L’objectif principal de cette thèse était d’obtenir, via l’électrophysiologie cognitive, des indices de fonctionnement post-traumatisme craniocérébral léger (TCCL) pour différents niveaux de traitement de l’information, soit l’attention sélective, les processus décisionnels visuoattentionnels et les processus associés à l’exécution d’une réponse volontaire. L’hypothèse centrale était que les mécanismes de production des lésions de même que la pathophysiologie caractérisant le TCCL engendrent des dysfonctions visuoattentionnelles, du moins pendant la période aiguë suivant le TCCL (i.e. entre 1 et 3 mois post-accident), telles que mesurées à l’aide d’un nouveau paradigme électrophysiologique conçu à cet effet. Cette thèse présente deux articles qui décrivent le travail effectué afin de rencontrer ces objectifs et ainsi vérifier les hypothèses émises. Le premier article présente la démarche réalisée afin de créer une nouvelle tâche d’attention visuospatiale permettant d’obtenir les indices électrophysiologiques (amplitude, latence) et comportementaux (temps de réaction) liés aux processus de traitement visuel et attentionnel précoce (P1, N1, N2-nogo, P2, Ptc) à l’attention visuelle sélective (N2pc, SPCN) et aux processus décisionnels (P3b, P3a) chez un groupe de participants sains (i.e. sans atteinte neurologique). Le deuxième article présente l’étude des effets persistants d’un TCCL sur les fonctions visuoattentionelles via l’obtention des indices électrophysiologiques ciblés (amplitude, latence) et de données comportementales (temps de réaction à la tâche et résultats aux tests neuropsychologiques) chez deux cohortes d’individus TCCL symptomatiques, l’une en phase subaigüe (3 premiers mois post-accident), l’autre en phase chronique (6 mois à 1 an post-accident), en comparaison à un groupe de participants témoins sains. Les résultats des articles présentés dans cette thèse montrent qu’il a été possible de créer une tâche simple qui permet d’étudier de façon rapide et peu coûteuse les différents niveaux de traitement de l’information impliqués dans le déploiement de l’attention visuospatiale. Par la suite, l’utilisation de cette tâche auprès d’individus atteints d’un TCCL testés en phase sub-aiguë ou en phase chronique a permis d’objectiver des profils d’atteintes et de récupération différentiels pour chacune des composantes étudiées. En effet, alors que les composantes associées au traitement précoce de l’information visuelle (P1, N1, N2) étaient intactes, certaines composantes attentionnelles (P2) et cognitivo-attentionnelles (P3a, P3b) étaient altérées, suggérant une dysfonction au niveau des dynamiques spatio-temporelles de l’attention, de l’orientation de l’attention et de la mémoire de travail, à court et/ou à long terme après le TCCL, ceci en présence de déficits neuropsychologiques en phase subaiguë surtout et d’une symptomatologie post-TCCL persistante. Cette thèse souligne l’importance de développer des outils diagnostics sensibles et exhaustifs permettant d’objectiver les divers processus et sous-processus cognitifs susceptible d’être atteints après un TCCL. / The main objective of this thesis was to obtain, using cognitive electrophysiology, biomarkers of mild traumatic brain injury (TBI) for different levels of information processing such as selective attention, visuo-attentional decision making and processes associated with the execution of a deliberate response. The fundamental assumption was that the lesion-producing mechanisms as well as the pathophysiology associated with mTBI leads to visuo-attentional dysfunctions, at least during the sub-acute period following the mTBI (i.e. between 1 and 3 months post-trauma), as measured by a novel electrophysiological paradigm developed for this purpose. This thesis presents two articles describing the work accomplished to meet these objectives, and verify the underlying assumptions. The first article presents the approach used to create a novel visuo-spatial attention task enabling the identification of electrophysiological (amplitude, latency) and behavioural (reaction time) indexes related to early visual and attentional processing (P1, N1, N2-nogo, P2, Ptc), selective visual attention (N2pc, SPCN) and decision-making processes (P3b, P3a) in a group of normal participants (i.e. without neurological injury). The second article presents a study of the persisting effects of a mTBI on visuo-attentional functions through the identification of targeted electrophysiological markers (amplitude, latency), and from behavioural data (task-related reaction time and neuropsychological tests results) in two cohorts of symptomatic mTBI individuals, one during the sub-acute phase (3 first months post-injury), the other during the chronic phase (6 months to 1 year post-injury), in comparison to a group of normal control participants. The results presented in this thesis indicate that it was has been possible to create a simple, rapid and low-cost task enabling the study of the various levels of information processing involved in the deployment of visuospatial attention. Subsequently, the use of this task in patients with mTBI tested during the sub-acute phase or the chronic phase allowed to identify differential impairment and recovery profiles for each of the components studied. Indeed, while the early components associated with early visual information processing (P1, N1, N2) were intact, certain attentional (P2) and cognitive-attentionnal (the P3a, P3b) components were affected, suggesting dysfunction in the spatio-temporal dynamics of attention, orientation of attention, and working memory, in the short- and/or long-term following mTBI, this is the presence of neuropsychological deficits mostly in the sub-acute phase and of persisting post-mTBI symptomatology. This thesis emphasizes the importance of developing sensitive and comprehensive diagnostic tools allowing to objectively identify the various cognitive processes and sub-processes that are likely to be affected after a mTBI.

Des études récentes ont rapporté que les individus âgés avec un trouble cognitif léger (TCL) ont de plus grandes activations en lien avec la réalisation d’une tâche cognitive que des personnes âgées saines. Des auteurs ont proposé que ces hyperactivations pourraient refléter des processus de plasticité cérébrale compensatoires ayant lieu pendant la phase précoce de la maladie d’Alzheimer. Des processus de compensations fonctionnelles pourraient émerger en réponse à une perte d’intégrité structurelle dans les régions du cerveau normalement requises pour compléter une tâche. Dans ce mémoire, j’ai évalué cette hypothèse chez des personnes avec TCL en faisant appel à une tâche de mémoire de travail comportant plusieurs niveaux de difficulté ainsi qu’aux techniques d’imagerie par résonnance magnétique (IRM) structurelle et fonctionnelle. Des analyses de régression multiples ont été utilisées afin d’identifier les régions cérébrales dont l’activité variait en fonction de l’intégrité neuronale telle que définie par le volume de l’hippocampe. Les valeurs estimées des paramètres du signal de ces régions furent ensuite extraites afin de procéder à des analyses corrélationnelles sur la performance ainsi que sur le volume de différentes structures cérébrales. Les résultats indiquent des hyperactivations dans les régions frontales droites chez les participants TCL souffrant d’une plus grande atteinte neuronale. De plus, le niveau d’activation est négativement corrélé au volume de structures frontales et pariétales. Ces résultats indique la présence d’une hyperactivation compensatoire dans la phase du TCL associée à la réalisation d’une tâche de mémoire de travail. / Recent studies have shown greater task-related activation in individuals with mild cognitive impairment (MCI) compared to healthy older adults. It has been suggested that these hyperactivations reflect compensatory processes of brain plasticity in the early phase of Alzheimer’s disease (AD). Functional compensation processes could emerge in response to a loss of structural integrity in brain regions typically required for the task. In this masters dissertation, I examined this hypothesis in MCI using a working memory task that incorporated a parametrical variation of difficulty level as well as functional and structural magnetic resonance imaging (MRI). Multiple regression analyses were used to identify areas of the brain in MCI in which functional activation varied as a function of neural injury as measured by hippocampal volume. Parameter estimates from these areas were then extracted and used for further correlational analyses with performance and structural volumes. Results indicate that MCI participants with high neural injury hyperactivated a subset of regions in the right frontal lobe. Furthermore, the level of activation was negatively correlated with the volume of frontal and parietal regions. These results indicate the presence of compensatory hyperactivations associated with a working memory task in persons with MCI.

The aim of this thesis is to analyse employment of people suffering from mild intellectual disability. The thesis briefly describes those learning difficulties and selects a mild intellectual disability from a wide range of other mental disabilities. The text is based on the fact that people with learning difficulties are able to work, live in a family and become members of the society as well as to be independent citizens. However, there is a necessity to help those people not only with regard to their educational process, but also on the labour market, which is apparently highly competitive even for people without any special needs. The thesis is also focused on various possibilities of people suffering from learning difficulties in the terms of enabling them to get a job. In accordance with the regulation on mild intellectual disability people, the thesis suggests many of suitable positions within service industry. Owing to the fact that people with this type of disease are under protection of the law, and that there are some incentives for employers, nowadays it is much easier to find them a job. Among other things, the thesis is also focused on economic, sociological and psychological aspects, so far as finding and keeping a job. For all people, their integration into society through the work...

Nous avons optimisé des liposomes thermosensibles, encapsulant un principe actif anticancéreux, le 5-Fluorouracile (5-FU), afin de déclencher sa libération par une hyperthermie locale modérée (39-42°C) induite par des ultrasons focalisés. L'hyperthermie sera appliquée au niveau de la tumeur, afin d'améliorer l’efficacité thérapeutique et de réduire la toxicité systémique. Les liposomes ont été formulés par hydratation du film lipidique en mélangeant la 1,2-dipalmitoyl-sn-glycéro-3-phosphocholine (DPPC) pour sa thermosensibilité à 41,5 ± 0,5°C, le cholestérol (CHOL) pour favoriser la stabilité des liposomes vis-à-vis des composants du sang, et le 1,2-distéaroyl-sn-glycéro-3-phosphoéthanolamine-N-[méthoxy(polyéthylène glycol)-2000] (DSPE-PEG) pour assurer la furtivité de la formulation. Les expériences ont confirmé que les liposomes formulés à base de DPPC/CHOL/DSPE-PEG dans un ratio molaire 90 : 5 : 5 mol% sont thermosensibles. Des liposomes composés du même mélange lipidique dans un rapport 65 : 30 : 5 mol% ont été considérés comme contrôle négatif non thermosensible. L’optimisation de l’encapsulation passive du 5-FU a permis d’obtenir une efficacité d’encapsulation (5-FU encapsulé/5-FU total) de 13%, mais le 5-FU est très faiblement retenu (12%) dans la cavité aqueuse des liposomes du fait du gradient osmotique à la dilution. La rétention du 5-FU a été optimisée (93%) par la technique d’encapsulation active basée sur la complexation intraliposomale du 5-FU avec le complexe cuivre-polyéthylèneimine préalablement encapsulé dans les liposomes. Cette technique a également permis d’améliorer l’efficacité d’encapsulation d’un facteur trois environ (37%), avec un taux de charge (ratio final 5-FU/lipides, mole/mole) de 50% environ. Nous avons alors obtenu des liposomes thermosensibles d'un diamètre hydrodynamique de 65 nm et de charge de surface de -10 mV. Les liposomes non thermosensibles, ont été caractérisés par un diamètre hydrodynamique de 105 nm et une charge de surface de -4,9 mV. La libération du 5-FU déclenchée par une hyperthermie induite par des ultrasons focalisés a été mesurée in vitro. En réponse à une hyperthermie de 42°C, les liposomes thermosensibles libèrent 68% de leur contenu, au bout de 10 min, alors que les liposomes non thermosensibles en libèrent moins de 20%. En outre, la cytotoxicité des liposomes encapsulant le complexe 5-FU-cuivre-polyéthylèneimine a été évaluée vis-à-vis de la lignée cellulaire HT-29 du carcinome colorectal humain. Les résultats ont révélé que les lipides à une concentration de 800 µM ne sont pas cytotoxiques (80% de viabilité). De plus, la complexation du 5-FU n’influence pas sa cytotoxicité ce qui prouve que la toxicité provient du 5-FU et non des excipients. En revanche, l’encapsulation du complexe 5-FU-cuivre-polyéthylèneimine dans les liposomes induit une diminution de la concentration inhibitrice médiane de 115 (solution du complexe) à 49 µM environ, corrélée à leur internalisation cellulaire. La pharmacocinétique chez des souris porteuses d’un modèle de tumeur colorectale HT-29 xénogreffée a montré que les liposomes permettent de prolonger d’un facteur 1,4 la demi-vie plasmatique de distribution du 5-FU. De plus, les aires sous la courbe des concentrations plasmatiques sur 24 h sont 1,9 et 2,9 fois plus élevées lorsque le 5-FU est administré sous forme de liposomes thermosensibles et non thermosensibles, respectivement, par rapport à la solution de 5-FU. Enfin, les liposomes non thermosensibles augmentent significativement d'un facteur 2 l'accumulation du 5-FU dans la tumeur par rapport à la solution de 5-FU. En conclusion, les liposomes thermosensibles développés présentent un fort intérêt pour une application thérapeutique en combinaison avec des ultrasons focalisés. / We optimized thermosensitive liposomes encapsulating an anticancer drug, 5-Fluorouracil (5-FU), in order to trigger the release upon focused ultrasound-mediated mild hyperthermia at the tumor. This approach would improve drug efficacy and would lower side effects. Liposomes were prepared by the lipid hydration method by mixing 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) for its temperature sensitivity at 41.5 ± 0.5°C, cholesterol (CHOL) to promote liposome stability towards blood components, and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (DSPE-PEG) to confer stealthiness to the formulation. The experiments confirmed that the liposomes formulated with DPPC/CHOL/DSPE-PEG in a molar ratio 90:5:5 mol% are thermosensitive, while liposomes composed of the same lipid mixture in a ratio 65:30:5 mol% were considered non thermosensitive negative control. The optimization of passive encapsulation of 5-FU yielded an encapsulation efficacy (encapsulated 5-FU/total 5-FU) of 13%. 5-FU was, however, very weakly retained (12%) in the aqueous core of liposomes following dilution due to the generation of an osmotic gradient. The retention of 5-FU has been optimized (93%) by the active encapsulation technique based on the intraliposomal complexation of 5FU with copper-polyethylenimine complex encapsulated beforehand into liposomes. This technique also improved 5-FU encapsulation efficacy by 3-fold (37%), yielding a loading efficiency (final drug/lipid ratio, mol/mol) of approximately 50%. The resulting thermosensitive liposomes and non thermosensitive liposomes have a hydrodynamic diameter and a surface charge around 65 nm and -10 mV, and 105 nm and -4.9 mV, respectively. Heat-triggered drug delivery was evaluated using focused ultrasound, and showed a release of 68% of the encapsulated 5-FU from thermosensitive liposomes, within 10 min, whereas release remained below 20% for the non thermosensitive formulation. Furthermore, the cytotoxicity of 5-FU-copper-polyethylenimine complex-loaded liposomes towards HT-29 human colorectal carcinoma cell line was evaluated. Results revealed that lipids at a concentration of 800 µM are not cytotoxic (80% viability). Moreover, 5-FU complexation has no impact on its cytotoxic activity, disclosing that liposomes toxicity arose from 5-FU and not from the excipients. Nevertheless, 5-FU-copper-polyethylenimine complex-loaded liposomes exhibited a lower half maximal inhibitory concentration of 49 µM compared to 115 µM for complex solution. This enhancement of cytotoxicity was attributed to the cellular internalization of liposomes. Pharmacokinetics in mice bearing HT-29 xenograft tumor showed that liposomes can extend the plasma distribution half-life of 5-FU by a factor 1.4. Furthermore, areas under the concentration-time curve over 24 h were higher by 1.9- and 2.9-fold when the drug was encapsulated into thermosensitive and non thermosensitive liposomes, respectively, compared to free 5-Fluorouracil. Finally, non thermosensitive liposomes significantly increased 5-FU accumulation in tumor by 2-fold, compared to 5-FU solution. In conclusion, these 5-FU-loaded thermosensitive liposomes represent valuable carriers to investigate the therapeutic efficacy following focused ultrasound-mediated heat application.

INTRODUÇÃO: O envelhecimento está associado, muitas vezes, a um declínio cognitivo frequentemente negligenciado, especialmente quando em formas brandas e/ou iniciais, com importante repercussão na vida das pessoas. Tais declínios podem regredir para a normalidade, estabilizar ou mesmo evoluir para quadro demenciais. O comprometimento cognitivo leve (CCL) é uma síndrome clínica de associada a um risco aumentado de demência, podendo ter várias etiologias e patologias. Até o momento, não existe ainda uma abordagem terapêutica, deixando uma lacuna no arsenal terapêutico tanto do especialista quanto do clínico geral. A estimulação magnética transcraniana é uma técnica não invasiva e promissora. Tem potencial para melhorar a memória e a cognição de idosos ativando redes neurais. OBJETIVOS: Este trabalho visa verificar os efeitos da estimulação magnética transcraniana repetitiva (EMTr) de alta frequência primeiramente sobre a memória e, secundariamente, sobre a cognição global de idosos com CCL. MÉTODOS: Trata-se de um estudo duplo cego, randomizado sham-controlado. Foram estimulados 32 idosos com idades entre 60-74 anos, totalmente independentes para as atividades instrumentais de vida diária (AIVDs), com queixas subjetivas de memória e evidência de algum prejuízo na avaliação neuropsicológica, caracterizando CCL. Os participantes foram divididos em dois grupos: (I) EMTr ativa (n=15) e (II) EMTr sham (n=17). O grupo ativo recebeu 10 sessões de EMTr a 10Hz (110% do limiar motor e 2.000 pulsos por sessão) sobre o córtex pré-frontal dorso lateral esquerdo.Foi utilizada uma bobina inativa (sham) para o grupo placebo. As baterias neuropsicológicas foram realizadas nos três tempos: antes (T0), logo após (T1) e um mês após (T2) a EMTr. RESULTADOS: Dos 109 pacientes triados, 36 foram elegíveis para o estudo. Houve 4 desistências, e 32 finalizaram o estudo. Os dados demográficos foram homogêneos. Os escores dos testes foram ajustados para a idade e escolaridade. O ponto de corte do Escore Isquêmico de Hachinski foi <=4. A medida de desfecho primário foi o teste ecológico Rivermead Behavioural Memory (RBMT) devido a sua alta capacidade de predizer problemas de memória diárias. As variáveis contínuas foaram avaliadas pelo teste t de Student. Análise de variância para medidas repetidas (ANOVA) foi utilizada para comparar as medidas de variáveis quantitativas ao longo dos instantes de medição. Houve interação (efeito de grupo) a favor do grupo ativo nas variáveis Rivermead Behavioural Memory Test (p=0,042) e teste de Stroop (retângulos) (p=0,044) em T0-T1; dígitos ordem direta (p=0,041) e trilhas B em T1-T2 (p=0,032). Houve interação no teste de memória lógica tardia em T0-T1 e T0-T2 (p=0,044 e 0,005, respectivamente) a favor do grupo sham; porém, o desfecho foi igual em T2 em ambos os grupos. Não houve interação no IQCODE e na escala de Bayer de funcionalidade. Os resultados mostram melhora significativa, a um nível de 5% de significância, na memória do dia a dia, da atenção e de função executiva dos idosos que se submeteram à EMTr de alta frequência, sugerindo seu potencial terapêutico no CCL. Trial registration: clinicaltrials.gov Identifier: NCT01292382. / BACKGROUND: Aging maybe associated with a cognitive decline often overlooked, especially in milder forms, with significant impact on people\'s lives. Such declines may regress to normal, or even stabilize, or progress to dementia. Mild cognitive impairment (MCI) is a clinical syndrome associated with an increased risk of dementia and may have different etiologies and pathologies. To date, there is still not a therapeutic approach, leaving a gap in the therapeutic armamentarium of both expert as the general practitioner. Transcranial magnetic stimulation is a promising and noninvasive technique with potential to improve memory and cognition in elderly by activating neural networks. OBJECTIVES: This study aims to assess the effects of high frequency repetitive transcranial magnetic stimulation (rTMS) primarily on memory and secondarily on global cognition in elderly people with MCI. METHODS: Double blind, randomized sham-controlled trial. Were stimulated 32 eldrely aged 60-74 years, totally independent for instrumental activities of daily living (IADL) with subjective memory complaints and evidence of some impairment in neuropsychological assessment, characterizing MCI. Subjects were divided into two groups: (I) active rTMS (n=15) and (II) rTMS sham (n=17). The active group received 10 sessions of 10 Hz rTMS (110% of motor threshold and 2000 pulses per session) over left dorsolateral prefrontal cortex. We used a inactive coil (sham) for the placebo group. The neuropsychological assessment were conducted in three stages: before (T0), immediately after (T1) and one month after (T2) rTMS. RESULTS: Of 109 patients screened, 36 were eligible for the study. There were 4 dropouts, and 32 completed the study. Demographic data were homogeneous. The test scores were adjusted for age and education. All subjects presented a cut-off score <=4 for the Hachinski Ischaemic Score. Continuous variables were evaluated by Student t test. Repeated measures of anayses of variance (ANOVA) were used to compare measures of quantitative variables along time. The primary outcome measure was a positive response on the ecological tool Rivermead Behavioural Memory Test (RBMT) because of its capacity to predict everyday memory problems. There was interaction (group effect) in favor of the active group over the variables RBMT (p=0.042) and Stroop test (colored rectangles) (p=0.044) at T0-T1; digit span direct order (p=0.041) and trail making B, T1-T2 (p=0.032). There was interaction in late logic memory test at T0-T1 and T0-T2 (p=0.044 and 0.005, respectively) for the sham group, but the outcome was the same in both groups at T2. There were no significant interaction at IQCODE and Bayer ADL Scale. The results present significant improvement, at a 5% level of significance, in everyday memory, attention and executive function of the elderly who underwent to high-frequency rTMS, suggesting its therapeutic potential in MCI. Trial registration: clinicaltrials.gov Identifier: NCT01292382.

O acelerado processo de envelhecimento tem trazido não só mudanças no perfil demográfico, mas também no perfil epidemiológico da população. Entre os problemas de saúde encontrados em idosos, merecem destaque os transtornos mentais, visto que acometem cerca de um terço dessa população, sendo os transtornos depressivos e a demência os problemas de saúde mental mais prevalentes. O transtorno depressivo maior (TDM), bem como o comprometimento cognitivo leve (CCL), tem sido associado prejuízo das funções cognitivas, além de aumentar o risco de desenvolvimento de demência, principalmente doença de Alzheimer (DA). Sendo assim, é importante que haja identificação preventiva de pessoas com maior risco para o desenvolvimento de DA a fim de proporcionar um tratamento precoce. Dessa maneira este estudo objetivou comparar os marcadores biológicos envolvidos na cascata amiloide, expressos em leucócitos e líquor, nas condições clínicas TDM, CCL, DA e controles saudáveis. Para tanto, foi determinada a expressão proteica das secretases ADAM10, BACE1 e PSEN1 e do peptídeo A? em leucócitos e líquor pelos métodos de Western Blotting, ELISA e Luminex. Ao analisarmos a expressão das secretases e do peptídeo Abeta em leucócitos não observamos diferenças estatisticamente significantes entre os grupos, exceto pela expressão da proteína PSEN1, que apresentou menores níveis em DA em relação à TDM. Em relação ao líquor, observamos uma significativa diminuição do peptídeo A? no grupo DA quando comparado aos grupos CCL, TDM e também a controles saudáveis; porém não foram observadas diferenças de expressão desse peptídeo entre CCL, TDM e controles saudáveis. Esses resultados sugerem que a matriz leucocitária, apesar de expressar os componentes desta via, sugerindo dispor da maquinaria enzimática necessária para o processamento da proteína precursora do amiloide (APP), não é a ideal para estudos sobre a cascata amiloide. Além disso, os resultados obtidos em amostras de líquor, de acordo com a casuística analisada, reforçam os dados da literatura que estabelecem a redução da concentração do peptídio Abeta no líquor como um biomarcador da DA, sem termos detectado alterações nos demais grupos estudados. Nossos resultados (negativos) em relação à expressão das APP-secretases no líquor acrescentam dados a este domínio ainda controverso da literatura. Assim sendo, mais estudos devem ser realizados para que possamos compreender melhor as vias relacionadas ao desenvolvimento da DA / The accelerated aging process has brought not only changes in the demographic profile, but also in the epidemiological profile of the population. Among the health problems found in the elderly, mental disorders are worth mentioning, since they affect about a third of this population, being the depressive disorders and dementia the most prevalent mental health problems. Major depressive disorder (MDD), as well as mild cognitive impairment (MCI), have been associated with higher levels of cognitive symptoms and increased risk of developing dementia, especially Alzheimer\'s disease (AD). Therefore, it is important to identify individuals at greater risk for the development of AD in order to provide treatment at early stages of the disease process. In this way, this study aimed to compare the biological markers involved in the amyloid cascade under the clinical conditions TDM, CCL, DA and healthy controls expressed in leukocytes and CSF. We determined the protein expression of ADAM10, BACE1 and PSEN1 and A? peptides in leucocytes and CSF using the Western Blotting, ELISA and Luminex methods. When analyzing the expression of the secretases and the A? peptide in leukocytes, we did not observe statistically significant differences between the groups, except for the expression of the PSEN1 protein, which presented lower levels in AD in relation to MDD. In relation to CSF, we observed a significant reduction of the Abeta peptide in AD when compared to MCI, TDM and also to healthy controls, but no differences in expression of this peptide were observed between MCI, MDD and healthy controls. These results suggest that the leukocytes, although expressing the key components and the enzymatic machinery necessary for the proteolytic processing of the amyloid precursor protein (APP), may not represent an adequate biological matrix for studies addessing the amyloid cascade. In addition, results obtained in CSF samples, according to the analyzed series, reinforce the literature data that establish the reduction of A? peptide concentration in CSF as a biomarker of AD, without detecting alterations in the other groups studied. Our (negative) results in relation to the expression of APP-secretases in CDescriptors: MSF add data to this still controversial domain of the literature. Therefore, more studies should be done so that we can better understand the pathways related to the development of AD

OBJETIVO: Este estudo teve por objetivo descrever o resultado dos casos de pieloectasia fetal leve bilateral, encaminhados ao serviço de Medicina Fetal do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP), avaliados com ultrassonografias obstétricas dos rins e do trato urinário do feto e propor, com base nos dados, o melhor acompanhamento em termos de frequência de repetição de exames de ultrassonografia (US), no período pré-natal. METODOLOGIA: Pesquisa longitudinal prospectiva com 62 fetos com diagnóstico ultrassonográfico de pieloectasia leve bilateral (PELB), encaminhados de unidades de cuidados primários, realizada no HCFMUSP. PELB foi considerada quando o diâmetro anteroposterior da pelve renal (DAPPR), media >= 5,0 mm, >= 7,0 mm e >= 10,0 mm à US, respectivamente, em idades gestacionais <= 23 semanas (s) 6 dias (d), 24 s a 31 s 6 d e >= 32 s gestação, sem dilatação de ureteres e cálices. A cada 3 semanas, as US verificaram se a PELB havia progredido, regredido ou tinha ficado inalterada. Assim, quando possível, era realizada uma US de rins e vias urinárias neonatais para confirmação dos desfechos. A progressão foi considerada quando o DAPPR aumentou ou a imagem calicial foi encontrada em um ou ambos os rins. Regressão ocorreu quando os DAPPR entraram nos valores normais. A estabilidade foi considerada quando os DAPPR permaneceram dentro dos parâmetros considerados para pieloectasia leve. RESULTADOS E DISCUSSÃO: A idade gestacional ao diagnóstico foi de 19,2 para 30,1 semanas (média de 23,2 s). Regressão ocorreu em 29 casos (46,7%). Em 24 casos (38,7%), encontrou-se estabilidade. Houve regressão e estado estabilidade em 53 casos (85,4%). Progressão ocorreu em nove casos (14,6%), sendo unilateral em todos. Não foram observados casos graves. Já na avaliação pós-natal, foram examinados 32 neonatos, com 20 casos (62,5%) apresentando regressão; seis (18,7%) de estabilidade da pieloectasia; e seis de progressão da lesão (18,7%). Desfechos de regressão e estabilidade da pieloectasia foram encontrados em 26 casos (81,2%). Os resultados sugerem que as US não devem ser realizadas com frequência em casos de dilatação leve das pelves renais, sem cálices ou ureteres. Uma avaliação ultrassonográfica no terceiro trimestre tardio pode ser suficiente como uma estratégia de acompanhamento rotineiro nesses casos e que essa informação é útil para cuidados pós-natais imediatos. CONCLUSÃO: Esta série indica que PELB fetal, sem cálices ou ureteres visíveis, pode ser controlada ultrassonograficamente no terceiro trimestre tardio e, como não há casos progredindo o suficiente para indicar intervenção fetal, os procedimentos devem ser deixados para o período neonatal. A realização de US seriadas pode ser estressante e inútil nesses casos particulares / OBJECTIVE: The objective of this study was to describe the outcome of cases of mild fetal bilateral pyelectasis, referred to the Fetal Medicine service of Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo (HCFMUSP), assessed with obstetric ultrasound of the kidneys and urinary tract of the fetus in order to propose the best follow-up in terms of repetition frequency of ultrasound examinations in the prenatal period, based on the data. METHODOLOGY: A prospective longitudinal study of 62 fetuses from primary care units with mild bilateral pyelectasis (MBPE) diagnosed using ultrasonography (US) was carried out at HCFMUSP. MBPE was considered when anteroposterior renal pelvis diameter (APRPD) measured >= 5.0 mm, >= 7.0 mm and >= 10.0 mm in US at <= 23 weeks (w) 6 days (d), 24 w to 31 w 6 d and >= 32w gestational age (GA) respectively, with no ureteric and calyces dilatation. US every 3 weeks checked if MBPE had progressed, regressed or remained unchanged. When possible, a neonatal US of kidneys and urinary tract of the newborn was performed to confirm outcomes. Progression was considered when renal pelvis (RP) dilatation increased or visible calyces was found in one or both kidneys. Regression occurred when RP presented normal values. Stability was considered when APRPD remained within the parameters considered for mild pyelectasis. RESULTS AND DISCUSSION: GA at diagnosis was 19.2 to 30.1 weeks (mean 23.2w). Regression occurred in 29 cases (46.7%). In 24 (38.7%) RP dilatation remained unchanged. Regression and unchanged status occurred in 53 cases (85.4%). Lesions worsened in 9 cases (14.6%, unilateral in all cases). No severe cases were observed. 32 newborns already on postnatal evaluation were examined, 20 cases (62.5%) showed involution; 6 cases with stable pyelectasis (18.7%), and 6 cases of lesion progression (18.7%). Outcomes: pyelectasis regression and stability was found in 26 cases (81.2%). Results suggest that US should not be performed too often in cases of RP dilatation with no visible calyces or ureter. A late third trimester US scan could be a sufficient routine follow up strategy in such cases and information is useful to immediate postnatal care. CONCLUSION: This study indicates that fetal MBPE with no visible calyces or ureter could be controlled at late third trimester and procedures should be left to the neonatal period as no cases progressed sufficiently to indicate fetal intervention. Proceeding serial ultrasound scans could be stressful and useless in these particular cases

INTRODUÇÃO: A busca pelo diagnóstico cada vez mais precoce das demências traz a necessidade de estratégias mais eficientes na utilização dos testes cognitivos. A definição dos parâmetros de normalidade para esses testes é particularmente desafiadora no contexto brasileiro de baixa escolaridade e grande heterogeneidade sociocultural. OBJETIVO: Avaliar os efeitos de diferentes estratégias de ajuste de normas nas propriedades do Mini-Exame do Estado Mental (MEEM). MÉTODOS: Duzentos e trinta idosos encaminhados a um serviço de Geriatria por suspeita de comprometimento cognitivo foram recrutados sequencialmente e submetidos ao MEEM. Todos os pacientes passaram por uma segunda avaliação cega para o resultado do MEEM, constituída de testagem neuropsicológica e entrevista com um informante para obtenção de diagnóstico padrão-ouro. Para o ajuste de normas, quatro fatores preditores foram testados: (1) características sociodemográficas; (2) uma classificação simples de alfabetismo funcional com quatro níveis; (3) um questionário de habilidades cognitivas pré-morbidas respondido pelo informante; (4) um teste de leitura de palavras aplicado diretamente ao paciente. Três técnicas de predição foram testadas: (1) agrupamento em níveis; (2) regressão linear; (3) regressão não-linear por modelo polinomial fracional. As combinações de fatores preditores e técnicas de predição deram origem a vinte modelos que foram testados individualmente na comparação com o MEEM sem ajuste. Os desfechos avaliados foram a acurácia do modelo na detecção de comprometimento cognitivo e a variação da sensibilidade e da especificidade entre os níveis socioeconômicos. RESULTADOS: Entre os 230 idosos recrutados, 106 (46%) apresentavam envelhecimento cognitivo normal, 56 (24%) comprometimento cognitivo sem demência e 68 (29%) demência. A classificação de alfabetismo funcional, o questionário de habilidades cognitivas pré-mórbidas e o teste de leitura de palavras não apresentaram propriedades adequadas para ajuste de normas, mas as limitações podem estar relacionadas a problemas específicos dos instrumentos utilizados e não devem ser generalizadas. Alguns modelos baseados em fatores sociodemográficos foram capazes de melhorar a acurácia do MEEM, resultado que diverge da literatura atual e que deve ser confirmado em outros estudos com populações de baixa escolaridade. Um modelo polinomial fracional utilizando variáveis sociodemográficas apresentou propriedades ótimas de acurácia e promoveu estabilização da sensibilidade e da especificidade entre os níveis socioeconômicos. A partir das equações geradas por esse modelo podem ser construídas tabelas simples de uso clínico para converter o resultado bruto em escore z ou percentil. CONCLUSÕES: Nossos resultados apontam o modelo polinomial fracional baseado em variáveis sociodemográficas como a melhor opção para ajuste de normas de testes cognitivos em nosso meio / INTRODUCTION: The need for diagnosing dementia early demands effective strategies on the use of cognitive tests. Establishing criteria of normality for these tests is a challenging task in environments of low education and enormous sociocultural heterogeneity such as observed in Brazil. OBJETIVE: To evaluate how different strategies for adjusting norms can change the properties of the Mini-Mental Status Examination (MMSE). METHODS: Two hundred and thirty older adults referred for a geriatric service because of suspected cognitive impairment were recruited sequentially and completed the MMSE. All the patients underwent a second assessment, blind to the result of the MMSE, which was composed of a neuropsychological battery and an interview with a close informant for the establishment a gold-standard diagnosis. For the adjustment of the norms, four predictive factors were evaluated: (1) demographic characteristics; (2) a simple classification of functional literacy with four levels; (3) a premorbid abilities questionnaire; (4) a word-reading test. Three techniques of prediction were evaluated: (1) grouping in demographic or ability levels; (2) simple or multivariate linear regression; (3) nonlinear regression by using a fractional polynomial model. Some possible combinations of predictive factors and prediction techniques originated twenty models that were assessed individually in comparison with the raw MMSE scores. The endpoints assessed were accuracy of the model for detecting cognitive impairment and the variation of the sensibility and specificity across socioeconomic levels. RESULTS: Of the 230 older adults recruited, 106 (46%) had normal cognitive aging, 56 (24%) presented cognitive impairment no dementia (CIND) and 68 (29%) had dementia. The functional literacy classification, the premorbid cognitive abilities questionnaire and the word-reading test did not present adequate properties for the adjustment of norms, but the limitations may be associated to specific problems of the instruments an cannot be generalized. Some models based on the demographic characteristics were able to improve the accuracy of the MMSE. This finding diverges from the currently available literature and should be confirmed in further studies with low-educated populations. A fractional polynomial model employing demographic factors presented very good properties and was able to stabilize the sensibility and the specificity across the socioeconomic levels. The equations generated by this model can be employed to construct practical tables for converting raw scores into z scores and percentiles. CONCLUSIONS: Our results point to the fractional polynomial model based on demographic variables as the best choice to adjust norms for cognitive tests in our context

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.

L'Assistance Ambiante est un domaine de recherche prometteur qui vise à utiliser les technologies de l'information pour venir en aide aux personnes dépendantes durant leur vie quotidienne. L'impact de ces recherches pourrait être déterminant pour de nombreux séniors ainsi que pour leurs proches. Cette discipline s'est développée régulièrement au cours des dernières années, mais tout de même plus lentement que la plupart des autres applications de l'internet des objets. Cela est dû à la complexité inhérente à l'Assistance Ambiante, qui nécessite une compréhension dynamique du contexte, ainsi que la mise en place de nombreux média de communication dans le lieu de vie de l'utilisateur. Plus précisément, les chercheurs rencontrent des difficultés avec l'étape déterminante de la reconnaissance d'activité, comme nous le montre la littérature.Mon équipe de recherche a déployé notre système dans plusieurs environnements, le plus récent consistant en une maison de retraite et trois maisons individuelles en France.Nous adoptons une approche centrée sur l'utilisateur, où l'utilisateur final définit ce qu'il attend, et nous fournit des réactions et conseils sur notre système.De cette manière, nous pouvons apprendre de nos déploiements, et obtenir des informations pour répondre aux défis de l'Assistance Ambiante, y compris la reconnaissance d'activité.Ainsi, la ligne directrice de cette thèse émerge des défis que nous avons rencontré durant nos déploiements.Au commencement de cette thèse, j'ai été confronté à la problématique concrète d'un déploiement réel de notre système.Je relate donc les besoins que nous avons vu émerger, par nos propres observations et par les retours des utilisateurs, ainsi que les problèmes techniques que nous avons rencontrés.Pour chacun de ces problèmes et besoins, je décris la solution que nous avons retenu et implémenté.Une fois le système installé, mon équipe et moi-même avons pu récolter de nombreuses données sur son fonctionnement.J'ai tout d'abord mis en place une plate-forme d'analyse de données en Assistance Ambiante, permettant un prototypage rapide lié à la reconnaissance d'activité.En tirant profit de cette plate-forme, j'ai observé le problème posé par la reconnaissance d'activité, qui est une étape critique, mais trop souvent inexacte dans ses conclusions.Pour faire face aux erreurs dans le raisonnement, je formalise la notion d'exactitude pour la reconnaissance d'activité, et fournit une méthode pour mesurer l'exactitude de notre moteur de raisonnement.Cela requiert d'abord d'observer une vérité terrain sur l'activité en cours, ou à défaut une estimation sur cette activité, d'une source autre que le raisonneur lui-même.Je cherche ensuite à améliorer la qualité de notre moteur de raisonnement.Pour y parvenir, je m'attache à regarder plus précisément certains raisonnements incorrects.J'y observe que les erreurs de raisonnement viennent parfois du fait que le raisonneur essaie d'être trop précis, ou qu'à l'inverse, il est parfois trop imprécis dans les activités qu'il infère.Je propose donc une méthode pour optimiser le moteur de raisonnement, de telle manière à ce qu'il conclue de la meilleure façon possible parmi plusieurs activités suspectées, en choisissant l'activité qui offre le meilleur compromis entre sa Précision et le risque d'Inexactitude de la part du moteur de raisonnement.Cette contribution me mène à introduire une hiérarchie entre les activités.En effet, en appliquant la méthode précédente sur un modèle hiérarchique d'activités, le raisonneur est calibré automatiquement, pour choisir à quel niveau de précision il pourra reconnaître une activité.Il va de soi que ces travaux sont validés formellement au sein de cette dissertation. / Ambient Assisted Living is a promising research area.It aims to use information technologies to assist dependent elderly people on their daily life.The impact of these technologies could be dramatic for millions of elderly people and for their caregivers.This research area has developed consistently over the past few years, although slower than most other applications of the Internet of Things.This is caused by the inner complexity of Ambient Assisted Living.Indeed, Ambient Assisted Living requires a dynamic understanding of the context, as well as the disposal of numerous communication media in the environment surrounding the end-user.More precisely, researchers face difficulties in recognizing end-users' activities, as we can observe in the literature.My research team have deployed our system in several environments, of which the most recent includes a nursing home and three houses in France.We adopt a user-centric approach, where end-users describe what they expect, and share with us their feedbacks and advices about our system.This approach guided me to identify activity recognition as a critical challenge that needs to be addressed for the usability and acceptability of Ambient Assisted Living solutions.Thus, the guiding line of this thesis work emerges naturally from the challenges we encountered during our deployments.In the beginning of this thesis, I have been facing the practical problem of putting into place an actual deployment of our system.In this document, I describe the needs that emerged from our own observations and from the users feedbacks, as well from as the technical problems we encountered.For each of these problems and needs, I describe the solution we have selected and implemented.From our deployments, my team and I were able to collect a large amount of operating data.I have created a platform to analyze Ambient Assisted Living data, also to allow rapid prototyping for activity recognition.By using this platform, I have observed problems with activity recognition, which is too often misleading and inaccurate.A first observation is that the sensor events are sometimes disturbed by multiuser situations, when several persons are active in the home.Activity recognition in these conditions is extremely difficult, and during this thesis my scope is solely focused on detecting multiuser situations, not recognizing activities in such situations.I then seek to improve the quality of our reasoning engine.To do so, I have looked more precisely at some incorrect reasoning.I observed that the errors in reasoning come from the fact that the reasoner tries to be too precise or that, conversely, it infers too imprecise activities.I therefore propose a method to optimize the reasoning engine, so that it concludes with the best possible activity among several possible activities, by choosing the one that offers the best compromise between Precision and the risk of Inaccuracy in activity recognition.It should be noted that this contribution is independent of the method used for activity recognition, and can work with any type of reasoning.I have formalized the concept of Accuracy, and provided a method to measure the Accuracy of a reasoning engine.This requires first to observe a ground-truth on the activity being performed.This contribution brought me to introduce a hierarchical model for activities.Indeed, by applying the method described above on a hierarchical model of activities, the reasoning engine can be calibrated automatically to choose how precise it should be at recognizing an activity.It goes without saying that these contributions are formally validated through this dissertation.