The hippocampus is a gray matter structure in the temporal lobe that plays a key role in memory processes and in many diseases (Alzheimer's disease, epilepsy, depression ...).The development of morphometric models is essential for the study of the functional anatomy and structure alterations associated with different pathologies. The objective of this thesis is to develop and validate methods for morphometry of the hippocampus in two contexts: the study of the external shape of the hippocampus from conventional MRI (1.5T or 3T) with millimeter resolution, and the study of its internal structure from 7T MRI with high spatial resolution. These two settings correspond to the two main parts of the thesis.In the first part, we propose a method for the automatic classification of patients from shape descriptors. This method is based on a spherical harmonic decomposition which is combined with a support vector machine classifier (SVM). The method is evaluated in the context of automatic classification of patients with Alzheimer's disease (AD) patients, mild cognitive impairment (MCI) patients and healthy elderly subjects. It is also compared to other approaches and a more comprehensive validation is available in a population of 509 subjects from the ADNI database. Finally, we present another application of morphometry to study structural alterations associated with the syndrome of Gilles de la Tourette.The second part of the thesis is devoted to the morphometry of the internal structure of the hippocampus from MRI at 7 Tesla. Indeed, the internal structure of the hippocampus is rich and complex but inaccessible to conventional MRI. We first propose an atlas of the internal structure of the hippocampus from postmortem data acquired at 9.4T. Then, we propose to model the Ammon's horn and the subiculum as a skeleton and a local measure thickness. To do this, we introduce a variational method using original Hilbert spaces reproducing kernels. The method is validated on the postmortem atlas and evaluated on in vivo data from healthy subjects and patients with epilepsy acquired at 7T.

Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 4 uppsatser.

Diss. (sammanfattning) Umeå : Univ., 2006. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2006. / Härtill 4 uppsatser.

Thesis (Ph.D.)--University of South Florida, 2004. / Includes vita. Includes bibliographical references (leaves 144-164).

Ce travail de thèse s’articule autour de trois études complémentaires. La première aborde la validation française d’un test rapide d’évaluation des fonctions supérieures: le Barrow Neurological Institute Screen for higher cerebral functions (B.N.I.S). Cette étude a permis de rendre disponible en langue française un outil rapide qui évalue les fonctions cognitives classiques mais aussi les capacités émotionnelles et sociocognitives, fonctions généralement non intégrées dans ce type de test. La seconde étude, menée auprès de participants présentant un Mild Cognitive Impairment (M.C.I), a ensuite permis de mettre en évidence la nécessité de prendre en compte l’évaluation émotionnelle. Les participants M.C.I présentent un profil spécifique au B.N.I.S., notamment aux subtests d’affectivité, d’orientation, de mémoire et d’auto-évaluation de la performance mnésique. Enfin, la troisième étude analyse les performances de reconnaissance faciale des émotions et de raisonnement social au cours du vieillissement normal, le Mild Cognitive Impairment et la démence de type Alzheimer (DTA) au stade débutant. Nous observons un déclin des capacités de reconnaissance faciale des émotions et de raisonnement social au cours du vieillissement normal qui s’accentue significativement au cours de la DTA. Un profil spécifique est retrouvé pour le M.C.I avec un déclin en raisonnement social mais des capacités de reconnaissance faciale émotionnelle comparables aux sujets âgés du groupe contrôle. L’évaluation des capacités émotionnelles devrait être davantage intégrée aux bilans neuropsychologiques afin de mieux orienter les modalités de prise en charge de la population vieillissante. / This research presents three complementary studies: (1) the french validation of the Barrow Neurological Institute Screen for higher cerebral functions (B.N.I.S), developed by G. Prigatano in 1991. We have assessed 167 subjects from 15 to 84 years within a french population. The goal is :1) to promote a new short screening instrument dedicated to cognitive and emotional functions, usually emotional functions are not integrated in neuropsychological assessments ; (2) to apply the B.N.I.S to Mild Cognitive Impairment (M.C.I) subjects (N=39) in order to highlighted the importance of the emotional assessment in this type of population and found a specific profile at the substests named: affectivity, orientation, memory and self-assessment of the mnesic performance ; (3) to analyze, with more precision, the performance of emotional facial recognition and social reasoning during normal ageing (N=54), M.C.I (N=25) and Alzheimer disease (AD) at the early stage (N=17). A decline of sociocognitive capacities is observed during the ageing and seems to become more important during the course of M.C.I and the AD. A specific profile was found for each group. The assessment of emotional capacities seems relevant and should be more integrated into the neuropsychological assessments, in order to improve diagnosis and to propose the best modalities of care for the ageing population.

A doença de Alzheimer (DA) é uma patologia neuropsiquiátrica caracterizada por perda cognitiva, com marcante déficit de memória desde o estágio inicial, degeneração neuronal progressiva, e constitui a principal causa de demência no mundo. Além disso, a DA é frequentemente agravada pela ocorrência de comorbidades. Dados epidemiológicos apontam para uma importante associação clínica entre a DA e a epilepsia. A ausência de um modelo de estudo relevante, entretanto, tem impedido o avanço do entendimento dos mecanismos moleculares que subjazem essa comorbidade. A cepa Wistar Audiogenic Rat (WAR) tem sido amplamente utilizada como modelo animal para o estudo de epilepsia e, recentemente, déficits de memória foram relatados em animais desta cepa, o que suscitou a possibilidade de constituírem um modelo experimental para o estudo da comorbidade entre DA e epilepsia. No presente estudo, foi avaliado o desempenho de WAR adultos em diferentes idades no teste de memória do labirinto aquático de Morris (LAM). Realizaram-se ainda análises bioquímicas e de imunoistoquímica dos principais biomarcadores celulares da DA, o peptídeo beta-amiloide (A?) e a proteína Tau hiperfosforilada (pTau), no hipocampo e no córtex pré-frontal de WAR e Wistar de idades pareadas. No LAM, os WAR de 9 meses apresentaram déficit de aprendizagem e de retenção de memória (24 horas após o treinamento), quando comparados aos Wistar de idade pareada, enquanto que aos 12 meses, os WAR apresentaram apenas déficit de aprendizagem. Os animais WAR de 12 meses apresentaram também aumento significativo nos níveis de pTau e Tau total em extratos de hipocampo, quando comparados aos Wistar controles de mesma idade, o que não foi observado para os extratos de córtex pré-frontal. Os WAR também apresentaram elevação idade-dependente nos níveis e distribuição anormal de pTau em algumas sub-regiões hipocampais, como avaliado por imunoistoquímica. Não foi possível quantificar A? endógeno por meio das estratégias utilizadas. Quando analisados em conjunto, os dados sugerem que os déficits de memória observados nos WAR podem ser reflexo da hiperfosforilação e consequente distribuição anormal da proteína neuronal Tau, por um mecanismo molecular a ser desvendado. Não foi possível, ainda, determinar se este mecanismo inclui aumento nos níveis de agregados de A?, como esperado em modelos de DA. Portanto, o emprego de cepa WAR como modelo experimental para o estudo dos fenômenos moleculares subjacentes à comorbidade entre epilepsia e doença de Alzheimer, embora promissor, ainda precisa ser melhor caracterizado. / Alzheimer disease (AD) is a neuropsychiatric disorder characterized by cognitive loss, marked memory deficit since the early stage, progressive neuronal degeneration, and it is the leading cause of dementia around the world. In addition, AD is often aggravated by the occurrence of comorbidities. Epidemiological data point to a clinical association between AD and epilepsy. The absence of a relevant model, however, has impaired the advance of the understanding about the molecular mechanisms that underlie this comorbidity. The Wistar Audiogenic Rat (WAR) strain has been widely used as an animal model to the study of epilepsy. Recently, memory deficits have been reported in WARs, which has raised the possibility that this strain may represent an experimental model to the study of comorbidity between AD and epilepsy. Here we evaluated the performance of WARs in the reference memory test Morris water maze (MWM) at different ages. Biochemical and immunohistochemical analyzes of the main AD biomarkers, beta-amyloid peptide (A?) and hyperphosphorylated Tau protein (pTau), were also performed in the hippocampus and prefrontal cortex of age-matched WARs and Wistar controls. In the LAM, middle-aged (9 months) WARs presented learning and memory retention deficits (24 hours after training session) when compared to age-matched Wistar rats, whereas at 12 months, WARs presented only learning deficits. Adult WAR animals showed a significant increase in the levels of pTau and total Tau in hippocampal extracts, when compared to Wistar controls, which was not observed in prefrontal cortex extracts. WARs also showed higher levels and abnormal distribution of pTau in some hippocampal subregions, as assessed by immunohistochemistry. It was not possible to detect endogenous A? by the strategies used. Taken together, these data suggest that memory deficits observed in WARs may be a consequence of hyperphosphorylation and consequent abnormal distribution of Tau triggered by a molecular mechanism yet to be identified. It has not yet been determined whether this mechanism includes increased levels of A? aggregates, as expected in AD models. Therefore, the use of the WAR strain as an experimental model to the study of the molecular phenomena underlying the comorbidity between epilepsy and Alzheimer disease, although promising, still needs to be further characterized.

Le Plan Alzheimer 2008-2012 a mis en lumière les représentations négatives de la maladie d’Alzheimer et leurs conséquences sur la mise en place de l’alliance thérapeutique. Les travaux récents montrent également l’impact de ces représentations chez des personnes exprimant une plainte mnésique subjective ou présentant des troubles cognitifs légers sans démence. L’objectif de ce projet était de mettre au point un questionnaire évaluant les perceptions des troubles mnésiques et d’analyser ces perceptions dans une population en cours de démarche diagnostique. Nous avons recruté des patients seuls ainsi que des dyades de patients et d’aidants. Nous cherchions à étudier l’influence des perceptions des troubles mnésiques sur l’humeur, les stratégies de coping et la qualité de vie. Les résultats mettent en lumière les facteurs d’entrée dans une démarche de soins ainsi que l’influence significative des perceptions des troubles mnésiques du patient sur ses stratégies de coping et sa qualité de vie. Nous avons également étudié l’influence des perceptions des troubles mnésiques dans une approche dyadique (patient et aidant). Ces analyses dyadiques montrent l’influence des perceptions du patient sur l’humeur et les stratégies de coping de l’aidant et l’influence des perceptions de l’aidant sur la qualité de vie psychique du patient. Ce travail de recherche souligne l’importance de mener des études longitudinales sur l’évolution des perceptions des troubles mnésiques avant et après l’annonce diagnostique afin de proposer des pistes de prise en charge adaptée aux patients et aux aidants. / The 2008-2012 Alzheimer French National Plan has highlighted the negative representations of Alzheimer's disease and their consequences on therapeutic alliance. Recent works also shows the impact of these representations in people with subjective memory complaint or with mild cognitive impairment.This research aims to develop a questionnaire evaluating the perceptions of memory disorders and to analyze these perceptions in a population engaged in a diagnosis process. We recruited a group of patients and a group of patient/caregiver dyads.We investigated the influence of subjective perceptions on mood, coping strategies and quality of life. Participants had to express a memory complaint and to start a diagnosis process at the Memory Center of Nancy. The results highlight the factors to beginning a diagnosis process and the significant influence of perceptions of memory disorders on coping strategies and quality of life. Actual level of cognitive disorders do not seem to be related to perceptions of memory disorders. We also studied the influence of perceptions of memory disorders in a dyadic approach (patient and caregiver). These dyadic analyzes show the influence of patient's perceptions on caregiver's mood and coping strategies and the influence of caregiver's perceptions on patient's quality of life. This research emphasizes the importance of conducting longitudinal studies on the evolution of perceptions of memory disorders before and after the diagnosis, in order to propose psychosocial interventions adapted to patients and caregivers

[pt] A Doença de Alzheimer (DA) é uma desordem cerebral degenerativa, sendo progressiva e fatal, a qual se caracteriza por disfunções cognitivas e da memória. Uma observação característica na DA é a presença de depósitos fibrilosos insolúveis do polipeptídeo b-amilóide (Ab), que ocorre predominantemente em duas formas, Ab (1-40) e Ab (1-42). Muitas evidências indicam que as interações de Ab com os íons Cu(II) e Zn(II) podem estar relacionadas aos processos que levam à agregação deste peptídeo, já que aqueles foram encontrados nessas placas. Além disso, o cobre, por suas características eletroativas, pode contribuir para a geração de radicais livres, aumentando, desta maneira, o estresse oxidativo. Assim, a prevenção da agregação e a diminuição do estresse oxidativo são consideradas estratégias terapêuticas em potencial para a doença. Assim, destacam-se os compostos atenuantes na interação metal-proteína (MPACs, em inglês), que estão relacionados com a normalização da repartição e da distribuição de biometais, interrompendo as interações anômalas entre os íons metálicos e o peptídeo Ab. Neste trabalho, foram sintetizados dois potenciais MPACs derivados do agente micobactericida isoniazida: um deles com o fragmento 8-hidroxiquinolina (H2L1) e o outro, HL2, estruturalmente relacionado à melatonina. Disto resultam dois ligantes interessantes, capazes de coordenar íons metálicos de importância biológica através de seus átomos doadores N e O. As interações destes compostos com os biometais cobre e zinco foram estudadas no estado sólido pela síntese e caracterização de quatro novos complexos, dois com o íon Cu(II) (complexos 2 e 4) e dois com o íon Zn(II) (complexos 1 e 3). Estudos potenciométricos em solução (meio água/etanol 30/70 porcento v/v) envolvendo ambos os ligantes foram feitos a fim de se determinar as respectivas constantes de protonação, bem como as constantes de formação dos complexos envolvendo os íons em estudo. Realizou-se, para os dois ligantes, uma análise farmacológica in silico, mostrando que eles são atóxicos e que possuem um elevado DrugScore. Experimentos de RMN realizados com H2L1, o mais solúvel dos ligantes, demonstraram que, embora o composto não interaja diretamente com Ab, ele compete efetivamente com este peptídeo pelos íons Cu(II) e Zn(II). Em testes efetuados com ratos Wistar machos, o composto mostrou não ser tóxico em doses de até 200 mg kg-1. Os níveis de GSH (um indicador de estresse oxidativo) e de metalotioneínas no cérebro das cobaias tratadas com o composto são estatisticamente os mesmos daqueles observados nos animais controle (não injetados). Comportamento similar foi observado para os biometais cobre, zinco e ferro. Dessa forma, tais estudos para H2L1, revelaram que ele pode atuar como um potencial MPAC. / [en] Alzheimer s disease (AD) is a progressive and fatal degenerative brain disorder, characterized by cognitive and memory disorders. A characteristic feature of this disease is the presence of insoluble fibrillary deposits of the b-amyloid polypeptide (Ab), which occurs predominantly in two forms, Ab (1-40) and Ab (1-42). Accumulated evidence indicates that Ab interactions with Cu(II) and Zn(II) may be related to the processes that lead to the aggregation of this peptide, since these ions have been found in these plaques. In addition, copper, due to its electroactive characteristics, may contribute to the generation of free radicals, increasing oxidative stress. Thus, the prevention of the peptide aggregation and reduction of oxidative stress are considered potential therapeutic strategies for the disease. In this context, metal-protein interaction attenuating compounds (MPACs) are highlighted, which are related to the normalization of the allocation and distribution of biometals, interrupting the anomalous interactions between metal ions and the Ab peptide. In this study, two potential MPACs derived from the mycobactericidal agent isoniazid were synthesized: one with the 8-hydroxyquinoline (H2L1) fragment and the other, HL2, structurally related to melatonin. This produced two interesting ligands capable of coordinating metal ions of biological importance through their donor atoms N and O. The interactions of these compounds with biometals copper and zinc were studied in solid state by the synthesis and characterization of four new complexes, two with the Cu(II) ion (complexes 2 and 4) and two with the Zn(II) ion (complexes 1 and 3). In-solution potentiometric studies (water/ethanol 30/70 percent v/v medium) involving both ligands were conducted in order to determine their protonation constants, in addition to the formation constants of the complexes involving the ions under study. Pharmacological in silico analyses were performed for the two ligands and demonstrated that both are non toxic and have a high DrugScore. NMR experiments performed with H2L1, the most soluble of the ligands, demonstrated that, although the compound does not interact directly with Ab, it competes effectively with this peptide for Cu(II) and Zn(II) ions. In experiments carried out with male Wistar rats, the compound was shown to be non-toxic in doses up to 200 mg kg-1. GSH (an indicator of oxidative stress) and metallothionein levels in the brains of the animals treated with the compound are statistically the same as those observed in control animals (not injected). Similar behavior was observed for biometals copper, zinc and iron. Thus, these studies to H2L1 revealed that it can act as a potential MPAC.

Made available in DSpace on 2015-07-22T20:50:16Z (GMT). No. of bitstreams: 0 Previous issue date: 2011-11-24 / A Doença de Alzheimer é a causa mais frequente de demência. Os sintomas clínicos da doença se iniciam com um comprometimento da memória e da função executiva, gradativamente há um envolvimento de outras funções como a linguagem, conhecimento semântico, pensamento abstrato, atenção e habilidades visuoespaciais. A função visuoespacial consiste na identificação de um estímulo e sua localização, e pode estar comprometida no início do quadro clínico. A bateria “Visual Object and Space Perception” (VOSP) se propõe a avaliar as funções visuoespaciais minimizando a interferência de outras funções cognitivas. Objetivos: Avaliar as funções visuoespaciais na doença de Alzheimer de intensidade leve; Avaliar a sensibilidade desta bateria em uma amostra brasileira; Determinar escores de corte preliminares para diferenciar idosos saudáveis de pacientes com doença de Alzheimer. Métodos: 31 pacientes com Doença de Alzheimer leve e 44 idosos saudáveis foram avaliados com uma bateria de testes neuropsicológicos e com a VOSP. Resultados: Controles tiveram melhor desempenho em todos os testes neuropsicológicos. Na VOSP, os pacientes com Doença de Alzheimer mostraram pior desempenho em todos os testes de percepção de objeto, e em dois testes de percepção de espaço (Localização de Numero e Análise de Cubos). Conclusões: A função visuoespacial mostra-se comprometida em estágios iniciais da doença de Alzheimer. A bateria VOSP demonstrou ser sensível a déficits visuoespaciais. / TEDE / BV UNIFESP: Teses e dissertações