La maladie d’Alzheimer (MA) est de loin le type de démence le plus répandu chez les personnes âgées. Il est maintenant possible de proposer un certain nombre d’interventions ou de stratégies préventives aux personnes portant un diagnostic de MA ou à risque de développer la maladie. Il est donc important de diagnostiquer cette maladie le plus tôt possible. Les personnes avec un trouble cognitif léger (TCL) représentent une population d’intérêt puisqu’elles sont à haut risque d’évoluer vers une démence et plusieurs d’entres elles seraient ainsi dans une phase prodromale de la MA. Les travaux de cette thèse visent à explorer les activations fonctionnelles associées à la mémoire épisodique et à la mémoire de travail dans le TCL ainsi qu’aux effets de la sévérité de la maladie et des caractéristiques de la tâche sur ces activations. Dans un premier temps, nous exposerons les connaissances relatives au niveau des atteintes cognitives, du patron d’activation fonctionnelle et des plus récents modèles élaborés pour expliquer les changements d’activation dans le vieillissement normal et pathologique (Chapitre 1). Par la suite, les études réalisées dans le cadre de cette thèse seront présentées. Nous avons d’abord étudié la fiabilité du signal d’activation chez les TCL et chez les personnes âgées saines (PA) à l’aide de tâches d’encodage et de récupération de mots (Chapitre 2). Nous avons ensuite comparé le patron d’activation cérébral des PA et des personnes TCL alors qu’elles réalisaient une tâche d’encodage et de récupération de mots. L’effet de la sévérité a été évalué en corrélant les activations des personnes TCL à leurs scores obtenu à une échelle évaluant leur cognition globale (Chapitre 3). L’effet de sévérité a ensuite été étudié de manière plus approfondie chez un plus grand nombre de TCL en utilisant la médiane du groupe à cette même échelle pour déterminer un groupe de TCL plus atteints et un groupe de TCL moins atteints. Ces deux groupes ont ensuite été comparés à un groupe de PA lors d’une tâche d’encodage de paires de mots reliés sémantiquement ou non-reliés (Chapitre 4), une tâche de reconnaissance de paires de mots mesurant principalement la familiarité ou principalement la recollection (Chapitre 5), ainsi que deux tâches impliquant des composantes différentes de la mémoire de travail et des fonctions exécutives, soit la manipulation de l’information et l’attention divisée (Chapitre 6). Les résultats présentés dans cette thèse ont mis en évidence une distinction entre le patron d’activation des TCL et des PA qui semble caractérisée par une interaction entre le niveau de sévérité de la maladie et les processus cognitifs impliqués dans la tâche. L’effet de sévérité a été observé lors de plusieurs tâches impliquant des processus cognitifs différents où les MCI moins atteints ont montré principalement des hyperactivations sous-tendant des mécanismes compensatoires et les MCI plus atteints ont montré principalement des hypoactivations soulignant la dégradation de ces mécanismes. Par ailleurs, les résultats de nos études ont aussi montré que cet effet de sévérité est modulé par le moment d’altération du processus cognitif impliqué dans la tâche: les processus altérés précocément dans le TCL sont caractériséees par des hyperactivations chez les TCL moins atteints tandis que les processus altérés plus tardivement ont plutôt élicité des hyperactivations chez les TCL plus atteints. Les implications de ces résultats, ainsi que les limites des études, sont discutés (Chapitre 7). / Alzheimer's disease (AD) is by far the type most common dementia in the elderly. It is now possible to propose a number of interventions or preventive strategies to individuals with a diagnosis of AD or at risk of developing the disease. It is therefore important to diagnose this disease as soon as possible. Individuals with mild cognitive impairment (MCI) represent a population of interest as they are at high risk of developing dementia and many of these persons might thus be in a prodromal phase of AD. The work of this thesis aims to explore the functional activations associated with episodic memory and working memory in MCI as well as studying the effects of disease severity and of task characteristics on these brain activations. Initially, we will review the current knowledge about the level of cognitive impairment, functional activation pattern and the more recent models developed to explain changes of functional activation in normal aging and disease (Chapter 1). Subsequently, the studies of this thesis will be presented. First, we studied the reliability of activation signal in people with MCI and healthy elderly individuals (HE) using tasks of encoding and retrieval of words (Chapter 2). We then compared the pattern of brain activation between HE and MCI persons while they were administered tasks of encoding and retrieval of words and pseudo-words. The effect of severity was assessed by correlating activations of MCI persons with their scores on a scale assessing their overall cognition (Chapter 3). The effect of severity was then examined in more details in a larger number of people using the median score of the MCI group on the scale of global cognitive assessment to determine a group of less impaired MCIs and a group of more impaired MCIs. These two groups were compared to a group of HE while conducting a task of encoding semantically related or unrelated pairs of words (Chapter 4), a recognition task of word pairs measuring either mainly familiarity processes or recollection processes (Chapter 5) and two tasks involving different components of working memory or executive functioning, the manipulation of information and division of attention (Chapter 6). The results presented in this thesis have highlighted a distinction between the functional activation pattern of MCI persons and HE which seems to be characterized by an interaction between level of disease severity and the cognitive processes involved in the task. The effect of severity was observed in several tasks involving different cognitive processes during which less impaired MCIs showed primarily hyperactivations underlying compensatory mechanisms and more impaired MCIs showed mainly hypoactivations suggesting a degradation of these mechanisms. Moreover, the results of our studies have also shown that the effect of severity is modulated by the time of alteration of the cognitive processes involved in the task: the process altered early in MCI are caracterized by hyperactivations in less impaired MCIs while processes that are altered later on elicited hyperactivations in more impaired MCIs. The implications of these findings and the limitations of the studies are discussed (Chapter 7).

Le trouble comportemental en sommeil paradoxal (TCSP) se caractérise par une perte de l’atonie musculaire en sommeil paradoxal et par des manifestations motrices élaborées souvent associées au contenu onirique. Le TCSP peut apparaître sous une forme idiopathique (TCSPi), mais il est fréquemment lié à certains désordres neurodégénératifs, dont les synucléinopathies. Des marqueurs biologiques des synucléinopathies, tels que la présence d’anomalies au plan de la motricité, de la détection des odeurs ainsi que de la discrimination des couleurs, ont été retrouvés dans le TCSPi. De plus, des perturbations de l’activité cérébrale en neuroimagerie ainsi que du fonctionnement cognitif ont été observées chez ces patients. Des études ont démontré que le TCSPi pouvait précéder l’apparition d’une maladie de Parkinson (MP) ou d’une démence à corps de Lewy (DCL). Ceci suggère que le TCSPi représenterait un facteur de risque des synucléinopathies. L’objectif principal du présent projet est d’étudier les anomalies du débit sanguin cérébral régional (DSCr) de repos avec la tomographie par émission monophotonique (TEM) dans le TCSPi. Deux études ont été réalisées. La première visait à comparer le DSCr entre des patients avec un TCSPi et des sujets sains, puis d’explorer la relation entre l’activité cérébrale et la présence de marqueurs biologiques des synucléinopathies. Les résultats ont montré une diminution de la perfusion cérébrale dans les régions frontales et pariétales ainsi qu’une augmentation de la perfusion au niveau du pont, du putamen et des hippocampes chez les patients avec un TCSPi. Une relation significative entre la performance des sujets avec un TCSPi à une épreuve de discrimination des couleurs et la perfusion cérébrale au niveau des régions frontales et occipitales a été mise en évidence. Dans l’ensemble, ces résultats ont démontré des anomalies du DSCr chez les patients avec un TCSPi qui sont similaires à celles observées par d’autres études en neuroimagerie dans la MP. Ceci suggère des atteintes neuroanatomiques semblables entre ces pathologies. La seconde étude en TEM a été effectuée dans le but d’examiner les modifications du DSCr associées aux perturbations du fonctionnement cognitif dans le TCSPi. Pour ce faire, le DSCr a été comparé entre un sous-groupe de patients avec un TCSPi et un trouble cognitif léger (TCL), un sous-groupe de patients avec un TCSPi sans TCL et un groupe de sujets sains. Les résultats ont montré que seuls les patients avec un TCSPi et un TCL présentaient une diminution de la perfusion cérébrale dans les aires corticales postérieures (occipitales et temporo-pariétales). Ces observations sont similaires à celles rapportées dans la MP avec démence et la DCL dans les études en neuroimagerie. En conclusion, les résultats de ces deux études ont montré des perturbations du DSCr dans le TCSPi, similaires à celles observées dans les synucléinopathies. Par ailleurs, nos résultats ont mis en évidence que les patients avec un TCSPi et un TCL présentaient les mêmes anomalies de la perfusion cérébrale que les patients avec une MP avec démence et/ou une DCL. La présence de tels marqueurs des synucléinopathies dans le TCSPi suggère que ces patients pourraient être plus à risque d’évoluer vers ce type de maladie neurodégénérative. / Rapid eye movement sleep behavior disorder (RBD) is a parasomnia characterized by intermittent loss of normal atonia during REM sleep and elaborate motor activity associated with dreams. RBD may occur in an idiopathic form (iRBD), but is frequent in neurodegenerative diseases characterized by alpha-synuclein deposition such as Parkinson’s disease (PD) and dementia with Lewy bodjes (DLB). Biomarkers of synucleinopathies, such as motor, olfaction and color discrimination dysfunctions have been found in patients with iRBD. Moreover, impaired cerebral activities with neuroimaging and cognitive perturbations have also been detected in those patients. Longitudinal studies have demonstrated that iRBD might precede PD or DLB by several years. This suggests that iRBD could represent a risk factor of synucleinopathies. The goal of the present research was to investigate the resting regional cerebral blood flow (rCBF) in an iRBD sample using single photon emission computerized tomography (SPECT) neuroimaging. This led to two different studies. The aim of the first study was to compare the rCBF between a group of patients with iRBD and a group of healthy control subjects, and to explore correlations between rCBF of iRBD patients and markers of synucleinopathies. The results of this study showed that compared to controls, iRBD patients had decreased perfusion in frontal and parietal cortical regions and an increased perfusion in pons, putamen and hippocampus bilaterally. Moreover, a significant correlation between brain perfusion in frontal and occipital cortex and performance on a color discrimination test was found in iRBD patients. The brain perfusion anomalies observed in our iRBD patients are similar to those observed in PD in functional neuroimaging studies, suggesting similar neuroanatomic basis between these two pathologies. The objective of the second study was to investigate brain perfusion changes associated with mild cognitive impairment (MCI) in iRBD. We compared rCBF of a sub-group of patients with iRBD and MCI, a sub-group of patients with iRBD without MCI and a group of healthy control subjects. The results showed that only iRBD with MCI showed decreased perfusion in posterior brain regions, in occipital and temporo-parietal areas. These anomalies found in iRBD with MCI are similar to those reported in other studies in PD patients with dementia (PDD) and DLB in neuroimaging studies. To conclude, the results of this research showed brain perfusion abnormalities in iRBD patients similar to those found in synucleinopathies. One of our studies demonstrated a specific pattern of cerebral anomalies with SPECT, similar to those found in PDD and DLB, in patients with iRBD and MCI compared to iRBD without MCI. These biomarkers of synucleinopathies in iRBD suggest that these patients might be at higher risk to develop a neurodegenerative disease associated with alpha synuclein deposition.

雙酚化合物在文獻報導中發現具有抗發炎和抗氧化的能力，因為其親脂性的特性，雙酚化合物可以輕易穿透血腦屏障到中樞神經系統發揮其藥理活性。因此，雙酚化合物被評估可做為潛在預防及治療神經退化性疾病如帕金森氏症的神經保護藥物。本研究目的為探討新合成的雙酚化合物MH101及MH102是否具有神經保護和治療效用，而對抗神經毒素(包含巴拉圭、過氧化氫及MPTP)引起的神經毒害及其誘發的動物行為異常(如: 學習、記憶及運動協調)。研究中應用Oregon-R的果蠅(年齡: 1-2, 7, 20 和 30天)做為檢測模式，果蠅暴露在巴拉圭 (5-20 mM)或過氧化氫(0.3 %-3 %)環境下，並且給予MH101 (0.1-3 μM)。結果顯示MH101未能有效地減緩巴拉圭及過氧化氫所引起果蠅壽命的下降。此外，給予雄性ICR小鼠 (25-30 g) 腹腔注射MPTP (25mg/kg)每天一次連續五天，觀察神經毒素誘發的行為異常和神經毒害。在觀察保護效果的研究中，雄性小鼠在給予MPTP前一小時腹腔注射MH101 (1-3 mg/kg) 或MH102 (0.1-3 mg/kg) 每天一次連續五天，之後單獨給予MH101或MH102治療連續九天。後處理的組別，雄性小鼠在給予MPTP每天一次連續五天後，每天腹腔注射MH101 (1-3 mg/kg) 或MH102 (0.1-3 mg/kg)連續九天。控制組組別，小鼠則給予生理食鹽水(0.9%)及玉米油的混合液。結果顯示，MH101、MH102及MPTP皆不影響小鼠橫桿行走試驗的運動平衡和協調能力。然而，在前處理和後處理MH101或MH102後用新位置辨識能力測試和新物體辨識能力測試觀察MPTP引起的認知缺失，實驗結果顯示MH101及MH102皆恢復短期記憶和長期記憶的認知辨識指標。另外，前處理和後處理MH101或MH102雖有些微恢復紋狀體內MPTP引起多巴胺神經損傷及多巴胺轉運子減少的趨勢，但不顯著。由此推論，雙酚化合物MH101及MH102具有預防及改善神經毒素所引發的認知與學習缺陷，未來可能發展成為神經退化性疾病如帕金森氏症之潛力治療藥物，另針對MH101及MH102在神經損傷及動物行為障礙的恢復和保護藥理機制則需進一步實驗探討。 / Biphenols which are the main constituents of the traditional herbs have been found to possess the antiinflammatory and antioxidative properties. Due to the lipophilic activity, biphenols can readily cross the blood brain barrier to exert their pharmacological effects in the central nervous system. Thus, biphenols are proposed to act as the novel neuroprotective agents for treatment of neurodegenerative disorders such as Parkinson’s disease (PD). The aim of the present study was to examine whether the new synthetic biphenolic compounds MH101 and MH102 have the neuroprotective and therapeutic actions against the neurotoxicity and the behavioral impairments (e.g. learning, memory, and motor coordination) induced by neurotoxins including paraquat, hydrogen peroxide, and MPTP in PD-like animal models. The following experiments examined the lifespan of flies from Oregon-R strain of Drosophoila melanogaster (age: 1-2, 7, 20 and 30 days) chronically exposed to paraquat (5-20 mM) or hydrogen peroxide (0.3 %-3 %) under MH101 (0.1-3 μM) treatment. Our results showed that MH101 could not effectively influence the reduced lifespan of the flies induced by paraquat and hydrogen peroxide. Furthermore, male ICR mice (25-30 g) were administrated with MPTP (25 mg/kg, i.p.) once daily for 5 consecutive days to induce neuronal damage and cognitive deficits. For the protective study, male mice were administrated with MH101 (1-3 mg/kg, i.p.) or MH102 (0.1-3 mg/kg, i.p.) 1 hour prior to MPTP injection once daily for 5 days, and followed daily treatment with MH101 or MH102 alone for consecutive 9 days after the final injection of MPTP. For the post-treatment study, male mice were administrated with MPTP (25 mg/kg, i.p.) once daily for 5 consecutive days, and followed by daily treatment of MH101 or MH102 for 9 days. Mice in control group were injected with vehicle (0.9% saline + corn oil). The results showed that MH101, MH102, and MPTP alone did not alter the motor functions of coordination and balance in beam walking test. On the other hand, both pre-treatment and post-treatment of MH101 and MH102 reversed the cognitive dysfunction induced by MPTP detected by novel location recognition test (NLRT) and novel object recognition test (NORT). Data demonstrated that MH101 and MH102 reversed the reduction in recognition index (RI) of short term memory and long term memory in MPTP-induced PD model. However, pre-treatment and post-treatment of MH101 or MH102 slightly recovered MPTP-induced loss of dopamine neurons and dopamine transporter in striatum. Therefore, the results suggest that biphenols including MH101 and MH102 may be the candidates for treatment of neurodegenerative diseases such as PD. In the future, it will need further study to determine the pharmacological mechanism of MH101 and MH102 in protection and restoration of neuronal injury and cognitive impairment.

The side-effects of chemotherapy treatment are an increasingly important research focus as more cancer patients are reaching survivorship. While treatment allows for survival, it can also lead to problems which can significantly affect quality of life. Cognitive impairments after chemotherapy treatment are one such factor. First presented as anecdotal patient reports, over the last decade empirical evidence for this cognitive concern has been obtained. Much attention has been focused on post-chemotherapy research, yet little attention has been granted to these same patients’ cognition before treatment commences. Breast cancer (BC) patients face many obstacles before chemotherapy treatment such as: surgery and side-effects of anesthesia, increased cytokine activity, stress of a new disease diagnosis and upcoming challenges, and emotional burdens such as depression and anxiety. Many of these factors have independently been shown to affect cognitive abilities in both healthy populations as well as other patient groups. Therefore, the pre-treatment (or baseline) BC patient status warrants systematic study. This would then reduce mistakenly attributing carried-over cognitive deficits to side effects of chemotherapy. As well, it is possible that certain confounding variables may have neural manifestations at baseline that could be exacerbated by chemotherapy agents. The following thesis first presents a review paper which critically describes the current literature examining chemotherapy-related cognitive impairments (CRCIs), as well as possible confound variables affecting this population. Subsequently, three original research papers present pre-chemotherapy data showing significant neuroanatomical and neurofunctional differences in BC patients compared to controls. In particular, these neural differences are present in brain regions that have been reported in post-chemotherapy papers. This, as well as the effects of variables such as the number of days since surgery, depression and anxiety scores and more, support the initiative that research attention should increase focus on these patients at baseline in order to better understand their post-chemotherapy results.

The dissertation thesis focuses on the topic of construction of new questionnaire, which is developed from four already existing questionnaires of activities of daily living. This new questionnaire summarizes strengths of those four and submits only those activities, which are affected at the early stage of Alzheimer's dementia. The topic is introduced in the broad context of social sciences, medical science and also submits the practical issues, considering effects of Alzheimer's disease to life of patient and his closest ones. New questionnaire, which is the result of empirical research, is based on correlation analysis of three commonly used screening cognitive tests and four questionnaires which evaluate activities of daily life, which are, used as best practice in the Counseling Center for Memory Disorders Clinic of Neurology of Faculty Hospital Kralovske Vinohrady in Prague. The research sample consists of patiens, who are affected with Alzheimer's disease already. That means, that the new questionnaire can be used as a tool for those, who are the patient's closest ones for purpose of screening and reviewing abilities of daily living over time. The questionnaire also presents comprehensively compiled a list of activities of daily living which Alzheimer's disease affects in early stage and this list...

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

Introducão: o comprometimento cognitivo leve (CCL) é reconhecido como um estágio transicional sintomático entre o envelhecimento normal e a demência, particularmente a doença de Alzheimer (DA). Apresenta como subtipos principais o amnéstico (CCLa), com comprometimento de memória, e o não amnéstico (CCLna), que apresenta perda de outras funções, principalmente executivas, de atenção, de linguagem e visuoespaciais. Aparentemente o CCLna tem menor taxa de conversão para demências ao longo do tempo que o subtipo amnéstico, particularmente para a DA. Dessa forma, o CCLna poderia apresentar um perfil de biomarcadores diferente do CCLa no momento do diagnóstico. Estudos na literatura investigando o padrão de biomarcadores no CCLna como grupo independente são raros, alguns destes indicando perfil menos relacionado à DA no CCLna que o visto no CCLa. Segundo nosso conhecimento, não há estudos investigando concomitantemente volume e metabolismo cerebrais, além de biomarcadores no LCR de uma mesma amostra de CCLna, em comparação com CCLa e um grupo de idosos cognitivamente normais. Objetivo: investigar as alterações de volume e metabolismo cerebral em grupos de indivíduos com os subtipos amnéstico e não amnésico de CCL, comparativamente a voluntários idosos sem comprometimento cognitivo, com o intuito de avaliar se há concordância entre estas alterações. Avaliou-se ainda possíveis associações entre os perfis dos estudos de imagem com padrões classicamente descritos na para CCL em risco de evolução para DA, investigando ainda a existência de correlações entre destes achados com o dos diferentes biomarcadores no LCR e com dados clínicos. Métodos: cento e quatorze voluntários foram incluídos em três diferentes grupos: gCCLna (N = 38), gCCLa (N = 46) e GC (N = 30). Após entrevista clínica, exame neurológico e classificação por uma bateria de testes neuropsicológicos, estes foram submetidos a exames de RM cerebral (para excluir outras causas de comprometimento cognitivo e para análise de morfometria baseada em voxels - VBM) e de PET-18FDG cerebral. Analisou-se ainda os valores de biomarcadores no LCR (A?, tau e p-tau) de uma subamostra de pacientes (CCLna = 33, CCLa = 38). Resultados: os três grupos não apresentaram diferenças em relação às variáveis idade, escolaridade, sexo, fatores de risco cardiovascular (exceto por maior prevalência de dislipidemia no gCCLa) e hiperintensidades de substância branca na RM. Menores valores de mini-exame do estado mental foram observado nos grupos CCLa e CCLna em relação ao GC. O subgrupo amnéstico apresentou redução de volume em porções mediais e polares de ambos os lobos temporais em comparação com GC e gCCLna, além de áreas de redução do metabolismo no giro do cíngulo posterior e pré-cúneo direitos e giro temporal médio esquerdo em relação ao GC. Esse padrão de redução volumétrica e metabólica não foi visto no gCCLna, que demonstrou discreta redução volumétrica nos giros temporal inferior esquerdo e frontal médio direito em comparação com o GC. Nenhuma alteração metabólica persistiu no subgrupo não amnéstico após correção para efeito de volume parcial em comparação com o GC, havendo redução metabólica bilateral no giro frontal médio em comparação com o gCCLa. Não houve diferenças significativas nos biomarcadores de LCR entre os grupos CCLa e CCLna. Houve, porém, tendência de menores valores de peptídeo A? no gCCLa. Observou-se correlação positiva entre metabolismo no giro temporal médio esquerdo e rendimento em testes de memória; correlação negativa também foi observada entre os valores de A? e os de tau e p-tau no LCR. Conclusão: os grupos CCLa e CCLna apresentaram alterações de volume e metabolismo diferentes em comparação com o grupo controle, e estas alterações não apresentaram concordância entre si. Também não foram encontradas correlações entre os diferentes biomarcadores de imagem e no LCR, notando-se apenas correlação positiva entre metabolismo temporal e desempenho em testes de memória. O gCCLa apresentou padrões de metabolismo e volume cerebrais classicamente relacionados a risco de evolução para DA. Por outro lado, o grupo CCLna apresentou um padrão diferente de alterações metabólicas e volumétricas, com áreas menores de redução de volume e padrão mais heterogêneo de alterações metabólicas em relação ao grupo controle. O conjunto de achados de biomarcadores no gCCLna não é indicativo de nenhum perfil específico de evolução para demências / Introduction: Mild cognitive impairment (MCI) is presumably a transitional stage between normal aging and dementia, particularly Alzheimer\'s disease (AD). Non-amnestic subtypes (naMCI) present with executive, attention, visuospatial and language dysfunctions. They have a lower conversion rate to dementia compared to amnestic subtypes (aMCI). Investigations regarding biomarker profiles of naMCI as an independent group are scarce. To our knowledge there is no study investigating the brain volumetric and metabolic features, as well as the profile of cerebrospinal fluid (CSF) biomarkers of naMCI patients as a single group in comparison to aMCI and cognitively normal elderly patients (control group - CG). Objective: to investigate the brain volumetric and metabolic changes in individuals presenting amnestic and non-amnestic MCI subtypes in comparison to elderly volunteers without cognitive impairment, aiming to verify if there are agreements between these changes. Possible associations between the imaging profile of these groups and classical patterns of high risk for developing AD were also evaluated, as well as possible correlations between imaging biomarkers, CSF biomarkers and clinical data. Methods: a hundred and fourteen (114) patients were included in three different groups: naMCIg (N = 38), aMCIg (N = 46) and CG (N = 30). Patients underwent brain MRI (in order to exclude other causes of the cognitive impairment but also for VBM analysis) and [18F]FDG-PET. A subsample (naMCIg = 33, aMCIg = 38) also underwent a lumbar puncture in order to assess the profile of amyloid-ß peptide, tau and phosphorylated tau protein levels in the CSF. Results: There was no difference in CSF biomarkers, education years, age, gender and cardiovascular risk factors between the naMCI and aMCI groups, except for a higher prevalence of dyslipidemia in aMCI. The amnestic MCI group had lower rBGM in relation to control group in the precuneus, posterior cingulate and left medium temporal gyrus. Compared to aMCIg, naMCIg presented with bilateral prefrontal cortex hypometabolism, but without metabolic changes in relation to CG after correction for partial volume effect. Amnestic MCI group had bilateral temporal lobe volume reduction in comparison to naMCI and CG, particularly in the polar and mesial parts of the temporal lobe. Non-amnestic MCI presented with discrete volumetric reductions in comparison to CG, Conclusion: Volumetric and metabolic alterations were different and essentially discordant between aMCI and naMCI groups in comparison to CG. Amnestic MCI showed metabolic and volumetric profiles classically related to MCI due to AD, while naMCI group presented with less-significant areas of volumetric and metabolic reductions in relation to control group. Our non-amnestic MCI group probably represents a heterogeneous group with a different pattern of neurodegeneration than the classical MCI due to AD

INTRODUÇÃO: O Comprometimento Cognitivo Leve amnéstico (CCL-A) frequentemente representa a zona de transição entre o envelhecimento saudável e a demência, sendo considerado um problema de saúde pública, sobretudo devido ao crescimento da população idosa. Assim, é crucial o desenvolvimento de tratamentos eficazes que possam minimizar os déficits cognitivos presentes, tal como o treino de estratégia de memória (TEM). Destaca-se o TEM com foco na associação entre faces e nomes, alvo relevante, uma vez que esquecer nomes é uma queixa frequente em idosos com CCL-A. Entretanto, até o momento há pouca evidência quanto à eficácia dessa modalidade de intervenção a essa população, assim como à generalização dos possíveis efeitos, e o correlato neural subjacente. OBJETIVO: Investigar a eficácia do TEM com foco na associação face-nome e o correlato neural através da ressonância magnética funcional (RMf), em comparação a um grupo controle ativo (Psicoeducação - PED), em idosos com CCL-A. MÉTODOS: Trinta idosos com CCL-A foram randomizados em dois grupos: Grupo Experimental (GE, N=15), submetido ao TEM, e o Grupo Controle (GC, N=15), submetido a PED. Em cada programa, os participantes completaram quatro sessões de uma hora cada, duas vezes por semana. Os participantes foram avaliados nos momentos pré e pós intervenção, através de testes neuropsicológicos, tarefas de associação face-nome, escalas de humor e metamemória, além de uma tarefa na RMf. Ademais, no momento préintervenção, os participantes realizaram a coleta do líquido cefalorraquidiano; e, após a intervenção, responderam a um questionário de avaliação dos programas. A fim de investigar a manutenção dos efeitos ao longo do tempo, os voluntários foram reavaliados após um mês e após três meses. RESULTADOS: Não houve diferenças significativas entre ambos os grupos quanto ao perfil clínico, neuropsicológico e biomarcadores liquóricos. Quanto às mudanças após as intervenções, o GE apresentou melhor desempenho que o GC na tarefa de associação face-nome para o material treinado, o que generalizou em parte para o material não-treinado, com benefícios persistindo após três meses. No que se refere à generalização para as medidas neuropsicológicas, o GE exibiu melhora em teste de memória visual, porém não houve mudanças em testes de memória verbal e de atenção após ambos os programas. Além disto, em relação ao GC, o GE reportou uso mais frequente de estratégia associativa, e menor frequência de falhas de memória no cotidiano. Após os programas, ambos os grupos reportaram sentimentos mais positivos quanto à própria memória e avaliaram positivamente as intervenções. Ademais, não foram observadas mudanças em sintomas de depressão e ansiedade após os programas. Os achados de neuroimagem indicam que após as intervenções o GE mostrou maior ativação cerebral que o GC em regiões parietais (pré-cuneo, cíngulo posterior e giro angular bilaterais) e frontais (giro frontal medial à esquerda, giros frontal médio e pré-central à direita) ao codificarem o material treinado. Quanto ao material não-treinado, o GE mostrou maior ativação cebrebral que o GC em região anterior temporal (sulco temporal superior, giro temporal superior e médio). CONCLUSÃO: Os benefícios do TEM são observáveis tanto nos estímulos treinados, como transferem, em parte, para estímulos não-treinados e testes neuropsicológicos padronizados. Além disto, após o TEM, houve aumento no uso de estratégias associativas e ganhos de metamemória. Embora o GE tenha reportado menos falhas de memória que o GC, este aspecto não parece associado ao humor, uma vez que não ocorreram mudanças em sintomas de depressão e ansiedade após os programas. Os dados de neuroimagem corroboram os achados comportamentais sugerindo que o cérebro de idosos com CCL-A permanece altamente plástico. O GE mostrou maior aumento de ativação cerebral que o GC em regiões consistentes com as estratégias treinadas, envolvendo recursos atencionais, memória episódica, semântica e subjetiva, imageria mental, pensamento associativo, processamento de faces e cognição social / INTRODUCTION: Amnestic mild cognitive impairment (A-MCI) often represents the transitional stage between healthy aging and dementia, and has been considered a public health matter due to the growth of elderly population. Thus, it is critical to develop effective treatments that can minimize the cognitive deficits, such as mnemonic strategy training (MST). We highlight the MST focused on face-name associations, a relevant target since forgetting names is a frequent complaint in elders with MCI. However, at the moment there is little evidence of the efficacy of this modality of MST to this population, as well as, its transfer effects and underlying neural correlate. OBJECTIVE: Investigate the efficacy of MST focused on face-name associations, and the underlying neural correlate, in comparison with an active control group (Psychoeducation - PED) in elders with A-MCI. METOHDS: Thirty elders with A-MCI were randomized in two groups: Experimental Group (EG, N=15), underwent to MST, and the Control Group (CG, N=15), underwent to PED. In each program, the participants completed four individual one-hour sessions, twice a week. The participants were assessed at pre and post intervention through neuropsychological tests, face-name association tasks, mood and metamemory scales, beside a fMRI task. Moreover, at pre-intervention, the participants performed the cerebral spinal fluid (CSF) puncture; and at post-intervention, answered a questionnaire to evaluate the programs. In order to investigate the maintenance of the effects over the time, the volunteers were reassessed after 1 and 3-months. RESULTS: There was no significant differente between groups regarding the clinical and neuropsychological profiles, as well as, the CSF biomarkers. With respect to the changes after intervention, the EG showed a better performance than CG in the face-name association task to the trained material, and transfered, in part, to the untrained material, with the benefits persisting after three months. Regarding the transfer effects to the neuropsychological measures, the EG exhibited an improvement in the visual memory test, however no changes were observed in the verbal memory and attention tests after both programs. In comparison to CG, the EG reported a more frequent use of associative strategy, and less frequent memory mistakes. After the programs, both groups reported more positive feelings regarding their own memory and evaluated positively the interventions. In addition, there was no change in depression and anxiety symptoms after the programs. The neuroimaging findings indicate that after the interventions the EG showed greater cerebral activation than CG in parietal (bilateral precuneus, posterior cingulare and angular gyru), and frontal regions (left medial frontal gyru, right precentral and middle frontal gyrus), when enconding the trained material. For the untrained material, the EG showed greater brain activation than CG in an anterior temporal region (superior temporal sulcus, superior and middle temporal gyru). CONCLUSION: The MST benefits were observed in the trained and transfer, in part, to the untrained stimuli and neuropsychological tests Moreover, after the MST, there was an increase of associative strategy use and gains in metamemory. Despite the EG has been reported less memory mistakes than the CG, this aspect does not seem related to mood, since there was no changes in depression and anxiety symptoms after the programs. The neuroimaging data corroborate the behavioral findings suggesting that the brain of elders with a-MCI remains highly plastic. The EG showed greater increase of brain activation than the CG in regions consistent with the training, involving attentional resourses, episodic, semântic and subjective memory, mental imagery, associative thinking, face processing and social cognition

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.