As demências Frontotemporais (DFT) compreendem 2 fenótipos clínicos: distúrbios comportamentais ou de linguagem. Coletivamente, as DFT podem ser causadas por um grupo diversas de doenças neurodegenerativas chamadas degeneração lobar frontotemporal (DLFT). Novas entidades têm sido descritas neste grupo e o conceito está em constante evolução. Parte dos mecanismos envolvidos na morte celular nas DLFTs também são observados n envelhecimento normal. Determinar as entidades e freqüência das DLFTs em uma série com utilização de imunoistoquímica. Uma série prospectiva de 833 casos avaliados prospectivamente no Centro de Pesquisas de Doença de Alzheimer da Washington University - EUA. Os casos de DFT foram selecionados por critérios clínicos e a classificação neuropatológica foi baseada em protocolos universalmente aceitos para DLFT. Dos casos de demência, 53(6,3%) atenderam aos critérios clínicos e neuropatológicos para DLFT. Outros 8 casos atenderam apenas aos critérios clínicos de DFT. As tauopatias representaram 40% dos casos. Entretanto, a maioria dos casos apresentava inclusões ubiquitina-positivas e tau-negativas. Esclerose hipocampal e alterações do tipo Doença de Alzheimer foram encontradas em 12 e 10 casos, respectivamente. Apesar da DLFT-U ter sido a entidade mais freqüente nesta série, entidades e menos comuns não incluídas nas recomendações de McKhann também podem apresentar fenótipo clínico de DFT. A inclusão destas novas entidades é mais uma evidência de que os sintomas clínicos são mais dependentes das áreas acometidas do que da entidade em si. A melhor compreensão desses mecanismos tem um grande potencial em auxiliar no desenvolvimento de medidas que possam modular ou retardar os efeitos do envelhecimento no cérebro, além é claro de trazer possibilidade de tratamento, hoje inexistente, para os pacientes acometidos. / Frontotemporal dementia (FTD) encompasses two clinical phenotypes: progressive behavioral change and language disorder. Collectively, FTD may be caused by a diverse group of neurodegenerative diseases called frontotemporal lobar degenerations (FTLDs). New entities have been described and the nosology of FTLDs continues to evolve. To determine the type and frequency of FTLDs in a series using contemporary immunohistochemical methods. Eight hundred and thirtythree dementia cases were prospectively assessed at Washington University Alzheimer Disease Research Center (WUADRC) and cases with clinical FTD were identified using existing diagnostic criteria and neuropathologic entities were ascertained using immunohistochemistry and contemporary diagnostic criteria. Of the dementia cases, 53(6.3%) met clinical criteria for FTD; 45(5.1%) fulfilled both clinical and neuropathological criteria for FTLD, and another 8 fulfilled only the clinical criteria. Forty percent of the cases were tauopathies. However, most FTLD cases were characterized by ubiquitin-positive, tau-negative inclusions. Co-existing hippocampal sclerosis and AD-type changes were observed in 12 and 10 cases, respectively. Although FTLD-MND-type is the most frequent FTLD in this prospectively assessed series, less common entities not included in the McKhann criteria, may also present clinically as FTD and should be considered as part of the neuropathologic spectrum of FTLDs that may be encountered in the dementia clinic. The better understanding of the cell death mechanisms related to those entities is likely to contribute for the development of a treatment for FTLD as well for a way of modulate brain aging.

Orientador: Elizabeth Maria Aparecida Barasnevicius Quagliato / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-25T22:29:43Z (GMT). No. of bitstreams: 1 Martins_SergilainePereira_D.pdf: 2688714 bytes, checksum: 50e69a64ddbe919094b642d6fcc2f77a (MD5) Previous issue date: 2014 / Resumo: A ressonância magnética por tensor de difusão (DTI) proporciona aumento da sensibilidade para estudar a alterações na microestrutura da substância branca aparentemente normal (SBAN) in vivo e é especialmente indicada para estudar doenças que apresentam lesão axonal e desmielinização. No presente estudo, sugerimos a hipótese de que a neurodegeneração produz alterações microestruturais na SBAN de indivíduos com DA e CCL, especialmente em regiões específicas do cérebro. Foram estudados 71 participantes (21 com DA leve, 25 com CCL e 25 controles normais-CN) que foram recrutados de serviço médico neurológico em Campinas. Os indivíduos foram avaliados por um protocolo de avaliação clínica padronizada que incluiu: escala de depressão geriátrica (GDS), questionário de atividades funcionais (FAQ - Pfeffer), mini exame do estado mental (MEEM), teste de aprendizado auditivo-verbal de REY (RAVLT), testes de memória prospectiva (MP) (consulta e pertence) (subtestes do Teste de Memória Comportamental Rivermead), teste de fluência verbal (FV) (animais e FAS), teste desenho do relógio (TDR) e teste de nomeação de Boston (TNB). As imagens de RNM foram adquiridas usando um scanner MRT 1.5. A anisotropia fracionada (FA) e as difusividades axial (DAx) e radial (DRa) foram analisadas em regiões de interesse (ROI) alocados nos lobos frontal, parietal, temporal e occipital. FA, DAx e DRa foram calculadas para cada ROI. Em seguida, calculamos as médias de todas as seções para FA, DAx, e DRa para cada região da SBAN bilateralmente. Resultados: Nossos resultados mostraram que: (1) Comparado com CN, o grupo CCL demonstrou diminuição da FA no lobo frontal (parte do fórceps menor e do fascículo uncinado e coroa radiada), região importante para a memória episódica. (2) Na avaliação por análise de regressão múltipla, FA e DAx frontal, DAx temporal e parietal e FA occipital formaram um padrão de parâmetros associados ao maior risco para CCL e DA. (3) O estudo da acurácia revelou que a DTI da região frontal é a que apresenta maior sensibilidade e especificidade para identificar CCL. Em relação à DA, as variáveis FA frontal e temporal e DAx parietal apresentaram maior especificidade para identificar DA. (4) Não encontramos correlação robusta entre variáveis neuropsicológicas e de neuroimagem / Abstract: MRI technique, diffusion tensor imaging (DTI), provides increased sensitivity to alterations in the microstructure of white matter in vivo and is especially indicative for diseases causing axonal damage and demyelination. In the present study, we hypothesized that neurodegeneration produces microstructural changes in the cerebral white matter of subjects with AD and MCI, especially in specific regions in the brain. We studied 71 participants (21 mild AD, 25 MCI, and 25 normal controls-NC) that were recruited from neurological medical service in Campinas. Subjects were evaluated by using a standardized clinical evaluation protocol, which included: Geriatric depression Scal (GDS), the functional activities questionnaire (FAQ-Pfeffer), mini-mental status examination (MMSE), Rey auditory verbal learning test (RAVLT), prospective memory (Rivermead Behavioral Memory Test), verbal fluency test (animal and FAS), clock drawing test and Boston naming test. MR images were acquired using a 1.5 T MR scanner. Fractional anisotropy (FA) and axial and radial diffusivities (DA and DR) were analyzed in regions of interest (ROIs) in frontal, parietal, temporal and occipital lobes. FA, DA, and DR were calculated for each ROI. Then the measures of FA, DA, and DR were averaged across all the sections of each white matter region bilaterally. Our results showed that: (1) Compared to NC, MCI group showed decreased FA in the frontal lobe (the minor forceps and the uncinate fasciculus, and corona radiata), important region to episodic memory. (2) The evaluation by multiple regression analysis, frontal FA and DA, temporal and parietal DA and occipital FA formed a pattern of parameters associated with increased risk for MCI and AD. (3) The accuracy revealed that the frontal area has the greatest sensitivity and specificity to identify MCI. Regarding the AD, the frontal FA and temporal and parietal DA have the greatest specificity for identifying AD. (4) We did not find correlation between neuropsychological and neuroimaging variables / Doutorado / Neurologia / Doutora em Ciências Médicas

Si la littérature fait état des réticences des aidants familiaux, à demander de l'aide, leurs ressortspsychiques restent mal connus. Pourtant le sentiment de culpabilité a déjà été repéré, comme un obstacle à lademande d'aide de l'aidant, mais ce facteur a été peu exploré dans un axe de recherche. Cette rechercherepose sur l'hypothèse que le sentiment de culpabilité de l'aidant familial, représenterait le principal frein,susceptible d'empêcher sa demande d'aide et de soutien, face à la maladie d'Alzheimer ou à la maladieapparentée de son proche, lorsque le patient vit à domicile. Une sous-hypothèse vise à situer différemment lesentiment de culpabilité de l'aidant familial, selon sa position de conjoint, ou plus largement de descendant(enfant, belle-fille, gendre...), dans la relation d'aide. Pour tester cette hypothèse trente huit entretiens semidirectifsont été réalisés, et complétés par la passation des échelles d'attachement (RSQ), du caregiver(CRA), et de dépression (Beck).Cette recherche vise à expliciter les fondements, et les mécanismes du sentiment de culpabilité des aidantsfamiliaux, en l'articulant à la problématique de perte, qui est coeur de la maladie d'Alzheimer ou desmaladies apparentées. Elle apporte donc un éclairage nouveau sur le travail psychique de l'aidant familial,qui s'écarte de son seul abord sous l'angle du fardeau et de l'épuisement, pour l'envisager à la lumière dutravail du pré-deuil, qui apparaît comme la clé de voûte de la relation d'aide. Par conséquent, la recherchesuivra le cycle de la dépendance du patient, pour dégager à chacun de ses stades, les incidences de la pertedans l'espace psychique et intersubjectif chez l'aidant familial, selon la nature des liens d'attachementdéveloppés avec le patient, mais aussi avec le groupe familial. A partir de là, nous tenterons de relier leregistre principal d'élaboration de la perte, à un profil d'aidant singulier dans la relation d'aide, afin d'éclairerles liens entre ses manifestations de culpabilité, et sa demande d'aide. / If the litterature states reservations of the family caregivers, to ask for help, their psychic springsremain badly known. Nevertheless the sense of guilt was already located, as an obstacle at the request ofhelp, of the caregiver, but this factor was little explored in a research theme. This research bases on thehypothesis that the sense of guilt of the family caregiver, would represent the main brake, susceptible toprevent his request of help and support, in front of the Alzheimer's disease or the related disease, when thepatient lives at home. A sub-hypothesis aims at placing differently the sense of guilt of the familiy caregiver,according to its spouse's position, or more widely of descendant (child, son-in-law, daughter-in-law) in therelation of help. To test this hypothesis, thirty eight semi-directive conversations were realized andcompleted by the signing of the scales of attachment (RSQ), the caregiver (CRA), and depression (Beck).This research aims at clarifying foudations, and mechanisms of the sense of guilt of the family caregivers, byarticulating it in the problem of loss, which is heart of Alzheimer's disease or the related diseases. It thusgives a new perspective on the psychic work of the family caregiver, which deviates from its only accessunder the angle of the burden and the exhaustion, to envisage it in the light of the work of the pre-mourning,which appears at the keystone of the relation of help. Consequently, the research will follow the cycle of thedependence of the patient, to release in each of its stages, the incidences of the loss in the psychic andintersubjective space at the family caregiver, according to the nature of the links of attachment developpedwith the patient, but also with the family group. From there, we shall try to connect the main register ofelaboration of the loss, in a profile of singular caregiver in the relation of help, to light the links between hisdemonstrations of guilt and his demand of help.

Chez les personnes âgées, la maladie d'Alzheimer et les pathologies apparentées représentent actuellement un véritable problème de santé publique. Si les lésions anatomo-pathologiques de ces maladies sont bien définies, leur étiologie reste incertaine et vraisemblablement plurifactorielle. En tant que psychologue clinicienne, ce sont les théories impliquant le psychisme dans l'étiologie des maladies démentielles de l'âgé qui ont d'abord retenu mon attention. Une revue de question a permis d'en dresser une liste qui se veut exhaustive et qui se découpe en trois grandes catégories : les théories psycho-dynamiques, les théories psychosociales et enfin les modèles intégratifs plurifactoriels. Parmi ces derniers, celui faisant intervenir les évènements de vie en tant que facteurs de risque a suscité cette double recherche.Ainsi, dans une démarche qualitative, deux études ont débuté en parallèle. La première rétrospective, qui porte sur les histoires de vie d'une population de 30 malades Alzheimer ou apparentés, hébergés dans une unité de vie protégée ; la seconde prospective, qui explore l'évolution cognitive sur plusieurs années de 30 personnes âgées indemnes de troubles au début de l'étude, selon que leurs histoires de vie soient riches ou pas en événements de vie.Si un certain nombre d'évènements perturbants sont relatés par l'entourage pour la plupart des patients de la recherche rétrospective, l'étude prospective montre qu'un nombre important d'évènements de vie n'est ni une condition suffisante, ni une condition nécessaire pour constituer un facteur de risque de troubles cognitifs. Par contre, l'élaboration ou non de ce(s) même(s) évènement(s), leur caractère traumatique ou non, en lien avec le soutien et les aides reçus ou non semblent déterminants dans l'évolution cognitive des sujets.Enfin, chez la plupart des sujets pour qui les évènements anciens se révèlent traumatiques, un épisode contemporain de type « perte » viendrait réactiver les souvenirs et serait un facteur précipitant de troubles cognitifs, voire de décompensation vers une pathologie de la mémoire. / Among the elderly, Alzheimer disease and related pathologies currently constitute a real public health issue. The anatomo-pathological lesions of these diseases may be clearly defined but their etiology remains uncertain and is likely multifactorial. As a clinician psychologist, theories involving psychism in the etiology of demential diseases among elderly, first held my attention. A review of the question enabled me to make a list supposed to be exhaustive and divided into 3 categories : psycho-dynamic, psycho-social theories and multifactorial integrative patterns. Among the latter, the one involving life events as risk factors motivated this double research. Thus is a qualitive procedure, 2 studies started in parallel. The first retrospective dealing with life stories of a population of 30 people affected by Alzheimer or related diseases, hosted in a protected life-unit ; the second prospective scanning through cognitive evolution based on several years for 30 elderly people unharmed by troubles at the start of the study (depending on their life stories having many or few life events). If a certain amount of disturbing events are recounted by relatives for most of the patients of the retrospective research, the prospective research shows that an important number of live events is neither a sufficient nor a necessary condition to represent a risk factor of cognitive troubles. On the other hand, the elaboration or non elaboration of there events, their traumatic or non traumatic aspect (linked with the received or not received support and help) seems to be determining in the cognitive evolution of the subjects. Finally, among most of the subjects for whom past events prove to be traumatic, a contemporary "loss"-like episode would revive memories and would be an accelerating factor of cognitive troubles and even a collapse to a memory pathology.

Alzheimer’s disease (AD), the most common form of dementia is associated with fibril formation of amyloid-ß peptides (Aß). Aß, proteolytically derived from Aß precursor protein (AßPP), is the major component of amyloid plaques in AD brains. Familial British and Danish dementias (FBD and FDD) share pathological and clinical characteristics with AD, and the underlying mechanisms are associated with amyloid formation of mutant peptides released from the Bri2 protein. Bri2 interacts with AßPP and its BRICHOS domain has been shown to delay Aß40 and Aß42 fibril formation and toxicity in vitro and in vivo. This makes Bri2 BRICHOS a promising anti-amyloid chaperone and a potential treatment strategy for AD. Furthermore, Bri2 BRICHOS possesses a general chaperone activity as it suppresses non-fibrillar aggregation of destabilized citrate synthase (CS). Recent findings show that Bri2 BRICHOS produced in E.coli can form different molecular weight assemblies, ranging from monomers to dimers and poly-disperse oligomers. The oligomers inhibit CS aggregation, whereas the monomers and dimers are more efficient against Aß42 fibrillation and neurotoxicity, respectively. The work in this thesis shows that similar Bri2 BRICHOS quaternary structures are formed in eukaryotic cells as in E.coli. Larger BRICHOS oligomers were found in cell media, derived from proteolytically processed endogenous Bri2 in SH-SY5Y cells, as well as in human embryonic kidney (HEK293) cells transfected with a Bri2 BRICHOS construct. Recombinant human Bri2 BRICHOS mutants with one or none of the two strictly conserved cysteine residues were studied. All mutant monomers become proteolytically degraded during purification, but form stable oligomers. Single Cys to Ser mutants form stable disulfide-dependent dimers that differ in ability to prevent Aß42 fibrillation, the most stable mutant (C164S) being even more efficient than the wildtype Bri2 BRICHOS dimer. This result suggests that intra or intermolecular disulfide(s) and oligomerization affect Bri2 BRICHOS stability and activity towards Aß42 fibril formation.

A Doença de Alzheimer (DA) é a doença mais prevalente entre as demências, retratada por déficits progressivos da memória, funções cognitivas e funcionalidade. Apesar das evidências dos benefícios do exercício físico nas funções cognitivas e no declínio funcional, há poucos estudos com idosos com DA, que incluem efeitos de programas multimodais de exercícios físicos comparados com idosos sem DA. Os objetivos foram comparar os efeitos do programa multimodal de exercícios físicos na capacidade funcional, memória e atenção em idosos sem e com DA. Foram randomizados vinte idosos sem DA para grupo controle (NDA-C) ou grupo treinamento físico (NDA-T) e 18 idosos com DA no grupo controle (DA-C) ou treinamento físico (DA-T). Todos realizaram avaliação do nível sócio econômico, nível de atividade física (Questionário Internacional de Atividade física), e avaliação neuropsicológica (Miniexame do Estado Mental, Teste Breve de Desempenho Cognitivo, Escore Clínico de Demência e Escala de Depressão Geriátrica). A avaliação funcional incluiu testes de resistência muscular de membros inferiores (MMII) e superiores (MMSS) (Teste de Sentar e levantar e Teste de Flexão do cotovelo), capacidade aeróbia (Teste de Marcha estacionária), flexibilidade de MMII e MMSS (Teste de Sentar e alcançar e Teste de Alcançar atrás) e agilidade/equilíbrio dinâmico (Teste de Levantar e ir). A avaliação da amplitude de movimento de ombro e tornozelo foi realizada através do Flexímetro. Os grupos DA-T e NDA-T participaram do programa durante 6 meses, 2 vezes/semana com duração de 75 minutos cada sessão. A análise estatística para verificar diferenças entre os quatro grupos no período inicial foi realizada por Análise de variância (ANOVA) de 1 fator. E para verificar diferenças entre os grupos antes e depois de 6 meses foi realizada ANOVA de 2 fatores. No caso de significância foi realizado uma análise de pos-hoc com Tukey. Admitiu-se, em todas as análises, o nível de significância de 5% (P 0,05). O programa aumentou significativamente (P < 0,05) o nível de atividade física no lazer, a força muscular de MMSS, capacidade aeróbia, flexibilidade de MMII e amplitude de extensão de tornozelo e ombro nos grupos NDA-T e DA- T. Os grupos NDA-T e DA-T melhoraram a capacidade de agilidade e equilibro dinâmico em relação ao grupo DA-C. O programa proporcionou melhora significativa (P < 0,05) na força muscular de MMII do grupo NDA-T e, na flexibilidade de MMSS e amplitude de flexão de tornozelo e ombro no grupo DA-T. Após a intervenção houve melhora significativa (P < 0,05) da memória dos grupos NDA-T e DA-T, e da atenção no grupo NDA-T. Conclui-se que o programa foi efetivo para aumentar o nível de atividade física no lazer, capacidade aeróbia, força muscular de MMSS, flexibilidade de MMII e amplitude de extensão de tornozelo e ombro, bem como a memória dos idosos, independente da presença da DA. O declínio da agilidade/equilibro dinâmico e da atenção do DA-T foi atenuado em relação ao DA-C. Estes benefícios contribuem para um melhor desempenho nas atividades da vida diária melhorando a qualidade de vida dos idosos com e sem DA / The Alzheimer Disease (AD) is the most prevalent disease between all the dementia, and it is portrayed by progressive deficits of memory and cognition. Besides all the evidences of the benefits of the physical exercises to the cognitive function, there are a few studies that include the effects of the multimodal programs on the physical function and cognitive functions, comparing older adults with and without AD. The goals were compare the multimodal program effects in functional capacity, memory and attention on older adults with and without AD. Twenty older adults without AD were randomized on Control Group (NAD-C) or Physical Training Group (NAD-T) and eighteen elderly with AD were randomized on control group (AD-C) or physical training group (AD-T). All patients realized socioeconomic evaluation, physical activities level (International Physical Activities Questionary), and neuropsychological evaluation (Mental State Miniexam, Syndrom Kurztest, Clinical Dementia Rating and Geriatric Depression Screening Scale). On the period of 6 months, the NAD-T and AD-T groups, participated on the multimodal program, the exercise routine was 2 times a week and the duration of 75 minutes. A measuring functional fitness of older adults were applied, the tests evaluated the Inferior and Superior liths muscular Resistance/Strenght (30-second Chair Stand and Arm Curl), Aerobic Capacity (2-minute Step), the lower and upper body flexibility (Chair Sit-and-Reach, and Back Scratch tests) and agility/dynamic balance (8-foot Up and Go). The shoulder and ankle amplitude evaluation tests were realized using a Fleximeter. The statistical analysis to verify if there was any difference between the four groups (NAD-C, NAD-T, AD-C and AD-T) on the initial period were realized using the Variance Analysis (ANOVA) 1way. The statistical analysis to verify the difference between the groups before and after the six months period was realized using the ANOVA 2way. In the case of significance, were used the Tukey Pos-Hoc analysis. In all analysis the level of significance was 5% (P 0.05). The multimodal exercise program was effective to increase the leisure time physical activity level of older adults with or without AD. The program, also contributed to increase the physical conditioning, getting a significant improvement (P<0.05) on the upper body muscular strength, aerobic capacity, upper and lower body flexibility, and, on the Shoulder and Ankle extension amplitude, in the NAD-T and AD-T groups. The NAD-T and AD-T groups improved agility/dynamic balance in relation to the AD-C group. Concerning the cognition, after exercise program, the groups NAD-T and AD-T showed an improvement on the memory (P<0.05). However, the attention only improved in the NAD-T group (P<0.05). Independent of multimodal physical exercise program was improve the leisure time physical activity level, aerobic capacity, upper body muscular strength, lower body flexibility shoulder and ankle extension, and memory in the older adults. The program attenuated the decline in agility/dynamic balance, and attention in DA-T group. These benefits contribute to a better performance in daily living activities which contributes to improve the quality of life of the older adults with and without AD

Esta pesquisa teve por objetivo desenvolver e avaliar um website com informações na área de Fonoaudiologia com enfoque na Doença de Alzheimer (DA). Foi elaborado um website contendo informações acerca da DA buscando-se uma linguagem simples e clara com conteúdo conciso. O conteúdo foi gerado por meio da coleta de informações em livros e artigos científicos indexados nas bases de dados. Utilizou-se o índice de Flesch para verificar a legibilidade do material, encontrando-se grande parte do conteúdo com percentil correspondente a fácil. A elaboração do website seguiu as etapas: análise e planejamento, modelagem, implementação e avaliação. Aspectos relacionados à acessibilidade compõem o website proporcionando maior abrangência e alcance. Foram convidados avaliadores que fizeram parte das categorias: idoso (I), cuidador de idoso (CI) e fonoaudiólogo (F). A amostra foi composta por 16 idosos (média etária de 74,13 anos), 12 cuidadores de idosos (média etária de 41,50 anos) e 28 fonoaudiólogos (média etária de 29,93 anos). A maioria dos indivíduos são (80,36%) do sexo feminino, que frequentemente acessavam a Internet (92,9%) e de diferentes níveis educacionais. A análise estatística foi realizada por meio do teste Kruskal-Wallis e Coeficiente de Correlação de Spearman. O conteúdo do website foi avaliado como excelente com maior classificação no submenu 6 (93,7%) e menor no submenu 2 (90%). Encontrou-se diferença significativa entre o escore geral da avaliação do conteúdo e as categorias I x F e I x CI (com melhores avaliações de F e CI, respectivamente). Ao analisar cada submenu, de acordo com as categorias, encontrou-se diferença estatística em submenu 2, 4 e 7 entre as categorias I x F (com melhor avaliação realizada pela categoria F). A avaliação da qualidade técnica do website apresentou-se como adequada, cuja subescala com maior classificação foi o Público (91,5%) e a menor foi Precisão (64%). Não houve diferença estatisticamente significativa entre as categorias e as subescalas ou o escore geral. Desta forma conclui-se que o website e seu conteúdo sobre a DA compõem uma fonte de consulta ou de complementação de informações fidedignas. / This research aimed to develop and evaluate a website with information on Speech, Language and Hearing Sciences area focusing on Alzheimer\'s Disease (AD). The website was developed containing information about AD attempting to use a simple and clear language with concise content. The content was created by collecting information about AD in books and scientific articles indexed in databases. It was used the Flesch index to check the material intelligibility, resulting most of the content with the corresponding percentile \"easy\". The website development followed the steps: analysis and planning, modelling, implementation and evaluation. Accessibility-related aspects composed the website providing greater scope and range. Invited evaluators were part of the categories: elderly (E), caregiver of elderly (CE) and speech language and hearing therapists (SLHT). The sample consisted of 16 elderly (mean age of 74.12 years), 12 caregivers of elderly (mean age of 41.50 years) and 28 SLHT (mean age of 29.93 years). The majority (80.36%) were females, who often accessed the Internet (92.9%) and from different educational levels. Statistical analysis was performed using the Kruskal-Wallis and Spearmans Correlation Coefficient test. The website content was rated as \"excellent\" with the highest rating in submenu 6 (93.7%) and the lowest in submenu 2 (90%). A significant difference was verified between the overall score of the content evaluation and the categories E x SLHT and E x CE (with better evaluations scored by SLHT and CE, respectively). By analyzing each submenu, according to the categories, it was found statistically significant differences in submenus 2, 4 and 7 between categories E x SLHT (with better evaluations performed by SLHT). The website technical quality evaluation presented as adequate, with the highest rating performed by the subscale \"public\" (91.5%) and the lowest \"accuracy\" (64%). There was no statistically significant difference between the categories and subscales or the overall score. Thus it is concluded that the website and its contents about AD are a reliable reference source or complementing information.

La maladie d'Alzheimer (MA) est un processus multifactoriel. La dysfonction vasculaire pourrait être impliquée dans sa progression. Les microhémorragies cérébrales (MH) sont fréquentes chez les patients atteints de MA, et pourraient jouer un rôle clé dans le lien qui relie la dysfonction vasculaire à la MA. Le sexe pourrait également impacter sur la sévérité des lésions. Les statines ont été proposées en prévention de maladies neurodégénératives dont la MA. Leur intérêt est encore débattu mais ces molécules ont une action pléiotrope. Ce travail a pour objectif d'étudier l'impact des lésions microhémorragiques sur le déclin cognitif dans la MA, le rôle du sexe et la modulation pharmacologique par Atorvastatine, dans une perspective translationnelle,i.e. en considérant à la fois l'aspect expérimental chez l'animal et l'aspect clinique. Pour la partie expérimentale, nous avons étudié à partir d'un modèle original de MH chez les souris femelles saines et pathologiques. La MHC est créée par injection stéréotaxique de Collagénase (0,8|uUI/|iL). L'atorvastatine est administrée dans l'alimentation quotidienne des rongeurs(5mg/Kg/J). Le suivi était multimodal à trois temps différents : six semaines, six mois et douze mois après la chirurgie. Au plan clinique, nous avons étudié une base de données de patients atteints de la MA, suivis de façon standardisée. Notre travail a mis en évidence, dans une approche translationnelle, un impact cognitif et non cognitif des MHs, en présence ou non d'une maladie d'Alzheimer chez le sexe féminin. Nos résultats tendent à confirmer l'intérêt de l'atorvastatine dans la neuroprotection, grâce à ses effets pléiotropes. D'une manière générale,notre travail souligne, une fois de plus, l'intérêt d'une prise en charge personnalisée, et précoce de la MA. / The physiopathology of Alzheimer disease (AD) is complex. Associated factors, in particular at the vascular level with damaged small blood vessels, might be involved. Cerebral microbleeds(CMB) in particular, could be one of the key contributing factor in AD. The cumulative evidence suggested a sex-specific patterns of disease. Furthermore, statins might be interesting by pleitropic effects. The objectives of this study was to evaluate the interaction between vascular and neurodegenerative lesions in Alzheimer, the influence of sex, and the pharmacological modulation by atorvastatin. This experimental model is designed in a multimodal approach to ensure its scientific relevance and to fit with clinical research. The third objective is indeed to confront theresulting experimental data to the clinical data of cohorts of Alzheimer patients. With an original model of CMB in female mice, we folio wed-up them from 1.5 months to 12 months postsurgery.For the clinical part, we studied patients with AD from a database of a tertiary memory center, with standardized framework. In a translational way, we observed a cognitive and a non cognitiveimpact of CMBs, differently in wild-type mice and in diseased mice. Different outcome was noticed for young female mice. And Atorvastatine offered a mild neuroprotection particularly in presymptomatic stage. Finally, the mechanism implied will be studied, in particular the inflammatory pathway, and will help to propose targeted pharmacological modulation in order to prevent or limit the impact of CMB on AD, by offering a personalized approach.

La prise en charge des personnes âgées présentant une maladie neurodégénérative aboutissant à des troubles cognitifs et une démence représente un enjeu majeur de santé. Il est important de concevoir des outils pour aider les cliniciens à mieux prendre en charge les patients par la stimulation. L’Environnement Enrichi – favorisant les stimulations cognitives, physiques et sociales dans un contexte émotionnel positif – apparait être une puissante stratégie non-médicamenteuse pour réduire ou retarder les évolutions des processus neurodégénératifs et les pertes cognitives. Dans cette approche, l’hypothèse de l’Enrichissement Cognitif stipule que les comportements qu’adopte un individu tout au long de sa vie vont avoir un impact sur le fonctionnement de son cerveau, même à l’âge avancé. C’est dans cette idée que les Jeux Vidéo et les Serious Games à activité physique sont utilisés. X-Torp est un Serious Game d’action conçu pour être accessible et stimulant pour les sujets âgés en bonne santé et présentant une Maladie Neurodégénérative due à un trouble cognitif léger ou une démence de type Alzheimer. Le joueur incarne un sous-marin et est plongé dans un monde quasi maritime où seules quelques îles sont en surface. Il doit ainsi évoluer dans un scénario pour monter en grade à travers la réalisation de missions et d’affrontements en mer. X-Torp est jouable sur Microsoft® Kinect™ pour PC. L’objectif de cette thèse est de présenter l’ensemble des travaux scientifiques entrepris pour (1) concevoir une première version du jeu ; (2) la tester chez les populations cibles et (3) concevoir en conséquence une seconde version commercialisable / The care of elderly people affected by neurodegenerative diseases leading to cognitive impairment and dementia represents a major challenge in the healthcare domain. It is important to design tools that can help clinicians to better treat these patients through stimulation. Enriched Environments - which favor cognitive and physical stimulations in a positive emotional context – look like a powerful non-pharmacological strategy to reduce or delay the evolution of neurodegenerative processes, and the consequent cognitive disorders. Based on this approach, the Enriched Environment hypothesis states that the behavior of an individual during the lifetime, even during old age, affect his brain functioning. Video Games and Serious Games implying physical activity are used in this context. X-Torp is an action Serious Game conceived to be usable and stimulating for healthy elderly people and people with neurodegenerative disorders leading to Mild Cognitive Impairment or to Alzheimer’s’ dementia. The player takes the command of a submarine and is immersed in a sea-world where only a few islands appear on the surface. The player needs to advance in the game scenario to improve his grade position accomplishing missions and battling over the sea. X-Torp is played with Microsoft® Kinect™ for PC. The aim of this thesis is to present the scientific work undergone to (1) conceive and design the first game version; (2) test this version on the target populations, and (3) based on the results, design a second game version ready to be commercialized

The current thesis investigated a potential relationship between Alzheimer disease and type-2 diabetes mellitus by analysing early gene expression related to insulin receptor signalling in the hippocampus as well as glucose metabolism in APP/PS1 mice, a model of familial Alzheimer disease. Compared to wild-type animals, a reduction in hippocampal insulin receptor and insulin-receptor substrate 2 transcripts in APP/PS1 mice three-month old as well as an increase in insulin-like growth factor 2 transcripts after six months was detected using real-time polymerase chain reaction. The alterations in hippocampal insulin signalling were accompanied by perturbation of glucose metabolism analysed by intraperitoneal glucose tolerance test. At the age of six months APP/PS1 mice developed glucose intolerance. Learning and recognition memory in APP/PS1 mice were tested using the Novel Object Recognition Test. Cognitive decline became evident in APP/PS1 mice at six months of age. Degradation of both insulin and amyloid β is mediated through insulin-degrading enzyme. However, expression of insulin-degrading enzyme in APP/PS1 mice was notdifferent from wild-type littermates. Changes in hippocampal phosphorylation of the tau phosphoepitopes serine 199, threonine 205, serine 396 and serine 404 were investigated using Western blot. Levels of three phosphoepitopes were increased significantly at either age.IV Protein expression of the phosphorylated form of glycogen synthase kinase 3β remained unchanged indicating an alternative pathway of tau phosphorylation in the APP/PS1 mouse model of familial Alzheimer disease. The current results demonstrate an increase in cyclin-dependant kinase 5 phosphoralyted at tyrosine 15 in APP/PS1 mice at three and six months of age. The correlation between elevated levels of phosphorylated tau and cyclin-dependant kinase 5 suggests that cyclin-dependant kinase 5 might contribute to tau phosphorylation in APP/PS1 mice. In general, this work corroborates common pathologic features in Alzheimer disease and diabetes mellitus. A significant cognitive decline in APP/PS1 mice was associated with changes in early gene expression of insulin-related molecules and perturbations in glucose metabolism. Cyclin-dependant kinase 5 is considered to coregulate tau phosphorylation in APP/PS1 mice, and to be part of a pathway contributing to pathology in Alzheimer disease