Alzheimer¿s disease is associated with aging and is characterised by a progressive cognitive decline. Its onset in women coincides with the abrupt depletion of ovarian steroids prompting the investigation of utilising oestrogen replacement therapy as restoration or a preventative measure. Gonadal steroids have also recently been implicated in other disease states, particularly schizophrenia. In addition to the cognitive decline, sufferers of Alzheimer¿s disease and schizophrenia display anxiety related behaviour which gonadal steroids have also been shown to ameliorate. In this thesis several paradigms were used to investigate the effects of oestradiol benzoate (EB) on cognition and anxiety, utilising the NMDA receptor antagonist PCP, the muscarinic receptor antagonist scopolamine and the dopamine releasing agent amphetamine to induce a cognitive deficit in rats by different pharmacological mechanisms. The thesis also investigated the effects of EB on a delay dependent cognitive deficit model of forgetfulness in natural aging. Results showed that subchronic PCP dosing failed to induce a significant deficit in the novel object recognition task. Locomotor activity tests demonstrated that the PCP treated rats were sensitised to the treatment suggesting that the PCP dosing regimen was successful. There was no significant effect of oestrogen in the reversal learning model or in the plus maze task designed to explore EB¿s effects on anxiety. However, in the latter task there was a trend towards an anxiogenic effect of EB. Results from the delay dependent model of forgetfulness in natural aging demonstrated that EB could enhance recognition memory, but not spatial memory. The results are discussed in the context of the role of gonadal steroids especially oestrogen in combating the cognitive decline seen in schizophrenia, neurodegenerative disease and natural aging.

Purpose: The objective was to study how sedentary behaviour (SB) and physical activity (PA)change during a 6-months multimodal lifestyle intervention including a Multimodal Lifestyle Intervention, a Multimodal Lifestyle and Medical food intervention and a control subgroup, for people with prodromal Alzheimer's disease (AD). Further, the aim was to explore the predictive value of outcome expectancies and self-efficacy beliefs on level of PA in the two intervention subgroups.  Methods: A secondary analysis of existing data (n=66) from MIND-AD trial with a descriptive evaluation design was conducted. Descriptive and non-parametric statistical analysis were used for between- and within groups analysis. To explore the predictive value of a model with self-efficacy and outcome expectancies at baseline on PA at 6 months, regression analysis was conducted. Effect size was calculated for between-group and withingroup differences. Results: Objectively measured PA increased in the Multimodal Intervention subgroup. SB did not change during the intervention. Outcome expectancies for that impact of exercise is beneficial for health in the long run increased during the intervention. Participants higherinitial outcome expectancies for the impact of exercise would lead to less AD-related difficulties predicted higher PA level at 6 months. Self-efficacy for exercise or outcome expectancies for the impact of exercise on AD-related difficulties did not change during the intervention. Conclusions: PA increased in the Multimodal Intervention subgroup. This difference could not be shown with PA measured by questionnaire which indicates that objective measurements are better suited to measuring PA in people with prodromal AD than subjective measurements. Increased outcome expectancies for that impact of exercise arebeneficial for health in the long run demonstrate the participants strengthened intentions to improve their long-term health. Increasing outcome expectancies to manage AD-related difficulties can be an important part of interventions targeting PA in people with prodromal AD.

No / The 5-HT1A receptor has been extensively studied over the last two decades. There is a plethora of information describing its anatomical, physiological and biochemical roles in the brain. In addition, the development of selective pharmacological tools coupled with our understanding of psychiatric pathology has lead to multiple hypotheses for the therapeutic utility of 5- and in particular 5-HT1A receptor antagonists. Over the last decade it has been suggested that 5-HT1A receptor antagonists may have therapeutic utility in such diseases as depression, anxiety, drug and nicotine withdrawal as well as schizophrenia. However, a very compelling rationale has been developed for the therapeutic potential of 5-HT1A receptor antagonists in Alzheimer s disease and potentially other diseases with associated cognitive dysfunction. Receptor blockade by a 5-HT1A receptor antagonist appears to enhance activation and signaling through heterosynaptic neuronal circuits known to be involved in cognitive processes and, as such, represents a novel therapeutic approach to the treatment of cognitive deficits associated with Alzheimer s disease and potentially other disorders with underlying cognitive dysfunction.

A Doença de Alzheimer é uma doença neurodegenerativa progressiva e de início tardio, que compromete principalmente as areas da cognição, julgamento e estabilidade emocional. Esta doença se caracteriza por dois tipos de lesões cerebrais características: emaranhados neurofibrilares e placas senis. Os emaranhados neurofibrilares são compostos por uma proteína do citoesqueleto (proteína tau) hiperfosforilada e agregada. As placas senis são formadas por agregados da proteína β-amilóide. A doença de Alzheimer é resultado dainteração de vários fatores ainda incompletamente elucidados; não obstante, o estresse oxidativo e os processos inflamatórios ocupam posição de destaque dentre esses fatores. Neste trabalho, avaliamos as atividades das enzimas eritrocitárias superóxido dismutase, catalase e glutationa peroxidase, assim como o conteúdo plasmático de glutationa total, vitamina C, α-tocoferol, β-caroteno, licopeno e coenzima Q10. A esses parâmetros antioxidantes foram contrapostas medidas de oxidação de lipídios e proteínas plasmáticas. Adicionalmente, efetuamos a avaliação das expressões monocitárias de HLADR e CD-11b, e das citocinas IL-6, IL-1α e TNF-α. Nossos resultados mostram que os pacientes de doença de Alzheimer possuem níveis circulantes de atocoferol inferiores aos pacientes controles, e possuem monócitos que apresentam maior expressão basal de HLA-DR e maior produção de IL-1α quando estimulados por LPS. Esses resultados fortalecem a hipótese inflamatória na doença de Alzheimer, de acordo com trabalhos recentes que apontam bons resultados com o a-tocoferol na sua prevenção e tratamento. / Alzheimer\'s disease is a late-onset, progressive degenerative disease that affects mainly the judgement, emotional stability and memory domains. This disease is characterized by two telltale cerebral lesions: neurofibrillary tangles and senile plaques. Neurofibrillary tangles are constituted by hyperphosphorylated cytoskeleton protein tau aggregates, while senile plaques are mainly composed by β-amyloid protein aggregates. Alzheimer\'s disease is the outcome of a complex interaction among several factors which are not fully understood yet; nevertheless it is clear thar oxidative stress and inflammatory pathways rate high among these factors. In this work, we evaluated the erythrocytic acitivities of superoxide dismutase, catalase and glutathione peroxidase, as well as the plasma levels of total glutathione, α-tocopherol, α-carotene, lycopene, and coenzyme Q10. These antioxidant parameters were confronted with plasmatic levels of protein and lipid oxidation products. Additionally, we measured the basal expression of monocyte HLA-DR and CD-11b, as well as the monocyte production of the cytokines IL1-α, IL-6 and TNF-α. Our results show that Alzheimer\'s Disease patients show lower plasmatic levels of α-tocopherol when compared to control patients, and have higher basal monocyte HLA-DR expression associated with higher IL-1α production when stimulated by LPS. These results lend support to the inflammatory theory of Alzheimer\'s disease, according to recent works that indicate good results of α-tocopherol administration in both its prevention and treatment.

A Doença de Alzheimer é uma doença neurodegenerativa progressiva e de início tardio, que compromete principalmente as areas da cognição, julgamento e estabilidade emocional. Esta doença se caracteriza por dois tipos de lesões cerebrais características: emaranhados neurofibrilares e placas senis. Os emaranhados neurofibrilares são compostos por uma proteína do citoesqueleto (proteína tau) hiperfosforilada e agregada. As placas senis são formadas por agregados da proteína β-amilóide. A doença de Alzheimer é resultado dainteração de vários fatores ainda incompletamente elucidados; não obstante, o estresse oxidativo e os processos inflamatórios ocupam posição de destaque dentre esses fatores. Neste trabalho, avaliamos as atividades das enzimas eritrocitárias superóxido dismutase, catalase e glutationa peroxidase, assim como o conteúdo plasmático de glutationa total, vitamina C, α-tocoferol, β-caroteno, licopeno e coenzima Q10. A esses parâmetros antioxidantes foram contrapostas medidas de oxidação de lipídios e proteínas plasmáticas. Adicionalmente, efetuamos a avaliação das expressões monocitárias de HLADR e CD-11b, e das citocinas IL-6, IL-1α e TNF-α. Nossos resultados mostram que os pacientes de doença de Alzheimer possuem níveis circulantes de atocoferol inferiores aos pacientes controles, e possuem monócitos que apresentam maior expressão basal de HLA-DR e maior produção de IL-1α quando estimulados por LPS. Esses resultados fortalecem a hipótese inflamatória na doença de Alzheimer, de acordo com trabalhos recentes que apontam bons resultados com o a-tocoferol na sua prevenção e tratamento. / Alzheimer\'s disease is a late-onset, progressive degenerative disease that affects mainly the judgement, emotional stability and memory domains. This disease is characterized by two telltale cerebral lesions: neurofibrillary tangles and senile plaques. Neurofibrillary tangles are constituted by hyperphosphorylated cytoskeleton protein tau aggregates, while senile plaques are mainly composed by β-amyloid protein aggregates. Alzheimer\'s disease is the outcome of a complex interaction among several factors which are not fully understood yet; nevertheless it is clear thar oxidative stress and inflammatory pathways rate high among these factors. In this work, we evaluated the erythrocytic acitivities of superoxide dismutase, catalase and glutathione peroxidase, as well as the plasma levels of total glutathione, α-tocopherol, α-carotene, lycopene, and coenzyme Q10. These antioxidant parameters were confronted with plasmatic levels of protein and lipid oxidation products. Additionally, we measured the basal expression of monocyte HLA-DR and CD-11b, as well as the monocyte production of the cytokines IL1-α, IL-6 and TNF-α. Our results show that Alzheimer\'s Disease patients show lower plasmatic levels of α-tocopherol when compared to control patients, and have higher basal monocyte HLA-DR expression associated with higher IL-1α production when stimulated by LPS. These results lend support to the inflammatory theory of Alzheimer\'s disease, according to recent works that indicate good results of α-tocopherol administration in both its prevention and treatment.

Tauopathien sind Krankheiten, die mit einer abnormen intrazellulären Tau-Protein-Faltung, Tau-Protein-Aggregation und Filament-Bildung im ZNS und PNS einhergehen. Die Alzheimer Demenz stellt die häufigste Tauopathie dar. Bei ihr kommt es zu einer intra- und extrazellulären Ablagerung fehlgefalteter amyloidogener Proteinaggregate, welche durch β Amyloid und Tau gebildet werden. Es resultiert eine Neurodegeneration. Ein multifaktorieller Prozess führt bei den Tauopathien zur Umwandlung des Tau-Proteins hin zu unlöslichen Fibrillenbündeln. Primär kommt es zur Bildung eines Dimers, das durch Disulfid- und Wasserstoffbrückenbindungen stabilisiert wird. Durch die Zusammenlagerung mehrer Dimere entstehen Tau-Oligomere. Diese gelten als die neurotoxischen Komponenten. Die Primärstruktur des Tau-Proteins beeinflusst den Aggregationsprozess. Dabei spielen die Anwesenheit der Aggregationsdomänen PHF6* und PHF6 und die Anzahl der Cystein-Seitenketten überragende Rollen. In dieser Arbeit wurden durch ortsspezifische Mutagenesen Tau-Konstrukte generiert, die sich in ihrer Anzahl der Aggregationsdomänen und der Cystein-Reste unterschieden. Es konnte gezeigt werden, dass die Aggregationstendenz der Tau-Proteine mit nur einer Aggregationsdomäne und keinem Sulfhydryl-Rest stark sinkt. Auch durch Veränderungen des Redoxmilieus lässt sich das Tau-Aggregationsverhalten beeinflussen. Es wurde gezeigt, dass die Substanz TCEP als starkes Reduktionsmittel die Aggregation der 2 humanen Tau-Isoformen 2N3R und 2N4R wirkungsvoll inhibiert. Auch GSSG als Oxidationsmittel verhinderte in bestimmten Konzentrationen die Aggregation dieser 2 Isoformen. Es wird angenommen, dass die Verhinderung der Bildung einer intermolekularen Disulfidbrückenbindung zu diesem Phänomen führt.

Introdução: a desorientação topográfica é um sintoma comum em pacientes com doença de Alzheimer (DA), no entanto não tem tão estudada quanto outros sintomas da DA. Objetivos: Verificar a ocorrência da desorientação topográfica em pacientes com DA e identificar quais transtornos neuropsicológicos estão relacionados com a desorientação. Métodos: Foram avaliados vinte e sete pacientes com DA provável (12 do sexo feminino, 14 com DA com demência de leve intensidade) e 30 indivíduos controles sem demência (21 do sexo feminino). Os pacientes foram submetidos a um questionário específico sobre orientação topográfica e foram submetidos aos seguintes testes: Mini Exame do Estado Mental, extensão de dígitos, fluência verbal, teste de cancelamento, teste dos blocos de Corsi, localização de pontos no espaço, julgamento de orientação de linhas, cópia de figuras em três dimensões e figuras sem sentido e testes de rotação mental. Foram realizados testes de reconhecimento de marcos topográficos, orientação pessoal, descrição de rotas, localização de cidade no mapa do Brasil. Resultados: Pacientes e controles não apresentaram diferença quanto à escolaridade e gênero. Houve diferença entre pacientes e controles no questionário sobre orientação topográfica e em todos os testes utilizados, exceto nas tarefas de funções vísuo-espaciais. O grupo de pacientes com demência de leve intensidade demonstrou diferença no questionário sobre orientação topográfica, descrição de rotas, reconhecimento de marcos topográficos, orientação espacial julgamento de orientação de linhas e localização de cidades no mapa. Apenas o reconhecimento de marcos topográficos, foi capaz de diferenciar entre pacientes com demência de leve ou de moderada intensidade. Conclusões: O questionário sobre orientação topográfica demonstrou que até mesmo os pacientes com DA com demência de leve intensidade tiveram desorientação topográfica. Os testes de reconhecimento de marcos topográficos, xi orientação pessoal egocêntrica e alocêntrica, estão alterados precocemente e podem contribuir para a desorientação topográfica, A memória operacional espacial e as funções visuo-espaciais não estão comprometidas inicialmente e provavelmente não contribuíram para a desorientação topográfica em pacientes com demência de leve intensidade. No entanto, pacientes com demência de intensidade moderada demonstraram comprometimento nas tarefas de memória operacional especial e testes de funções vísuoespaciais, o que provavelmente contribuiu para a desorientação topográfica nestes pacientes / Background: Topographical disorientation is a common symptom in patients with Alzheimer´s disease (AD) that has not been as extensively studied as other common manifestations of this disease. Objective: To verify the occurrence of topographical disorientation in patients with Alzheimer\'s disease (AD) and to identify which neuropsychological dysfunctions are causally related to the presence of this manifestation. Methods: Twenty seven patients meeting criteria for probable AD (12 female, 14 with mild dementia) and 30 subjects (21 female) without dementia were analyzed. The subjects and the caregivers were interviewed with a questionnaire on topographical orientation. The following tests were given: Mini mental state examination (MMSE), digit span, verbal fluency, cancellation task, Corsi\'s block tapping test, point localization, line orientation judgment, three dimension and nonsense figure copy and mental rotation tests. Landmarks recognition, personal orientation, recalling routes were tested in a descriptive task and geographic knowledge was evaluated with a Brazilian map. Results: Patients and control subjects were not different regarding schooling years and gender. There were differences between patients and controls in the questionnaire on topographical orientation and in all tests except in visual spatial tasks. Patients with mild dementia had difference in the questionnaire, recalling routes, landmark recognition, personal orientation, geographical knowledge and line orientation judgment. Only the landmark recognition test was found to differentiate between patients with mild or moderate dementia. Conclusions: The topographic orientation questionnaire showed that even in mild dementia, AD patients have topographical disorientation. The landmark recognition, self-centered and world-centered orientation were precociously affected and may contribute for topographical disorientation. Spatial working memory and spatial visual functions are not compromised initially and xiii probably did not contribute for topographical disorientation in the patients with mild dementia. However, patients with moderate dementia showed impairment in spatial working memory and spatial visual tests, which may have contributed to the topographic disorientation of these patients

Doenças neurodegenerativas vem sendo relacionadas a alterações no metabolismo de glicose e deficiência e/ou resistência à insulina encefálica. Além desta relação, parece existir uma modulação dos hormônios tireoideanos (HT) sobre a sinalização de insulina e a função do sistema nervoso central (SNC). O objetivo desse trabalho foi analisar a relação entre o hipertireoidismo e o SNC, associados a DM. Para isso, ratos Wistar adultos foram injetados com monoidratado de aloxana ou veículo e tratados com T3 durante 30 dias, sendo avaliados em testes comportamentais e posteriormente analises proteicas de regiões do córtex e hipocampo. O tratamento crônico com T3 produziu um efeito ansiolítico e um atraso na aquisição de informações aprendidas, apesar da consolidação não ser modificada. Por outro lado, o T3 promoveu a melhora do processo neurodegenerativo e na via da sinalização da insulina no hipocampo de animais diabéticos. Esses dados sugerem, de modo geral, um efeito benéfico do HT sobre o a função encefálica de animais diabéticos. / Neurodegenerative diseases has been related to changes in glucose metabolism and deficiency and /or resistance to brain insulin. In this respect, there appears to be a modulation of thyroid hormones (TH) on insulin signaling and function of the central nervous system (CNS). The objective of this study was to analyze the relationship between hyperthyroidism and the CNS associated with DM. For this, Wistar adult rats were injected with alloxan monohydrate or treated with vehicle and T3 for 30 days and evaluated in behavioral tests and subsequent analyzes of protein in the cortex and hippocampus regions. Chronic treatment with T3 produced an anxiolytic effect and a delay in the acquisition of information, although consolidation not be modified. Furthermore, T3 allowed improvement of the neurodegenerative process and pathway of insulin signaling in the hippocampus of diabetic rats. These data suggest, in general, a beneficial effect of TH on the brain function of the diabetic animals.

INTRODUÇÃO. O objetivo deste estudo foi responder se a transformada wavelet Morlet e as técnicas de aprendizagem de Máquina (ML), chamada Máquinas de Vetores de Suporte (SVM) são adequadas para procurar padrões no EEG que diferenciem controles normais de pacientes com DA. Não há um teste de diagnóstico específico para a doença de Alzheimer (DA). O diagnóstico da DA baseia-se na história clínica, neuropsicológica, exames laboratoriais, neuroimagem e eletroencefalografia. Portanto, novas abordagens são necessárias para permitir um diagnóstico mais precoce e preciso e para medir a resposta ao tratamento. EEG quantitativo (EEGq) pode ser utilizado como uma ferramenta de diagnóstico em casos selecionados. MÉTODOS: Os pacientes eram provenientes do Ambulatório do Grupo de Neurologia Cognitiva e do Comportamento (GNCC) da Divisão de Clínica Neurológica do HCFMUSP ou foram avaliados pelo grupo do Laboratório de Eletrencefalografia Cognitiva do CEREDIC HC-FMUSP. Estudamos EEGs de 74 indivíduos normais (33 mulheres/41 homens, com idade média de 67 anos) e 84 pacientes com provável DA leve a moderada (52 mulheres/32 homens, idade média de 74,7 anos. A transformada wavelet e a seleção de atributos foram processadas pelo software Letswave. A análise SVM dos atributos (bandas delta, teta, alfa e beta) foi calculada usando-se a ferramenta WEKA (Waikato Ambiente para Análise do Conhecimento). RESULTADOS: Na classificação dos grupos controles e DA obteve-se Acurácia de 90,74% e área ROC de 0,90. Na identificação de um único probando dentre todos os demais se conseguiu acurácia de 81,01% e área ROC de 0,80. Desenvolveu-se um método de processamento de EEG quantitativo (EEGq) para uso na diferenciação automática de pacientes com DA versus indivíduos normais. O processo destina-se a contribuir como complemento ao diagnóstico de demência provável principalmente em serviços de saúde onde os recursos sejam limitados / INTRODUCTION. The aim of this study was to answer if Morlet wavelet transform and machine learning techniques (ML), called Support Vector Machines (SVM) are suitable to look for patterns in EEG to differentiate normal controls from patients with AD. There is not a specific diagnostic test for Alzheimer\'s disease (AD). The diagnosis of AD is based on clinical history, neuropsychological testing, laboratory, neuroimaging and electroencephalography. Therefore, new approaches are needed to allow an early diagnosis and accurate to measure response to treatment. Quantitative EEG (qEEG) can be used as a diagnostic tool in selected cases. METHODS: The patients came from the Clinic Group Cognitive Neurology and Behavior (GNCC), Division of Clinical Neurology HCFMUSP or evaluated by the group of the Laboratory of Cognitive electroencephalography CEREDIC HCFMUSP. We studied EEGs of 74 normal subjects (33 females/41 men, mean age 67 years) and 84 patients with mild to moderate probable AD (52 females/32 men, mean age 74.7 years. Wavelet transform and the selection of attributes were processed by software Letswave. SVM analysis of attributes (bands delta, theta, alpha and beta) was calculated using the tool WEKA (Waikato Environment for Knowledge analysis). RESULTS: The group classification of controls and DA obtained an accuracy of 90.74% and ROC area 0.90. The identification of a unique proband among all others was achieved with accuracy of 81.01% and ROC area 0.80. It was developed a method of processing EEG quantitative (qEEG) for use in automatic differentiation of AD patients versus normal subjects. This process is intended to complement the diagnosis of probable dementia primarily in health services where resources are limited

The Mediterranean diet (Medi) has been highlighted as the golden diet rich in protective properties associated with cognitive- and emotional health. The foundation of the Medi comprises vegetables, fruits, nuts and seeds, legumes, and extra virgin olive oil. Research has been conducted in both holistic dietary approach and single nutrient approach regarding the impact of nutrition and diet, in this case, the Medi‟s effect on brain health. This review aims to give an up to date overview of the Mediterranean diet, outline some of the diet's abundant nutrients, and discuss studies linking the nutrient's potential effect on depression, cognitive decline, dementia, and brain structure and function. In addition, this review will attempt to assess whether the Medi as a whole or if a single nutrient approach is accountable for the health-promoting findings. Furthermore, the gut-brain axis, and other potential underlying mechanisms involved in the modulation of food- and nutrient intake and their effects on the brain, will be outlined. A diet high in fruit-, vegetable-, polyunsaturated fatty acid-, and monounsaturated fatty acid content has great power for health-maintenance and decreases the risk of suffering cognitive decline, dementia, and potentially depression. More randomized controlled trials are however eagerly awaited to give more substance to previous findings.