INTRODUCCIÓN: El envejecimiento es un factor de riesgo para enfermedades neurodegenerativas como la Enfermedad de Alzheimer (EA), que constituye la demencia más frecuente. Uno de los objetivos de la comunidad científica, actualmente, es el diagnóstico precoz de la EA en fases previas de la demencia, es decir, detectar muy tempranamente el daño cerebral que inicialmente se manifiesta como un síndrome de la memoria y que con el tiempo evolucionará a un síndrome de demencia. Esta tesis se centrado en la EA y su fase prodrómica que se manifiesta como el síndrome denominado Deterioro Cognitivo Leve (DCL), y especialmente, en el estudio de las características cerebrales que confieren a determinadas personas una resistencia a la manifestación del daño cerebral asociado al envejecimiento o a los estadios iniciales de la demencia, ya que es un área de máximo interés en investigación en neurociencia, ya que si se consiguen comprender los mecanismos específicos, podrán mejorarse las estrategias dirigidas a paliar el impacto del deterioro cognitivo en la edad avanzada. METODOLOGÍA: La presente tesis consiste en cuatro estudios, prospectivos transversales, que examinan cómo las bases neuroanatómicas y neurofuncionales de la RC modulan tanto la estructura cómo la función cerebral en envejecimiento sano y patológico. Para la realización de los estudios se ha utilizado una muestra y diversas aproximaciones neuropsicológicas y de resonancia magnética estructural y funcional. OBJETIVO: Investigar los correlatos neuroanatómicos y neurofuncionales de la reserva cognitiva o cerebral en CTR, DCL-a y EA. RESULTADOS:En el envejecimiento sano, los sujetos con altos índices de RC, volumétricamente, muestran una mayor preservación de la integridad de la SB. Funcionalmente, se observa utilización de menos recursos cerebrales durante el procesamiento de tareas cognitivas de comprensión lingüística y percepción visual compleja.En la patología, altos índices de RC comportan una mayor atrofia cerebral y daño en la sustancia blanca. Funcionalmente, correlacionan positivamente con la intensidad de activaciones y negativamente con las desactivaciones del ‘patrón de activación por reposo’ o ‘default mode network’ (DMN) durante el procesamiento cognitivo. Altos índices de RC permite a los pacientes con DCL-a el uso de redes cerebrales alternativas.CONCLUSIONES: Los estudios descritos en esta tesis aportan evidencia de que el nivel de implicación a lo largo de la vida en actividades de tipo mental o intelectual, social y físico modula la estructura y función del cerebro. En definitiva, el concepto de RC permite explicar la resistencia y compensación que muestran algunos cerebros a manifestar clínicamente un proceso patológico subyacente.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2010. / Härtill 4 uppsatser.

The purpose of the current thesis was twofold: (1) to examine various factors that might be contributing to age-related learning and memory deficits specifically related to the hippocampus, and (2) to validate our rat model of aging, employing a multilevel analysis. We found age-related deficits on both spatial and non-spatial hippocampus-dependent taks that were accompanied by structural alterations observed in vivo (volune, but not neuronal metabolic function) and post mortem (neuronal density and neurogenesis, but not synaptic or mitochondrial density). Furthermore, our results suggest that the observed hippocampal structural changes, named decreased volume and neurogenesis, predict learning and memory deficits, and both can be accounted for by neurogenic reduction. In addition, the above-mentioned pattern of age-related deficits closely resembles that seen in humans, suggesting the present rat version of aging to be a very useful model for investigating hippocampal aging in humans. / iii, 236 leaves : ill. (some col.) ; 29 cm.

Diffusion Tensor Magnetic Resonance Imaging was used to examine the age-related changes in white matter structural integrity in the common chimpanzee. Fractional Anisotropy(FA), a measure derived from the diffusion tensor data is sensitive to developmental and pathological changes in axonal density, myelination, size and coherence of organization of fibers within a voxel and thus reflects the white matter structural integrity. There is substantial evidence that white matter structural integrity decreases with age in humans. The long-term goal of this study is to compare the age-related changes in the white matter structural integrity among humans and chimpanzess to provide potential insights into the unique features of human aging. Different methods, including Region Of Interest (ROI) analysis, Tract Based Spatial Statistics (TBSS) are used to describe age-related changes in FA in a group of 21 chimpanzees. Strengths and limitations of these methods were discussed.

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

Obesity is an important global health factor due to associated comorbidities and its pervasive occurrence. In my thesis, I aimed to contribute to a better understanding of the mechanisms that underlie obesity development as well as its adverse consequences in the brain. Both studies analyzed subsets of the LIFE-Adult study, a deeply-phenotyped, cross-sectional cohort study based on the general population of Leipzig. In the first study, I investigated the association of compulsive eating, a specific type of obesity-associated eating behavior, body mass index (BMI) and gray matter structure. Compulsive eating behavior, was selectively associated with cortical thickness of the right lateral orbitofrontal cortex, a region important for impulse control. Higher BMI was related to widespread reductions of cortical thickness. Orbitofrontal cortex structure may therefore predict compulsive eating behavior, while higher BMI is associated with decreased cortical thickness even in young and middle-aged adults. In the second study, I focused on the link between BMI, functional brain networks and cognitive function in older adults. Here, higher BMI was related to reduced connectivity of the default mode network, a network of brain regions known as a biomarker of aging and dementia. This finding demonstrates that functional connectivity may be an biomarker allowing to detect obesity-associated brain changes at an early stage. Taken together, these findings support the view of obesity as a risk factor for brain health. Yet, more longitudinal studies are needed to confirm this and reveal the underlying mechanisms.:List of Abbreviations i Table of Figures ii 1. Introduction 1 1.1 Central regulation of food intake 1 1.2 Characteristics of addictive-like eating behavior 3 1.3 Obesity as a risk factor for brain damage and cognitive decline 5 1.4 Assessment of brain structure and function with magnetic resonance imaging 8 1.4.1 A very short introduction to MRI 8 1.4.2 Structural MRI: Measuring the size and shape of the brain 8 1.4.3 Resting state functional MRI: Investigating the intrinsic brain architecture 10 2. Published studies 12 2.1 Neuroanatomical correlates of food addiction symptoms and body mass index in the general population 12 2.2 Higher body mass index is associated with reduced posterior default mode connectivity in older adults 24 3. Summary 38 References 43 Appendix 54 Supplementary Information for “Neuroanatomical correlates of food addiction symptoms and body mass index in the general population” 54 Author contributions to the publication “Neuroanatomical correlates of food addiction and body mass index in the general population” 59 Author contributions to the publication “Higher body mass index is associated with reduced posterior default mode connectivity in older adults” 60 Declaration of Authenticity 61 Curriculum Vitae 62 List of publications 63 List of conference contributions 65 Acknowledgments 66

Brain aging is a heterogeneous phenomenon, and this thesis illustrates how the course of aging can vary within individuals over time and between individuals as a function of age, sex, and genetic variability. We used two contrasts from magnetic resonance imaging (MRI), namely spin-lattice T1-weighted imaging, and quantitative susceptibility mapping (QSM) from gradient-echo images, to picture the aging brain, by means of morphometric measures and brain-iron concentrations. Within each study, the same rigorous imaging acquisitioning protocols were used over large samples sizes of 167-183 individuals, which contribute to the uniqueness of the studies. Most of the current knowledge about the aging brain rests on the foundation of cross-sectional age-related differences, and studies I and III contribute to current knowledge with longitudinal designs to investigate individual rates of change. The importance of genetic variation in relation to regional brain changes was addressed with a specific emphasis on functional polymorphisms involved in pro-inflammatory responses. These studies further shed light on the importance of bi-directional relations between structural integrity and maintained cognitive abilities over time. Study II is the largest study to date to have quantitative susceptibility estimates examined in healthy adults, and the first in-vivo report to show a lowering in overall subcortical brain iron estimates in women from midlife to old age. Studies I and III are unique by examining longitudinal differences in anatomical brain regions using high resolution images from a 4 Tesla scanner. Peripheral vascular risk factors were not strong determinants of either brain- or cognitive changes in the studied samples. The results are discussed in the context of cognitive reserve, the brain maintenance hypothesis, and potential influences of hormones, inflammation and oxidative stress.

No description available.

L’augmentation de la longévité et une meilleure prise en charge des maladies cardiovasculaires entraînent un accroissement de la fréquence des maladies liées au vieillissement cérébral, les accidents vasculaires cérébraux (AVC) et la démence étant les plus fréquents. Les marqueurs IRM de vieillissement cérébrovasculaire (hypersignaux de la substance blanche [HSB], infarctus silencieux, microhémorragies) sont de forts prédicteurs d’AVC et de démence, très fréquents en population générale âgée et facilement mesurables. Nous avons étudié l’association entre des composantes du métabolisme lipidique (taux de lipides plasmatiques, génotype ε de l’Apolipoprotéine E [APOE]) et les marqueurs IRM de vieillissement cérébrovasculaire. Nous rapportons dans une revue systématique et méta-analyse que l’allèle APOEε4 est associé à un volume accru de HSB et à un risque accru de microhémorragies et que l’allèle APOEε2 est associé avec un volume accru de HSB et une fréquence plus élevée d’infarctus silencieux. Nous rapportons dans les études 3C-Dijon et EVA, que les taux croissants de triglycérides (TG) sont associés à un volume accru de HSB et à une fréquence plus élevée de lacunes (petits infarctus silencieux). Enfin nous avons exploré la signification clinique de ces associations dans l’étude 3C. Nous rapportons que des taux plus élevés de TG, LDL-cholestérol, et cholestérol total sont associés à un risque accru de démence et de ses sous-types, en population générale âgée de 74 ans à l’inclusion et suivie pendant 12 ans. Nous concluons que le métabolisme lipidique est associé aux marqueurs IRM de vieillissement cérébrovasculaire et à la démence. / Increasing longevity and improved management of cardiovascular diseases has led to an increase in the frequency of age-related neurological diseases, especially stroke and dementia. MRI markers of vascular brain injury (white matter hyperintensities [WMH], silent infarcts and microbleeds) are powerful predictors of stroke and dementia, very frequent in the elderly, and can be measured easily. We studied the association between some components of lipid metabolism (plasma lipid levels, Apolipoprotein E [APOE] ε genotype) and MRI markers of vascular brain injury. We found in a systematic review with meta-analysis that the ε4 allele of the APOE gene is associated with larger WMH volume and a higher frequency of cerebral microbleeds, and that the APOEε2 allele is associated with larger WMH volume and a higher frequency of silent brain infarcts. We also report in the 3C-Dijon Study and in the EVA study that higher triglyceride levels are associated with an increased WMH volume and with a higher frequency of silent lacunar (small subcortical) brain infarcts. Finally, we investigated the clinical significance of these associations the 3C Study. We observed that higher triglycerides, LDL-cholesterol and total cholesterol levels, were associated with an increased risk of all dementia and its subtypes, in community persons aged 74 years at baseline and followed for up to 12 years. We conclude that lipid metabolism is associated with MRI-markers of cerebrovascular aging and dementia.

O processo de envelhecimento é acompanhado por um declínio nas funções cognitivas, principalmente, de funções fluidas ou de processamento. Essas diminuições são pelo menos, em parte, devido a alterações estruturais e funcionais do sistema nervoso central. Uma abordagem para estudar as mudanças funcionais é a medição da utilização metabólica regional da glicose, ou, alternativamente, um parâmetro físico correlacionado ao metabolismo cerebral e à atividade funcional local, como o fluxo sanguíneo cerebral (CBF). Neste contexto, em Imagens por Ressonância Magnética (IRM), a técnica de Marcação dos Spins Arteriais (ASL) surge como uma importante ferramenta não invasiva para análises perfusionais. Seu uso não só permite avaliar a perfusão sanguínea cerebral, gerando mapas quantitativos de CBF, mas também fornecer uma alternativa para estudar a conectividade funcional (FC), um parâmetro importante para descrição da topologia e funcionalidade cerebral. Sessenta e três indivíduos saudáveis, na faixa etária entre dezoito à setenta e dois anos, foram recrutados para participar deste estudo. Análises estatísticas mostram uma diminuição de CBF em várias regiões cerebrais, especialmente nos lobos frontal e temporal, que acompanham o processo de envelhecimento. As medidas de FC foram obtidas em análises por regiões de interesse e teoria de grafos; estas também demostraram uma diminuição, com o avanço da idade, em regiões presentes nos lobos frontal e temporal, mas também relataram um maior número de regiões prejudicadas no lobo parietal. Portanto, usando uma técnica de imagem não invasiva, foi possível observar déficits de CBF além de alterações de aspectos da organização funcional, oferecendo valores quantitativos que podem ajudar na melhor descrição dos efeitos do envelhecimento na hemodinâmica cerebral. / Aging process is accompanied by a decline in cognitive functions foremost comprise fluid or processing-based functions. These decreases are at least partly due to structural and functional deteriorating changes of the central nervous system. One approach to study these functional changes is the measurement of the regional metabolic utilization of glucose, or, alternatively, a physical quantity correlated to cerebral metabolism and local functional activity, such as the cerebral blood flow (CBF). In this context, Arterial spin labeling (ASL) emerges as a noninvasive Magnetic Resonance Imaging (MRI) perfusion technique. Its use not only allows assessing cerebral perfusion, by generating CBF values, but also can provide an alternative to study functional connectivity (FC), which is an important parameter that describes the brain topology and functionality. Sixty-three healthy subjects, from age eighteen to seventy-two years, were recruited to participate in this study. ASL-CBF maps showed a decrease in several brain regions, especially in frontal and temporal lobes that follows aging process. FC measures were assessed with regions of interest (ROI-to-ROI) and graph theory analysis, also showing a decrease in regions present in frontal and temporal lobes, and also more impaired regions in the parietal lobe. Therefore, using a noninvasive imaging technique it was possible to observe CBF deficits besides alteration in aspects on functional organization, offering quantitative values that can help to describe better the aging effects on cerebral hemodynamics.