Brain-reactive antibodies (BRA) increase in frequency with age in several mammalian species and may be involved in the pathogenesis of age-related dementia. In this experiment, the molecular specificity of BRA in mouse sera was determined using an immunoblot assay, and the relationship of BRA to longevity was studied by comparing the rate of formation of specific BRAs in diet restricted C57BL/6NNia, B6D2F1/NNia, and DBA/2NNia, genotypes which differ markedly in life-span.

The role cholesterol plays in the brain has long been underappreciated even though the brain contains a disproportionately high percentage of body cholesterol. Recent studies have found a link between the dysregulation of lipid metabolism and the risk of acquiring Alzheimer’s disease (AD) as well as a predisposition to cognitive decline. The goal of these studies was to elucidate the possible role lipid metabolism plays in pathological and normal brain aging by pharmacologically manipulating lipid metabolism and determining effects on key hippocampal biomarkers of AD and age-related cognitive decline. One series of experiments used an agonist (TO901317) to the liver X receptor (LXR) in two transgenic AD mouse models. Chronic LXR activation reduced AD associated pathology and improved cognitive performance in AD mouse models. However, long-term potentiation (LTP) was not enhanced and peripheral side effects were observed. In another series of experiments the effects of chronically inhibiting cholesterol synthesis on cognitive aging in rats was determined. Animals were treated with either of two commonly prescribed statins, simvastatin or atorvastatin. Simvastatin, the more lipophilic statin, increased LTP and reduced the duration of the afterhyperpolarization (AHP). In addition, simvastatin upregulated key genes of the cholesterol synthesis pathway in the hippocampus as revealed by microarray analyses, but was associated with impaired performance in the Morris Water Maze, a hippocampal dependent task. Atorvastatin, a less lipophilic statin, reduced the AHP, but did not affect LTP or cognitive performance. Atorvastatin modulated a very different set of genes and reduced brain cholesterol more than simvastatin. These results suggest that manipulation of cholesterol metabolism selectively modulates key aspects of AD and brain aging.

Numerous studies have suggested that neuropsychological test performance is affected by demographic variables such as age and education. This study examined the effects of age and education on the Trail Making Test, the Digit Symbol Sub-Test, and the Finger Tapping Test in a non-clinical sample of community dwellers with a relatively low level of education (8 to 12 years) in South Africa. The sample consisted of 161 participants across six age groups: 20-39, 40-59, 69-69, 70-79, 80-89 and 90-95 years. Results were examined for mean age effects and variability trends. Highly significant age effects were present across the age groups for all tests, however, there was no uniform pattern of variability across the tests. The Digit Symbol Substitution Test and the Finger Tapping Tests showed a pattern of increasing variability with increasing age, followed by a decrease in very old age while no trend was evident for the Digit Symbol extensions (the Immediate and Delayed Recall tests). The Trail Making Test, Parts A and B, showed a consistent trend of increasing variability across the age groups. Data from the present study was compared with existing data from two relatively high education samples, with equivalent age groupings, to examine education effects. Results showed an education effect for all tests with the high education groups outperforming the low education groups. Although the effects of education became less potent with advancing age, the mean performance of the oldest (80-89 years) high education age group was superior to that of the equivalent low education age group. Comparison of variability trends across both samples showed that the highest variability (the shuttle bulge) was present at the same point along the age axis, or at a later point, for the low education group, as that for the high education group. This finding is inconsistent with Jordan's (1997) 'shuttle model of variability' which predicts an earlier occurrence of the shuttle bulge (left shuttle shift effect) for a low education sample. This study demonstrated that performance on neuropsychological tests is influenced by age and education and highlighted the dangers inherent in unquestionably applying norms, which have not been corrected for age and education, when assessing the older adult.

No description available.

The hypothesis that the right cerebral hemisphere declines more quickly than the left cerebral hemisphere in the normal aging process was tested in two studies using a facial recognition and a response time task. In Study 1, subjects (N=60) were asked to identify facial affect fram 50 standardized photographs of 5 affective categories: Happy, Neutral, Sad, Angry, and Fearful, and were asked to rate the intensity of each photograph. The results of the analysis indicate that the elderly group was significantly less accurate at identifying negative and neutral affective expressions than the younger group, with no significant differences seen between groups in the identification of positive affect. The results also indicate that the elderly rated the affective expressions as being significantly more intense than the younger group. Study 2 (N=60) investigated response times for the recognition of the affective stimuli as 4 function of visual field of presentation and valence of the stimuli, using the same subject population. The results of this analysis reveal that the elderly show an increase in cerebral lateralization in comparison to the younger group. The elderly exhibited increased response times to negative affect presented to the left hemisphere. The results of this study also indicate that both groups had faster response times to positive affect, and that both groups had a response bias in favor of positive affect when neutral facial affective slides were presented to the left hemisphere. The results are interpreted as partially supporting the right hemi-aging theory. The elderly showed a diminished ability to identify negative affect across both studies, suggestive of lowered right hemisphere functioning. However, the increased rather than decreased cerebral asymmetry in the response time task, and slower response times to negative affect presented to the left hemisphere are suggestive of bilateral changes in affective processing for the elderly. Overall, these findings suggest that the elderly have more difficulty processing negative affect, while their ability to process positive affect remains intact. This finding has implications for research using facial affective paradigms designed for use with younger subjects, and suggests the need for more studies of emotional aging processes in normal populations. / Ph. D.

Much of the research on differential hemispheric activation as a function of age or the presence of depression suggests that a relative decrease in left hemisphere activation is associated with depression, while a decrease of right hemisphere activation is associated with age. Recent research, however, has demonstrated the role of the right hemisphere in maintaining general behavioral arousal. Pilot data suggest that elderly people experience behavioral over-arousal when presented with stressful or novel environmental stimuli. Equally interesting is the finding in a single-case study that ambient light and noise have a differential effect on behavior presumed to be representative of the left and the right cerebral hemispheres. The left hemisphere appears to be more responsive to ambient light level, with the right hemisphere being more responsive to ambient noise level. The present study sought to provide further support of selective hemispheric activation to bright light, and to examine the relationships among hemi-activation, age and depression by using behavioral measures of lateral anterior (finger tapping rate) and posterior (dichotic listening) cortical functioning. Two identical experiments were employed to evaluate old and young, and depressed and non-depressed sUbjects. Direct evidence of right herni-aging effects on laterality was not significant in the first experiment, but data suggested the possibility of a ceiling effect for behavioral arousal in the older group which was not seen in younger subjects. The second experiment yielded no significant results between depressed and non-depressed groups. Hypotheses of under and over arousal in subjects are proposed to explain findings. Possible implications for treatment and recommendations for further research are proposed. / Ph. D.

<p>The aim of the present thesis was to study sex differences in memory and other cognitive bilities in healthy adults. In Study I, participants performed a number of episodic memory tasks that were more or less verbal in nature. Results showed that women performed on a higher level than did men in the episodic memory tasks where it was possible to use verbal labels, whereas men performed on a higher level than did women in a visuospatial episodic memory task. In Study II, women’s advantage in face recognition was investigated.Results showed that women performed at a higher level than did men only in the recognition of other women’s faces. In Study III, sex differences in cognitive tasks as well as brain measures were investigated in healthy older adults. Results showed that only the sex differences in a motor task could, to some extent, be explained by sex differences in one of the brain measures. The findings, as well as possible explanations for these patterns of results, are discussed in a theoretical context.</p>

Com a redução progressiva dos custos de sequenciamento completo do genoma humano, os estudos populacionais tornam-se viáveis. A interpretação dos dados e integração com informações clínicas, entretanto, apresentam-se como desafios crescentes. O conhecimento sobre a variabilidade genética e sua interação com fenótipos complexos podem ser ampliados com estudos de grande porte em populações miscigenadas, em particular de sociedades com heterogeneidades sociais, culturais e históricas, ainda pouco representadas globalmente na área da genômica. Este trabalho apresenta um conjunto de estudos colaborativos que se basearam em uma amostra de natureza representativa de idosos da cidade de São Paulo (amostra SABE, aproximadamente 1400 indivíduos) e em de octogenários cognitivamente saudáveis (amostra 80+, aproximadamente 130 indivíduos). Além de questionários e testes, DNA dos participantes foi obtido e exomas sequenciados para cerca de 600 indivíduos. Esta base permitiu a construção de grupos controles para diversos estudos de associação de variantes causais ou de suscetibilidade a doenças raras como distrofia muscular de cinturas, tumores do sistema endócrino e síndrome de Noonan, entre outras, além de integrar, como referência populacional local, o sistema de análise de variantes do serviço de diagnóstico molecular do Centro de Pesquisas sobre o Genoma Humano e Células-tronco da Universidade de São Paulo. Por ser uma amostra de idosos, além de permitir a construção de uma base eficiente para controles comparativos de doenças raras ou de início precoce, tornou-se possível a execução de projetos sobre envelhecimento cerebral através do recrutamento cerca de 580 indivíduos para ressonância magnética. Estudos com marcadores de demências, como polimorfismos do gene APOE (associado à doença de Alzheimer) indicaram que a população brasileira apresenta riscos diferenciais em relação a populações de outros países, provavelmente devido à estrutura populacional única do ponto de vista de ancestralidade genética e composição socio-econômica. Por fim, os estudos com ressonância magnética e genômica permitiram a investigação do fenótipo de lateralidade cerebral, que engloba dominâncias manual e de linguagem, que está presente de forma variável em seres humanos e está envolvida com distúrbios neuropsiquiátricos como dislexia e esquizofrenia. Foi possível detectar associação entre variantes do gene FOXP2, implicado no neurodesenvolvimento da linguagem, e endofenótipos assimétricos de tratos de substância branca envolvidos na produção da fala. O presente trabalho abre caminho para diversos novos projetos dada a escala de dados sociodemográficas, clínicos, funcionais e genômicos / Due to the progressive reduction of genome sequencing costs, population studies become feasible. Interpretation of subsequent data and integration with clinical information, however, impose a growing challenge. The knowledge about genetic variability and its interaction with complex phenotypes could be expanded with large scale admixed population studies, particularly in those samples that live in socially, culturally and historically heterogeneous communities, so far globally underrepresented in the genomics field. This thesis presents a collection of collaborative studies that were based on a population-representative sample of elderly from the city of São Paulo (SABE sample, approximately 1400 subjects) and a cognitively healthy octogenarians sample (80+ group, approximately 130 subjects). Comprehensive questionnaires and functional tests were obtained, along with DNA from all subjects and exome sequences from about 600 of them. This database allowed the assembly of control groups to several association studies with causal and susceptibility variants to rare disorders such as limb-girdle muscular dystrophy, endocrine system tumors and Noonan syndrome, among others, and, in addition, composed as a local population reference the analyses\' protocols in the molecular diagnosis service of the Human Genome and Stem-cell Research Center at the University of São Paulo. As this is an elderly sample, it was possible not only to build an efficient control group to compare with patients affected by rare or early onset disorders, but to promote projects on brain aging through recruitment of about 580 subjects to magnetic resonance imaging (MRI). Studies with markers of dementia, such as APOE gene polymorphisms (involved in Alzheimer\'s disease), suggested that the Brazilian population might present different risks compared to other countries, probably due to its unique population structure from the genetic ancestry standpoint and socioeconomic composition. As a final project, MRI and genomics studies were performed to investigate the phenotype of brain laterality, which comprises handedness and language dominance and it is variable among humans, with involvement with neuropsychiatric disorders such as dyslexia and schizophrenia. It was possible to detect an association between variants of FOXP2 gene, which is involved in neurodevelopmental processes of language, and asymmetry endophenotypes of white matter tracts that form the speech production circuitry. This effort opens several pathways to develop new projects due to the scale of sociodemographic, clinical, functional and genomic data

La tomographie par émission de positons au 18F-Fluorodésoxyglucose (TEP au 18F-FDG) est une technique d’imagerie permettant de quantifier le métabolisme glycolytique cérébral. L’objectif de nos travaux de thèse était d’essayer de caractériser au mieux les modifications cérébrales liées au vieillissement, y compris la partie possiblement liée à des dysfonctions vasculaires, grâce à une analyse quantitative tridimensionnelle voxel-à-voxel des images de TEP au 18F-FDG. Nos travaux montrent, tout d’abord, qu’il existe un intérêt pratique à utiliser un logiciel de normalisation spatial particulier (BM : Block Matching) pour l’analyse quantitative cérébrale, au moins pour la fabrication de modèles anatomiques (« template ») adaptés à chaque population étudiée. Cet intérêt a été tout d’abord montré pour localiser des foyers épileptiques temporaux, puis pour quantifier l’impact de l’âge sur le métabolisme cérébral (détermination plus précise des aires cérébrales affectées). Avec cette méthode, il est possible d’observer une diminution du métabolisme cérébral tout au long de la vie, en particulier dans certaines aires frontales. Nous avons essayé de déterminer la composante du vieillissement cérébral qui est possiblement liée à une dysfonction vasculaire et qui serait donc susceptible d’être traitée ou prévenue par des thérapeutiques vasculaires appropriées. Dans ce domaine de recherche, nous avons pu montrer que les anomalies micro-vasculaires de la substance blanche, appelées leucoaraïose, étaient associées à une diminution du métabolisme de la substance grise, en particulier au niveau frontal. Cet effet était indépendant de l’effet spécifique de l’âge et du phénomène d’atrophie corticale. Enfin, dans une population de patients âgés et à forte prévalence d’hypertension artérielle, nous avons montré que la pression artérielle était étroitement corrélée au remodelage métabolique cérébral, en particulier lorsque cette pression est mesurée au niveau central et lorsque l’on tient compte de la pression différentielle, avec alors une valeur seuil de 50 mmHg. Le vieillissement cérébral global et l’accélération qui peut être liée à des facteurs vasculaires sont des données qui peuvent être estimées en TEP au 18F-FDG, avec une méthode d’analyse quantitative voxel-à-voxel adaptée. Cette identification pourrait peut-être guider la prescription de traitements vasculaires appropriés et aussi, aider à différencier ces atteintes liées à l’âge ou d’origine vasculaire des autres maladies cérébrales. / 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) is a brain-imaging technique allowing brain glycolytic metabolism to be quantified. The aim of this doctoral thesis work was to try to better characterize the aging-related changes in brain metabolism, including the part with a possible vascular origin, thanks to a three-dimensional voxel-based quantitative analysis of 18F-FDG PET images. Our work shows firstly that there is a clear advantage to use a particular spatial normalization software (BM: Block Matching) for the brain quantitative analysis, at least for the providing of templates adapted to each study population. This advantage was shown, initially, for the localization of temporal epileptic foci and thereafter, for quantifying the age-related changes in brain metabolism (enhanced determination of the involved brain areas). With this method, a decrease in brain metabolism could be documented throughout the life especially within certain frontal areas. In addition, we tried to determine the component of cerebral aging, which might be of a vascular origin and thus, susceptible to be treated or prevented by vascular treatments. In this research field, we have shown that microvascular abnormalities, setting within white-matter and called leukoaraiosis, were associated with a decrease in the grey-matter metabolism, in particular within certain frontal areas. This effect was independent of the inherent effect of age and of cortical atrophy. Finally, in a population of older patients with a high prevalence of hypertension, we showed that the blood pressure level was correlated to a brain metabolic remodeling, especially when this pressure was measured at central level and when considering the pulse pressure and a threshold value of 50 mmHg. The global cerebral aging and its acceleration in relation to vascular factors may be assessed by 18F-FDG PET when using an adapted voxel-based quantitative method. This assessment could potentially be useful for the monitoring of vascular treatments and for differentiating the aging- and vascular-related metabolic changes to those corresponding to brain diseases of other origins.

The aim of the present thesis was to study sex differences in memory and other cognitive bilities in healthy adults. In Study I, participants performed a number of episodic memory tasks that were more or less verbal in nature. Results showed that women performed on a higher level than did men in the episodic memory tasks where it was possible to use verbal labels, whereas men performed on a higher level than did women in a visuospatial episodic memory task. In Study II, women’s advantage in face recognition was investigated.Results showed that women performed at a higher level than did men only in the recognition of other women’s faces. In Study III, sex differences in cognitive tasks as well as brain measures were investigated in healthy older adults. Results showed that only the sex differences in a motor task could, to some extent, be explained by sex differences in one of the brain measures. The findings, as well as possible explanations for these patterns of results, are discussed in a theoretical context.