La mémoire de reconnaissance visuelle (MRV) est atteinte précocement dans la maladie d'Alzheimer (MA). Or, elle reposerait sur deux processus : la familiarité (simple sentiment d'avoir déjà rencontré un item) et la recollection (récupération de détails associés à l'item lors de son encodage). Si la recollection est clairement atteinte au début de la MA, les résultats concernant la familiarité sont à ce jour contradictoires. Supposée plus rapide que la recollection, la familiarité devrait pouvoir être évaluée directement par une approche temporelle. Son atteinte dans la MA pourrait alors être mieux comprise.Pour tester ces hypthèses, la procédure comportementale SAB (Speed and Accuracy Boosting) a été créée. Permettant d'étudier les propriétés de la MRV (sa vitesse-limite, Articles 1 et 2, ou sa nature « bottom-up », Article 3), ainsi que l'hypothèse que la familiarité est plus rapide que la recollection, cette méthode s'est montrée évaluer majoritairement la familiarité (Article 1). Chez des patients à risque de MA, une dissociation inattendue au sein de la familiarité a alors pu être révélée, avec une atteinte des signaux tardifs de familiarité (utilisés lors d'un jugement classique), mais une préservation des premiers signaux (supportant la détection rapide évaluée en SAB) (Article 4).En outre, la segmentation manuelle d'images IRM du lobe temporal interne (premières régions cérébrales touchées dans la MA, et clées pour la MRV) a été appliquée à la problématique connexe de l'effet de l'âge au début de la MA (Article 5).Indépendamment, ces méthodes ont permis de mieux comprendre la MRV et son atteinte au début de la MA ; leur combinaison s'annonce très prometteuse. / Visual recognition memory (VRM) is impaired early in Alzheimer's Disease (AD), but would rely on two processes : familiarity (mere feeling that an item has been seen previously) and recollection (retrieval of details associated to the item at encoding). If recollection is clearly impaired in early AD, results concerning familiarity remain contradictory. Supposed to be faster than recollection, familiarity should be better understood using a temporal approach. Its possible impairment in AD could then be better understood.In order to test this, a behavioural procedure was designed: the SAB (Speed and Accuracy Boosting). Revealing different properties of VRM (its speed-limit, Articles 1 and 2; its « bottom-up » nature, Article 3) and some of its processes (familiarity appeares indeed faster than recollection, Article 1), results showed that the SAB procedure was mainly assessing familiarity (Article 1). In patients at risk of AD, an unexpected dissociation within familiarity processes was evidenced, with an impairment of late signals of familiarity (as used for classical judgements), but a preservation of the first signals (supporting fast detection assessed with the SAB) (Article 4).Last, manual segmentation of MRI images of the medial temporal lobe (first cerebral regions affected in AD, known for their key role in VRM) was also used to assess age effect at the early stage of AD (Article 5).Independently, both methods allowed understanding better the VRM and its impairment in early AD; their combination appears very promising.

Diese Schrift faßt in zwei Abschnitten eigene Beiträge zur Einführung der lokalisierten Magnetresonanzspektroskopie (MRS) und der funktionellen Magnetresonanztomografie (fMRT) in die diagnostische Medizin zusammen. Im ersten Teil wird beschrieben, wie die biochemischen Metabolite N-Azetylaspartat, Kreatin und Phosphokreatin, cholin-enthaltende Verbindungen und Laktat durch die Einführung der stimulierten Echo-Akquisitionsmethode (STEAM) als Lokalisationstechnik in die diagnostische Magnetresonanzspektroskopie in definierten Hirnregionen gesunder Versuchspersonen nichtinvasiv zugänglich gemacht und erstmals in Form von In-vivo-Konzentrationen quantifiziert werden konnten. Daraufhin wird gezeigt, wie die Weiterentwicklung der robusten STEAM-Technik zu kurzen Echozeiten das Signal-zu-Rauschverhältnis und damit die Messung kleinerer Untersuchungsvolumina erheblich verbesserte. Zudem wurde dadurch die Erkennung und Quantifizierung weiterer Metabolite wie z. B. des myo- und scyllo-Inosits, des Glutamats und Glutamins, des N-Azetylaspartylglutamats und der Glukose ermöglicht. Diese Methode setzte damit zusammen mit der verwendeten linearen Kombinationsmethode (LCModel) zur Konzentrationsbestimmung den spektralen Qualitätsstandard des gesamten letzten Jahrzehnts. Ferner werden die parallelen Pionierarbeiten zu Hirnerkrankungen fokaler und generalisierter Art beleuchtet. Diese Anwendungen der lokalisierten STEAM-Protonenspektroskopie in Einzelvolumentechnik zur Messung umschriebener Prozesse umfassen zerebrale Tumore und Infarkte, Plaques der multiplen Sklerose sowie andere entzündliche und degenerative Läsionen. Auch die lokalisierte STEAM-Phosphorspektroskopie und nichtzerebrale Anwendungen wie die lokalisierte Protonenspektroskopie von Faserbündeln des Skelettmuskels und der Niere bauen weitgehend auf diesem Fortschritt in der Methode auf. Zusätzlich werden Anwendungen bei generalisierten Erkrankungen gestreift, speziell angeborenen Stoffwechselerkrankungen des Kindesalters wie mitochondrialen und lysosomalen Defekten, Stoffwechselentgleisungen bei Diabetes mellitus und Leberzirrhose, psychiatrischen Erkrankungen wie der Alzheimer-Demenz. Die weitere Verbreitung dieser Erkenntnisse in die klinische Diagnostik wird entscheidend von der Beachtung des hier eingeführten Qualitätsmaßstabs und der darauf aufbauenden absoluten Metabolitquantifizierung abhängen. Der zweite Teil dieser Arbeit faßt ausgehend von funktionellen protonenspektroskopischen Untersuchungen des visuellen Kortex bei photischer Aktivierung Fortschritte zusammen, die bei der Entwicklung und Anwendung der suszeptibilitätsempfindlichen MR-Tomografie zur Messung physiologischer Hirnaktivierung mit dem Modell der visuellen Stimulation erzielt wurden. Während die Belastung des Energiestoffwechsels im angeregten striatären Kortex anhand abgesunkener Gewebespiegel von Glukose und angestiegener Laktatkonzentrationen mithilfe der zeitaufgelösten Spektroskopie beobachtet werden konnte, gelang die Demarkierung der Ausdehnung der Hirngewebeaktivierung mithilfe der T2*-gewichteten FLASH-MRT, die begleitende Verminderungen des paramagnetischen Desoxyhämoglobins im funktionell aktiven Gewebe mit Anstiegen der Bildsignalintensität wiedergibt. Schließlich werden Untersuchungen beschrieben, die die Empfindlichkeit dieses endogenen, sauerstoffspiegelabhängigen Suszeptibilitätskontrastes für die Wirkung verschiedener Medikamente bzw. pharmakologischer Stimulantien zeigen, die direkt oder indirekt über bestimmte vaskuläre Rezeptoren wirken. Diese Untersuchungen befördern wiederum ein neues Gebiet der Bildgebung, die pharmakologische MRT. / This work has two main parts that summarize pioneering contributions to localized magnetic resonance spectroscopy (MRS), functional magnetic resonance tomography (fMRI), and the introduction of these modalities into diagnostic medicine. First, it is described how biochemical metabolites such as the intracellular pools of N-acetylaspartate, creatine and phosphocreatine, choline-containing compounds, and lactate have been made accessible to noninvasive detection and to the quantification of their respective concentrations in vivo in defined cerebral regions of healthy subjects by utilizing the stimulated echo-acquisition mode (STEAM) localization technique. Then it is shown that further development of the robust STEAM technique to short echo times not only increased the signal-to-noise of the measurement, thereby providing access to smaller volumes-of-interest, but also allowed for the detection and quantification of additional metabolites such as myo- and scyllo-inositol, glutamate, glutamine, N-acetylaspartylglutamate, and glucose. Thus, together with the adoption of the linear combination method (LCModel) for concentration calculation, this method has set the standard for spectroscopic state-of-the-art in the field well over the last decade. Moreover, pioneering achievements have been highlighted with regard to applications in brain diseases of focal and generalized nature. Pertinent applications of localized single-volume STEAM proton spectroscopy to circumscribed processes include cerebral tumors, cerebral infarction, multiple sclerosis plaques, and other inflammatory and degenerative lesions. Also localized STEAM phosphorus spectroscopy and non-cerebral applications including localized proton spectroscopy of skeletal muscle and kidney largely depend on the short-echo time STEAM technique. In addition, applications in generalized disorders have been explored, which include inborn errors of metabolism in childhood, such as mitochondrial and lysosomal defects, metabolic disturbances in diabetes mellitus and liver cirrhosis, and psychiatric diseases such as Alzheimer's dementia. The further utilization of these novel methods in clinical diagnostics will heavily depend on quality measures and the mastering of a true quantification procedure as demonstrated. Second, this work summarizes achievements made in developing and applying both proton MR spectroscopy and susceptibility-sensitized MR imaging to measure physiologic brain activation using visual stimulation as a model. Whereas metabolic stress, brought upon the bioenergetic steady state in the responding striate cortex, was detected by decreased parenchymal glucose and increased lactate using time-resolved spectroscopy, mapping the extent of parenchymal activation was found to be possible by increases of image intensity in T2*-weighted FLASH MRI made sensitive to concomitant decreases of paramagnetic deoxyhemoglobin in the functionally active tissue. Finally, studies are described, which show the sensitivity of this endogenous, susceptibility-sensitive contrast, now generally known as BOLD effect, to various drugs or pharmacologic stimuli acting either directly or indirectly on vascular receptors. These latter studies open up again a new field of imaging, dubbed pharmacologic MRI.

INTRODUÇÃO: Os fatores de risco cardiovascular (FRCV) afetam o fluxo sanguíneo cerebral, contribuindo possivelmente para o declínio cognitivo e a emergência da Doença de Alzheimer (DA), a forma mais comum de demência. A tomografia por emissão de pósitrons (positron emission tomography, PET) com fluordesoxiglucose F18 (18F-FDG) é largamente usada para demonstrar o padrão específico de metabolismo cerebral de glicose reduzido em sujeitos com DA e em indivíduos não-demenciados portadores do alelo e4 da apolipoproteína E (APOE e4), o maior fator de risco genético para DA. Entretanto, estudos de PET investigando o impacto dos FRCV no metabolismo cerebral são escassos. OBJETIVO: Examinar se níveis diferentes de FRCV estariam associados com reduções na taxa de metabolismo cerebral de glicose (TMCG), envolvendo as regiões cerebrais afetadas nos estágios iniciais da DA (pré-cúneo e giro do cíngulo posterior, neocórtex parieto-temporal lateral e região hipocampal). MÉTODOS: Nós avaliamos 59 indivíduos cognitivamente preservados (66-75 anos) subdivididos em três grupos de acordo com seu escore para Framingham Coronary Heart Disease Risk (FCHDR) (alto-risco, médio-risco e baixo-risco) para os exames de ressonância magnética (RM) e de PET-FDG. Dados de PET foram corrigidos para os efeitos de volume parcial a fim de evitar efeitos confundidores devido à atrofia cerebral regional. Nós realizamos uma análise de covariância global (ANCOVA) para investigar as reduções de TMCG em associação com os três grupos, comparações entre dois grupos para as diferenças de TMCG pelo teste-t, e índices de correlação linear voxel-a-voxel entre os valores de TMCG e escores FCHDR. Todas as análises incluíram a presença ou a ausência do APOE e4 como covariada confundidora de interesse. RESULTADOS: A investigação ANCOVA de diferenças de TMCG entre os três grupos mostraram significantes diferenças de TMCG somente no giro parahipocampal direito (p=0,032). Nas comparações entre dois grupos, reduções de TMCG significantes foram detectadas no grupo de altorisco comparado ao baixo-risco no pré-cúneo esquerdo (p=0,008) e o giro do cíngulo posterior esquerdo (p=0,007). Focos inesperados de reduções de TMCG no grupo baixo-risco comparado ao grupo alto-risco no giro parahipocampal foram detectados em ambos os hemisférios direito (p=0,001) e esquerdo (p=0,045). Havia também uma significante correlação linear positiva entre valores de TMCG e escores FCHDR no giro parahipocampal em ambos os lados direito (p=0,007) e esquerdo (p=0,025). CONCLUSÃO: Depois de controlar para a presença do APOE 4, nossos achados de hipofunção cerebral regional relacionado a FRCV mantiveram a significância estatística no pré-cúneo e no giro do cíngulo posterior, as duas regiões cerebrais onde comprometimentos funcionais são os mais consistentemente detectados nos estágios incipientes da DA. Isso sugere que os achados de hipometabolismo cerebral similares àqueles vistos nos sujeitos com DA podem ser vistos em associação com a gravidade de FRCV em amostras de indivíduos cognitivamente preservados. Uma possível explicação para o hipermetabolismo relativo no giro parahipocampal nos indivíduos com elevados FRCV seria um viés na seleção da amostra. É possível que nós tenhamos excluídos os sujeitos com os níveis mais graves de risco cardiovascular que teriam exibido os padrões de reduções de TMCG no giro parahipocampal, forçando a seleção de indivíduos que estão para o alto risco cardiovascular, mas que são capazes de exibir mecanismos compensatórios para manter o funcionamento metabólico adequado para as regiões temporolímbicas, as quais são vulneráveis às mudanças microvasculares / INTRODUCTION: Cardiovascular risk factors (CVRF) are known to affect cerebral blood flow, possibly contributing to cognitive decline and to the emergence of Alzheimers disease (AD), the commonest form of dementia. Positron emission tomography (PET) with 18-fluoro-2-deoxyglucose (18FFDG) has been widely used to demonstrate specific patterns of reduced brain glucose metabolism in AD subjects and in non-demented individuals carriers of the apolipoprotein e4 allele (APOE e4), the major genetic risk factor for DA. However, PET studies investigating the impact of CVRF on cerebral metabolism have been scarce to date. OBJECTIVE: To examine whether different levels of CVRF would be associated with cerebral metabolic rate of glucose (CMRgl) reductions, involving brain regions affected in early stages of DA (precuneus and posterior cingulate gyrus, lateral temporalparietal neocortices and hippocampal region). METHODS: We assessed 59 cognitively preserved individuals (66-75 years), subdivided into three groups according to their Framingham Coronary Heart Disease Risk (FCHDR) score (high-risk, medium-risk, and low-risk), both with magnetic resonance imaging (MRI) and FDG-PET scans. PET data were corrected for partial volume effects to avoid confounding effects due to regional brain atrophy. We performed an overall analysis of covariance (ANCOVA) to investigate CMRgl reductions in association with the three groups, two-group comparisons of CMRgl differences by t-tests, and voxelwise linear correlation indices between CMRgl values and FCHDR scores. All analysis included the presence or absence of the APOE 4 allele as a confounding covariate of interest. RESULTS: The ANCOVA investigation of CMRgl differences across the three groups showed significant CMRgl differences only in the right parahippocampal gyrus (p=0.032). In the two-group comparisons, significant CMRgl reductions were detected in the high-risk group compared to the lowrisk group in the left precuneus (p=0.008); and the left posterior cingulate gyrus (p=0.007). Unexpected foci of CMRgl reductions in the low-risk compared to the high-risk group in the parahippocampal gyrus were detected, both on the right (p=0.001) and left (p=0.045) hemispheres. There was also a significant positive linear correlation between CMRgl values and FCHDR scores in the parahippocampal gyrus both for the right (p=0.007) and left (p=0.025) sides. CONCLUSION: After controlling for the presence of the APOE 4 allele, our findings of CVRF-related regional brain hypofunction retained statistical significance in the precuneus and posterior cingulate gyrus, the two brain regions where functional impairments are most consistently detected in incipient stages of AD. This suggests that findings of brain hypometabolism similar to those seen in AD subjects can be seen in association with the severity of CVRF in samples of cognitively preserved individuals. One possible explanation for the relative hypermetabolism in the parahippocampal gyrus in high CVRF individuals would be a bias in the sample selection. It is possible that we have excluded subjects with severest levels of cardiovascular risk who would have displayed patterns of reduced CMRgl in the parahippocampal gyrus, forcing the selection of individuals who are at high cardiovascular risk but are capable of displaying compensatory mechanisms to maintain adequate metabolic functioning in temporolimbic regions vulnerable to microvascular changes

Introdução: A deglutição resulta de um complexo mecanismo sensoriomotor, regulado pelo sistema nervoso central. Dado seu componente voluntário, nas fases antecipatória e oral, pode sofrer influências funcionais e cognitivas associadas àquelas determinadas por doenças sistêmicas que limitam a auto-regulação, percepção e controle de fatores de risco, e o desenvolvimento de estratégias compensatórias. Na doença de Alzheimer (DA) com comprometimento dos aspectos cognitivos, das atividades de vida diária e do comportamento nas fases moderada e grave da doença ocorrem os problemas de alimentação e deglutição o que traz maiores dificuldades ao cuidador. Objetivos: Traduzir e adaptar as escalas Questionário de Habilidades de Alimentação e Deglutição (QHAD) e Questionário para Avaliação da Comunicação Funcional na Afasia (QACF-A). Verificar a correlação entre os aspectos cognitivos e funcionais da deglutição e alimentação. Verificar fatores preditivos da funcionalidade da deglutição em sujeitos com doença de Alzheimer moderada e grave. Método: Neste estudo transversal e randomizado foram incluídos 50 idosos portadores de DA de ambos os sexos, com escolaridade e idades variadas, em fases moderada e grave, e seus 50 cuidadores. Foi feita avaliação dos aspectos cognitivos em que foi aplicado com o paciente o Mini- Exame do Estado Mental (MEEM). Em avaliação funcional foi aplicado com o cuidador o Índice das Atividades de Vida Diária (AVD), o Questionário para Avaliação da Comunicação Funcional na Afasia (QACF-A). A funcionalidade da deglutição foi graduada pela Escala de gravidade da deglutição (EGD). A avaliação das dificuldades de alimentação e deglutição foi feita a partir do Questionário de Habilidades de Alimentação e Deglutição (QHAD). Resultados: A escala QHAD mostrou boa consistência enquanto o QACF-A apresentou ótima confiabilidade em todos os domínios (AC > 0,9). Foi encontrada correlação entre o domínio Situação de alimentação e habilidades (QHAD) com todos os domínios do QACF-A. A maioria dos domínios do QHAD e todos do QACF-A mostraram correlação com o MEEM, AVD e EGD. O domínio Situação de alimentação e habilidades no QHAD foi o de maior representatividade em regressão linear com o MEEM, AVD e EGD (r >0,6). Quanto o QACF-A, o domínio Realização de pedidos rotineiros foi o de maior representatividade com o MEEM e AVD (r > 0,8). Na fase moderada da DA, Estado mental e comportamento e Itens relativos à comida, bebida e deglutição (QHAD) foram os domínios que apresentaram correlação significativa com a EGD (r >0,5). Na fase grave, a Situação de alimentação e habilidades (QHAD) mostrou correlação com todos os domínios do QACF-A (r > 0,6) e também com o AVD (r=0,601) e EGD (r=0,592). Também na fase grave da DA, todos os domínios do QACF-A apresentaram correlação com o MEEM, AVD e EGD (r > 0,6). Os domínios de maior representatividade juntos aos aspectos cognitivos e funcionais foram Situação de alimentação e habilidades (QHAD) e Realização de pedidos rotineiros (QACF-A). Conclusão: Dada as alterações funcionais inexoráveis no curso da doença, é imprescindível a sua observação em pacientes com prejuízos na alimentação e nos mecanismos da deglutição. O presente estudo fornece instrumentos de avaliação para orientar cuidadores e profissionais quanto à alimentação e deglutição de pacientes com doença de DA em fases avançadas. / Introduction: Swallowing results from a complex sensory-motor mechanism regulated by central nervous system. Given the voluntary component, in anticipatory and oral phases, it can suffer functional and cognitive influences associated to those determined by systemic diseases that limit self-regulation, perception and control of risk factors and development of compensating strategies. In moderate and severe phases of Alzheimer disease (AD), with cognitive, functional daily-living and behavioral aspects compromised feeding and swallowing problems create greater difficulties for the caregiver. Objectives: to translate and adapt the scales of Assessment of Feeding and Swallowing Difficulties in Dementia (AFSDD) e Functional Outcome Questionnaire for Aphasia (FOQ-A). To verify the correlation between cognitive and functional aspects of feeding and swallowing. To verify predictive factors of swallowing functionality in patients with moderate and severe AD. Method: In this randomised and transversal study 50 elderly diagnosed with moderate and severe AD, according to Clinical Dementia Rating (CDR), of both genders, varied ages and schooling and 50 caregivers were included. The Mini-Mental Estate Examination (MMSE) was applied to evaluate cognitive conditions of the patients. The Activities of Daily Living (ADL) Index and the Functional Outcome Questionnaire for Aphasia (FOQ-A), were applied to the caregiver for patient functional evaluation. Swallowing functionality was graded by the Swallowing Rating Scale American Speech-Language-Hearing Association ASHA. The evaluation of feeding and swallowing difficulties was done by the Assessment of feeding and swallowing difficulties in dementia (AFSDD). Results: Analysis of AFSDD verified good internal consistency in most of the domains, while the FOQ-A presented excellent internal consistency in all domains (AC>0.9). There was a correlation between most of AFSDD and FOQ-A with MMSE and ADL. The domain of Feeding situation and skills in AFSDD was the most representative in linear regression, considering the MMSE, ADL and ASHA (r>0.6). Considering the FOQ-A the domain of Making routine requests was the most representative with the MMSE and ADL (r>0.8). In moderate phase of AD, Mental estate and behavior and Issues related to food, drink, and swallowing (AFSDD) were the domains that had significant correlation with ASHA (r> 0,5). In severe phase, the Feeding situation and skills (AFSDD) showed correlation with all domains of FOQ-A (r>0,6), and with ADL (r=0,601) e ASHA (r=0,592). In severe phase was observed that all domains of FOQ-A had correlation with MMSE, ADL and ASHA (r>0,6). The domains with greater representation in the cognitive and functional aspects were Feeding situation and skills (AFSDD) and Making Routing Requests (FOQ-A). Conclusion: Given the inexorable functional alterations of the disease, observing the feeding and swallowing compromises of the patients is indispensable. This study discloses instruments to evaluate and orient caregivers and other professionals regarding feeding and swallowing in patients in advanced phases of AD.

INTRODUÇÃO. Embora esteja bem estabelecida a relação neuropatológica da síndrome de Down (SD) com a doença de Alzheimer (DA), os primeiros sintomas de demência na população com SD são considerados atípicos. Estudos indicam que os sintomas iniciais estão relacionados à disfunção comportamental que envolvem circuitos cerebrais fronto-subcorticais, como mudança de comportamento e disfunção executiva. O presente estudo teve como objetivo investigar fatores associados ao funcionamento do lobo frontal (disfunção executiva, desinibição e apatia) durante o declínio cognitivo e a DA em adultos com SD. MÉTODOS. 92 indivíduos com SD com idade acima de 30 anos foram alocados em três diferentes grupos diagnósticos (cognição estável, demência prodrômica e DA) por meio da avaliação com o instrumento Exame Cambridge para Transtornos Mentais em Adultos com Síndrome de Down e Deficiência Intelectual (CAMDEX-DS), previamente validado como parte da metodologia de trabalho. Os participantes foram avaliados com um protocolo de funções executivas desenvolvido para pessoas com deficiência intelectual por pesquisadores da Universidade de Cambridge e classificados para a presença de disfunção executiva, desinibição e apatia através da entrevista com um informante utilizando a Escala de Personalidade Frontal. Além disso, dados sobre características de comportamentos resultantes de disfunções frontais, memória e orientação foram analisados por meio do CAMDEX-DS em conjunto com uma amostra inglesa totalizando amostra combinada de 162 participantes com SD com mais de 30 anos e divididos em quatro grupos: cognição estável abaixo de 45 anos, cognição estável acima de 45 anos, demência prodrômica e DA. RESULTADOS. Os relatos de disfunção executiva, desinibição e apatia através da Escala de Personalidade Frontal foram correlacionados com o desempenho cognitivo dos participantes: quanto maior a disfunção comportamental nestas áreas, pior o desempenho cognitivo nas tarefas executivas. A desinibição e a disfunção executiva foram associadas aos diferentes diagnósticos. A probabilidade de ter DA aumentou com elevações nos escores da Escala de Personalidade Frontal (p <= 0,5). Na análise com o CAMDEX-DS, os sintomas frontais, assim como as queixas de memória e orientação, estavam presentes antes da evidência de declínio cognitivo. Diante do diagnóstico prodrômico e de DA, esses sintomas se agravaram. O impacto da deterioração cognitiva ocorreu em memória e orientação (odds ratio 35,07; P < 0,001) e disfunção executiva (odds ratio 7,16; P < 0,001) para o grupo prodrômico em relação à cognição estável; desinibição (odds ratio 3,54; P = 0,04) para DA em relação ao grupo prodrômico; e apatia (odds ratio 34,18; P < 0,001) para DA em relação à cognição estável. CONCLUSÃO. Disfunção executiva, desinibição e apatia estiveram presentes em indivíduos com SD e cognição estável. Estas medidas se agravam no declínio cognitivo inicial (prodrômico) e na DA nessa população e estão associados ao desempenho cognitivo em tarefas de funções executivas. Disfunções comportamentais devem ser levadas em consideração durante a avaliação clínica. Estudos futuros considerando a interseção entre neuropatologia, conectividade cerebral e expressão de comportamento podem agregar conhecimento sobre a base e a natureza dessas associações e servirem de base para a criação de estratégias preventivas eficazes / INTRODUCTION. Although a neuropathological correlation has been established between Down syndrome (DS) and Alzheimer\'s disease (AD), the early symptoms of dementia present atypically in the DS population. There is evidence that frontal-subcortical circuits play an important role in the initial presentation of dementia in DS, including changes in behaviour and executive dysfunction. The present study aimed to investigate factors associated with frontal lobe functioning (executive dysfunction, disinhibition and apathy) during cognitive decline and AD in adults with DS. METHODS. 92 individuals with DS aged over 30 years were evaluated and divided into three groups of diagnosis (stable cognition, prodromal dementia and AD) using the Cambridge Examination for Mental Disorders in Adults with Down Syndrome and others with Intellectual Disability (CAMDEX-DS), previously validated as part of our methodology. Participants were assessed with an executive function protocol developed for people with intellectual disabilities by researchers from University of Cambridge, and were rated for executive dysfunction, disinhibition and apathy by an informant using the Frontal Systems Behavior Scale (FrSBe). In addition, data on characteristics of frontal behaviour, memory and orientation were analysed through CAMDEX-DS in conjunction with an English sample totalling 162 participants with DS over 30 years old and divided into four groups: stable cognition under 45 years, stable cognition above 45 years, prodromal dementia and AD. RESULTS. Reports of executive dysfunction, disinhibition and apathy through FrSBe were correlated with participants\' cognitive performance: the higher the behavioural dysfunction in these areas, the worse the cognitive performance in executive tasks. Disinhibition and executive dysfunction were associated with diagnoses. The odds of having AD increased in parallel with increases in FrSBe scores (p <= 0.5). In the CAMDEX-DS analysis, amnestic and non-amnestic symptoms were found to be present before there was evidence of a cognitive decline. During the progression to dementia, those symptoms tended to worsen. Memory and orientation were poorer in the prodromal dementia group than in the stable cognition group (odds ratio 35.07, P < 0.001) as was executive function (odds ratio 7.16, P < 0.001). Disinhibition was greater in the AD group than in the prodromal dementia group (odds ratio 3.54, P = 0.04), and apathy was more pronounced in the AD group than in the stable cognition group (odds ratio 34.18; P < 0.001). CONCLUSION. Executive dysfunction, disinhibition and apathy were present in individuals with DS and stable cognition. These measures hasten the initial cognitive decline of AD and are related with cognitive performance in executive function tasks. Frontally mediated behaviour should be taken into consideration during the clinical evaluation of adults with DS. Future studies considering the intersection of neuropathology, brain connectivity, and behaviour may aggregate knowledge about the basis and nature of these associations, leading to the development of effective preventive strategies

Obesidade na idade adulta é um fator de risco para o desenvolvimento de demência. O aumento da prevalência de obesidade, assim como o aumento da expectativa de vida na população tornam mais importante avaliar estratégias de prevenção e tratamento que possam diminuir o risco de declínio cognitivo. Neste estudo, foi avaliado se, em idosos obesos com Comprometimento Cognitivo Leve, a perda de peso induzida por dieta poderia melhorar aspectos da cognição, e se o genótipo para apoliproteína E, perfil metabólico e marcadores inflamatórios também teriam influência. Foi realizado um ensaio clínico prospectivo, randomizado de 1:1, de 12 meses, no Ambulatório de Endocrinologia do Hospital das Clínicas da Faculdade de Medicina da USP, entre 2011 e 2013, incluindo pacientes com 60 anos ou mais, com índice de massa corporal maior ou igual a 30 kg/m2, com Comprometimento cognitivo leve. Eles foram randomizados em dois grupos, um com assistência médica convencional (grupo convencional), outro adicionalmente com reuniões de orientação alimentar (26 a 28 sessões em 12 meses), com objetivo de obter maior perda de peso (grupo intensivo). Dos 1605 voluntários foram selecionados 80 pacientes, com idade média de 68,1 ±4,9 anos, escolaridade de 8,8 ±4,6 anos, IMC 35,5±4,4kg/m2; 13 (16,3%) eram do sexo masculino, 67 (83,6%) apresentavam síndrome metabólica; 50 (62,5%) eram fisicamente ativos. Os grupos eram semelhantes quanto às características iniciais. Após 12 meses, houve diminuição média de IMC de 1,7±1,8kg/m2 (4,9% do peso), e 85% da perda de peso foi em gordura corporal; sendo a variação semelhante entre os grupos. Para a maioria dos testes cognitivos aplicados houve melhora, sem diferença estatisticamente significativa entre os grupos. Na análise do grupo todo, a perda de peso induzida por dieta foi associada a melhora em avaliação de memória, função executiva, atenção e queixas subjetivas, tendo sido essa associação mais forte abaixo dos 70 anos e em carreadores do alelo 4 da apoliproteína E. Variação de insulinemia, HOMA-IR, triglicérides, proteína C reativa e leptina estiveram associadas à melhora em alguns testes cognitivos; risco maior de piora foi associado a níveis mais altos de pressão arterial (memória e cognição global) e de hemoglobina glicada (executivo/visuo-espacial) e de IL6 (atenção e velocidade de processamento); adiponectina mais alta diminuiu risco de piora (memória visual/verbal). Houve melhora principalmente em memória verbal, visual e memória de trabalho associadas à dieta, com relação à diminuição de consumo calórico, de carboidratos e gorduras, e sem relação com diminuição de consumo proteico. Houve melhora na avaliação funcional em relação à velocidade de marcha e força de membros inferiores e melhora na qualidade de vida associada à capacidade funcional, mostrando que a intervenção não trouxe prejuízo a essas áreas. A intervenção com restrição calórica em idosos obesos, com objetivo de promover perda de peso, foi benéfica em diversos aspectos da cognição e segura do ponto de vista funcional / Obesity in adulthood is a risk factor for developing dementia. The populational rise in obesity and life expectancy increase the importance of search for strategies for prevention and treatment to reduce the risk of cognitive decline. In this study we evaluated if in elderly obese with Mild Cognitive Impairment, weight loss induced by diet could improve aspects of cognition, and if the apolipoprotein E genotype, metabolic profile and inflammatory markers also influence these tests. A prospective, randomized clinical trial was conducted at Ambulatório de Endocrinologia do Hospital das Clínicas da Faculdade de Medicina da USP, between 2011 and 2013, including patients 60 years or older, with a body mass index greater than or equal to 30 kg/m2, with mild cognitive impairment. They were randomized into two groups and followed by 12 months, one with conventional medical care (conventional group), another with also group meetings with nutricionists (26-28 sessions over 12 months), in order to achieve greater weight loss (intensive group). Of the 1605 volunteers were selected 80 subjects, mean age 68.1 ± 4.9 years, education 8.8 ± 4.6 years, BMI 35.5 ± 4.4kg/m2; 13 were male (16.3%), 67 (83.6%) had metabolic syndrome; 50 were physically active. The groups had similar baseline characteristics. After 12 months there was a decrease in BMI of 1.7 ± 1.8 kg/m2 (4.9% of weight), and 85% weight loss was in fat; similar between groups. There was improvement for most of the cognitive tests, without difference between groups. In the analysis of the whole group, the weight loss induced by diet was associated with improvements in memory, executive function, attention and subjective complaints, though this association was strongest under 70 years of age and in carriers of the ?4 allele of apolipoprotein E. Changes in insulin, HOMA-IR, triglycerides, C-reactive protein and leptin were associated with improvement in some cognitive tests; increased risk of worsening was associated with higher blood pressure levels (memory and global cognition), HbA1c (executive / visuospatial) and IL6 (attention and processing speed); higher adiponectin decreased risk of worsening (visual memory/verbal). There was improvement in verbal, visual and working memory associated with diet, with respect to decreased caloric intake, carbohydrates and fats, and unrelated to decreased protein intake memory. There was improvement in functional assessment in relation to gait speed and lower limb strength and improvement in quality of life associated with functional capacity, showing that the intervention did not bring damage to these areas. Intervention with caloric restriction in obese elderly, in order to promote weight loss was safe and had beneficial effects in cognition

Chang, Jianfang. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2011. / Includes bibliographical references (leaves 183-217). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

INTRODUÇÃO. Embora esteja bem estabelecida a relação neuropatológica da síndrome de Down (SD) com a doença de Alzheimer (DA), os primeiros sintomas de demência na população com SD são considerados atípicos. Estudos indicam que os sintomas iniciais estão relacionados à disfunção comportamental que envolvem circuitos cerebrais fronto-subcorticais, como mudança de comportamento e disfunção executiva. O presente estudo teve como objetivo investigar fatores associados ao funcionamento do lobo frontal (disfunção executiva, desinibição e apatia) durante o declínio cognitivo e a DA em adultos com SD. MÉTODOS. 92 indivíduos com SD com idade acima de 30 anos foram alocados em três diferentes grupos diagnósticos (cognição estável, demência prodrômica e DA) por meio da avaliação com o instrumento Exame Cambridge para Transtornos Mentais em Adultos com Síndrome de Down e Deficiência Intelectual (CAMDEX-DS), previamente validado como parte da metodologia de trabalho. Os participantes foram avaliados com um protocolo de funções executivas desenvolvido para pessoas com deficiência intelectual por pesquisadores da Universidade de Cambridge e classificados para a presença de disfunção executiva, desinibição e apatia através da entrevista com um informante utilizando a Escala de Personalidade Frontal. Além disso, dados sobre características de comportamentos resultantes de disfunções frontais, memória e orientação foram analisados por meio do CAMDEX-DS em conjunto com uma amostra inglesa totalizando amostra combinada de 162 participantes com SD com mais de 30 anos e divididos em quatro grupos: cognição estável abaixo de 45 anos, cognição estável acima de 45 anos, demência prodrômica e DA. RESULTADOS. Os relatos de disfunção executiva, desinibição e apatia através da Escala de Personalidade Frontal foram correlacionados com o desempenho cognitivo dos participantes: quanto maior a disfunção comportamental nestas áreas, pior o desempenho cognitivo nas tarefas executivas. A desinibição e a disfunção executiva foram associadas aos diferentes diagnósticos. A probabilidade de ter DA aumentou com elevações nos escores da Escala de Personalidade Frontal (p <= 0,5). Na análise com o CAMDEX-DS, os sintomas frontais, assim como as queixas de memória e orientação, estavam presentes antes da evidência de declínio cognitivo. Diante do diagnóstico prodrômico e de DA, esses sintomas se agravaram. O impacto da deterioração cognitiva ocorreu em memória e orientação (odds ratio 35,07; P < 0,001) e disfunção executiva (odds ratio 7,16; P < 0,001) para o grupo prodrômico em relação à cognição estável; desinibição (odds ratio 3,54; P = 0,04) para DA em relação ao grupo prodrômico; e apatia (odds ratio 34,18; P < 0,001) para DA em relação à cognição estável. CONCLUSÃO. Disfunção executiva, desinibição e apatia estiveram presentes em indivíduos com SD e cognição estável. Estas medidas se agravam no declínio cognitivo inicial (prodrômico) e na DA nessa população e estão associados ao desempenho cognitivo em tarefas de funções executivas. Disfunções comportamentais devem ser levadas em consideração durante a avaliação clínica. Estudos futuros considerando a interseção entre neuropatologia, conectividade cerebral e expressão de comportamento podem agregar conhecimento sobre a base e a natureza dessas associações e servirem de base para a criação de estratégias preventivas eficazes / INTRODUCTION. Although a neuropathological correlation has been established between Down syndrome (DS) and Alzheimer\'s disease (AD), the early symptoms of dementia present atypically in the DS population. There is evidence that frontal-subcortical circuits play an important role in the initial presentation of dementia in DS, including changes in behaviour and executive dysfunction. The present study aimed to investigate factors associated with frontal lobe functioning (executive dysfunction, disinhibition and apathy) during cognitive decline and AD in adults with DS. METHODS. 92 individuals with DS aged over 30 years were evaluated and divided into three groups of diagnosis (stable cognition, prodromal dementia and AD) using the Cambridge Examination for Mental Disorders in Adults with Down Syndrome and others with Intellectual Disability (CAMDEX-DS), previously validated as part of our methodology. Participants were assessed with an executive function protocol developed for people with intellectual disabilities by researchers from University of Cambridge, and were rated for executive dysfunction, disinhibition and apathy by an informant using the Frontal Systems Behavior Scale (FrSBe). In addition, data on characteristics of frontal behaviour, memory and orientation were analysed through CAMDEX-DS in conjunction with an English sample totalling 162 participants with DS over 30 years old and divided into four groups: stable cognition under 45 years, stable cognition above 45 years, prodromal dementia and AD. RESULTS. Reports of executive dysfunction, disinhibition and apathy through FrSBe were correlated with participants\' cognitive performance: the higher the behavioural dysfunction in these areas, the worse the cognitive performance in executive tasks. Disinhibition and executive dysfunction were associated with diagnoses. The odds of having AD increased in parallel with increases in FrSBe scores (p <= 0.5). In the CAMDEX-DS analysis, amnestic and non-amnestic symptoms were found to be present before there was evidence of a cognitive decline. During the progression to dementia, those symptoms tended to worsen. Memory and orientation were poorer in the prodromal dementia group than in the stable cognition group (odds ratio 35.07, P < 0.001) as was executive function (odds ratio 7.16, P < 0.001). Disinhibition was greater in the AD group than in the prodromal dementia group (odds ratio 3.54, P = 0.04), and apathy was more pronounced in the AD group than in the stable cognition group (odds ratio 34.18; P < 0.001). CONCLUSION. Executive dysfunction, disinhibition and apathy were present in individuals with DS and stable cognition. These measures hasten the initial cognitive decline of AD and are related with cognitive performance in executive function tasks. Frontally mediated behaviour should be taken into consideration during the clinical evaluation of adults with DS. Future studies considering the intersection of neuropathology, brain connectivity, and behaviour may aggregate knowledge about the basis and nature of these associations, leading to the development of effective preventive strategies

Hoi, Chu Peng. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2007. / Includes bibliographical references (leaves 81-103). / Abstracts in English and Chinese. / Acknowledgements --- p.II / Abstract --- p.III / Abstract (in Chinese) --- p.V / List of Abbreviations --- p.VI / List of Figures --- p.VIII / List of Tables --- p.X / Table of Contents --- p.XI / Chapter Chapter One --- General introduction --- p.1 / Chapter 1.1 --- Alzheimer's disease --- p.1 / Chapter 1.1.1 --- Epidemiology and risk factors --- p.2 / Chapter 1.1.2 --- Clinical manifestation and course --- p.4 / Chapter 1.1.3 --- Clinical diagnosis --- p.5 / Chapter 1.1.4 --- Neuropathology and pathogenesis of AD --- p.8 / Chapter 1.1.5 --- Drug therapy of AD --- p.11 / Chapter 1.1.5.1 --- Drugs for symptomatic treatment --- p.11 / Chapter 1.1.5.2 --- Drugs based on epidemiology --- p.12 / Chapter 1.1.5.3 --- Drugs with potential disease-modifying effects --- p.14 / Chapter 1.1.5.4 --- Herbal supplements --- p.15 / Chapter 1.2 --- Models for drug discovery in Alzheimer Disease --- p.15 / Chapter 1.2.1 --- In vivo (animal) models --- p.16 / Chapter 1.2.2 --- In vitro (cellular) models --- p.18 / Chapter 1.3 --- Chinese herbs for the treatment of AD --- p.20 / Chapter 1.3.1 --- Ginkgo biloba L --- p.21 / Chapter 1.3.2 --- Magnolia officinalis --- p.24 / Chapter 1.3.3 --- Acori graminei Rhizoma (AGR) --- p.26 / Chapter 1.3.4 --- Gastrodia elata (G. elata) --- p.27 / Chapter 1.3.5 --- Rhodiola rosea L.( R. rosea) --- p.29 / Chapter 1.3.6 --- Scutellariae baicalensis --- p.30 / Chapter 1.3.7 --- Curcuma longa L.(Zingiberaceae) --- p.31 / Chapter 1.4 --- Aims of the study --- p.33 / Chapter Chapter Two --- Materials and Methods --- p.34 / Chapter 2.1 --- Materials --- p.34 / Chapter 2.1.1 --- Chemicals and reagents --- p.34 / Chapter 2.1.2 --- Materials for cell culture --- p.35 / Chapter 2.1.3 --- Instruments --- p.35 / Chapter 2.2 --- Methods --- p.36 / Chapter 2.2.1 --- Cell culture --- p.36 / Chapter 2.2.2 --- MTT cell viability assay --- p.38 / Chapter 2.2.3 --- Characterization of the cytotoxicity of Aβ peptide in NGF-differentiated PC 12 cells --- p.38 / Chapter 2.2.4 --- Screening of the neuroprotective effect of major principles from selected herbs on PC 12 cells against Aβ-induced cytotoxicity --- p.39 / Chapter 2.2.5 --- Measurement of reactive oxygen species (ROS) --- p.40 / Chapter 2.2.6 --- Measurement of intracellular calcium levels --- p.41 / Chapter 2.2.7 --- Measurement of caspase-3 activity --- p.42 / Chapter 2.2.8 --- Propidium iodide (PI) staining to evaluate apoptosis and necrosis --- p.43 / Chapter 2.3 --- Statistics --- p.45 / Chapter Chapter Three --- Results --- p.46 / Chapter 3.1 --- NGF-differentiated PC 12 cells --- p.46 / Chapter 3.1.1 --- Determination of an appropriate cell density for the screening experiments --- p.46 / Chapter 3.1.2 --- Characterization of Aβ-induced cytotoxicity in NGF-differentiated PC 12 cells --- p.47 / Chapter 3.1.2.1 --- Cytotoxicity of Aβ-related fragments in NGF-differentiated PC 12 cells --- p.48 / Chapter 3.1.2.2 --- Dose-dependent cytotoxic effect of Aβ on PC 12 cells --- p.48 / Chapter 3.1.2.3 --- Time-dependent effect of Aβ-induced toxicity on PC12 cells --- p.50 / Chapter 3.1.3 --- Protective effect of selected active principles against Aβ1-4-induced toxicity in PC 12 cells --- p.51 / Chapter 3.2 --- Measurement of reactive oxygen species (ROS) --- p.54 / Chapter 3.2.1 --- Measurement of ROS induced by H202 --- p.54 / Chapter 3.2.2 --- Measurement of ROS induced by Aβ --- p.56 / Chapter 3.3 --- Measurement of Intracellular calcium levels --- p.57 / Chapter 3.4 --- Measurement of caspase-3 activity --- p.58 / Chapter 3.4.1 --- AMC reference standard curve --- p.59 / Chapter 3.4.2 --- Measurement of caspase-3 activity --- p.59 / Chapter 3.5 --- PI staining for evaluate apoptosis and necrosis --- p.60 / Chapter Chapter Four --- Discussion --- p.64 / Chapter 4.1 --- Aβ-induced cytotoxicity in NGF-differentiated PC 12 cells as an in vitro model of Alzheimer's disease --- p.64 / Chapter 4.1.1 --- Cell line selection --- p.65 / Chapter 4.1.2 --- Characterization of Aβ-induced cytotoxicity in NGF-differentiated PC 12 cells --- p.66 / Chapter 4.2 --- Screening of the neuroprotective effects of selected active principles against Aβ-induced cytotoxicity in NGF-differentiated PC 12 cells --- p.67 / Chapter 4.3 --- Neuroprotection via inhibition of the ROS generation --- p.71 / Chapter 4.4 --- Neuroprotection via suppression of calcium homeostasis --- p.73 / Chapter 4.5 --- Neuroprotective via inhibition of Aβ-induced apoptosis --- p.75 / Chapter 4.5.1 --- Inhibition of caspase-3 activation --- p.75 / Chapter 4.5.2 --- PI staining for evaluation of apoptosis and necrosis --- p.76 / Chapter Chapter Five --- Conclusion and future work --- p.79 / Chapter 5.1 --- Conclusion --- p.79 / Chapter 5.2 --- Future work --- p.80 / References --- p.81

Introdução: Na Doença de Alzheimer, o comprometimento no desempenho nas Atividades de Vida Diária (AVD) impacta diretamente a autonomia e independência do indivíduo. A capacidade funcional determina o nível de auxílio que uma pessoa irá necessitar no cotidiano para uma vida em segurança e com autonomia. Dentre os domínios cognitivos, a Função Executiva tem sido relatada como a mais associada com o desempenho de funcionalidade. Há a necessidade de instrumentos válidos para avaliar os déficits das funções executivas no desempenho de tarefas de mundo real em pacientes com doença de Alzheimer (DA) no Brasil. Objetivo: Validar a versão brasileira do teste Executive Performance Test (EFPT) em pacientes com doença de Alzheimer (DA). Métodos: Adaptação cultural do EFPT para o português do Brasil. Os estudos de confiabilidade e validade foram realizados com três grupos de idosos: controles, DA leve e DA moderada. Este estudo examinou a estabilidade do instrumento, a consistência interna (alfa de Cronbach), a validade de constructo e de critério e análises de precisão. Resultados: A amostra foi composta de 83 participantes com 60 anos ou mais, distribuídos em três grupos: controle, DA leve e DA moderada. A confiabilidade inter examinadores foi alta (ICC = 0,985), com alta consistência interna (Cronbach ? = 0,967). Houve forte correlação entre EFPT-Br Total e DAFS-BR (r = -0.762), correlação fraca a moderada com a bateria cognitiva e correlação moderada a forte com a bateria funcional. Foi realizado o cálculo da da ROC multiclasse área sob a curva de 0,8933, a pontuação sugerida para diferenciar os grupos : menor que 8 para controles; entre 9 e 27 para DA leve; e acima de 28 para DA moderada, para discriminar grupos. Conclusão: O EFPT-BR é um teste válido, com parâmetros psicométricos satisfatórios, para discriminar pacientes saudáveis, com DA leve e DA moderada na realização de tarefas instrumentais. O teste fornece informações consistentes para auxiliar a compreensão do desempenho de pacientes com DA na realização de atividades de vida diária com mais autonomia e segurança / Background: In Alzheimer\'s disease, the impairment in performing Activities of Daily Life (ADL) directly affects the autonomy and independence of the individual. The functionality determine a person needs for a safe and autonomous life. Among the cognitive domains, Executive Function has been reported as the most associated with functionality performance. There is a need for valid assessments to evaluate the deficits of executive functions in performing of real world tasks with patients with Alzheimer\'s disease (AD) in Brazil. Objective: To validate to Brazilian Portuguese version of the Executive Function Performance Test (EFPT) in Alzheimer disease (AD) patients. Methods: Cultural adaptation of EFPT to Brazilian Portuguese. The reliability and validity studies were performed with three groups of elderly: controls, mild AD and moderate AD. This study examines instrument stability, an internal consistency (Cronbach\'s alpha), a construct and criterion validity, and precision analyzes. Results: The sample consisted of 83 participants aged 60 years and over, divided into three groups: control, mild AD and moderate AD. The inter-examiner reliability was high (ICC = 0.985), with high internal consistency (Cronbach ? = 0.967). There was a strong correlation between EFPT-Br Total and DAFS-BR (r = -0.762), weak to moderate correlation with a cognitive battery and moderate to strong correlation with the functional battery. We performed the calculation of the ROC multiclass area under the curve of 0.8933, a score suggested to differentiate the groups: less than 8 for controls; between 9 and 27 for mild AD; and above 28 for moderate AD, to discriminate groups. Conclusion: EFPT-BR is a valid test with satisfactory psychometric parameters to discriminate healthy patients with mild AD and moderate AD in performing instrumental tasks. The test provides consistent information to assist in understanding the performance of AD patients in carrying out more autonomous and safe daily life activities