Au-delà des symptômes moteurs classiques de la maladie de Parkinson, d’autres troubles neuropsychiatriques, émotionnels ou cognitifs sont fréquemment observés chez le patient parkinsonien. L’apathie, définie comme une importante diminution des comportements motivés dirigés vers un but, est l’un des troubles neuropsychiatriques le plus souvent rapporté en clinique. Si ce symptôme est relativement bien maitrisé par les traitements dopaminergiques, l’application de la stimulation haute fréquence du noyau subthalamique (SHF-NST), traitement neurochirurgical de référence, entraîne sa résurgence chez environ 50 % des patients stimulés. De nombreuses données suggèrent que cette résurgence est liée à la diminution du traitement dopaminergique, permise grâce aux effets spectaculaires de la SHF-NST sur les symptômes moteurs. Au contraire, d’autres études proposent un rôle délétère direct de la SHF-NST sur les comportements motivés. Malheureusement, chez le patient, il n’est pas possible de dissocier l’effet des différents traitements. Ainsi, afin de comprendre les bases neurobiologiques de l’apathie dans la maladie de parkinson, notre laboratoire a récemment développé un modèle animal chez le rat, basé sur des approches de lésions sélectives, partielles et bilatérales des neurones dopaminergiques du mésencéphale, reproduisant un déficit motivationnel pouvant s’apparenter à l’apathie parkinsonienne.L’objectif de ce travail doctoral a été d’étudier l’effet de la SHF-NST sur les comportements motivés chez le rat sain et dans ce modèle animal, et d’en comprendre les mécanismes neurobiologiques. Pour cela, nous avons utilisé un nouveau système de stimulation portatif chez le rat, permettant d’appliquer une SHF-NST chronique et ininterrompue chez l’animal libre de ses mouvements. Dans un premier temps, nous avons évalué l’effet motivationnel de la SHF-NST chez le rat sain et parkinsonien à l’aide de tests de référence. Nous avons ainsi pu montrer que la SHF-NST induisait un déficit motivationnel sévère chez le rat sain, ou exacerbait le déficit présent chez le rat lésé. Dans un deuxième temps, compte tenu de l’efficacité chez le patient des agonistes des récepteurs dopaminergiques D2 et D3 (RD2 et RD3) sur l’apathie pré ou post opératoire, nous avons voulu corriger ce trouble induit par la SHF-NST avec un tel traitement. Cette étude pharmacologique nous a amené à montrer que le pramipexole, un agoniste D2 D3, permet de traiter complétement le déficit induit par la SHF-NST. Enfin, compte tenu de ces résultats pharmacologiques, nous avons voulu vérifier si les effets délétères de la SHF-NST ou thérapeutiques du pramipexole, étaient sous-tendus par une modification d’expression des récepteurs D2 et D3. Pour cela nous avons utilisé une nouvelle technique d’hybridation in situ pour quantifier les transcrits D2 et D3. Si la SHF-NST ne semble pas impacter l’expression de ces récepteurs, l’effet thérapeutique du pramipexole pourrait être sous tendu par une baisse d’expression du RD3 au sein du noyau accumbens.Les données obtenues au cours de ce travail doctoral suggèrent donc fortement que la SHF-NST pourrait en elle-même induire de l’apathie post opératoire. De plus, malgré l’apport thérapeutique de l’activation des RD2 et RD3 sur ce symptôme, son origine serait sous tendue par un autre mécanisme qui reste à être élucider. / Apart from the classical motor symptoms of Parkinson’s disease, neuropsychiatric, emotional or cognitive impairments are also commonly observed in parkinsonian patients. Apathy, defined as a decrease in goal directed motivated behaviours, is one of the most frequently reported neuropsychiatric symptom in PD. This impairment is relatively well alleviated by dopaminergic treatment, but subthalamic nucleus high frequency stimulation (STN-HFS), the gold standard neurosurgical treatment, leads to the resurgence of this symptom in 50% of patients. Clinical evidence suggests that this is due to the reduction of the dopaminergic treatment, made possible by the great effect of STN-HFS on motor symptoms. However, some studies propose a direct deleterious action of STN-HFS on motivated behaviors. Unfortunately, it is impossible to dissociate the effect of the different treatments in patients. Thus, in order to better understand the neurobiological basis of apathy in Parkinson’s disease, our laboratory recently developed a rodent model, based on selective, partial and bilateral lesion of mesencephalic dopaminergic neurons, reproducing a motivational deficit reminiscent of parkinsonian apathy.The aim of this thesis project is to assess the effect of STN-HFS on motivated behaviours in normal and parkinsonian rats, and to unravel the essential mechanisms. We have used a new micro-stimulation system, allowing chronic STN-HFS in freely moving animals. First, we evaluated the motivational effect of STN-HFS in healthy and lesioned rats, using appropriate behavioural tests. We showed that STN-HFS induces a motivational impairment in healthy rats, and exacerbates the deficit observed in parkinsonian rats. Then, considering their therapeutic effect on apathy before or after STN-HFS in patients, we used D2 and D3 dopaminergic receptor agonists to try to manage this deficit in rats. It was thus demonstrated that pramipexole, a D2 D3 agonist, completely alleviated this STN-HFS induced deficit. This result prompted to assess whether the deleterious effect of STN-HFS, or the beneficial effect of pramipexole, depended on modulation of D2 and D3 expression. We therefore applied a new in situ hybridization technique to quantify D2 and D3 mRNAs. We found that STN-HFS alone did not modify their expressions, but the therapeutic effect of pramipexole could be liked to down-regulation of D3 receptors within the nucleus accumbens.Our data strongly suggest that STN-HFS itself may induce post-operative apathy. Moreover, despite the beneficial effect of D2 and D3 agonist on this symptom, its origin could depend on other mechanisms that will need to be deciphered.

[pt] A falta de consciência da doença, também denominada anosognosia, é um sintoma comum da Doença de Alzheimer (DA). Sua estrutura funcional e seus mecanismos subjacentes, contudo, não são inteiramente compreendidos. O nível de consciência possui grande relevância para o sucesso do tratamento e para o fardo do cuidador. Outro fator de considerável impacto nas relações interpessoais e, portanto, no bem-estar dos pacientes e cuidadores, é o processamento emocional. A presente tese explora esses tópicos através de quatro artigos. No Artigo 1, utiliza-se a modelagem de equações estruturais (SEM, do inglês structural equation modeling) em uma grande amostra de pessoas com DA para investigar a natureza da relação entre função cognitiva, estado de humor e funcionalidade na previsão do nível de consciência da condição. Os resultados demonstraram que uma menor funcionalidade cognitiva e um maior nível de estado depressivo de humor influenciaram negativamente a capacidade dos pacientes de realizar atividades da vida cotidiana, o que, por sua vez, se mostrou associada a uma maior consciência da doença. O Artigo 2 investigou as origens executivas e mnemônicas da anosognosia na DA, utilizando uma tarefa de tempo de reação e medindo a consciência a respeito da performance na tarefa. Os dados demonstraram que o monitoramento online dos pacientes estava preservado, enquanto o monitoramento a médio e longo prazo esteve comprometido. Tal achado foi corroborado por resultados de dados eletrofisiológicos. Dessa forma, os resultados fortalecem as evidências favoráveis a uma natureza mnemônica, e não executiva, da anosognosia na DA, o que se mostra de acordo com o Cognitive Awareness Model (CAM). O Artigo 3 investigou a reatividade emocional a imagens negativas, auto-relevantes e neutras utilizando medidas de excitação e valência, gravações de expressões faciais e dados eletrofisiológicos. A reatividade emocional dos pacientes de DA foi similar à de jovens adultos, mas as respostas eletrofisiológicas foram elevadas quando comparadas às de idosos saudáveis, o que pode ser explicado por uma falta de mecanismos de controle cognitivo. A apatia esteve associada a menores respostas eletrofisiológicas a figuras negativas, e a consciência de prejuízos sociais se relacionou com maiores níveis de excitação em imagens auto-relevantes. Por sua vez, o Artigo 4 discutiu como a DA afeta as habilidades emocionais através de uma revisão de literatura sobre a empatia desses pacientes. Os aspectos afetivos da empatia deste grupo clínico estiveram relativamente preservados, enquanto foram apresentados déficits nos componentes cognitivos. Os prejuízos relacionados aos componentes afetivos foram principalmente atribuídos a um declínio cognitivo geral. Nossos achados ressaltam que diferentes fatores influenciam a consciência da doença na DA, enfatizando o papel de sintomas neuropsiquiátricos, do funcionamento cognitivo e das atividades da vida diária. Além disso, processos executivos pareceram estar preservados, ao passo que dificuldades em atualizar e consolidar esse conhecimento podem ser uma possível causa de anosognosia na DA. Ademais, sugerimos que as habilidades emocionais são amplamente preservadas em pacientes de DA. Tais resultados são de grande importância para a prática clínica. Pesquisas translacionais são necessárias para implementar os achados de pesquisas em abordagens terapêuticas específicas. / [en] Lack of awareness of condition, also termed anosognosia, is a common symptom in Alzheimer s disease (AD). However, its functional structure and underlying mechanisms are not fully understood. Level of awareness has great relevance for treatment success and caregiver burden. Another factor that has considerable impact on interpersonal relationships and thus on well-being of patients and caregivers is emotional processing. The current thesis explores these topics through four articles. In Article 1, structural equation modeling (SEM) was used in a large sample of people with AD (PwAD) to investigate the nature of the relationship between cognitive function, mood state, and functionality in predicting awareness. Results showed that lower cognitive function and higher level of depressive mood state negatively influenced PwAD s ability to perform daily living activities, which in turn were associated with better awareness. Article 2 investigated executive and mnemonic origins of anosognosia in AD, with a reaction time task being applied to examine awareness of task performance. The findings demonstrated that online monitoring was preserved, while medium- and long-term monitoring were impaired. This was supported by results from electrophysiological data. The results strengthen the evidence for a mnemonic rather than executive nature of anosognosia in PwAD in accordance with the Cognitive Awareness Model (CAM). Article 3 investigated emotional reactivity to negative, self-relevant, and neutral pictures using ratings of arousal and valence, facial expression recordings and electrophysiological data. Emotional reactivity of PwAD was similar to young adults, but electrophysiological responses were elevated compared to healthy older adults, which might be explained by a lack of cognitive control mechanisms. Apathy was associated with reduced electrophysiological responses for negative pictures, and awareness of social impairments was linked to higher arousal ratings of self-relevant pictures. Article 4 discussed how higher emotional abilities are affected by AD, through a review of the literature on empathy in this clinical group. PwAD showed a pattern of relatively preserved affective aspects and impairments in cognitive components of empathy, whereby impairments in affective components can mainly be attributed to a general cognitive decline. Our findings highlight that different factors influence awareness in AD, emphasizing the role of neuropsychiatric symptoms (NPS), cognitive functioning and activities of daily living. Moreover, executive processes seem to be preserved, whereas impairments in updating and consolidation of this knowledge seem to be a possible cause for anosognosia in AD. Furthermore, we suggested that emotional abilities are largely preserved in PwAD. Our results have great significance for clinical practice. Translational research is needed to implement research findings into specific therapeutic approaches.

Background: Data regarding both drug-related and non-drug-related costs in patients with Parkinson's disease (PD) are scarce, mainly due to the difficulties in data acquisition in experimental designs. Likewise, the reported impact of drug costs on total direct costs varies across different studies. In addition, the influence of comorbidities on both treatment costs and health-related quality of life has not been adequately evaluated. Methods: A sample of office-based neurologists (n = 315) in Germany was asked to examine up to five consecutive patients with PD (n = 1449) on a specified day during the study period. Patients of all ages were eligible and their evaluation was performed using standardized questionnaires. Results: PD-specific therapy costs increased with the stage of the disease, early onset of the disease and disease duration. The major costs were due to PD-related therapy, whereas other medications only resulted in minor costs. Disease stage mainly influenced direct therapy costs, with an observed increase of total daily costs from €7.3 to €11.3/day. In addition, disease onset at age < 65 years resulted in total daily costs of €11.2 compared to late onset of disease (> 75 years) with daily therapy costs of €5.3. In this patient group neuropsychiatric comorbidities such as dementia and depression were only insufficiently treated. In addition, these comorbidities severely affected health-related quality of life. Conclusion: Therapy costs were influenced by disease stage, disease onset as well as present comorbidities. Furthermore, comorbidities such as depression and dementia were diagnosed but were not adequately treated.

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