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No / Flavonoids are plant-derived polyphenolic compounds with neuroprotective properties. Recent work suggests that, in addition to acting as hydrogen donors, they activate protective signalling pathways. The anti-oxidant response element (ARE) promotes the expression of protective proteins including those required for glutathione synthesis (xCT cystine antiporter, gamma-glutamylcysteine synthetase and glutathione synthase). The use of a luciferase reporter (ARE-luc) assay showed that the dietary flavan-3-ol (-)epicatechin activates this pathway in primary cortical astrocytes but not neurones. We also examined the distribution of NF-E2-related factor-2 (Nrf2), a key transcription factor in ARE-mediated gene expression. We found, using immunocytochemistry, that Nrf2 accumulated in the nuclei of astrocytes following exposure to tert-butylhydroquinone (100 microM) and (-)epicatechin (100 nM). (-)Epicatechin signalling via Nrf2 was inhibited by wortmannin implicating a phosphatidylinositol 3-kinase-dependent pathway. Finally, (-)epicatechin increased glutathione levels in astrocytes consistent with an up-regulation of ARE-mediated gene expression. Together, this suggests that flavonoids may be cytoprotective by increasing anti-oxidant gene expression.

La complexité de la forme de la surface est une caractéristique morphologique des surfaces pliées. Dans cette thèse, nous visons à développer des méthodes spectrales pour quantifier cette caractéristique du cortex cérébral humain reconstruit à partir d'images MR structurales. Tout d'abord, nous suggérons certaines propriétés qu'une mesure standard de la complexité de surface devrait posséder. Ensuite, nous proposons deux définitions claires de la complexité de la surface en fonction des propriétés de flexion de surface. Pour quantifier ces définitions, nous avons étendu la transformée de Fourier à fenêtres illustrée récemment pour transformer en maillage des surfaces. Grâce à certaines expériences sur les surfaces synthétiques, nous montrons que nos mesures basées sur la courbure permettent de surmonter les surfaces classiques basées sur la surface, ce qui ne distingue pas les plis profonds des oscillants ayant une surface égale. La méthode proposée est appliquée à une base de données de 124 sujets adultes en bonne santé. Nous définissons également la complexité de la surface par la régularité de Hölder des mouvements browniens fractionnés définis sur les collecteurs. Ensuite, pour la première fois, nous développons un algorithme de régression spectrale pour quantifier la régularité de Hölder d'une surface brownienne fractionnée donnée en estimant son paramètre Hurst H. La méthode proposée est évaluée sur un ensemble de sphères browniennes fractionnées simulées. En outre, en supposant que le cortex cérébral est une surface brownienne fractionnée, l'algorithme proposé est appliqué pour estimer les paramètres Hurst d'un ensemble de 14 corticus cérébraux fœtaux. / Surface shape complexity is a morphological characteristic of folded surfaces. In this thesis, we aim at developing some spectral methods to quantify this feature of the human cerebral cortex reconstructed from structural MR images. First, we suggest some properties that a standard measure of surface complexity should possess. Then, we propose two clear definitions of surface complexity based on surface bending properties. To quantify these definitions, we extended the recently introduced graph windowed Fourier transform to mesh model of surfaces. Through some experiments on synthetic surfaces, we show that our curvature-based measurements overcome the classic surface area-based ones which may not distinguish deep folds from oscillating ones with equal area. The proposed method is applied to a database of 124 healthy adult subjects. We also define the surface complexity by the Hölder regularity of fractional Brownian motions defined on manifolds. Then, for the first time, we develop a spectral-regression algorithm to quantify the Hölder regularity of a given fractional Brownian surface by estimating its Hurst parameter H. The proposed method is evaluated on a set of simulated fractional Brownian spheres. Moreover, assuming the cerebral cortex is a fractional Brownian surface, the proposed algorithm is applied to estimate the Hurst parameters of a set of 14 fetal cerebral cortices.

Indiana University-Purdue University Indianapolis (IUPUI) / Epigenetic alterations have been shown to control cell type specification and differentiation leading to the changes in chromatin structure and organization of many genes. HDACs have been well documented to play an important role in both neurogenesis and gliogenesis in ganglionic eminence and cortex-derived cultures. However, the role of HDACs in glial cell type specification and differentiation in the optic nerve has not been well described. As a first step towards understanding their role in glial cell type specification, we have examined histone acetylation and methylation levels as well as the expression levels and patterns of the classical HDACs in both murine and chick optic nerve. Analysis of mRNA and protein levels in the developing optic nerve indicated that all 11 members of the classical HDAC family were expressed, with a majority declining in expression as development proceeded. Based on the localization pattern in both chick and murine optic nerve glial cells, we were able to group the classical HDACs: predominantly nuclear, nuclear and cytoplasmic, predominantly cytoplasmic. Nuclear expression of HDACs during different stages of development studied in this project in both murine and chick optic nerve glial cells suggests that HDACs play a role in stage-dependent changes in gene expression that accompany differentiation of astrocytes and oligodendrocytes. Examination of localization pattern of the HDACs is the first step towards identifying the specific HDACs involved directly in specification and differentiation of glia in optic nerve.

No / Recent studies have revealed extensive cortical demyelination in patients with progressive multiple sclerosis (MS). Demyelination in gray matter lesions is associated with activation of microglia. Macrophages and microglia are known to express myeloperoxidase (MPO) and generate reactive oxygen species during myelin phagocytosis in the white matter. In the present study we examined the extent of microglial activation in the cerebral cortex and the relationship of microglial activation and MPO activity to cortical demyelination. Twenty-one cases of neuropathologically confirmed multiple sclerosis, with 34 cortical lesions, were used to assess microglial activation. HLA-DR immunolabeling of activated microglia was significantly higher in demyelinated MS cortex than control cortex and, within the MS cohort, was significantly greater within cortical lesions than in matched non-demyelinated areas of cortex. In homogenates of MS cortex, cortical demyelination was associated with significantly elevated MPO activity. Immunohistochemistry revealed MPO in CD68-positive microglia within cortical plaques, particularly toward the edge of the plaques, but not in microglia in adjacent non-demyelinated cortex. Cortical demyelination in MS is associated with increased activity of MPO, which is expressed by a CD68-positive subset of activated microglia, suggesting that microglial production of reactive oxygen species is likely to be involved in cortical demyelination.

INTRODUÇÃO: Apesar da importância dos medicamentos antidepressivos no tratamento dos transtornos de humor e de ansiedade, sua ação sobre sistemas cerebrais responsáveis pela expressão emocional ainda não foram claramente estabelecidos. Estudos recentes têm examinando o sinal dependente de nível de oxigenação sanguínea (do inglês, \"BOLD\") durante estímulos emocionais em indivíduos saudáveis sob uso de antidepressivos. Nesse estudo, pretendemos estender essa avaliação às alterações do humor e comportamento emocional devido ao uso prolongado de um antidepressivo bloqueador de serotonina e noradrenalina em pessoas saudáveis. MÉTODOS: foram selecionados dezesseis voluntários, sem antecedentes psiquiátricos pessoais ou familiares, que participaram de um ensaio farmacológico simples-cego de quatro semanas de doses baixas de clomipramina (até 40 mg/dia). Ao final desse período, dez sujeitos foram selecionados como não responsivos, e os restantes seis sujeitos foram selecionados como responsivos por apresentarem claras mudanças em três dos quatro seguintes critérios: tolerância interpessoal, eficiência, bem estar, e mudança substancial em sua auto percepção. O grupo de sujeitos classificados como responsivos foram submetidos a um ensaio controlado duplo-cego confirmatório. A aquisição de imagens cerebrais ocorreu após quatro semanas de uso de medicação (simples cego) e quatro semanas após a sua suspensão, ao final da participação no ensaio farmacológico. O imageamento cerebral foi realizado durante a indução de estados afetivos de felicidade, irritabilidade e neutros por relatos autobiográficos. A resposta emocional desses estados foi obtida por escalas de auto avaliação de ansiedade, irritabilidade e felicidade. As diferenças de sinal entre os estados afetivos foram utilizadas para a análise estatística da interação dos efeitos estado medicamentoso e grupo por testes ANOVA. RESULTADOS: Foi encontrada uma interação significativa entre o efeito de grupo e o estado medicamentoso sobre os estados afetivos de irritabilidade, mas não sobre os de felicidade. Se observou redução na auto avaliação de ansiedade no grupo responsivo com o uso de medicação na diferença entre os estados induzidos de irritabilidade e felicidade, em comparação com o efeito no grupo não responsivo; e também, redução na auto avaliação de felicidade com o uso de clomipramina na totalidade da amostra, na diferença entre o estados induzidos de irritabilidade e neutro. A alteração sobre o efeito BOLD (p < 0,005) foi localizada em regiões adjacentes à junção frontoparietal para a indução de irritabilidade em relação à felicidade e em relação aos estados neutros, no grupo responsivo em relação ao não responsivo, durante o período em uso relativo àquele sem uso de clomipramina, e na junção têmporo-paríeto-occipital, exclusivamente para a diferença irritabilidade-felicidade. CONCLUSÕES: a modificação favorável que sujeitos saudáveis apresentaram ao uso prolongado de um antidepressivo bloqueador da serotonina e noradrenalina, pode estar relacionada à modificação no processamento cerebral da memória autobiográfica de emoções negativas / INTRODUCTION: despite the importance of antidepressant agents to the treatment of anxiety and depressive disorders, there is not yet a clear understanding of their actions upon specific brain systems relevant to emotional processing. Recent studies have examined blood oxygen level dependent (BOLD) signal during emotion stimuli in healthy individuals in antidepressant use. The study intends to extend these measures to the changes over mood and emotional behavior by prolonged use of a serotonin and noradrenaline blocker antidepressant. METHODS: we selected sixteen subjects, with no personal or family history of psychiatric disorders, which participated of a four-week single-blind trial with low doses of clomipramine (up to 40mg/day). After this period, ten subjects were classified as non responsives, the remaining six subjects being classified as responsives because clomipramine provided positive changes in three of four of the following criteria: interpersonal tolerance, self-efficacy, mood and self-perception of a substantial change. Responsives were included in a placebo-controlled confirmatory trial. Imaging sessions occurred at the end of the four-week course of clomipramine and again after a four-week clomipramine washout period, at the end of pharmacological trial. Subjects were scanned during the induction of irritability, happiness and neutral affective states by autobiographical recall. Self-report assessment was performed for each induction by anxiety, irritability and happiness scales. Inter-condition differences (affective induction) were used in the analysis of interaction of medication status and group effects by ANOVA tests. RESULTS: A significant interaction was found between group and treatment during irritability, but not during happiness emotions. It was observed a reduction in the scale of self-evaluation of anxiety in responsive group with the use of medication to the difference between irritability-happiness states, compared to the non responsive group; and a reduction in auto evaluation of happiness, in the totality of the sample in use of clomipramine, in difference irritability-neutral. There was a significant increase of BOLD effect in the responsive group during use relative to the period without use of clomipramine, compared to the effect on non-responsive group (p < 0.005). This effect was located in regions that surround the frontoparietal junction to the irritability relative to happiness and to irritability relative to neutral induction, and in the temporo-parieto-occipital junction, exclusively to the irritability relative to happiness induction. CONCLUSIONS: The favorably changes in healthy subjects who respond to prolonged serotonin and noradrenaline blocker use, may relate to changes in neural processes of autobiographical memory of negative emotions

Aquesta tesi demostra que el peroxinitrit produït com a conseqüència del pèptid beta-amiloide (A&#61538;) contribueix l'augment de la relació A&#61538;42/A&#61538;40 que ocorre a la malaltia d'Alzheimer. L'A&#61538;42 contribueix a l'aparició de la malaltia degut a la seva major toxicitat (quan es compara amb l'A&#61538;40) que resulta d'una gran estabilitat i capacitat agregativa. A més el peroxinitrit incrementa la toxicitat d'aquest degut a què potencia la seva agregació en forma d'oligomers altament tòxics. De fet els oligomers formats de nitro-A&#61538;42 presenten una major toxicitat que aquells formats de A&#61538;42 . En conjunt aquest resultats senyalen l'important paper que l'A&#61538;42 té en la malaltia d'Alzheimer. Per altra banda, des de la identificació dels agregats d'A&#61538; i la subseqüent formació dels cabdells neurofibrilars (NFT) com a els dos trets distintius de la malaltia, un gran esforç s'ha dedicat a establir els mecanismes moleculars que uneixen ambdós processos. Aquesta tesi demostra que el peroxinitrit format a partir de l'agregació de d'A&#61538;&#61472;i la conseqüent nitrotirosinació de proteïnes, potencia l'agregació de la proteïna tau en forma de fibres. D'aquesta forma, la nitrotirosinació de la proteïna triosafosfat isomerasa (TPI) podria ser el vincle entre la toxicitat derivada del agregats d'A&#61538;&#61472;i la patologia derivada de la proteïna tau. Per tant, la nitrotirosinació de la TPI podria explicar la progressió temporal que ocorre als cervells de pacients amb la malaltia d'Alzheimer des de la toxicitat induïda per l'A&#61538;&#61472;i l'aparició dels NFT. Els resultats presentats en aquesta tesi podrien obrir nous aspectes en la recerca de la malaltia d'Alzheimer així com en altres malalties que cursin amb estrès oxidatiu i plegament erroni de proteïnes. / This thesis demonstrates that amyloid ß-peptide (Aß)-induced peroxynitrite contributes to the switch of the A&#946;42/A&#946;40 ratio that occurs in Alzheimer's disease (AD). Since A&#946;42 is more toxic due to its higher aggregation and stability, it contributes to the trigger of the disease. In addition the aggregation of A&#946;42 in form of the highly toxic oligomers is incremented by the presence of peroxynitrite. Moreover, these nitro-Aß42 oligomers are more toxic than those non-nitrated. All these results support the important role of peroxynitrite in AD etiology. Furthermore, since the identification of Aß accumulation and the subsequent formation of neurofibrillary tangles (NFT) as the two defining pathological hallmarks of AD, a fair amount of research on AD has been driven by the need to find the molecular mechanism linking Aß and NFT. This thesis shows the Aß-induced peroxynitrite, and the consequent nitrotyrosination of proteins, promotes tau fibrillization. Thus triosephosphate isomerase (TPI) nitrotyrosination could be the link between Aß-induced toxicity and tau pathology. Therefore, TPI nitrotyrosination may explain the temporal progression from Aß toxicity to NFT formation in AD brain. The work presented in this thesis could open a novel angle in the research of the pathophysiology of AD and could also have an impact to the research in other neurodegenerative diseases involving oxidative stress and protein misfolding.

INTRODUÇÃO: Apesar da importância dos medicamentos antidepressivos no tratamento dos transtornos de humor e de ansiedade, sua ação sobre sistemas cerebrais responsáveis pela expressão emocional ainda não foram claramente estabelecidos. Estudos recentes têm examinando o sinal dependente de nível de oxigenação sanguínea (do inglês, \"BOLD\") durante estímulos emocionais em indivíduos saudáveis sob uso de antidepressivos. Nesse estudo, pretendemos estender essa avaliação às alterações do humor e comportamento emocional devido ao uso prolongado de um antidepressivo bloqueador de serotonina e noradrenalina em pessoas saudáveis. MÉTODOS: foram selecionados dezesseis voluntários, sem antecedentes psiquiátricos pessoais ou familiares, que participaram de um ensaio farmacológico simples-cego de quatro semanas de doses baixas de clomipramina (até 40 mg/dia). Ao final desse período, dez sujeitos foram selecionados como não responsivos, e os restantes seis sujeitos foram selecionados como responsivos por apresentarem claras mudanças em três dos quatro seguintes critérios: tolerância interpessoal, eficiência, bem estar, e mudança substancial em sua auto percepção. O grupo de sujeitos classificados como responsivos foram submetidos a um ensaio controlado duplo-cego confirmatório. A aquisição de imagens cerebrais ocorreu após quatro semanas de uso de medicação (simples cego) e quatro semanas após a sua suspensão, ao final da participação no ensaio farmacológico. O imageamento cerebral foi realizado durante a indução de estados afetivos de felicidade, irritabilidade e neutros por relatos autobiográficos. A resposta emocional desses estados foi obtida por escalas de auto avaliação de ansiedade, irritabilidade e felicidade. As diferenças de sinal entre os estados afetivos foram utilizadas para a análise estatística da interação dos efeitos estado medicamentoso e grupo por testes ANOVA. RESULTADOS: Foi encontrada uma interação significativa entre o efeito de grupo e o estado medicamentoso sobre os estados afetivos de irritabilidade, mas não sobre os de felicidade. Se observou redução na auto avaliação de ansiedade no grupo responsivo com o uso de medicação na diferença entre os estados induzidos de irritabilidade e felicidade, em comparação com o efeito no grupo não responsivo; e também, redução na auto avaliação de felicidade com o uso de clomipramina na totalidade da amostra, na diferença entre o estados induzidos de irritabilidade e neutro. A alteração sobre o efeito BOLD (p < 0,005) foi localizada em regiões adjacentes à junção frontoparietal para a indução de irritabilidade em relação à felicidade e em relação aos estados neutros, no grupo responsivo em relação ao não responsivo, durante o período em uso relativo àquele sem uso de clomipramina, e na junção têmporo-paríeto-occipital, exclusivamente para a diferença irritabilidade-felicidade. CONCLUSÕES: a modificação favorável que sujeitos saudáveis apresentaram ao uso prolongado de um antidepressivo bloqueador da serotonina e noradrenalina, pode estar relacionada à modificação no processamento cerebral da memória autobiográfica de emoções negativas / INTRODUCTION: despite the importance of antidepressant agents to the treatment of anxiety and depressive disorders, there is not yet a clear understanding of their actions upon specific brain systems relevant to emotional processing. Recent studies have examined blood oxygen level dependent (BOLD) signal during emotion stimuli in healthy individuals in antidepressant use. The study intends to extend these measures to the changes over mood and emotional behavior by prolonged use of a serotonin and noradrenaline blocker antidepressant. METHODS: we selected sixteen subjects, with no personal or family history of psychiatric disorders, which participated of a four-week single-blind trial with low doses of clomipramine (up to 40mg/day). After this period, ten subjects were classified as non responsives, the remaining six subjects being classified as responsives because clomipramine provided positive changes in three of four of the following criteria: interpersonal tolerance, self-efficacy, mood and self-perception of a substantial change. Responsives were included in a placebo-controlled confirmatory trial. Imaging sessions occurred at the end of the four-week course of clomipramine and again after a four-week clomipramine washout period, at the end of pharmacological trial. Subjects were scanned during the induction of irritability, happiness and neutral affective states by autobiographical recall. Self-report assessment was performed for each induction by anxiety, irritability and happiness scales. Inter-condition differences (affective induction) were used in the analysis of interaction of medication status and group effects by ANOVA tests. RESULTS: A significant interaction was found between group and treatment during irritability, but not during happiness emotions. It was observed a reduction in the scale of self-evaluation of anxiety in responsive group with the use of medication to the difference between irritability-happiness states, compared to the non responsive group; and a reduction in auto evaluation of happiness, in the totality of the sample in use of clomipramine, in difference irritability-neutral. There was a significant increase of BOLD effect in the responsive group during use relative to the period without use of clomipramine, compared to the effect on non-responsive group (p < 0.005). This effect was located in regions that surround the frontoparietal junction to the irritability relative to happiness and to irritability relative to neutral induction, and in the temporo-parieto-occipital junction, exclusively to the irritability relative to happiness induction. CONCLUSIONS: The favorably changes in healthy subjects who respond to prolonged serotonin and noradrenaline blocker use, may relate to changes in neural processes of autobiographical memory of negative emotions

Indiana University-Purdue University Indianapolis (IUPUI) / Magnetic resonance (MR) spectroscopy is a neuroimaging technique. It is widely used to quantify the concentration of important metabolites in a brain tissue. Imbalance in concentration of brain metabolites has been found to be associated with development of neurological impairment. There has been increasing trend of using MR spectroscopy as a diagnosis tool for neurological disorders. We established statistical methodology to analyze data obtained from the MR spectroscopy in the context of the HIV associated neurological disorder. First, we have developed novel methodology to study the association of marker of neurological disorder with MR spectrum from brain and how this association evolves with time. The entire problem fits into the framework of scalar-on-function regression model with individual spectrum being the functional predictor. We have extended one of the existing cross-sectional scalar-on-function regression techniques to longitudinal set-up. Advantage of proposed method includes: 1) ability to model flexible time-varying association between response and functional predictor and (2) ability to incorporate prior information. Second part of research attempts to study the influence of the clinical and demographic factors on the progression of brain metabolites over time. In order to understand the influence of these factors in fully non-parametric way, we proposed LongCART algorithm to construct regression tree with longitudinal data. Such a regression tree helps to identify smaller subpopulations (characterized by baseline factors) with differential longitudinal profile and hence helps us to identify influence of baseline factors. Advantage of LongCART algorithm includes: (1) it maintains of type-I error in determining best split, (2) substantially reduces computation time and (2) applicable even observations are taken at subject-specific time-points. Finally, we carried out an in-depth analysis of longitudinal changes in the brain metabolite concentrations in three brain regions, namely, white matter, gray matter and basal ganglia in chronically infected HIV patients enrolled in HIV Neuroimaging Consortium study. We studied the influence of important baseline factors (clinical and demographic) on these longitudinal profiles of brain metabolites using LongCART algorithm in order to identify subgroup of patients at higher risk of neurological impairment. / Partial research support was provided by the National Institutes of Health grants U01-MH083545, R01-CA126205 and U01-CA086368