Memoria para optar al Título de Bioquímico / La enfermedad de Alzheimer (EA) es una patología neurodegenerativa progresiva caracterizada principalmente por agregados proteicos intracelulares (ovillos neurofibrilares) y extracelulares (placas seniles o amiloides). Estos últimos están formados por un péptido de 39 a 43 aminoácidos, conocido como péptido ß amiloide (Aß), el que se genera por proteólisis de la Proteína Precursora del Amiloide (APP). Existen dos formas principales del péptido Aß, una de 40 aminoácidos presente en personas sanas, y otra de 42 aminoácidos, constituyente principal de las placas observadas en pacientes de EA. Estas placas se forman a partir de la agregación de monómeros (M) que forman oligómeros solubles (O), los que formarían posteriormente protofibrillas y finalmente las fibras insolubles. La falta de correlación entre el grado de demencia y la cantidad de placas ha sugerido que los oligómeros solubles podrían ser los responsables de los síntomas iniciales. Si bien no están claros los blancos específicos del péptido Aß, uno de los principales candidatos son las sinapsis excitatorias que responden a glutamato. Estas sinapsis poseen una especialización de membrana conocida como densidad postsináptica (DPS), estructura que contiene a los receptores para neurotransmisores y proteínas asociadas a la regulación de la función sináptica, agrupadas por proteínas de andamio. Dentro de los receptores para glutamato, el R-NMDA es de gran importancia en procesos de memoria y aprendizaje, y su actividad puede ser modulada por el receptor para neurotrofinas p75NTR. Este receptor también está contenido en la DPS, y participa tanto en sobrevida como en apoptosis neuronal. Además, posee la capacidad de unirse a ligandos estructuralmente no relacionados, entre los que se encuentra el péptido Aß, postulándose como potencial blanco molecular del péptido. Nuestra hipótesis es que El péptido Aß en concentraciones nanomolares es capaz de inhibir la actividad del R-NMDA en la DPS por interacción con el receptor p75NTR. Para este trabajo, se obtuvieron DPS de corteza de rata adulta, las cuales fueron microinyectadas en ovocitos de Xenopus laevis. Estos ovocitos son sometidos a estudios de fijación de potencial con 2 electrodos (voltage clamp), y se midieron las respuestas obtenidas con el agonista NMDA en presencia de distintas concentraciones del péptido Aß1-40(M) y Aß1-42(M) y (O). En el caso del péptido Aß1-42(M), se observa una inhibición a todas las concentraciones utilizadas, sin ser dependiente de la dosis. Por otro lado, los péptidos Aß1-40(M) y Aß1-42(O) poseen efectos duales sobre las corrientes de NMDA: a bajas concentraciones producen un efecto inhibitorio y a altas concentraciones un efecto potenciador. En el caso del péptido Aß1-40(M), la inhibición se logra usando una concentración de 50 nM, mientras que en el caso del Aß1-42(O) se logra con una concentración de 5 nM. En ambos casos la potenciación ocurre al usar una concentración de 1 uM. Adicionalmente, el efecto Aß1-42(O) está mediado por el receptor p75NTR, ya que el uso de un anticuerpo que produce pérdida de función del receptor es capaz de revertir tanto el efecto inhibidor como potenciador del péptido. Estos datos permiten confirmar que existe participación del receptor p75NTR en los efectos sinápticos causados por el péptido, especialmente sobre la actividad del RNMDA, apuntando al rol fisiológico del péptido y su relación con la patología de la EA. / Alzheimer’s disease (AD) is a neurodegenerative progressive pathology characterized mainly by protein intracellular (neurofibrillary tangles) and extracellular (Amyloid plaques) aggregates. The latter are formed by 39-43 aminoacids peptide, known as amyloid ß(Aß), generated by proteolysis of Amyloid Precursor Protein (APP). There are two principal forms, one of 40 aminoacids, present in healthy people, and other of 42 aminoacids, main constituent of plaques seen in AD patients. These plaques are formed by aggregation of monomers (M), which form oligomers (O), then protofibrils and finally insoluble fiber. The lack of correlation between grade of dementia and number of plaques has suggested that soluble oligomers could be the responsible of initial symptoms. Although there is no clarity about specific targets of Aß peptide, one of the most named are excitatory synapses activated by glutamate. These synapses have a membrane specialization known as postsynaptic density (PSD), structure that contains the neurotransmitter receptors and proteins associated with regulation of synaptic function, grouped by scaffolding proteins. Between glutamate receptors, NMDA-R has great importance in memory and learning process, and his activity can be modulated by the neurotrophin receptor p75NTR. This receptor is also present in PSD and participates in both survival and neuronal apoptosis. In addition, it has the ability to bind ligands structurally unrelated, including Aß peptide, postulating the p75NTR as a potential molecular target of the peptide. Our hypothesis is that Aß peptide in nanomolar concentration is able to inhibit R-NMDA activity in PSD by interacting with p75NTR. For this work, we obtained PSD from adult rat cortex, which were microinjected into Xenopus laevis oocytes. These oocytes were subjected to 2-electrodes voltage clamp, and responses to agonist NMDA were acquired in presence of different concentrations of Aß1-40(M) and Aß1-42(M) and (O). In the case of Aß1-42(M), inhibition was non dose-dependent. On the other hand, Aß1-40(M) and Aß1-42(O) have dual effect on NMDA-R currents: at low concentrations the peptides have an inhibitory effect and at high concentrations a potentiation effect. In the case of Aß1-40(M), inhibition is obtained using a concentration of 50 nM, whereas for the Aß1-42(O) is obtained with a concentration of 5 nM. In both cases, potentiation occurs when a concentration of 1 uM is used. Additionally, the effect of Aß1-42(O) is p75NTR-mediated, because the use of loss-of-function antibody reversed both inhibition and potentiation effect. These data allow us to confirm that there is participation of p75NTR in synaptic effects caused by Aß peptide, specially on NMDA-R activity, pointing to the physiological function of the peptide and its relationship with AD pathology.

Dissertação (mestrado) - Universidade Federal de Santa Catarina, Centro de Ciências Biológicas. Programa de Pós-Graduação em Farmacologia, Florianópolis, 2016 / Made available in DSpace on 2016-09-20T04:24:08Z (GMT). No. of bitstreams: 1 340468.pdf: 3410319 bytes, checksum: 41ab0f54ad8814a84b7fb10ab3dcc4d1 (MD5) Previous issue date: 2016 / Diversas evidências indicam que há um comprometimento da sinalização do neuropeptídeo Y (NPY) no sistema nervoso central (SNC) tanto no envelhecimento quanto na doença de Alzheimer (DA), e que este possa representar um novo alvo terapêutico para o alívio de diversos sintomas associados a estas condições. Nesse trabalho foi avaliado o efeito da administração central do NPY sobre prejuízos cognitivos associados ao envelhecimento em camundongos C57BL/6 com 2 e 11 meses de idade. Também foi avaliado o efeito do pré-tratamento com NPY ou com o agonista seletivo do receptor Y2 (NPY(13-36)) sobre os prejuízos comportamentais induzidos por oligômeros de ß-amilóide (AßO) em camundongos suíços adultos, um modelo animal da DA. Ademais, foram avaliados os efeitos do NPY e do NPY(13-36) sobre a produção de espécies reativas de oxigênio (ROS) induzida por AßO em cultura neuronal hipocampal de ratos Wistar. Uma única injeção intracerebroventricular (i.c.v.) de NPY (23,4 pmol) foi capaz de reverter o prejuízo de memória espacial associado ao envelhecimento em camundongos C57BL/6 com 11 meses de idade avaliados no teste de localização de objetos. Entretanto, a administração i.c.v. da mesma dose de NPY prejudicou o desempenho de camundongos com 2 meses de idade no mesmo teste. A injeção i.c.v. de AßO (10 pmol) em camundongos suíços induziu prejuízos em memórias de reconhecimento e espacial de curto prazo, evidenciados pelos testes de reconhecimento e localização de objetos, respectivamente, sendo que o pré-tratamento com NPY (23,4 pmol, i.c.v.) foi capaz de prevenir estes prejuízos induzidos pelos AßO. A ativação dos receptores Y2 pelo agonista NPY(13-36) (23,4 pmol, i.c.v.) foi capaz de prevenir os prejuízos na memória espacial de curto prazo nos camundongos, além de prevenir a geração de ROS induzidas por AßO (0,5 µM) in vitro. Nenhum dos compostos avaliados (NPY, NPY(13-36) e AßO) alterou significativamente os parâmetros comportamentais relacionados à emocionalidade avaliados nos testes do splash e nado forçado. Por fim, a administração do NPY prejudicou a discriminação olfatória de camundongos suíços. Os resultados desse trabalho em conjunto com a literatura suportam a hipótese de que a restauração dos níveis de NPY e o uso de agonistas dos receptores Y2 representam estratégias com potencial para o controle dos prejuízos cognitivos associados ao envelhecimento e observados em fases iniciais da DA. <br> / Abstract : Several evidences indicate that the neuropeptide Y (NPY) signaling is compromised in the central nervous system during ageing and Alzheimer s disease (AD), and that this may represent a new therapy target for the relief of symptoms associated with these conditions. At the present work, the effect of central administration of NPY over the cognitive deficits associated to ageing was evaluated in C57BL/6 mice at 2 and 11 months of age. It was also evaluated the effect of pre-treatment with NPY or the Y2 receptor selective agonist NPY(13-36) over the behavioral deficits due to amyloid-ß oligomers (AßO) administration in adult Swiss mice, an animal model of AD. Moreover, the effects of NPY or NPY(13-36) over the reactive oxygen species production (ROS) induced by AßO were evaluated in a Wistar rat neuronal hippocampi cell culture. A solely NPY (23,4 pmol) intracerebroventricular (i.c.v.) injection was enough to revert the spatial memory deficit associated with ageing evaluated by the object location test in C57BL/6 mice at 11 months of age. However, the same dose of NPY impaired the performance of mice at 2 months of age at the same test. An i.c.v. injection of AßO (10 pmol) induced recognition and spatial shot-term memory deficits highlighted by the object recognition and location tests, respectively, in Swiss mice, and the pre-treatment with NPY (23,4 pmol, i.c.v.) was able to prevent those deficits induced by AßO. The Y2 receptor activation by its agonist NPY(13-36) (23,4 pmol, i.c.v.) was enough to prevent these spatial short-term memory deficits in mice in addition to prevent the ROS generation induced by AßO (0,5 µM) in vitro. None of the compounds evaluated (NPY, NPY(13-36) and AßO) significantly altered the behavioral parameters related to emotionality evaluated in the splash and forced swim tests. At last, NPY administration damaged the olfactory discrimination in Swiss mice. The results found at the present work together with the literature support the hypothesis that NPY levels restoration and the use of Y2 receptor agonists are potential strategies for the management of age-associated cognitive deficits as well as those present in initial stages of AD.

Tesis presentada a la Universidad de Chile para optar al grado de Doctor en Farmacología / No autorizada por el autor para ser publicada a texto completo en el Portal de Tesis Electrónicas / La polimerización y agregación del péptido Aβ1-42 son procesos poco dilucidados hasta el momento, sin embargo, están fuertemente relacionados al desarrollo de la Enfermedad de Alzheimer, trastorno neurodegenerativo, causante principal de demencia senil para el cual no existe cura o prevención efectiva hasta nuestros días. Una de las estrategias estudiadas con el fin de prevenir y buscar la cura de esta enfermedad es la de buscar compuestos que inhiban la agregación de Aβ1-42 y consecuentemente la formación de especies tóxicas que causan la muerte neuronal y el desarrollo de la enfermedad. En esta tesis se evaluó la acción inhibidora de la agregación de una serie de 6 derivados dihidropiridínicos (fenil-DHP, 3-OH-DHP, 4-OH-DHP, 3,4-OH-DHP, 3,5-OH- DHP y 3,4,5-OH-DHP) que difieren en el número y posición de hidroxilos en la molécula que por semejanzas estructurales con otros compuestos encontrados en la literatura se constituyeron en buenos candidatos para este fin. Estos compuestos poseen además las propiedades de ser inhibidores de la generación de radicales libres, inhibidores de canales de calcio y posibles antihipertensivos, constituyéndose en compuestos aún más atractivos, ya que el estrés oxidativo, el desbalance en la homeostasis de calcio y la hipertensión, son también factores desencadenantes de la EA. Mediante las técnicas de Fluorescencia por Interacción con tioflavina-T, Electroforesis en Geles y TEM, los resultados demostraron que los compuestos con uno o ningún grupo hidroxilo (fenil-DHP, 3-OH-DHP y 4-OH-DHP) no son inhibidores de la agregación de Aβ1-42. Sin embargo, los compuestos , 3,4-OH-DHP, 3,5-OH-DHP y 3,4,5-OH-DHP son inhibidores de la agregación siendo 3,4-OH-DHP el compuesto más eficaz con una inhibición máxima de 88±5% y una IC50 de 5.6±0.1µM siendo significativamente más potente que el resveratrol (IC50=9.8±1.3 µM), compuesto polifenólico usado como control en esta tesis. Los efectos sobre la toxicidad celular inducida por fibras amiloides fueron evaluados, para los compuestos activos, en cultivo primario de hipocampo de ratas E18; observándose que una inhibición en la agregación de Aβ1-42 está relacionada con una inhibición de la muerte celular inducida por fibras amiloides. Por otra parte, en esta tesis se desarrolló un nuevo método electroquímico que permite evaluar el proceso de agregación y desagregación de Aβ1-42 con el fin de complementar, con nueva información, la metodología existente, ya que los métodos convencionales poseen diversas limitaciones y no pueden ser constituidos como un único método válido. Se generaron electrodos de carbón vítreo modificados con nanotubos de carbono y fue posible seguir el proceso de agregación mediante la señal de oxidación del residuo de Tyr en estadios tempranos cuando oligómeros pequeños son formados, revelando información conformacional del extremo N-terminal de la molécula. Además, este nuevo método fue útil para evaluar la desagregación del péptido LPFFD-NH2, conocido desagregante. / Polymerization and aggregation of the Aβ1-42 peptide are not complete elucidated processes until now, however, they are strongly related to the development of Alzheimer's disease, a neurodegenerative disorder, the primary cause of dementia for which no cure or effective prevention exist so far. One of the strategies studied in order to prevent and to find a cure for this disease is to find compounds that inhibit the aggregation of Aβ1-42 and consequently the formation of toxic species that cause neuronal death and disease development. In this thesis, the aggregation inhibitory activity of a series of 6 dihydropyridine derivatives (phenyl-DHP, 3-OH-DHP, 4-OH-DHP, 3,4-OH-DHP, 3,5-OH-DHP and 3,4,5- OH-DHP) was evaluated. These compounds differ to each other in the number and position of hydroxyl groups in the molecule and since they have structural similarities with other compounds found in the literature they are constituted in good candidates for this purpose. These compounds also have other characteristics like inhibitors of free radical generation, calcium channel blockers and potential antihypertensive activity that make them more attractive since oxidative stress, the imbalance in calcium homeostasis and hypertension, are also triggers factors of Alzheimer's disease. By mean of Thioflavin-T Fluorescence Assay, Gel Electrophoresis and TEM the results demonstrated that the compounds with one or no hydroxyl group (phenyl-DHP, 3-OH-DHP and 4-OH-DHP) are not inhibitors of Aβ1-42 aggregation. However, the compounds, 3,4-OH-DHP, 3,5-OH-DHP and 3,4,5-OH-DHP are inhibitors of the aggregation being 3.4-OH-DHP the inhibitor compound with the highest maximum inhibition of 88 ± 5% and an IC50 of 5.6 ± 0.1μM being significantly more potent than resveratrol (IC50 = 9.8 ± 1.3 µM), a polyphenolic compound used as a control in this thesis. The effects on cellular toxicity induced by amyloid fibrils were evaluated for these compounds in primary cultures of E18 rat hippocampus. It was observed that the inhibition on the aggregation of Aβ1-42 is related to the inhibition of cell death induced by amyloid fibers. On the other hand, in this thesis was developed a new electrochemical method to assess the process of aggregation and disaggregation of Aβ1-42 in order to supplement, with new information, the existing methodology, since conventional methods have several limitations and cannot be constituted as a single valid method. Glassy carbon electrodes modified with carbon nanotube were generated and it was possible to follow up the aggregation process by mean of the oxidation signal of Tyr residue in the early stages when small oligomers are formed, revealing conformational information of the N-terminal part of the molecule. In addition, this new methodology was useful for assessing the disaggregation activity of LPFFD-NH2 peptide, a known disaggregating compound. / Fondecyt

Informe de Seminario para optar al grado de Licenciado en Lengua y Literatura Hispánica mención Lingüística

Indiana University-Purdue University Indianapolis (IUPUI) / Large-scale genome-wide association studies for Alzheimer’s disease (AD) have identified more than 20 risk loci and several pathways including lipid metabolism. Lipids are fundamental to cellular structure and organization, where they compose biological bilayer membranes surrounding the cell. In their structural role, lipids provide a scaffold for cell signaling, such as neurotransmission. There is a large body of evidence linking lipids and AD, yet the relationship between AD pathogenesis and lipid dyshomeostasis is not well understood. Here, we performed manual PubMed searches to identify the most studied lipid classes and risk genes in AD. We discussed pathological alterations of the key lipids and their potential contribution to the recent NIA-AA “A/T/N” framework. We also summarized what is known between the key lipids and etiological hypotheses of AD. Finally, we characterized relationship of the key lipids with AD genomic risk factors to identify possible downstream mechanisms of lipid dysfunction in AD. There is a large body of evidence linking lipids and AD, yet the relationship between AD pathogenesis and lipid dyshomeostasis is not well understood. In particular, we investigated the association between triglyceride (TG) species and AD. The overall goal was to test the hypothesis that TGs would associate with AD endophenotypes, based on their fatty acid composition. Diagnostic groups (cognitively normal older adults (CN), mild cognitive impairment (MCI), and AD) differed on two principal components extracted from 84 serum TG levels. Fish oil-type and olive oil-type TGs were significantly lower in MCI and AD compared to CN. Next, association analysis of TG principal components with “A/T/N/V” (amyloid-β, tau, neurodegeneration, and cerebrovascular) biomarkers for AD showed that the fish oil-type and olive oil-type TGs were also significantly associated with atrophy on MRI. Finally, a mixed model regression analysis investigated the association between baseline TGs and longitudinal changes of AD endophenotypes to show that olive oil-type TGs predicted changes in AD brain atrophy. Our results indicate that a specific subcategory of TGs is associated with an early prodromal stage of cognitive impairment and early-stage biomarkers for AD, providing the foundation for future therapeutic development related to TG metabolism. / 2023-05-05

No description available.

by Lan Chen. / "June 1999." / Thesis (Ph.D.)--Chinese University of Hong Kong, 1999. / Includes bibliographical references. / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web. / Abstracts in English and Chinese.

by Tam Shuk Yin, Jeanny. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1999. / Includes bibliographical references (leaves 26-29). / Abstract and appendix in English and Chinese. / ABSTRACT --- p.ii / ACKNOWLEDGEMENTS --- p.iii / TABLE OF CONTENTS --- p.iv / LIST OF TABLES --- p.v / LIST OF FIGURES --- p.vi / Chapter CHAPTER I - --- INTRODUCTION --- p.1 / Chapter CHAPTER II - --- METHOD --- p.5 / Chapter CHAPTER III - --- RESULTS --- p.12 / Chapter CHAPTER IV - --- DISCUSSION --- p.22 / REFERENCES --- p.26 / APPENDICES --- p.30

by Ma Suk Ling. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2003. / Includes bibliographical references (leaves 106-129). / Abstracts in English and Chinese. / Abstract --- p.i / 摘要 --- p.iii / Acknowledgements --- p.v / Publications --- p.vi / Abbreviations --- p.vii / Chapter Chapter 1 --- General Introduction --- p.1 / Chapter 1.1 --- Epidemiology of AD --- p.2 / Chapter 1.2 --- Clinical and pathological features of AD --- p.3 / Chapter 1.2.1 --- Clinical features of AD --- p.3 / Chapter 1.2.2. --- Pathological features of AD --- p.3 / Chapter 1.3 --- Diagnosis of AD --- p.4 / Chapter 1.4 --- Classification of AD --- p.5 / Chapter 1.5 --- Causes of AD --- p.5 / Chapter 1.6 --- Risk factors --- p.5 / Chapter 1.6.1 --- Age --- p.5 / Chapter 1.6.2 --- Family history --- p.6 / Chapter 1.6.3 --- Genetics --- p.6 / Chapter 1.6.3.1 --- Autosomal dominant mutations --- p.6 / Chapter 1.6.3.2 --- Genotypes of Apolipoprotein E --- p.6 / Chapter 1.6.4 --- Environmental factors --- p.7 / Chapter Chapter 2 --- Pathology in Alzheimer's disease --- p.8 / Chapter 2.1 --- Overview of Alzheimer's disease pathology --- p.8 / Chapter 2.2 --- Amyloid plaques --- p.8 / Chapter 2.2.1 --- Amyloid precursor protein --- p.8 / Chapter 2.2.2 --- Processing ofAPP --- p.9 / Chapter 2.2.3 --- Amyloid β (Aβ) --- p.12 / Chapter 2.2.4 --- APP mutations and AD --- p.12 / Chapter 2.3 --- Neurofibrillary tangles (NFT) --- p.15 / Chapter 2.3.1 --- Tau --- p.15 / Chapter 2.3.2 --- Tau mutation and neurodegeneration --- p.17 / Chapter 2.4 --- Hypotheses for AD pathology --- p.18 / Chapter 2.4.1 --- Amyloid cascade hypothesis --- p.18 / Chapter 2.4.2 --- Inflammatory hypothesis --- p.20 / Chapter 2.4.2.1 --- Microglia and astrocytes --- p.21 / Chapter 2.4.2.2 --- Inflammatory cytokines --- p.23 / Chapter 2.4.2.3 --- Inflammation and AD --- p.25 / Chapter 2.4.3 --- ApoE hypothesis --- p.27 / Chapter 2.4.3.1 --- Apolipoprotein E --- p.27 / Chapter 2.4.3.2 --- ApoE and AD --- p.28 / Chapter 2.5 --- Theory towards the pathology of AD --- p.30 / Chapter Chapter 3 --- ApoE genotyping --- p.32 / Chapter 3.1 --- Introduction --- p.32 / Chapter 3.2 --- Materials and methods --- p.32 / Chapter 3.2.1 --- Patients and control subjects --- p.32 / Chapter 3.2.2 --- Blood sampling --- p.33 / Chapter 3.2.3 --- DNA genotyping --- p.34 / Chapter 3.2.4 --- Statistical analysis --- p.35 / Chapter 3.3 --- Results --- p.35 / Chapter 3.. --- Discussion --- p.38 / Chapter Chapter 4 --- IL-1β polymorphism in relation to the risk of ADin Chinese --- p.39 / Chapter 4.1 --- Introduction --- p.39 / Chapter 4.2 --- Materials and methods --- p.44 / Chapter 4.2.1 --- Patients and control subjects --- p.44 / Chapter 4.2.2 --- Blood sampling --- p.44 / Chapter 4.2.3 --- DNA genotyping --- p.44 / Chapter 4.2.4 --- Statistical analysis --- p.48 / Chapter 4.3 --- Results --- p.48 / Chapter 4.4 --- Discussion --- p.53 / Chapter Chapter 5 --- TNFα polymorphism in relation to the risk of ADin Chinese --- p.63 / Chapter 5.1 --- Introduction --- p.63 / Chapter 5.2 --- Materials and methods --- p.66 / Chapter 5.2.1 --- Patients and control subjects --- p.66 / Chapter 5.2.2 --- Blood sampling --- p.66 / Chapter 5.2.3 --- DNA genotyping --- p.66 / Chapter 5.2.4 --- Haplotype determination --- p.70 / Chapter 5.2.5 --- Statistical analysis --- p.70 / Chapter 5.3 --- Results --- p.70 / Chapter 5.4 --- Discussion --- p.75 / Chapter Chapter 6 --- LRP8 polymorphism in relation to the risk of ADin Chinese --- p.81 / Chapter 6.1 --- Introduction --- p.81 / Chapter 6.2 --- Materials and methods --- p.87 / Chapter 6.2.1 --- Patients and control subjects --- p.87 / Chapter 6.2.2 --- Blood sampling --- p.87 / Chapter 6.2.3 --- DNA genotyping --- p.87 / Chapter 6.2.4 --- Statistical analysis --- p.89 / Chapter 6.3 --- Results --- p.91 / Chapter 6.4 --- Discussion --- p.98 / Chapter Chapter 7 --- Conclusions and prospects for future work --- p.102 / Chapter 7.1 --- Conclusion --- p.102 / Chapter 7.2 --- Prospects for future work --- p.105 / Reference --- p.106

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