Orientador: Man Chin Chung / Banca: Renato Farina Menegon / Banca: Luiz Fernando Takase / Banca: Cintia Duarte de Freitas Milagre / Banca: Rafael Victório Carvalho Guido / Resumo: A doença de Alzheimer (DA) é uma doença neurodegenerativa progressiva, que leva a perda de neurônios no hipocampo e córtex cerebral, comprometendo funções cognitivas, como memória e raciocínio. As principais características neuropatológicas da DA são a formação e agregação de peptídeos β-amiloide (βA), originando as placas senis; e a hiperfosforilação da proteína tau, resultando na deposição de emaranhados neurofibrilares (ENF). Juntamente a estes processos ocorre a neuroinflamação e estresse oxidativo, que em conjunto resultam em danos aos neurônios. A DA não possui tratamento capaz de curar ou reduzir a progressão da doença, por conseguinte, há uma clara necessidade que se desenvolva novas abordagens terapêuticas capazes de retardar ou impedir a progressão desta. Este trabalho visa o planejamento, síntese e avaliação da atividade de novas estruturas químicas hibridas, derivadas de ftalimida e furoxano. Os compostos foram idealizados com o intuito de possuir propriedade anti-inflamatória, estabilizadora de microtúbulos e doadoras de óxido nítrico (NO). Dessa forma, espera-se reduzir o processo de neuroinflamação, associado à deposição de proteínas, além de contribuir com a plasticidade sináptica, cognição e memória, atenuando assim os efeitos associados à perda de neurônios nos pacientes. Neste trabalho foram sintetizados 42 compostos finais, destes 36 inéditos. Os resultados obtidos demonstra que moléculas foram capazes de liberar NO em uma faixa de 1,77 a 52,64 % (mol/mol)... (Resumo completo, clicar acesso eletrônico abaixo) / Alzheimer's disease (AD) is a progressive neurodegenerative disease, which leads to loss of neurons in the hippocampus and cerebral cortex, compromising cognitive functions such as memory and reasoning. The main neuropathological characteristics of AD are the formation and aggregation of β-amyloid peptides (βA), giving rise to the senile plaques; and hyperphosphorylation of tau protein, resulting in the deposition of neurofibrillary tangles (NFT). These processes occur along with neuroinflammation and oxidative stress, which together result in damage to neurons. AD has no treatment capable of curing or reducing the progression of the disease, therefore, there is a clear need to develop new therapeutic approaches capable of delaying or preventing the progression of the disease. This work aims at the planning, synthesis and evaluation of the activity of new hybrid chemical structures, derived from phthalimide and furoxane. The compounds were designed to possess antiinflammatory, microtubule-stabilizing and nitric oxide (NO) donor properties. Thus, it is expected to reduce the neuroinflammation process, associated with protein deposition, besides contributing to synaptic plasticity, cognition and memory, attenuating the effects associated with the loss of neurons in patients. A total of 42 hybrid compounds were obtained, 36 unpublished. The results show that molecules were capable of releasing NO in a range of 1.77 to 52.64% (mol/mol), the arylsulfonyl furoxane derivatives showed the highest donation values. The partition coefficient (LogP) value of the molecules varied from 1.63 to 6.14, values acceptable for drugs that act on the central nervous system (CNS). The evaluation of the activity in microtubules (MT) showed that the compounds presented varied activity, and in some cases induce the polymerization of the tubulin... (Complete abstract click electronic access below) / Doutor

Pan, Tak Yin. / Thesis submitted in: November 2007. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2008. / Includes bibliographical references. / Abstracts in English and Chinese. / Acknowledgements --- p.i / Abstract (English) --- p.ii / Abstract (Chinese) --- p.iv / Content --- p.v / Abbreviations --- p.x / List of Figures --- p.xi / List of Tables --- p.xii / Chapter Chapter 1: --- Introduction --- p.1 / Chapter 1.1 --- Alzheimer's Disease --- p.1 / Chapter 1.1.1 --- Cholinergic hypothesis --- p.2 / Chapter 1.1.2 --- p-amyloid hypothesis --- p.2 / Chapter 1.1.3 --- Taupathy hypothesis --- p.3 / Chapter 1.1.4 --- Current therapies --- p.4 / Chapter 1.2 --- Proteins Involved in Alzhemer's Disease --- p.5 / Chapter 1.2.1 --- Acetylcholinesterase (AChE) --- p.5 / Chapter 1.2.2 --- p-amyloid --- p.6 / Chapter 1.2.3 --- Paired helical filaments (PHF) --- p.7 / Chapter 1.2.4 --- Protein kinases --- p.8 / Chapter 1.2.4.1 --- Glycogen synthase kinase-3 (GSK-3) --- p.9 / Chapter 1.2.4.2 --- Cyclin-dependent kinase-5 (CDK-5) --- p.9 / Chapter 1.2.5 --- Protein phosphatase (PP) --- p.10 / Chapter 1.2.5.1 --- Protein phosphatase 1 (PP-1) --- p.11 / Chapter 1.2.5.2 --- Protein phosphatise 2A (PP-2A) --- p.12 / Chapter 1.2.5.3 --- Protein phosphatise 2B (PP-2B) --- p.13 / Chapter 1.2.6 --- Apoptotic and Anti-apoptotic proteins --- p.14 / Chapter 1.2.6.1 --- Caspase-3 --- p.15 / Chapter 1.2.6.2 --- Bcl-2 --- p.15 / Chapter 1.3 --- Flavonoids --- p.16 / Chapter 1.3.1 --- Biosynthesis of flavonoids --- p.17 / Chapter 1.3.2 --- Biological functions of flavonoids in plants --- p.18 / Chapter 1.3.3 --- Beneficial effects of flavonoids on human health --- p.19 / Chapter Chapter 2: --- Materials and Methods --- p.20 / Chapter 2.1 --- Differentiation of SHSY-5Y cells --- p.20 / Chapter 2.1.1 --- SHSY-5Y cell culture --- p.20 / Chapter 2.1.2 --- Counting cells --- p.20 / Chapter 2.1.3 --- Retinoic acid differentiation --- p.21 / Chapter 2.2 --- Western blot analysis --- p.21 / Chapter 2.2.1 --- Extraction of proteins from mammalian cells --- p.21 / Chapter 2.2.2 --- Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) --- p.22 / Chapter 2.2.3 --- Semi-dry protein transfer to nitrocellulose membrane --- p.23 / Chapter 2.2.4. --- Membrane blocking and immunostaining --- p.24 / Chapter 2.3 --- MTT assay --- p.25 / Chapter 2.4 --- Hoechst 33342 Nuclei staining --- p.25 / Chapter 2.5 --- Cell cycle analysis --- p.25 / Chapter 2.5.1 --- Ethanol fixation --- p.25 / Chapter 2.5.2 --- Propidium iodide staining --- p.26 / Chapter 2.6 --- Annexin V-FITC & Propidium iodide staining --- p.26 / Chapter 2.7 --- DNA fragmentation analysis --- p.26 / Chapter 2.7.1 --- Phenol/Chloroform extraction of DNA --- p.26 / Chapter 2.7.2 --- Ethanol precipitation of DNA --- p.27 / Chapter 2.7.3 --- Agarose gel electrophoresis of DNA --- p.27 / Chapter 2.8 --- Proteomic analysis --- p.28 / Chapter 2.8.1 --- First dimension: isoelectric focusing --- p.28 / Chapter 2.8.2 --- Second dimension: SDS PAGE --- p.29 / Chapter 2.8.3 --- Gel staining --- p.30 / Chapter 2.8.3.1 --- Silver staining --- p.30 / Chapter 2.8.3.2 --- SYBRO Ruby staining --- p.31 / Chapter 2.8.4 --- Gel scanning and image analysis --- p.31 / Chapter 2.8.5 --- ln-gel digestion --- p.32 / Chapter 2.8.6 --- Zip Tip for desalting the digested sample --- p.33 / Chapter 2.8.7 --- Protein identification with mass spectrometry and database search --- p.33 / Chapter Chapter 3: --- Characterization of Okadaic acid-induced tail hyperphosphorylation in SHSY-5Y cells --- p.35 / Chapter 3.1 --- Introduction --- p.35 / Chapter 3.2 --- Objectives --- p.37 / Chapter 3.3 --- Results --- p.38 / Chapter 3.3.1 --- Differentiation of SH-SY5Y cell --- p.38 / Chapter 3.3.2 --- Changes of protein expression after okadaic acid treatment --- p.40 / Chapter 3.3.3 --- Neurite Retraction Induced by okadaic acid --- p.42 / Chapter 3.3.4 --- Okadaic acid-induced Cell Death measured by MTT assay --- p.44 / Chapter 3.3.5 --- Hoechst 33342 Nuclei Staining --- p.44 / Chapter 3.3.6 --- Cell cycle analysis by propidium iodide staining --- p.47 / Chapter 3.3.7 --- Early Apoptotic cells detection by Annexin V/PI staini --- p.49 / Chapter 3.3.8 --- DNA fragmentation --- p.51 / Chapter 3.4 --- Discussion --- p.53 / Chapter Chapter 4: --- Flavonoids screening for protecting neuronal death by preventing tau hyperphosphorylation --- p.57 / Chapter 4.1 --- Introduction --- p.57 / Chapter 4.2 --- Objectives --- p.58 / Chapter 4.3 --- Tested flavonoids --- p.59 / Chapter 4.4 --- Results --- p.60 / Chapter 4.4.1 --- Toxicity of flavonoids --- p.60 / Chapter 4.4.2 --- Effects of flavonoid pre-treatment on OA-induced neu retractions and cell death --- p.62 / Chapter 4.4.3 --- Western blot analysis --- p.65 / Chapter 4.4.4 --- The effect of different concentrations of hesperidin or OA treatment --- p.70 / Chapter 4.4.5 --- Proteomic analysis --- p.74 / Chapter 4.5 --- Discussion --- p.78 / Chapter Chapter 5: --- General Discussion --- p.82 / References

Cheung, Kwok Kuen. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2011. / Includes bibliographical references (leaves 226-263). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

Introdução: A demência devido à Doença de Alzheimer (DDA) é uma alteração neurodegenerativa primária, progressiva, que se manifesta por deterioração cognitiva, particularmente a memória. O número de pessoas no mundo acima de 60 anos com diagnóstico de DDA foi estimado em 35 milhões em 2010. Essa doença apresenta atrofia predominantemente da região do hipocampo e outras regiões corticais. A maioria dos estudos avaliam os estágios pré-clínicos e iniciais da doença por meio de avaliação clínica correlacionada aos biomarcadores. Contudo, os biomarcadores não são usualmente avaliados para a doença moderada à grave, sendo sustentado apenas de forma hipotética. Objetivos: Avaliar a morfometria cerebral de controles e portadores de DDA em todos os estágios. Encontrar o perfil de neurodegeneração estrutural para todas as fases da DDA. Casuística e métodos: Foram selecionados idosos acima de 60 anos portadores de DDA (n=44) acompanhados no serviço de Geriatria do Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto (HCFMRP) e como grupo controle idosos cognitivamente saudáveis (n=16), provenientes dos diversos serviços do HCFMRP e da comunidade com idades semelhantes às do grupo de pacientes. Sujeitos com critério de demência vascular ou outras demências foram excluídos. Imagens de todo os indivíduos foram adquiridas no equipamento de Ressonância Magnética (RM) de 3T do HCFMRP por meio da sequência de imagem Gradiente Eco 3D ponderada em T1, sem agente de contraste. Dados quantitativos de volumetria e espessura cortical foram obtidos para regiões cerebrais definidas pelos atlas de subdivisões Desikan e Deutriox. Foi realizada segmentação automática com o programa Freesurfer® sem modificação. A volumetria de cada região foi normalizada pela volumetria cerebral total para minimizar o efeito de atrofia com a idade. Resultados: Como já reportadas em estudo prévios nos estágios iniciais na DDA, as regiões acometidas também apresentaram atrofia nos estágios mais avançados da doença. Não foi observada correlação significativa entre volumetria, idade e anos de escolaridade. Por outro lado, apresentou correlação significativa com o índice de avaliação cognitiva Clinical Dementia Rating (CDR) e mini-exame do estado mental (MEEM). Observamos redução da espessura cortical para a região do giro parahipocampal em todas as fases da progressão da DDA em concordância com a literatura que, no entanto, avaliaram somente as fases iniciais. Para demais regiões descritas, como assinatura cortical, lobo temporal, parietal e frontal observamos redução somente nos estágios moderados e avançados da DDA. Discussão e Conclusão: Concluímos que as regiões cerebrais mais afetadas pela DDA atrofiam linearmente com a progressão da doença, até as fases mais avançadas. Ao contrário de modelos hipotéticos que consideravam maior atrofia volumétrica nas fases iniciais e um platô nas fases avançadas. Essas regiões estão muito relacionadas à perda neuronal e gliose já descrita há 40 anos e ao dano patológico da doença. Enfim, os resultados de morfometria por RM indicam a atrofia como biomarcador mesmo nas fases avançadas da DDA. Esses achados possibilitam maior compreensão do processo fisiopatológico e o acompanhamento de potenciais drogas modificadoras da doença mesmo nas fases mais avançadas. Palavras-chave: Doença de Alzheimer, Idosos, Volumetria, Progressão da doença de Alzheimer / Background: Dementia due to Alzheimer\'s disease (DAD) is a primary neurodegenerative disorder, progressive, manifested by cognitive impairment, particularly memory. The number of people worldwide over age 60 diagnosed with DAD has been estimated at 35 million in 2010. This disease has predominantly atrophy of the hippocampus and other cortical regions. Most studies evaluate the preclinical and early stages of the disease through clinical evaluation correlated the biomarkers. However, it is not often evaluated biomarkers for moderate to severe disease, being sustained only hypothetically. Objective: To evaluate the brain morphometry of controls and patients with DAD at all stages. Finding the structural neurodegeneration profile for all stages of Alzheimer\'s disease. Methods: We selected DAD patients (n = 44), over 60 years, followed at the Geriatric Service HCFMRP and individuals cognitively healthy for control group (n = 16) with age paired, from the different departments of HCFMRP. Subjects with vascular dementia criteria or other dementias were excluded. Images were acquired of all individuals in 3T equipment at HCFMRP by the sequence of 3D image weighted Gradient Echo T1 without contrast agent. Quantitative data of volumetry and cortical thickness were obtained for brain regions defined by Desikan and Deutriox subdivisions atlas. Automatic segmentation was performed with Freesurfer® program without modification. The volumetry of each region was normalized by the total volumetric brain to minimize the effect of atrophy with age. Results: The regions affected in DAD in the early stages, as reported in previous study, also showed atrophy in the later stages of the disease. There was no significant correlation between volumes, age and years of schooling. On the other hand, showed a significant correlation with cognitive evaluation indexes MMSE and CDR. We observed a reduction of the cortical thickness for the parahippocampal gyrus for all stages of the progression of DAD in agreement with the literature have evaluated the early stages only. For other regions described as cortical signature, temporal lobe, parietal and frontal observed reduction only in moderate and advanced stages of the DDA. Discussion and Conclusion: We conclude that the brain regions most affected on DDA atrophy linearly with disease progression until more advanced stages. Unlike hypothetical models considered higher volumetric atrophy in the early stages and a plateau in the advanced stages. These regions are closely related to neuronal loss and gliosis already described 40 years ago and the pathological damage of the disease. Anyway, the results of morphometry MRI indicate atrophy biomarker even in advanced stages of the DDA. These findings enable greater understanding of the pathophysiological process and monitoring of potential disease-modifying drugs even in the later stages

Alzheimer\'s disease (AD) is one of the main causes of dependency and disability in the elderly population. A number of investigations have been seeking its prevention and/or management. In this context, it is important to highlight the role of modifiable risk factors, such as nutrition. This study aims to conduct a systematic review and subsequent meta-analysis, to assess the effect of food and/or nutrients for the management of AD at different stages. This work was steered based on the Cochrane Handbook for systematic reviews of interventions and the PRISMA Statement. Electronic databases were searched up to 2014, in Portuguese, English or Spanish. Relevant publications were identified by title and abstract using key search terms referring to Alzheimer\'s disease, nutrition interventions and type of study. Trials\' risk of bias was appraised by applying the Cochrane\'s tool for assessing risk of bias. The main outcome measures comprise neuropsychological tests such as MMSE, ADCS-ADL, NPI and CDR-sob, biomarkers and brain imaging. Pairwise meta-analyses were performed in a random-effect model by estimating the weighted mean differences between treatment and placebo groups, with 95% confidence intervals for outcome measures by treatment. Network meta-analysis and the ranking probability of treatment for each nutrition intervention were undertaken on cognitive outcome. The strength and quality of evidence were rated according to the GRADE approach. From the whole research, 182 studies met the systematic review\'s purpose. Thirty-five clinical trials complied with eligibility criteria and risk of bias assessment. Included studies utilized: antioxidants, B-vitamin complex, carbohydrates, lipids, omega-3 fatty acids, polymeric formulas, polypeptide and vitamin D. Estimates treatment effects from pairwise meta-analyses show a significant positive effect from the supplementation with proline-rich polypeptide (WMD 12.00 [95% CI 10.20, 13.80] P < 0.00001) and B-vitamin complex (WMD 0.44 [95% CI 0.09, 0.79] P = 0.01) on cognitive function measured by the MMSE. Remaining nutrients supplementation did not show any significant effect on functional, behavioral, global performance, biomarkers or brain imaging outcomes. Isolated nutrient supplementations show no convincing evidence of providing a significant benefit on clinical manifestations or neuropathology of AD. As a treatment strategy, nutrients did not show any effect when delivered individually, probably due to their synergistic work on brain function at different domains. Nevertheless, nutrients represent a potential preventive approach and an adjuvant treatment for patients with AD at earlier stages. / A doença de Alzheimer (DA) é uma das maiores causas de dependência e incapacidade na população idosa, o que tem levado a inúmeras investigações sobre sua prevenção e ou manejo. Neste contexto, é importante destacar o papel desempenhado pelos fatores de risco modificáveis, como a nutrição. Este estudo trata de uma revisão sistemática e meta-análise, para avaliar o efeito das intervenções nutricionais no manejo da DA, em seus diferentes estágios. Este trabalho segue as propostas da Colaboração Cochrane e a declaração PRISMA. Bases de dados eletrônicas foram pesquisadas a partir do seu início até o 2014, em Português, Inglês ou Espanhol. Estudos relevantes foram identificados por título e resumo usando as palavras-chave referente à doença de Alzheimer, intervenções nutricionais e tipo de estudo. A qualidade dos estudos foi avaliada mediante a ferramenta da Cochrane para avaliação do risco de viés. As principais medidas de desfechos compreenderam os testes neuropsicológicos MEEM, AVD, NPI e CDR-sob, biomarcadores e neuroimagem. As meta-análises em pares foram realizadas em modelo de efeito aleatório pela estimativa de diferença de médias ponderadas entre os grupos de tratamento e placebo, com 95% de intervalo de confiança para as medidas de desfecho segundo a intervenção. A meta-análise em rede e a probabilidade da posição do tratamento para cada intervenção nutricional foi realizada para o desfecho cognitivo. A força e a qualidade da evidência foram avaliadas de acordo com o método GRADE. Da busca total inicial, 182 estudos cumpriam com o propósito desta revisão sistemática. Ainda, 35 ensaios clínicos preencheram os critérios de elegibilidade e avaliação de risco de viés. Os estudos incluídos usaram: antioxidantes, vitaminas do complexo B, carboidratos, lipídeos, ácidos graxos ômega-3, formula poliméricas, polipeptídios e vitamina D. As estimativas de efeito do tratamento das meta-análises em pares mostraram um efeito positivo significativo a partir da suplementação com um polipeptídio rico em prolina (MD 12.00 [95% IC 10.20, 13.80] P < 0.00001) e com as vitaminas do complexo B (MD 0.44 [95% IC 0.09, 0.79] P = 0.01) na função cognitiva avaliada pelo MEEM. A suplementação com os demais nutrientes não mostrou um efeito significativo na funcionalidade, comportamento, desempenho global, biomarcadores da DA, nem desfechos de imagem. A suplementação com nutrientes isolados não mostrou um efeito significativo nas manifestações clínicas ou neuropatologicas da DA. Como estratégia de tratamento, os nutrientes não demonstraram um efeito separadamente, provavelmente devido a seu trabalho sinérgico nos diferentes domínios da função cerebral. Ainda assim, os nutrientes representam uma abordagem preventiva potencial e um tratamento adjuvante nas pessoas com DA nos estágios iniciais.

A Doença de Alzheimer (DA) vem apresentando aumento progressivo, sendo a causa de demência mais comum nos idosos (acima de 60 anos). Diante disso, há preocupação com alterações do estado de saúde dos cuidadores que compreendem na sua maioria familiares. Cuidar dos pacientes com demência por Doença de Alzheimer pode levar ao estresse crônico e má qualidade de vida. O presente estudo teve como objetivo avaliar fatores de risco cardiovascular, cognição e humor em cuidadoras idosas de pacientes com demência por Doença de Alzheimer, comparando-as com as não cuidadoras. As cuidadoras foram selecionadas por meio da revisão de prontuários do Hospital das Clínicas e do Centro de Saúde Escola da FMRP-USP. As idosas do grupo controle foram selecionadas na mesma área de moradia das idosas cuidadoras. Todas as participantes assinaram o Termo de Consentimento Livre e Esclarecido. Foram realizadas visitas previamente agendadas na casa de todas as participantes. Critérios de exclusão: diabetes; neoplasias malignas e doenças autoimunes, além de outras doenças debilitantes. Foram avaliadas idade, escolaridade, peso, altura, circunferência abdominal e Indice de Massa corpórea (IMC). Foi realizada avaliação laboratorial: dosagem de insulina de jejum; glicemia de jejum; colesterol total e HDL; triglicérides; creatinina; ureia; sódio; potássio; cálcio e TSH. Além disso, foi feita a avaliação da pressão arterial (PA) em domicílio pela pesquisadora e com a Medida Residencial de Pressão Arterial (MRPA), além da avaliação da cognição e humor, com a Escala de Depressão Geriátrica (EDG), Mini Exame do Estado Mental (MEEM) e Mini International Neuropsychiatric Interview (M.I.N.I.). A análise estatística foi realizada com o Teste Quiquadrado, Teste \"t\" de Student, Mann-Whiney e regressão logística simples e múltipla para a estimação do Odds Ratio bruto e ajustado (ORA). Foram avaliadas 62 idosas, sendo 31 cuidadoras de pacientes com Doença de Alzheimer e 31 do grupo controle. Verificou-se que os níveis de colesterol total foram mais elevados em idosas cuidadoras. Não houve diferenças entre os valores de PA sistólica e diastólica entre os grupos em relação às medidas realizadas pela pesquisadora e com a MRPA. De acordo com os resultados, as idosas cuidadoras apresentaram rastreio positivo para depressão em 58%, enquanto que o grupo controle apresentou apenas 16% (ORA=6,62, p<0,01). Em relação ao diagnóstico feito pelo M.I.N.I, 38,7% das cuidadoras apresentaram episódio depressivo, sendo superior ao controle (9,7%) (ORA=5,42, p=0,02). Verificouse que 35,5% das cuidadoras apresentaram transtorno de ansiedade diagnosticado, com 16% no grupo controle (ORA=4,79, p=0,03). A presença do companheiro interferiu para que as cuidadoras apresentassem mais transtorno de ansiedade (p=0,04). Não houve diferença entre a cognição dos grupos pela avaliação do MEEM. Cuidadoras idosas de pacientes dementados com Doença de Alzheimer apresentaram níveis de colesterol mais elevados, mais episódios depressivos e mais transtorno de ansiedade do que as não cuidadoras. A presença do companheiro interferiu para que apresentassem mais transtorno de ansiedade / Alzheimer´s disease (AD) has shown a progressive increase in incidence, being the most common cause of dementia in the older individuals (above 60 years old). Therefore, there is concern with health status change in caregivers, who are mostly relatives. Taking care of AD patients with dementia can lead to chronic stress and poor quality of life. This study aimed to evaluate cardiovascular risk factors, cognition and mood in older caregivers of patients with AD dementia, comparing them with non-caregivers. The caregivers were selected through the review of the Hospital\'s medical records and School Health Center of FMRP-USP. Control group of elderly women were selected in the same housing area of older caregivers. All participants signed a consent form. Visits were previously scheduled and were at the home of all participants. Exclusion criteria: diabetes; malignancies and autoimmune diseases, and other debilitating diseases. Were evaluated: age, education, weight, height, waist circumference and body mass index (BMI). Laboratory testing was performed: fasting insulin; fasting glucose; Total and HDL cholesterol; triglycerides; creatinine; urea; sodium; potassium; calcium and TSH. In addition, blood pressure (BP) evaluation was made at home by the researcher and by the Home Blood Pressure Monitoring (HBPM), and the assessment of cognition and mood, with the Geriatric Depression Scale (GDS), Mini Exam Mental State Examination (MMSE) and Mini International Neuropsychiatric Interview (MINI). Statistical analysis was performed with Chi-square test, test \"t\" test, Mann-whiney and multiple logistic regression and simple to estimate the gross and adjusted Odds Ratio (AOR). 62 older women were assessed, 31 caregivers of demented AD patients and 31 control group It was found that the total cholesterol levels were higher in elderly caregivers (AOR = 3.57, p = 0.03). There was no difference between the systolic and diastolic values between the groups in relation to the measures carried out by the researcher and HBPM. According to the results, older caregivers had a positive screening for depression in 58%, while the control group showed only 16% (AOR = 6.62, p <0.01). Regarding the diagnosis made by M.I.N.I, 38.7% of caregivers had depressive episode, higher than the control (9.7%) (AOR = 5.42, p = 0.02). It was found that 35.5% of caregivers had diagnosis of anxiety disorder, with 16% in the control group (AOR = 4.79, p = 0.03). The presence of the companion interfered, so that the caregivers presented more anxiety disorder (p = 0.04). There was no difference between cognition groups by assessing the MMSE. Concluding, caregivers of patients with AD have higher cholesterol levels, more depressive episodes and anxiety disorder than non-caregivers. The presence of the companion interfered to submit more anxiety disorder

No description available.

The APOE gene is of profound importance regarding the onset of Alzheimer's disease (AD). From the small physical differences among the protein products of the isoforms of this gene arises a profound difference in their physiologies. For example, the APOE2 isoform confers resistance to AD, the APOE3 isoform confers neutral susceptibility to AD, and the APOE4 isoform confers proneness to AD. L-cysteine is an amino acid that has several anti-AD properties, among which are its ability to sequester iron and form glutathione – a powerful antioxidant – and therefore may be a promising potential dietary supplement for ameliorating AD pathology. In our experiment, we fed Mus musculus (mice) homozygous for APOE2, APOE3, and APOE4 either a control diet or a diet high in L-cysteine. Using Western blotting analysis, we quantified Amyloid β (Aβ), hyper-phosphorylated Tau (HP-Tau), and the three APOE proteins that we extracted from post-mortem brains of APOE2, APOE3, and APOE4 homozygous mice of 3-, 6-, 9-, and 12-month ages. We calculated a three-way ANOVA on a sample of 86 mice to examine the effect of age, genotype, and diet on protein quantities. We found that administration of L-cysteine trends towards lowering levels of Aβ in each cohort, but this effect is statistically insignificant. On the other hand, L-cysteine caused a significant decrease in APOE production with regard to diet [F(1,62) = 6.17, p=0.02], indicating that less APOE is produced due to the decrease in Aβ burden. Furthermore, administration of L-cysteine revealed no significant impact on or trends regarding HP-Tau deposition between diet types for each cohort. However, we observed that L-cysteine appeared to nullify the increasing trend in HP-Tau deposition between APOE2 and APOE4 cohorts. Thus, L-cysteine may be weakly affecting HP-Tau deposition via its ability to somewhat reduce Aβ burden and consequently prevent the shutdown of the proteosomes responsible for the degradation and clearance of HP-Tau. Taken together, these data suggest that L-cysteine should be considered as an intervention for AD pathology.

Alzheimer’s disease is an insidious neurodegenerative disease that affects millions of people worldwide. Currently, there are no determinants that can accurately predict the onset cognitive decline in AD. This thesis investigates and defines changes in the lipidome that are linked to symptomatic onset and cognitive impairment in mouse models of AD. Using a targeted lipidomic approach employing high performance liquid chromatography electrospray ionization tandom mass spectrometry, direct biochemical assessments, and behavioural evaluation, I was able to (a) profile and quantify cortical and hippocampal glycerophosphocholine and glycerophosphoethanolamine metabolites and signaling molecules in the APPSwe/PS1dE9 and the N5 TgCRND8 murine models of AD and (b) associate changes in lipid metabolism with learning and memory impairment. I demonstrate that glycerophosphocholine metabolism in the cortex but not the hippocampus is altered at symptomatic onset in both mouse models. These same metabolic changes were seen in younger animals exposed to chronic intermittent hypoxia, an environmental risk factor that accelerates their phenoconversion. In fully impaired transgenic mice, I defined metabolic changes associated with disease progression. To further assess the impact of sex, another risk factor of Alzheimer’s disease cognitive decline, I characterized an AD model of sex-specific cognitive resistance. I demonstrated that transgenic males but not females exhibit behavioural indices of cognitive reserve when tested in the Morris Water Maze. Using this mouse line, I then investigated how measures of learning and memory associated with glycerophosphocholine and glycerophosphoethanolamine metabolism. I identified increases in critical glycerophosphoethanolamine metabolites linked to spatial learning and memory impairment in the cortex of N5 TgCNRD8 mice and demonstrated that these changes could be predicted by profiling the plasma glycerophosphoethanolamine lipidome. Taken together, this thesis links glycerophospholipid metabolism to the onset and progression of learning and memory impairment in experimental models of AD and provides the first evidence that changes in cortical lipid metabolism can be predicted by changes in the plasma lipidome.

Alzheimer's Disease and Related Disorders (ADRD) are a major public health problems. Major sources of care provision are family members in the community and these ADRD caregivers encounter a variety of stressor. Currently there continues to be a need to develop and test Internet based interventions designed to reduce stress for caregivers for persons with ADRD. The web-based Structured Written Emotional Expressions (SWEE) was developed to manage ADRD caregivers stress related to caregiving experiences through writing about their thoughts and feelings. However, differences between provided services by researchers (the web-based SWEE) and the desired services of ADRD caregivers could be a barrier to ADRD caregivers' acceptance and use of the web-based SWEE. The purpose of this study was to assess the acceptability of implementing a web-based nursing intervention for ADRD caregivers and to describe participants' experiences in using the website to understand ADRD caregivers' website usage. An experimental design was used to determine whether the web-based SWEE helped to manage ADRD caregivers' stress through writing interventions. In addition, the UTAUT model was employed for a theoretical framework to explain and predict the web-based SWEE usage behavior by ADRD caregivers. The Finding Meaning Through Caregiving Scale (FMTCS) was used to evaluate finding-meaning related to caregiving experiences as a mediator between performance expectancy and behavioral intention to use in the UTAUT model. Furthermore, the web-based research methods were assessed throughout the web-based SWEE implementing process. Both web-based and paper-based methods were used for recruiting potential participants. Most people who contacted the researcher were recruited by the web-based method. Structural Equation Modeling (SEM) was used for test ADRD caregivers' acceptability of the web-based SWEE and direct content analysis was used for describing participants' experiences in using the web-based SWEE. Fifty people completed the study out of the 90 people who enrolled. Of these 50 participants, 31 completed the study as intended and on schedule. The research showed a good model fit with a Chi-square value (df=43) of 57.191 (p>0.05). The findings showed that performance expectancy had a significant effect on participants' behavioral intention to use (β=0.620, p<0.01) and that effort expectancy also affected the behavioral intention to use the web-based SWEE (β=0.293, p<0.01). Performance expectancy showed stronger effects than effort expectancy. This model explained 52% of variance in behavioral intention to use. However, the effects of facilitating conditions on actual usage and effects of behavioral intention to use on actual usage were not supported by this research. The finding-meaning measure did not show a significant mediating effect on the relationship between performance expectancy and behavioral intention to use. Findings suggested that recruitment methods which use the Internet were an effective way to find potential study participants. Regardless of the topic, the writing intervention helped ADRD caregivers to express stress related to caregiving experiences. In addition, the perceived usefulness of this nursing intervention (performance expectancy) and the perceived ease of use (effort expectancy) were two important constructs which predicted and explained the acceptance of the web-based SWEE by ADRD caregivers. Finally, even though the UATAUT model was only partially supported by a good model fit, this study's findings showed the potential of the UTAUT model for providing health consumer information systems in nursing.