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.

Fear is an innate emotion and an adaptive response to provide protection from potential harm. When fear is excessive and out of proportion in relation to the confronted situation, it can lead to the development of an anxiety disorder. Many individuals feel anxious at some point, but not all experience clinical anxiety or meet the diagnostic criteria of an anxiety disorder. Still, anxiety disorders are the most prevalent form of psychiatric disorder in the general population. More often than not people suffering from one anxiety disorder also present other psychiatric conditions. As of today, cognitive and behavioural treatments have been tested and found to positively affect anxiety disorders, making them the treatment of choice. Nevertheless, many patients do not seek or receive adequate treatment. One common critique of the research trials from which the recommendations for treatments stem is the use of a single protocol targeting only one diagnosis. This is because many people suffer from comorbidities. Another problem connected to the recommendation that cognitive behavioural therapy (CBT) should be the treatment of choice for anxiety disorders is the lack of therapists with adequate training. One possible way of dealing both with the shortcoming of therapists and making CBT more accessible is the use of the Internet. Internet-based CBT (ICBT) has been tested in numerous trials during the last 15 years, showing positive outcomes for a large variety of disorders. Many ICBT trials also make use of a single protocol. Another way of dealing with comorbidities might be to tailor the treatment to let characteristics and preferences of the patient guide the design of the protocol. Little is known about possible effects of tailoring the ICBT, the effects of therapeutic relationships in ICBT, and the effectiveness and cost-effectiveness of these treatments. This thesis is based on three studies on two separate randomized controlled trials (RCTs) using the same set of modules accessible for the tailored protocol. Study I was an RCT investigating treatment effects up to two-year after completion, showing favourable outcomes of the treatment in a self-recruited sample at all measure points. Study II was a secondary analysis exploring possible relations between working alliance and treatment outcome for participants in the treatment group recruited for Study I indicating that working alliance predict outcome in this tailored treatment. The second RCT was an effectiveness trial (Study III) analysing treatment effects and cost-effectiveness of the treatment up to one year post treatment in a primary-care population. This study showed positive treatment effects both regarding symptom reduction and cost-effectiveness, and that effects were sustained at one year post treatment. Conclusions drawn from these studies are that individually tailored ICBT seems to be a feasible approach for patients with anxiety disorders regardless of comorbidities, and a responsible choice in terms of societal costs. / Rädsla är en medfödd känsla och en adaptiv respons för att skydda organismen från potentiell skada. När rädslan blir överdriven och oproportionerlig i relation till den konfronterade situationen, kan det leda till utvecklandet av ångestsyndrom. Många personer upplever någon gång ångest, men inte alla upplever klinisk ångest eller uppfyller de diagnostiska kriterierna för något ångestsyndrom. Trots detta är ångest det vanligaste psykiatriska tillståndet i befolkningen i stort och oftast uppfyller personer som lider av ett ångestsyndrom även andra  psykiatriska tillstånd. Till dags dato har både kognitiva och beteendeinriktade behandlingar testats och visat sig verksamma vid ångestproblem, vilket gjort dem till de behandlingar som rekommenderas för dessa tillstånd. Trots god effekt av behandling söker många patienter ändå inte hjälp, alternativt erhåller inte adekvat behandling. En vanlig kritik mot den forskning från vilka behandlingsrekommendationerna för ångestsyndrom stammar är att många använt en manual eller ett protokoll som riktar sig mot bara en diagnos. Detta på grund av den stora komorbiditeten. Ett annat problem kopplat till rekommendationerna att kognitiv beteendeterapi (KBT) ska vara förstahandsval vid behandling av ångest är bristen på behandlare med adekvat utbildning. Ett möjligt sätt att göra KBT mer tillgängligt är att använda Internet. Internet- förmedlad KBT (IKBT) har prövats i ett stort antal studier de senaste 15 åren dessa har visat positiva resultat vid ett stort antal psykiatriska tillstånd. Flertalet av dessa studier har dock använt ett enda behandlingsprotokoll. En annan möjlighet att hantera komorbiditet kan vara att skräddarsy behandlingen för att låta patientens egenskaper och preferenser vara med och styra utformningen av behandlingsprotokollet. Möjliga effekter av att skräddarsy IKBT är relativt lite undersökt, likaså effekterna av terapeutiska relationer i IKBT samt klinisk effektivitet och kostnadseffektiviteten för dessa behandlingar. Denna avhandling bygger på tre studier från två randomiserade kontrollerade studier med samma uppsättning av moduler tillgängliga för att skräddarsy behandlingsprotokollen. I Studie I undersöktes behandlingseffekter upp till två år efter avslutad behandling i en självrekryterad grupp patienter. Studie II var en sekundäranalys av behandlingsgruppen från Studie I där eventuella samband mellan arbetsallians och behandlingsresultat undersöktes. Den andra randomiserade kontrollerade studien var en prövning av huruvida denna behandling var effektiv för en klinisk population (Studie III) rekryterad via primärvården. Förutom behandlingseffekter undersöktes även kostnadseffektiviteten upp till ett år efter behandlingsavslut. De slutsatser som dras utifrån dessa studier är att skräddarsydd IKBT verkar vara en framkomlig väg för patienter med ångest oavsett komorbiditet, att arbetsalliansen kan vara en faktor som påverkar utfallet, samt att det är ett ansvarsfullt val vad gäller samhälleliga kostnader.

Multiple health issues are associated with obesity and numerous factors are causative of the disease. The role of genetic factors is well established, as is the knowledge that dietary and sedentary behavior promotes weight gain. Although there is strong suspicion towards the role of epigenetics as a driving force toward disease, this field remains l in the context of obesity. DNA methylation correlation networks were profiled from blood samples of 69 adolescents of two distinct weight-classes; obese (n=35) and normal-weight (n=34). The network analysis revealed major differences in the organization of the networks where the network of the obese had less modularity compared to normal-weight. This is manifested by more and smaller clusters in the obese, pertaining to genes of related functions and pathways, than the network of the normal-weight. Consequently, this suggests that biological pathways have a lower order of coordination between each other in means of DNA methylation in obese than normal-weight. Analysis of highly connected genes, hubs, in the two networks suggests that the difference in coordination between biological pathways may be derived by changes of the methylation pattern of these hubs; highly connected genes in one network had an intriguingly low connectivity in the other. In conclusion, the results suggest differential regulation of transcription through changes in the coordination of DNA methylation in overweight and normal weighted individuals. The findings of this study are a major step towards understanding the role of DNA methylation in obesity and provide potential biomarkers for diagnosing and predicting obesity.

Les troubles du comportement alimentaire (TCA) touchent une part importante de la population et constitue un réel problème de santé publique, il est indispensable d’approfondir nos connaissances sur la physiopathologie des TCA afin d’identifier des perspectives thérapeutiques. L’écriture d’une revue systématique a permis d’évaluer la prévalence des TCA selon le sexe, l’origine géographique ou l’âge de la population étudiée et confirme son augmentation au cours des 15 dernières années. L’analyse des données épidémiologiques des patients avec un TCA de la cohorte Eating Disorder and Longitudinal Survey (EDILS) a souligné le stress et le régime alimentaire comme facteurs de survenue et des similarités entre les comorbidités des 3 catégories larges de TCA (Restrictive, boulimique et compulsive). Ces comorbidités étaient fortement associées entre elles et, selon un cercle vicieux pourrait contribuer au maintien de la physiopathologie des TCA. La littérature suggère l’implication d’une dérégulation peptidergique de la prise alimentaire au cours des TCA qui pourrait inclure un mécanisme immunitaire. Les analyses des échantillons plasmatiques de la cohorte ont permis de mieux définir les profils biologiques de peptides et immunoglobulines associés aux 3 catégories larges de TCA et d’évaluer leur utilité pour le phénotypage des patients. La collecte de selles dans la cohorte offre également la possibilité de préciser les profils de microbiote au cours des différents types de TCA. Cette thèse a donc permis de mieux définir les caractéristiques cliniques des TCA et les perturbations de l’axe microbiote-intestin-cerveau associées, en particulier les dérèglements biologiques. / Eating disorders (ED) affect a large population and are a serious public health issue. It is thus essential to deepen our knowledge of ED pathophysiology in order to open new therapeutic perspectives. The prevalence of ED according to sex, geographical origin or age of the study population and its increase over the last 15 years has been highlighted in a systematic review. The analysis of patients with ED from the Eating Disorder and Longitudinal Survey (EDILS) cohort underlined stress and / or diet as triggering factors and noted similarities between the comorbidities of the 3 broad categories of ED (Restrictive, bulimic and compulsive). These comorbidities were strongly associated with each other, and contributed in a vicious circle to the perpetuation of ED. The literature suggests during ED a dysregulation of neuropeptide signaling of food intake that may include some immunological mechanisms. Analyzes of plasma samples from the EDILS cohort allowed a better definition of the peptides and immunoglobulins profiles associated with the 3 broad categories of ED and to evaluate their utility for phenotyping patients. The collection of feces in the cohort offers the possibility of refining the specificity of the microbiota according to different type of ED. This thesis allows to better define the clinical characteristics of 3 broad categories of ED and disturbances of the microbiota-intestine-brain axis, particularly the associated biological dysregulations of neuropeptide signaling.

Le traumatisme craniocérébral (TCC) modéré à sévère constitue une cause majeure d’invalidité chez les jeunes adultes. Il entraine des séquelles physiologiques, comportementales, cognitives et affectives qui entravent le devenir fonctionnel et psychosocial des survivants. Les perturbations de la qualité du sommeil et de l’éveil figurent parmi les plaintes les plus fréquentes et persistantes à la suite d’un TCC modéré à sévère, mais on ignore si celles-ci sont associées à une atteinte de l’intégrité du sommeil. Cette question est primordiale puisque le sommeil est central pour maintenir les capacités d’éveil et un fonctionnement cognitif optimal, ce qui est d’autant plus essentiel lorsque le cerveau est lésé. Cette thèse vise ainsi à caractériser la nature et les corrélats des perturbations du sommeil et de l’éveil durant la phase chronique d’un TCC modéré à sévère. L’association entre les capacités d’apprentissage post-TCC et l’activité à ondes lentes, une caractéristique du sommeil lent connue pour jouer un rôle dans la plasticité synaptique et la mémoire, est également explorée. Pour ce faire, des mesures objectives (actigraphie, polysomnographie) et subjectives (agenda de sommeil et questionnaires) de sommeil-éveil ont été conduites chez des survivants d’un TCC modéré à sévère et des sujets contrôles en bonne santé. La sévérité du trauma, la présence de comorbidités (anxiété, dépression, douleur) et la prise de médicaments psychotropes ont aussi été documentées. La première étude a montré que comparativement aux contrôles, les personnes ayant subi un TCC modéré à sévère rapportent un niveau significativement plus élevé de difficultés d’endormissement, de mauvaise qualité de sommeil, de somnolence diurne et de fatigue. L’actigraphie enregistrée sur une semaine à domicile n’a en revanche pas montrée de perturbations de la qualité du sommeil nocturne. Au contraire, la durée de sommeil sur une période de 24h était significativement supérieure chez les participants TCC par rapport aux contrôles, et cela particulièrement dans un sous-groupe de participants TCC sous médication psychotrope et qui ont subi un trauma global plus sévère. La présence de comorbidités était par ailleurs associée aux plaintes de sommeil-éveil dans le groupe TCC. Dans la deuxième étude, l’architecture du sommeil telle que mesurée par la polysomnographie a été évaluée. Là encore, les résultats indiquent que malgré des plaintes significatives de sommeil-éveil chez le groupe TCC, la macro- et microarchitecture du sommeil étaient similaires chez ces derniers comparativement au groupe contrôle. Toutefois, une association a été montrée entre la qualité du sommeil et la cognition post-TCC, de sorte que plus i l’activité à ondes lentes est élevée au cours du sommeil lent, meilleures sont les performances d’apprentissage et de mémoire épisodique du lendemain. Cette association était plus forte à la suite de la survenue d’un TCC plus sévère par rapport à un TCC moins sévère, suggérant une plus forte dépendance des survivants ayant subi un TCC sévère à l’activité à ondes lentes au cours du sommeil pour apprendre de nouvelles informations. Cette thèse apporte de nouvelles évidences que le cerveau lésé à la suite d’un TCC modéré à sévère semble capable de produire une architecture de sommeil comparable à celle de sujets contrôles en santé. Les plaintes de sommeil-éveil persistantes à la suite d’un TCC modéré à sévère apparaissent influencées par d’autres facteurs, notamment la survenue d’un trauma plus complexe nécessitant une prise en charge pharmacologique, ainsi que des facteurs environnementaux et comorbides. En outre, cette thèse supporte le besoin d’explorer davantage le rôle du sommeil dans les capacités cognitives post-TCC. / Moderate to severe traumatic brain injury (TBI) is a major cause of disability in young adults. It causes physiological, behavioral, cognitive and emotional sequelae that hinder functional and psychosocial outcomes. Disturbances in sleep quality and wakefulness are among the most common and persistent complaints in moderate to severe TBI survivors. However it is unclear if these complaints are associated with impaired sleep integrity. This question is crucial as sleep is central in wakefulness-promoting and optimal cognitive functioning, which is particularly essential when the brain is injured. This thesis aims to characterize the nature and correlates of sleep and wakefulness disturbances during the chronic phase of moderate to severe TBI. The association between post-TBI learning capacity and slow-wave activity, a sleep characteristic known to play a role in synaptic plasticity and memory, is also explored. To do this, objective (actigraphy, polysomnography) and subjective (sleep diary and questionnaires) sleep-wake measures were used in moderate to severe TBI survivors and healthy control subjects. The severity of the trauma, the presence of comorbidities (anxiety, depression, pain) and the use of psychotropic medications have also been documented. The first study showed that compared to controls, people with moderate to severe TBI reported significantly lower sleep quality, and higher levels of daytime sleepiness and fatigue. Yet, a seven-day actigraphy recording did not show any disturbances in the nighttime sleep efficiency. Rather, sleep duration over a 24h period was significantly increased in participants with TBI compared to controls, particularly in a subgroup of TBI who used psychotropic medications and suffered a more severe overall trauma. The presence of comorbidities was also associated with sleep-wake complaints in TBI group. In the second study, the sleep architecture as measured by polysomnography was evaluated. Again, the results indicated that despite significant sleep-wake complaints in TBI group, the macro- and micro-architecture of sleep measured in the TBI group were similar to those in the control group. However, an association between sleep quality and post-TBI cognition was shown, as higher slow-wave-activity sleep was associated with better memory performance the day after. This association was stronger following more severe TBI compared to milder TBI, suggesting that adults who sustained more severe TBI are more dependent on sleep slow-wave-activity for next- day memory function. iii This thesis brings new evidence that the injured brain following moderate to severe TBI appears to be able to produce sleep architecture comparable to healthy control subjects. Persistent sleep- wake complaints following moderate-to-severe TBI appear to be influenced by other factors, including the occurrence of more complex trauma requiring pharmacological management, as well as environmental and comorbid factors. In addition, this thesis supports the need to further explore the role of sleep in post-TBI cognitive abilities.

Abstract Background: The world population is aging and the number of older adults with bipolar disorder is increasing. Digital technologies are viewed as a framework to improve care of older adults with bipolar disorder. This analysis quantifes Internet use by older adults with bipolar disorder as part of a larger survey project about information seeking. Methods: A paper-based survey about information seeking by patients with bipolar disorder was developed and translated into 12 languages. The survey was anonymous and completed between March 2014 and January 2016 by 1222 patients in 17 countries. All patients were diagnosed by a psychiatrist. General estimating equations were used to account for correlated data. Results: Overall, 47% of older adults (age 60 years or older) used the Internet versus 87% of younger adults (less than 60 years). More education and having symptoms that interfered with regular activities increased the odds of using the Internet, while being age 60 years or older decreased the odds. Data from 187 older adults and 1021 younger adults were included in the analysis excluding missing values. Conclusions: Older adults with bipolar disorder use the Internet much less frequently than younger adults. Many older adults do not use the Internet, and technology tools are suitable for some but not all older adults. As more health services are only available online, and more digital tools are developed, there is concern about growing health disparities based on age. Mental health experts should participate in determining the appropriate role for digital tools for older adults with bipolar disorder.

Le syndrome de Gilles de la Tourette (SGT) est une condition neuropsychiatrique qui se caractérise par la présence de tics moteurs et vocaux. Au-delà des tics, le SGT s’accompagne souvent de troubles concomitants, tels que le trouble de déficit de l’attention avec ou sans hyperactivité et le trouble obsessionnel compulsif. Plusieurs études ont rapporté que les adultes atteints du SGT sont plus susceptibles de souffrir de dépression et de troubles anxieux comorbides que les personnes neurotypiques. Bien que les tics soient la caractéristique déterminante du SGT, les comorbidités engendrent de multiples conséquences psychologiques, sociales et comportementales, en plus d’avoir un impact considérable sur la qualité de vie des personnes qui en souffre. Jusqu'à présent, les études neuropsychologiques auprès de cette population ont révélé des résultats parfois conflictuels quant à leurs performances cognitives, notamment au niveau de l’inhibition, des processus moteurs et des capacités visuospatiales. Ces disparités peuvent être attribuées à divers facteurs, y compris la présence de comorbidités. L’objectif général de ce mémoire est d’apporter une meilleure compréhension du profil neuropsychologique des individus atteints du SGT, en tenant compte de la comorbidité anxiodépressive. Notre échantillon est composé de 128 participants divisés en trois groupes : un groupe SGT+ présentant une comorbidité anxieuse et/ou dépressive (n = 21), un groupe clinique SGT- sans comorbidité significative (n = 37) et un groupe contrôle neurotypique (n = 70). Ils ont été soumis à des mesures neuropsychologiques, dont le Stroop Color-Word Test (SCWT), le Purdue Pegboard Test (PPT) et la figure complexe de Rey-Osterrieth (ROCF). Concernant les capacités d’inhibition, aucune différence n'a été observée entre les groupes cliniques et les neurotypiques. Les patients SGT- et SGT+ ont tous deux montré une dextérité motrice supérieure. Toutefois, seuls les participants atteints de SGT+ ont présenté des déficits au niveau des fonctions visuoconstructives et de la mémoire non verbale. Les résultats suggèrent que les individus atteints du SGT avec une comorbidité anxiodépressive pourraient présenter des déficits supplémentaires dans certains domaines spécifiques. Néanmoins, des recherches supplémentaires axées sur ces conditions comorbides sont nécessaires pour tirer des conclusions robustes. / Tourette's syndrome (TS) is a neuropsychiatric condition characterized by the presence of motor and vocal tics. Beyond tics, TS is often accompanied by co-occurring disorders, such as attention deficit disorder with or without hyperactivity and obsessive-compulsive disorder. Several studies have reported that adults with TS are more likely to suffer from depression and comorbid anxiety disorders than neurotypical people. Although tics are the defining characteristic of TS, comorbidities have multiple psychological, social, and behavioural consequences, and they considerably impact the quality of life of those who suffer from them. So far, neuropsychological studies in this population have revealed sometimes conflicting results regarding their cognitive performance, particularly in inhibition, motor processes and visuospatial abilities. These disparities can be attributed to a variety of factors, including the presence of comorbidities. The general objective of this thesis is to provide a better understanding of the neuropsychological profile of individuals with TS, considering anxiodepressive comorbidity. Our sample consisted of 128 participants divided into three groups: a TS+ group with an anxiety and/or depressive comorbidity (n = 21), a clinical group TS- without significant comorbidity (n = 37) and a neurotypical control group (n = 70). They were subjected to neuropsychological measures, including the Stroop Color- Word Test (SCWT), the Purdue Pegboard Test (PPT), and the Rey-Osterrieth Complex Figure (ROCF). Regarding inhibition abilities, no differences were observed between clinical and neurotypical groups. Both TS- and TS+ patients showed superior motor dexterity. However, only participants with TS+ had deficits in visuoconstructive function and nonverbal memory. The results suggest that individuals with TS with an anxiodepressive comorbidity may have additional deficits in some specific areas. Nevertheless, further research focused on these comorbid conditions is needed to draw robust conclusions.

Following acute pulmonary embolism (PE), a relevant number of patients experience decreased exercise capacity which can be associated with disturbed pulmonary perfusion. Cardiopulmonary exercise testing (CPET) shows several patterns typical for disturbed pulmonary perfusion. Research question: We aimed to examine whether CPET can also provide prognostic information in chronic thromboembolic pulmonary hypertension (CTEPH). Study Design and Methods: We performed a multicenter retrospective chart review in Germany between 2002 and 2020. Patients with CTEPH were included if they had 6 months of follow-up and complete CPET and hemodynamic data. Symptom-limited CPET was performed using a cycle ergometer (ramp or Jones protocol). The association of anthropometric data, comorbidities, symptoms, lung function, and echocardiographic, hemodynamic, and CPET parameters with survival was examined. Mortality prediction models were calculated by Cox regression with backward selection. Results: 345 patients (1532 person-years) were included; 138 underwent surgical treatment (pulmonary endarterectomy or balloon pulmonary angioplasty) and 207 received only non-surgical treatment. During follow-up (median 3.5 years), 78 patients died. The death rate per 1000 person-years was 24.9 and 74.2 in the surgical and non-surgical groups, respectively (p < 0.001). In age- and sex-adjusted Cox regression analyses, CPET parameters including peak oxygen uptake (VO2peak, reflecting cardiopulmonary exercise capacity) were prognostic in the non-surgical group but not in the surgical group. In mortality prediction models, age, sex, VO2peak (% predicted), and carbon monoxide transfer coefficient (% predicted) showed significant prognostic relevance in both the overall cohort and the non-surgical group. In the non-surgical group, Kaplan–Meier analysis showed that patients with VO2peak below 53.4% predicted (threshold identified by receiver operating characteristic analysis) had increased mortality (p = 0.007). Interpretation: The additional measurement of cardiopulmonary exercise capacity by CPET allows a more precise prognostic evaluation in patients with CTEPH. CPET might therefore be helpful for risk-adapted treatment of CTEPH.