and Hispanic subjects with various degrees of cognitive ability. Each subject was carefully evaluated using standardized diagnostic protocols that included clinical review of brain magnetic resonance image (MRI) to arrive at a clinical diagnosis of normal cognition, mild cognitive impairment or dementia. Each MRI was then independently quantified for measures of brain, white matter hyperintensities, and hippocampal volumes by a technician blind to subject age, sex, ethnicity, race, and diagnostic category. The appearance of infarction on MRI was also rated by examining neurologists. Regression analyses were used to assess associations with various MRI measures across clinical diagnostic categories in relation to racial and ethnic differences. Hispanic subjects were, on average, significantly younger and had less years of education than African Americans or whites. Whites with dementia were significantly older than both African American and Hispanic dementia patients. Highly significant differences in MRI measures were associated with clinical diagnoses for the group as a whole after adjusting for the effects of age, sex, education, race, and ethnicity. Subsequent independent analyses by racial and ethnic status revealed consistent relationships between diagnostic category and MRI measures. Clinical diagnoses were associated with consistent differences in brain structure among a group of racially and ethnically diverse individuals. We believe these results help to validate current diagnostic assessment of individuals across a broad range of racial, ethnic, linguistic, and educational backgrounds. Moreover, interesting and potentially biologically relevant differences were found that might stimulate further research related to the understanding of dementia etiology within an increasingly racially and ethnically diverse population.

Amplitude-integrated EEG in newborns with critical congenital heart disease predicts preoperative brain magnetic resonance imaging findings.

PubMed

Mulkey, Sarah B; Yap, Vivien L; Bai, Shasha; Ramakrishnaiah, Raghu H; Glasier, Charles M; Bornemeier, Renee A; Schmitz, Michael L; Bhutta, Adnan T

2015-06-01

The study aims are to evaluate cerebral background patterns using amplitude-integrated electroencephalography in newborns with critical congenital heart disease, determine if amplitude-integrated electroencephalography is predictive of preoperative brain injury, and assess the incidence of preoperative seizures. We hypothesize that amplitude-integrated electroencephalography will show abnormal background patterns in the early preoperative period in infants with congenital heart disease that have preoperative brain injury on magnetic resonance imaging. Twenty-four newborns with congenital heart disease requiring surgery at younger than 30 days of age were prospectively enrolled within the first 3 days of age at a tertiary care pediatric hospital. Infants had amplitude-integrated electroencephalography for 24 hours beginning close to birth and preoperative brain magnetic resonance imaging. The amplitude-integrated electroencephalographies were read to determine if the background pattern was normal, mildly abnormal, or severely abnormal. The presence of seizures and sleep-wake cycling were noted. The preoperative brain magnetic resonance imaging scans were used for brain injury and brain atrophy assessment. Fifteen of 24 infants had abnormal amplitude-integrated electroencephalography at 0.71 (0-2) (mean [range]) days of age. In five infants, the background pattern was severely abnormal. (burst suppression and/or continuous low voltage). Of the 15 infants with abnormal amplitude-integrated electroencephalography, 9 (60%) had brain injury. One infant with brain injury had a seizure on amplitude-integrated electroencephalography. A severely abnormal background pattern on amplitude-integrated electroencephalography was associated with brain atrophy (P = 0.03) and absent sleep-wake cycling (P = 0.022). Background cerebral activity is abnormal on amplitude-integrated electroencephalography following birth in newborns with congenital heart disease who have findings of brain injury and/or brain atrophy on preoperative brain magnetic resonance imaging. Copyright © 2015 Elsevier Inc. All rights reserved.

Maternal high-fat feeding leads to alterations of brain glucose metabolism in the offspring: positron emission tomography study in a porcine model.

PubMed

Sanguinetti, Elena; Liistro, Tiziana; Mainardi, Marco; Pardini, Silvia; Salvadori, Piero A; Vannucci, Alessandro; Burchielli, Silvia; Iozzo, Patricia

2016-04-01

Maternal obesity negatively affects fetal development. Abnormalities in brain glucose metabolism are predictive of metabolic-cognitive disorders. We studied the offspring (aged 0, 1, 6, 12 months) of minipigs fed a normal vs high-fat diet (HFD), by positron emission tomography (PET) to measure brain glucose metabolism, and ex vivo assessments of brain insulin receptors (IRβ) and GLUT4. At birth, brain glucose metabolism and IRβ were twice as high in the offspring of HFD-fed than control mothers. During infancy and youth, brain glucose uptake, GLUT4 and IRβ increased in the offspring of control mothers and decreased in those of HFD-fed mothers, leading to a 40-85% difference (p < 0.05), and severe glycogen depletion, lasting until adulthood. Maternal high-fat feeding leads to brain glucose overexposure during fetal development, followed by long-lasting depression in brain glucose metabolism in minipigs. These features may predispose the offspring to develop metabolic-neurodegenerative diseases.

Lenticular nucleus hyperechogenicity in Wilson's disease reflects local copper, but not iron accumulation.

PubMed

Walter, Uwe; Skowrońska, Marta; Litwin, Tomasz; Szpak, Grażyna Maria; Jabłonka-Salach, Katarzyna; Skoloudík, David; Bulska, Ewa; Członkowska, Anna

2014-10-01

In patients with Wilson's disease (WD) transcranial brain sonography typically reveals areas of increased echogenicity (hyperechogenicity) of the lenticular nucleus (LN). Correlation with T2-hypointensity on magnetic resonance images suggested that LN hyperechogenicity in WD is caused by trace metal accumulation. Accumulation of both, copper and iron, in the brain of WD patients has been reported. The present study was designed to elucidate whether LN hyperechogenicity in WD reflects accumulation of copper or iron. Post-mortem brains of 15 WD patients and one non-WD subject were studied with ultrasonography in an investigator-blinded fashion. LN hyperechogenicity was measured planimetrically by manual tracing as well as using digitized image analysis. The putaminal copper content was determined in samples of 11 WD brains and the non-WD brains using inductively coupled plasma mass spectrometry, and iron content was assessed using flame atomic absorption spectroscopy. LN was normal on ultrasonography only in the non-WD brain, but abnormal (hyperechogenic) in all WD brains. Digitized image analysis measures of LN hyperechogenicity and, by trend, manual measures correlated with putaminal copper content (Pearson test; digitized: r = 0.77, p = 0.04; manual: r = 0.57, p = 0.051) but not with iron content (each, p > 0.18). LN hyperechogenicity measures were unrelated to age at death of patients, age at onset of WD, WD duration, age of brain specimen, serum copper or serum ceruloplasmin (each, p > 0.1). We conclude that LN hyperechogenicity in WD reflects copper, but not iron accumulation. Further studies are warranted to elucidate the use of transcranial brain sonography for monitoring therapeutic effects of chelating agents in WD patients.

Dissociation between iron accumulation and ferritin upregulation in the aged substantia nigra: attenuation by dietary restriction

PubMed Central

Walker, Thomas; Michaelides, Christos; Ekonomou, Antigoni; Geraki, Kalotina; Parkes, Harold G; Suessmilch, Maria; Herlihy, Amy H; Crum, William R; So, Po-Wah

2016-01-01

Despite regulation, brain iron increases with aging and may enhance aging processes including neuroinflammation. Increases in magnetic resonance imaging transverse relaxation rates, R2 and R2*, in the brain have been observed during aging. We show R2 and R2* correlate well with iron content via direct correlation to semi-quantitative synchrotron-based X-ray fluorescence iron mapping, with age-associated R2 and R2* increases reflecting iron accumulation. Iron accumulation was concomitant with increased ferritin immunoreactivity in basal ganglia regions except in the substantia nigra (SN). The unexpected dissociation of iron accumulation from ferritin-upregulation in the SN suggests iron dyshomeostasis in the SN. Occurring alongside microgliosis and astrogliosis, iron dyshomeotasis may contribute to the particular vulnerability of the SN. Dietary restriction (DR) has long been touted to ameliorate brain aging and we show DR attenuated agerelated in vivo R2 increases in the SN over ages 7 – 19 months, concomitant with normal iron-induction of ferritin expression and decreased microgliosis. Iron is known to induce microgliosis and conversely, microgliosis can induce iron accumulation, which of these may be the initial pathological aging event warrants further investigation. We suggest iron chelation therapies and anti-inflammatory treatments may be putative ‘antibrain aging’ therapies and combining these strategies may be synergistic. PMID:27743512

RNA sequencing reveals pronounced changes in the noncoding transcriptome of aging synaptosomes.

PubMed

Chen, Bei Jun; Ueberham, Uwe; Mills, James D; Kirazov, Ludmil; Kirazov, Evgeni; Knobloch, Mara; Bochmann, Jana; Jendrek, Renate; Takenaka, Konii; Bliim, Nicola; Arendt, Thomas; Janitz, Michael

2017-08-01

Normal aging is associated with impairments in cognitive functions. These alterations are caused by diminutive changes in the biology of synapses, and ineffective neurotransmission, rather than loss of neurons. Hitherto, only a few studies, exploring molecular mechanisms of healthy brain aging in higher vertebrates, utilized synaptosomal fractions to survey local changes in aging-related transcriptome dynamics. Here we present, for the first time, a comparative analysis of the synaptosomes transcriptome in the aging mouse brain using RNA sequencing. Our results show changes in the expression of genes contributing to biological pathways related to neurite guidance, synaptosomal physiology, and RNA splicing. More intriguingly, we also discovered alterations in the expression of thousands of novel, unannotated lincRNAs during aging. Further, detailed characterization of the cleavage and polyadenylation factor I subunit 1 (Clp1) mRNA and protein expression indicates its increased expression in neuronal processes of hippocampal stratum radiatum in aging mice. Together, our study uncovers a new layer of transcriptional regulation which is targeted by aging within the local environment of interconnecting neuronal cells. Copyright © 2017 Elsevier Inc. All rights reserved.

On aerobic exercise and behavioral and neural plasticity.

PubMed

Swain, Rodney A; Berggren, Kiersten L; Kerr, Abigail L; Patel, Ami; Peplinski, Caitlin; Sikorski, Angela M

2012-11-29

Aerobic exercise promotes rapid and profound alterations in the brain. Depending upon the pattern and duration of exercise, these changes in the brain may extend beyond traditional motor areas to regions and structures normally linked to learning, cognition, and emotion. Exercise-induced alterations may include changes in blood flow, hormone and growth factor release, receptor expression, angiogenesis, apoptosis, neurogenesis, and synaptogenesis. Together, we believe that these changes underlie elevations of mood and prompt the heightened behavioral plasticity commonly observed following adoption of a chronic exercise regimen. In the following paper, we will explore both the psychological and psychobiological literatures relating to exercise effects on brain in both human and non-human animals and will attempt to link plastic changes in these neural structures to modifications in learned behavior and emotional expression. In addition, we will explore the therapeutic potential of exercise given recent reports that aerobic exercise may serve as a neuroprotectant and can also slow cognitive decline during normal and pathological aging.

On Aerobic Exercise and Behavioral and Neural Plasticity

PubMed Central

Swain, Rodney A.; Berggren, Kiersten L.; Kerr, Abigail L.; Patel, Ami; Peplinski, Caitlin; Sikorski, Angela M.

2012-01-01

Aerobic exercise promotes rapid and profound alterations in the brain. Depending upon the pattern and duration of exercise, these changes in the brain may extend beyond traditional motor areas to regions and structures normally linked to learning, cognition, and emotion. Exercise-induced alterations may include changes in blood flow, hormone and growth factor release, receptor expression, angiogenesis, apoptosis, neurogenesis, and synaptogenesis. Together, we believe that these changes underlie elevations of mood and prompt the heightened behavioral plasticity commonly observed following adoption of a chronic exercise regimen. In the following paper, we will explore both the psychological and psychobiological literatures relating to exercise effects on brain in both human and non-human animals and will attempt to link plastic changes in these neural structures to modifications in learned behavior and emotional expression. In addition, we will explore the therapeutic potential of exercise given recent reports that aerobic exercise may serve as a neuroprotectant and can also slow cognitive decline during normal and pathological aging. PMID:24961267

[Electroencephalogram power development of cognitive function at age 7 to 12 years: a comparative study between attention deficit hyperactivity disorder and healthy children].

PubMed

Cheng, Q R; Shen, H J; Tu, W J; Zhang, Q F; Dong, X

2016-12-02

Objective: To compare brain electrical cognitive tasks and brain development between study about 7 to 12 years old attention deficit hyperactivity disorder (ADHD) and normal children. Method: Prospectic case-control study was used. A total of 110 children with ADHD (63 boys and 47 girls) and 116 normal children (66 boys and 50 girls), were enrolled in this study. The electroencephalogram (EEG) was recorded when attention tasks were conducted, the EEG power was extracted from the original data and comparatively analyzed the absolute power (θ, α, β spectrum) and relative power (θ/total, α/total, θ/α, θ/β). Result: (1) Absolute power: ADHD children θ absolute power was higher than that of normal children in Pz lead ((52±28) vs . (40±30)μV 2 , t =3.906, P <0.05), with statistical significance. (2) Relative power: θ/total, θ/α, θ/β in ADHD are higher than normal children(0.23±0.07 vs . 0.20±0.05, 1.35±0.76 vs . 1.00±0.56, 4.75±2.49 vs . 3.56±2.08, t =2.900 and 3.954 and 3.901, P =0.004 and 0.000 and 0.000), α/total in ADHD is lower (0.21±0.09 vs. 0.24±0.10, t =-2.517, P =0.013). (3) The comparative study of the development of EEG power θ/β between ADHD and normal children showed age-related correlation in both groups ( r =-0.378 and -0.398, P =0.000 for both). Conclusion: ADHD children's EEG power on slow spectrum was higher than that of the normal children, it was more significant in the parietal region than in frontal region. With the increase of age, the θ relative power in ADHD and normal children gradually declined, in the normal children it linearly related, but in ADHD there was no significant regularity. θ/β can be used as a sensitive index to assess ADHD children's cognitive function.

Cerebrospinal Fluid Biomarkers and Reserve Variables as Predictors of Future "Non-Cognitive" Outcomes of Alzheimer's Disease.

PubMed

Ingber, Adam P; Hassenstab, Jason; Fagan, Anne M; Benzinger, Tammie L S; Grant, Elizabeth A; Holtzman, David M; Morris, John C; Roe, Catherine M

2016-01-01

The influence of reserve variables and Alzheimer's disease (AD) biomarkers on cognitive test performance has been fairly well-characterized. However, less is known about the influence of these factors on "non-cognitive" outcomes, including functional abilities and mood. We examined whether cognitive and brain reserve variables mediate how AD biomarker levels in cognitively normal persons predict future changes in function, mood, and neuropsychiatric behavior. Non-cognitive outcomes were examined in 328 individuals 50 years and older enrolled in ongoing studies of aging and dementia at the Knight Alzheimer Disease Research Center (ADRC). All participants were cognitively normal at baseline (Clinical Dementia Rating [CDR] 0), completed cerebrospinal fluid (CSF) and structural neuroimaging studies within one year of baseline, and were followed for an average of 4.6 annual visits. Linear mixed effects models explored how cognitive reserve and brain reserve variables mediate the relationships between AD biomarker levels and changes in function, mood, and neuropsychiatric behavior in cognitively normal participants. Education levels did not have a significant effect on predicting non-cognitive decline. However, participants with smaller brain volumes exhibited the worst outcomes on measures of mood, functional abilities, and behavioral disturbance. This effect was most pronounced in individuals who also had abnormal CSF biomarkers. The findings suggest that brain reserve plays a stronger, or earlier, role than cognitive reserve in protecting against non-cognitive impairment in AD.

Cerebrovascular Smooth Muscle Actin Is Increased in Non-Demented Subjects with Frequent Senile Plaques at Autopsy: Implications for the Pathogenesis of Alzheimer Disease

PubMed Central

Hulette, Christine M.; Ervin, John F.; Edmonds, Yvette; Antoine, Samantha; Stewart, Nicolas; Szymanski, Mari H.; Hayden, Kathleen M; Pieper, Carl F.; Burke, James R.; Welsh-Bohmer, Kathleen A.

2009-01-01

We previously found that vascular smooth muscle actin (SMA) is reduced in the brains of patients with late stage Alzheimer disease (AD) compared to brains of non-demented, neuropathologically normal subjects. To assess the pathogenetic significance and disease specificity of this finding, we studied 3 additional patient groups: non-demented subjects without significant AD type pathology (“Normal”, n = 20); non-demented subjects with frequent senile plaques at autopsy (“Preclinical AD”, n = 20); and subjects with frontotemporal dementia, (“FTD”, n = 10). The groups were matched for gender and age with those previously reported; SMA immunohistochemistry and image analysis were performed as previously described. Surprisingly, SMA expression in arachnoid, cerebral cortex and white matter arterioles was greater in the Preclinical AD group than in the Normal and FTD groups. The plaques were not associated with amyloid angiopathy or other vascular disease in this group. SMA expression in the brains of the Normal group was intermediate between the Preclinical AD and FTD groups. All 3 groups exhibited much greater SMA expression than in our previous report. The presence of frequent plaques and increased arteriolar SMA expression in the brains of non-demented subjects suggest that increased SMA expression might represent a physiologic response to neurodegeneration that could prevent or delay overt expression dementia in AD. PMID:19287310

ERP C250 Shows the Elderly (Cognitively Normal, Alzheimer’s Disease) Store More Stimuli in Short-Term Memory than Young Adults Do

PubMed Central

Chapman, Robert M.; Gardner, Margaret N.; Mapstone, Mark; Klorman, Rafael; Porsteinsson, Anton P.; Dupree, Haley M.; Antonsdottir, Inga M.; Kamalyan, Lily

2016-01-01

Objective To determine how aging and dementia affect the brain’s initial storing of task-relevant and irrelevant information in short-term memory. Methods We used brain Event-Related Potentials (ERPs) to measure short-term memory storage (ERP component C250) in 36 Young Adults, 36 Normal Elderly, and 36 early-stage AD subjects. Participants performed the Number-Letter task, a cognitive paradigm requiring memory storage of a first relevant stimulus to compare it with a second stimulus. Results In Young Adults, C250 was more positive for the first task-relevant stimulus compared to all other stimuli. C250 in Normal Elderly and AD subjects was roughly the same to relevant and irrelevant stimuli in intratrial parts 1–3 but not 4. The AD group had lower C250 to relevant stimuli in part 1. Conclusions Both normal aging and dementia cause less differentiation of relevant from irrelevant information in initial storage. There was a large aging effect involving differences in the pattern of C250 responses of the Young Adult versus the Normal Elderly/AD groups. Also, a potential dementia effect was obtained. Significance C250 is a candidate tool for measuring short-term memory performance on a biological level, as well as a potential marker for memory changes due to normal aging and dementia. PMID:27178862

Functional connectivity with the retrosplenial cortex predicts cognitive aging in rats.

PubMed

Ash, Jessica A; Lu, Hanbing; Taxier, Lisa R; Long, Jeffrey M; Yang, Yihong; Stein, Elliot A; Rapp, Peter R

2016-10-25

Changes in the functional connectivity (FC) of large-scale brain networks are a prominent feature of brain aging, but defining their relationship to variability along the continuum of normal and pathological cognitive outcomes has proved challenging. Here we took advantage of a well-characterized rat model that displays substantial individual differences in hippocampal memory during aging, uncontaminated by slowly progressive, spontaneous neurodegenerative disease. By this approach, we aimed to interrogate the underlying neural network substrates that mediate aging as a uniquely permissive condition and the primary risk for neurodegeneration. Using resting state (rs) blood oxygenation level-dependent fMRI and a restrosplenial/posterior cingulate cortex seed, aged rats demonstrated a large-scale network that had a spatial distribution similar to the default mode network (DMN) in humans, consistent with earlier findings in younger animals. Between-group whole brain contrasts revealed that aged subjects with documented deficits in memory (aged impaired) displayed widespread reductions in cortical FC, prominently including many areas outside the DMN, relative to both young adults (Y) and aged rats with preserved memory (aged unimpaired, AU). Whereas functional connectivity was relatively preserved in AU rats, they exhibited a qualitatively distinct network signature, comprising the loss of an anticorrelated network observed in Y adults. Together the findings demonstrate that changes in rs-FC are specifically coupled to variability in the cognitive outcome of aging, and that successful neurocognitive aging is associated with adaptive remodeling, not simply the persistence of youthful network dynamics.

Differential Age-Related Changes in Structural Covariance Networks of Human Anterior and Posterior Hippocampus.

PubMed

Li, Xinwei; Li, Qiongling; Wang, Xuetong; Li, Deyu; Li, Shuyu

2018-01-01

The hippocampus plays an important role in memory function relying on information interaction between distributed brain areas. The hippocampus can be divided into the anterior and posterior sections with different structure and function along its long axis. The aim of this study is to investigate the effects of normal aging on the structural covariance of the anterior hippocampus (aHPC) and the posterior hippocampus (pHPC). In this study, 240 healthy subjects aged 18-89 years were selected and subdivided into young (18-23 years), middle-aged (30-58 years), and older (61-89 years) groups. The aHPC and pHPC was divided based on the location of uncal apex in the MNI space. Then, the structural covariance networks were constructed by examining their covariance in gray matter volumes with other brain regions. Finally, the influence of age on the structural covariance of these hippocampal sections was explored. We found that the aHPC and pHPC had different structural covariance patterns, but both of them were associated with the medial temporal lobe and insula. Moreover, both increased and decreased covariances were found with the aHPC but only increased covariance was found with the pHPC with age ( p < 0.05, family-wise error corrected). These decreased connections occurred within the default mode network, while the increased connectivity mainly occurred in other memory systems that differ from the hippocampus. This study reveals different age-related influence on the structural networks of the aHPC and pHPC, providing an essential insight into the mechanisms of the hippocampus in normal aging.

Normalizing motor-related brain activity: subthalamic nucleus stimulation in Parkinson disease.

PubMed

Grafton, S T; Turner, R S; Desmurget, M; Bakay, R; Delong, M; Vitek, J; Crutcher, M

2006-04-25

To test whether therapeutic unilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN) in patients with Parkinson disease (PD) leads to normalization in the pattern of brain activation during movement execution and control of movement extent. Six patients with PD were imaged off medication by PET during performance of a visually guided tracking task with the DBS voltage programmed for therapeutic (effective) or subtherapeutic (ineffective) stimulation. Data from patients with PD during ineffective stimulation were compared with a group of 13 age-matched control subjects to identify sites with abnormal patterns of activation. Conjunction analysis was used to identify those areas in patients with PD where activity normalized when they were treated with effective stimulation. For movement execution, effective DBS caused an increase of activation in the supplementary motor area (SMA), superior parietal cortex, and cerebellum toward a more normal pattern. At rest, effective stimulation reduced overactivity of SMA. Therapeutic stimulation also induced reductions of movement related "overactivity" compared with healthy subjects in prefrontal, temporal lobe, and basal ganglia circuits, consistent with the notion that many areas are recruited to compensate for ineffective motor initiation. Normalization of activity related to the control of movement extent was associated with reductions of activity in primary motor cortex, SMA, and basal ganglia. Effective subthalamic nucleus stimulation leads to task-specific modifications with appropriate recruitment of motor areas as well as widespread, nonspecific reductions of compensatory or competing cortical activity.

Age-related white matter integrity differences in oldest-old without dementia.

PubMed

Bennett, Ilana J; Greenia, Dana E; Maillard, Pauline; Sajjadi, S Ahmad; DeCarli, Charles; Corrada, Maria M; Kawas, Claudia H

2017-08-01

Aging is known to have deleterious effects on cerebral white matter, yet little is known about these white matter alterations in advanced age. In this study, 94 oldest-old adults without dementia (90-103 years) underwent diffusion tensor imaging to assess relationships between chronological age and multiple measures of integrity in 18 white matter regions across the brain. Results revealed significant age-related declines in integrity in regions previously identified as being sensitive to aging in younger-old adults (corpus callosum, fornix, cingulum, external capsule). For the corpus callosum, the effect of age on genu fractional anisotropy was significantly weaker than the relationship between age and splenium fractional anisotropy. Importantly, age-related declines in white matter integrity did not differ in cognitively normal and cognitively impaired not demented oldest-old, suggesting that they were not solely driven by cognitive dysfunction or preclinical dementia in this advanced age group. Instead, white matter in these regions appears to remain vulnerable to normal aging processes through the 10th decade of life. Copyright © 2017 Elsevier Inc. All rights reserved.

Neural correlates of lexical-semantic memory: A voxel-based morphometry study in mild AD, aMCI and normal aging

PubMed Central

Balthazar, Marcio L.F.; Yasuda, Clarissa L.; Lopes, Tátila M.; Pereira, Fabrício R.S.; Damasceno, Benito Pereira; Cendes, Fernando

2011-01-01

Neuroanatomical correlations of naming and lexical-semantic memory are not yet fully understood. The most influential approaches share the view that semantic representations reflect the manner in which information has been acquired through perception and action, and that each brain area processes different modalities of semantic representations. Despite these anatomical differences in semantic processing, generalization across different features that have similar semantic significance is one of the main characteristics of human cognition. Methods We evaluated the brain regions related to naming, and to the semantic generalization, of visually presented drawings of objects from the Boston Naming Test (BNT), which comprises different categories, such as animals, vegetables, tools, food, and furniture. In order to create a model of lesion method, a sample of 48 subjects presenting with a continuous decline both in cognitive functions, including naming skills, and in grey matter density (GMD) was compared to normal young adults with normal aging, amnestic mild cognitive impairment (aMCI) and mild Alzheimer’s disease (AD). Semantic errors on the BNT, as well as naming performance, were correlated with whole brain GMD as measured by voxel-based morphometry (VBM). Results The areas most strongly related to naming and to semantic errors were the medial temporal structures, thalami, superior and inferior temporal gyri, especially their anterior parts, as well as prefrontal cortices (inferior and superior frontal gyri). Conclusion The possible role of each of these areas in the lexical-semantic networks was discussed, along with their contribution to the models of semantic memory organization. PMID:29213726

Hypertonic Lactate to Improve Cerebral Perfusion and Glucose Availability After Acute Brain Injury.

PubMed

Carteron, Laurent; Solari, Daria; Patet, Camille; Quintard, Hervé; Miroz, John-Paul; Bloch, Jocelyne; Daniel, Roy T; Hirt, Lorenz; Eckert, Philippe; Magistretti, Pierre J; Oddo, Mauro

2018-06-19

Lactate promotes cerebral blood flow and is an efficient substrate for the brain, particularly at times of glucose shortage. Hypertonic lactate is neuroprotective after experimental brain injury; however, human data are limited. Prospective study (clinicaltrials.gov NCT01573507). Academic ICU. Twenty-three brain-injured subjects (13 traumatic brain injury/10 subarachnoid hemorrhage; median age, 59 yr [41-65 yr]; median Glasgow Coma Scale, 6 [3-7]). Three-hour IV infusion of hypertonic lactate (sodium lactate, 1,000 mmol/L; concentration, 30 µmol/kg/min) administered 39 hours (26-49 hr) from injury. We examined the effect of hypertonic lactate on cerebral perfusion (using transcranial Doppler) and brain energy metabolism (using cerebral microdialysis). The majority of subjects (13/23 = 57%) had reduced brain glucose availability (baseline pretreatment cerebral microdialysis glucose, < 1 mmol/L) despite normal baseline intracranial pressure (10 [7-15] mm Hg). Hypertonic lactate was associated with increased cerebral microdialysis lactate (+55% [31-80%]) that was paralleled by an increase in middle cerebral artery mean cerebral blood flow velocities (+36% [21-66%]) and a decrease in pulsatility index (-21% [13-26%]; all p < 0.001). Cerebral microdialysis glucose increased above normal range during hypertonic lactate (+42% [30-78%]; p < 0.05); reduced brain glucose availability correlated with a greater improvement of cerebral microdialysis glucose (Spearman r = -0.53; p = 0.009). No significant changes in cerebral perfusion pressure, mean arterial pressure, systemic carbon dioxide, and blood glucose were observed during hypertonic lactate (all p > 0.1). This is the first clinical demonstration that hypertonic lactate resuscitation improves both cerebral perfusion and brain glucose availability after brain injury. These cerebral vascular and metabolic effects appeared related to brain lactate supplementation rather than to systemic effects.

William's syndrome: gene expression is related to parental origin and regional coordinate control

PubMed Central

Collette, Jeremy C; Chen, Xiao-Ning; Mills, Debra L; Galaburda, Albert M; Reiss, Allan L; Bellugi, Ursula; Korenberg, Julie R

2013-01-01

William's syndrome (WS) features a spectrum of neurocognitive and behavioral abnormalities due to a rare 1.5MB deletion that includes about 24–28 genes on chromosome band 7q11.23. Study of the expression of these genes from the single normal copy provides an opportunity to elucidate the genetic and epigenetic controls on these genes as well as their roles in both WS and normal brain development and function. We used quantitative RT-PCR to determine the transcriptional level of 14 WS gene markers in a cohort of 77 persons with WS and 48 normal controls. Results reported here: (1) show that the expression of the genes deleted in WS is decreased in some but not all cases, (2) demonstrate that the parental origin of the deletion contributes to the level of expression of GTF2I independently of age and gender and (3) indicate that the correlation of expression between GTF2I and some other genes in the WS region differs in WS subjects and normal controls, which in turn points toward a regulatory role for this gene. Interspecies comparisons suggest GTF2I may play a key role in normal brain development. PMID:19282872

Pathological Correlates of Cognitive Impairment in The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age.

PubMed

Robinson, Andrew C; Davidson, Yvonne S; Horan, Michael A; Pendleton, Neil; Mann, David M A

2018-01-01

The neuropathological changes responsible for cognitive impairment and dementia remain incompletely understood. Longitudinal studies with a brain donation end point allow the opportunity to examine relationships between cognitive status and neuropathology. We report on the first 97 participants coming to autopsy with sufficient clinical information from The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age. This study began in 1983 and recruited 6,542 healthy individuals between 1983 and 1994, 312 of whom consented to brain donation. Alzheimer-type pathology was common throughout the cohort and generally correlated well with cognitive status. However, there was some overlap between cognitive status and measures of Alzheimer pathology with 26% of cognitively intact participants reaching either CERAD B or C, 11% reaching Thal phase 4 or 5, and 29% reaching Braak stage III- VI. Cerebral amyloid angiopathy(CAA), α-synuclein, and TDP-43 pathology was less common, but when present correlated well with cognitive status. Possession of APOEɛ4 allele(s) was associated with more severe Alzheimer-type and CAA pathology and earlier death, whereas possession of APOEɛ2 allele(s) had no effect on pathology but was more common in cognitively intact individuals. The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age cohort is pathologically representative when compared with similar studies. Cognitive impairment in life correlates strongly with all pathologies examined and the APOE status of an individual can affect pathology severity and longevity.

Serum zinc, senile plaques, and neurofibrillary tangles: findings from the Nun Study.

PubMed

Tully, C L; Snowdon, D A; Markesbery, W R

1995-11-13

Zinc appears to have a role in binding amyloid precursor protein in vitro, but it is not known whether zinc plays a role in senile plaque formation in vivo in humans. Serum zinc concentrations were available from 12 sisters who died in the Nun Study, a longitudinal study of aging and Alzheimer's disease. Fasting serum zinc concentrations, determined approximately 1 year before death, showed moderate to strong negative correlations with senile plaque counts in seven brain regions. In all brain regions combined, the age-adjusted negative correlations with serum zinc were statistically significant for total senile plaques and diffuse plaques, and suggestive for neuritic plaques. Thus serum zinc in the normal range may be associated with low senile plaque counts in the elderly.

Brain perfusion correlates of visuoperceptual deficits in Mild Cognitive Impairment and mild Alzheimer’s disease

PubMed Central

Alegret, Montserrat; Vinyes-Junqué, Georgina; Boada, Mercè; Martínez-Lage, Pablo; Cuberas, Gemma; Espinosa, Ana; Roca, Isabel; Hernández, Isabel; Valero, Sergi; Rosende-Roca, Maitée; Mauleón, Ana; Becker, James T.; Tárraga, Lluís

2012-01-01

Background Visuoperceptual processing is impaired early in the clinical course of Alzheimer’s disease (AD). The 15-Objects Test (15-OT) detects such subtle performance deficits in Mild Cognitive Impairment (MCI) and mild AD. Reduced brain perfusion in the temporal, parietal and prefrontal regions have been found in early AD and MCI patients. Objectives To confirm the role of the 15-OT in the diagnosis of MCI and AD, and to investigate the brain perfusion correlates of visuoperceptual dysfunction (15-OT) in subjects with MCI, AD and normal aging. Methods Forty-two AD, 42 MCI and 42 healthy elderly control (EC) subjects underwent a brain Single Photon Emission Tomography (SPECT) and separately completed the 15-OT. An analysis of variance compared 15-OT scores between groups. SPM5 was used to analyse the SPECT data. Results 15-OT performace was impaired in the MCI and AD patients. In terms of the SPECT scans, AD patients showed reduced perfusion in temporal-parietal regions, while the MCI subjects had decreased perfusion in the middle and posterior cingulate. When MCI and AD groups were compared, a significant brain perfusion reduction was found in temporo-parietal regions. In the whole sample, 15-OT performance was significantly correlated with the clinical dementia rating scores, and with the perfusion in the bilateral posterior cingulate and the right temporal pole, with no significant correlation in each separate group. Conclusion Our findings suggest that the 15-OT performance provides a useful gradation of impairment from normal aging to AD, and it seems to be related to perfusion in the bilateral posterior cingulate and the right temporal pole. PMID:20555146

What you see is what you eat: an ALE meta-analysis of the neural correlates of food viewing in children and adolescents.

PubMed

van Meer, Floor; van der Laan, Laura N; Adan, Roger A H; Viergever, Max A; Smeets, Paul A M

2015-01-01

Food cues are omnipresent and may enhance overconsumption. In the last two decades the prevalence of childhood obesity has increased dramatically all over the world, largely due to overconsumption. Understanding children's neural responses to food may help to develop better interventions for preventing or reducing overconsumption. We aimed to determine which brain regions are concurrently activated in children/adolescents in response to viewing food pictures, and how these relate to adult findings. Two activation likelihood estimation (ALE) meta-analyses were performed: one with studies in normal weight children/adolescents (aged 8-18, 8 studies, 137 foci) and one with studies in normal weight adults (aged 18-45, 16 studies, 178 foci). A contrast analysis was performed for children/adolescents vs. adults. In children/adolescents, the most concurrent clusters were in the left lateral orbitofrontal cortex (OFC), the bilateral fusiform gyrus, and the right superior parietal lobule. In adults, clusters in similar areas were found. Although the number of studies for a direct statistical comparison between the groups was relatively low, there were indications that children/adolescents may not activate areas important for cognitive control. Overall, the number of studies that contributed to the significant clusters was moderate (6-75%). In summary, the brain areas most consistently activated in children/adolescents by food viewing are part of the appetitive brain network and overlap with those found in adults. However, the age range of the children studied was rather broad. This study offers important recommendations for future research; studies making a direct comparison between adults and children in a sufficiently narrow age range would further elucidate how neural responses to food cues change during development. Copyright © 2014 Elsevier Inc. All rights reserved.

Collision avoidance in persons with homonymous visual field defects under virtual reality conditions.

PubMed

Papageorgiou, Eleni; Hardiess, Gregor; Ackermann, Hermann; Wiethoelter, Horst; Dietz, Klaus; Mallot, Hanspeter A; Schiefer, Ulrich

2012-01-01

The aim of the present study was to examine the effect of homonymous visual field defects (HVFDs) on collision avoidance of dynamic obstacles at an intersection under virtual reality (VR) conditions. Overall performance was quantitatively assessed as the number of collisions at a virtual intersection at two difficulty levels. HVFDs were assessed by binocular semi-automated kinetic perimetry within the 90° visual field, stimulus III4e and the area of sparing within the affected hemifield (A-SPAR in deg(2)) was calculated. The effect of A-SPAR, age, gender, side of brain lesion, time since brain lesion and presence of macular sparing on the number of collisions, as well as performance over time were investigated. Thirty patients (10 female, 20 male, age range: 19-71 years) with HVFDs due to unilateral vascular brain lesions and 30 group-age-matched subjects with normal visual fields were examined. The mean number of collisions was higher for patients and in the more difficult level they experienced more collisions with vehicles approaching from the blind side than the seeing side. Lower A-SPAR and increasing age were associated with decreasing performance. However, in agreement with previous studies, wide variability in performance among patients with identical visual field defects was observed and performance of some patients was similar to that of normal subjects. Both patients and healthy subjects displayed equal improvement of performance over time in the more difficult level. In conclusion, our results suggest that visual-field related parameters per se are inadequate in predicting successful collision avoidance. Individualized approaches which also consider compensatory strategies by means of eye and head movements should be introduced. Copyright © 2011 Elsevier Ltd. All rights reserved.

[Caloric restriction and memory during aging].

PubMed

Marti-Nicolovius, M; Arevalo-Garcia, R

2018-06-16

To understand the underlying brain mechanisms involved in the aging process and mental deterioration could be key to the development of behavioral patterns that guarantee reaching advanced ages with the highest possible quality of life and reduce the cognitive loss associated with senescence. To describe and analyze different animal and human studies that demonstrate that a caloric restriction diet may rescue cerebral aging and the cognitive decline associated to aging. For more than 100 years it has been known that caloric restriction extends life span in many laboratory animal. This effect seems to derive from the reduction of age-related symptoms, such as obesity, the onset of cancerous tumors and some metabolic diseases. However, while the consequences of caloric restriction on health are well-established, their ability to reverse age-dependent memory deficits remains a controversial issue. The analyses of the effects of caloric restriction on different animals provides progress for the understanding of its beneficial effects on the neurobiology of cognitive processes during aging. Caloric restriction attenuates the normal or pathological aging of the brain and reduces age-related memory problems. Dietary intervention could become a very effective method to promote a better quality of life and prevent the age-related cognitive deficits.

Ecology of the aging human brain.

PubMed

Sonnen, Joshua A; Santa Cruz, Karen; Hemmy, Laura S; Woltjer, Randall; Leverenz, James B; Montine, Kathleen S; Jack, Clifford R; Kaye, Jeffrey; Lim, Kelvin; Larson, Eric B; White, Lon; Montine, Thomas J

2011-08-01

Alzheimer disease, cerebral vascular brain injury, and isocortical Lewy body disease (LBD) are the major contributors to dementia in community- and population-based studies. To estimate the prevalence of clinically silent forms of these diseases in cognitively normal (CN) adults. Autopsy study. Community- and population based. A total of 1672 brain autopsies from the Adult Changes in Thought study, Honolulu-Asia Aging Study, Nun Study, and Oregon Brain Aging Study, of which 424 met the criteria for CN. Of these, 336 cases had a comprehensive neuropathologic examination of neuritic plaque density, Braak stage for neurofibrillary tangles, LB distribution, and number of cerebral microinfarcts. Forty-seven percent of CN cases had moderate or frequent neuritic plaque density; of these, 6% also had Braak stage V or VI for neurofibrillary tangles. Fifteen percent of CN cases had medullary LBD; 8% also had nigral and 4% isocortical LBD. The presence of any cerebral microinfarcts was identified in 33% and of high-level cerebral microinfarcts in 10% of CN individuals. Overall, the burden of lesions in each individual and their comorbidity varied widely within each study but were similar across studies. These data show an individually varying complex convergence of subclinical diseases in the brain of older CN adults. Appreciating this ecology should help guide future biomarker and neuroimaging studies and clinical trials that focus on community- and population-based cohorts.

Boosting Classification Accuracy of Diffusion MRI Derived Brain Networks for the Subtypes of Mild Cognitive Impairment Using Higher Order Singular Value Decomposition

PubMed Central

Zhan, L.; Liu, Y.; Zhou, J.; Ye, J.; Thompson, P.M.

2015-01-01

Mild cognitive impairment (MCI) is an intermediate stage between normal aging and Alzheimer's disease (AD), and around 10-15% of people with MCI develop AD each year. More recently, MCI has been further subdivided into early and late stages, and there is interest in identifying sensitive brain imaging biomarkers that help to differentiate stages of MCI. Here, we focused on anatomical brain networks computed from diffusion MRI and proposed a new feature extraction and classification framework based on higher order singular value decomposition and sparse logistic regression. In tests on publicly available data from the Alzheimer's Disease Neuroimaging Initiative, our proposed framework showed promise in detecting brain network differences that help in classifying early versus late MCI. PMID:26413202

Brain MRI signal abnormalities and right-to-left shunting in asymptomatic military divers.

PubMed

Gempp, Emmanuel; Sbardella, Fabrice; Stephant, Eric; Constantin, Pascal; De Maistre, Sebastien; Louge, Pierre; Blatteau, Jean-Eric

2010-11-01

We conducted a controlled study to assess the prevalence of brain MRI hyperintense signals and their correlation with right-to-left shunting (RLS) in military divers. We prospectively enrolled 32 asymptomatic military divers under 41 yr of age and 32 non-diving healthy subjects matched with respect to age and vascular disease risk factors. We examined both groups with a 3-Tesla brain MRI; RLS was detected using transcranial pulsed Doppler in divers only. Hyperintense spots were observed in 43.7% of the divers and 21.8% of the control subjects. In particular, divers with significant shunting exhibited a higher prevalence of hyperintensities compared to those with slight or no RLS (75% vs. 25%, respectively). Linear trend analysis also revealed a positive correlation between focal white matter changes, determined using a validated visual rating scale and the RLS grade. Healthy military divers with a hemodynamically relevant RLS have an increased likelihood of cerebral hyperintense spots compared to age-matched normal subjects. The clinical relevance of these MRI signal abnormalities and their causal relationship with diving remain unclear.

Indications of Brain Computed Tomography Scan in Children Younger Than 3 Years of Age with Minor Head Trauma

PubMed Central

Gülşen, İsmail; Ak, Hakan; Karadaş, Sevdegül; Demır, İsmail; Bulut, Mehmet Deniz; Yaycioğlu, Soner

2014-01-01

Objective. To investigate the indications to receive brain computed tomography (CT) scan and to define the pathological findings in children younger than three years of age with minor head trauma in emergency departments. Methods. In this study, hospital case notes of 1350 children attending the emergency department of Bitlis State Hospital between January 2011 and June 2013 were retrospectively reviewed. 508 children under 3 years of age with minor head trauma were included in this study. We also asked 37 physicians about the indications for requiring CT in these children. Results. This study included 508 children, 233 (45,9%) of whom were female and 275 were male. In 476 (93,7%) children, the brain CT was completely normal. 89,2% of physicians asked in the emergency department during that time interval reported that they requested CT scan to protect themselves against malpractice litigation. Conclusion. In infants and children with minor head trauma, most CT scans were unnecessary and the fear of malpractice litigation of physicians was the most common reason for requesting a CT. PMID:24724031

Variation in orbitofrontal cortex volume: relation to sex, emotion regulation and affect.

PubMed

Welborn, B Locke; Papademetris, Xenophon; Reis, Deidre L; Rajeevan, Nallakkandi; Bloise, Suzanne M; Gray, Jeremy R

2009-12-01

Sex differences in brain structure have been examined extensively but are not completely understood, especially in relation to possible functional correlates. Our two aims in this study were to investigate sex differences in brain structure, and to investigate a possible relation between orbitofrontal cortex subregions and affective individual differences. We used tensor-based morphometry to estimate local brain volume from MPRAGE images in 117 healthy right-handed adults (58 female), age 18-40 years. We entered estimates of local brain volume as the dependent variable in a GLM, controlling for age, intelligence and whole-brain volume. Men had larger left planum temporale. Women had larger ventromedial prefrontal cortex (vmPFC), right lateral orbitofrontal (rlOFC), cerebellum, and bilateral basal ganglia and nearby white matter. vmPFC but not rlOFC volume covaried with self-reported emotion regulation strategies (reappraisal, suppression), expressivity of positive emotions (but not of negative), strength of emotional impulses, and cognitive but not somatic anxiety. vmPFC volume statistically mediated sex differences in emotion suppression. The results confirm prior reports of sex differences in orbitofrontal cortex structure, and are the first to show that normal variation in vmPFC volume is systematically related to emotion regulation and affective individual differences.

Validation of voxel-based morphometry (VBM) based on MRI

NASA Astrophysics Data System (ADS)

Yang, Xueyu; Chen, Kewei; Guo, Xiaojuan; Yao, Li

2007-03-01

Voxel-based morphometry (VBM) is an automated and objective image analysis technique for detecting differences in regional concentration or volume of brain tissue composition based on structural magnetic resonance (MR) images. VBM has been used widely to evaluate brain morphometric differences between different populations, but there isn't an evaluation system for its validation until now. In this study, a quantitative and objective evaluation system was established in order to assess VBM performance. We recruited twenty normal volunteers (10 males and 10 females, age range 20-26 years, mean age 22.6 years). Firstly, several focal lesions (hippocampus, frontal lobe, anterior cingulate, back of hippocampus, back of anterior cingulate) were simulated in selected brain regions using real MRI data. Secondly, optimized VBM was performed to detect structural differences between groups. Thirdly, one-way ANOVA and post-hoc test were used to assess the accuracy and sensitivity of VBM analysis. The results revealed that VBM was a good detective tool in majority of brain regions, even in controversial brain region such as hippocampus in VBM study. Generally speaking, much more severity of focal lesion was, better VBM performance was. However size of focal lesion had little effects on VBM analysis.

Effects of long-term administration of a cocoa polyphenolic extract (Acticoa powder) on cognitive performances in aged rats.

PubMed

Bisson, Jean-François; Nejdi, Amine; Rozan, Pascale; Hidalgo, Sophie; Lalonde, Robert; Messaoudi, Michaël

2008-07-01

Numerous studies have indicated that increased vulnerability to oxidative stress may be the main factor involved in functional declines during normal and pathological ageing, and that antioxidant agents, such as polyphenols, may improve or prevent these deficits. We examined whether 1-year administration of a cocoa polyphenolic extract (Acticoa powder), orally delivered at the dose of 24 mg/kg per d between 15 and 27 months of age, affects the onset of age-related cognitive deficits, urinary free dopamine levels and lifespan in old Wistar-Unilever rats. Acticoa powder improved cognitive performances in light extinction and water maze paradigms, increased lifespan and preserved high urinary free dopamine levels. These results suggest that Acticoa powder may be beneficial in retarding age-related brain impairments, including cognitive deficits in normal ageing and perhaps neurodegenerative diseases. Further studies are required to elucidate the mechanisms of cocoa polyphenols in neuroprotection and to explore their effects in man.

Occult White Matter Damage Contributes to Intellectual Disability in Tuberous Sclerosis Complex

ERIC Educational Resources Information Center

Yu, Chunshui; Lin, Fuchun; Zhao, Li; Ye, Jing; Qin, Wen

2009-01-01

Whether patients with tuberous sclerosis complex (TSC) have brain normal-appearing white matter (NAWM) damage and whether such damage contributes to their intellectual disability were examined in 15 TSC patients and 15 gender- and age-matched healthy controls using diffusion tensor imaging (DTI). Histogram and region of interest (ROI) analyses of…

Cerebral Folate Deficiency

ERIC Educational Resources Information Center

Gordon, Neil

2009-01-01

Cerebral folate deficiency (CFD) is associated with low levels of 5-methyltetrahydrofolate in the cerebrospinal fluid (CSF) with normal folate levels in the plasma and red blood cells. The onset of symptoms caused by the deficiency of folates in the brain is at around 4 to 6 months of age. This is followed by delayed development, with deceleration…

Effect of Exercise Training on Hippocampal Volume in Humans: A Pilot Study

ERIC Educational Resources Information Center

Parker, Beth A.; Thompson, Paul D.; Jordan, Kathryn C.; Grimaldi, Adam S.; Assaf, Michal; Jagannathan, Kanchana; Pearlson, Godfrey D.

2011-01-01

The hippocampus is the primary site of memory and learning in the brain. Both normal aging and various disease pathologies (e.g., alcoholism, schizophrenia, and major depressive disorder) are associated with lower hippocampal volumes in humans and hippocampal atrophy predicts progression of Alzheimers disease. In animals, there is convincing…

White matter hyperintensities and imaging patterns of brain ageing in the general population.

PubMed

Habes, Mohamad; Erus, Guray; Toledo, Jon B; Zhang, Tianhao; Bryan, Nick; Launer, Lenore J; Rosseel, Yves; Janowitz, Deborah; Doshi, Jimit; Van der Auwera, Sandra; von Sarnowski, Bettina; Hegenscheid, Katrin; Hosten, Norbert; Homuth, Georg; Völzke, Henry; Schminke, Ulf; Hoffmann, Wolfgang; Grabe, Hans J; Davatzikos, Christos

2016-04-01

White matter hyperintensities are associated with increased risk of dementia and cognitive decline. The current study investigates the relationship between white matter hyperintensities burden and patterns of brain atrophy associated with brain ageing and Alzheimer's disease in a large populatison-based sample (n = 2367) encompassing a wide age range (20-90 years), from the Study of Health in Pomerania. We quantified white matter hyperintensities using automated segmentation and summarized atrophy patterns using machine learning methods resulting in two indices: the SPARE-BA index (capturing age-related brain atrophy), and the SPARE-AD index (previously developed to capture patterns of atrophy found in patients with Alzheimer's disease). A characteristic pattern of age-related accumulation of white matter hyperintensities in both periventricular and deep white matter areas was found. Individuals with high white matter hyperintensities burden showed significantly (P < 0.0001) lower SPARE-BA and higher SPARE-AD values compared to those with low white matter hyperintensities burden, indicating that the former had more patterns of atrophy in brain regions typically affected by ageing and Alzheimer's disease dementia. To investigate a possibly causal role of white matter hyperintensities, structural equation modelling was used to quantify the effect of Framingham cardiovascular disease risk score and white matter hyperintensities burden on SPARE-BA, revealing a statistically significant (P < 0.0001) causal relationship between them. Structural equation modelling showed that the age effect on SPARE-BA was mediated by white matter hyperintensities and cardiovascular risk score each explaining 10.4% and 21.6% of the variance, respectively. The direct age effect explained 70.2% of the SPARE-BA variance. Only white matter hyperintensities significantly mediated the age effect on SPARE-AD explaining 32.8% of the variance. The direct age effect explained 66.0% of the SPARE-AD variance. Multivariable regression showed significant relationship between white matter hyperintensities volume and hypertension (P = 0.001), diabetes mellitus (P = 0.023), smoking (P = 0.002) and education level (P = 0.003). The only significant association with cognitive tests was with the immediate recall of the California verbal and learning memory test. No significant association was present with the APOE genotype. These results support the hypothesis that white matter hyperintensities contribute to patterns of brain atrophy found in beyond-normal brain ageing in the general population. White matter hyperintensities also contribute to brain atrophy patterns in regions related to Alzheimer's disease dementia, in agreement with their known additive role to the likelihood of dementia. Preventive strategies reducing the odds to develop cardiovascular disease and white matter hyperintensities could decrease the incidence or delay the onset of dementia. © The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

The Reduction of Ventrolateral Prefrontal Cortex Gray Matter Volume Correlates with Loss of Economic Rationality in Aging.

PubMed

Chung, Hui-Kuan; Tymula, Agnieszka; Glimcher, Paul

2017-12-06

The population of people above 65 years old continues to grow, and there is mounting evidence that as humans age they are more likely to make errors. However, the specific effect of neuroanatomical aging on the efficiency of economic decision-making is poorly understood. We used whole-brain voxel-based morphometry analysis to determine where reduction of gray matter volume in healthy female and male adults over the age of 65 years correlates with a classic measure of economic irrationality: violations of the Generalized Axiom of Revealed Preference. All participants were functionally normal with Mini-Mental State Examination scores ranging between 26 and 30. While our elders showed the previously reported decline in rationality compared with younger subjects, chronological age per se did not correlate with rationality measures within our population of elders. Instead, reduction of gray matter density in ventrolateral prefrontal cortex correlates tightly with irrational behavior. Interestingly, using a large fMRI sample and meta-analytic tool with Neurosynth, we found that this brain area shows strong coactivation patterns with nearly all of the value-associated regions identified in previous studies. These findings point toward a neuroanatomic locus for economic rationality in the aging brain and highlight the importance of understanding both anatomy and function in the study of aging, cognition, and decision-making. SIGNIFICANCE STATEMENT Age is a crucial factor in decision-making, with older individuals making more errors in choices. Using whole-brain voxel-based morphometry analysis, we found that reduction of gray matter density in ventrolateral prefrontal cortex correlates with economic irrationality: reduced gray matter volume in this area correlates with the frequency and severity of violations of the Generalized Axiom of Revealed Preference. Furthermore, this brain area strongly coactivates with other reward-associated regions identified with Neurosynth. These findings point toward a role for neuroscientific discoveries in shaping long-standing economic views of decision-making. Copyright © 2017 the authors 0270-6474/17/3712068-10$15.00/0.

The Reduction of Ventrolateral Prefrontal Cortex Gray Matter Volume Correlates with Loss of Economic Rationality in Aging

PubMed Central

Tymula, Agnieszka

2017-01-01

The population of people above 65 years old continues to grow, and there is mounting evidence that as humans age they are more likely to make errors. However, the specific effect of neuroanatomical aging on the efficiency of economic decision-making is poorly understood. We used whole-brain voxel-based morphometry analysis to determine where reduction of gray matter volume in healthy female and male adults over the age of 65 years correlates with a classic measure of economic irrationality: violations of the Generalized Axiom of Revealed Preference. All participants were functionally normal with Mini-Mental State Examination scores ranging between 26 and 30. While our elders showed the previously reported decline in rationality compared with younger subjects, chronological age per se did not correlate with rationality measures within our population of elders. Instead, reduction of gray matter density in ventrolateral prefrontal cortex correlates tightly with irrational behavior. Interestingly, using a large fMRI sample and meta-analytic tool with Neurosynth, we found that this brain area shows strong coactivation patterns with nearly all of the value-associated regions identified in previous studies. These findings point toward a neuroanatomic locus for economic rationality in the aging brain and highlight the importance of understanding both anatomy and function in the study of aging, cognition, and decision-making. SIGNIFICANCE STATEMENT Age is a crucial factor in decision-making, with older individuals making more errors in choices. Using whole-brain voxel-based morphometry analysis, we found that reduction of gray matter density in ventrolateral prefrontal cortex correlates with economic irrationality: reduced gray matter volume in this area correlates with the frequency and severity of violations of the Generalized Axiom of Revealed Preference. Furthermore, this brain area strongly coactivates with other reward-associated regions identified with Neurosynth. These findings point toward a role for neuroscientific discoveries in shaping long-standing economic views of decision-making. PMID:28982708

Motor outcome at the age of one after perinatal hypoxic-ischemic encephalopathy.

PubMed

van Schie, P E M; Becher, J G; Dallmeijer, A J; Barkhof, F; Weissenbruch, M M; Vermeulen, R J

2007-04-01

The aim of this report is to describe the motor outcome in one year-old children who were born at full-term with perinatal hypoxic-ischemic encephalopathy (HIE). Relationships between motor ability tests and neurological examination at one year, and between these tests and neonatal brain magnetic resonance imaging (MRI) were investigated. 32 surviving children, born full-term with perinatal HIE, are included in this report. All children had a neonatal MRI. At one year, motor ability was assessed with the Alberta Infant Motor Scale and the Bayley Scales of Infant Development (2nd version). Neurological examinations included the neurological optimality score (NOS). At one year, 14 children (44%) had normal motor ability, nine (28%) had mildly delayed, and nine had significantly delayed motor ability. The NOS ranged from 14.6-27 points. All children with normal motor ability had (near) optimal NOS, however, not all children with high NOS had normal motor ability. Eleven children (34%) had normal neonatal MRI; at one year, six of them had normal, and five had mildly delayed motor ability. Eight children with normal motor ability showed abnormalities on neonatal MRI. Neonatal brain MRI does not predict motor outcome at one year. Motor ability tests and neurological examinations should be used in a complementary manner to describe outcome after HIE.

Alterations in Sociability and Functional Brain Connectivity Caused by Early-Life Seizures is Reversed by Bumetanide

PubMed Central

Holmes, Gregory L.; Tian, Chengju; Hernan, Amanda E.; Flynn, Sean; Camp, Devon; Barry, Jeremy

2015-01-01

There is a well-described association between infantile epilepsy and pervasive cognitive and behavioral deficits, including a high incidence of autism spectrum disorders. Despite the robustness of the relationship between early-life seizures and the development of autism, the pathophysiological mechanism by which this occurs has not been explored. As a result of increasing evidence that autism is a disorder of brain connectivity we hypothesized that early-life seizures would interrupt normal brain connectivity during brain maturation and result in an autistic phenotype. Normal rat pups underwent recurrent flurothyl-induced seizures from postnatal (P) day 5-14 and then tested, along with controls, for developmental alterations of development brain oscillatory activity from P18-25. Specifically we wished to understand how normal changes in rhythmicity in and between brain regions change as a function of age and if this rhythmicity is altered or interrupted by early life seizures. In rat pups with early-life seizures, field recordings from dorsal and ventral hippocampus and prefrontal cortex demonstrated marked increase in coherence as well as a decrease in voltage correlation at all bandwidths compared to controls while there were minimal differences in total power and relative power spectral densities. Rats with early-life seizures had resulting impairment in the sociability and social novelty tests but demonstrated no evidence of increased activity or generalized anxiety as measured in the open field. In addition, rats with early-life seizures had lower seizure thresholds than controls, indicating long-standing alterations in the excitatory/inhibition balance. Bumetanide, a pharmacological agent that blocks the activity of NKCC1 and induces a significant shift of ECl toward more hyperpolarized values, administration at the time of the seizures precluded the subsequent abnormalities in coherence and voltage correlation and resulted in normal sociability and seizure threshold. Taken together these findings indicate that early-life seizures alter the development of oscillations and result in autistic-like behaviors. The altered communication between these brain regions could reflect the physiological underpinnings underlying social cognitive deficits seen in autism spectrum disorders. PMID:25766676

Brain responses to bladder filling in older women without urgency incontinence.

PubMed

Tadic, Stasa D; Tannenbaum, Cara; Resnick, Neil M; Griffiths, Derek

2013-06-01

To investigate normal brain responses to bladder filling, especially when there is little or no sensation as in much of daily life. We performed an functional magnetic resonance imaging (fMRI) study of brain responses to bladder filling in normal female subjects, evoked by infusion and withdrawal of fluid in and out of the bladder. Using the contrast (infusion-withdrawal), we imaged brain activity at small bladder volumes with weak filling sensation and also with full bladder and strong desire to void. Eleven women, average age 65 years (range: 60-71 years) were included. With full bladder and strong desire to void, filling provoked a well-known pattern of activation near the right insula and (as a trend) in the dorsal anterior cingulate cortex and supplementary motor area. There was no significant deactivation. With small bladder volume filling provoked widespread apparent deactivation and no significant activation. Apparent deactivation was associated with increased fMRI signal during withdrawal rather than decrease during infusion, suggesting artifact. A correction for global changes in cerebral blood flow eliminated it and revealed significant subcortical activation, although none in frontal or parietal cortex. In older women with normal bladder function, infusion into an already full bladder resulted in strong sensation and brain activation near the insula and in the dorsal anterior cingulate/supplementary motor complex. With near-empty bladder and little sensation, the situation during much of daily life, these cortical areas were not detectably activated, but activation in midbrain and parahippocampal regions presumably indicated unconscious monitoring of ascending bladder signals. Copyright © 2013 Wiley Periodicals, Inc.

Cortical Thickness and Depressive Symptoms in Cognitively Normal Individuals: The Mayo Clinic Study of Aging.

PubMed

Pink, Anna; Przybelski, Scott A; Krell-Roesch, Janina; Stokin, Gorazd B; Roberts, Rosebud O; Mielke, Michelle M; Knopman, David S; Jack, Clifford R; Petersen, Ronald C; Geda, Yonas E

2017-01-01

Altered cortical thickness has been observed in aging and various neurodegenerative disorders. Furthermore, reduced hippocampal volume has been reported in late-life depression. Even mild depressive symptoms are common in the elderly. However, little is known about the structural MRI measures of depressive symptoms in normal cognitive aging. Thus we sought to examine the association between depressive symptoms with cortical thickness and hippocampal volume as measured by brain MRI among community-dwelling participants. We conducted a cross-sectional study derived from the ongoing population-based Mayo Clinic Study of Aging, involving cognitively normal participants (N = 1,507) aged≥70 years. We observed that depressive symptoms were associated with lower global cortical thickness and lower thickness in specific prefrontal and temporal cortical regions, labeled by FreeSurfer software, version 5.3. As expected, the strength of correlation was very small, given that participants were community-dwelling with only mild depressive symptoms. We did not observe associations between hippocampal volume and depressive symptoms. These findings may provide insight into the structural correlates of mild depressive symptoms in elderly participants.

Craniofacial and brain abnormalities in Laron syndrome (primary growth hormone insensitivity).

PubMed

Kornreich, L; Horev, G; Schwarz, M; Karmazyn, B; Laron, Z

2002-04-01

To investigate abnormalities in the craniofacial structures and in the brain in patients with Laron syndrome. Eleven patients with classical Laron syndrome, nine untreated adults aged 36-68 years and two children aged 4 and 9 years (the latter treated by IGF-I), were studied. Magnetic resonance images of the brain were obtained in all the patients. One patient also underwent computed tomography. The maximal diameter of the maxillary and frontal sinuses was measured and compared with reference values, the size of the sphenoid sinus was evaluated in relation to the sella, and the mastoids were evaluated qualitatively (small or normal). The brain was evaluated for congenital anomalies and parenchymal lesions. In the adult untreated patients, the paranasal sinuses and mastoids were small; in six patients, the bone marrow in the base of the skull was not mature. The diploe of the calvaria was thin. On computed tomography in one adult patient, the sutures were still open. A minimal or mild degree of diffuse brain parenchymal loss was seen in ten patients. One patient demonstrated a lacunar infarct and another periventricular high signals on T2-weighted images. Two patients had cerebellar atrophy. The present study has demonstrated the important role IGF-I plays in the development of the brain and bony structures of the cranium.

Pathological changes in Alzheimer"s brain evaluated with fluorescence emission analysis (FEA)

NASA Astrophysics Data System (ADS)

Christov, Alexander; Ottman, Todd; Grammas, Paula

2004-07-01

Development of AD is associated with cerebrovascular deposition of amyloid beta (Aβ) as well as a progressive increase in vasular collagen content. Both AΒ and collagen are naturally fluorescent compounds when exposed to UV light. We analyzed autofluorescence emitted from brain tissue samples and isolated brain resistance vessels harvested postmortem from patients with Alzheimer's disease (AD) and age-matched controls. Fluorescence emission, excited at 355 nm with an Nd:YAG laser, was measured using a fiber-optic based fluorescence spectroscopic system for tissue analysis. Significantly higher values of fluorescence emission intensity (P<0.001) in the spectral region from 465 to 490 nm were detected in brain resistance vessel samples from AD patients compared to the normal individuals. Results from western blot analysis showed elevated levels of type I and type III collagen, and reduced levels of type IV collagen in resistance vessels from AD patients, compared to control samples. In addition, using direct scanning of the cortical suface for fluoresxcence emission by the laser-induced fluorescence spectroscopy system we detected a significantly (P<0.05) higher level of apoptosis in AD brain tissue compared to age-matched controls. Fluorescence emission analysis (FEA) appears to be a sensitive technique for detecting structural changes in AD brain tissue.

Brain mitochondrial bioenergetics change with rapid and prolonged shifts in aggression in the honey bee, Apis mellifera.

PubMed

Rittschof, Clare C; Vekaria, Hemendra J; Palmer, Joseph H; Sullivan, Patrick G

2018-04-25

Neuronal function demands high-level energy production, and as such, a decline in mitochondrial respiration characterizes brain injury and disease. A growing number of studies, however, link brain mitochondrial function to behavioral modulation in non-diseased contexts. In the honey bee, we show for the first time that an acute social interaction, which invokes an aggressive response, may also cause a rapid decline in brain mitochondrial bioenergetics. The degree and speed of this decline has only been previously observed in the context of brain injury. Furthermore, in the honey bee, age-related increases in aggressive tendency are associated with increased baseline brain mitochondrial respiration, as well as increased plasticity in response to metabolic fuel type in vitro Similarly, diet restriction and ketone body feeding, which commonly enhance mammalian brain mitochondrial function in vivo , cause increased aggression. Thus, even in normal behavioral contexts, brain mitochondria show a surprising degree of variation in function over both rapid and prolonged time scales, with age predicting both baseline function and plasticity in function. These results suggest that mitochondrial function is integral to modulating aggression-related neuronal signaling. We hypothesize that variation in function reflects mitochondrial calcium buffering activity, and that shifts in mitochondrial function signal to the neuronal soma to regulate gene expression and neural energetic state. Modulating brain energetic state is emerging as a critical component of the regulation of behavior in non-diseased contexts. © 2018. Published by The Company of Biologists Ltd.

Brain surface contraction mapped in first-episode schizophrenia: a longitudinal magnetic resonance imaging study

PubMed Central

Sun, D; Stuart, GW; Jenkinson, M; Wood, SJ; McGorry, PD; Velakoulis, D; van Erp, TGM; Thompson, PM; Toga, AW; Smith, DJ; Cannon, TD; Pantelis, C

2009-01-01

Schizophrenia is associated with structural brain abnormalities, but the timing of onset and course of these changes remains unclear. Longitudinal magnetic resonance imaging (MRI) studies have demonstrated progressive brain volume decreases in patients around and after the onset of illness, although considerable discrepancies exist regarding which brain regions are affected. The anatomical pattern of these progressive changes in schizophrenia is largely unknown. In this study, MRI scans were acquired repeatedly from 16 schizophrenia patients approximately 2 years apart following their first episode of illness, and also from 14 age-matched healthy subjects. Cortical Pattern Matching, in combination with Structural Image Evaluation, using Normalisation, of Atrophy, was applied to compare the rates of cortical surface contraction between patients and controls. Surface contraction in the dorsal surfaces of the frontal lobe was significantly greater in patients with first-episode schizophrenia (FESZ) compared with healthy controls. Overall, brain surface contraction in patients and healthy controls showed similar anatomical patterns, with that of the former group exaggerated in magnitude across the entire brain surface. That the pattern of structural change in the early course of schizophrenia corresponds so closely to that associated with normal development is consistent with the hypothesis that a schizophrenia-related factor interacts with normal adolescent brain developmental processes in the pathophysiology of schizophrenia. The exaggerated progressive changes seen in patients with schizophrenia may reflect an increased rate of synaptic pruning, resulting in excessive loss of neuronal connectivity, as predicted by the late neurodevelopmental hypothesis of the illness. PMID:18607377

Association Between Anticholinergic Medication Use and Cognition, Brain Metabolism, and Brain Atrophy in Cognitively Normal Older Adults.

PubMed

Risacher, Shannon L; McDonald, Brenna C; Tallman, Eileen F; West, John D; Farlow, Martin R; Unverzagt, Fredrick W; Gao, Sujuan; Boustani, Malaz; Crane, Paul K; Petersen, Ronald C; Jack, Clifford R; Jagust, William J; Aisen, Paul S; Weiner, Michael W; Saykin, Andrew J

2016-06-01

The use of anticholinergic (AC) medication is linked to cognitive impairment and an increased risk of dementia. To our knowledge, this is the first study to investigate the association between AC medication use and neuroimaging biomarkers of brain metabolism and atrophy as a proxy for understanding the underlying biology of the clinical effects of AC medications. To assess the association between AC medication use and cognition, glucose metabolism, and brain atrophy in cognitively normal older adults from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the Indiana Memory and Aging Study (IMAS). The ADNI and IMAS are longitudinal studies with cognitive, neuroimaging, and other data collected at regular intervals in clinical and academic research settings. For the participants in the ADNI, visits are repeated 3, 6, and 12 months after the baseline visit and then annually. For the participants in the IMAS, visits are repeated every 18 months after the baseline visit (402 cognitively normal older adults in the ADNI and 49 cognitively normal older adults in the IMAS were included in the present analysis). Participants were either taking (hereafter referred to as the AC+ participants [52 from the ADNI and 8 from the IMAS]) or not taking (hereafter referred to as the AC- participants [350 from the ADNI and 41 from the IMAS]) at least 1 medication with medium or high AC activity. Data analysis for this study was performed in November 2015. Cognitive scores, mean fludeoxyglucose F 18 standardized uptake value ratio (participants from the ADNI only), and brain atrophy measures from structural magnetic resonance imaging were compared between AC+ participants and AC- participants after adjusting for potential confounders. The total AC burden score was calculated and was related to target measures. The association of AC use and longitudinal clinical decline (mean [SD] follow-up period, 32.1 [24.7] months [range, 6-108 months]) was examined using Cox regression. The 52 AC+ participants (mean [SD] age, 73.3 [6.6] years) from the ADNI showed lower mean scores on Weschler Memory Scale-Revised Logical Memory Immediate Recall (raw mean scores: 13.27 for AC+ participants and 14.16 for AC- participants; P = .04) and the Trail Making Test Part B (raw mean scores: 97.85 seconds for AC+ participants and 82.61 seconds for AC- participants; P = .04) and a lower executive function composite score (raw mean scores: 0.58 for AC+ participants and 0.78 for AC- participants; P = .04) than the 350 AC- participants (mean [SD] age, 73.3 [5.8] years) from the ADNI. Reduced total cortical volume and temporal lobe cortical thickness and greater lateral ventricle and inferior lateral ventricle volumes were seen in the AC+ participants relative to the AC- participants. The use of AC medication was associated with increased brain atrophy and dysfunction and clinical decline. Thus, use of AC medication among older adults should likely be discouraged if alternative therapies are available.

Bayesian Optimization for Neuroimaging Pre-processing in Brain Age Classification and Prediction

PubMed Central

Lancaster, Jenessa; Lorenz, Romy; Leech, Rob; Cole, James H.

2018-01-01

Neuroimaging-based age prediction using machine learning is proposed as a biomarker of brain aging, relating to cognitive performance, health outcomes and progression of neurodegenerative disease. However, even leading age-prediction algorithms contain measurement error, motivating efforts to improve experimental pipelines. T1-weighted MRI is commonly used for age prediction, and the pre-processing of these scans involves normalization to a common template and resampling to a common voxel size, followed by spatial smoothing. Resampling parameters are often selected arbitrarily. Here, we sought to improve brain-age prediction accuracy by optimizing resampling parameters using Bayesian optimization. Using data on N = 2003 healthy individuals (aged 16–90 years) we trained support vector machines to (i) distinguish between young (<22 years) and old (>50 years) brains (classification) and (ii) predict chronological age (regression). We also evaluated generalisability of the age-regression model to an independent dataset (CamCAN, N = 648, aged 18–88 years). Bayesian optimization was used to identify optimal voxel size and smoothing kernel size for each task. This procedure adaptively samples the parameter space to evaluate accuracy across a range of possible parameters, using independent sub-samples to iteratively assess different parameter combinations to arrive at optimal values. When distinguishing between young and old brains a classification accuracy of 88.1% was achieved, (optimal voxel size = 11.5 mm3, smoothing kernel = 2.3 mm). For predicting chronological age, a mean absolute error (MAE) of 5.08 years was achieved, (optimal voxel size = 3.73 mm3, smoothing kernel = 3.68 mm). This was compared to performance using default values of 1.5 mm3 and 4mm respectively, resulting in MAE = 5.48 years, though this 7.3% improvement was not statistically significant. When assessing generalisability, best performance was achieved when applying the entire Bayesian optimization framework to the new dataset, out-performing the parameters optimized for the initial training dataset. Our study outlines the proof-of-principle that neuroimaging models for brain-age prediction can use Bayesian optimization to derive case-specific pre-processing parameters. Our results suggest that different pre-processing parameters are selected when optimization is conducted in specific contexts. This potentially motivates use of optimization techniques at many different points during the experimental process, which may improve statistical sensitivity and reduce opportunities for experimenter-led bias. PMID:29483870

A young infant with musicogenic epilepsy.

PubMed

Lin, Kuang-Lin; Wang, Huei-Shyong; Kao, Pan-Fu

2003-05-01

Musicogenic epilepsy is a relatively rare form of epilepsy. In its pure form, it is characterized by epileptic seizures that are provoked exclusively by listening to music. The usual type of seizure is partial complex or generalized tonic-clonic. Precipitating factors are quite specific, such as listening to only one composition or the actual playing of music on an instrument. However, simple sound also can be a trigger. We report a 6-month-old infant with musicogenic epilepsy. She manifested right-sided focal seizures with occasional generalization. The seizures were frequently triggered by loud music, especially that by the Beatles. The interictal electroencephalography results were normal. Ictal spikes were present throughout the left temporal area during continuous electroencephalograpic monitoring. Brain magnetic resonance imaging results were normal, whereas single-photon emission computed tomography of the brain revealed hypoperfusion of the left temporal area. The young age and epileptogenic left temporal lobe lesion in this patient with musicogenic epilepsy were unusual characteristics. Theoretically, three levels of integration are involved in music processing in the brain. The involved integration of this infant's brain may be the sensory level rather than the emotional level. Nevertheless, the personal musicality and musical style of the Beatles might play an important role in this patient's epilepsy.

Altered Effective Connectivity of Hippocampus-Dependent Episodic Memory Network in mTBI Survivors

PubMed Central

2016-01-01

Traumatic brain injuries (TBIs) are generally recognized to affect episodic memory. However, less is known regarding how external force altered the way functionally connected brain structures of the episodic memory system interact. To address this issue, we adopted an effective connectivity based analysis, namely, multivariate Granger causality approach, to explore causal interactions within the brain network of interest. Results presented that TBI induced increased bilateral and decreased ipsilateral effective connectivity in the episodic memory network in comparison with that of normal controls. Moreover, the left anterior superior temporal gyrus (aSTG, the concept forming hub), left hippocampus (the personal experience binding hub), and left parahippocampal gyrus (the contextual association hub) were no longer network hubs in TBI survivors, who compensated for hippocampal deficits by relying more on the right hippocampus (underlying perceptual memory) and the right medial frontal gyrus (MeFG) in the anterior prefrontal cortex (PFC). We postulated that the overrecruitment of the right anterior PFC caused dysfunction of the strategic component of episodic memory, which caused deteriorating episodic memory in mTBI survivors. Our findings also suggested that the pattern of brain network changes in TBI survivors presented similar functional consequences to normal aging. PMID:28074162

A paradigm of undernourishing and neonatal rehabilitation in the newborn rat.

PubMed

Perez-Torrero, Esther; Torrerob, Carmen; Collado, Paloma; Salas, Manuel

2003-04-01

Perinatal undernutrition as a deficiency of nutrient availability, affects body and brain developmental processes and promotes recurrent health problems. Thus, altered mother-litter bonds and deficient environmental interactions may interfere with the brain pluripotential capabilities of the newborn. To gather information concerning the mechanisms underlying perinatal undernutrition we designed a paradigm of undernutrition and neonatal rehabilitation in the rat. An underfed group came from pregnant Wistar rats fed with 50% of the diet from G6 to G12 and with 60% from G13 until G21. After birth, pups were daily undernourished during 12 h daily by rotating a pair of lactating well-nourished dams which had one of their nipples subcutaneously ligated. The rehabilitated animals were undernourished pups neonatally fed by a pair of normally lactating dams. Controls received plenty of food during the pre- and neonatal periods. Pups were sacrificed at 12, 20 and 30 days of age. Perinatal underfeeding significantly reduced body and brain weights and neuronal morphometric parameters. Normal neonatal feeding in the newborn ameliorated the damages associated to food deprivation. The current undernourishing paradigm may be helpful to assess brain development alterations, as well as to study the compensatory mechanisms associated to salutary epigenetic influences.

COBRA: A prospective multimodal imaging study of dopamine, brain structure and function, and cognition.

PubMed

Nevalainen, N; Riklund, K; Andersson, M; Axelsson, J; Ögren, M; Lövdén, M; Lindenberger, U; Bäckman, L; Nyberg, L

2015-07-01

Cognitive decline is a characteristic feature of normal human aging. Previous work has demonstrated marked interindividual variability in onset and rate of decline. Such variability has been linked to factors such as maintenance of functional and structural brain integrity, genetics, and lifestyle. Still, few, if any, studies have combined a longitudinal design with repeated multimodal imaging and a comprehensive assessment of cognition as well as genetic and lifestyle factors. The present paper introduces the Cognition, Brain, and Aging (COBRA) study, in which cognitive performance and brain structure and function are measured in a cohort of 181 older adults aged 64 to 68 years at baseline. Participants will be followed longitudinally over a 10-year period, resulting in a total of three equally spaced measurement occasions. The measurement protocol at each occasion comprises a comprehensive set of behavioral and imaging measures. Cognitive performance is evaluated via computerized testing of working memory, episodic memory, perceptual speed, motor speed, implicit sequence learning, and vocabulary. Brain imaging is performed using positron emission tomography with [(11)C]-raclopride to assess dopamine D2/D3 receptor availability. Structural magnetic resonance imaging (MRI) is used for assessment of white and gray-matter integrity and cerebrovascular perfusion, and functional MRI maps brain activation during rest and active task conditions. Lifestyle descriptives are collected, and blood samples are obtained and stored for future evaluation. Here, we present selected results from the baseline assessment along with a discussion of sample characteristics and methodological considerations that determined the design of the study. This article is part of a Special Issue entitled SI: Memory & Aging. Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.

Mechanisms of n-3 fatty acid-mediated development and maintenance of learning memory performance.

PubMed

Su, Hui-Min

2010-05-01

Docosahexaenoic acid (DHA, 22:6n-3) is specifically enriched in the brain and mainly anchored in the neuronal membrane, where it is involved in the maintenance of normal neurological function. Most DHA accumulation in the brain takes place during brain development in the perinatal period. However, hippocampal DHA levels decrease with age and in the brain disorder Alzheimer's disease (AD), and this decrease is associated with reduced hippocampal-dependent spatial learning memory ability. A potential mechanism is proposed by which the n-3 fatty acids DHA and eicosapentaenoic acid (20:5n-3) aid the development and maintenance of spatial learning memory performance. The developing brain or hippocampal neurons can synthesize and take up DHA and incorporate it into membrane phospholipids, especially phosphatidylethanolamine, resulting in enhanced neurite outgrowth, synaptogenesis and neurogenesis. Exposure to n-3 fatty acids enhances synaptic plasticity by increasing long-term potentiation and synaptic protein expression to increase the dendritic spine density, number of c-Fos-positive neurons and neurogenesis in the hippocampus for learning memory processing. In aged rats, n-3 fatty acid supplementation reverses age-related changes and maintains learning memory performance. n-3 fatty acids have anti-oxidative stress, anti-inflammation, and anti-apoptosis effects, leading to neuron protection in the aged, damaged, and AD brain. Retinoid signaling may be involved in the effects of DHA on learning memory performance. Estrogen has similar effects to n-3 fatty acids on hippocampal function. It would be interesting to know if there is any interaction between DHA and estrogen so as to provide a better strategy for the development and maintenance of learning memory. Copyright 2010 Elsevier Inc. All rights reserved.

T2 Relaxometry MRI Predicts Cerebral Palsy in Preterm Infants.

PubMed

Chen, L-W; Wang, S-T; Huang, C-C; Tu, Y-F; Tsai, Y-S

2018-01-18

T2-relaxometry brain MR imaging enables objective measurement of brain maturation based on the water-macromolecule ratio in white matter, but the outcome correlation is not established in preterm infants. Our study aimed to predict neurodevelopment with T2-relaxation values of brain MR imaging among preterm infants. From January 1, 2012, to May 31, 2015, preterm infants who underwent both T2-relaxometry brain MR imaging and neurodevelopmental follow-up were retrospectively reviewed. T2-relaxation values were measured over the periventricular white matter, including sections through the frontal horns, midbody of the lateral ventricles, and centrum semiovale. Periventricular T2 relaxometry in relation to corrected age was analyzed with restricted cubic spline regression. Prediction of cerebral palsy was examined with the receiver operating characteristic curve. Thirty-eight preterm infants were enrolled for analysis. Twenty patients (52.6%) had neurodevelopmental abnormalities, including 8 (21%) with developmental delay without cerebral palsy and 12 (31.6%) with cerebral palsy. The periventricular T2-relaxation values in relation to age were curvilinear in preterm infants with normal development, linear in those with developmental delay without cerebral palsy, and flat in those with cerebral palsy. When MR imaging was performed at >1 month corrected age, cerebral palsy could be predicted with T2 relaxometry of the periventricular white matter on sections through the midbody of the lateral ventricles (area under the receiver operating characteristic curve = 0.738; cutoff value of >217.4 with 63.6% sensitivity and 100.0% specificity). T2-relaxometry brain MR imaging could provide prognostic prediction of neurodevelopmental outcomes in premature infants. Age-dependent and area-selective interpretation in preterm brains should be emphasized. © 2018 by American Journal of Neuroradiology.

Iron in Chronic Brain Disorders: Imaging and Neurotherapeutic Implications

PubMed Central

Stankiewicz, James; Panter, Scott S; Neema, Mohit; Arora, Ashish; Batt, Courtney; Bakshi, Rohit

2007-01-01

Summary Iron is important for brain oxygen transport, electron transfer, neurotransmitter synthesis, and myelin production. Though iron deposition has been observed in the brain with normal aging, increased iron has also been shown in many chronic neurologic disorders including Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis. In vitro studies have demonstrated that excessive iron can lead to free radical production, which can promote neurotoxicity. However, the link between observed iron deposition and pathologic processes underlying various diseases of the brain is not well understood. It is not known whether excessive in vivo iron directly contributes to tissue damage or is solely an epiphenomenon. In this article we focus on the imaging of brain iron and the underlying physiology and metabolism relating to iron deposition. We conclude with a discussion of the potential implications of iron-related toxicity to neurotherapeutic development. PMID:17599703

Brain magnetic resonance imaging and motor and intellectual functioning in 86 patients born at term with spastic diplegia.

PubMed

Numata, Yurika; Onuma, Akira; Kobayashi, Yasuko; Sato-Shirai, Ikuko; Tanaka, Soichiro; Kobayashi, Satoru; Wakusawa, Keisuke; Inui, Takehiko; Kure, Shigeo; Haginoya, Kazuhiro

2013-02-01

To investigate the association between magnetic resonance imaging (MRI) patterns and motor function, epileptic episodes, and IQ or developmental quotient in patients born at term with spastic diplegia. Eighty-six patients born at term with cerebral palsy (CP) and spastic diplegia (54 males, 32 females; median age 20 y, range 7-42 y) among 829 patients with CP underwent brain MRI between 1990 and 2008. The MRI and clinical findings were analysed retrospectively. Intellectual disability was classified according to the Enjoji developmental test or the Wechsler Intelligence Scale for Children (3rd edition). The median ages at diagnosis of CP, assignment of Gross Motor Function Classification System (GMFCS) level, cognitive assessment, and MRI were 2 years (range 5 mo-8 y), 6 years (2 y 8 mo-19 y), 6 years (1 y 4 mo-19 y), and 7 years (10 mo-30 y) respectively. MRI included normal findings (41.9%), periventricular leukomalacia, hypomyelination, and porencephaly/periventricular venous infarction. The frequency of patients in GMFCS levels III to V and intellectual disability did not differ between those with normal and abnormal MRI findings. Patients with normal MRI findings had significantly fewer epileptic episodes than those with abnormal ones (p=0.001). Varied MRI findings, as well as the presence of severe motor dysfunction and intellectual disability (despite normal MRI), suggest that patients born at term with spastic diplegia had heterogeneous and unidentified pathophysiology. © The Authors. Developmental Medicine & Child Neurology © 2012 Mac Keith Press.

Quantitative Susceptibility Mapping Indicates a Disturbed Brain Iron Homeostasis in Neuromyelitis Optica - A Pilot Study.

PubMed

Doring, Thomas Martin; Granado, Vanessa; Rueda, Fernanda; Deistung, Andreas; Reichenbach, Juergen R; Tukamoto, Gustavo; Gasparetto, Emerson Leandro; Schweser, Ferdinand

2016-01-01

Dysregulation of brain iron homeostasis is a hallmark of many neurodegenerative diseases and can be associated with oxidative stress. The objective of this study was to investigate brain iron in patients with Neuromyelitis Optica (NMO) using quantitative susceptibility mapping (QSM), a quantitative iron-sensitive MRI technique. 12 clinically confirmed NMO patients (6 female and 6 male; age 35.4y±14.2y) and 12 age- and sex-matched healthy controls (7 female and 5 male; age 33.9±11.3y) underwent MRI of the brain at 3 Tesla. Quantitative maps of the effective transverse relaxation rate (R2*) and magnetic susceptibility were calculated and a blinded ROI-based group comparison analysis was performed. Normality of the data and differences between patients and controls were tested by Kolmogorov-Smirnov and t-test, respectively. Correlation with age was studied using Spearman's rank correlation and an ANCOVA-like analysis. Magnetic susceptibility values were decreased in the red nucleus (p<0.01; d>0.95; between -15 and -22 ppb depending on reference region) with a trend toward increasing differences with age. R2* revealed significantly decreased relaxation in the optic radiations of five of the 12 patients (p<0.0001; -3.136±0.567 s-1). Decreased relaxation in the optic radiation is indicative for demyelination, which is in line with previous findings. Decreased magnetic susceptibility in the red nucleus is indicative for a lower brain iron concentration, a chemical redistribution of iron into less magnetic forms, or both. Further investigations are necessary to elucidate the pathological cause or consequence of this finding.

Traumatic axonal injury: the prognostic value of lesion load in corpus callosum, brain stem, and thalamus in different magnetic resonance imaging sequences.

PubMed

Moen, Kent G; Brezova, Veronika; Skandsen, Toril; Håberg, Asta K; Folvik, Mari; Vik, Anne

2014-09-01

The aim of this study was to explore the prognostic value of visible traumatic axonal injury (TAI) loads in different MRI sequences from the early phase after adjusting for established prognostic factors. Likewise, we sought to explore the prognostic role of early apparent diffusion coefficient (ADC) values in normal-appearing corpus callosum. In this prospective study, 128 patients (mean age, 33.9 years; range, 11-69) with moderate (n = 64) and severe traumatic brain injury (TBI) were examined with MRI at a median of 8 days (range, 0-28) postinjury. TAI lesions in fluid-attenuated inversion recovery (FLAIR), diffusion-weighted imaging (DWI), and T2*-weighted gradient echo (T2*GRE) sequences were counted and FLAIR lesion volumes estimated. In patients and 47 healthy controls, mean ADC values were computed in 10 regions of interests in the normal-appearing corpus callosum. Outcome measure was the Glasgow Outcome Scale-Extended (GOS-E) at 12 months. In patients with severe TBI, number of DWI lesions and volume of FLAIR lesions in the corpus callosum, brain stem, and thalamus predicted outcome in analyses with adjustment for age, Glasgow Coma Scale score, and pupillary dilation (odds ratio, 1.3-6.9; p = <0.001-0.017). The addition of Rotterdam CT score and DWI lesions in the corpus callosum yielded the highest R2 (0.24), compared to all other MRI variables, including brain stem lesions. For patients with moderate TBI only the number of cortical contusions (p = 0.089) and Rotterdam CT score (p = 0.065) tended to predict outcome. Numbers of T2*GRE lesions did not affect outcome. Mean ADC values in the normal-appearing corpus callosum did not differ from controls. In conclusion, the loads of visible TAI lesions in the corpus callosum, brain stem, and thalamus in DWI and FLAIR were independent prognostic factors in patients with severe TBI. DWI lesions in the corpus callosum were the most important predictive MRI variable. Interestingly, number of cortical contusions in MRI and CT findings seemed more important for patients with moderate TBI.

Life and death in the trash heap: The ubiquitin proteasome pathway and UCHL1 in brain aging, neurodegenerative disease and cerebral Ischemia.

PubMed

Graham, Steven H; Liu, Hao

2017-03-01

The ubiquitin proteasome pathway (UPP) is essential for removing abnormal proteins and preventing accumulation of potentially toxic proteins within the neuron. UPP dysfunction occurs with normal aging and is associated with abnormal accumulation of protein aggregates within neurons in neurodegenerative diseases. Ischemia disrupts UPP function and thus may contribute to UPP dysfunction seen in the aging brain and in neurodegenerative diseases. Ubiquitin carboxy-terminal hydrolase L1 (UCHL1), an important component of the UPP in the neuron, is covalently modified and its activity inhibited by reactive lipids produced after ischemia. As a result, degradation of toxic proteins is impaired which may exacerbate neuronal function and cell death in stroke and neurodegenerative diseases. Preserving or restoring UCHL1 activity may be an effective therapeutic strategy in stroke and neurodegenerative diseases. Published by Elsevier B.V.

Brain MRI white matter hyperintensities and one-carbon cycle metabolism in non-geriatric outpatients with major depressive disorder (Part I).

PubMed

Iosifescu, Dan V; Papakostas, George I; Lyoo, In Kyoon; Lee, Ho Kyu; Renshaw, Perry F; Alpert, Jonathan E; Nierenberg, Andrew; Fava, Maurizio

2005-12-30

The objective of the present work was to study the interrelationship between white matter hyperintensities (WMHs), cardiovascular risk factors and elements of the one-carbon cycle including serum folate, vitamin B12, and homocysteine levels in a relatively young sample of outpatients with major depressive disorder (MDD), and to compare the severity of white matter hyperintensities in MDD patients and healthy volunteers. Fifty MDD outpatients (34% women, age 40.6+/-10.3 years), free of psychotropic medications for at least 2 weeks before enrollment, underwent magnetic resonance imaging (MRI) scans of the brain to detect T2 WMHs and also had (1) serum folate, vitamin B12, homocysteine and cholesterol levels measured, and (2) cardiovascular risk factors assessed during the same study visit. Thirty-five healthy comparison subjects (40% women, age 39.2+/-9.8 years) also underwent brain MRI scans. Hypofolatemia, hypertension and age independently predicted a greater severity of total brain WMHs. Separately, the same factors also predicted a greater severity of subcortical WMHs. Hypofolatemic and hypertensive patients had more severe WMHs than normal controls. In light of the adverse impact of WMHs on a number of health-related outcomes later in life, hypofolatemia and hypertension may represent modifiable risk factors to prevent the occurrence of such adverse outcomes.

Brain injury following trial of hypothermia for neonatal hypoxic–ischaemic encephalopathy

PubMed Central

Shankaran, Seetha; Barnes, Patrick D; Hintz, Susan R; Laptook, Abbott R; Zaterka-Baxter, Kristin M; McDonald, Scott A; Ehrenkranz, Richard A; Walsh, Michele C; Tyson, Jon E; Donovan, Edward F; Goldberg, Ronald N; Bara, Rebecca; Das, Abhik; Finer, Neil N; Sanchez, Pablo J; Poindexter, Brenda B; Van Meurs, Krisa P; Carlo, Waldemar A; Stoll, Barbara J; Duara, Shahnaz; Guillet, Ronnie; Higgins, Rosemary D

2013-01-01

Objective The objective of our study was to examine the relationship between brain injury and outcome following neonatal hypoxic–ischaemic encephalopathy treated with hypothermia. Design and patients Neonatal MRI scans were evaluated in the National Institute of Child Health and Human Development (NICHD) randomised controlled trial of whole-body hypothermia and each infant was categorised based upon the pattern of brain injury on the MRI findings. Brain injury patterns were assessed as a marker of death or disability at 18–22 months of age. Results Scans were obtained on 136 of 208 trial participants (65%); 73 in the hypothermia and 63 in the control group. Normal scans were noted in 38 of 73 infants (52%) in the hypothermia group and 22 of 63 infants (35%) in the control group. Infants in the hypothermia group had fewer areas of infarction (12%) compared to infants in the control group (22%). Fifty-one of the 136 infants died or had moderate or severe disability at 18 months. The brain injury pattern correlated with outcome of death or disability and with disability among survivors. Each point increase in the severity of the pattern of brain injury was independently associated with a twofold increase in the odds of death or disability. Conclusions Fewer areas of infarction and a trend towards more normal scans were noted in brain MRI following whole-body hypothermia. Presence of the NICHD pattern of brain injury is a marker of death or moderate or severe disability at 18–22 months following hypothermia for neonatal encephalopathy. PMID:23080477

Sex hormones, aging, and Alzheimer’s disease

PubMed Central

Barron, Anna M.; Pike, Christian J.

2012-01-01

A promising strategy to delay and perhaps prevent Alzheimer’s disease (AD) is to identify the age-related changes that put the brain at risk for the disease. A significant normal age change known to result in tissue-specific dysfunction is the depletion of sex hormones. In women, menopause results in a relatively rapid loss of estradiol and progesterone. In men, aging is associated with a comparatively gradual yet significant decrease in testosterone. We review a broad literature that indicates age-related losses of estrogens in women and testosterone in men are risk factors for AD. Both estrogens and androgens exert a wide range of protective actions that improve multiple aspects of neural health, suggesting that hormone therapies have the potential to combat AD pathogenesis. However, translation of experimental findings into effective therapies has proven challenging. One emerging treatment option is the development of novel hormone mimetics termed selective estrogen and androgen receptor modulators. Continued research of sex hormones and their roles in the aging brain is expected to yield valuable approaches to reducing the risk of AD. PMID:22201929

Early Childhood Stuttering and Electrophysiological Indices of Language Processing

PubMed Central

Weber-Fox, Christine; Wray, Amanda Hampton; Arnold, Hayley

2013-01-01

We examined neural activity mediating semantic and syntactic processing in 27 preschool-age children who stutter (CWS) and 27 preschool-age children who do not stutter (CWNS) matched for age, nonverbal IQ and language abilities. All participants displayed language abilities and nonverbal IQ within the normal range. Event-related brain potentials (ERPs) were elicited while participants watched a cartoon video and heard naturally spoken sentences that were either correct or contained semantic or syntactic (phrase structure) violations. ERPs in CWS, compared to CWNS, were characterized by longer N400 peak latencies elicited by semantic processing. In the CWS, syntactic violations elicited greater negative amplitudes for the early time window (150–350 ms) over medial sites compared to CWNS. Additionally, the amplitude of the P600 elicited by syntactic violations relative to control words was significant over the left hemisphere for the CWNS but showed the reverse pattern in CWS, a robust effect only over the right hemisphere. Both groups of preschoolage children demonstrated marked and differential effects for neural processes elicited by semantic and phrase structure violations; however, a significant proportion of young CWS exhibit differences in the neural functions mediating language processing compared to CWNS despite normal language abilities. These results are the first to show that differences in event-related brain potentials reflecting language processing occur as early as the preschool years in CWS and provide the first evidence that atypical lateralization of hemispheric speech/language functions previously observed in the brains of adults who stutter begin to emerge near the onset of developmental stuttering. PMID:23773672

[Behavior and functional state of the dopaminergic brain system in pups of depressive WAG/Rij rats].

PubMed

Malyshev, A V; Razumkina, E V; Rogozinskaia, É Ia; Sarkisova, K Iu; Dybynin, V A

2014-01-01

In the present work, it has been studied for the first time behavior and functional state of the dopaminergic brain system in pups of "depressive" WAG/Rij rats. Offspring of "depressive" WAG/Rij rats at age of 6-16 days compared with offspring of "normal" (non-depressed) outbred rats of the same age exhibited reduced rate of pshychomotor development, lower body weight, attenuation in integration of coordinated reflexes and vestibular function (greater latency of righting reflex, abnormal negative geotaxis), hyper-reactivity to tactile stimulation, reduced motivation to contact with mother (reduced infant-mother attachment). Differences in a nest seeking response induced by olfactory stimuli (olfactory discrimination test) and in locomotor activity (tests "gait reflex" and "small open field") have not been revealed. Acute injection of the antagonist of D2-like dopamine receptors clebopride 20 min before testing aggravated mother-oriented behavior in 15-days-old pups of both "depressive" and "non-depressive" rats. However this effect was greater in pups of "depressive" WAG/Rij rats compared with pups of "normal" rats that may indicate reduced functional activity of the dopaminergic brain system in offspring of "depressive" rats. It is proposed that reduced attachment behavior in pups of "depressive" WAG/Rij rats might be a consequence of maternal depression and associated with it reduced maternal care. Moreover, reduced attachment behavior in pups of "depressive" rats might be an early precursor (a marker) of depressive-like pathology which become apparent later in life (approximately at age of 3 months).

FDG-PET and Neuropsychiatric Symptoms among Cognitively Normal Elderly Persons: The Mayo Clinic Study of Aging.

PubMed

Krell-Roesch, Janina; Ruider, Hanna; Lowe, Val J; Stokin, Gorazd B; Pink, Anna; Roberts, Rosebud O; Mielke, Michelle M; Knopman, David S; Christianson, Teresa J; Machulda, Mary M; Jack, Clifford R; Petersen, Ronald C; Geda, Yonas E

2016-07-14

One of the key research agenda of the field of aging is investigation of presymptomatic Alzheimer's disease (AD). Furthermore, abnormalities in brain glucose metabolism (as measured by FDG-PET) have been reported among cognitively normal elderly persons. However, little is known about the association of FDG-PET abnormalities with neuropsychiatric symptoms (NPS) in a population-based setting. Thus, we conducted a cross-sectional study derived from the ongoing population-based Mayo Clinic Study of Aging in order to examine the association between brain glucose metabolism and NPS among cognitively normal (CN) persons aged > 70 years. Participants underwent FDG-PET and completed the Neuropsychiatric Inventory Questionnaire (NPI-Q), Beck Depression Inventory (BDI), and Beck Anxiety Inventory (BAI). Cognitive classification was made by an expert consensus panel. We conducted multivariable logistic regression analyses to compute odds ratios (OR) and 95% confidence intervals after adjusting for age, sex, and education. For continuous variables, we used linear regression and Spearman rank-order correlations. Of 668 CN participants (median 78.1 years, 55.4% males), 205 had an abnormal FDG-PET (i.e., standardized uptake value ratio < 1.32 in AD-related regions). Abnormal FDG-PET was associated with depression as measured by NPI-Q (OR = 2.12; 1.23-3.64); the point estimate was further elevated for APOE ɛ4 carriers (OR = 2.59; 1.00-6.69), though marginally significant. Additionally, we observed a significant association between abnormal FDG-PET and depressive and anxiety symptoms when treated as continuous measures. These findings indicate that NPS, even in community-based samples, can be an important additional tool to the biomarker-based investigation of presymptomatic AD.

Neuropathological and neuropsychological changes in "normal" aging: evidence for preclinical Alzheimer disease in cognitively normal individuals.

PubMed

Hulette, C M; Welsh-Bohmer, K A; Murray, M G; Saunders, A M; Mash, D C; McIntyre, L M

1998-12-01

The presence of diffuse or primitive senile plaques in the neocortex of cognitively normal elderly at autopsy has been presumed to represent normal aging. Alternatively, these patients may have developed dementia and clinical Alzheimer disease (AD) if they had survived. In this setting, these patients could be subjects for cognitive or pharmacologic intervention to delay disease onset. We have thus followed a cohort of cognitively normal elderly subjects with a Clinical Dementia Rating (CDR) of 0 at autopsy. Thirty-one brains were examined at postmortem according to Consortium to Establish a Registry for Alzheimer Disease (CERAD) criteria and staged according to Braak. Ten patients were pathologically normal according to CERAD criteria (1a). Two of these patients were Braak Stage II. Seven very elderly subjects exhibited a few primitive neuritic plaques in the cortex and thus represented CERAD 1b. These individuals ranged in age from 85 to 105 years and were thus older than the CERAD la group that ranged in age from 72 to 93. Fourteen patients displayed Possible AD according to CERAD with ages ranging from 66 to 95. Three of these were Braak Stage I, 4 were Braak Stage II, and 7 were Braak Stage III. The Apolipoprotein E4 allele was over-represented in this possible AD group. Neuropsychological data were available on 12 individuals. In these 12 individuals, Possible AD at autopsy could be predicted by cognitive deficits in 1 or more areas including savings scores on memory testing and overall performance on some measures of frontal executive function.

Brain-derived neurotrophic factor (BDNF) in children with ASD and their parents: a 3-year follow-up.

PubMed

Francis, K; Dougali, A; Sideri, K; Kroupis, C; Vasdekis, V; Dima, K; Douzenis, A

2018-05-01

Several lines of evidence point to a probable relationship between brain-derived neurotrophic factor (BDNF) and autism spectrum disorder (ASD), but studies have yielded inconsistent findings on the BDNF serum level in ASD. The study aimed to assess those levels in children with ASD and their families. BDNF serum levels were measured in 45 ASD children without intellectual disability (ID) and allergies, age 30-42 months and age-matched normal controls. BDNF serum levels in the parents of the ASD subjects were compared to normal controls. BDNF serum levels in the ASD subjects were followed up for 3 years and correlated with adaptive functioning changes. BDNF serum levels were measured to be lower in children with ASD and independent of all the major baseline characteristics of the subjects. Having a child with ASD raises the BDNF levels in parents comparing to controls. Prospectively, no correlation between the change of BDNF variables in time and the change of the Vineland scores was found. Our results contradict those from recent published meta-analyses with the age, the presence of ID and allergies being possible contributing factors. The parents' data indeed point to a role of BDNF in the pathophysiology of ASD. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Reduced Brain GABA in Primary Insomnia: Preliminary Data from 4T Proton Magnetic Resonance Spectroscopy (1H-MRS)

PubMed Central

Winkelman, John W.; Buxton, Orfeu M.; Jensen, J. Eric; Benson, Kathleen L.; O'Connor, Shawn P.; Wang, Wei; Renshaw, Perry F.

2008-01-01

Study Objectives: Both basic and clinical data suggest a potential significant role for GABA in the etiology and maintenance of primary insomnia (PI). Proton magnetic resonance spectroscopy (1H-MRS) can non-invasively determine GABA levels in human brain. Our objective was to assess GABA levels in unmedicated individuals with PI, using 1H-MRS. Design and Setting: Matched-groups, cross-sectional study conducted at two university-based hospitals. Participants: Sixteen non-medicated individuals (8 women) with PI (mean age = 37.3 +/− 8.1) and 16 (7 women) well-screened normal sleepers (mean age = 37.6 +/− 4.5). Methods and Measurements: PI was established with an unstructured clinical interview, a Structured Clinical Interview for DSM-IV (SCID), sleep diary, actigraphy and polysomnography (PSG). 1H-MRS data were collected on a Varian 4 Tesla magnetic resonance imaging/spectroscopy scanner. Global brain GABA levels were averaged from samples in the basal ganglia, thalamus, and temporal, parietal, and occipital white-matter and cortex. Results: Average brain GABA levels were nearly 30% lower in patients with PI (.18 +/− .06) compared to controls (.25 +/− .11). GABA levels were negatively correlated with wake after sleep onset (WASO) on two independent PSGs (r = −0.71, p = 0.0024 and −0.70, p = 0.0048). Conclusions: Our preliminary finding of a global reduction in GABA in non-medicated individuals with PI is the first demonstration of a neurochemical difference in the brains of those with PI compared to normal sleeping controls. 1H-MRS is a valuable tool to assess GABA in vivo, and may provide a means to shed further light on the neurobiology of insomnia. Citation: Winkelman JW; Buxton OM; Jensen JE; Benson KL; O'Connor SP; Wang W; Renshaw PF. Reduced brain GABA in primary insomnia: preliminary data from 4T proton magnetic resonance spectroscopy (1H-MRS). SLEEP 2008;31(11):1499–1506. PMID:19014069

Post-stroke acquired amusia: A comparison between right- and left-brain hemispheric damages.

PubMed

Jafari, Zahra; Esmaili, Mahdiye; Delbari, Ahmad; Mehrpour, Masoud; Mohajerani, Majid H

2017-01-01

Although extensive research has been published about the emotional consequences of stroke, most studies have focused on emotional words, speech prosody, voices, or facial expressions. The emotional processing of musical excerpts following stroke has been relatively unexplored. The present study was conducted to investigate the effects of chronic stroke on the recognition of basic emotions in music. Seventy persons, including 25 normal controls (NC), 25 persons with right brain damage (RBD) from stroke, and 20 persons with left brain damage (LBD) from stroke between the ages of 31-71 years were studied. The Musical Emotional Bursts (MEB) test, which consists of a set of short musical pieces expressing basic emotional states (happiness, sadness, and fear) and neutrality, was used to test musical emotional perception. Both stroke groups were significantly poorer than normal controls for the MEB total score and its subtests (p < 0.001). The RBD group was significantly less able than the LBD group to recognize sadness (p = 0.047) and neutrality (p = 0.015). Negative correlations were found between age and MEB scores for all groups, particularly the NC and RBD groups. Our findings indicated that stroke affecting the auditory cerebrum can cause acquired amusia with greater severity in RBD than LBD. These results supported the "valence hypothesis" of right hemisphere dominance in processing negative emotions.

Aging process alters hippocampal and cortical secretase activities of Wistar rats.

PubMed

Bertoldi, Karine; Cechinel, Laura Reck; Schallenberger, Bruna; Meireles, Louisiana; Basso, Carla; Lovatel, Gisele Agustini; Bernardi, Lisiane; Lamers, Marcelo Lazzaron; Siqueira, Ionara Rodrigues

2017-01-15

A growing body of evidence has demonstrated amyloid plaques in aged brain; however, little attention has been given to amyloid precursor protein (APP) processing machinery during the healthy aging process. The amyloidogenic and non-amyloidogenic pathways, represented respectively by β- and α-secretases (BACE and TACE), are responsible for APP cleavage. Our working hypothesis is that the normal aging process could imbalance amyloidogenic and non-amyloidogenic pathways specifically BACE and TACE activities. Besides, although it has been showed that exercise can modulate secretase activities in Alzheimer Disease models the relationship between exercise effects and APP processing during healthy aging process is rarely studied. Our aim was to investigate the aging process and the exercise effects on cortical and hippocampal BACE and TACE activities and aversive memory performance. Young adult and aged Wistar rats were subjected to an exercise protocol (20min/day for 2 weeks) and to inhibitory avoidance task. Biochemical parameters were evaluated 1h and 18h after the last exercise session in order to verify transitory and delayed exercise effects. Aged rats exhibited impaired aversive memory and diminished cortical TACE activity. Moreover, an imbalance between TACE and BACE activities in favor of BACE activity was observed in aged brain. Moderate treadmill exercise was unable to alter secretase activities in any brain areas or time points evaluated. Our results suggest that aging-related aversive memory decline is partly linked to decreased cortical TACE activity. Additionally, an imbalance between secretase activities can be related to the higher vulnerability to neurodegenerative diseases induced by aging. Copyright © 2016 Elsevier B.V. All rights reserved.

Neocortical glial cell numbers in human brains.

PubMed

Pelvig, D P; Pakkenberg, H; Stark, A K; Pakkenberg, B

2008-11-01

Stereological cell counting was applied to post-mortem neocortices of human brains from 31 normal individuals, age 18-93 years, 18 females (average age 65 years, range 18-93) and 13 males (average age 57 years, range 19-87). The cells were differentiated in astrocytes, oligodendrocytes, microglia and neurons and counting were done in each of the four lobes. The study showed that the different subpopulations of glial cells behave differently as a function of age; the number of oligodendrocytes showed a significant 27% decrease over adult life and a strong correlation to the total number of neurons while the total astrocyte number is constant through life; finally males have a 28% higher number of neocortical glial cells and a 19% higher neocortical neuron number than females. The overall total number of neocortical neurons and glial cells was 49.3 billion in females and 65.2 billion in males, a difference of 24% with a high biological variance. These numbers can serve as reference values in quantitative studies of the human neocortex.

Changes in period mRNA levels in the brain and division of labor in honey bee colonies

PubMed Central

Toma, Dan P.; Bloch, Guy; Moore, Darrell; Robinson, Gene E.

2000-01-01

Previous research showed that age-related division of labor in honey bees is associated with changes in activity rhythms; young adult bees perform hive tasks with no daily rhythms, whereas older bees forage with strong daily rhythms. We report that this division of labor is also associated with differences in both circadian rhythms and mRNA levels of period, a gene well known for its role in circadian rhythms. The level of period mRNA in the brain oscillated in bees of all ages, but was significantly higher at all times in foragers. Elevated period mRNA levels cannot be attributed exclusively to aging, because bees induced to forage precociously because of a change in social environment had levels similar to normal age foragers. These results extend the regulation of a “clock gene” to a social context and suggest that there are connections at the molecular level between division of labor and chronobiology in social insects. PMID:10841583

Alterations in expression of Cat-315 epitope of perineuronal nets during normal ageing, and its modulation by an open-channel NMDA receptor blocker, memantine.

PubMed

Yamada, Jun; Ohgomori, Tomohiro; Jinno, Shozo

2017-06-15

The perineuronal net (PNN), a specialized aggregate of the extracellular matrix, is involved in neuroprotection against oxidative stress, which is now recognized as a major contributor to age-related decline in brain functions. In this study, we investigated the age-related molecular changes of PNNs using monoclonal antibody Cat-315, which recognizes human natural killer-1 (HNK-1) glycan on aggrecan-based PNNs. Western blot analysis showed that the expression levels of Cat-315 epitope in the hippocampus were higher in middle-aged (MA, 12-month-old) mice than in young adult (YA, 2-month-old) mice. Although there were no differences in the expression levels of Cat-315 epitope between old age (OA, 20-month-old) and MA mice, Cat-315 immunoreactivity was also detected in astrocytes of OA mice. To focus on Cat-315 epitope in PNNs, we used YA and MA mice in the following experiments. Optical disector analysis showed that there were no differences in the numbers of Cat-315-positive (Cat-315 + ) PNNs between YA and MA mice. Fluorescence intensity analysis indicated that Cat-315 immunoreactivity in PNNs increased with age in the dorsal hippocampus, which is mainly involved in cognitive functions. Administration of an open-channel blocker of NMDA receptor, memantine, reduced the expression levels of Cat-315 epitope in the hippocampus. Furthermore, the numbers of glutamatergic and GABAergic terminals colocalized with Cat-315 epitope around parvalbumin-positive neurons were decreased by memantine. These findings provide novel insight into the involvement of PNNs in normal brain ageing, and suggest that memantine may counteract the age-related alterations in expression levels of Cat-315 epitope via regulation of its subcellular localization. © 2017 Wiley Periodicals, Inc.

Impacts of Chromatin States and Long-Range Genomic Segments on Aging and DNA Methylation

PubMed Central

Sun, Dan; Yi, Soojin V.

2015-01-01

Understanding the fundamental dynamics of epigenome variation during normal aging is critical for elucidating key epigenetic alterations that affect development, cell differentiation and diseases. Advances in the field of aging and DNA methylation strongly support the aging epigenetic drift model. Although this model aligns with previous studies, the role of other epigenetic marks, such as histone modification, as well as the impact of sampling specific CpGs, must be evaluated. Ultimately, it is crucial to investigate how all CpGs in the human genome change their methylation with aging in their specific genomic and epigenomic contexts. Here, we analyze whole genome bisulfite sequencing DNA methylation maps of brain frontal cortex from individuals of diverse ages. Comparisons with blood data reveal tissue-specific patterns of epigenetic drift. By integrating chromatin state information, divergent degrees and directions of aging-associated methylation in different genomic regions are revealed. Whole genome bisulfite sequencing data also open a new door to investigate whether adjacent CpG sites exhibit coordinated DNA methylation changes with aging. We identified significant ‘aging-segments’, which are clusters of nearby CpGs that respond to aging by similar DNA methylation changes. These segments not only capture previously identified aging-CpGs but also include specific functional categories of genes with implications on epigenetic regulation of aging. For example, genes associated with development are highly enriched in positive aging segments, which are gradually hyper-methylated with aging. On the other hand, regions that are gradually hypo-methylated with aging (‘negative aging segments’) in the brain harbor genes involved in metabolism and protein ubiquitination. Given the importance of protein ubiquitination in proteome homeostasis of aging brains and neurodegenerative disorders, our finding suggests the significance of epigenetic regulation of this posttranslational modification pathway in the aging brain. Utilizing aging segments rather than individual CpGs will provide more comprehensive genomic and epigenomic contexts to understand the intricate associations between genomic neighborhoods and developmental and aging processes. These results complement the aging epigenetic drift model and provide new insights. PMID:26091484

Resilient protein co-expression network in male orbitofrontal cortex layer 2/3 during human aging.

PubMed

Pabba, Mohan; Scifo, Enzo; Kapadia, Fenika; Nikolova, Yuliya S; Ma, Tianzhou; Mechawar, Naguib; Tseng, George C; Sibille, Etienne

2017-10-01

The orbitofrontal cortex (OFC) is vulnerable to normal and pathologic aging. Currently, layer resolution large-scale proteomic studies describing "normal" age-related alterations at OFC are not available. Here, we performed a large-scale exploratory high-throughput mass spectrometry-based protein analysis on OFC layer 2/3 from 15 "young" (15-43 years) and 18 "old" (62-88 years) human male subjects. We detected 4193 proteins and identified 127 differentially expressed (DE) proteins (p-value ≤0.05; effect size >20%), including 65 up- and 62 downregulated proteins (e.g., GFAP, CALB1). Using a previously described categorization of biological aging based on somatic tissues, that is, peripheral "hallmarks of aging," and considering overlap in protein function, we show the highest representation of altered cell-cell communication (54%), deregulated nutrient sensing (39%), and loss of proteostasis (35%) in the set of OFC layer 2/3 DE proteins. DE proteins also showed a significant association with several neurologic disorders; for example, Alzheimer's disease and schizophrenia. Notably, despite age-related changes in individual protein levels, protein co-expression modules were remarkably conserved across age groups, suggesting robust functional homeostasis. Collectively, these results provide biological insight into aging and associated homeostatic mechanisms that maintain normal brain function with advancing age. Copyright © 2017 Elsevier Inc. All rights reserved.