Submitted by Fabio Sobreira Campos da Costa (fabio.sobreira@ufpe.br) on 2017-07-28T14:50:20Z No. of bitstreams: 2 license_rdf: 811 bytes, checksum: e39d27027a6cc9cb039ad269a5db8e34 (MD5) ATIVIDADE ANTICOLINESTERÁSICA DE PLANTAS DA CAATINGA COM INDICAÇÃO POPULAR PARA DISTÚRBIOS DO SIS.pdf: 10498637 bytes, checksum: 6697d682e5713ad3939431b53b38ec0b (MD5) / Made available in DSpace on 2017-07-28T14:50:20Z (GMT). No. of bitstreams: 2 license_rdf: 811 bytes, checksum: e39d27027a6cc9cb039ad269a5db8e34 (MD5) ATIVIDADE ANTICOLINESTERÁSICA DE PLANTAS DA CAATINGA COM INDICAÇÃO POPULAR PARA DISTÚRBIOS DO SIS.pdf: 10498637 bytes, checksum: 6697d682e5713ad3939431b53b38ec0b (MD5) Previous issue date: 2016-03-18 / FACEPE / No Brasil e no mundo há um crescimento na população de idosos e conforme as pesquisas demográficas recentes, esse aumento se explica como consequência de uma redução da fertilidade e mortalidade observada ao longo do século XX. A idade pode ser considerada como um dos fatores de risco melhor aceito para o desenvolvimento de diversas doenças, destacando-se entre elas a Doença de Alzheimer (DA). No entanto até hoje, não existe uma causa única que pode levar ao desenvolvimento da DA, mas sim um conjunto de fatores, a exemplo do estresse, danos físicos (traumas ou pancadas), déficit no metabolismo e vascularização cerebral, que associados a hipótese colinérgica, poderiam explicar melhor o surgimento desta doença. Atualmente, a terapêutica disponível para a DA baseia-se principalmente nesta hipótese, não sendo possível a cura, mas apenas o retardo da evolução da doença bem como o alívio nos sintomas que a mesma apresenta, que de certa forma contribui com a qualidade de vida dos pacientes. No entanto, estão em fase não clínica de testes alguns candidatos que poderiam atuar sobre a formação das placas amilóides e diminuição dos agregados protéicos insolúveis, o que poderia evitar a evolução da doença para etapas mais severas. Na perspectiva de busca de novos fármacos, os produtos naturais apresentam relevância e as endemias de algumas espécies vegetais as deixam com composição química características daquele local específico. A Caatinga, por exemplo, é um bioma dominado por um dos tipos de vegetação cuja distribuição é totalmente restrita ao Brasil. Diante disto, o presente trabalho teve como objetivo buscar novas substâncias com potencial atividade anticolinesterásica e que possam servir como alternativa para o tratamento da DA, levando em consideração a hipótese colinérgica como uma das principais causas da doença. Partindo de uma pesquisa etnofarmacológica com indicação de plantas medicinais utilizadas para patologias que pudessem ter relação ao sistema nervoso, foram coletadas 23 espécies, sendo duas partes diferentes de duas espécies particularmente, e obtidos extratos com três polaridades para cada uma, gerando 75 amostras para estudo. Apenas 26,7% apresentaram resultado positivo no pre-teste qualitativo de inibição da enzima AChE. Quando realizado o teste falso positivo, este número diminuiu para 30% do resultado positivo, sendo representado por 8% do total de amostras analisadas. Das 30 amostras analisadas quantitativamente, apenas 13,3% apresentaram fraca atividade inibitória da AChE, 43,3% apresentaram moderada atividade e 43,3%, apresentaram potente atividade, sempre levando-se em consideração a menor concentração estudada (0,5 mg/mL). Destacaram-se com melhores resultados Citrus limonum, Ricinus communis e Senna occidentalis, com porcentagem de inibição da atividade anticolinesterásica variando de 50% até 65%, na menor concentração. Estas espécies tiverem seus extratos de média e baixa polaridade submetidas a Cromatografia Gasosa-Espectrometria de Massa. Foi possível perceber a presença de classes de compostos em comum entre as amostras, como os derivados de terpenoides e cumarinas, que em alguns estudos na literatura científica são citados com a atividade anticolinesterásica. Com maior frequência entre os melhores resultados, C. limonum foi escolhida para os testes de isolamento e doseamento de cumarinas, para o qual foram encontrados teores de 688,57 ±3,94 mg/g de extrato para fração de diclorometano. Ao ser particionada, esta amostra apresentou resultados de porcentagem de inibição anticolinesterásica entre 74,6% a 94,4%, sendo possível isolar o composto caracterizado como 2H-1-Benzopiran-2-ona-5,7-dimetoxi. As frações da amostra de metanol apresentaram inibição da AChE entre 92,3% e 100%. Os resultados obtidos para C. limonum mostram o potencial desta espécie para o tratamento da DA. / In Brazil, as well as in the world, there is an increase in the elderly population, and according to recent demographic research this increase is explained as a consequence of decreased fertility and mortality observed throughout the twentieth century. Age can be considered as one of the most accepted risk factors for the development of several diseases, for example Alzheimer's disease (AD). However, until today, a single cause cannot lead to the development of AD, but a set of factors, such as stress, physical injury (trauma or strokes), deficits in metabolism and brain vasculature that associated with cholinergic hypothesis could better explain the emergence of this disease. Currently, the treatment available for AD is mainly based on this assumption, it is not possible to cure, but the disease progression can be delayed, relieving the symptoms presented which in a certain way contributes to the patients‟ quality of life. However, in preclinical testing there are some candidates that could act on the formation of amyloid plaques and reduction of insoluble protein aggregates, which could prevent the disease progression to more severe stages. In the search for new drugs, natural products have relevance, and the endemic of some species of plants let them with anatomy and chemistry characteristics of that specific location. The Caatinga, for example, is a biome dominated by one type of vegetation which distribution is completely restricted to Brazil. Therefore, this study was aimed at seeking new substances with potential acetylcholinesterase activity, which could serve as an alternative for the treatment of AD, taking into consideration the cholinergic hypothesis as one of the main causes of the disease, starting from an ethnopharmacological research with medicinal plants used for diseases that could be related to the nervous system. Twenty-three species were collected, and it was obtained extracts with three polarities for each one, generating 75 samples to study. Only 26.7% were positive in the qualitative test of AChE enzyme. When the false positive test is performed this number decreases to 30% of the positive results, being represented by 8% of the total samples. From the 30 samples analyzed quantitatively, only 13.3% had weak inhibitory activity of AChE, 43.3% had moderate activity and 43.3% showed potent activity, always taking into account the lowest concentration studied (0.5 mg / mL). Those with the best results were Citrus limonum, Ricinus communis and Senna occidentalis, with percentage of inhibition of acetylcholinesterase activity varying from 50% to 65%, at lowest concentration. These species had their average and low polarity extracts subjected to Gas Chromatography-Mass Spectrometry. It was possible to perceive the presence of classes of compounds in common between the species, such as terpenes and coumarin, which in some studies in the scientific literature are cited with the activity in question. With a higher frequency among the best results, C. limonum was chosen for the isolation and dosing tests of Coumarins, in which were found levels of 688.57 ± 3.94 mg / g for fraction of extract of dichloromethane. By being partitioned, this sample showed results of acetylcholinesterase inhibition percentage of 74.6% to 94.4%, being possible to isolate the compound described as 2H-1-benzopyran-2one-5,7-dimethoxy. The fractions of methanol sample showed inhibiting between 92.3% and 100%. The results for C. limonum showed the potential of this species for the treatment of AD.

Les récepteurs purinergiques P2X4 (P2X4R) sont des récepteurs canaux exprimés par lesneurones et les microglies du système nerveux central et sont impliqués dans de nombreuxprocessus physiologiques et pathologiques. Des études préliminaires, menées au sein dulaboratoire, ont permis de mettre en évidence une interaction entre P2X4R etl’Apolipoprotéine E (ApoE), ainsi qu’une augmentation d’ApoE dans les macrophages et lesmicroglies provenant de souris déficientes pour P2X4R. Basée sur ces observations, lapremière partie de cette thèse a cherché à caractériser les mécanismes impliquant P2X4R danscet effet. ApoE étant un facteur de risque majeur dans la maladie d’Alzheimer, la deuxièmepartie de cette thèse a été consacrée à étudier l’implication de P2X4R dans cette pathologie.Les résultats présentés montrent que P2X4R module l’activité de la cathepsine B, enzymeresponsable de la dégradation lysosomale d’ApoE. L’utilisation de souris APP/PS1 a permisde montrer que l’absence de P2X4R conduit à une amélioration des capacités mnésiques, unediminution de la concentration de peptide Aβ soluble ainsi qu’à une augmentation d’ApoEmicrogliale.Ces résultats indiquent que P2X4R régule la dégradation d’ApoE par un mécanismedépendant de la cathepsine B, et que son invalidation permet d’améliorer les symptômescognitifs de la maladie d’Alzheimer. / P2X4 receptors (P2X4R) are purinergic ion channels expressed on neurons and microglia inthe central nervous system. They have been widely studied and have been implicated in manyphysiological and pathological processes. Previous studies conducted in the laboratoryrevealed an interaction between P2X4R and the Apolipoprotein E (ApoE), as well as anincrease in ApoE level in primary macrophages and microglia obtained from mice lackingP2X4R. Based on these results, this thesis aimed to decipher the mechanisms underlyingP2X4R regulation of ApoE levels. In addition, ApoE being a major risk factor forAlzheimer’s disease, part of this work investigated potential implications of P2X4R in thispathology.Results show that P2X4R modulates cathepsin B activity, which in turn promotes ApoElysosomal degradation. APP/PS1 mice lacking P2X4R show an increase in cognitiveperformances, a decrease in soluble Aβ peptide and an increase of microglia ApoE level.These results support that P2X4R modulates ApoE degradation in a cathepsin B-dependantmanner and that its invalidation leads to an improvement in Alzheimer’s pathology.

Dans les tauopathies, telle la maladie d'Alzheimer, la protéine tau devient anormalement hyperphosphorylée ce qui conduit à son accumulation et à son agrégation intracellulaire. Ce processus aboutit progressivement à une perte neuronale et un déclin cognitif. L'immunothérapie anti-tau est de plus en plus considérée comme un traitement potentiel en vue de bloquer la progression des tauopathies.Récemment, l’entreprise UCB BioPharma a montré que l’anticorps D, anticorps ciblant la protéine tau en un épitope central (aa 235 à 250), était en mesure de bloquer, in vitro, l'agrégation intracellulaire de protéines tau, induite par des PHFs purifiés au départ de cerveaux Alzheimer. L’anticorps A, de même isotype, associé à des propriétés de liaison comparables mais reconnaissant la protéine tau en son extrémité N-terminale (aa 15 à 24), n’est pas en mesure de prévenir l’agrégation dans ce même modèle, ce qui souligne l’importance du choix de l’épitope en vue de neutraliser les amorces pathologiques issues de cerveaux Alzheimer.En vue d’étudier les propriétés de l’anticorps D in vivo, nous avons développé deux modèles murins de tauopathies. Premièrement, un modèle étudiant les phénomènes de recrutement et nucléation, basé sur l'injection unilatérale d’un homogénat de cerveau Alzheimer dans l'hippocampe de jeunes souris transgéniques (Tg30tau). Deuxièmement, un modèle permettant l’étude de la propagation intercellulaire de formes pathologiques de tau, par injection unilatérale de fibrilles P301L-K18 dans l’hippocampe de souris transgéniques (hTauP301L). Les tauopathies induites par ces injections intracérébrales ont été quantifiées dans l'hippocampe ipsi et controlatéral, en présence de traitements immunothérapeutiques utilisant les anticorps anti-tau A et D ou un anticorps témoin négatif de même isotype. La quantification des formes hyperphosphorylées et agrégées de tau a été réalisée par des approches immunohistochimique ou biochimique.Dans le modèle de nucléation, l’anticorps D est en mesure de prévenir significativement l’apparition des formes hyperphosphorylées et agrégées de tau à la fois dans l’hippocampe ipsilatéral (injecté avec l’homogénat Alzheimer) et contralatéral. A l’opposé, l’anticorps A n’est pas en mesure de prévenir l’apparition de la tauopathie dans ce modèle. Dans le modèle de propagation, basé sur l'injection unilatérale hippocampique de fibrilles P301L-K18, le traitement immunothérapeutique utilisant l’anticorps D réduit significativement la propagation d’espèces pathologiques de la protéine tau dans l'hippocampe controlatéral.De par l’utilisation de ces deux modèles murins de tauopathies, nous avons pu confirmer in vivo, la capacité de l’anticorps D à neutraliser les espèces pathologiques contenues dans un homogénat de cerveau Alzheimer et avons démontré sa capacité à s’opposer à la propagation intercellulaire de la tauopathie in vivo. Dans le modèle de nucléation, l’anticorps A n’a pas été en mesure de s’opposer à l’apparition de la tauopathie. Les résultats obtenus confirment ceux décrits par l’entreprise UCB BioPharma dans leur modèle d’agrégation in vitro et confirme l’importance considérable du choix de l’épitope en vue de prévenir efficacement le développement de tauopathies in vivo. / In tauopathies, such as Alzheimer's disease, tau protein becomes abnormally hyperphosphorylated which leads to its accumulation and intracellular aggregation. This process gradually leads to neuronal loss and cognitive decline. Anti-tau immunotherapy is increasingly considered as a potential treatment to block tauopathies’s progression.UCB BioPharma recently showed that antibody D, targeting an epitope in the central region of tau (aa 235-250), is able to block, in vitro, the intracellular seeding of tau proteins induced by PHFs purified from the brain of Alzheimer's patients. The antibody A, same isotype and associated with similar binding properties but recognizing the N-terminal region of tau (aa 15 to 24) is not able to prevent tau seeding in this cell based assay. This observation underlines the importance of the targeted epitope on tau protein in order to neutralize pathological species contained in Alzheimer's brains (Courade et al., 2018).In order to study the properties of antibody D in vivo, we developed two murine models of tauopathies. First, a seeding model based on a unilateral injection of Alzheimer's brain homogenate into the hippocampus of young Tg30tau mice. Secondly, a spreading model to study the propagation of pathological tau seeds, based on unilateral hippocampal injection of P301L-K18 fibrils in hTauP301L transgenic mice. Tauopathies induced in these models were quantified in the ipsi and contralateral hippocampus in the presence of immunotherapeutic treatments with anti-tau antibodies (D, A) or a negative control antibody. Quantification of hyperphosphorylated and aggregated tau was performed by immunohistochemical or biochemical analyses.In the seeding model, antibody D significantly reduces the appearance of hyperphosphorylated and aggregated tau both in the ipsi and contralateral CA1 regions of hippocampus. In contrast, antibody A is not able to prevent the appearance of pathological tau in this model. In the spreading model, immunotherapeutic treatments with antibody D significantly reduces the spread of pathological tau seeds in the contralateral hippocampus.From these two murine models of tauopathies, we confirmed in vivo the ability of antibody D to neutralize the pathological tau species contained in an Alzheimer's brains homogenate and demonstrated its capacity to reduce the intercellular propagation of tauopathies. In the seeding model, antibody A wasn’t able to affect the onset of tauopathy. These results confirm those described by UCB BioPharma based on their in vitro aggregation assay and confirm the importance of the targeted epitope in order to effectively prevent the development of tauopathies in vivo.

El Alzheimer es una epidemia silenciosa que genera mitos y creencias que influyen en el comportamiento y actitud de la sociedad y por ende en la familia, la cual adopta conductas, que afectan a estas personas, estigmatizándolas y generando en ellas poco a poco la pérdida de su identidad o muerte social; en ese sentido, este trabajo se justifica, porque logra conocer y profundizar la construcción social de la imagen del Alzheimer, a partir de la información generada por el censo común, teniendo como objetivos caracterizar, analizar y discutir la representación social del Alzheimer desde la perspectiva de la familia. Los presupuestos teóricos que respaldan la investigación son: Sergio Moscovici (1979) y Jodelet (1984) para los conceptos de representación social, De la Cuesta (2004) y Feria (2005) para los conceptos de Alzheimer, y finalmente Marta Aja Abelán (1998) y Karol Wojtyla (1999) para los conceptos de familia. La metodología utilizada fue cualitativa con enfoque de representación social. Los sujetos de estudio fueron comprendidos por los familiares de los adultos mayores diagnosticados con Alzheimer que están inscritos en la Asociación “Ayudémonos”. Para la recolección de datos se utilizó como instrumentos el cuestionario sociodemográfico y la entrevista semiestructurada. Y para su análisis se utilizó el método asociación de contenido. Las tres categorías que emergieron del tratamiento de datos son: El Alzheimer representado como enfermedad progresiva-crónica, deterioro físico-mental y dependencia; El Alzheimer como etiqueta desaprobatoria, pérdida de identidad, estigma y muerte social y El Alzheimer ancorado como sufrimiento, estrés y necesidad de cuidado. Se tuvo en cuenta los principios éticos personalistas de Elio Sgreccia y los criterios de cientificidad. / Tesis

Ratten, die intrazerebroventricular (icv) mit Streptozotocin (STZ) behandelt werden, eignen sich gut als Tiermodelle für die sporadische Alzheimererkrankung (sAD). In der hier vorgelegten Arbeit wurden Veränderungen bezüglich der Insulinkonzentration sowie einiger Bestandteile der Insulinrezeptor (IR) – Signalkaskade in Rattengehirnen, welche icv mit STZ behandelt wurden, zu verschiedenen Zeitpunkten untersucht. Die Auswirkungen von STZ auf die zerebrale IR-Signalkaskade wurden dann mit denen von chronisch erhöhten Corticosteronkonzentrationen verglichen. In dieser Studie wurde im Hippocampus eine verminderte mRNA-Expression von Insulin, der IR sowie des insulinabbauenden Enzyms (IDE) nachgewiesen; bezüglich der tau-mRNA-Expression konnten jedoch in diesem Gehirnareal der mit STZ behandelten Ratten keine Veränderungen beobachtet werden. Die Resultate der Insulin-, IR- und IDE-mRNA-Expression fielen bei den mit Corticosteron behandelten Ratten ähnlich aus Im Gegensatz hierzu nahm die tau-mRNA-Expression bei Ratten, die mit Corticosterone behandelt wurden, zu, was auch für eine sAD kennzeichnend ist. Sowohl bei den mit STZ als auch bei den mit Corticosteronen behandelten Ratten konnten Verhaltensanomalien beobachtet werden. Die in dieser Arbeit erzielten Resultate deuten darauf hin, dass viele Merkmale einer sAD experimentell durch eine Beeinträchtigung des Insulin/IR-Signalwegs sowie eine chronische Erhöhung der Corticosteronkonzentration hervorgerufen werden können. Dies untermauert wiederum unsere Hypothese, dass es sich bei sAD um eine neuroendokrine Störung handelt, die mit gehirnspezifischen Fehlfunktionen in der Insulin/IR-Signalkaskade einhergeht, welche zum Teil durch erhöhte Corticosteronkonzentrationen ausgelöst werden können. Auf Grund der in dieser Arbeit erzielten Resultate stellt sich die Frage, ob -Amyloid (A) ein Auslöser oder eine Konsequenz einer sAD darstellt. Die hier vorgelegte Arbeit last den Schlus zu, dass bei sAD-Tiermodellen ein Zusammenhang zwischen primären Fehlfunktionen im zerebralen Insulinsystem und dadwol sekundär ausgeloster A-Pathologie besteht. Weiterfübende Untersuchungen wird aber notwendig um diese Aussagen zu bestätigen. / This research was aimed to evaluate the time-course of changes in the brain insulin and some elements of the insulin receptor (IR) signalling cascade in the streptozotocin-intracerebroventricullarly (STZ-icv) treated rats representing experimental model of sporadic Alzheimer’s disease (sAD) and to compare them with effects of chronically increased corticosterone on the brain insulin system. This study shows down-regulation in mRNA expression of insulin, insulin receptor (IR), and insulin degrading enzyme (IDE) but no changes were observed in the expression of tau mRNA in hippocampus of STZ-icv treated rats. Comparing these results to the ones found in corticosterone treated rats similarities at the level of insulin, IR and IDE mRNA expression can be assumed. In contrast tau mRNA expression in corticosterone treated rats were increased, data which are in line with sAD. Behavioural deficits were found in both STZ-icv and corticosterone treated rats. In conclusion, these results demonstrate that many of the characteristic features of sporadic Alzheimer’s disease (sAD) can be produced experimentally by impairing the insulin/IR signaling pathway combined with a chronic increase of corticosterone. This supports our hypothesis that sAD represents a neuro-endocrine disorder associated with brain-specific disregulation in insulin and IR signaling, caused in part by increased level of corticosterone. In line with that our study puts a question on the classical amyloid β (Aβ) hypothesis, supporting the view of brain insulin system dysfunction as a trigger for the Aβ pathology in an experimental sAD model.

Alzheimer's disease (AD) is a worldwide, incurable disease, and the most common form of dementia. Numbers of cases are rising, and since its discovery the only approved medications have treated only the symptoms, not the pathological cause. With the cost to society rising, the debilitating nature of the disease and the pressure put on the family members and support network of patients, disease modifying therapies are in dire need. Current models have proven an invaluable tool with which to study certain aspects of the disease and the genetics behind it, however the lack of clinically approved medications in the last 20 years suggests new models are needed. Based on the amyloid cascade hypothesis, this thesis initially characterises two models of β-Amyloid oligomer (Aβo) induced cognitive deficits. Both models are created by ICV injection of soluble Aβo into the brain of rat. The models differ only by the molecular weight of the Aβo 1-42, one, referred to as low molecular weight (LMW) Aβo, with stable dimers, trimers and tetramers, the other, referred to as high molecular weight (HMW) Aβo, consisting of assemblies ranging from ~50 to ~150 kDa. It was found that behavioural deficits were similar between the two, with a robust object recognition deficit, but no working memory deficit. Both models also showed a deficit in the synaptic marker PSD-95; however the LMW Aβo caused a deficit in the frontal cortex, whereas the HMW Aβo caused a hippocampal deficit. The role of the cellular prion protein (PrPC) was explored, by blocking its binding to Aβo with the antibody 6D11. Interestingly the two models showed different results. The HMW Aβo deficits were completely blocked by the 6D11 application, however the LMW Aβo deficits were only partially prevented. Finally, Fasudil, a vasodilator approved in parts of Asia, was used to inhibit Rho-kinase, showing a prevention of the cognitive deficits in the HMW Aβo model. The results of this thesis show the ICV administration of Aβo to be a useful model for investigating the effects of Aβo, provides a platform with which to study the differing effects of Aβo with different oligomeric assemblies, and a model to test therapeutic strategies with relevance to AD.

Progression of Alzheimer's disease has been associated with the deposition of aggregated amyloid beta (Aβ) protein in the brain. Though first described in post-mortal tissue, the development of Aβ specific tracers for positron emission tomography (PET) permits in-vivo mapping of its distribution in the brain. One of the well-known and early-developed tracers is the Pittsburgh Compound B (PiB) (Klunk et al., 2004). However, the challenge with PiB lies in the stability of the radioisotope 11C. 11C's short half-life of only 20 minutes hinders its transportation and usage at imaging facilities that are not in close proximity with the radioisotopes manufacturer. Recently, an alternative Aβ tracer has been developed, Florbetapir (Wong et al, 2010.), with a half-life of 110 minutes that should allow wider accessibility to imaging sites while improve the detection of Aβ. To define better the specificity and utility of Florbetapir, we propose to utilize existing PET data acquired with the radioactive tracer Florbetapir from the Alzheimer's disease Neuroimaging Initiative (ADNI). Our goal is to characterize the symmetry of Aβ protein deposition in the brain of patients with Alzheimer's disease. While a previous study has investigated this issue using PiB, Florbetapir has not been used. Our project will involve data post-processing by segmenting out non-brain tissues. Segmented data is then normalized by the pixel intensity and a distribution curve is created using MathCad program. In addition, we will calculate the asymmetry score for Regions of Interest. This will permit comparison of the uptakes of tracer between brain hemispheres to be made. Results from our project can provide insight into Florbetapir's binding affinity for Aβ. In addition, Florbetapir's potential as a better alternative to PiB can also be evaluated.

Made available in DSpace on 2019-03-29T23:13:00Z (GMT). No. of bitstreams: 0 Previous issue date: 2008-12-29 / This work presents a hybrid model, combining Influence Diagrams and the Multicriteria Method, for aiding to discover, from a battery of tests, which are the most attractive questions, in relation to the stages of CDR (Clinical Dementia Rating) in decision making for the diagnosis of Alzheimer's disease. Due to the increase in life expectancy there is higher incidence of dementias. Alzheimer's disease is the most common dementia (alone or together with other dementias), accounting for 50% of the cases. Because of this and due to limitations in treatment at late stages of the disease early diagnosis is fundamental because it improves quality of life for patients and their families. Influence Diagram is implemented using GeNie tool. Next, the judgment matrixes are constructed to obtain cardinal value scales which are implemented through MACBETH Multicriteria Methodology. The modeling and evaluation processes were carried out through a battery of standardized assessments for the evaluation of cases with Alzheimer's disease developed by Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Keywords: Alzheimer's Disease, Diagnosis, Multicriteria Method, Bayesian Network, Influence Diagram. / Devido à elevação da expectativa de vida, ocorre como conseqüência, o aumento da prevalência de demências. A doença de Alzheimer, dentre as demências, é a mais freqüente e responde (isoladamente ou em associação) por cerca de 50% dos casos. Por conta deste quadro e das limitações terapêuticas nos estágios mais avançados da doença, o diagnóstico nas fases iniciais torna-se fundamental, pois pode proporcionar melhores condições de vida aos pacientes e seus familiares. Apresenta-se um modelo híbrido, estruturado em Diagramas de Influência e Multicritério, objetivando descobrir, a partir de uma bateria de testes, quais são as questões mais atrativas, em relação aos estágios da CDR (Clinical Dementia Rating), na tomada de decisão do diagnóstico da doença de Alzheimer. O Diagrama de Influência é apresentado aplicando-se a ferramenta GeNie, em seguida são construídas as matrizes de juízos de valor e obtenção das escalas de valor cardinal através da metodologia MACBETH. Os processos de modelagem e avaliação foram realizados através de uma bateria neuropsicológica de avaliação padronizada, desenvolvida pelo CERAD (Consortium to Establish a Registry for Alzheimer's Disease). Palavras-chave: Doença de Alzheimer, Diagnóstico, Multicritério, Redes Bayesianas, Diagramas de Influência.

Muitos trabalhos têm demonstrado a correlação existente entre gênero e prevalência da doença de Alzheimer (DA), sendo que as mulheres compreendem dois terços dos pacientes afetados. A estreptozotocina (STZ) é uma substância que vem sendo muito utilizada, por administração intracerebroventricular, para produzir um modelo de doença de Alzheimer esporádica com características neuroquímicas e fisiopatológicas semelhantes à DA, em roedores. Dessa forma, essa tese teve como objetivo avaliar as alterações comportamentais cognitivas e parâmetros neuroquímicos (ChAT, S100B, GFAP, GSH e captação de glicose) em hipocampo e cerebelo de ratos e ratas expostas ao modelo de doença de Alzheimer por STZ. Para um melhor entendimento das alterações, as avaliações foram realizadas em três diferentes tempos após a indução do modelo: duas, quatro e oito semanas. Como resultado, encontramos declínio cognitivo e alterações neuroquímicas hipocampais e cerebelares. Interessantemente, machos e fêmeas apresentaram distintas respostas frente ao insulto por STZ, mostrando ser este um campo interessante para caracterização e aprofundamento do modelo que utilizamos. Este trabalho confirma o comprometimento cognitivo e as alterações neuroquímicas presentes no modelo e estes se somam às variações funcionais encontradas nos astrócitos. Tais alterações também estão presentes na DA, apontando a interação neuroglial como um importante alvo de estudo na doença e, consequentemente, na busca por alternativas terapêuticas. / Many studies have demonstrated the correlation between gender and prevalence of Alzheimer's disease (AD), with women comprising two thirds of the affected patients. Streptozotocin (STZ) is a substance that has been widely used by intracerebroventricular administration to produce a model of sporadic Alzheimer's disease with neurochemical and pathophysiological characteristics similar to AD, in rodents. Thus, this thesis aimed to evaluate cognitive behavioral changes and neurochemical parameters (ChAT, S100B, GFAP, GSH and glucose uptake) in the hippocampus and cerebellum of rats (males and females) exposed to the model of sporadic Alzheimer's disease by STZ. For the best comprehension of the changes, the evaluations were performed at three different times after the induction of the model: two, four and eight weeks. As a result, we found cognitive decline and hippocampal and cerebellar neurochemical changes. Interestingly, males and females presented different responses to STZ damage, showing that this is an interesting field for characterization and deepening of the model we use. This work confirms the cognitive impairment and the neurochemical changes present in the model and these are added to the functional shifts found in the astrocytes. These alterations are also present in AD, pointing to neuroglial interaction as an important target for the study of the disease and, consequently, the search for therapeutic alternatives.

Made available in DSpace on 2019-04-05T23:01:42Z (GMT). No. of bitstreams: 0 Previous issue date: 2003-04-30 / A doença de Alzheimer (DA) é uma patologia neurodegenerativa progressiva, irreversível que compromete as áreas do cérebro responsáveis pela memória, pensamento e linguagem. A presente dissertação se propõe a discorrer sobre o uso dos escritos autobiográficos na clínica da Terapia Ocupacional com portadores da doença de Alzheimer. Esses escritos podem se constituir mobilizadores de atividades a serem realizados na clínica da Terapia Ocupacional, uma vez que propiciam a valorização do sujeito pelo resgate de sua historicidade e identidade, bem como da memória e da manutenção das funções cognitivas, promovendo assim laços sociais. Daí a relação entre escritos autobiográficos e a D.A. A escrita autobiográfica como gênero da história de vida foi o escolhido, já que permite ao sujeito narrar sua própria vida, realizando uma articulação entre a dimensão do passado às circunstancias do presente e as projeções em relação ao futuro. A pesquisa foi do tipo qualitativa a partir de três casos clínicos, cujos atendimentos em Terapia Ocupacional a escrita autobiográfica ocupou um lugar de destaque. Foram realizados relatos dos casos clínicos, investigação dos escritos em termos de forma e conteúdo e repercussão no portador da Doença de Alzheimer. Os dados para a análise dos escritos autobiográficos foram classificados nas seguintes categorias temáticas: identificação de si e descrição de si; relações familiares; figura do pai e da mãe; irmãos; marido e mulher; filhos; histórico escolar; histórico profissional e memória coletiva. Ressaltamos os resultados referentes aos escritos autobiográficos como um espaço de atribuição de sentido às vivencias do paciente, como promotor do resgate da memória e identidade do paciente, como forma de redimensionar sua posição frente à doença e reconfiguração dos elos familiares, e , o mais importante, a partir dos escritos autobiográficos houve a produção de novos escritos como textos, contos, cartas que organizam, constróem e expressam a vida cotidiana.