Les commotions cérébrales ont longtemps été considérées comme une blessure ne comportant que peu ou pas de conséquences. Cependant, la mise à la retraite forcée de plusieurs athlètes de haut niveau, liée au fait d'avoir subi des commotions cérébrales multiples, a porté cette question au premier plan de la culture scientifique et sportive. Malgré la sensibilisation croissante du public et la compréhension scientifique accrue des commotions cérébrales, il reste encore beaucoup d’inconnus au sujet de ces blessures. En effet, il est difficile de comprendre comment cette atteinte peut avoir des effets si profonds malgré le fait qu’elle n’entraîne apparemment pas de conséquences physiques apparentes lorsque les techniques traditionnelles d’imagerie cérébrale sont utilisées. Les techniques de neuroimagerie fonctionnelle ont cependant contribué à répondre aux nombreuses questions entourant les conséquences des commotions cérébrales ainsi qu'à accroître la compréhension générale de la physiopathologie de commotions cérébrales. Bien que les techniques de base telles que l'imagerie structurelle comme les scans TC et IRM soient incapables de détecter des changements structurels dans la grande majorité des cas (Ellemberg, Henry, Macciocchi, Guskiewicz, & Broglio, 2009; Johnston, Ptito, Chankowsky, & Chen, 2001), d'autres techniques plus précises et plus sensibles ont été en mesure de détecter avec succès des changements dans le cerveau commotionné. Des études d’IRM fonctionelle ont entre autres établi une solide relation entre les altérations fonctionnelles et les symptômes post-commotionels (Chen, Johnston, Collie, McCrory, & Ptito, 2007; Chen et al., 2004; Chen, Johnston, Petrides, & Ptito, 2008; Fazio, Lovell, Pardini, & Collins, 2007). Les mesures électrophysiologiques telles que les potentiels évoqués cognitifs (ERP) (Gaetz, Goodman, & Weinberg, 2000; Gaetz & Weinberg, 2000; Theriault, De Beaumont, Gosselin, Filipinni, & Lassonde, 2009; Theriault, De Beaumont, Tremblay, Lassonde, & Jolicoeur, 2010) et la stimulation magnétique transcrânienne ou SMT (De Beaumont, Brisson, Lassonde, & Jolicoeur, 2007; De Beaumont, Lassonde, Leclerc, & Theoret, 2007; De Beaumont et al., 2009) ont systématiquement démontré des altérations fonctionnelles chez les athlètes commotionnés. Cependant, très peu de recherches ont tenté d'explorer davantage certaines conséquences spécifiques des commotions cérébrales, entre autres sur les plans structural et métabolique. La première étude de cette thèse a évalué les changements structurels chez les athlètes commotionnés à l’aide de l'imagerie en tenseur de diffusion (DTI) qui mesure la diffusion de l'eau dans la matière blanche, permettant ainsi de visualiser des altérations des fibres nerveuses. Nous avons comparé les athlètes commotionnés à des athlètes de contrôle non-commotionnés quelques jours après la commotion et de nouveau six mois plus tard. Nos résultats indiquent un patron constant de diffusion accrue le long des voies cortico-spinales et dans la partie du corps calleux reliant les régions motrices. De plus, ces changements étaient encore présents six mois après la commotion, ce qui suggère que les effets de la commotion cérébrale persistent bien après la phase aiguë. Les deuxième et troisième études ont employé la spectroscopie par résonance magnétique afin d'étudier les changements neurométaboliques qui se produisent dans le cerveau commotionné. La première de ces études a évalué les changements neurométaboliques, les aspects neuropsychologiques, et la symptomatologie dans la phase aiguë post-commotion. Bien que les tests neuropsychologiques aient été incapables de démontrer des différences entre les athlètes commotionnés et non-commotionnés, des altérations neurométaboliques ont été notées dans le cortex préfrontal dorsolatéral ainsi que dans le cortex moteur primaire, lesquelles se sont avérées corréler avec les symptômes rapportés. La deuxième de ces études a comparé les changements neurométaboliques immédiatement après une commotion cérébrale et de nouveau six mois après l’atteinte. Les résultats ont démontré des altérations dans le cortex préfrontal dorsolatéral et moteur primaire dans la phase aiguë post-traumatique, mais seules les altérations du cortex moteur primaire ont persisté six mois après la commotion. Ces résultats indiquent que les commotions cérébrales peuvent affecter les propriétés physiques du cerveau, spécialement au niveau moteur. Il importe donc de mener davantage de recherches afin de mieux caractériser les effets moteurs des commotions cérébrales sur le plan fonctionnel. / Concussions had long been considered an injury of little to no consequence. However, the forced retirement of several high profile athletes due to the impact of having suffered multiple concussions has pushed the issue to the forefront of scientific and sports culture alike. Despite the growing public awareness and the ever-expanding scientific understanding of concussions there is still much that remains unknown about these injuries. Indeed, understanding how an injury can have such profound effects, though mostly transient, without any apparent physical consequence continues to confound how concussions are conceptualized in research. Neuroimaging techniques have helped answer many of the questions surrounding the physical consequences of concussions on the brain as well as increasing the general understanding of the pathophysiology of concussions. While basic structural imaging techniques such as CT scans and MRI are unable to detect any structural changes in the vast majority of cases (Ellemberg, et al., 2009; Johnston, et al., 2001), other more precise and sensitive techniques have been able to successfully detect changes in the concussed brain. Functional MRI studies have further established a strong relationship between functional alterations and post-concussion symptoms (Chen, et al., 2007; Chen, et al., 2004; Chen, et al., 2008; Fazio, et al., 2007). Electrophysiological measures such as ERP (Gaetz, et al., 2000; Gaetz & Weinberg, 2000; Theriault, et al., 2009; Theriault, et al., 2010) and TMS (De Beaumont, Brisson, et al., 2007; De Beaumont, Lassonde, et al., 2007; De Beaumont, et al., 2009) have consistently demonstrated alterations in concussed athletes. However, there has been very little research that has attempted to further explore the specific structural and metabolic aspects of concussion. The first study assessed structural changes in concussed athletes using diffusion tensor imaging which measures water diffusion in white matter. We compared concussed athletes with non-concussed control athletes in the days immediately after injury and again six months later. Our results indicated a consistent pattern of increased diffusion along neural tracts of the cortical spinal tract and in the corpus callosum underlying motor cortex. Furthermore, these changes were still present six months after injury suggesting that the effects of concussion are persistent past the acute phase. The second and third studies employed magnetic resonance spectroscopy as a means of investigating the neurometabolic changes that occur in the concussed brain. The first of these studies investigated the neurometabolic changes, neuropsychological aspects, and symptomatology in the acute post-injury phase. While neuropsychological testing was unable to show differences between concussed and non-concussed athletes, neurometabolic alterations were noted in the dorsal lateral prefrontal cortex as well as in primary motor cortex which correlated with reported symptoms. The second study investigated neurometabolic changes immediately after concussion and again six months after injury. Results indicated alterations in the dorsolateral prefrontal and primary motor cortices in the acute post-injury phase, but only those in primary motor cortex persisted to the six month time point.

INTRODUCTION: The association of Sleep-Related Movement Disorders (SRMDs) such as Restless Legs Syndrome (RLS) and Periodic Limb Movements (PLMs) with cerebrovascular disease is underexplored. Emerging evidence links them to vascular disease, for which white matter hyperintensities (WMHs) are a well-recognized biomarker. METHODS: We conducted a cross-sectional hospital-based observational study in which high-risk TIA and minor stroke patients were assessed for vascular risk factors, WMHs and polysomnography-determined sleep variables. RESULTS: Ninety-seven patients were enrolled, of whom 44 completed polysomnography. Twenty-five percent had RLS, which was associated with lower quality of life. Independent of the effect of classical vascular risk factors, PLMs (but not RLS) were associated with WMHs on linear regression analyses (p=0.016). CONCLUSIONS: SRMDs are prevalent after minor stroke/TIA. RLS is associated with poor quality of life, while PLMs are associated with WMHs. Whether PLMs are implicated in the pathogenesis of WMHs or whether WMHs exacerbate PLMs remains uncertain.

La stimulation magnétique transcrânienne (TMS) est une technique de stimulation corticale non-invasive.Depuis son apparition au milieu des années 1980, les évolutions technologiques qu’elle a connues ontconsidérablement amélioré sa fiabilité, sa précision ainsi que sa reproductibilité. Ces progrès ont favorisél’émergence d’un grand nombre d’applications, tant dans le domaine de la recherche fondamentale enneurosciences cognitives que dans celui de la recherche clinique. Cette thèse a pour objectif d’étudierles apports méthodologiques et fondamentaux de la TMS robotisée, dernière avancée technologique dudomaine. Grâce à un placement et un suivi automatisés de la bobine de stimulation, la TMS robotiséeouvre en effet la voie à l’automatisation des protocoles, ainsi qu’à l’élaboration de nouvelles approchesen neuroimagerie fonctionnelle. Les deux premières études de ce travail abordent ce premier point, enproposant le développement de deux outils nécessaires à l’automatisation du paramétrage des protocolesde TMS : CortExTool et AutoHS. CortExTool est une boîte à outils qui permet l’analyse automatisée dessignaux électromyographiques évalués durant le paramétrage, et AutoHS un modèle bayésien assurantune recherche automatique du point chaud moteur, étape essentielle de la procédure. Testée sur donnéesvirtuelles et comparée expérimentalement à la pratique manuelle d’experts sur 19 volontaires sains, laprocédure automatisée proposée ici apparaît au moins aussi fiable, tout en étant plus rapide et repro-ductible. La troisième et dernière étude de cette thèse s’attache quant à elle aux apports fondamentauxpossibles de cette technologie. Elle propose un protocole qui permet la cartographie extensive des ré-ponses électroencéphalographiques évoquées par la TMS sur 18 aires corticales réparties sur l’ensembledu néocortex. Appliquée sur 22 volontaires sains, l’analyse des propriétés dynamiques de ces réponses faitapparaître des spécificités régionales ainsi que des réseaux corticaux partageant des propriétés communes.Celles-ci étant liées aux caractéristiques cytoarchitecturales des aires stimulées, nos résultats apportent lapreuve de concept pour la cytoarchitectonie fonctionnelle, qui pourrait aboutir à une nouvelle méthodede parcellisation in vivo du cortex chez l’Homme. L’ensemble des résultats de cette thèse confirme l’intérêtde la robotisation de cette technique, qui pourrait à terme faciliter la mise en œuvre des protocoles par lescentres cliniques, et amener de nouveaux outils d’exploration fonctionnelle pour un meilleur diagnosticdes pathologies psychiatriques et neurologiques. / Transcranial Magnetic Stimulation (TMS) is a non invasive cortical stimulation tool. Major technologicalevolution has continuously increased the spatial reliability and reproducibility of TMS since its beginningin the middle of the 80’s, by minimizing the influence of human and experimental factors. Therefore, TMSestablished itself as a powerful technique for probing and treating the human brain. The aim of this thesisis to study the methodological and basics contribution of robotized TMS, as being the last technologicaladvance to date. By means of the automatic handling of the TMS coil, robotized TMS opens new avenues forthe automation of stimulation protocol, and to new approaches in functional neuroimaging. The two firststudies of this work aim at developing two tools that are still needed to achieve the automation of set-upprocedures of TMS protocols : CortExTool and AutoHS. CortExTool is a toolbox allowing the automaticanalysis of electromyographic signals, while AutoHS is a Bayesian model aiming at automatically finding themotor hotspot, which are two critical ingredients used during such procedures. We validated our automaticset-up procedure on both virtual and real data, during an experimental comparison against manual set-upprocedures on 19 healthy volunteers. Results showed that the automatic procedure was at least as reliableas the manual one, while being faster and more reproducible. The third and last study of this thesis aimed atexploring new basics approaches offered by this technology. We developed a protocol allowing the extensivemapping of evoked electroencephalographic responses on 18 cortical targets covering the whole neocortex,and tested it on 22 healthy volunteers. The analysis of the dynamical properties of these responses revealedregional specificities as well as cortical networks sharing similar properties. Our results provide the proofof concept of functional cytoarchitectonics, that would guide the parcellation of the human cortex in vivobased on its intrinsic responses to local perturbations. The results of this thesis are promising regarding thenew possibilities offered by robotized TMS. Its use could decrease the experimental variability, facilitatethe handling of TMS protocols used for research and clinical routine, and finally offer new functionalexploration approaches that could allow a better diagnosis of psychiatric and neurological pathologies.

Depuis des années, l’imagerie TEP des récepteurs 5-HT1A a permis une compréhension accrue du rôle physiopathologique de ces récepteurs. Toutefois les radiotraceurs actuels ne permettent pas d’évaluer le couplage entre récepteurs 5-HT1A et protéines G, susceptible d’être altéré au cours de pathologies. Les travaux effectués au cours de cette thèse visent à promouvoir l’utilisation de techniques d’imagerie translationnelles pour explorer le couplage des récepteurs 5-HT1A in vivo. La première partie a consisté à évaluer un agoniste des récepteurs 5-HT1A, le F13640, comme potentiel radiotraceur TEP. L’ensemble des résultats suggère que le [18F]F13640 est spécifique des récepteurs 5-HT1A couplés, avec des propriétés inédites par rapport aux radiotraceurs classiques.La deuxième partie a consisté à évaluer l’intérêt de l’imagerie des récepteurs 5-HT1A couplés. Les variations de densité de récepteurs couplés et totaux ont été comparées en autoradiographie postmortem au cours de la maladie d’Alzheimer. La fixation du [18F]F13640 dans l’hippocampe est diminuée dès les premiers stades, tandis que la fixation du [18F]MPPF n’est réduite qu’aux stades avancés. Ces observations démontrent la complémentarité entre traceurs agonistes et antagonistes des récepteurs 5-HT1A en imagerie TEP.La dernière partie s’est focalisée sur le concept d’agonisme biaisé, impliquant la possibilité de cibler différentes populations de récepteurs 5-HT1A en fonction de leur couplage aux protéines G. Le F13640 a été comparé au F15599 à doses pharmacologiques en imagerie TEP et en IRMf. Chez le rat, ces deux agonistes produisent des réponses hémodynamiques et métaboliques différentes. Chez le chat, ils diffèrent également en termes d’occupation des récepteurs et de réponse hémodynamique conséquente. L’ensemble des données est en faveur d’une stimulation préférentielle des récepteurs postsynaptiques par le F15599 par rapport aux autorécepteurs, contrairement au F13640 / Since the 1990s, PET imaging of 5-HT1A receptors has led to an increased understanding of the pathophysiological role of these receptors. However, the coupling between 5-HT1A receptors and G-proteins, which may be altered during pathologies, cannot be explored using current radiotracers. The work carried out in this thesis aims to promote the use of translational imaging techniques to explore the coupling of 5-HT1A receptors in vivo. In the first part, we evaluated the 5-HT1A receptor agonist F13640 as a PET radiotracer candidate. Taken together, the results suggest that [18F]F13640 binds specifically to coupled 5-HT1A receptors and displays novel properties and distribution pattern compared to classical 5-HT1A radiotracers. The second part was a proof-of-concept study regarding the interest of coupled 5-HT1A receptors imaging. Densities of coupled and total receptors were compared in postmortem autoradiography during Alzheimer’s disease. [18F]F13640 binding in hippocampus was decreased in the early stages, whereas [18F]MPPF binding was reduced in the advanced stages only. These results confirm the complementarity between 5-HT1A receptor agonists and antagonist tracers in PET imaging.In the last part we focused on the concept of biased agonism, which implies the possibility of targeting different populations of 5-HT1A receptors depending on their coupling with G-proteins. F13640 and F15599 were compared at pharmacological doses using PET and fMRI imaging. The two agonists produce different hemodynamic and metabolic responses in rat brain. They also differ in cat brain in terms of receptor occupancy and subsequent hemodynamic responses. Taken together, the results are consistent with a preferential stimulation of postsynaptic receptors over autoreceptors for F15599, in contrast with F13640

Introdução: Os glicocorticoides (GCs) estão envolvidos na regulação e adaptação da resposta ao estresse, exercendo seus efeitos através de seus receptores. Variações polimórficas no gene do receptor de glicocorticoide (GR) têm sido caracterizadas funcionalmente. O polimorfismo A3669G do gene do GR está relacionado a modificações na sensibilidade aos GCs e mudanças no perfil metabólico. Concentrações fisiológicas de GCs estimulam a ingestão calórica e, na presença de insulina, modificam a preferência alimentar. A variante A3669G do gene do GR parece levar a um menor risco para diabetes, em pacientes com Síndrome de Cushing, e para o tabagismo, quando associado a um polimorfismo do gene do receptor de mineralocorticoide, sugerindo uma modulação na via de recompensa. O objetivo deste trabalho é avaliar a associação de variantes do polimorfismo A3669G do gene do GR com o comportamento alimentar e parâmetros metabólicos em uma amostra de estudantes, correlacionando com dados de neuroimagem funcional. Métodos: A amostra provém de alunos de 6 escolas de Porto Alegre, avaliados em 2008 e em 2013. Em 2008, 131 indivíduos apresentavam o protocolo completo de avaliação e, destes, 74 retornaram em 2013. A avaliação incluiu genotipagem, antropometria, exames laboratoriais, comportamento alimentar e um paradigma avaliando a ativação cerebral em resposta a visualização de imagens de alimentos palatáveis, não palatáveis e de objetos neutros. A análise da associação com os fenótipos foi realizada através do teste t de Student e Chi quadrado; os dados do estudo longitudinal foram analisados por meio de Equações de Estimatição Generalizada. Resultados: A variante G do polimorfismo A3669G do gene do GR foi encontrado em 17,6% em 2008 e em 14,9% da amostra em 2013. Não houve diferença entre os grupos de carreadores do alelo G e não carreadores quanto a diferentes confundidores; a comparação entre as médias dos dois grupos sobre o consumo calórico proveniente de proteínas, carboidratos e gorduras em 2008 não revelou diferenças significativas; nesta etapa, as análises evidenciaram maior consumo de açúcares e de calorias totais no grupo não carreador do alelo G. Em 2013, estes indivíduos não carreadores do alelo G do polimorfismo A3669G apresentaram maior insulinemia e além de aumento no índice de resistência à insulina, sem diferenças no consumo alimentar. Os dados de neuroimagem funcional indicaram que a visualização de imagens de alimentos palatáveis pelo grupo não carreador do alelo G ativou o giro occipital médio, uma região implicada no processamento visual, mostrando menor ativação em giro pré central e nas áreas de Brodmann 4 e 6, relacionadas ao planejamento motor e sensibilidade ao sabor. Conclusão: Os resultados mostram que os indivíduos não carreadores da variante G do polimorfismo A3669G do gene do GR apresentaram menor sensibilidade à insulina, precedidos pela modulação na preferência alimentar. Os achados em neuroimagem funcional indicam maior saliência de incentivo aos alimentos palatáveis e predisposição à impulsividade no grupo não carreador do alelo G. Sugere-se que a redução na sensibilidade em nível celular aos GCs relacionada à presença do alelo G, afete a ingestão alimentar, reduzindo o consumo de alimentos palatáveis, diminuindo o risco para doenças metabólicas. / Introduction: Glucocorticoids are involved in regulation and adaptation of the stress response, exerting effects through its receptors. Variations on the glucocorticoid receptors genes have been characterized functionally. The A3669G polymorphism of the glucocorticoid receptor gene is related to a change in the tissue sensitivity to glucocorticoids and altered metabolic profile. Physiological concentrations of glucocorticoids stimulate food intake and in the presence of insulin affect food preferences. The G variant of the A3669G polymorphism appears to lead to a lower risk for diabetes, in patients with Cushing's syndrome, and smoking, when associated with a polymorphism of the mineralocorticoid receptor gene, suggesting a modulation in reward pathways. The objective of this study is to evaluate the association of A3669G polymorphism variants with feeding behavior and metabolic parameters in a sample of students correlating with functional neuroimaging data. Methods: The sample includes students of 6 schools in Porto Alegre, evaluated at two occasions 2008 and in 2013. In 2008, 131 individuals had complete protocol assessment and, from these, 74 returned in for re- evaluation in 2013. The evaluation included genotyping, anthropometry, laboratory tests, feeding behavior and a functional MRI paradigm to verify brain activation in response to the visualization of palatable, non- palatable foods and neutral items. The association with phenotypes was performed using Student's t test and Chi-square; longitudinal study data were evaluated using Generalized Estimating Equations. Results: The variant of the A3669G polymorphism was found in 17.6% of the students in 2008 and 14.9% of the sample in 2013. There was no difference between groups in the sample composition; the comparison between groups of the mean caloric intake originating from proteins, carbohydrates and fats in 2008 revealed no significant differences; at this time, analysis showed lower consumption of sugars and total calories in the G carrier group. In 2013, these individuals showed a reduction in insulin level and resistance, with no differences in food intake. The fMRI data indicated that viewing a food palatable image by the wild-type allele carrier group activated a region involved in visual processing (middle occipital gyrus) and deactivated an area related to motor planning and sensitivity to taste (pre central gyrus). Conclusion: The results showed that G carriers of the A3669G polymorphism of glucocorticoid receptor gene had lower insulin resistance levels, preceded by modulation of their food preference. The findings in functional neuroimaging showed increased incentive salience on viewing palatable food images and a predisposition for impulsivity in noncarriers. Data suggest that reduction in glucocorticoids sensitivity at a cellular level affects food intake, by reducing consumption of palatable foods, possibly decreasing the risk for metabolic diseases.

Orientador: Luiz Eduardo Gomes Garcia Betting / Resumo: A conectividade funcional é anormal na epilepsia do lobo temporal mesial (ELTm). O objetivo deste estudo foi investigar os efeitos de fármacos antiepilépticos (FAES) na conectividade funcional de pacientes com ELTm. Para isso, 31 pacientes com ELTm (16 à direita e 15 à esquerda) e 36 controles foram investigados. Sequências 3D volumétricas T1 e imagens funcionais a partir de sinal BOLD foram adquiridas em um equipamento 3T. Os dados da ressonância magnética funcional (RMf) em repouso foram processados e analisados utilizando o programa CONN. Para cada sujeito, duas formas de análise foram realizadas: uma de correlação entre as várias regiões de interesse e outra de região interesse para todos os voxels. A análise de grupos foi feita utilizando um modelo linear geral com nível de significância de p < 0,05 corrigido para múltiplas comparações. Foram realizadas comparações entre pacientes com ELTm (direita ou esquerda) e controles, seguidas de comparações de acordo com a carga de FAEs. A partir dessas análises, foi constatado uma redução de conectividade com volume total de 9092 mm3 (p<0,0001), em pacientes com ELTm esquerda e 5234 mm3 (p<0,0001), em pacientes com ELTm direita . Quando considerada a carga de medicação, pacientes com ELTm esquerda, recebendo doses altas, apresentaram redução de conectividade nas regiões temporais. Nos pacientes que recebiam doses baixas, essa redução atingiu uma área total mais extensa, no córtex frontal medial, na região posterior do cíngulo e p... (Resumo completo, clicar acesso eletrônico abaixo) / Doutor

Introdução: Os glicocorticoides (GCs) estão envolvidos na regulação e adaptação da resposta ao estresse, exercendo seus efeitos através de seus receptores. Variações polimórficas no gene do receptor de glicocorticoide (GR) têm sido caracterizadas funcionalmente. O polimorfismo A3669G do gene do GR está relacionado a modificações na sensibilidade aos GCs e mudanças no perfil metabólico. Concentrações fisiológicas de GCs estimulam a ingestão calórica e, na presença de insulina, modificam a preferência alimentar. A variante A3669G do gene do GR parece levar a um menor risco para diabetes, em pacientes com Síndrome de Cushing, e para o tabagismo, quando associado a um polimorfismo do gene do receptor de mineralocorticoide, sugerindo uma modulação na via de recompensa. O objetivo deste trabalho é avaliar a associação de variantes do polimorfismo A3669G do gene do GR com o comportamento alimentar e parâmetros metabólicos em uma amostra de estudantes, correlacionando com dados de neuroimagem funcional. Métodos: A amostra provém de alunos de 6 escolas de Porto Alegre, avaliados em 2008 e em 2013. Em 2008, 131 indivíduos apresentavam o protocolo completo de avaliação e, destes, 74 retornaram em 2013. A avaliação incluiu genotipagem, antropometria, exames laboratoriais, comportamento alimentar e um paradigma avaliando a ativação cerebral em resposta a visualização de imagens de alimentos palatáveis, não palatáveis e de objetos neutros. A análise da associação com os fenótipos foi realizada através do teste t de Student e Chi quadrado; os dados do estudo longitudinal foram analisados por meio de Equações de Estimatição Generalizada. Resultados: A variante G do polimorfismo A3669G do gene do GR foi encontrado em 17,6% em 2008 e em 14,9% da amostra em 2013. Não houve diferença entre os grupos de carreadores do alelo G e não carreadores quanto a diferentes confundidores; a comparação entre as médias dos dois grupos sobre o consumo calórico proveniente de proteínas, carboidratos e gorduras em 2008 não revelou diferenças significativas; nesta etapa, as análises evidenciaram maior consumo de açúcares e de calorias totais no grupo não carreador do alelo G. Em 2013, estes indivíduos não carreadores do alelo G do polimorfismo A3669G apresentaram maior insulinemia e além de aumento no índice de resistência à insulina, sem diferenças no consumo alimentar. Os dados de neuroimagem funcional indicaram que a visualização de imagens de alimentos palatáveis pelo grupo não carreador do alelo G ativou o giro occipital médio, uma região implicada no processamento visual, mostrando menor ativação em giro pré central e nas áreas de Brodmann 4 e 6, relacionadas ao planejamento motor e sensibilidade ao sabor. Conclusão: Os resultados mostram que os indivíduos não carreadores da variante G do polimorfismo A3669G do gene do GR apresentaram menor sensibilidade à insulina, precedidos pela modulação na preferência alimentar. Os achados em neuroimagem funcional indicam maior saliência de incentivo aos alimentos palatáveis e predisposição à impulsividade no grupo não carreador do alelo G. Sugere-se que a redução na sensibilidade em nível celular aos GCs relacionada à presença do alelo G, afete a ingestão alimentar, reduzindo o consumo de alimentos palatáveis, diminuindo o risco para doenças metabólicas. / Introduction: Glucocorticoids are involved in regulation and adaptation of the stress response, exerting effects through its receptors. Variations on the glucocorticoid receptors genes have been characterized functionally. The A3669G polymorphism of the glucocorticoid receptor gene is related to a change in the tissue sensitivity to glucocorticoids and altered metabolic profile. Physiological concentrations of glucocorticoids stimulate food intake and in the presence of insulin affect food preferences. The G variant of the A3669G polymorphism appears to lead to a lower risk for diabetes, in patients with Cushing's syndrome, and smoking, when associated with a polymorphism of the mineralocorticoid receptor gene, suggesting a modulation in reward pathways. The objective of this study is to evaluate the association of A3669G polymorphism variants with feeding behavior and metabolic parameters in a sample of students correlating with functional neuroimaging data. Methods: The sample includes students of 6 schools in Porto Alegre, evaluated at two occasions 2008 and in 2013. In 2008, 131 individuals had complete protocol assessment and, from these, 74 returned in for re- evaluation in 2013. The evaluation included genotyping, anthropometry, laboratory tests, feeding behavior and a functional MRI paradigm to verify brain activation in response to the visualization of palatable, non- palatable foods and neutral items. The association with phenotypes was performed using Student's t test and Chi-square; longitudinal study data were evaluated using Generalized Estimating Equations. Results: The variant of the A3669G polymorphism was found in 17.6% of the students in 2008 and 14.9% of the sample in 2013. There was no difference between groups in the sample composition; the comparison between groups of the mean caloric intake originating from proteins, carbohydrates and fats in 2008 revealed no significant differences; at this time, analysis showed lower consumption of sugars and total calories in the G carrier group. In 2013, these individuals showed a reduction in insulin level and resistance, with no differences in food intake. The fMRI data indicated that viewing a food palatable image by the wild-type allele carrier group activated a region involved in visual processing (middle occipital gyrus) and deactivated an area related to motor planning and sensitivity to taste (pre central gyrus). Conclusion: The results showed that G carriers of the A3669G polymorphism of glucocorticoid receptor gene had lower insulin resistance levels, preceded by modulation of their food preference. The findings in functional neuroimaging showed increased incentive salience on viewing palatable food images and a predisposition for impulsivity in noncarriers. Data suggest that reduction in glucocorticoids sensitivity at a cellular level affects food intake, by reducing consumption of palatable foods, possibly decreasing the risk for metabolic diseases.

Orientador: Simone Appenzeller / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-25T13:41:07Z (GMT). No. of bitstreams: 1 Barbosa_Renata_M.pdf: 1172344 bytes, checksum: 3fc9e9d779a4b94077d1d56223dc0d79 (MD5) Previous issue date: 2014 / Resumo: O nosso objetivo foi determinar a prevalência de atrofia hipocampal no lúpus eritematoso sistêmico juvenil (LESj) determinando a volumetria hipocampal por ressonância magnética e avaliar a possível relação entre atrofia hipocampal e fatores associados. Todos os pacientes com quatro ou mais critérios classificatórios de LES seguidos no ambulatório de reumatologia pediátrica com início da doença até aos 18 anos foram incluídos. Uma análise clínica e neurológica foi realizada de acordo com os critérios classificatórios do Colégio Americano de Reumatologia. Dados laboratoriais e de tratamento foram obtidos através da revisão criteriosa dos prontuários clínicos. Observamos que os volumes hipocampais dos nossos pacientes foram significativamente menores quando comparados aos volumes hipocampais dos nossos controles (p<0,001). A atrofia hipocampal foi identificada em 25 pacientes (34,72%) e no grupo controle 1 indivíduo (1,38%) apresentou atrofia hipocampal direita. A esclerose hipocampal esteve presente em 1(4%) paciente e o hipersinal em 13 (52%) pacientes. Em relação ao tratamento medicamentoso a atrofia hipocampal no LESj esteve associada ao uso de corticosteroides (p= 0,008), micofenolato mofetil (p=0,012), ciclosporina (p=0,018) e ciclosfosfamida (p=0,037). A idade de início da doença (p= 0,038) e dano cumulativo (p= 0,040) também se mostraram associados. Quanto à análise de dados laboratoriais, apenas o anticoagulante lúpico (p= 0,017) e a diminuição do complemento (p= 0,018) se mostraram associados. A esclerose hipocampal apresentou relação com pulso metilprednisolona no início da doença (p=0,023), ciclofosfamida (p=0,023) e com a função cognitiva organização perceptual, planejamento e praxia (p< 0,001). O hipersinal demonstrou associação com atrofia hipocampal (p=0,024), volume hipocampal direito (p=0,024), volume hipocampal esquerdo (p=0,007), no entanto a presença de hipersinal no hipocampo esquerdo apresentou associação apenas com a dose total de corticosteróides (p=0,034). Em relação aos domínios cognitivos, o raciocínio espacial apresentou uma correlação inversa com o volume hipocampal esquerdo (p=0,041; r= -0,281). A memória visográfica apresentou uma correlação direta com o volume hipocampal direito (p=0,042; r= 0,281). A velocidade de processamento associou-se com atrofia hipocampal (p=0,026). O raciocínio temporal demonstrou uma associação com atrofia hipocampal direita (p=0,015), atrofia hipocampal bilateral (p=0,012), e uma correlação inversa com o volume hipocampal direito (p=0,008; r= - 0,359) e volume hipocampal esquerdo (p=0,003; r= -0,400). A atrofia hipocampal é frequente no LESj. A idade de início da doença, tratamento medicamentoso e anticorpos antifosfolípides estão associados à sua ocorrência / Abstract: Our aimed was to determine the prevalence of hippocampal atrophy in childhood-onset SLE (cSLE) using manual magnetic resonance imaging (MRI) volumetric measurements and to evaluate the possible relationship between hippocampal atrophy and associated factors. All patients with four or more classification criteria for SLE, followed at the Pediatric Rheumatology Unit with diagnosis up to 18 years old was included. A clinical analysis and neurological evaluation was analyzed according to the American College of Rheumatology (ACR) classification criteria. Laboratory and treatment features were obtained through a review of clinical records. We observed that the hippocampal volumes of our patients were significantly smaller when compared hippocampal volumes to our controls (p <0.001). Hippocampal atrophy was identified in 25 patients (34.72%) and 1 (1.38%) control at the right hippocampus atrophy. Hippocampal sclerosis was present in 1 (4%) and increased signal in 13 (52%) patients. In relation to drug treatment in cSLE hippocampal atrophy was associated with the use of corticosteroids (p=0.008), mycophenolate mofetil (p=0.012), cyclosporine (p=0.018) e cyclophosphamide (p=0.037).The age of onset (p= 0.038) and cumulative damage (p= 0.040) were also associated. However the analysis of laboratory features, only lupus anticoagulant (p=0.017) and decreased complement (p=0.018) were associated. Hippocampal sclerosis showed relation with pulse methylprednisolone at disease onset (p=0.023), cyclophosphamide (p = 0.023) and cognitive function perceptual organization, planning and praxis (p <0.001). Increased signal showed association with hippocampal atrophy (p=0.024), right hippocampal volume (p=0.024), left hippocampal volume (p = 0.007). However presence of increased signal in the left hippocampus was associated with total corticosteroid dose (p=0.034). Considering cognitive domains, spatial reasoning showed inverse correlation with left hippocampal volume (p = 0.041, r = -0.281). Visografica memory showed a direct correlation with the right hippocampal volume (p= 0.042, r = 0.281). Processing speed is associated with hippocampal atrophy (p = 0.026). Temporal reasoning demonstrated an association with right hippocampal atrophy (p = 0.015), bilateral atrophy (p = 0.012) and inverse correlation with right hippocampal volume (p=0.008, r= -0.359) and left hippocampal volume (p = 0.003, r = -0.400). Hippocampal atrophy is prevalent in cSLE. The age of onset of disease, drug treatment and antiphospholipid antibodies are associated / Mestrado / Saude da Criança e do Adolescente / Mestra em Ciências

Orientadores: Leonilda Maria Barbosa dos Santos, Benito Pereira Damasceno / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-22T19:26:19Z (GMT). No. of bitstreams: 1 Silva_FelipevonGlehn_D.pdf: 6687964 bytes, checksum: 5e92607a118fbc6e4c8085aa93b540a0 (MD5) Previous issue date: 2013 / Resumo: A Neuromielite óptica (NMO) é uma doença inflamatória e desmielinizante do SNC, de natureza autoimune, caracterizada por surtos graves de neurite óptica e mielite transversa, de evolução mais freqüente na forma recidivante-remitente, com pouca remissão dos déficits entre as crises, altamente incapacitante. A presença do anticorpo anti-aquaporina 4 (anti-AQP4) foi descrito em 73% a 91% dos pacientes com diagnóstico de NMO. Doenças autoimunes podem frequentemente ser desencadeadas após infecções por micro-organismos, como agentes virais. A NMO e a infecção pelo HTLV-1 possuem prevalência coincidentemente elevada em certas áreas do globo, como o Brasil. Com o objetivo de avaliar a associação do HTLV-1 com a NMO, foi pesquisada a presença de anti-AQP4 e anti-HTLV-1 em 34 pacientes com DENMO, 43 pacientes infectados com HTLV-1, assintomáticos ou com a doença mielopatia associada ao HTLV-1 (HAM/TSP) e 23 controles sadios. Nenhum paciente com DENMO apresentou sorologia positiva para HTLV-1. Nenhum paciente infectado pelo HTLV-1 apresentou soropositividade para anti-AQP4. 60% dos casos de DENMO foram positivos para anti-AQP4. Esses resultados sugerem que a mielopatia associada à variante aguda da HAM/TSP e aquela associada ao anticorpo anti-AQP4 são entidades clínicas distintas, e provalvemente, não relacionadas de forma patogênica ao HTLV-1 em nosso meio. O cérebro humano expressa amplamente AQP4, mas estudos anatomopatológicos e de neuroimagem não detectaram lesões corticais desmielinizantes ou infiltrados inflamatórios no DENMO. A fim de avaliar melhor a presença de alterações estruturais nas substâncias cinzenta e branca encefálicas no DENMO, foram estudados 34 pacientes por RNM de 3T e tomografia de coerência óptica retiniana pareados com controles sadios, divididos nas apresentações NMO, mielite transversa longitudinal extensa (MTLE) e neurite óptica (NO), além de soropositivos versus soronegativo para anti-AQP4 e 5 anos ou menos de doença versus mais de 5 anos de doença. Houve maior grau de atrofia retiniana nos grupos NMO e NO, além dos grupos anti-AQP4+ e mais de 5 anos de doença. Foi constatado maior grau de atrofia cortical cerebral e estruturas da substância branca nos grupos NMO e MTLE, anti-AQP4+ e mais de 5 anos de doença. A atrofia retiniana se correlacionou positivamente com a atrofia do lobo occipital. Esses dados sugerem que o DENMO está associado à atrofia de estruturas das substâncias cinzenta e branca cerebrais; que a atrofia não se limita apenas às áreas das vias sensorial, motora e visual, mas é mais difusa; que quanto maior o tempo de doença e a presença do anticorpo anti-AQP4, maior é o grau de atrofia cortical, configurando estes fatores, tempo e anti-AQP4+, como de pior prognóstico; e a correlação positiva entre atrofia da camada de fibras nervosas retinianas e atrofia pericalcarina, além da escala de incapacidade funcional expandida (EDSS), sugere que a degeneração neuronal retrógrada e/ou anterógrada do tipo Walleriana é um importante causador da atrofia cortical no DENMO / Abstract: Neuromyelitis optica (NMO) is an inflammatory disease of the central nervous system (CNS) of putative autoimmune aetiology, which is characterized by severe attacks of myelitis and optic neuritis (ON). A relapsing course with rapid accumulation of neurological deficits with little or no remission is common. The NMO is autoimmune in nature and antibodies to Aquaporin 4 (AQP4) are associated with the development of the disease. AQP4 is the most common water channel protein of CNS; present in astrocytes processes, endothelium and piamater meninges. It predominates at some sites of the CNS, as optic nerve, brain stem and gray matter of medulla, the same sites of the usual inflammatory lesions. Autoimmune diseases may be triggered by microorganism infections and NMO and HTLV-1 infection have coincidentally high prevalence in certain areas of the world including Brazil. To study a possible relationship between these two diseases, we determined the seroprevalence of antibodies to AQP4 in 43 patients with HTLV-1 infection, asymptomatic or with HTLV-1 associated myelopathy (HAM/TSP) and that of HTLV-1 antibodies in patients with neuromyelitis optica spectrum disorders (NMOSD). AQP4ab positivity was found in 60% of NMOSD patients, but in none of the HAM/TSP patients and none of the asymptomatic HTLV-1 infected individuals. Conversely, all AQP4-Ab-positive NMOSD patients were negative for HTLV-1 antibodies. The results argue both against a role of antibodies to AQP4 in the pathogenesis of HAM/TSP and against an association between HTLV-1 infection and the development of AQP4-Ab. Moreover, the absence of HTLV-1 in all patients with NMOSD suggests that HTLV-1 is not a common trigger of acute attacks in patients with AQP4-Ab positive NMOSD in populations with high HTLV-1 seroprevalence. Although AQP4 is also expressed widely in the human brain cortex, beyond the common sites of lesions in NMO, recent studies have found no MRI or histopathological evidence for cortical demyelination. To investigate magnetic resonance imaging (MRI) patterns of gray matter (GM) and white matter (WM) abnormalities in patients with NMO and its incomplete forms, isolated longitudinally extensive transverse myelitis and optic neuritis, and to assess the prognostic impact of GM and WM abnormalities in these conditions, we performed both 3T high-resolution T1-weighted and diffusion tensor MRI in thirty-four patients with NMO spectrum disorders (NMOSD) and 34 matched healthy controls. Voxel-based morphometry (SPM8/MATLAB2012b), cortical analyses (Freesurfer), and diffusion tensor imaging analyses (TBSS-FSL) were used to investigate brain abnormalities. In addition, retinal nerve fiber layer was measured by means of optic coherence tomography (OCT). These analyses resulted in following findings: (1) NMOSD is associated with GM and WM atrophy, which encompasses more brain structures than the motor, sensory, and visual pathways; (2) this atrophy is more widespread in patients with NMO and LETM than in patients with ON; (3) the extent of GM atrophy correlates with disease duration, and (4) GM/WM atrophy in NMOSD is more pronounced in AQP4 antibody-seropositive than in -seronegative patients. Furthermore, it was demonstrated for the first time in NMOSD a correlation between RNFL atrophy and GM atrophy in the occipital lobes as assessed by OCT, indicating a role for retrograde degeneration in GM atrophy and suggesting that the extent of brain GM/WM atrophy may be of prognostic relevance in NMOSD / Doutorado / Neurologia / Doutor em Ciências Médicas

Le développement de nouveaux médicaments, la validation et la standardisation des marqueurs de neuroimagerie et biochimie de la Maladie d'Alzheimer (MA) seront les principaux objectifs de la recherche de cette maladie dans les années à venir. La présente thèse vise à aborder ces questions cruciales. La première partie de la thèse fait le point sur l’application correcte des Procédures Opérationelles Standards (SOPs) pour l'acquisition de protocoles de neuroimagerie structurelle et l’application des marqueurs de neuroimagerie cérébrale dans 10 cliniques italiennes spécialisées dans les troubles de la mémoire. La deuxième partie traite de l'application de plusieurs marqueurs de neuroimagerie structurelle et fonctionnelle dans le cadre des études cliniques sur des patients ayant des troubles précoces de la maladie d'Alzheimer. Les résultats ont révélé que la mise en oeuvre des SOPs pour l’acquisition des séquences d’imagerie par résonance magnétique (IRM), au niveau multicentrique, réduit la variance des mesures des marqueurs de neuroimagerie détectée par différents scanners. En outre, les résultats de la deuxième partie de la thèse ont montré un impact significatif des thérapies anticholinestérasiques pour réduire l'atrophie de l'hippocampe, l'amincissement cortical ainsi que une augmentation de l'activation de zones du cerveau liées à l'IRM fonctionnelle chez des patients ayant des troubles précoces de la MA. Ces résultats prometteurs confirment l'hypothèse que les marqueurs de neuroimagerie structurelle et fonctionnelle appliqués avec SOPs pourraient être utilisés comme critère d'évaluation substitutif dans les études cliniques pour les patients ayant des troubles précoces de la maladie d'Alzheimer. / The development of new drugs and the validation and standardization of neuroimaging and biological markers for Alzheimer’s Disease (AD) clinical treatment trials is expected to be one of the major goals of AD research in the upcoming years. The present thesis aims to adress these critical issues. The first part of the thesis is focused on the proper application of Standard Operating Procedures (SOPs) for the structural neuroimaging protocols of acquisition and the implementation of neuroimaging markers in 10 Italian Memory Clinics. The second part of the thesis deals with the application of several structural and functional neuroimaging markers in the context of clinical trials investigation in mild cognitive impairment individuals. Results revealed that the implementation of SOPs at multicentre level reduces the variance of neuroimaging markers measurement detected by different scanners. Moreover, results from the employment of neuroimaging markers in pre-dementia trials in mild cognitive impairment individuals showed a significant impact of anticholinesterase therapies in reducing the hippocampal rate of atrophy, the cortical thinning as well as in increasing the activation of brain areas related to functional Magnetic Resonance Imaging (fMRI) face and location macthing tasks. These promising results support the hypothesis that structural and functional neuroimaging markers applied in a standardized manner migh be utilized as candidate surrogate outcomes in future pre-dementia trials for AD.