A Neurodegenerative Disease (ND) is progressive damage to brain neurons, which the human body cannot repair or replace. The well-known examples of such conditions are Dementia and Alzheimer’s Disease (AD), which affect millions of lives each year. Although conducting numerous researches, there are no effective treatments for the mentioned diseases today. However, early diagnosis is crucial in disease management. Diagnosing NDs is challenging for neurologists and requires years of training and experience. So, there has been a trend to harness the power of deep learning, including state-of-the-art Convolutional Neural Network (CNN), to assist doctors in diagnosing such conditions using brain scans. The CNN models lead to promising results comparable to experienced neurologists in their diagnosis. But, the advent of transformers in the Natural Language Processing (NLP) domain and their outstanding performance persuaded Computer Vision (CV) researchers to adapt them to solve various CV tasks in multiple areas, including the medical field. This research aims to develop Vision Transformer (ViT) models using Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset to classify NDs. More specifically, the models can classify three categories (Cognitively Normal (CN), Mild Cognitive Impairment (MCI), Alzheimer’s Disease (AD)) using brain Fluorodeoxyglucose (18F-FDG) Positron Emission Tomography (PET) scans. Also, we take advantage of Automated Anatomical Labeling (AAL) brain atlas and attention maps to develop explainable models. We propose three ViTs, the best of which obtains an accuracy of 82% on the test dataset with the help of transfer learning. Also, we encode the AAL brain atlas information into the best performing ViT, so the model outputs the predicted label, the most critical region in its prediction, and overlaid attention map on the input scan with the crucial areas highlighted. Furthermore, we develop two CNN models with 2D and 3D convolutional kernels as baselines to classify NDs, which achieve accuracy of 77% and 73%, respectively, on the test dataset. We also conduct a study to find out the importance of brain regions and their combinations in classifying NDs using ViTs and the AAL brain atlas. / <p>This thesis was awarded a prize of 50,000 SEK by Getinge Sterilization for projects within Health Innovation.</p>

Hintergrund Ziel der vorliegenden Untersuchung war die Erfassung der Lebensqualität von älteren Menschen mit leichten kognitiven Störungen im Vergleich zu kognitiv gesunden älteren Menschen. Die Prävalenz von leichten kognitiven Störungen in der Bevölkerung wird in epidemiologischen Studien mit 3 bis 19 % der über 65-Jährigen angegeben (Ritchie, 2004). Methode Es handelt sich um eine 2012 bundesweit durchgeführte bevölkerungsrepräsentative Befragung zur subjektiven Lebensqualität von 997 Probanden (60 Jahre und älter). Die Erfassung erfolgte mittels der Messinstrumente WHOQOL-BREF und dem speziell für ältere Menschen entwickelten WHOQOL-OLD. Zudem wurden die ermittelten Werte für die Lebensqualität in den soziodemografischen Kontext gesetzt, um eventuelle Faktoren zu ermitteln, die die unterschiedlichen Bereiche der Lebensqualität beeinflussen. Zur Identifikation kognitiver Störungen wurde der DemTect eingesetzt. Bei Verdacht auf Demenz fand das Interview nicht statt. Probanden mit leichten kognitiven Beeinträchtigungen wurden interviewt. Das Ergebnis des DemTects bestimmte die Zuteilung der Probanden in die jeweilige Gruppe (leichte kognitive Störungen vs. kognitiv gesund). Die Kriterien für die Gruppe der Probanden mit leichten kognitiven Störungen erfüllten 267 Probanden, für 730 Teilnehmer fanden sich keine Anzeichen einer kognitiven Beeinträchtigung. Ergebnis Die befragten Probanden im Alter ab 60 Jahre mit leichten kognitiven Störungen schätzten ihre Lebensqualität in allen Bereichen des WHOQOL-BREF und WHOQOL-OLD (außer im Bereich Ängste und Befürchtungen hinsichtlich Tod und Sterben) geringer ein als kognitiv gesunde Probanden. Schlussfolgerung Es konnte gezeigt werden, dass bereits leichte kognitive Störungen mit einer erheblichen Reduktion der subjektiven Lebensqualität einhergehen.:Bibliografische Zusammenfassung 3 Abkürzungsverzeichnis 4 Abbildungs- und Tabellenverzeichnis 6 1 Einleitung 7 1.1 Lebensqualität und ihre Erfassungsinstrumente 8 1.2 Leichte kognitive Störungen und ihre Diagnostik 13 2 Theorie und Stand der Forschung 17 2.1 Theoretischer Ansatz 17 2.2 Stand der Forschung 18 3 Fragestellungen und Ziele der Studie 39 4 Methodisches Vorgehen 41 4.1 Auswahl der Probanden 41 4.2 Datenerhebung 41 4.3 Beschreibung der Erhebungsinstrumente 42 4.4 Statistische Auswertung 44 5 Ergebnisse 45 5.1 Soziodemografische Merkmale der Studienteilnehmer 45 5.2 Mittelwerte WHOQOL-BREF 48 5.3 Mittelwerte WHOQOL-OLD 49 5.4 Einfluss von soziodemografischen und gesundheitsbezogenen Determinanten auf die Lebensqualität 50 5.4.1 Lebensqualitätsbereiche des WHOQOL-BREF 51 5.4.2 Lebensqualitätsbereiche des WHOQOL-OLD 54 6 Diskussion 57 7 Schlussfolgerungen und Ausblick 69 8 Zusammenfassung der Arbeit 70 9 Literaturverzeichnis 72 Erklärung über die eigenständige Abfassung der Arbeit 89 Lebenslauf 90 Publikationen 91 Danksagung 92

The number of dementia cases is increasing worldwide. Most research and development in this area is related to the prevention of dementia, and to the development of various prediction tools for dementia. The tools made available take most of the medical data into account while calculating risk scores, with only a small amount of non-medical data. There is a lot of data related to medical and non-medical risk factors available from various sources which can be retrieved and analysed in real time, but this is today not used in any risk score tool for risk score calculation. As part of the project Multimodal strategies to promote a healthy brain in ageing: Innovative evidence-based tools (MULTI-MODE), a new risk score is being developed to be used in a new ICT-based tool for dementia prediction. Identification of non-medical data and a good model to fill the gap between data available at the server and using this data in risk score calculation may help in increasing the predictability of tools. In this thesis, some of the existing risk factors for the prediction of dementia are described, and the importance of non-medical factors in calculating risk scores is discussed. Additional non-medical factors are identified that could be included in future versions of the risk score. A database design for storing risk score information efficiently is presented, as is an app structure that can be used at the server side to validate the user input and to increase the effectiveness of a prediction tool. / Antal demensfall ökar över hela världen. Forskning och utveckling inom detta område är relaterat till att förebygga demens och att utveckla olika prognosverktyg för demens. Flera tillgängliga verktyg tar hänsyn till medicinska data i beräkning av riskpoäng, med endast en liten mängd av icke-medicinska data. Det finns en hel del data om medicinska och icke-medicinska faktorer online, men de används idag inte för riskpoängberäkning. Som en del av projektet Multimodala strategier för att främja en frisk hjärna i åldrande: Innovativa evidensbaserade verktyg (MULTI-MODE), så har en ny metod utvecklats för att användas i ett nytt IT-baserat verktyg för demensförutsägelse. Identifiering av icke-medicinska data och en bra modell för att överbrygga gapet mellan tillgängliga data på servern och använda dessa data i riskberäkning kan bidra till att öka precisionen hos verktyg. I den här studien beskrivs en del befintliga riskfaktorer för förutsägelse av demens och vikten av icke-medicinska faktorer i beräkning av risk diskuteras. Ytterligare icke-medicinska faktorer identifieras som skulle kunna ingå i framtida versioner av riskverktyg (såsom appar). Vissa identifierade riskfaktorer har analyserats och visade att effekten av att införa icke-medicinska faktorer ökar precisionen i resultaten. En databasdesign för lagring av riskinformation på ett effektivt sätt presenteras, liksom en appstruktur som kan användas på serversidan för att validera några av de parametrar som kan öka effektiviteten av verktyget.

Alzheimer's disease (AD) is an increasing problem in modern society, both with regards to public health and cost of care. The causes of AD are not yet fully understood, and there is no cure or inhibiting drug. The aim of this thesis is to investigate the association between the bile acid profile as an indicator of dysbiosis and AD and mild cognitive impairment (MCI) using machine learning algorithms. The hypothesis that bile acid data can be used to predict AD or MCI at the time of diagnosis has been tested, and could not be confirmed. Somewhat better test results were obtained for the transition from normal cognitive function to MCI and from MCI to AD over time. Limitations relevant for this study included the possible uncertainties in the diagnostic patient data as well as in the relationship between bile acids and dysbiosis. The results from transitions in patient's diagnosis could warrant further research on the relationship between the bile acid profile or dysbiosis and changes in cognitive function. We suggest such research is conducted with more sophisticated models. / Alzheimers sjukdom (AD) är ett viktigt och ökande problem i dagens samhälle, både vad gäller folkhälsan och kostnaderna för samhället. Orsakerna bakom AD är än idag inte helt utredda och det finns inget botemedel eller bromsmedicin. Målet med den här studien är att undersöka sambandet mellan gallsyraprofilen som en indikator på dysbios och AD och mild kognitiv störning (MCI) med hjälp av maskininlärningsalgoritmer. Hypotesen att gallsyraprofilen kan användas för att förutsäga AD eller MCI vid diagnostillfället har studerats och kunde inte fastställas. Något bättre resultat erhölls vad gäller övergången från normal kognitiv funktion till MCI och från MCI till AD över tid. Begränsningar som är relavanta för studien inkluderar möjlig osäkerhet vad gäller diagnosen och även vad gäller sambandet mellan gallsyraprofilen och dysbios. Resultaten från förändringen i patienters diagnos kan vara en grund för fortsatt forskning om samband mellan gallsyraprofilen eller dysbios och förändringar i kognitiv funktion. Vi föreslår att mer sofistikerade modeller används för sådan forskning.

Les symptômes neuropsychiatriques (SNP), des perturbations comportementales et psychologiques, surviennent fréquemment dans la démence de la maladie d’Alzheimer. En plus d’être un facteur de risque d’institutionnalisation précoce et de constituer une charge pour les aidants, ils peuvent aussi être associés à un déclin cognitif accéléré ou à des troubles cognitifs plus importants lorsqu’ils surviennent dans les stades pré-démentiels des maladies (avant ou pendant le trouble cognitif léger). Considérant la diversité des résultats d’études antérieures, la relation entre ces SNP, le déclin cognitif et la survenue/évolution des maladies neurodégénératives est encore pleine de mystères. En effet, il a pu être mis en évidence que la dépression, l’apathie, ou encore l’anxiété étaient des facteurs de risques de conversion en maladie d’Alzheimer, ou de déclin cognitif accéléré chez des individus ayant un trouble cognitif léger ou une cognition normale. Ils ont aussi pu être associés à des changements des structures ou du métabolisme cérébraux, limbiques et associatifs. Cependant, le rôle et la position exacte des SNP dans le décours temporel des maladies restent incertains : conséquences de la neurodégénérescence ? Conséquence psychologique de la survenue de troubles cognitifs ? Cause de troubles cognitifs par réorientation des ressources exécutives et comportementales ? Stade prodromal des maladies ? Conséquence d’une structure de personnalité antérieure ? Ce travail propose d’aborder différentes problématiques de recherches liées aux SNP, notamment leurs associations cognitives en fonction de facteurs démographiques, psychologiques ou psychiatriques dans différents stades de déclins cognitifs ; leurs associations neurostructurelles ou métaboliques cérébrales, en devis transversal, rétrospectif ou longitudinal. L’objectif étant de conforter certaines données de la littérature sur l’impact des SNP sur les performances cognitives et leur évolution dans le vieillissement normal et pathologique, et comprendre l’apport de certaines analyses prédictives et de facteurs de risques afin d’en dégager des pistes d’applications cliniques dans une visée d’anticipation du déclin cognitif. Pour cela, différentes bases de données sont traitées afin d’extraire différents types de variables d’intérêt (démographiques, neuropsychiatriques, neuropsychologiques, neuroimagerie, statuts génétiques et diagnostiques, facteurs psychologiques…). Au total, c’est près de 5000 participants qui ont été extraits et analysés au travers des différentes bases de données. Les principaux résultats ont permis de montrer : 1) des associations SNP/performances cognitives différentes entre les femmes et les hommes ; 2) des relations neurostructurelles différentes entre les SNP et les différents stades de déclin cognitif de la maladie d’Alzheimer ; 3) le rôle prédictif des SNP dans la conversion du trouble cognitif léger en maladie d’Alzheimer expliqué par l’altération des habiletés fonctionnelles des individus ; 4) des implications de traits de personnalité dans le déclin cognitif et cérébral chez des individus développant ou non démence de type Alzheimer. Ces données consolident les résultats de la littérature et soutiennent l’utilité de certains modèles statistiques et de prédictions dans l’établissement des facteurs de risques de déclin et l’estimation de l’importance du déclin basé sur ces facteurs, à la fois chez des individus cognitivement sains, et des individus à risque de développer une démence. / Neuropsychiatric symptoms (NPS), behavioral and psychological disturbances, occur frequently in Alzheimer's dementia. In addition to being a risk factor for early institutionalization and a burden to caregivers, they may also be associated with accelerated cognitive decline or greater cognitive impairment when they occur in the pre-dementia stages of the diseases (before or during mild cognitive impairment). Considering the diversity of results of previous studies, the relationship between these NPS, cognitive decline and the occurrence/evolution of neurodegenerative diseases is still full of mysteries. Indeed, it has been shown that depression, apathy, or anxiety were risk factors for conversion to Alzheimer's disease, or for accelerated cognitive decline in individuals with mild cognitive impairment or normal cognition. They could also be associated with changes in brain, limbic and associative structures or metabolism. However, the exact role and position of NPS in the temporal course of diseases remains uncertain: consequences of neurodegeneration? Psychological consequence of the onset of cognitive disorders? Cause of cognitive disorders by redirection of executive and behavioral resources? Prodromal stage of diseases ? Consequence of a previous personality structure? This work proposes to address different research issues related to NPS, in particular their cognitive associations according to demographic, psychological or psychiatric factors in different stages of cognitive decline; their neurostructural or cerebral metabolic associations, in crosssectional, retrospective or longitudinal specifications. The objective is to confirm certain data in the literature on the impact of NPS on cognitive performance and its evolution in normal and pathological aging, and to understand the contribution of certain predictive analyses and risk factors in order to identify avenues of clinical application with a view to anticipating cognitive decline. For this purpose, different databases are processed in order to extract different types of variables of interest (demographic, neuropsychiatric, neuropsychological, neuroimaging, genetic and diagnostic status, psychological factors...). In total, nearly 5000 participants were extracted and analyzed through the different databases. The main results showed: 1) different NPS/cognitive performance associations between women and men; 2) different neurostructural relationships between NPS and different stages of cognitive decline in Alzheimer's disease; 3) the predictive role of NPS in the conversion of mild cognitive impairment to Alzheimer's disease explained by the alteration of individuals' functional abilities; 4) implications of personality traits in cognitive and brain decline in individuals developing or not dementia of the Alzheimer’s type. These data consolidate the findings of the literature and support the utility of certain statistical and predictive models in establishing risk factors for decline and estimating the magnitude of decline based on these factors, both in cognitively healthy individuals, and individuals at risk of developing dementia.

No description available.

L’apnée obstructive du sommeil (AOS) est l’un des troubles du sommeil les plus fréquents chez l’adulte et sa prévalence augmente avec l’âge. Elle se caractérise par des arrêts répétés de la respiration au cours du sommeil, menant à la présence de fragmentation du sommeil et à de l’hypoxémie intermittente. Lorsque non traité, ce trouble peut mener à diverses conséquences non négligeables sur la santé des individus qui en sont atteints, incluant sur la santé du cerveau. L’AOS est d’ailleurs de plus en plus reconnue comme étant un possible facteur de risque de déclin cognitif et de démence. Dans ce contexte, quelques études transversales ont caractérisé le volume de la substance grise cérébrale chez des adultes vieillissants atteints d’AOS, avec des résultats variables. En effet, certaines études ont noté de plus grands volumes de substance grise chez les personnes avec une AOS plus sévère, alors que d’autres ont retrouvé des plus petits volumes chez cette même population. Ce qui explique la variabilité entre les études demeure à ce jour mal compris, bien que certaines hypothèses aient émergé. Ainsi, cette thèse vise à évaluer l’association entre la sévérité de l’AOS et le volume de substance grise cérébrale chez des personnes d’âge moyen et âgées de manière transversale et longitudinale. La première étude de cette thèse se base sur des techniques de neuroimagerie afin d’évaluer les liens entre la sévérité de l’AOS et le volume de la substance grise cérébrale des sous-régions du lobe temporal médian, soit l’hippocampe, le cortex entorhinal et le cortex parahippocampique. Celles-ci ont été ciblées puisqu’elles peuvent être affectées tôt dans la progression de la pathologie de la maladie d’Alzheimer (MA). De plus, nous avons testé l’effet d’une correction de la portion d’eau libre sur les volumes cérébraux. Finalement, nous avions comme objectif de mieux comprendre si certaines caractéristiques démographiques ou cliniques de nos participants pouvaient avoir un impact sur les associations observées. Nous avons observé qu’une AOS plus sévère était associée à des volumes de substance grise plus grands de certaines sous-régions du lobe temporal médian (hippocampe et cortex entorhinal), mais seulement chez des groupes de participants spécifiques, soit les femmes, les participants plus âgés et ceux présentant un trouble cognitif léger de type amnésique. Le fait d’apporter une correction pour la portion d’eau libre aux volumes mesurés a rendu non significatives les associations observées. Il est donc possible que la présence accrue d’eau extracellulaire, suggérant de l’œdème cérébral, puisse expliquer la présence de plus grands volumes chez les participants présentant une AOS plus sévère. La deuxième étude visait quant à elle à évaluer les changements structurels des sous-régions du lobe temporal médian associés à la sévérité de l’AOS chez des personnes d’âge moyen et âgées sur une période d’environ 2 ans. Nous avons démontré que chez nos participants n’ayant pas utilisé un traitement pour l’AOS, la présence d’interaction entre la sévérité de l’AOS et l’âge permettait d’expliquer les changements annuels de volume de substance grise. De fait, les participants plus jeunes de notre échantillon (< 65 ans) avec une AOS plus sévère présentaient un plus grand taux de changement annuel de volume de substance grise, soulignant la présence d’hypertrophie dans ce sous-groupe. Ceci a été mis en lumière pour l’ensemble des sous-régions du lobe temporal médian. Chez les participants âgés entre 65 et 75 ans, aucune association entre la sévérité de l’AOS et les changements de volume au fil du temps n’a pu être soulignée. Les participants plus âgés (> 75 ans) avec une plus grande sévérité d’AOS présentaient quant à eux une plus grande atrophie au fil du temps dans certaines régions, soit l’hippocampe et le cortex entorhinal. Ces résultats supportent donc une hypothèse biphasique des changements au niveau de la substance grise cérébrale chez les gens présentant de l’AOS, avec une première phase caractérisée par des augmentations de volume chez les adultes plus jeunes, menant éventuellement à de l’atrophie chez les personnes plus âgées. Cette thèse permet d’avoir un portrait plus clair sur la nature des changements et des mécanismes impliqués dans l’association entre la sévérité de l’AOS et les volumes de substance grise. L’un des apports importants est l’utilisation d’une nouvelle méthodologie afin d’obtenir une portion d’eau libre, ce qui a permis de mieux comprendre l’apport potentiel de mécanismes pouvant sous-tendre les changements structuraux observés, notamment l’œdème cérébral. De plus, l’évaluation des caractéristiques individuelles des participants a permis d’expliquer partiellement les incongruences entre les études précédentes. Dans le cadre des études incluses dans cette thèse, nous avons observé des changements plus marqués chez les femmes. Nous avons également pu démontrer que l’âge des individus atteints d’AOS pouvait influencer significativement le patron de changements observés. Les résultats de cette thèse pourraient donc permettre de mieux cibler les personnes avec AOS qui pourraient le plus bénéficier d’un traitement pour maintenir leur santé cérébrale. / Obstructive sleep apnea (OSA) is one of the most common sleep disorders in adults, and its prevalence increases with age. It is characterized by repeated pauses in breathing during sleep, leading to sleep fragmentation and intermittent hypoxemia. If left untreated, this disorder can have numerous consequences, including on the brain’s health. OSA is increasingly recognized as a risk factor for cognitive decline and dementia. In this context, cross-sectional studies have characterized brain gray matter volume in aging adults with OSA, with variable results. Indeed, some studies have noted greater gray matter volumes in people with more severe OSA, while others have found smaller volumes in this same population. What explains the variability between studies remains poorly understood, although some hypotheses have emerged. Thus, this thesis aims to assess the association between OSA severity and cerebral gray matter volume in middle-aged and elderly individuals using cross-sectional and longitudinal designs. The first study in this thesis uses neuroimaging techniques to assess the links between OSA severity and cerebral gray matter volume of the medial temporal lobe subregions, i.e. the hippocampus, entorhinal cortex and parahippocampal cortex. These were chosen as they can be affected early in the progression of Alzheimer's disease (AD) pathology. We also corrected our brain volumes for free-water portion. Finally, we aimed to better understand whether certain demographic or clinical characteristics of our participants might have an impact on the associations observed. We noted that more severe OSA was associated with larger gray matter volumes in certain subregions of the medial temporal lobe (hippocampus and enthorinal cortex), but only in specific groups of participants: women, older participants and those with amnestic mild cognitive impairment. Correcting our volumes for free-water portion rendered the associations nonsignificant. It is therefore possible that the presence of extracellular water, suggestive of cerebral edema, could explain the presence of larger volumes in participants with more severe OSA. The second study aimed to assess longitudinal structural changes associated with OSA severity in middle-aged and elderly people over a period of around 2 years. We found that in participants who did not use treatment for OSA, the presence of interactions between OSA severity and age were associated with the annual changes in gray matter volume. Indeed, younger participants (< 65 years old) in our sample with more severe OSA showed a greater rate of annual change in gray matter volume, highlighting the presence of hypertrophy in this subgroup. This was underlined in all medial temporal lobe subregions. In participants aged between 65 and 75, no association between OSA severity and volume changes over time could be highlighted. Older participants (>75 years old) with greater OSA severity showed greater hippocampal and entorhinal cortex atrophy over time. These results therefore support a biphasic hypothesis of changes in cerebral gray matter in people with OSA, with an initial phase characterized by volume increases in younger adults, eventually leading to atrophy in older people. This thesis provides a clearer picture of the nature of the changes and mechanisms involved in the association between OSA severity and gray matter volumes. An important contribution is the use of a new methodology to obtain a free-water portion, which allows to better understand the potential contribution of mechanisms that may underlie the structural changes observed, notably cerebral edema. In addition, the assessment of participants' individual characteristics helped to partially explain incongruities between previous studies. Indeed, in the studies included in this thesis, we observed more marked changes in certain subgroups of participants, notably women. We were also able to demonstrate that the age of individuals with OSA could significantly influence the pattern of changes observed, either gray matter hypertrophy or atrophy. The results of this thesis could therefore make it possible to target specific subgroups of individuals suffering from OSA who may be at greater risk of displaying changes in gray matter structure, and thus promote screening and treatment when necessary.

Introdução: A tomografia por emissão de pósitrons (PET) permite a avaliação in vivo de alvos moleculares em doenças neurodegenerativas, como a doença de Alzheimer (DA). A deposição de placa Beta-amiloide pode ser avaliada por PET 11C-PIB, enquanto o PET 18F-FDG é utilizado para avaliar o metabolismo da glicose cerebral, que pode ser um indicador de lesão neuronal e disfunção sináptica. Além disso, a captação cerebral precoce de radiofármacos de PETamiloide pode determinar o fluxo sanguíneo cerebral regional. Mais estudos correlacionando a fase inicial de perfusão do 11C-PIB (11C-pPIB) e 18F-FDG ainda são necessários, considerando que o fluxo sanguíneo e o metabolismo da glicose cerebral são geralmente acoplados em repouso e durante as ativações neuronais. Objetivo: Avaliar se existe concordância diagnóstica e/ou topográfica entre a imagem na fase de perfusão do 11C-PIB (11C-pPIB), obtida entre 0 e 10 minutos, e a imagem metabólica de PET 18F-FDG através da quantificação por SPM (Statistical Parametric Mapping) e por análise visual, em sujeitos com DA e CCLa comparados aos controles idosos saudáveis. Métodos: CAPEPesq: Nº1.454.598. Noventa e três sujeitos foram alocados em três grupos de acordo com o diagnóstico clínico: doença de Alzheimer (DA - n = 27); Comprometimento Cognitivo Leve amnéstico (CCLa - n = 39); Controle idosos saudáveis (n = 27), estes foram submetidos a exames de imagens de RM ponderada em T1 e de PET/CT. A PET/CT 18F-FDG foi realizada 30 minutos após a injeção do radiofármaco e a PET/CT 11C-pPIB foi adquirida imediatamente após a injeção do radiofármaco, e os primeiros 10 minutos da aquisição foram considerados na análise. Imagens de PET foram corrigidas para efeito de volume parcial e as imagens foram espacialmente normalizadas utilizando um modelo anatômico personalizado da própria amostra (template), para análise por Mapa Estatístico Paramétrico (SPM8). A análise visual e individual foi realizada por dois médicos nucleares com experiência na área, cegos em relação à identificação das imagens, seus respectivos radiofármacos e diagnóstico clínico. Eles foram solicitados a fornecer um diagnóstico e indicar uma classificação com base na inspeção visual das imagens de 18F-FDG e 11CpPIB, e também na avaliação individual dos mapas-t de SPM (análise baseada em voxel comparando um único sujeito do grupo DA com um grupo de controle cognitivamente normal). Resultados e Discussão: Na análise por SPM, o 11CpPIB mostrou menor captação difusa cortical do que 18F-FDG. Na análise entre grupos, há uma diferença na captação de 11C-pPIB e 18F-FDG, o que é esperado, uma vez que a biodistribuição é uma propriedade particular de cada biomarcador de PET. Na comparação do grupo DA em relação ao grupo controle, os indivíduos com DA apresentaram diminuição da captação de 11C-pPIB nas regiões temporo-límbicas: amígdala e hipocampo (E = esquerdo) P = 0,006, amígdala e hipocampo (D = direito) P = 0,023; giro parahipocampal (E) P = 0,008 (D) P = 0,015; temporal superior (E) P = 0,012 (D) P = 0,015. No 18F-FDG, houve diminuição da captação no grupo DA comparado ao grupo controle nas seguintes regiões: córtex do cíngulo posterior (E) P = 0,028; pré-cuneus (E) P= 0,029; giro temporal médio (E) P = 0,039; giro temporal inferior (E) P = 0,044. Na comparação do grupo CCLa em relação ao grupo controle, os indivíduos com CCLa apresentaram diminuição da captação de 11C-pPIB na região do giro parahipocampal (E) P = 0,012. Na identificação visual, 100% das imagens PET 18F-FDG e 99% das imagens PET 11C-pPIB foram corretamente identificadas. Na análise visual e individual, foram observadas reduções na captação de 11CpPIB envolvendo a região temporal medial nos indivíduos com DA que não foi detectada pelo 18F-FDG. Isso poderia significar algum tipo de dissociação entre a perfusão e o metabolismo. Conclusão: Nossos achados sugerem que não há concordância diagnóstica e topográfica perfeita entre a imagem do metabolismo de glicose por PET com 18F-FDG e o padrão de perfusão cerebral usando o marcador PET 11C-PIB em certas estruturas cerebrais em idosos saudáveis, CCLa e pacientes com DA, na quantificação por SPM e na análise visual. Como um biomarcador duplo, a PET 11C-pPIB pode fornecer informações complementares sobre alterações fisiológicas no envelhecimento, e ajudar a elucidar e entender melhor a patologia das doenças relacionadas a memória / Introduction: Positron emission tomography (PET) allows in vivo evaluation of molecular targets in neurodegenerative diseases, such as Alzheimer´s Disease (AD). Beta-amyloid plaque deposition can be assessed by 11C-PIB PET while 18FFDG PET is used to assess cerebral glucose metabolism, which can be an indicator for neuronal injury and synaptic dysfunction. In addition, early cerebral uptake of PET-amyloid radiopharmaceuticals can determine regional cerebral blood flow. More studies correlating early-phase 11C-PIB (11C-pPIB) and 18F-FDG are still needed considering that blood flow and cerebral glucose metabolism are usually coupled at rest and during neuronal activations. The aim of this study is to evaluate topographic similarities and differences between cerebral perfusion images obtained with early 11C-PIB PET images and the metabolic images obtained with 18F-FDG PET. Methods: CAPEPesq: Nº1.454.598. Ninety-three subjects were allocated into three groups according to clinical diagnosis: Alzheimer\'s disease (AD, n=27); Mild Cognitive Impairment amnestic (aMCI, n=39); Elderly healthy control (n=27), they underwent T1-weighted MRI and PET/CT imaging. 18F-FDG PET/CT acquisition was performed 30 minutes after tracer injection and 11C-pPIB PET/CT was acquired immediately after the tracer injection and the first 10 minutes of the acquisition was considered in the analysis. PET images were corrected for partial volume effect and the images were spatially normalized using a custom anatomical template of the sample itself, for analysis by Statistical Parametric Mapping (SPM8). Visual and individual analysis were performed by two experient nuclear medicine physicians, blind in relation to the identification of the images, their respective radiopharmaceuticals and clinical diagnosis. They were asked to provide a diagnosis and to indicate their level of confidence on the basis of visual inspection of 18F-FDG and 11C-pPIB images, and also individual assessment of SPM t-maps (voxel-based analysis comparing a single subject of AD group to a cognitively normal control group). Results and Discussion: In the analysis by SPM, the 11C-pPIB showed lower cortical diffuse uptake than 18F-FDG. In the analysis between groups, there is a difference in 11CpPIB and 18F-FDG uptake, what is expected since biodistribution is a particular propriety of each PET tracer. The control group versus the AD group, individuals with AD presented a decreased 11C-pPIB uptake in the temporo-limbic regions: amygdala and hippocampal (L = left) P = 0.006; amygdala and hippocampal (R = right) P = 0.023; parahippocampal gyrus (L) P = 0.008 (R) P = 0.015; and superior temporal (L) P = 0.012 (R) P = 0.015. In the 18F-FDG, there was a decreased uptake in the AD group compared to the control group in the following regions: posterior cingulate cortex (L) P = 0.028; precuneus (L) P= 0.029; medial temporal gyrus (L) P = 0.039; and inferior temporal gyrus (L) P = 0.044. In the comparison of aMCI group versus the control group, individuals with aMCI presented a decreased 11C-pPIB uptake in the region: parahippocampal gyrus (L) P = 0.012. In the visual identification, 100% of 18F-FDG PET images and 99% of 11C-pPIB PET images were correctly recognized. In the visual and individual analysis, it was observed reductions in 11C-pPIB uptake involving medial temporal region in the AD subjects that was not detected by 18F-FDG.This could mean some kind of decoupling between perfusion and metabolism. Conclusion: Our findings suggest that there is no perfect diagnostic and topographical concordance between the imaging of 18F-FDG PET glucose and the cerebral perfusion pattern using the 11C-PIB PET marker in certain brain structures in healthy elderly, aMCI and patients suggestive of AD, quantification by SPM and visual analysis. As a double biomarker, 11C-PIB can provide complementary information on pathological aging of the brain, and it could help elucidate and better understand the pathology of memory-related diseases

Introdução: segundo a literatura, sais de lítio podem produzir redução da função renal. A magnitude dessa informação é debatível, uma vez que não há estudo clínico randomizado e controlado entre usuários de lítio, em sua maioria pacientes com depressão ou transtorno bipolar. A possibilidade do uso do lítio para o tratamento da demência de Alzheimer prodrômica reforça a necessidade de maior investigação de efeitos adversos atribuídos ao lítio, especialmente com relação à função renal. Objetivos: avaliar a segurança da utilização do lítio em baixa dosagem com relação à função renal de pacientes idosos. Como objetivos secundários serão avaliadas: a segurança clínica através de exame e questionário específico, as funções tireoidiana, imunológica e o metabolismo glicêmico. Métodos: estudo randomizado e placebo controlado de 2 anos, seguido de fase aberta por mais 2 anos. Foram avaliados 59 idosos com comprometimento cognitivo leve com seguimento mínimo de dois anos (fase controlada). A função renal foi estimada através das fórmulas aMDRD e CKD- EPI, a partir de exames laboratoriais e dados clínicos coletados durante o estudo. As funções tireoidiana, imunológica e glicêmica foram avaliadas respectivamente através de TSH, T4 livre, leucócitos total, neutrófilos, linfócitos, glicemia e insulinemia de jejum, e HOMA-IR. A segurança clínica foi avaliada através de entrevista sistemática realizada a cada 3 meses, utilizando exame físico e a escala UKU para efeitos adversos. Resultados: não houve piora da função renal com o uso do lítio (litemia entre 0,25-0,5 mmol/l) tanto pela aMDRD (p=0,453) como pela CKD-EPI (p=0,181). Houve aumento significativo de neutrófilos (p=0,038) e do TSH (p=0,034). O grupo lítio apresentou incidência significativamente maior de diabetes mellitus (p=0,037) e arritmias (p=0,028), maior ganho de peso (p=0,015), mais sintomas na escala UKU (p=0,045), e maior interferência dos efeitos adversos do lítio em atividades diárias (p<0,001). Houve correlação entre a opinião de médico e do paciente nas interferências das atividades diárias atribuídas aos sintomas adversos (p<0,001). Conclusões: o uso de lítio em baixa dose não alterou a função renal, produziu alterações no sistema imunológico e tireoidiano sem impacto clínico, e foi seguro clinicamente. As razões do aumento de incidência de diabetes e arritmias merecem investigação posterior / Introduction: according to the literature, lithium salts may produce a reduction in kidney function. The magnitude of this information is debatable because there is no randomized and controlled clinical trial among lithium users, being mostly patients with depression or bipolar disorder. The possibility of using lithium for the treatment of prodromal Alzheimer\'s disease dementia increases the need for further investigation of adverse effects attributed to lithium, especially regarding to renal function. Objectives: To evaluate the safety of using low-dose lithium with respect to renal function in elderly patients. Secondary objectives were the evaluation of the clinical safety through specific questionnaire and clinical assessment, and to assess thyroid, immunological and glycemic function. Methods: a randomized and placebo controlled study for 2 years, followed by an open label follow-up of 2 years. We evaluated 59 elderly patients with mild cognitive impairment with accomplishment of at least two years of the controlled phase. Renal function was estimated by the aMDRD and CKD-EPI equation, and by laboratory and clinical data collected during the trial. The thyroid, immunological and glycemic functions were respectively evaluated by TSH, free T4, leukocyte count, neutrophil count, lymphocyte count, fasting plasma glucose and insulin, and the HOMA-IR. The clinical safety was evaluated through systematic examination performed every 3 months, with physical examination, clinical interview and UKU scale for adverse effects. Results: There was no decline of renal function with the use of lithium (litemia between 0.25-0.5 mmol/l) both in the aMDRD (p=0.453) and CKD-EPI (p=0.181) equations. A significant increase of neutrophils (p=0.038) and TSH (p=0.034) were observed. The lithium group showed significantly higher incidence of diabetes mellitus (p=0.037), arrhythmias (p=0.028), weight gain (p=0.015), more symptoms of UKU scale (p=0.045), and greater interference from the adverse effects of lithium during daily activities (p<0.001). There was an observed correlation between the opinion of the attending physician and the patient in respect to the interference in daily activities secondary to the adverse symptoms (p<0.001). Conclusions: The use of lithium in low doses did not result in renal function impairment, produced subtle changes in the immunological system and thyroid function, and was clinically safe for adverse effects. The reasons for the increased incidence of arrhythmias and diabetes mellitus deserve further investigation

O presente estudo consistiu-se na avaliação clínica e aplicação de testes cognitivos, além da realização de ressonância magnética (RM), de 3 tesla, do cérebro, processada com a técnica de \"Voxel-based Morphometry\" (VBM) e \"Skull Strip\", e 18F-FDG PET -CT processado com \"Statistical Parametric Mapping\" (SPM8) e correção de volume parcial (PVELab), em idosos sem déficits cognitivos (CDR=0), com comprometimento cognitivo leve amnéstico (CCL) (CDR=0,5) e com Doença de Alzheimer leve (DA leve)(CDR de 0,5 a 1). Os objetivos foram comparar os padrões de neuroimagem estrutural e metabólica entre os grupos, assim como correlacionar alterações estruturais volumétricas da RM e alterações metabólicas cerebrais do PET-CT, a um teste funcional, o \"Informant Questionnaire on Cognitive Decline in the Elderly\" (IQCODE), nessa mesma amostra. Cada um dos grupo 3 grupos, pareados por idade, contém 30 indivíduos, totalizando amostra de 90. Os resultados dos exames de Neuroimagens, divididos por comparações entre os grupos, e corrigidos pela escolaridade, foram considerados significativos todos os achados nos quais a significância corrigida for <= 0,05 (p-FWEcorr <= 0,05). No CCL x DA foi observado hipometabolismo Giro do Cíngulo à Direita. No grupo DA x CCL foram observados hipometabolismos no Giro do Cíngulo à Esquerda, no Precuneus Esquerdo, Precuneus Direito e na parte inferior do Lobo Parietal Esquerdo. Na DA x Controle, utilizando-se pesquisa de área a priori e filtros gaussiano de 8mm e 4mm, foi observada redução estatisticamente significante quanto ao volume de substância cinzenta na Amígdala Esquerda e na Amígdala Direita. No PET - CT, da DA, em relação ao grupo controle foram observadas áreas de hipometabolismos no Giro do Cíngulo à Esquerda, no Precuneus Direito e no Giro Temporal Medial Direito. Na correlação direta do IQCODE, na comparação DA x Controle, no PET - CT evidenciou-se hipometabolismo no Giro Fusiforme Direito. Em conclusão, os resultados das comparações entre os grupos foram semelhantes ao encontrado na literatura para fases iniciais (leves) da patologia e mostraram, ainda, uma tendência a um \"continuum\" do controle até a DA. Por outro lado à correlação do IQCODE no DA x Controle carece de comprovação por outros trabalhos e com outros constructos estatísticos / This study consisted in the clinical evaluation and application of cognitive tests, in addition to magnetic resonance imaging (MRI) of 3 Tesla, of brain, processed with the technique of \"Voxel-based Morphometry\" (VBM) and \"Skull Strip\", and 18F-FDG PET-CT processed by \"Statistical Parametric Mapping\" (SPM8) and partial volume correction (PVELab) in subjects without cognitive impairment (CDR = 0), with amnestic mild cognitive impairment (MCI)(CDR = 0.5) and with mild Alzheimer \'s disease (AD mild)(CDRs of 0.5 to 1). The objectives were to compare the patterns of structural and metabolic neuroimaging between groups, as well as correlate MRI\'s volumetric structural changes and PET-CT\'s metabolic brain with a functional test, the \"Informant Questionnaire on Cognitive Decline in the Elderly\" (IQCODE) in this same sample. Each one of three groups, matched by age, contains 30 subjects, totaling 90. The test results of neuroimaging, divided by comparisons between groups, and corrected by education, were considered significant the findings that corrected significance is <= 0.05 (p-FWEcorr <= 0.05). In CCL x DA was observed hypometabolism right cingulate gyrus. In DA x CCL hypometabolism were observed in the left cingulate gyrus, the left precuneus, right precuneus and left inferior parietal lobe. In DA x Control, using the \"a priori\" research area and gaussian filters 8mm and 4mm was observed statistically significant reduction on the volume of gray matter in the left and right amygdala. In PET - CT of DA relative to control group were observed areas of hypometabolisms in left cingulate, right precuneus and in the right medial temporal gyrus. In direct correlation of the IQCODE, compared DA x Control on PET - CT revealed a hypometabolism in the right fusiform gyrus. In conclusion, the results of the comparisons between groups were similar to those found in the literature for early (mild) pathology and showed a \"continuum\" of control to the DA. On the other hand the correlation of the IQCODE in DA x Control lacks confirmation by other studies and other statistical constructs