Le vieillissement est un phénomène biologique complexe et inévitable associé à un déclin progressif des fonctions cognitives, sensorielles et motrices qui affecte la qualité de vie et la santé des sujets âgés. Le vieillissement normal s'accompagne de changements structuraux et fonctionnels, conduisant au déclin cognitif. Parmi ces changements, les altérations du système noradrénergique semblent contribuer de façon significative aux déficits cognitifs. Inversement, le maintien de l'intégrité du Locus Coeruleus semble participer à la préservation des performances. Par ailleurs, une stratégie pour promouvoir le bien vieillir propose de booster la réserve cognitive associée à un haut niveau de stimulation cérébrale et à des modulations de l'activation et de la connectivité cérébrales chez l'humain. Chez les rongeurs, l'enrichissement environnemental promouvant les stimulations sensorielles, l'activité motrice et les interactions sociales, mime les conditions de mise en place de la réserve cognitive chez l'homme et a largement montré ses effets bénéfiques sur la cognition. Les objectifs de cette thèse sont premièrement, d'étudier le rôle de la NA dans le maintien de la plasticité structurale et des capacités de discrimination olfactive chez la souris âgée, puis dans un second temps de tester l'enrichissement olfactif comme modèle de construction de la réserve cognitive. Dans une première étude, nous avons utilisé le modèle d'apprentissage perceptif olfactif pour étudier la contribution de la Noradrénaline au maintien de la plasticité structurale et des performances cognitives au cours du vieillissement chez la souris. Cet apprentissage consiste en une amélioration de la discrimination entre deux odorants proches sur le plan perceptif après une exposition répétée à ces odorants. Nos résultats suggèrent que la libération de Noradrénaline dans le bulbe olfactif via une stimulation optogénétique des fibres issues du Locus Coeruleus maintient les capacités de discrimination au cours du vieillissement. Nos données révèlent aussi une forme de plasticité du réseau noradrénergique dans le bulbe olfactif âgé. Ces résultats soutiennent l'hypothèse d'une contribution importante de la Noradrénaline au bien vieillir cérébral. Dans une deuxième étude, nous avons utilisé une stratégie basée sur un enrichissement olfactif, manipulation capable de mobiliser la Noradrénaline, proposé tout au long de la vie de l'animal, dans le but de permettre le développement d'une réserve cognitive. Nos résultats montrent qu'un tel enrichissement améliore les capacités de discrimination olfactive même à un âge avancé. De façon intéressante, les performances non olfactives de mémoire spatiale et de flexibilité sont aussi améliorées. Ces résultats indiquent que les effets bénéfiques de l'enrichissement s'étendent au-delà de la sphère olfactive et incluent des bénéfices sur différentes performances cognitives sensibles à l'âge. Nous proposons donc l'enrichissement olfactif comme un modèle de la construction d'une réserve cognitive qui nous permettra par la suite d'identifier les bases cellulaires du bien vieillir et de tester la contribution de la Noradrénaline dans la construction de la réserve cognitive / Aging is an inevitable and complex biological phenomenon associated with a progressive decline of sensory, motor and cognitive functions with time, affecting life quality and health. Normal brain aging is accompanied by functional and structural changes, leading to cognitive decline. Among these changes, age-related alterations of the noradrenergic system seem to contribute significantly to cognitive deficits. Conversely, the integrity of the Locus Coeruleus seems to allow healthy cognitive aging. A potentially powerful tool to achieve successful brain aging is to boost the cognitive reserve, associated with higher level of brain stimulation and modulations in brain activation and connectivity in humans. In rodents, environmental enrichment, increasing sensory stimulations, motor activity and social interactions, mimics the conditions leading to constitution of the cognitive reserve in humans and has largely proven cognitive benefits.The goals of this thesis are, in the first place, to study the role of Noradrenaline in the maintenance of structural plasticity and olfactory discrimination abilities in aged mice, then secondly, to test the olfactory enrichment as a model of the cognitive reserve build-up.In the first study, we used the olfactory perceptual learning paradigm to investigate the contribution of Noradrenaline to the maintenance of structural plasticity and cognitive abilities during aging in mice. This learning consists in an improvement of the discrimination between perceptually close odorants after repeated exposure to these odorants. Our results suggest that the local release of Noradrenaline in the olfactory bulb, by optogenetic stimulation of Locus Coeruleus fibers allows the maintenance of discrimination abilities during aging. Our data also reveal a form of structural plasticity of the noradrenergic innervation in the aged olfactory bulb. The overall work supports a contribution of Noradrenaline to healthy brain aging.In a second study, we used a strategy based on repeated olfactory enrichment during the whole life of the animal in order to enable the cognitive reserve buildup. Such enrichment maintained olfactory discrimination performances at late ages. Interestingly, mice’s performances in spatial memory and cognitive flexibility improved too. This result indicates that the benefits of an odor-based enrichment extend beyond the olfactory sphere and include broader cognitive benefits on age-sensitive functions. We thus propose lifelong olfactory enrichment as model of the cognitive reserve build-up to further identify its cellular basis and test the contribution of Noradrenaline to cognitive reserve build-up and healthy brain aging

Individuals who speak more than one language have been found to enjoy a number of benefits not directly associated with the use of the languages themselves. One of these benefits is that bilingual individuals appear to develop symptoms of dementia 4-5 years later than comparable individuals who speak just one language. Studies on this topic, however, do not consistently account for factors including if the individual learned their second language as a child or later in life, or their language proficiency. In an attempt to more carefully examine these variables, this study looks at structural and resting-state functional MRI scans of the default mode network, English and Spanish (where applicable) proficiency, language background, and demographics of young healthy adults who fall into one of three groups: early bilinguals, late bilinguals, and monolinguals. Of the three groups, late bilinguals were found to have a small but statistically significantly higher level of connectivity compared with early bilinguals in the region of the medial prefrontal cortex; patterns found examining number of languages and language proficiency in relation to functional connectivity and research group also supported this finding. These results indicate studying a language after adolescence could provide neuroprotective benefits of a nature that could potentially help delay symptoms of dementia. Age, gender, ethnicity, level of education, English language proficiency, and Spanish language use did not result in statistically significant findings, the latter of which challenges using frequency of language use to define bilingualism.

Alzheimer’s disease is an insidious neurodegenerative disease that affects millions of people worldwide. Currently, there are no determinants that can accurately predict the onset cognitive decline in AD. This thesis investigates and defines changes in the lipidome that are linked to symptomatic onset and cognitive impairment in mouse models of AD. Using a targeted lipidomic approach employing high performance liquid chromatography electrospray ionization tandom mass spectrometry, direct biochemical assessments, and behavioural evaluation, I was able to (a) profile and quantify cortical and hippocampal glycerophosphocholine and glycerophosphoethanolamine metabolites and signaling molecules in the APPSwe/PS1dE9 and the N5 TgCRND8 murine models of AD and (b) associate changes in lipid metabolism with learning and memory impairment. I demonstrate that glycerophosphocholine metabolism in the cortex but not the hippocampus is altered at symptomatic onset in both mouse models. These same metabolic changes were seen in younger animals exposed to chronic intermittent hypoxia, an environmental risk factor that accelerates their phenoconversion. In fully impaired transgenic mice, I defined metabolic changes associated with disease progression. To further assess the impact of sex, another risk factor of Alzheimer’s disease cognitive decline, I characterized an AD model of sex-specific cognitive resistance. I demonstrated that transgenic males but not females exhibit behavioural indices of cognitive reserve when tested in the Morris Water Maze. Using this mouse line, I then investigated how measures of learning and memory associated with glycerophosphocholine and glycerophosphoethanolamine metabolism. I identified increases in critical glycerophosphoethanolamine metabolites linked to spatial learning and memory impairment in the cortex of N5 TgCNRD8 mice and demonstrated that these changes could be predicted by profiling the plasma glycerophosphoethanolamine lipidome. Taken together, this thesis links glycerophospholipid metabolism to the onset and progression of learning and memory impairment in experimental models of AD and provides the first evidence that changes in cortical lipid metabolism can be predicted by changes in the plasma lipidome.

According to the theory of cognitive reserve, cognitively enriching aspects of life experience (e.g., education, occupation, and leisure activity) foster the development of more efficient neural networks and cognitive strategies, enabling individuals to cope more effectively with the pathology of dementia. Using extant data from a population-based study, we examined: (1) the effect of reserve accrued through middle life on course of neuropsychological decline; and (2) the role of ongoing engagement in mentally stimulating leisure activities in rate of general cognitive and functional deterioration. In linear mixed models, level of occupational attainment did not affect rate of cognitive or functional decline, although women were found to undergo more rapid deterioration in cognitive ability. Occupational skill area was associated with trajectory of decline in several neuropsychological domains. Specifically, vocations emphasizing practical, hands-on skills were associated with slower deterioration in auditory-verbal and visual memory, as well as visuospatial and constructional abilities. Teaching and helping professions, in contrast, were associated with more rapid decline in memory and executive functioning. Increased engagement in cognitive leisure activities through late life was associated with slower deterioration in general cognitive ability in mild dementia, but its effects were no longer evident in more severe AD. An understanding of how rate of decline intersects with patients' past histories and efforts to maintain and enhance cognitive capacity will enable clinicians to target areas for cognitive training and rehabilitative therapy.

According to cognitive reserve theory, challenging and/or stimulating cognitive activities can build a theoretical reserve, which may lead to a delay in the clinical expression of dementia and/or Alzheimer's Disease. These cognitively stimulating activities are thought to build cognitive strategies and neural pathways that are more efficient, enabling the individual to live symptom-free for a longer period of time. One mechanism through which cognitive reserve can be built is by participating in an occupation high in cognitive complexity. When individuals hold an occupation that is high in complexity, they may build their cognitive reserve in such a manner as to reduce their risk for dementia in late life. Using extant data from an existing longitudinal, population-based study, we examined the effect of various subdomains of cognitive complexity of the longest-held job on dementia risk. In cox regression models, individuals holding agricultural occupations and occupations high in complexity of interaction with machinery, equipment, tools and inanimate objects ("Things") had an increased risk for both AD and dementia. Socioeconomic status was found to partially mediate the relationship between high Things complexity and dementia/AD risk, as well as the relationship between agricultural occupations and dementia/AD risk. While there has been some debate regarding whether results reflect a true effect of occupational complexity or simply an effect of education, results from this study indicate that both occupational complexity and education contribute unique effects to dementia/AD risk. Gender, job duration, and APOE genotype were not found to moderate any of the above associations. An understanding of how occupational complexity impacts cognitive reserve and risk for dementia/AD will enable individuals as well as clinicians to implement activities that enhance cognitive reserve and lead to a greater number of years lived symptom-free from dementia/AD.

<p>Recurrent stress has been found to impair brain structures essential to memory. The cognitive reserve model suggests that physical activity supplies protection against memory decline in neuropathologies. The purpose of the present study was to explore whether leisure physical activity modifies the predicted negative effect stress has on memory. A sub-sample derived from the Betula Study comprised 267 participants between 50 and 65 years. Memory was assessed by a SPT free recall and stress by a self-report. Low and High frequency exercisers were analyzed separately. After age, sex and education were controlled for in hierarchical regression, results showed that stress significantly improved memory performance in Low exercisers but no significant effect in High exercisers. Thus, frequency of physical activity did not explain variation in memory performance. However, higher age did not have a negative influence on memory performance for the High exercisers.</p>

Recurrent stress has been found to impair brain structures essential to memory. The cognitive reserve model suggests that physical activity supplies protection against memory decline in neuropathologies. The purpose of the present study was to explore whether leisure physical activity modifies the predicted negative effect stress has on memory. A sub-sample derived from the Betula Study comprised 267 participants between 50 and 65 years. Memory was assessed by a SPT free recall and stress by a self-report. Low and High frequency exercisers were analyzed separately. After age, sex and education were controlled for in hierarchical regression, results showed that stress significantly improved memory performance in Low exercisers but no significant effect in High exercisers. Thus, frequency of physical activity did not explain variation in memory performance. However, higher age did not have a negative influence on memory performance for the High exercisers.

Background Dementia is a national priority for Scotland, and as such, fast and accurate diagnosis plus responsive and well-evidenced interventions post-diagnosis are key. Accurately estimating an individual’s level of premorbid functioning can be a crucial part of establishing that cognitive decline has taken place, enabling clinicians to be more confident and accurate in their diagnosis. Measures that assess premorbid ability should be able to 1) capture current ability in healthy controls and 2) resist the effects of cognitive decline when used in individuals with dementia. At the post-diagnostic stage, there is a growing evidence base for non-pharmacological, tailored interventions for individuals with dementia. However, the evidence base is limited, particularly so for Cognitive Rehabilitation. Objectives An empirical study was conducted in order to assess whether a newly developed measure that aims to capture lifelong cognitive reserve (the brain’s ability to withstand pathological change), the Cognitive Reserve Index Questionnaire (CRIq), can capture premorbid ability. Three research questions were addressed; 1) does the CRIq capture current ability in healthy controls? 2) is it resistant to cognitive decline when used with a patient group with dementia? and 3) how does the CRIq compare to a traditional measure of premorbid ability, the NART (National Adult Reading Test)? Another focus of development and innovation in dementia research is that of post-diagnostic interventions. A systematic review was therefore conducted in order to evaluate the effectiveness of Cognitive Rehabilitation for mild-moderate dementia (Alzheimer disease or mixed dementia) in relation to cognitive and functional outcomes. Due to the limited number of RCTs in this field precluding a clear understanding of the evidence base, the additional contribution of non-RCTs was also evaluated. Method For the empirical study N=20 healthy older controls and N=13 patients with dementia were recruited. In order to appropriately address the three research questions both groups were assessed using the NART, the CRIq and the MOCA (Montreal Cognitive Assessment). In addition, the control group were assessed on a measure of current ability, the WAIS-IV Perceptual Reasoning Index. For the systematic review of Cognitive Rehabilitation the CDCIG Specialised Register, ALOIS, was searched in order to identify relevant studies. In addition, previous reviews were searched to identify studies excluded on the basis that they were not an RCT. Results Results for the empirical study show both CRIq and NART were strongly correlated to current ability (performance on WAIS-IV PRI) in controls, although both significantly overestimated ability. CRIq performance was not affected by the presence of dementia whereas NART predicted premorbid ability was. CRIq and NART showed a different pattern of results between controls and patients, indicating that CRIq may more resistant to the effects of cognitive decline. Ten studies were identified for the systematic review; five RCT and five non-RCT. Study quality was assessed using a well-validated quality assessment tool, and indicated large variability. Eight of the ten studies reported a positive effect of Cognitive Rehabilitation. However, several studies were of poor quality and included aspects of other approaches in their intervention (e.g. Cognitive Training, Cognitive-Behaviour Therapy). Conclusions The empirical study found that CRIq over-estimated current ability in controls, but was resistant to cognitive decline in patients. The over-estimation of current ability may be accounted for by the CRIq being normed on an Italian population, thus not reflecting UK cultural norms (e.g. for length of schooling). When the NART and the CRIq were directly compared, the two measures were found to be related, but yet produced significantly different estimates of premorbid ability. This suggests that they may capture different facets of premorbid functioning, with the NART being primarily a verbal performance-based measure, and the CRIq capturing aspects of global cognitive functioning. Clinical implications include the potential utility of the CRIq for patients with language impairment. However the study conclusions are limited by a low N, and therefore have restricted generalisability. In the systematic review, the literature was exhaustively searched and evidence was found for the effectiveness of Cognitive Rehabilitation for mild-moderate Alzheimer disease and mixed dementia. Methodological limitations of the included studies are discussed, and clinical implications are identified. Both the empirical study and the systematic review highlight the need for greater research and development of methods by which dementia care is supported; through more effective methods of diagnosis, to a better evidence base for post-diagnostic interventions.

A Doença de Parkinson (DP) é uma das doenças degenerativas do Sistema Nervoso Central que mais acomete indivíduos no mundo. Apesar de a DP ser descrita classicamente como desordem do movimento, sintomas não motores também fazem parte da apresentação da doença, como as alterações cognitivas, que podem estar presentes antes mesmo de os sintomas motores serem percebidos. Os principais domínios cognitivos afetados na DP são as funções executivas (FE). Estas consistem num contingente de funções de ordem superior, que são cruciais para cognição, emoção e comportamento. Muitos estudos abordam a influência das FE no controle da marcha, já que esta não é mais considerada como um ato motor puramente automático. De fato, existem componentes cognitivos na generalização e manutenção de um padrão de marcha consistente e normal, o que justifica os prejuízos neste controle interdependente entre FE e marcha na DP. O objetivo deste estudo foi avaliar a eficiência de um treino original de marcha com demandas motoras e cognitivas desafiadoras, integradas em um contexto funcional em pacientes com DP em estágio inicial. Trata-se de um ensaio clínico cego e randomizado realizado na Associação Brasil Parkinson em São Paulo. Participaram do estudo 25 pacientes com DP nos estágios 1 a 2,5 da escala Hoehn & Yahr. Eles foram distribuídos aleatoriamente nos grupos experimental (GE: 13 sujeitos) e controle (GC: 12 sujeitos). Os dois grupos foram submetidos a 10 sessões de treinamento, com duração de 60 minutos cada uma (divididos em 25 minutos de exercícios de mobilidade global e 35 minutos para os treinos específicos), com frequência de duas vezes por semana, por 5 semanas. O treino experimental consistiu em treino de marcha com demandas motoras desafiadoras e demandas cognitivas constituídas por seis tarefas que exigiam as principais FE envolvidas na realização da marcha, que foram integradas em um contexto funcional. O treino 12 controle consistiu apenas de demandas motoras desafiadoras. As principais medidas foram: (1) Dynamic Gait Index (DGI); (2) Montreal Cognitive Assessment (MoCA); (3) teste de marcha em 30 segundos em dupla-tarefa cognitiva; (4) sessão II da Escala Unificada da Doença de Parkinson (UPDRS). Anova de medidas repetidas seguida de teste de Tukey avaliou a existência de diferenças dentro de cada grupo, em avaliações realizadas antes (AT), depois (DT) e após 60 dias do final do treinamento (RET). Resultados mostraram melhora estatisticamente significativa no DGI, MoCA, teste de marcha em dupla tarefa cognitiva, e sessão II da UPDRS. Entretanto, na medida de seguimento após 60 dias, para várias medidas foram observadas diferentes tendências entre os grupos: o GE apresentou uma tendência à manutenção dos ganhos, ao passo que o GC apresentou uma tendência à remissão dos ganhos. Conclui-se que os pacientes com DP lograram melhoras nos âmbitos motor, cognitivo e funcional por meio de um treinamento baseado na associação de tarefas cognitivas à marcha dentro de um contexto funcional, ganhos estes possivelmente mais estáveis em comparação aos oriundos do treino motor isolado / Parkinson\'s disease (PD) is one of the most frequent degenerative diseases of the central nervous system. Despite being classically described as a motor disorder, non-motor symptoms such as cognitive disorders are also part of the disease, and may be present even before patients become aware of their motor disorders. The main cognitive domains that are affected in PD are executive functions (EF). They consist of a number of higher-order functions, which are crucial for cognition, emotion and behavior. Several studies address influence of EF upon gait control, since gait is no longer considered as a purely automatic motor act. In fact, there are cognitive components in the generalization and maintenance of a normal consistent gait pattern. This helps explain why damages in EF affect gait control in PD, and gait affects EF. The study aimed to assess the effectiveness of an original gait training with challenging motor and cognitive demands, which are integrated in a functional context in patients with early PD. It consists of a blind randomized clinical trial, which was conducted at the Brazil Parkinson\'s Association in Sao Paulo. In the procedure 25 patients, with PD in stages 1 to 2.5 on Hoehn & Yahr scale, were randomly assigned to experimental group (13 subjects) and control group (12 subjects). Training consisted of 10 sessions, 60 minutes each. Sessions were divided into global mobility exercises (25 minutes) and training (35 minutes). Sessions occurred twice a week over five weeks. Experimental training consisted of a gait training with challenging motor demands and cognitive demands. There were six tasks that demanded important EF involved in gait performance, which were integrated into a functional context. Control training consisted only of challenging motor demands. Measures included: (1) Dynamic Gait Index (DGI); (2) Montreal Cognitive Assessment (MoCA); (3) gait test for 30 seconds in dual-cognitive task; (4) session II of the Unified Parkinsons Disease Rating Scale (UPDRS). Repeated measures ANOVA followed by Tukey tests were used to assess the existence of differences 14 within each group, in measures taken before training, after training, and in a follow-up 60 days after training. Both groups showed improvement in DGI, MoCA, gait test in dual-cognitive task, and session II of the UPDRS. However, in the follow-up assessment 60 days after training different trends were observed between the groups: EG showed a tendency to maintain gains, whereas CG showed a tendency to remission of gains. In conclusion, PD patients showed improvements in motor, cognitive and functional areas through a combination of a training based on challenging cognitive tasks on gait integrated in a functional context. Such gains were possibly more stable than those derived from gait training alone

Antalet med en demenssjukdom ökar i världen och siffran drabbade förväntas stiga till 132 miljoner år 2050. Kartläggning av riskfaktorer är en viktig del av det preventiva arbetet. Vissa studier har visat att socioekonomisk status och utbildning har ett samband med risk för att drabbas av demenssjukdom. I denna studie undersöktes relationen mellan utbildning, yrkesbaserad socioekonomisk status och risk för demenssjukdom, samt ifall utfallet ser olika ut för män respektive kvinnor. Ett stickprov med 489 personer från ett longitudinellt forskningsprojekt i Umeå undersöktes varav 70 personer var drabbade av demenssjukdom. Låg yrkesbaserad socioekonomisk status visade sig mer än fördubbla risken att insjukna i en demenssjukdom jämfört med de som hade en hög yrkesbaserad socioekonomisk status. Inget signifikant samband identifierades mellan utbildningslängd och demensinsjuknande, däremot observerades en interaktionseffekt mellan kön och utbildningsnivå där kvinnor med längre utbildning verkade få ett ökat skydd mot att insjukna i demens. Resultaten går till viss del i linje med kognitiv reservteori som bland annat menar att ett högstatusyrke med mer kognitiv stimulans under livet gör individer mer motståndskraftiga mot ett demensinsjuknande. Det är även möjligt att faktorer tidigt i livet, såsom socioekonomisk status under barndomen och kognitiv förmåga, medierar associationen mellan socioekonomisk status och demens. Detta undersöktes dock inte i denna studie men skulle kunna vara av intresse att inkludera i framtida och större longitudinella studier. / The prevalence of dementia in the world is rising and is expected to reach 132 million in the year 2050. Investigating risk factors is an important part of preventive efforts. Some studies have shown that socioeconomic status and education is associated with an increased risk of dementia. This study investigated the association between education, occupational socioeconomic status and dementia. Furthermore, outcomes for men and women were investigated. A sample of 489 people from a longitudinal study in Umeå, Sweden, was examined and 70 people in the sample was afflicted by dementia. Low occupational socioeconomic status was shown to more than double the risk of being afflicted by dementia compared to those with a high occupational socioeconomic status. No significant association could be identified between the length of education and dementia but an interaction between gender and length of education was identified where more years of education had a protective effect for women. The findings are partially consistent with the cognitive reserve theory, which states that having an occupation with higher status and more cognitive stimulation during life will postpone dementia onset. It is also possible that early life circumstances like childhood socioeconomic status and cognitive ability mediates the association between socioeconomic status and dementia which makes this an interesting area of exploration for future research.