INTRODUÇÃO: Julgamento é a capacidade de tomar decisões após cuidadosa consideração das informações disponíveis, soluções possíveis, resultados prováveis e fatores contextuais. Do ponto de vista neuropsicológico, o conceito de julgamento envolve memória, linguagem, atenção, raciocínio e principalmente funções executivas. Perda de julgamento tem sido descrita em Comprometimento Cognitivo Leve (CCL) e demência. O Test of Practical Judgment (TOP-J) é uma medida originalmente americana, desenvolvida para avaliar o julgamento prático em adultos mais velhos. É um questionário aberto de 15 itens (TOP-J/15) ou de 9 itens (TOP-J/9) no qual os participantes escutam breves cenários sobre os problemas cotidianos e relatam em voz alta as soluções propostas. Este estudo teve como objetivos a adaptação do TOP-J para uso no Brasil, a elaboração de uma versão reduzida deste instrumento e verificação da acurácia de ambas a versões em amostra da população brasileira composta de controles cognitivamente saudáveis e pacientes com Comprometimento Cognitivo Leve (CCL), doença de Alzheimer (DA) e demência frontotemporal variante comportamental (DFT). MÉTODOS: A amostra foi composta por 85 indivíduos, com idade mínima de 50 anos e escolaridade mínima de 4 anos, sendo 24 controles, 26 CCL, 20 DA e 15 DFT. Os participantes foram submetidos a avaliação neuropsicológica e ao TOP-J. RESULTADOS: No TOP-J/15 versão brasileira (TOP-J/15-Br) e no TOP-J/9 versão brasileira (TOP-J/9-Br) (versão reduzida), o desempenho de controles foi estatisticamente superior ao desempenho de pacientes com CCL, DA e DFT e o desempenho de CCL foi superior ao de pacientes com DA e DFT. No TOP-J/15-Br, a confiabilidade verificada pelo alfa de Cronbach foi de 0,69 e o melhor ponto de corte para distinção de controles e pacientes foi de 30 (sensibilidade de 91,7%; especificidade de 59% e área sob a curva de 0,80). No TOP-J/9-Br, o alfa de Cronbach foi de 0,68 e o melhor ponto de corte para distinção entre julgamento de controles e de pacientes foi 19, com sensibilidade de 79,2, especificidade de 72,1 e área sob a curva de 0,82. CONCLUSÕES: O TOP-J/15-Br e o TOP-J/9-Br apresentaram características psicométricas robustas para o uso pretendido com amostra da população brasileira. Ambos foram capazes de identificar prejuízo de julgamento já em pacientes com CCL e diferenciaram julgamento de controles do julgamento de pacientes com boa sensibilidade e especificidade / INTRODUCTION: Judgment is the ability to make sound decisions after careful consideration of available information, possible solutions, likely outcomes and contextual factors. From a neuropsychological perspective, the concept of judgment involves memory, language, attention, reasoning and specially the executive functions. Loss of judgment has been described in Mild Cognitive Impairment (MCI) and dementia. The Test of Practical Judgment (TOP-J) is an originally American measure created for evaluate practical judgment in older adults. It is a 15-item (TOP-J/15) or 9- item (TOP-J/9) open-ended questionnaire in which participants listen to brief scenarios about everyday problems and report aloud their proposed solutions. This study aimed the adaptation of the TOP-J for use in Brazil, the development of a reduced version of this instrument and the verification of accuracy of both the versions in Brazilian sample composed of cognitively healthy controls and patients with mild cognitive impairment (MCI), Alzheimer\'s disease (AD) and frontotemporal dementia behavioral variant (FTD). METHODS: The sample consisted of 85 subjects with a minimum age of 50 years and minimum education of 4 years, being 24 controls, 26 MCI, 20 AD e 15 FTD. The participants were submitted to a neuropsychological assessment and TOP-J. RESULTS: In the TOP-J/15 Brazilian version (TOP-J/15-Br) and in the TOP-J/9 Brazilian version (TOP-J/9-Br) (reduced version), performance of controls was statistically better than the performance of MCI, AD and FTD patients, and performance of MCI was statistically better than AD and FTD patients. In TOP-J/15-Br, the reliability verified by Cronbach\'s alpha was 0.69 and the best cutoff for distinction between controls and patients was 30 (sensibility of 91,7%; specificity of 59% and area under the curve of 0,8). In the TOP-J/9-Br, Cronbach\'s alpha was 0.68 and the best cutoff point for distinguishing between judgment of controls and judgment of patients is 19, with a sensitivity of 79,2, specificity of 72,1 and area under the curve of 0.82. CONCLUSIONS: The TOP-J/15-Br and the TOP-J/9-Br showed robust psychometric characteristics for the intended use with a sample of the Brazilian population. Both were able to identify deficits of impaired of judgment already in patients with MCI and were able to distinguish judgment of controls from judgment of patients with good sensitivity and specificity

Introdução: Entre as lesões encefálicas adquiridas (LEAs) causadas por processos degenerativos, destaca-se a doença de Alzheimer (DA), que é uma demência que acomete uma grande parcela da população idosa e caracteriza-se pela presença de emaranhados neurofibrilares e placas senis. Exames de ressonância magnética (RM) mostram atrofia do córtex entorrinal, hipocampo, amígdala e da região para-hipocampal. Já a tomografia por emissão de pósitrons (PET) aponta redução do metabolismo cerebral de glicose em regiões como o lobo temporal e cíngulo posterior. O alentecimento do eletroencefalograma (EEG) pelo aumento das ondas teta e a diminuição da frequência alfa são mais evidentes em indivíduos com algum tipo de lesão encefálica. O traumatismo cranioencefálico (TCE) caracteriza-se por ser uma LEA não degenerativa e não congênita e é provocado por uma força mecânica externa. Espera-se um prejuízo, permanente ou temporário, nas funções cognitiva, física e psicossocial, com diminuição ou alteração do estado de consciência. Uma das principais causas de TCE é a lesão axonial difusa (LAD), causada por mecanismos de aceleração-desaceleração. Frequentemente as regiões ventral e lateral dos lobos frontal e temporal são danificadas. Objetivo: Entender as diferenças dos mecanismos funcionais entre os grupos - DA e LAD - com queixa de memória, sob o ponto de vista eletroencefalográfico. Métodos: Participaram deste estudo 85 indivíduos adultos. Destes, 34 haviam recebido o diagnóstico de DA, 32 de LAD e 19 eram adultos saudáveis. Foram aplicados o Mini-Exame do Estado Mental (MEEM), o teste do desenho do relógio (TDR) e o teste de fluência verbal (FV) para a categoria animais. Os indivíduos foram submetidos ao EEG de alta resolução com 128 canais. As fontes corticais dos ritmos do EEG foram estimadas pela análise por tomografia eletromagnética exata de baixa resolução (eLORETA). Resultados: Observou-se que a média da frequência registrada no EEG está dentro da normalidade nos grupos DA e LAD. A análise por eLORETA mostrou que, em comparação ao grupo controle (CTL), o grupo DA apresentou aumento da atividade teta nos lobos parietal e frontal e diminuição da atividade alfa 2 nos lobos parietal, frontal, límbico e occipital. Em comparação ao grupo CTL, o grupo LAD apresentou aumento da atividade teta nas áreas límbica, occipital sub-lobar e temporal. Conclusão: Os resultados sugerem que os indivíduos com DA e com LAD apresentam comprometimento da atividade elétrica em áreas importantes para a memória e aprendizagem / Introduction: Acquired brain injuries (ABI) caused by degenerative processes include Alzheimer\'s disease (DA), which is a dementia that affects a large part of the elderly population and is characterized by the presence of neurofibrillary tangles and senile plaques. Magnetic resonance (MR) imaging shows atrophy of the entorhinal cortex, hippocampus, amygdala and para-hippocampal area. Positron emission tomography (PET) points to a reduction in the cerebral metabolism of glucose in regions such as the temporal lobe and posterior cingulate. Traumatic brain injury (TBI) is a non-degenerative and non-congenital ABI and is caused by an external mechanical force. Impairment, permanent or temporary, is expected in cognitive, physical and psychosocial functions, with a decrease or alteration of the state of consciousness. One of the main causes of TBI is diffuse axonal injury (DAI), caused by acceleration-deceleration mechanisms. Often the ventral and lateral regions of the frontal and temporal lobes are damaged. Objective: To understand the differences in the functional mechanisms between the AD and DAI groups - with memory complaints, from the electroencephalographic point of view. Methods: The study included 85 adult subjects. Of these, 34 had received the diagnosis of AD, 32 of DAI and 19 were healthy adults. The Mini-Mental State Examination (MMSE), the clock drawing test (CDT) and the verbal fluency test (VF) for the animals category were applied. Subjects were submitted to high resolution EEG with 128 channels. Cortical sources of EEG rhythms were estimated by exact low resolution electromagnetic tomography (eLORETA) analysis. Results: The eLORETA analysis showed that, in comparison to the control (CTL) group, the AD group presented increased theta activity in the parietal and frontal lobes and decreased alpha 2 activity in the parietal, frontal, limbic and occipital lobes. In comparison to the CTL group, the DAI group presented increased theta activity in the limbic, occipital sublobar and temporal areas. Conclusion: The results suggest that individuals with AD and DAI have impairment of electrical activity in areas important for memory and learning

A Doença de Alzheimer (DA) é o tipo mais comum de demência em idosos, a etiologia é multifatorial e a fisiopatologia da doença é complexa, com um novo caso acontecendo a cada sete segundos; globalmente, a doença está se tornando em uma lenta pandemia. Bioquimicamente, a DA é caracterizada pela presença das placas neuríticas (PNs) e os novelos neurofibrilares (NNFs). O peptídeo beta peptide1-42 (A?(1-42)) é o principal componente das placas neuríticas e tem sido fortemente associado ao estresse oxidativo, desregulação colinérgica e morte celular. Os múltiplos mecanismos envolvidos na patogênese criam consideráveis dificuldades para identificar alvos terapêuticos apropriados. As abordagens terapêuticas atuais melhoram temporariamente os sintomas da DA; no entanto, apesar de esforços intensivos, nenhum dos tratamentos disponíveis hoje conseguiu alterar o curso da doença. Porém, algumas das terapias mais relevantes para o tratamento da doença estão baseadas na atividade inibidora da acetilcolinesterase (AChE). Nos últimos anos, os alcaloides pertencentes à família Amaryllidaceae têm recebido muita atenção devido à atividade anticolinérgica e antioxidante. A galantamina foi o primeiro alcaloide isolado a partir de diferentes espécies de Amaryllidaceas e é o mais recente inibidor da AChE aprovado para o tratamento sintomático da DA. Este fato tem motivado a pesquisa de outros alcaloides como possíveis moduladores da doença em adição à atividade inibitória da AChE. Diante disso, o objetivo deste estudo foi investigar se o extrato de Caliphruria subedentata e a galantamina modulam a neurotoxicidade induzida pelo A?(1-42) na linhagem celular SH-SY5Y indiferenciada. Para compreender os mecanismos de neuroproteção, um conjunto de ensaios foi realizado tais como atividade inibitória da AChE, ensaios clonogênico, micronúcleos com bloqueio na citocinese celular (CBMNcyt), cometa; análises por microscopia eletrônica de transmissão (MET) e de metilação. Os resultados mostraram que tanto o extrato quanto a galantamina diminuíram significativamente a citotoxicidade e genotoxicidade induzida pelo A?(1-42). Além disso, ambos os tratamentos modularam alterações morfológicas mitocondriais induzidas pelo peptídeo. Em conclusão, os resultados deste estudo demonstraram que, em adição à atividade inibitória da AChE, tanto o extrato de C. subedentata quanto a galantamina exercem propriedades antigenotóxicas. Essas propriedades relevantes da Amaryllidaceaes e o fármaco tornam-se um potencial valioso para continuar sendo explorado. / Alzheimer´s disease (AD) is the most common type of dementia in elderly population, the etiology is multifactorial and the pathophysiology of the disease is complex, with a new case occurring every seven seconds; globally, the disease itself is becoming a slowly pandemic. Biochemically, the AD is characterized by presence of the neuritic plaques and neurofibrillary tangles. Amyloid beta peptide1-42 (A?(1-42)) is the principal component of neuritic plaques and it has been strongly associated with oxidative stress, cholinergic deregulation and cell death. The multiple mechanisms involved in the pathogenesis create considerable difficulty to identify appropriate targets. The current therapeutics approaches for AD improve temporally the symptoms; and despite intensive efforts, none of the treatments available today alter the course of disease. Nervertheless, some of the most relevant therapies for the treatment of disease are based on acetylcholinesterase (AChE) inhibitor activity. In recent years, alkaloids belonging Amaryllidaceae family have received great attention due to the well-known anticholinergic and antioxidant activity and the galanthamine was the first alkaloid isolated from different species of Amaryllidacea and it is the most recently AChE inhibitor approved for the symptomatic treatment of AD. This fact has motivated the screening of other alkaloids as possible modulators of disease in addition acetylcholinesterase activity. Purpose this study was to investigate whether C. subedentata extract and galanthamine modulate A?(1-42)- induced neurotoxicity in the undifferentiated SH-SY5Y cell line. To understand the mechanisms of the neuroprotection, a set of biomarkers such as AChE activity, clonogenic, cytokinesis block micronucleus cytome (CBMNcyt) and comet assays; beside transmission electron microscope (TEM) and methylation analyses were realized. The results showed that C. subedentata extract and galanthamine were capable to significantly reduce the A?(1-42)- induced cytotoxicity and genotoxicity. Furthermore both treatments modulated A?(1-42)- induced mitochondrial morphological alterations. In conclusion, this study demonstrated that in addition to inhibition of acetylcholinesterase (AChE), the extract of C. subedentata and galanthamine exert antigenotoxic properties. This relevant property of Amaryllidaceaes and galanthamine are worthwhile exploring further which may improve the development of new diseases-modifying agents.

Com a preocupação voltada para a qualidade dos alimentos de consumo humano, a presente pesquisa tem a finalidade de avaliar a transferência dos metais alumínio (Al), cromo (Cr), ferro (Fe) e níquel (Ni) durante o cozimento dos alimentos arroz e feijão em recipientes de alumínio e aço inoxidável. Inicialmente foram preparadas águas padrões, sob diferentes condições de pH e salinidade, com a água proveniente do sistema de distribuição do município de Ribeirão Preto. Estas combinações tiveram o intuito de verificar qual a condição em que ocorreria uma maior transferência de metais, em especial o alumínio. As águas padrões foram levadas à fervura por um tempo determinado, em recipientes de alumínio, e várias alíquotas de amostras foram recolhidas no decorrer do aquecimento. Posteriormente, foi realizada a quantificação dos metais nas amostras de água e constatou-se que com o aumento do pH e da salinidade, ocorre um aumento da transferência de alumínio e ferro, principalmente, do recipiente para a água. A partir daí foram preparadas apenas águas padrões de pH básico e salinidades altas para o cozimento dos alimentos. No decorrer do preparo dos alimentos também foram retiradas alíquotas de amostras, a fim de mostrar uma possível elevação da transferência de metais com a prolongação do tempo de cozimento. As amostras recolhidas sofreram digestão via úmida (ácidos nítrico e clorídrico) e, finalmente, foram analisadas empregando-se a técnica de Espectrometria de Emissão Óptica em Plasma de Argônio Indutivamente Acoplado (ICP OES) através do uso do equipamento ICP da marca PerkinElmer, modelo Optima 2000. Os resultados analíticos dos metais supracitados estão expressos em gráficos e tabelas, tanto em base úmida quanto em base seca. O equipamento pertence à empresa Ambiental 2000 Ltda., sendo que a calibração do ICP foi efetuada com água proveniente por um sistema de purificação através de membrana de osmose-reversa. No final da pesquisa também foi realizada uma experiência com água contaminada com alumínio para cocção de arroz e feijão em recipientes de teflon para verificação do comportamento de migração do íon alumínio. Existiu uma preocupação especial com a transferência do alumínio, em virtude de haver inúmeros artigos publicados considerando este metal como potencial etiológico para a doença de Mal de Alzheimer, pois, apesar dos esforços sensíveis da ciência em busca da cura para esta moléstia, o tratamento atual permite apenas suavizar seus efeitos. Os resultados obtidos nesta pesquisa serão subsídios para posteriores pesquisas na área médica comparando-se, por exemplo, doenças como o Mal de Alzheimer, Anemia, etc com a prática do uso de recipientes específicos para a cocção de alimentos / With the preocupation gone back to the quality of the foods of human consumption, the present research has the purpose of evaluating the transfer of the metals aluminum (Al), chrome (Cr), iron (Fe) and nickel (Ni) during the cooking of the foods rice and bean in containers of aluminum and stainless steel. Initially they were prepared waters patterns, under different pH conditions and salinity, with the originating from water the system of distribution of the municipal district of Ribeirão Preto. These combinations had the intention of verifying which the condition in that it would happen a larger transfer of metals, especially the aluminum. The waters patterns were taken to the ebullition by a certain time, in containers of aluminum, and several brackets of samples were collected in elapsing of the heating. Later, the quantification of the metals was accomplished in the samples of water and it was verified that with the increase of the pH and of the salinity, it happens an increase of the transfer of aluminum and iron, mainly, of the container for the water. Since then they were prepared just waters standard of basic pH and high salinities for the cooking of the foods. In elapsing of the preparation of the foods brackets of samples were also removed, in order to show a possible elevation of the transfer of metals with the continuation of the time of cooking. The collected samples suffered digestion saw humid (acids nitric and hydrochloric) and, finally, they were analyzed being used the technique of Spectrometer of Optical Emission in Plasma of Argon Coupled Inductively (ICP OES) through the use of the equipment ICP of the mark PerkinElmer, model Optima 2000. The analytical results of the foregoing metals are expressed in graphs and tables, in humid base and in base it dries. The equipment belongs to the Ambiental 2000 company, and the calibration of ICP was made with coming water by a purification system through membrane of osmosis-reverse. In the end of the research an experience was also accomplished with polluted water with aluminum for cooking of rice and bean in teflon containers for verification of the behavior of migration of the aluminum ion. A special concern existed with the transfer of the aluminum, because of there being countless published goods considering this metal as etiological potential for the disease of Evil of Alzheimer, because, in spite of the sensitive efforts of the science in search of the cure for this disease, the current treatment just allows to soften their effects. The results obtained in this research will be subsidies for subsequent researches in the medical area being compared, for instance, diseases as the Evil of Alzheimer, Anemia, etc with the practice of the use of specific containers for the cooking of foods

Avec près d'un million de cas de démence en France en 2010, la maladie d'Alzheimer (MA) et les syndromes apparentés constituent un enjeu majeur de santé publique. A l'heure actuelle, il n'existe aucun traitement médicamenteux permettant de guérir de la MA. Ces médicaments visent à ralentir la progression de la maladie en améliorant certains symptômes. De ce fait, il semblait utile et nécessaire de disposer d'indicateurs permettant d'évaluer les prises en charge mises en place pour ces patients. La qualité de vie liée à la santé (QDV) est donc devenue un critère d'évaluation indispensable tant pour les chercheurs que pour les cliniciens.Les outils de QDV génériques sont en général moins sensibles pour une maladie donnée. C'est pourquoi d'autres outils spécifiques à la MA se sont développés. Aucun parmi eux n'était validé en langue française. L'objectif de cette thèse était donc, après une revue de la littérature, de réaliser la validation transculturelle puis psychométrique du « Quality of Life in Alzheimer's Disease » (QoL-AD) et du « Dementia Quality of Life » (DQoL). Ces deux questionnaires étaient d'après la littérature les plus utilisés en langue anglaise dans cette maladie.Ce travail de thèse a été réalisé sur les données du PHRC National 2004 « Evaluation de la qualité de vie chez le sujet âgé dément : validation d'un instrument spécifique ». Cette étude a permis de recueillir des données d'un total de 155 couples patient-aidant recrutés au sein de sept centres hospitaliers français et d'un centre suisse francophone participant à l'étude. Les patients présentaient une MA au stade léger ou stade modéré (Mini Mental State Examination > ou = 10). Le QoL-AD et le DQoL ont été administrés par un enquêteur. Le QoL-AD aidants a été auto-administré. L'adaptation transculturelle puis la validation psychométrique ont donc été réalisées pour ces deux questionnaires.Nous disposons donc désormais d'une version française du QoL-AD et d'une version française du DQoL, ayant bénéficié d'une adaptation transculturelle effectuée selon les recommandations internationales, et qui présentent toutes deux de bonnes propriétés psychométriques. / With nearly one million cases of dementia in France in 2010, Alzheimer's disease (AD) and related syndromes are a major public health issue. Up to now, there is no drug for treatment or preventing for AD. The only available drugs aim to slow down the progression of the disease by improving some symptoms. Therefore, it seemed necessary to have indicators enabling assessment of treatment strategies for these patients. So, health related quality of life (HRQoL) became an essential criterion for evaluation for both researchers and clinicians.Generic HRQoL tools are generally less sensitive for a given disease. That is why other specific tools for AD have been developed. None of them was validated in French. The aim of this thesis was therefore, after a review of the literature, to achieve a cross-cultural adaptation and psychometric validation of the "Quality of Life in Alzheimer's Disease" (QoL-AD) and "Dementia Quality of Life" (DQoL). These two questionnaires were selected because they were the most popular in English-language literature for this disease.This thesis was conducted on data collected during the PHRC National 2004 "Evaluation of the quality of life in elderly demented people: validation of a specific instrument". This study concerned a total of 155 patient-caregiver pairs recruited from seven French hospitals and a Francophone Swiss center. Patients had a confirmed diagnosis of AD (mild to moderate stage: Mini Mental State Examination > ou = 10). QoL-AD and DQoL were administered by an interviewer. The caregiver sheet of QoL-AD was self-administered. Cross-cultural adaptation and psychometric validation have been carried out for these two questionnaires.We now have at disposal two HRQoL questionnaires specifics for AD in French language. They are issued from a cross-cultural adaptation performed according to international quidelines and both have good psychometric properties. So they can be used to evaluate quality of life in Alzheimer's disease on French speaking population.

La maladie d'Alzheimer (AD) est un désordre neurodégénératif progressif et la forme la plus commune de démence. A l’heure actuelle, il n'y a aucun remède et la maladie est toujours fatale. Une des caractéristiques histopathologiques de l'AD est la présence de dépôts protéiques, les plaques amyloïdes, dans le cerveau. Ces plaques sont formées par les peptides amyloïdes β (Aβ) de 40 et 42 résidus, qui sont les produits de clivage par des protéases de la protéine précurseur de l’amyloïde (l'APP). L'élucidation de certains des processus clés dans la cause et le développement de l'AD est une étape cruciale pour le développement de traitements nouveaux et efficaces.<p><p>Les propriétés conformationnelles du segment transmembranaire (TM) de l’APP peuvent affecter sa protéolyse par la γ-sécrétase. Ces propriétés ne sont pas encore clairement établies. Afin de comprendre le rôle des variations structurelles du TM dans le traitement de l'APP, des détails structurels des peptides APP_TM4K, chimiquement synthétisés, ont été étudiés dans la bicouche lipidique en utilisant la réflexion totale atténuée par spectroscopie infrarouge à transformée de Fourier (ATR-FTIR) et la résonance magnétique nucléaire à l’état solide (ssNMR). Tandis que la structure secondaire globale du peptide APP_TM4K est hélicoidale, une hétérogénéité conformationnelle et orientée a été observée pour le site de clivage γ et, dans une plus faible mesure, pour le site de clivage ζ. Ces variabilités conformationnelles autour des sites de clivage γ et ζ peuvent avoir des implications importantes dans le mécanisme de clivage et donc dans la production d’Aβ. Il a été aussi démontré que la dernière glycine dans le motif de dimérisation GxxxG est transmembranaire. Ceci peut impliquer que la dimérisation via ce motif pourrait servir d’ancrage et conférer une orientation transmembranaire stable au segment transmembranaire de l’APP.<p><p>Le peptide amyloïde β est directement lié à la maladie d’Alzheimer. Partant de sa forme monomérique, l’Aβ s'agrège pour produire en final des fibrilles et aussi de manière transitoire toute une gamme d'oligomères, ces derniers étant la plupart neurotoxiques. Une dérégulation de l’homéostasie du Ca2+ dans le cerveau vieillissant et dans des troubles neurodégénératifs joue un rôle crucial dans de nombreux processus et contribue au dysfonctionnement et à la mort cellulaire. Nous avons postulé que le calcium peut permettre ou accélérer l'accumulation d'Aβ. Le modèle d'accumulation d'Aβ (1-40) et celui d'Aβ (1-40) E22G, un peptide amyloïde portant la mutation arctique qui cause une apparition prématurée de la maladie, ont été comparé. Nous avons constaté qu'en présence de Ca2+, l’Aβ (1-40) forme de préférence des oligomères semblables à ceux formés par l’Aβ (1-40) E22G avec ou sans Ca2+, tandis qu'en absence de Ca2+ l'Aβ (1-40) s’agrège sous forme de fibrilles. Les ressemblances morphologiques entre oligomères ont été confirmées par microscopie de force atomique. La distribution des oligomères et des fibrilles dans des échantillons différents a été détectée par électrophorèse sur gel suivie d’une analyse par Western blot, dont les résultats ont été confirmés par des expériences de fluorescence à la thioflavine T. Dans les échantillons sans Ca2+, l’ATR-FTIR révèle la conversion des oligomères en feuillets β antiparallèles en la conformation caractéristique des fibrilles en feuillets β parallèles. En général, ces résultats nous ont ameré à conclure que les ions calcium stimulent la formation d'oligomères d'Aβ (1-40), qui sont impliqués dans la pathogénèse d'AD.<p><p>Malgré les progrès énormes obtenus dans la compréhension de la maladie (AD), il reste un défi majeur, celui du développement de médicaments nouveaux et efficaces. Afin d’obtenir des éclaircissements sur le mécanisme d'action de deux nouveaux puissants modulateurs de la γ-sécrétase - le benzyl-carprofen et le sulfonyl-carprofen dans la bicouche lipidique, la technique de RMN à l’état solide a été employée. Précédemment, les dérivés du carprofen ont été localisés dans des membranes de lipides par des expériences de diffusion (scattering) des neutrons. Les contraintes déterminées à partir des expériences de ssNMR ont permis d’affiner leurs positions et d’obtenir une orientation précise dans la double couche lipidique. Ces résultats combinés indiquent que le mécanisme probable de modulation du clivage par la γ-sécrétase est une interaction directe des carprofènes avec le domaine TM de l’APP. Une telle interaction, empêcherait à la formation de dimères d'APP, dimérisation nécessaire au clivage séquentiel par la γ-sécrétase, diminuant ou réduisant ainsi énormément la production d’Aβ, tout particulièrement d’Aβ42.<p><p>Les résultats de ce travail apporte de nouvelles informations sur les processus clés impliqués dans l'AD; Production de l'Aβ à partir de l'APP, formation des oligomères d'Aβ et mécanisme d'action potentiel de molécules thérapeutiques. Nous pensons que ces résultats pourront permettre une meilleure compréhension de la maladie et pourront aider dans la conception de nouveaux médicaments contre cette maladie.<p><p>Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common form of dementia. There is no cure and the disease is fatal. One of the characteristic histopathological markers of AD is the presence of proteinaceous deposits, amyloid plaques, in the brain. These plaques are formed by the amyloid β-peptides (Aβ) 40- and 42-residue-long, which are protease cleavage products of the amyloid precursor protein (APP). Elucidation of some of the key processes in the cause and the development of AD is crucial for the development of new and efficient treatments.<p><p>Conformational properties of the transmembrane (TM) segment of APP may affect its proteolytic processing by γ-secretase. These properties have not been definitely established. In addressing the role of structural variations of the TM sequence in APP processing, structural details of the chemically synthesized APP_TM4K peptides within the membrane bilayers were studied using Attenuated total reflection Fourier transform spectroscopy (ATR-FTIR) and solid-state nuclear magnetic resonance (ssNMR) techniques. While the overall secondary structure of the APP_TM4K peptide is an α-helix, conformational and orientational heterogeneity was observed for the γ-cleavage site and, to a smaller extent, for the ζ-cleavage site. Evidence for the conformational variability around γ- and ζ-cleavage sites may have important implications for the cleavage mechanism and hence for the Aβ production. It was also found that the last glycine within the sequence of GxxxG motifs is in the transmembrane orientation, implying that dimerization via these motifs may act as an anchor, confining the TM dimer to the stable transmembrane orientation. <p><p>Amyloid β-peptide is directly linked to AD. Starting from its monomeric form, Aβ aggregates into fibrils and / or oligomers, the latter being the most neurotoxic. Dysregulation of Ca2+ homeostasis in aging brains and in neurodegenerative disorders plays a crucial role in numerous processes and contributes to cell dysfunction and death. Here we postulated that calcium may enable or accelerate the aggregation of Aβ. The aggregation pattern of Aβ(1-40) and of Aβ(1-40)E22G, an amyloid peptide carrying the Arctic mutation that causes early onset of the disease, were compared. We found that in the presence of Ca2+, Aβ(1-40) preferentially formed oligomers similar to those formed by Aβ(1-40)E22G with or without added Ca2+, whereas in the absence of added Ca2+ the Aβ(1-40) aggregated to form fibrils. Morphological similarities of the oligomers were confirmed by contact mode atomic force microscopy (AFM) imaging. The distribution of oligomeric and fibrillar species in different samples was detected by gel electrophoresis and Western blot analysis, the results which were further supported by thioflavin T fluorescence experiments. In the samples without Ca2+, Fourier transform infrared spectroscopy revealed conversion of oligomers from an anti-parallel β-sheet to the parallel β-sheet conformation characteristic of fibrils. Overall, these results led us to conclude that calcium ions stimulate the formation of oligomers of Aβ(1-40), that have been implicated in the pathogenesis of AD. <p><p>Despite the tremendous progress in understanding AD, there remains the challenge of the development of new and efficient drugs. In order to shed light onto the mechanism of action of two new potent γ-secretase modulators -- benzyl-carprofen and sulfonyl-carprofen within lipid bilayers, ssNMR technique was employed. Using neutron scattering experiments it was previously found that sulfonyl-carprofen and benzyl-carprofen partition into the headgroup region of the lipid bilayer. The orientational constraints derived from the ssNMR experiments refined their position into precise orientation. Combined, these results indicate that carprofen-derivatives can directly interact with the region of APP that mediates dimerization. Such interaction, would interfere with proper APP-dimer formation, which is necessary for the sequential cleavage by γ-secretase, diminishing or greatly reducing Aβ42 production.<p><p>Results obtained during this work shed new light onto some of the key processes in AD: Aβ production from APP, formation of Aβ oligomers and insights into the mechanism of action of potential therapeutics. We believe that these results will promote a better understanding of the disease and will help in future drug design.<p> / Doctorat en Sciences / info:eu-repo/semantics/nonPublished

Ce travail de thèse s’intéresse à la Théorie de l’Esprit (TdE) dans les stades précoces de la maladie d’Alzheimer (MA) et le Mild Cognitive Impairment (MCI). La TdE est un processus central de la cognition sociale permettant d’inférer les états mentaux d’autrui et de nous adapter aux interactions sociales auxquelles nous sommes confrontés chaque jour. Des travaux ont mis en évidence un déficit de TdE chez le patient MA mais son authenticité reste discutée et celui-ci est attribuer aux autres troubles cognitifs des patients. Par ailleurs, une seule étude à ce jour s’était intéressée à la TdE chez le patient MCI, laissant un champ d’étude inexploré malgré l'intérêt de cet état pour le diagnostic précoce des pathologies dégénératives. Ce travail a pour but d’approfondir les données existantes sur le fonctionnement de la TdE dans la MA et le MCI et présente également l’ambition d’évaluer, pour la première fois dans ces populations, la TdE au plus près de son fonctionnement quotidien dans une tâche impliquant le patient dans une vraie interaction sociale. Les résultats montrent que les patients présentent bien un déficit de TdE y compris sur la tâche immersive, suggérant que ce déficit est observable dans des situations proches de la vie quotidienne. Les patients présentent également un déficit sur une tâche plus classique de TdE, la nature de leurs erreurs témoignant de l’authenticité de ce déficit. Ce travail tend donc à confirmer la présence d’un dysfonctionnement de la TdE dans les stades débutants de la MA et dans le MCI. Ce déficit est précoce, authentique et observé pour la première fois dans une situation d’interaction sociale réelle. / This work investigates Theory of Mind (ToM) ability in early Alzheimer’s disease (AD) and Mild Cognitive Impairment (MCI). ToM is a core feature of social cognition allowing us to infer and understand other’s mental states (i.e. beliefs, intentions, knowledge), in order to adapt our behavior in everyday social interactions. Previous works evidenced ToM deficit in AD patients, but the authenticity of this deficit is still debated and is attributed to other cognitive dysfunctions of patients. Moreover, only one study investigated ToM in MCI. This area thus requires further investigation since MCI represents an interesting concept for early diagnosis of neurodegenerative disorders. The purpose of this work is to further investigate ToM functioning in both AD and MCI with the ambition to evaluate for the first time ToM in close-to-everyday conditions with a task involving the patient in a real interaction. Results show that patients present ToM impairment even in a real interactive task suggesting that this deficit is noticeable in naturalistic conditions closed to everyday interactions. Patients also present difficulties in a classical ToM task, the nature of their errors suggesting genuine ToM difficulties. This work therefore confirms the presence of a ToM impairment in early AD and MCI. This impairment is precocious, authentic and is observed for the first time in a real social interaction.

INTRODUÇÃO: O envelhecimento da população é uma tendência social conhecida em países desenvolvidos e cada vez mais pronunciada em países em desenvolvimento. A demência é considerada um dos principais problemas de saúde devido ao rápido crescimento populacional de idosos, sendo os distúrbios de linguagem considerados importantes nesses quadros. O discurso tem ganhado destaque para a identificação dos distúrbios linguísticos nas demências assim como no seguimento desses pacientes. A caracterização das diferenças pode auxiliar no diagnóstico diferencial e contribuir para a criação de ferramentas futuras que auxiliem na intervenção clínica e ajudem a evitar a evolução e/ou progressão dos quadros demenciais. O processo de transcrição e análise do discurso é bastante laborioso, desta forma o uso de métodos computacionais tem auxiliado na identificação e extração de características linguísticas. OBJETIVO: identificar alterações em aspectos micro e macrolinguísticos que diferenciem indivíduos com doença de Alzheimer, comprometimento cognitivo leve e idosos sem comprometimento cognitivo na tarefa de narrativa de figuras em sequência e explorar a ferramenta computacional (Coh-Metrix-Dementia) para análise do discurso desses sujeitos. MÉTODO: Foram avaliados 60 indivíduos, sendo 20 em cada grupo de pesquisa (doença de Alzheimer leve - GDA, comprometimento cognitivo leve amnéstico - GCCLa e controle - GC). Os indivíduos foram solicitados a enunciar uma narrativa baseada em 22 cenas em sequência, que retratam a história da \"Cinderela\". Foram aplicados também os seguintes testes linguístico-cognitivos: Fluência Verbal, Teste de Nomeação do Boston e Camel and Cactus test. Utilizou-se o Coh-Metrix- Dementia para extração automática das métricas. RESULTADOS: Os valores extraídos pelo Coh-Metrix-Dementia foram tratados estatisticamente sendo possível levantar métricas capazes de distinguir os grupos estudados. Em relação aos aspectos microlinguísticos destacaram-se a redução nas habilidades sintáticas, maior dificuldade no resgate verbal, discursos com menor coesão e coerência local no GDA. No nível macrolinguístico o GDA apresentou os discursos menos informativos, com maior prejuízo em relação a coerência global e maior número de modalizações. O GDA também apresentou maior comprometimento da estrutura narrativa. Não foi possível discriminar o GCCLa e GC em nenhuma métrica do discurso deste estudo. Foram feitas adaptações em relação a segmentação das sentenças para um melhor funcionamento da ferramenta computacional. CONCLUSÃO: Os indivíduos do GDA apresentaram discursos com maior comprometimento macro e microestrutural. O uso da ferramenta computacional se mostrou um importante aliado para análises discursivas / INTRODUCTION: Population aging is a social trend known in developed countries and increasingly pronounced in developing countries. Dementia is considered one of the main health problems due to the rapid population growth of the elderly, and language disorders are considered important in these settings. The discourse is important for the identification of linguistic disorders in dementias as well as in the follow-up of these patients. The discourse differences characterization can help on the differential diagnosis and contribute to the creation of future tools for clinical intervention and help prevent the evolution and/or progression of dementia. The transcription and discourse analysis are laborius, thus the use of computational methods helped in the identification and extraction of linguistic characteristics. OBJECTIVE: The objective of this study was to identify changes in micro and macrolinguistic aspects that differentiate individuals with Alzheimer\'s disease, mild cognitive impairment and healthy elderly individuals during narrative of figures in sequence and to explore the computational tool (Coh-Metrix-Dementia) to analyze the subjects\' discourse. METHODS: 60 subjects were evaluated, 20 of them in each research group (mild Alzheimer\'s disease - GDA, amnestic cognitive impairment - GCCLa and control - CG). The subjects were asked to construct a narrative based on sequence of pictures, about the \"Cinderella´s Story\". The following linguistic-cognitive tests were also applied: Verbal Fluency, Boston Naming Test, and Camel and Cactus test. Coh-Metrix-Dementia was used for automatic metrics extraction. RESULTS: The values extracted by Coh-Metrix-Dementia were statistically treated and it was possible to obtain metrics capable of distinguishing the studied groups. In relation to the microlinguistic aspects, it was found the reduction in syntactic abilities, greater difficulty in verbal rescue, discourses with less cohesion and local coherence in the GDA. In the macrolinguistic level the GDA presented the less informative discourses, with greater loss in global coherence and the greater number of modalizations. The GDA also presented greater impairment on narrative structure. It was not possible to discriminate GCCLa and GC in any discourse´s metric in this study tool functioning. CONCLUSION: The GDA subjects presented discourses with greater macro and microstructural impairment. The computational tool usage proved to be an important ally for discursive analysis

Alzheimer's Disease (AD) prevalence is 47 million in the world, 160,000 in Sweden. AD will increase by 70% in 50 years. AD cost is $7.9 trillion dollars in medicine and healthcare costs annually. Modifiable risk factors need to be mapped. Objective: Explore the relationship between sleep disorders and AD. Method: Searching PubMed and ScienceDirect for a literature review with 20 articles that were quality-reviewed. Result: Sleep-related factors that increase the risk of AD 1) Sleep disorders, sleep disturbed breathing, sleep apnea and insomnia. 2) The influence on cognitive ability, learning and memory showed correlation with sleep parameters. Sleep longer than 9 hours or less than 7 hours, daily naps longer than one hour were associated with increased AD risk 3) Other diseases and interfering factors, depression, cognitive impairment. Carriers of the APOE4-e4 gene with depression or cognitive impairment. IL-1b, a marker for inflammation, increases the risk of sleep disorders. People with clinician-verified depression and APOE-e4 were associated with a very high risk of AD, people with APOE-e4 and sleep disorders were associated with a high risk of AD. Symptoms of poor sleep that may be a sign of mechanisms are inflammation and tau / Ab accumulation as a sign of neurodegeneration. Conclusion: Sleep disorders, sleep parameters, disturbed REM sleep and genes are important for AD incidence. Programs to improve health literacy, control and treatment of sleep disorders and depression, limitation of risk factors, training in risk factors and sleep interventions. Interdisciplinary AD research needs to address the problem through transdisciplinary collaboration. / Prevalensen för Alzheimers sjukdom (AD) är 47 miljoner i världen varav 160 000 i Sverige. Antalet personer med AD kommer att öka med 70 % om 50 år. Kostnaderna för AD är 7900 miljarder dollar i medicin och vårdkostnader årligen. Påverkbara riskfaktorer kan därför behöva kartläggas. Syfte: Att kartlägga kunskapsläget kring och samband mellan sömnstörningar och AD. Metod: Sökning i PubMed och ScienceDirekt för en litteraturöversikt med 20 artiklar som kvalitetsgranskades och analyserades. Resultat: Sömnrelaterade faktorer som ökar risken för AD 1) Sömnsjukdomar, sömnrelaterad andningsstörning, sömnapné och insomni 2) Sömnpåverkan, fragmenterad sömn, otillräcklig sömnkvalitet, otillräcklig REM sömnslängd och ”REM latency”. Påverkan på kognitiv förmåga, inlärning och minne visade samband med sömnparametrar. Sömn längre än 9 timmar eller kortare än 7 timmar, dagliga tupplurar längre än en timme var associerat med ökad AD risk 3) Andra sjukdomar och samverkande faktorer, depression, kognitiv påverkan. Bärare av APOE4-e4 genen som hade depression eller kognitiv nedsättning. IL-1b, en markör för inflammation ger större risk för sömnstörningar. Personer med kliniskt etablerad depression och APOE-e4 associerades med mycket hög risk för AD, personer med APOE-e4 och sömnstörningar associerades hög risk för AD. Symptom vid sämre sömn som kan vara tecken på mekanismer är inflammation samt tau/Ab ansamling som tecken på neurodegeneration. Slutsats: Sömnstörningar, störd REM sömn och gener har betydelse för AD incidens. Program med hälsoinformation för att öka hälsolitteracitet behövs samt kontroll och behandling av sömnstörningar, depression och begränsning av riskfaktorer, utbildning i riskfaktorer och sömninterventioner. Tvärvetenskaplig AD forskning behöver hantera problemet genom ämnesövergripande samverkan.

Les symptômes psychologiques et comportementaux de la démence (SPCD) sont fréquents et peuvent concerner jusqu’à 90 % des patients atteints de la maladie d’Alzheimer. Considérant l’efficacité limitée et l’ampleur des effets secondaires observés avec les traitements psychotropes en France, la majorité des directives existantes soulignent l’importance de la recherche clinique sur la maladie d’Alzheimer et une amélioration de l’évaluation des approches non pharmacologiques (ANP). En 2016, Le recours à la médiation animale, comme prise en soins, en établissements d’hébergement pour personnes âgées dépendantes (EHPAD) est de plus en plus fréquent. Nous avions montré les bienfaits de cette ANP sur l'apathie dans la maladie d'Alzheimer et avons souhaité en démontrer son efficacité. Notre étude évalue et mesure, principalement à l’aide de l’Inventaire Neuropsychiatrique version Equipe soignante (NPI-ES), comment la présence du chien dans la psychothérapie des malades Alzheimer est associée à des niveaux de SPCD chez des femmes et des hommes, âgés en moyenne de 85 ans qui vivent en institution. Nous nous sommes concentrés sur le bien-être et la construction d’émotions positives de la personne âgée démente, en particulier sur la revalorisation de l’estime de soi, la stimulation, la remobilisation et le maintien des capacités cognitives préservées, comme base thérapeutique possible dans l’association de la présence du chien avec la diminution significative des SPCD. / Today, the use of animal mediation as a form of treatment in nursing homes has become more and more common. Our study assesses and measures, largely through the use of the Neuropsychiatric Inventory for Nursing Home (NPI-NH), how the presence of a dog in Alzheimer’s patient psychotherapy affects psycho-behavioral disorder (BPSD) levels in French men and women with a mean age of 85 years living in an institution. Our study focuses on well-being and on building positive emotion in the elderly with dementia, particularly through regaining self-esteem, stimulation, remobilization and maintenance of preserved cognitive abilities. This therapeutic basis is made possible through exposure to a dog with the goal of decreasing BPSD.