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

A terapia de quelação tem sido descrita na literatura como uma ferramenta importante no combate de processos neurodegenerativos como a doença de Alzheimer (AD). Esta doença é caracterizada pela agregação de peptídeos β-amiloides, formando fibrilas, que parece ser induzida ou facilitada em presença de íons metálicos como Cu2+, Zn2+ ou Fe3+. Vários compostos já foram testados e descritos como ligantes competitivos para coordenar e retirar estes íons dos agregados proteicos em condições patológicas, na chamada hipótese da cascata amiloide. O presente projeto visou investigar a reatividade de ligantes imínicos, derivados de oxindóis, na quelação de cobre(II) e zinco(II), numa tentativa de inibir ou evitar a formação de agregados relacionados à AD. Foram sintetizados seis compostos imínicos, sendo duas hidrazonas inéditas: isahim e isahpy e quatro bases de Schiff: isapn, misapn, isaen e misaen, as três últimas também inéditas. Os compostos foram caracterizados por espectroscopia FTIR, RMN, UV/VIS e por análise elementar CHN e espectrometria de massas ESI-MS/MS. Os valores das constantes de estabilidade (log β 2,7 - 5,1) para a formação dos complexos [ML]2+ e do aduto [(Aβ1-16)2•isahim] em solução aquosa foram determinadas por espectroscopia UV/VIS. As formas de interação dos compostos isapn, misapn e isahim com o peptídeo Aβ1-16 foram analisadas por espectroscopia 1H RMN, observando-se uma forte interação com as histidinas His6, His13 e His14 e com os carboxilatos do peptídeo. A eficácia dos ligantes foi testada frente ao processo de inibição da agregação do peptídeo Aβ1-40 na presença e ausência de íons Cu2+ ou Zn2+ por turbidimetria. Estudos de docking e dinâmica molecular suportam que a interação dos ligantes imínicos com o peptídeo Aβ1-16 ocorre nos mesmos sítios de coordenação dos íons metálicos. Os resultados indicam que os compostos aqui estudados podem atuar como eficientes inibidores de agregação dos peptídeos amiloides implicados na AD. / Chelation therapy has been considered in the literature an important tool in neurodegenerative processes like Alzheimer disease (AD). This disease is characterized by aggregation of β-amyloid peptides that seems to be improved in the presence of metal ions, particularly copper, zinc and iron. Several compounds have been tested and reported as competitive ligands to withdrawal these metal ions from protein aggregates in pathologic conditions, in the \"amyloid cascade hypothesis\". The present project aims to investigate the reactivity of imine ligands, particularly those derived from oxindoles, in the chelation of copper(II) and zinc(II) ions trying to inhibit or avoid aggregate formation related to AD. Six iminic compounds were synthesized, being two of them hydrazones: isahim and isahpy and four Schiff bases: isapn, misapn, isaen, and misaen. The compounds were characterized by spectroscopic analysis (FTIR, NMR, UV/VIS), elemental analysis CHN and mass spectrometry ESI-MS/MS. The corresponding stability constants (log β 2,7-5,1) for each complex formation [ML]2+ as well as for the adduct [(Aβ1-16)2•isahim] in aqueous solution were determined by UV/VIS spectroscopy. Interactions of compounds isapn, misapn and isahim with the Aβ1-16 peptide were detected and analyzed by 1H NMR spectroscopy, indicating a strong interaction among the compounds and the histidines His6, His13 e His14 as well as the carboxylate residues in the peptides. The ligands efficiency toward the inhibition aggregation process for the Aβ1-40 peptide were evaluated in the presence, and in absence of Cu2+ or Zn2+ ions by turbidimetry. Computational calculations (docking and molecular dynamics) indicated that the interaction of the imine ligand with the Aβ1-16 peptide occurs in the metal coordination sites. The results indicate that these imine compounds studied may act as efficient inhibitors of amyloid peptides implicated in AD.

INTRODUÇÃO: A apatia constitui o transtorno neuropsiquiátrico mais prevalente na doença de Alzheimer (DA) e se relaciona com uma série de desfechos deletérios. Sua neurobiologia ainda é pouco compreendida, e alguns autores postulam sua associação com disfunção de circuitos fronto-estriatais. A maior parte da evidência disponível sobre essa relação provém de estudos em que foram avaliados pacientes com DA leve a moderada. OBJETIVO: Investigar a associação entre apatia e disfunção executiva em estágios bastante iniciais do processo de declínio cognitivo no contexto da DA. MÉTODOS: Foram avaliados 87 indivíduos, sendo 28 deles com DA leve, 26 com Comprometimento Cognitivo Leve de subtipo amnéstico (CCLa) e 33 controles. Os participantes foram submetidos a uma bateria de avaliações da qual constavam a Bateria Breve de Rastreio Cognitivo (BBRC-Edu), o Mini-Exame do Estado Mental (MEEM), a Entrevisa Executiva (EXIT-25), a Bateria de Avaliação Frontal (BAF), a Escala de Avaliação de Demência (DRS), o Teste de Aprendizagem Auditivo Verbal de Rey (RAVLT), a Escala de Avaliação de Incapacidade na Demência (DAD) e a Escala de Apatia (EA). Explorou-se correlações entre o desempenho nos testes empregados e os escores aferidos pela EA, nos grupos com comprometimento cognitivo (DA ou CCLa), e em grupos constituídos a partir da combinação deles, considerando os pacientes com CCLa conversores à DA no seguimento. RESULTADOS: O grupo de pacientes com DA apresentava média de idade de 81,9 ± 4,8 anos e escolaridade média de 2,5 ± 2,0 anos. O grupo com CCLa apresentava média de idade de 80,8 ± 3,7 anos e escolaridade média de 3,7 ± 2,8 anos. O grupo dos controles apresentava média de idade de 79,5 ± 3,5 anos e escolaridade média de 3,7 ± 3,3 anos. Os três grupos não se distinguiam significativamente quanto às suas características sociodemográficas. Não foram observadas correlações entre o desempenho em quaisquer dos testes de função executiva empregados e os escores obtidos por meio da EA. Observou-se correlação forte entre o desempenho funcional auferido através da DAD e os escores na EA (rho= -0,7; p<0,001) no grupo DA. Documentou-se correlação moderada entre a sintomatologia apática e o desempenho na subescala Atenção da DRS (rho= -0,59; p<0,01) e em tarefas de evocação tardia nos testes de memória episódica da BBRC (rho=-0,37; p<0,05) e do RAVLT (rho= -0,47; p< 0,001), quando analisados em conjunto os pacientes com DA e aqueles com CCLa que converteram para DA. CONCLUSÃO: Nesta amostra de indivíduos com baixa escolaridade, composta por pacientes com DA leve e CCLa, não se observou associação entre o desempenho em testes de função executiva e a sintomatologia apática medida pela EA / INTRODUCTION: Apathy is the most prevalent neuropsychiatric disorder in Alzheimer disease (AD), and has been related to several deleterious outcomes. Its neurobiology is still poorly understood, and some studies have suggested an association with frontostriatal circuits dysfunction. Most of this evidence comes from studies with mild to moderate AD patients. OBJECTIVE: To investigate the association between apathy and executive dysfunction in the very early stages of cognitive impairment in the context of AD. METHODS: 87 subjects were evaluated, being 28 with mild AD, 26 with amnestic Mild Cognitive Impairment (aMCI) and 33 controls. The participants were submitted to a comprehensively evaluation consisting on the Brief Cognitive Screening Battery (BCSC), the Mini-Mental State Examination (MMSE), the Executive Interview (EXIT-25), the Frontal Assessment Battery (FAB), the Mattis Dementia Rating Scale (DRS), the Rey Auditory Verbal Learning Test (RAVLT), the Disability Assessment in Dementia (DAD), and the Apathy Scale (AS). Correlations were investigated between AS scores and the performance in the cognitive measures within the two cognitively impaired groups (AD or aMCI) and also within combinations of them, considering aMCI convertion to AD. RESULTS: The AD group had mean age of 81.9 ± 4.8 years, and 2.5 ± 2.0 mean years of formal education, while the aMCI group had mean age of 80.8 ± 3.7 years and a mean of 3.7 ± 2.8 years of schooling. Controls were aged 79.5 ± 3.5 years, with 3.7 ± 3.3 years of education. The three groups did not differ statistically from each other regarding the main sociodemographic features. There was no correlation between any executive measure and AS scores. We found strong correlations between AS scores and functional performance evaluated with the DAD (rho= -0.70; p <0.001) in the AD group. There were also modest to moderate correlations between AS scores and DRS Attention subscale (rho= -0.59; p<0.01), and with delayed recall tasks of episodic memory tests from the BCSB (rho=-0.37; p<0.05) and the RAVLT (rho= -0.47 ; p< 0.05), when AD and aMCI converters were analysed toghether as a group. CONCLUSION: In this sample consisting of mild AD and aMCI subjects, with very low educational level, we failed to find any association between executive function tests performance and apathy symptoms measured with the AS

<p>Studien utforskade de närståendes livsvärld när partnern drabbats av Alzheimers sjukdom. Deras livsvärld och existentiella villkor var i fokus. Studien utgick från ett existentiellt fenomenologiskt tolkande perspektiv. Den teoretiska grunden bestod av ett tänkande kring de närståendes livsvärld utifrån fyra existentialer: det levda rummet, den levda tiden, den levda kroppen och den levda relationen. Datainsamling skedde utifrån Max van Manens utforskande intervjuer med tio närstående, fem kvinnor och fem män i yrkesverksam ålder 40 till 64 år, de levde alla tillsammans med en partner som fått sin diagnos för ett år sedan eller längre. Data analyserades genom att lyssna igenom de digitala inspelningarna flera gånger, transkribering av desamma och genomläsning av de utskrivna texterna, nya genomlyssningar och genomläsningar. Analysen utvecklades genom en hermeneutisk, fenomenologisk reflektion beskriven av van Manen. Studiens resultat kategoriserades och dessa analyserades sedan i fyra delar utifrån de fyra existentialerna. Resultatet visade att upplevelsen av den levda tiden blev annorlunda mot tidigare då framtiden fick stå tillbaka för nuet, som var det som de närstående måste förhålla sig till för att vardagen skulle fungera. Det levda rummets aspekter förändrades utifrån skyddsaspekten och nya roller inom familjen. Den levda kroppen krävde egen återhämtning och längtade efter närhet. Den levda relationen förändrades, när upplevelsen av närhet och behovet av distans ändrades. De existentiella villkoren förändrades radikalt och nya strategier gav en ny livsstil i en förändrad och sammanflätad livsvärld.</p> / <p>The study explored the lifeworld of being a partner to a person with Alzheimer’s disease. Lived experience and existential conditions were focused. The study has an existential phenomenological hermeneutic perspective. The theoretical underpinnings consist of thinking of lifeworld by means of four life existentials: lived space, lived body, lived time and lived relations. Data collection was done by Max van Manens reflective dialog interview with ten respondents, five women and five men at age between 40 and 64, living with a partner who had had their diagnosis the last year or longer. Data analyses took place listening and re-listening the recorded interviews, transcribing, reading and re-reading the texts. The analysis evolved through hermeneutic, phenomenological reflection described by van Manen. The result of the study was categorized and the analysis was done in four parts following the four life existentials. The result showed that lived time is different than before since the future has to stand back in favour of here and now in order to be able to cope with everyday life. The lived space changed to secure the partner and everyday roles changed in the family. The lived body needed to rest and longed for closeness. The lived relation changed when the need of closeness and distance changed. The existential conditions changed radically and a new way of living was found in new strategies in a changed and interlaced lifeworld.</p>

Alzheimer’s disease (AD), the most common cause of dementia in the elderly, is a gradually progressive degenerative neurological disorder that is characterized by increasing cognitive impairment, characteristic degenerative pathology and brain atrophy. Studies have shown that the progression of AD pathology in the brain develops in a predictable pattern and the pathological changes that take place in brain begin at the microscopic level long before the first signs of memory loss. Structural Magnetic Resonance Imaging (MRI), which has exceptional soft tissue contrast and detailed resolution, is the best way to noninvasively examine changes which occur early in the course of AD. For this dissertation, our aim is to improve the methods for measuring the atrophy of brain structures in AD, as seen on MRI, and to apply these methods to subjects with cognitive impairment. This study has established a new coordinate template to replace the widely used Montreal Neurological Institute (MNI) template for the atlas-based segmentation procedure. The new template was derived from the same structural image as the one used by the Automated Anatomical Labeling (AAL) procedure. The agreement of the newly developed coordinate template and AAL helps to estimate accurate spatial transformation parameters used in warping the AAL to individual subject images. The new template combines the spatial information of the structural image and the frequency information of MNI template. Based on the same principle, a set of customized templates has been developed. The customized template, associated atlas and customized priors match more closely the aging population than the previous template, so as to improve the atlas-based segmentation of regions of interest in AD assessment. Visual Rating System (VRS) of a single coronal slice (MB slice) in MRI has been another valuable method in the assessment of medial temporal lobe atrophy. An automated procedure has been developed in this study to measure the hippocampal area on the same coronal slice so that the labor of human experts in the VRS assessment of hippocampus will be significantly reduced. Finally the methods and materials (template and atlas) developed in this dissertation were applied to cross-sectional studies of subjects with cognitive impairment. We conducted volumetric analysis on subjects and conclude that the data from the new approaches have higher correlations with clinical data, and therefore can be reliably used as part of an AD assessment tool.

Studien utforskade de närståendes livsvärld när partnern drabbats av Alzheimers sjukdom. Deras livsvärld och existentiella villkor var i fokus. Studien utgick från ett existentiellt fenomenologiskt tolkande perspektiv. Den teoretiska grunden bestod av ett tänkande kring de närståendes livsvärld utifrån fyra existentialer: det levda rummet, den levda tiden, den levda kroppen och den levda relationen. Datainsamling skedde utifrån Max van Manens utforskande intervjuer med tio närstående, fem kvinnor och fem män i yrkesverksam ålder 40 till 64 år, de levde alla tillsammans med en partner som fått sin diagnos för ett år sedan eller längre. Data analyserades genom att lyssna igenom de digitala inspelningarna flera gånger, transkribering av desamma och genomläsning av de utskrivna texterna, nya genomlyssningar och genomläsningar. Analysen utvecklades genom en hermeneutisk, fenomenologisk reflektion beskriven av van Manen. Studiens resultat kategoriserades och dessa analyserades sedan i fyra delar utifrån de fyra existentialerna. Resultatet visade att upplevelsen av den levda tiden blev annorlunda mot tidigare då framtiden fick stå tillbaka för nuet, som var det som de närstående måste förhålla sig till för att vardagen skulle fungera. Det levda rummets aspekter förändrades utifrån skyddsaspekten och nya roller inom familjen. Den levda kroppen krävde egen återhämtning och längtade efter närhet. Den levda relationen förändrades, när upplevelsen av närhet och behovet av distans ändrades. De existentiella villkoren förändrades radikalt och nya strategier gav en ny livsstil i en förändrad och sammanflätad livsvärld. / The study explored the lifeworld of being a partner to a person with Alzheimer’s disease. Lived experience and existential conditions were focused. The study has an existential phenomenological hermeneutic perspective. The theoretical underpinnings consist of thinking of lifeworld by means of four life existentials: lived space, lived body, lived time and lived relations. Data collection was done by Max van Manens reflective dialog interview with ten respondents, five women and five men at age between 40 and 64, living with a partner who had had their diagnosis the last year or longer. Data analyses took place listening and re-listening the recorded interviews, transcribing, reading and re-reading the texts. The analysis evolved through hermeneutic, phenomenological reflection described by van Manen. The result of the study was categorized and the analysis was done in four parts following the four life existentials. The result showed that lived time is different than before since the future has to stand back in favour of here and now in order to be able to cope with everyday life. The lived space changed to secure the partner and everyday roles changed in the family. The lived body needed to rest and longed for closeness. The lived relation changed when the need of closeness and distance changed. The existential conditions changed radically and a new way of living was found in new strategies in a changed and interlaced lifeworld.

Thesis (Ph. D.)--University of Washington, 2002. / Vita. Includes bibliographical references (leaves 93-113).

Dissertation (Ph.D.)--University of South Florida, 2008. / Includes vita. Includes bibliographical references. Also available online.

Diese Arbeit verbindet zwei Publikationen, die sich mit beeinträchtigter Krankheitseinsicht (Anosognosie) bei Patienten mit Alzheimer-Demenz (AD) befassen, sowie mit den Erfassungsmethoden und der Frage, ob Anosognosie bestimmte Bereiche besonders betrifft. Die erste Veröffentlichung stellt die Ergebnisse einer systematischen Literaturübersicht zum Forschungsstand zu Anosognosie bei AD und zu den verschiedenen Erfassungsmethoden für die Krankheitseinsicht von AD-Patienten dar. In der zweiten Publikation sind die Ergebnisse einer empirischen Studie zur Anosognosie bei Patienten mit leichter AD veröffentlicht. Die Ergebnisse dieser Studie weisen zum einen darauf hin, dass die drei Erfassungsmethoden für Anosognosie (klinisches Urteil, Diskrepanz zwischen Selbst- und Fremdeinschätzung, Diskrepanz zwischen Selbsteinschätzung und Testleistung) teils unterschiedliche Facetten der Selbsteinschätzung abbilden. Zum anderen deuten die Befunde darauf hin, dass Unterschiede zwischen den Diskrepanzen zwischen Selbst- und Fremdeinschätzung in verschiedenen Symptombereichen maßgeblich auf unterschiedliche Grade der Beeinträchtigung zurückzuführen sind und nicht Ausdruck einer domänenspezifischen Ausprägung der Einsichtsfähigkeit bei AD-Patienten sind. Diese Studienergebnisse werden in der vorliegenden Arbeit im Zusammenhang mit Erklärungsansätzen für Anosognosie bei AD diskutiert.

Dissertation (Ph.D.)--University of South Florida, 2007. / Title from PDF of title page. Document formatted into pages; contains 142 pages. Includes vita. Includes bibliographical references.