Cette thèse vise à nuancer la problématique de la souffrance qui entoure la maladie d’Alzheimer, et notamment celle des malades, des proches et des soignants. Cette souffrance, que nous appelons souffrance Alzheimer, n’est pas uniforme, n’est pas constante, peut arriver à différentes étapes de la maladie chez différents sujets, elle n’est pas toujours liée directement à la maladie d’Alzheimer, même si la maladie peut favoriser son apparition. Cette souffrance Alzheimer n’est pas isolée, elle s’inscrit dans un contexte plus général de la souffrance psychique et sociale. Les réponses possibles afin de la soulager ou diminuer sont multiples : elles peuvent être individuelles (chaque sujet tente, en mesure de ses possibilités de faire face) ou collectives (associations, groupes de paroles), subjectives (la création) ou scientifiques (traitements), ainsi que politiques ou sociétales / This thesis aims to show that the suffering that surrounds Alzheimer’s disease is by no means uniform without nuances. This is especially true for patients, their loved ones and carers. This particular suffering which we have named ‘Alzheimer suffering’ may occur at different stages of the disease in different persons. Neither is it always linked directly to the disease, even if the disease can favour its emergence. Alzheimer suffering is not isolated , being related to an overall context of psychological and social suffering. A number of different solutions to relieve or diminish suffering may be employed. These may be individual (each person does his or her best to cope) or collective (associations, group counselling), subjective (creation) or scientific (treatments) as well as political or societal

Orientador: Wanda Pereira Almeida / Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Química / Made available in DSpace on 2018-08-24T01:24:55Z (GMT). No. of bitstreams: 1 Silva_GiseleSilvestreda_M.pdf: 8524593 bytes, checksum: e3f6789232b8b6dc82852428db406fbf (MD5) Previous issue date: 2013 / Resumo: A Doença de Alzheimer (DA) é uma doença neurodegenerativa, que compromete as funções cognitivas. A acetilcolinesterase (AChE), enzima responsável pela hidrólise da acetilcolina (ACh), é um importante alvo para o desenvolvimento de candidatos a fármacos para tratar a DA. A AChE possui dois sítios ligantes: o catalítico e o periférico, envolvidos com a hidrólise da AChE e com o processo de formação de fibrilas do peptídeo b-amilóide, respectivamente. Neste trabalho propusemos a síntese e avaliação biológica de dois híbridos, ambos contendo porção tetraidroacridina baseado na estrutura da tacrina O hibrido I contem uma subunidade indanona baseado na donepezila e o híbrido II contém uma porção anti-inflamatória do ibuprofeno. O híbrido I e o híbrido II comportaram-se como um simples ligante e um híbrido molecular multipotente, respectivamente. Em ambos os casos foram escolhidos híbridos contendo duas unidades metilênicas. Um intermediário tetraidroacridínico contendo um grupo aminoálcool (6), que também se liga ao sítio catalítico da AChE, foi sintetizado a partir do ácido antranílico em uma sequência de três etapas. Todas as tentativas de acoplar este intermediário ao ibuprofeno fracassaram. Face a estes resultados, voltamos nossa atenção para as quinolonas, compostos planares que como a tacrina poderiam interagir com o sítio catalítico da AChE. Assim, nós sintetizamos quatro derivados da 4-quinolona. A síntese envolveu a ciclização catalisada por TFA do aduto de Morita-Baylis-Hillman, derivado do 2-nitrobenzaldeído, levando ao correspondente N-óxido (32). Em seguida, ele foi tratado com hexacarbonilmolibdato para fornecer a 3- carboetoxi-4-quinolona (38) em 33 % de rendimento global. O ácido carboxílico correspondente e derivados N-etilados também foram preparados. O efeito de três destes derivados quinolônicos sobre a atividade da acetilcolinesterase foi estudado. A N-alquil-3- carboetoxi-4-quinolona (40) foi o mais ativo dos derivados (IC50 ~84mmol/L). Estudo de docking molecular corroboraram nossas observações / Abstract: AlzheimerLs disease (AD) is a neurodegenerative pathology, which compromises the cognitive functions. Acetylcholinesterase (AChE) is the enzyme involved in the hydrolysis of neurotransmitter acetylcholine (ACh) and has been highlighted as an important target for the design of drugs to treat AD. AChE has two binding sites: a catalytic site and the peripheral one, which are involved in the acetylcholine hydrolysis and the formation of Ab42 peptide fibrils, respectively. In this work we proposed the synthesis and biological evaluation of two hybrids based on the tacrine structure, both containing portion tetrahydroacridine based on the structure of tacrine. The hybrid I has donepezil moieties and the hybrid II has anti-inflammatory portion. The hybrid I and hybrid II behave as a simple ligand and molecular hybrid, respectively. We have found that linkers with two and three methylene units generate suitable hybrids to bind to the catalytic site of the AChE. A key tetrahydroacridine bearing an amino alcohol function (6) also binds to the catalytic site of the AChE. It was synthesized from anthranilic acid in three steps sequence. All attempts to couple 6 and ibuprofen failed. In view of these results, we turn our attention to other planar structures which could interact with the catalytic site of the AChE. Thus, we synthesized four 4-quinolone derivatives. The synthesis involved a TFA mediated cyclization of the Morita-Baylis-Hillman adduct, derived from 2-nitrobenzaldehyde, leading to the corresponding N-Oxide (32). Then, it was treated with hexacarbonyl molibdate to afford 3-carboethoxy-4-quinolone (38) in 33% overall yield. We have also prepared: the corresponding carboxylic acid and the N-ethyl derivatives. The effect of three of them on the acetylcholinesterase activity was evaluated. The N-alkyl-3-carboethoxy-4- quinolone (40) was the most active (IC50 ~84mmol/L). Molecular docking studies corroborated our observations / Mestrado / Quimica Organica / Mestra em Química

Orientador: Meire Cachioni / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-22T03:03:58Z (GMT). No. of bitstreams: 1 Lopes_LaisdeOliveira_M.pdf: 2003500 bytes, checksum: d72be147c3b29dfc875042acb3e7f7ea (MD5) Previous issue date: 2013 / Resumo: Objetivo: Investigar o impacto de um programa psicoeducacional dirigido a cuidadores familiares de idosos com Doença de Alzheimer (DA) a partir das avaliações desses cuidadores sobre o seu bem-estar subjetivo e sobre os ônus e benefícios do cuidado. Método: Trata-se de um estudo quase experimental. Foram utilizados os seguintes instrumentos: ficha de caracterização sociodemográfica do participante; roteiro para avaliar o contexto do cuidado; Escala de Satisfação Geral com a Vida; Escala de Satisfação Geral com a Vida Referenciada a Domínios; Inventário de Ônus e Benefícios associados ao Cuidado; Escala de Afetos Positivos e Afetos Negativos e Escala de Depressão Geriátrica. Tais instrumentos foram aplicados em 21 cuidadores antes e após a intervenção, composta por 15 sessões. Resultados: A intervenção apresentou impacto positivo sobre o bem-estar subjetivo, sobre as variáveis de satisfação geral com a vida, satisfação com o envolvimento social e equilíbrio entre afetos positivos e afetos negativos. Em relação ao ônus e aos benefícios percebidos, houve aumento de respostas nos domínios psicológico positivo e social positivo após a participação na intervenção. Conclusão: A intervenção psicoeducacional investigada apresentou um impacto positivo no bem-estar subjetivo em relação às variáveis de satisfação geral com a vida, satisfação com o envolvimento social e equilíbrio entre afetos positivos e afetos negativos. Além disso, os dados desse estudo mostraram que intervenções psicoeducacionais podem contribuir para o aumento de benefícios psicológicos e sociais em relação ao contexto do cuidado. É importante considerar as peculiaridades das diferentes etapas de vida em que o cuidador está vivendo, bem como a faixa etária, a renda, o gênero, as relações de parentesco e o tempo de cuidado, para que o desenvolvimento das intervenções atinja o objetivo proposto / Abstract: Objective: To investigate the impact of a psychoeducational program aimed at family caregivers of elders with Alzheimer's disease (AD) in relation to assessments of these caregivers about their subjective well-being and about the benefits and burdens of care. Method: This was a quasi-experimental study. The following instruments were used: plug sociodemographic characteristics of the participant; script to evaluate the context of care; General Satisfaction with Life Scale; General Satisfaction with Life Referenced to Domains Scale; Inventory of Burden and Benefits of the Care; The Positive and Negative Affects Scale, and the Geriatric Depression Scale. These instruments were applied in 21 caregivers before and after the intervention, consisting of 15 sessions. Results: The intervention investigated showed a positive impact on subjective well-being in relation to variables of overall satisfaction with life, satisfaction with social involvement and balance between positive and negative effect. Regarding the perceived burden and benefits, there was an increase of positive responses in the psychological and social impact after the participation in the intervention. Conclusion: The investigated psychoeducational intervention had a positive impact on subjective well-being in relation to variables of overall satisfaction with life, satisfaction with social involvement and balance between positive and negative effect. Furthermore, the data from this study showed that psychoeducational interventions can contribute to increased psychological and social benefits in relation to the context of care. It is important to consider the peculiarities of the different stages of life in which the caregiver is living, as well as age, income, gender, kinship relations and time of care, so the development of interventions achieve the proposed objective / Mestrado / Gerontologia / Mestra em Gerontologia

The genome-wide association study (GWAS) approach has identified novel loci for a variety of complex diseases. However, for most of these disorder much of the heritability is not explained by this approach, which focuses on identifying common variants that are associated with disease risk. The unexplained heritability may be due to genetic or phenotypic heterogeneity or the influence of rare variants. The motivation behind this thesis was to uncover the unexplained heritability by applying joint analyses of sets of variants (gene-based association test) and multiple disease-related phenotypes (called multivariate gene-based association test). First, we evaluated multivariate gene-based methods for detecting association of common genetic variants with correlated phenotypes. An extensive simulation study showed that the method combining the MultiPhen and GATES software performed best for most tested scenarios especially when correlations among phenotypes are relatively low. We developed a new multivariate gene-based test using rare variants called VEMPHAS. A simulation study using VEMPHAS showed that this method correctly controls for type I error in all tested scenarios. We applied VEMPHAS to analysis of various phenotypes related to Alzheimer disease (AD) and found suggestive association (P < 4.15x10-6) with the gene TRIM22, which has been identified in a previous sequencing study of AD onset in PSEN1/2 mutation carriers. We also developed software with a graphical user interface which is designed for integrating information from different types of data sources including genetic data (from GWAS or sequencing), expression data (from RNA-Seq), and protein structures (from protein data banks). This software has several features including 1) testing associations between genetic variants and gene expressions; 2) locating amino acids, encoded by the variants, in a protein structure; and 3) retrieving genetic locations (chromosome and base pair positions) of amino acids of interest in the protein structure. The last feature can be applied for prioritizing coding variants for gene-based association testing. The methods and strategies developed for this dissertation project can effectively uncover a portion of the remaining heritability of complex diseases that is unexplained by traditional GWAS approaches.

En à peine plus de deux décennies, la maladie d’Alzheimer est devenue un objet de préoccupation majeure du monde de la prise en charge professionnelle des personnes âgées. Une démographie croissante des personnes concernées parmi le public du secteur ainsi qu’une mobilisation de l’action publique autour du phénomène ont contribué à en faire un problème de santé publique prioritaire. La thèse analyse la manière dont les pratiques professionnelles, en particulier dans les établissements d’hébergement pour personnes âgées, se sont réorganisées autour de cet enjeu. Elle éclaire le processus de spécialisation que connaissent ces institutions, dès lors qu’elles circonscrivent une partie de la population hébergée en la considérant comme spécifique et en développant pour elle des traitements particuliers. L’analyse repose sur une enquête ethnographique mobilisant observations, entretiens et analyse documentaire, menée dans deux établissements, l’un sanitaire, l’autre médico-social. Elle permet de documenter les cadres de compréhension des difficultés qui se font jour dans l’accompagnement de certaines personnes, ainsi que les solutions et adaptations qui sont développées pour y répondre. L’enquête met en évidence un processus de spécialisation affectant les pratiques professionnelles à trois niveaux différents. Au niveau de l’institution, elle montre qu’il se traduit par une évolution de l’organisation institutionnelle, qui prend en particulier la forme de dispositifs de prise en charge temporaire dédiés à la maladie d'Alzheimer et spatialement séparés du reste des lieux d’hébergement. Cette apparente mise à l’écart prend son sens dans la perspective du temps long : l’histoire des établissements d’hébergement pour personnes âgées permet en effet d’appréhender ce que la spécialisation institutionnelle doit à l’évolution contemporaine du mandat de ces institutions. Le mouvement de spécialisation autour de la maladie d'Alzheimer est ensuite saisi au niveau de l’éthique professionnelle qui s’organise autour du soin. Les épreuves produites aux yeux des professionnels par les particularités d’un public qui ne semble pouvoir s’inscrire dans les modalités ordinaires de la relation de soin amènent à des modulations de cette éthique, voire même à une remise en cause du sens que donnent les soignants à l’accompagnement et au soin. Enfin, le processus de spécialisation affecte les métiers impliqués dans la prise en charge. L’enquête fait apparaître l’évolution de leur contenu, mais aussi les réorganisations des relations entre les métiers que la spécialisation Alzheimer induit dans l’écologie professionnelle du secteur gérontologique. / Over the last two decades, Alzheimer's disease has become a major preoccupation for those working within the sector of aged care. The number of persons concerned as well as a growing public concern and policy interventions by the French public authorities have contributed towards maling the treatment of Alzheimer's disease a significant public health priority. This

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Alzheimer's disease (AD) is the most common form of dementia, currently affecting around 17--25 million people worldwide. The typical neuropathological hallmarks of AD are amyloid beta (Abeta) deposition, presence of neurofibrillary tangles and neuronal cell death. Evidence from ongoing studies on the pathogenesis of AD, suggests that several different mechanisms are involved in neurons loss and thus decline of cognitive function. These include the metabolism of amyloid peptide, inflammation, cholesterol metabolism, and hormonal factors. / I have focused on the role of inflammation in the progression of AD. The inflammation hypothesis is based on findings of (1) elevated levels of inflammatory cytokines, such as IL-1, IL-6, TNFalpha, (2) the reduced levels of anti-inflammatory cytokines, like IL-10 in CSF and the blood of AD patients, and (3) activated microglia in the histological section of the patient's brain. On the other hand, the effects of the ApoE gene and differential age of onset between the two sexes suggested a modulation role for cholesterol and sex hormone like estrogen, which may influence the inflammatory response in the brain, so as to modulate the risk of AD. / In this project, the genetic risk factors predisposing to AD were investigated by genetic association studies of candidate genes. Candidate genes were shortlisted by two approaches. (I) Linkage-based candidate genes: Candidate genes were identified from reported loci with linkage to AD genome scan studies. Previous linkage studies of AD families revealed linked loci at 1p36, 1q23, 3p14, 4q32, 6p21, 6q27, 9q22, 10q24, 13q32, 15q26, 19q13 and 21q22. Several candidate genes from these loci including TNFalpha-related genes, TLR2, IGF-1, IFNalpha and MTHFR were selected for this project. (II) Hypothesis-based candidate genes: Candidate genes were selected according to their possible involvement in the inflammation hypothesis of AD. Under the hypothesis-based candidate gene approach, genes that might contribute to the inflammatory response of amyloid deposition were identified. These genes were validated by their expression level in the central nervous system. A further priorization step was carried out to select those genes showing a higher degree of inter-individual variation. Therefore, these genes were more likely to have a genetic/inherited variation at the population level. In other words, they are more likely to be the predisposition genes than genes without inter-individual variation (house-keeping genes are examples of genes showing little inter-individual variation). In this project, genes involved in the inflammatory pathway in the brain, such as IL-10 and HLA-A, and also genes that interact with the inflammatory pathway such as cholesterol related enzymes and estrogen receptors were investigated under the hypothesis-based approach. / This project is based on a case-control genetic association study which comprised of NINCDS-ADRDA diagnosed Chinese patients with AD (n=259) and age-matched non-demented subjects (n=248). Three genes PTGS2 (encoding for COX-2), MxA and ESR1 were selected for an intensive study by investigating their linkage disequilibrium pattern and using tagSNP strategy. TagSNPs selected for each gene were genotyped to investigate their association with the risk of AD. / This study showed that MTHFR, IL-10, HLA-A, CYP46A1, PTGS2 (COX-2) and ESR1 were associated with the risk of AD, and MxA, identified for the first time, was associated with the age of onset of AD. In conclusion, the results of my study further suggested the roles of inflammation in the pathogenesis of AD. / Ma Suk Ling. / "June 2006." / Advisers: Linda C. W. Lam; Nelson L. S. Tang. / Source: Dissertation Abstracts International, Volume: 68-03, Section: B, page: 1417. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2006. / Includes bibliographical references (p. 169-204). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese. / School code: 1307.

In conclusion, gene expression profiling in blood may have potential to be an adjuvant marker for early detection of AD. Expression marker panel is more informative than single gene expression signature. Further validation in prospective studies will substantiate its clinical application and explore its potential to differentiate AD from other dementias and to predict the progression from MCI to AD. (Abstract shortened by UMI.) / In the study, the profile of 12 target gene expression levels in peripheral blood cells were determined in 96 AD, 145 MCI and 167 normal controls (NC) by quantitative real-time RT-PCR. The genes were identified with (i) high expression in blood and brain; (ii) differential expression between AD and control; (iii) AD related candidate genes. Then, a list of genes were selected including CTSB, CTSD, DDT, ITPKB, NDUFA6, NRD1, PIN1, SNX2, TSC1, UQCRC1, CNR2, GSTM3. Seven genes were found to be differentially expressed between AD and NC group, with upregulation of CTSB, CTSD, DDT, TSC1 and UQCRC1, and downregulation of ITPKB and PIN1 in AD patients. Expression levels of two genes were increased in the MCI compared with NC group, including CTSB and CTSD. In addition, an upregulation of CTSD, UQCRC1, NRD1 and downregulation of ITPKB were observed in AD subjects in comparison to the MCI group (Mann-Whitney U test, p&lt;0.05). After adjusting for confounding factors of age, gender, education level, ApoE4 status and the total CIRS score, expression level of any single gene was not associated with the classfication of AD or MCI (Logistic regression, p>0.05). A five gene biomarker panel, including DDT, ITPKB, PIN1, TSC1 and UQCRC1 was identified with logistic regression analysis. The function of Logit(P)= ln(P/(1-P))= b0+b1RatioDDT+ b2RatioITPKB + b3Ratio PIN1 +b4 RatioTSC1+b5Ratio UQCRC1 were defined as the probability of a subject to be diagnosed as "AD" or "MCI' by using 5-gene biomarker panel. ROC analysis showed that the AUC for the 5-gene biomarkers panel in differentiating between AD and NC, between MCI and NC, between AD and MCI were 0.79 (95% CI, 0.72-0.86; p&lt;0.001), 0.61 (95% CI, 0.53-0.69; p=0.007) and 0.68 (95% CI, 0.60-0.76; p&lt;0.001) respectively. The 5-gene combination was found to discriminate AD subjects from normal controls with good sensitivity and specificity of 70.7% and 86.7% respectively at an optimal cut-off point of 0.486. Low sensitivity (42.4%) and acceptable specificity (76.2%) were observed at a cut-off threshold of 0.505 when differentiating MCI from NC subjects. Between AD and MCI subjects, gene combination showed a sensitivity of 61% and specificity of 73.7% at a cut-off value of 0.496. / Several genes including CTSD, DDT, NDUFA6, TSC1 and UQCRC1 were found in association with the cognitive and psychiatric symptoms, indicating the role of genetic factors in moderating the presence of cognitive and NP profiles in demented individuals. / The aim of the present study is to evaluate the gene expression profiling of peripheral leukocytes in Chinese subjects with Alzheimer's disease (AD) and explored its potential of clinical application. Behavioral phenotypes of cognitive performance and neuropsychiatric assessment were also investigated in association with gene expression in AD. Persons with mild cognitive impairment (MCI), as an at-risk state between normal aging and clinical dementia, was also assessed in consideration that the information may provide a better understanding of the mechanisms involved in clinical progression of AD. / The genes identified in this study were involved in processes implicated in neurodegneration, including protein isomerization (PIN1), calcium disequilibrium and mitochondria insufficiency (ITPKB and UQCRC1), increased inflammatory response (DDT), apoptosis (CTSB and CTSD) and neurogeneration (NRD1 and TSC1). / Fu, Yan. / Adviser: Chiu Wa Lam. / Source: Dissertation Abstracts International, Volume: 73-02, Section: B, page: . / Thesis (Ph.D.)--Chinese University of Hong Kong, 2010. / Includes bibliographical references (leaves 132-168). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [201-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 5 uppsatser.