Vários estudos têm sugerido que o estresse pode ser um dos fatores relacionados com à grande variabilidade cognitiva observada em idosos. Esta associação se explica porque o cortisol, principal classe de hormônios do estresse em humanos, apresenta alta afinidade por receptores específicos localizados no hipocampo, amígdala e região pré-frontal, estruturas associadas ao aprendizado e à memória. Concentrações cronicamente elevadas de cortisol estão associadas à atrofia hipocampal e baixo desempenho cognitivo. Entretanto, o efeito do estresse agudo no desempenho da memória ainda se encontra inconclusivo em idosos. Isto é particularmente relevante, uma vez que, idosos com comprometimento cognitivo patológico apresentam concentração elevada de cortisol, que por sua vez, está associada com rápida progressão da doença. Assim, o objetivo do estudo foi analisar a relação entre desempenho da memória e resposta neuroendócrina e cardiovascular de estresse em idosos saudáveis. Foram selecionados aleatoriamente 100 idosos alfabetizados, predominantemente do sexo feminino, sem prejuízo cognitivo e funcional, moradores da cidade de São Paulo. A resposta neuroendócrina de estresse foi avaliada a partir concentração de cortisol salivar enquanto que a reação cardiovascular a partir da pressão arterial e frequência cardíaca antes, durante e após a exposição do participante a um estressor psicossocial agudo (Trier Social Stress Test TSST). O TSST envolve duas tarefas: falar em público e realizar cálculos aritméticos mentalmente diante de uma banca examinadora. O desempenho da memória foi avaliado mediante aplicação do teste Pares de Palavras (PP) 20 minutos antes do TSST para evocação imediata e aprendizado e 15 minutos após o fim do TSST para evocação tardia. Foi observado aumento de 96% na concentração de cortisol 15 minutos após o TSST, bem como elevação da pressão arterial em relação à situação basal. Ademais, observamos redução significativa do escore do teste PP após o TSST e correlação negativa entre concentração de cortisol, evocação imediata e tardia dos PP. Os resultados revelam influência do estresse agudo no desempenho da memória, particularmente da evocação tardia, de idosos, destacando a vulnerabilidade destes indivíduos aos efeitos neurotóxicos do cortisol na memória e, consequentemente ao desenvolvimento de transtornos cognitivos. / Several studies have suggested that stress may be a factor related to cognitive variability observed in the elderly. This association exists because cortisol, the main class of stress hormones in humans, has a high affinity to specific receptors located in the hippocampus, amygdala and prefrontal regions, structures associated with learning and memory. Chronically elevated cortisol concentrations are associated with hippocampal atrophy and low cognitive performance. However, the effect of acute stress on memory performance is still inconclusive in the elderly. This is particularly relevant, since elderly patients with pathological cognitive impairment present high cortisol level, which in turn is associated with rapid disease progression. The objective of the study was to analyze the relationship between memory performance and neuroendocrine as well as cardiovascular response stress in healthy elderly. One hundred elderly randomly selected, literate, predominantly female, with no cognitive impairment and functional, residents of the city of São Paulo were included. The neuroendocrine response to stress was evaluated using salivary cortisol while the cardiovascular reactivity was assessed through blood pressure and heart rate measured before, during and after exposure to a participant\'s acute psychosocial stressor (\"Trier Social Stress Test\" - TSST). The TSST involves two tasks: public speaking and performing mental arithmetic in front of an examining board. The memory performance was evaluated by the Pairs of Words test (PW) 20 minutes before the TSST for immediate recall and learning and 15 minutes after the end of TSST for delayed recall. It was observed an increase of 96% in the cortisol concentration 15 minutes after the TSST, as well as increased blood pressure compared to baseline. Furthermore, we observed significant reduction in the PP score after TSST and negative correlation between cortisol concentration, immediate and delayed recall of PP. The results revealed influence of acute stress on memory performance, particularly to delayed recall, of older adults, highlighting the vulnerability of older adults to the neurotoxic effects of cortisol on memory and, therefore, to the development of cognitive disorders.

Fatigue is common in the general population, and is the hallmark of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). Although the occurrence of sleep difficulties is known to be common in subjects with fatigue, research on insomnia in such subjects is absent. The current study sought to examine the impact comorbid insomnia has on level of fatigue in subjects with chronic fatigue. The aim of this study is to assess the relationship between insomnia and chronic fatigue, and examine if the relationship is affected by the endocrine activity in the HPA axis. The following hypotheses were tested: 1) Do patients with chronic fatigue and comorbid insomnia experience more fatigue than patients with chronic fatigue without comorbid insomnia? 2) Do patients with chronic fatigue and with initially comorbid insomnia experience more fatigue after treatment than chronic fatigue patients without comorbid insomnia? 3) Do patients with chronic fatigue who experience improvement in insomnia after treatment also experience less fatigue by the end of treatment compared with patients who do not experience improvement in insomnia? 4) Is the potential relationship between insomnia and chronic fatigue influenced by the activity of the HPA axis as expressed by variation in cortisol output measured by Trier Social Stress Test for Groups (TSST-G)? The study sample consisted of 75 patients with chronic fatigue. Thirty-three met criteria for insomnia, while 42 did not. While staying at Hysnes Rehabilitation Center in Trondheim, Norway, they received a work-related Acceptance and Commitment Therapy (ACT) treatment intervention lasting 3.5 weeks. In addition, they participated in a standardized stress test (Trier Social Stress Test) pre- and post-treatment. Saliva cortisol samples were collected during the test in order to measure variation in cortisol output. The current finding is the first description of how insomnia in patients with chronic fatigue is associated with higher levels of fatigue (p < .05). Further, this study gives preliminary support indicating that remission of insomnia in patients with chronic fatigue can significantly reduce levels of fatigue (p < .05), and furthermore improve the physiological stress-response (p < .05). These results might encourage clinicians to assess and provide specific treatment for insomnia in patients with chronic fatigue as this might improve their treatment results. An aim for further research should be to investigate the effect of specified treatment for insomnia in patients with chronic fatigue.

Thesis (Ph. D.)--Ohio State University, 2006. / Available online via OhioLINK's ETD Center; full text release delayed at author's request until 2009 May 24

Introdução: A vulnerabilidade dos profissionais de enfermagem ao estresse está associada à exposição crônica aos estressores cotidianos de trabalho e, consequentemente, aos efeitos cumulativos dos mediadores primários e secundários do estresse. Embora vários estudos tenham relatado o elevado nível de estresse dos profissionais de enfermagem, pouco se sabe a respeito das implicações biológicas do estresse no trabalho, expressas na carga alostática e no ritmo de secreção dos hormônios de cortisol um dos principais hormônios do estresse. Isto particularmente é importante visto que a carga alostática aumenta o risco do indivíduo desenvolver transtornos relacionados ao estresse como síndromes cardiovasculares, metabólicas, endócrinas, emocionais e cognitivas. Neste sentido, questiona-se se os profissionais de enfermagem apresentam sobrecarga do sistema adaptativo de reação do estresse (carga alostática), bem como alterações no ritmo de secreção de cortisol (hiper ou hipocortisolemia) ao longo do dia e o risco para o desenvolvimento de doenças relacionadas ao estresse. Objetivo: Descrever a frequência de profissionais de enfermagem com carga alostática elevada e ritmo atípico de secreção de cortisol. Analisar se a carga alostática elevada está associada ao ritmo atípico de secreção de cortisol. Método: Foram incluídos 142 profissionais de enfermagem do turno diurno randomicamente selecionados, alocados nas unidades ambulatório, clínica médica, clínica cirúrgica, centro cirúrgico, pronto socorro infantil e adulto, unidade de terapia intensiva adulto e pediátrica de um hospital universitário. Para avaliação do padrão diurno de secreção de cortisol foram coletadas amostras de saliva em dois dias úteis consecutivos de trabalho e, para a análise dos biomarcadores foram coletadas, em um único dia, amostras de sangue de todos os participantes, bem como, verificada sua pressão arterial e medidas antropométricas. A carga alostática foi analisada por mediadores neuroendócrinos, metabólicos, cardiovasculares e imunológicos. Os dados foram armazenados e analisados utilizando o programa estatístico SPSS versão 14.0 e o nível de significância adotado foi de 5%. Resultados: 31% dos profissionais de enfermagem apresentaram padrão atípico (inconsistente ou flat) de secreção de cortisol e 47,2% carga alostática elevada. Não houve associação entre o ritmo de secreção de cortisol e a carga alostática. Conclusão: Quase metade dos profissionais de enfermagem apresentaram sinais de desgaste do sistema biológico regulador da resposta de estresse, sugerindo que o trabalho possa estar associado a esta sobrecarga e destacando a vulnerabilidade destes trabalhadores ao desenvolvimento de doenças relacionadas ao estresse / Background: The vulnerability of nursing professionals to stress is associated with chronic exposure to everyday stressors and, therefore, with the cumulative effects of primary and secondary stress mediators. Despite the fact that several studies have reported the high stress level of nursing professionals, little is known about the biological implications of stress at work, expressed in the allostatic load and in the rhythm of cortisol secretion, one of the main hormones of stress. This is especially important since the allostatic load increases the risk of an individual to develop stress-related disorders like cardiovascular syndromes, metabolic, endocrine, cognitive and emotional. In this aspect, there are questions whether the nursing professionals present overload on the stress adaptive reaction system (allostatic load), as well as, changes in the rhythm of cortisol secretion (hyper or hypocortisolemia) throughout the day and the risk of developing stress-related diseases. Objective: To describe the frequency of nursing professionals with high allostatic load and atypical rhythm of cortisol secretion. To analyze whether the high allostatic load is associated with atypical rhythm of cortisol secretion. Methods: We included 142 nursing professionals day shift randomly selected, allocated in the outpatient units, medical clinic, surgical clinic, surgery, children and adults emergency room and adult intensive care unit in a pediatric teaching hospital. To evaluate the daytime pattern of cortisol secretion, saliva samples were collected in two work day and, for the analysis of biomarkers, were collected in a single day, blood samples from all participants, as well as, checked his blood pressure and anthropometric measurements. Allostatic load was analized by neuroendocrine, metabolic, cardiovascular and immune mediators. The data was stored and analyzed using the program SPSS version 14.0 and the statistical significance level adopted was 5%. Results: 31% of nursing professionals showed atypical pattern (inconsistent or \"flat\") of secretion of cortisol and 47.2% showed high allostatic load. There was no association between the rate of secretion of cortisol and the allostatic load. Conclusion: Nearly half of nursing professionals showed signs of wear in the biological system stress response regulator, suggesting that the job can be associated with this overload and highlighting the vulnerability of these workers to the development of stress-related diseases.

Vários estudos têm sugerido que o estresse pode ser um dos fatores relacionados com à grande variabilidade cognitiva observada em idosos. Esta associação se explica porque o cortisol, principal classe de hormônios do estresse em humanos, apresenta alta afinidade por receptores específicos localizados no hipocampo, amígdala e região pré-frontal, estruturas associadas ao aprendizado e à memória. Concentrações cronicamente elevadas de cortisol estão associadas à atrofia hipocampal e baixo desempenho cognitivo. Entretanto, o efeito do estresse agudo no desempenho da memória ainda se encontra inconclusivo em idosos. Isto é particularmente relevante, uma vez que, idosos com comprometimento cognitivo patológico apresentam concentração elevada de cortisol, que por sua vez, está associada com rápida progressão da doença. Assim, o objetivo do estudo foi analisar a relação entre desempenho da memória e resposta neuroendócrina e cardiovascular de estresse em idosos saudáveis. Foram selecionados aleatoriamente 100 idosos alfabetizados, predominantemente do sexo feminino, sem prejuízo cognitivo e funcional, moradores da cidade de São Paulo. A resposta neuroendócrina de estresse foi avaliada a partir concentração de cortisol salivar enquanto que a reação cardiovascular a partir da pressão arterial e frequência cardíaca antes, durante e após a exposição do participante a um estressor psicossocial agudo (Trier Social Stress Test TSST). O TSST envolve duas tarefas: falar em público e realizar cálculos aritméticos mentalmente diante de uma banca examinadora. O desempenho da memória foi avaliado mediante aplicação do teste Pares de Palavras (PP) 20 minutos antes do TSST para evocação imediata e aprendizado e 15 minutos após o fim do TSST para evocação tardia. Foi observado aumento de 96% na concentração de cortisol 15 minutos após o TSST, bem como elevação da pressão arterial em relação à situação basal. Ademais, observamos redução significativa do escore do teste PP após o TSST e correlação negativa entre concentração de cortisol, evocação imediata e tardia dos PP. Os resultados revelam influência do estresse agudo no desempenho da memória, particularmente da evocação tardia, de idosos, destacando a vulnerabilidade destes indivíduos aos efeitos neurotóxicos do cortisol na memória e, consequentemente ao desenvolvimento de transtornos cognitivos. / Several studies have suggested that stress may be a factor related to cognitive variability observed in the elderly. This association exists because cortisol, the main class of stress hormones in humans, has a high affinity to specific receptors located in the hippocampus, amygdala and prefrontal regions, structures associated with learning and memory. Chronically elevated cortisol concentrations are associated with hippocampal atrophy and low cognitive performance. However, the effect of acute stress on memory performance is still inconclusive in the elderly. This is particularly relevant, since elderly patients with pathological cognitive impairment present high cortisol level, which in turn is associated with rapid disease progression. The objective of the study was to analyze the relationship between memory performance and neuroendocrine as well as cardiovascular response stress in healthy elderly. One hundred elderly randomly selected, literate, predominantly female, with no cognitive impairment and functional, residents of the city of São Paulo were included. The neuroendocrine response to stress was evaluated using salivary cortisol while the cardiovascular reactivity was assessed through blood pressure and heart rate measured before, during and after exposure to a participant\'s acute psychosocial stressor (\"Trier Social Stress Test\" - TSST). The TSST involves two tasks: public speaking and performing mental arithmetic in front of an examining board. The memory performance was evaluated by the Pairs of Words test (PW) 20 minutes before the TSST for immediate recall and learning and 15 minutes after the end of TSST for delayed recall. It was observed an increase of 96% in the cortisol concentration 15 minutes after the TSST, as well as increased blood pressure compared to baseline. Furthermore, we observed significant reduction in the PP score after TSST and negative correlation between cortisol concentration, immediate and delayed recall of PP. The results revealed influence of acute stress on memory performance, particularly to delayed recall, of older adults, highlighting the vulnerability of older adults to the neurotoxic effects of cortisol on memory and, therefore, to the development of cognitive disorders.

Le travail de cette thèse s’inscrit dans le cadre du projet ANR SUSoSTRESS qui a pour objectif la compréhension des mécanismes moléculaireset génétiques sous-jacents à la variabilité individuelle de réponses de stress et a collecté des données longitudinales à plusieurs niveaux biologiquessur une population d’étude porcine (race Large White). La thèse est organisé en deux partie. La première partie s’articule autour de l’analyse de données cliniques et transcriptomiques collectées à plusieurs pas de temps avant et après application de deux types de stress : injection d’ACTH et de LPS. Dans cettepartie, on cherche à développer d’un modèle fonctionnel permettant de décrire et d’intégrer au mieux l’ensemble des sources de variation génétique du fonctionnement de l’axe corticotrope et plus généralement des réponses de stress dans notre population d’étude. Plus précisément, il s’agit d’élaborer un modèle (au sens biologique du terme) décrivant les différentes réponses biologiques de stress et l’influence des variations génétiques (simples et en interaction), dans le but de prédire les leviers les plus efficaces en fonction de l’objectif de sélection. Ce travail a mis en évidence une liste de 65 gènes différentiellement exprimé au cours des réponses au stress, dont un ensemble de 8 gènes liés au au cortisol (l’hormone principale du stress) par NR3C1, le récepteur aux glucocorticoides. Ces gènes sont des biomarqueurs potentiels pouvant être fournis aux éleveurs en tant que leviers de sélection permettant un meilleur équilibre entre amélioration des caractères de production et des caractères de robustesse. La deuxième partie de ce travail s’articule autour du développement d’un outil d’analyse statistiques adapté à l’intégration de données ’omiques longitudinalesavec une variable cible d’intérêt.Nous proposons la «multiway-SIR », qui étend la méthode dual-STATIS, une méthode d’analyse de données cubiques non supervisée, au cadre de la SIR, une méthode de régression semi-paramétrique pouvant être utilisée à des fins exploratoires. Cette méthode est appliquée sur les données cliniques de l’expérience d’ACTHet permet d’y explorer l’influence de la variabilité de la réponse du cortisol à une injection d’ACTH. / This PhD thesis is part of the SUSoSTRESS project. This ANR funded project aims at improving the knowledge about molecular and genetic mechanisms underlying inter-individual variability in stress responses. Longitudinal data were collected at several biological levels on a porcine population (Large White). This work is structured in 2 parts. The first part is built around clinical and transcriptomic longitudinal data analyses collected before and after 2 types of stress factors : ACTH and LPS injection. The aim of this contribution is to develop a functional model describing all sources of genetic variation in the HPA axis activity and in stress responses in our study population.More precisely, it aims at defining a model describing the different biological stress responses and the influence of genetic variations in order to identify the most efficient selection levers according to selection goals. This work allowed for the identification of 65 differentially expressed genes during stress responses. Among them, 8 genes were highly linked to cortisol (the main stress hormone) through NR3C1 (glucocorticoid receptor (GR)). These genes are potential biomarkers and can be communicated to breeders as selection levers for a better trade-off between production and robustness traits in farmanimals. The second part is built around the development of a statistical tool suited for the data integration of repeated omicmeasurements with a real target variable.We introduce the "multiway-SIR" approach which extends the dual-STATIS (an approach to study 3-way datasets) method to the SIR framework (a semi-parametric regression model that can be used in an exploratory way). This method is illustrated on clinical data from the ACTH experiment. It allows for the exploration of the link between clinical variable response over time and inter-individual variability in the cortisol response to an ACTH injection.

BACKGROUND: Obesity is a leading health burden of the 21st century. Alterations of the individual endocrine stress response and the monoamine system may pathophysiologically contribute to the obesity pandemic and its metabolic and mental complications. OBJECTIVES: (i) to measure hypothalamic-pituitary-adrenal (HPA) axis responsiveness and its relation to serum concentrations of the arginine-vasopressin (AVP) surrogate copeptin in subjects with obesity (OB) compared to non-obesity controls (NOC), (ii) to test whether HPA axis responsiveness and copeptin are related to central noradrenaline (NA) transporter (NAT) availability, (iii) to assess brain serotonin transporter (SERT) binding potentials in OB compared to NOC. METHODS: 40 subjects with obesity (BMI > 35kg/m2) were compared to 25 non-obesity controls, matched for age and sex. (i) All individuals underwent the combined dexamethasone/corticotropin releasing hormone (dex/CRH) test. Plasma ACTH and cortisol curve parameters were derived, and copeptin was assessed in the 1500h sample. (ii) Positron emission tomography (PET) was applied in 10 OB and 10 NOC using the NAT-selective radiotracer S,S-[11C]O-methylreboxetine (MRB) and associated to curve indicators derived from the dex/CRH test as well as to copeptin. (iii) PET using the SERT selective radiotracer [11C] DASB was performed in 30 OB and 15 NOC for intergroup comparison. RESULTS: (i) OB subjects showed an increased HPA axis responsiveness as measured by cortisol concentrations after CRH stimulation. Correspondingly, the AVP surrogate copeptin was higher in OB along with being significantly associated to HPA axis reactivity. OB subjects had a higher adrenal sensitivity as measured by a lower ACTH/cortisol ratio. (ii) In NOC, the HPA response was related to NAT availability of the amygdala and the orbitofrontal cortex while in OB, this association was located in the hypothalamus. (iii) There were no differences in SERT availability between OB and NOC, but a higher inter-regional SERT connectivity was observed in OB. CONCLUSION: This work supports the notion of an increased endocrine stress response in human obesity, pointing to interacting alterations of the HPA and neurohypophyseal axes. Normally, these stress axes seem to be linked to prefrontal-limbic NA signaling, whereas a loss of this association in favor of a hypothalamic-centered relation is observed in OB. The SERT network pattern is more closely inter-related in OB, albeit central SERT concentrations per se do not differ between OB and NOC.:ABBREVIATIONS 4 LIST OF FIGURES 5 I. BIBLIOGRAPHIC DESCRIPTION 6 II. INTRODUCTION 7 2.1 Obesity as a global health burden 7 2.2 Neurobiology of stress 8 2.3 Stress and obesity 8 2.4 Neuroendocrine correlates of the stress response – The hypothalamic pituitary-adrenaland neurohypophyseal axes 9 2.4.1 Anatomy of the hypothalamic-pituitary-adrenal and neurohypophyseal axes 10 2.4.2 The role of CRH, ACTH and cortisol in the context of metabolism and obesity 11 2.4.3 The role of AVP in the context of metabolism and obesity 12 2.4.4 Measuring HPA axis responsiveness by means of the combined dexamethasonecorticotropin-releasing hormone (dex/CRH) test 12 2.4.5 Measuring AVP secretion by its equally-released surrogate copeptin 14 2.5 The noradrenergic system in the context of obesity and stress axis modulation 14 2.5.1 NA and its influence on feeding behavior16 2.5.2 The association of the noradrenergic system with the HPA and neurohypophyseal axes 16 2.5.3 Monoamine transporters as regulators of neurotransmitter signaling 17 2.5.4 Noradrenaline transporter imaging 18 2.6 The serotonergic system in obesity 19 2.6.1 Role of serotonin in the context of feeding behavior and metabolism 20 2.6.3 5-HTT imaging 21 2.7 Objectives and hypotheses 22 2.8 Study design 23 III. RESULTS 24 3. 1 Post-dexamethasone serum copeptin corresponds to HPA axis responsiveness in human obesity 24 3. 2 Central noradrenaline transporter availability is linked with HPA axis responsiveness and copeptin in human obesity and non-obese controls 34 3. 3 Central serotonin transporter availability in highly obese individuals compared with nonobese controls: A [11C] DASB positron emission tomography study 46 IV. SUMMARY 56 4.1 Subjects with obesity show an enhanced HPA axis responsiveness which correlates to serum concentrations of the AVP surrogate copeptin and abdominal fat distribution 56 4.2 HPA axis responsiveness and copeptin concentrations are differentially related to central NAT availability in subjects with obesity compared to non-obesity controls 58 4.3 Central serotonin transporter availability does not significantly differ in subjects with obesity compared to their non-obesity counterparts 59 4.4 Future direction 61 V. References 62 VI. APPENDICES 79 6.1 Curriculum vitae 79 6.2 Publications 81 6.3 Scientific contribution of the doctoral candidate to the publications 82 6.4 Declaration of the independent writing of this thesis 83 6.5 Acknowledgements 84

Posttraumatic stress disorder (PTSD) is a trauma-related disorder that may develop in response to traumatic or stressful events. Dysfunction of the Hypothalamic-Pituitary-Adrenal (HPA) axis has been implicated in the disorder. Studies support such dysfunction as being a consequence of PTSD, rather than a precursor. However, most studies of the HPA are either cross-sectional or have been carried out in adults. The aim of the present study was to identify whether HPA dysregulation interacts with stressful experiences to increase the likelihood of developing PTSD symptoms in a community-recruited sample of healthy adolescent girls. Adolescent girls (N = 550) and one of their parents participated. Adolescents’ clinical symptoms were assessed at baseline and at a nine month follow-up. Saliva samples were collected from all adolescent participants at waking, 30 minutes after waking, and 8 pm on 3 consecutive days. Flattened diurnal slope of cortisol at baseline was associated with increased PTSD symptoms nine months later. Baseline cortisol awakening response (CAR) per se was not prospectively related to developing PTSD symptoms, but its interactions with stressful experience was associated with elevated PTSD symptoms at follow-up. Effects were small and need to be replicated in samples with more severe stressors, as well as more clinical levels of PTSD. Nevertheless, findings suggest that dysregulated basal HPA functioning may be involved in the development of PTSD symptoms.

BACKGROUND: The neurotransmitter noradrenaline (NA) mediates arousal, attention and mood and exerts anti-inflammatory and neuroprotective effects. Its projections reach hypothalamic nuclei which regulate the neuroendocrine stress response. Changes in noradrenergic signalling were reported in multiple sclerosis (MS) and psychiatric illness and may account for the high prevalence of comorbid depression and fatigue in MS patients. Associated studies of our study group—investigating stress response in obese and non-obese subjects—have shown increased activity of the stress axes including an association between hypothalamic-pituitary-adrenal (HPA) axis responsiveness and central noradrenaline transporter. OBJECTIVES: (i) To evaluate central NA transporter (NAT) availability in vivo in immunotherapy-naïve relapsing-remitting multiple sclerosis (RRMS) patients compared to healthy controls (HC), (ii) to measure hypothalamic-pituitary-adrenal (HPA) axis responsiveness and the arginine-vasopressin surrogate (AVP) copeptin in patients with RRMS and clinically isolated syndrome (CIS) compared to HC, (iii) to test whether HPA axis responsiveness is differentially associated to NAT availability in RRMS patients and HC. METHODS: 22 patients (11 RRMS, 11 CIS) were enrolled and compared to 22 sex- and age-matched HC. (i) Positron emission tomography (PET) was performed in 11 RRMS and 12 HC applying the NAT-selective radiotracer S,S-[11C]O-methylreboxetine ([11C]MRB) for intergroup comparison. (ii) All patients underwent the combined dexamethasone/corticotropin releasing hormone (dex/CRH) test. Plasma ACTH and cortisol curve parameters, and copeptin after dexamethasone intake were derived. (iii) MRB-PET imaging data were correlated to curve indicators and copeptin obtained from the dex/CRH test in RRMS patients. RESULTS: (i) RRMS patients show increased NAT availability in almost all subcortical regions, reaching statistical significance in the thalamus, amygdala, putamen and pons/midbrain. No association with clinical or psychometric variables was found. (ii) Immunotherapy-naïve RRMS patients show no significant changes in cortisol, ACTH or copeptin indices. (iii) There is no correlation between HPA axis indicators and NAT availability in RRMS patients. In HC, NAT availability correlated positively with cortisol curve indicators. CONCLUSION: This study supports the evidence for increased NAT availability in immunotherapy-naïve RRMS patients compared to HC. The increased NAT availability was shown in the subcortical brain regions (relevant to attention and emotional regulation) of the RRMS patients. In this cohort, no correlation with physical or psychometric scores was found. It will be further of interest, if these NAT changes longitudinally predispose to the psychiatric comorbidities which are frequently seen in MS patients or if they do in larger, more heterogenous sample sizes. Our cohort of early RRMS and CIS did not display a statistically significant alteration in the HPA axis responsiveness compared to HC. No association between NAT availability and HPA axis responsiveness could be detected in RRMS patients.:TABLE OF CONTENTS LIST OF ABBREVIATIONS…………………….………………………………………......4 LIST OF FIGURES…..….………………………….….……..…………………………..…5 I BIBLIOGRAPHIC DESCRIPTION…………………………..……………………………6 II INTRODUCTION…..…..………………………………………………………….............7 2.1 Multiple sclerosis — Background and scope……………....…………………..........7 2.1.1 Diagnostic criteria, subtypes and clinical features……….............….…………....7 2.1.2 Multiple sclerosis and its impact on daily life: fatigue.…...…...….............………9 2.2. Noradrenaline — neurotransmitter and immunomodulator…...…………….........10 2.2.1 Noradrenaline in the context of multiple sclerosis…………………….................11 2.2.2 Noradrenaline in the context of neuroinflammation and neurogenesis.............12 2.3 Noradrenaline transporter as regulator of noradrenergic transmission….…........13 2.3.1 Noradrenaline transporter imaging……………………………............................14 2.4 Neuroendocrine stress response……...…..……………………..……..……….......14 2.4.1 Noradrenaline in the context of stress response regulation…...........................15 2.4.2 Stress axis regulation in multiple sclerosis……….............……….....................16 III METHODS……………......……………………………………………………..……....19 3.1 Objectives and hypotheses.....……..…………………………………………….......19 3.2 Study design………………..….....………………………………….…..…………….20 3.3 Hypothalamic-pituitary-adrenal axis assessment using the combined dexamethasone/CRH test…….……...........……….....................................................21 3.4 Questionnaires……...…………………….....…………………………………………22 3.4.1 Beck-Depression-Inventory……………….............……….………………………22 3.4.2 Würzburger Erschöpfungsinventar bei MS….…………..….............……………22 3.5 PET imaging, imaging data processing and analysis………………….....………..23 3.6 Statistical analysis………………….………………………………………….....……23 IV RESULTS………….......……………………………………………….........................24 4.1 Changes of central noradrenaline transporter availability in immunotherapy-naïve multiple sclerosis patients – Publication….....……...…………24 4.2 HPA axis responsiveness does not differ between HC and RRMS or CIS patients…...………………………………...……………………………………….25 4.3 In RRMS patients, noradrenaline transporter availability of selected brain regions does not correlate with neuroendocrine indicators of stress responsiveness, but do positively correlate in healthy controls………………..….…..25 V SUMMARY………………….…………………………………………………………….31 5.1 Significantly changed noradrenaline transporter availability in RRMS patients in brain regions relevant to attention, vigilance and mood………….............31 5.2 Noradrenaline transporter availability is not significantly associated with psychometric and physical scores……..…………………...........................................32 5.3 HPA responsiveness does not significantly differ between early-stage RRMS patients, CIS patients and healthy controls………..…………………..............32 5.4 NAT DVR of selected brain regions do not reveal a significant association to HPA response in RRMS patients, but in healthy controls………...……..................33 5.5 Limitations..………………………………………………………………………….....35 5.6 Future directions…………………………………………………………………….....35 VI PUBLICATION BIBLIOGRAPHY…….……………………....…………….................36 VII ANHANG…….………..…...…..………..………………………………………………49 7.1 Publikationen…………..……….....…..……………………………………................49 7.1.1 Publikationen als Ko-Autorin…...…………..………..............…………………….50 7.1.1.1 Central noradrenaline transporter availability is linked with HPA axis responsiveness and copeptin in human obesity and non-obese controls……..50 7.1.1.2 Post-dexamethasone serum copeptin corresponds to HPA axis responsiveness in human obesity...............................................................................51 7.2 Erklärung zum wissenschaftlichen Beitrag der Promovendin zur Publikationspromotion…………...........………………………………………………52 7.3 Erklärung über die eigenständige Abfassung der Arbeit...…....…………...…......53

There is now considerable evidence that both schizophrenia and affective disorders have their origin at least in part in events that occur during early pre- and post-natal development. In the case of schizophrenia, many observations, for example, increased risk for schizophrenia in the offspring of mothers who had influenza A during their second trimester of pregnancy and evidence for abnormal neuronal migration in the cerebral cortex of post mortem tissue from schizophrenic patients, suggest that a second trimester insult may have occurred and that this insult may have increased the risk for the development of schizophrenia in late adolescence or early adulthood. Animal studies have found that rats that undergo excitotxic damage to the ventral hippocampus on postnatal day 7 develop exaggerated sensitivity to dopamine-stimulating drugs or to stressful stimuli that becomes apparent after sexual maturity but not before, providing a neurodevelopmental model of schizophrenia. Similarly, post-weaning social isolation leads to nehanced responses to dopaminergic drgus and to stress that emerges after sexual maturity. These animal models are proving to be valuable tools to study the neurobiological mechanisms mediating the influence of early insults to the nervous system on later behavioural functins. In the case of affective disorders, although the evidence is not as strong, a number of the same observations have been made suggesting that an insult during early ontogeny may lead to the development of affective disorders later in life. For example, retrospective studies of people with affective disorders showed that they were more likely to have attained motor milestones at a later age and to have had poorer academic performance as children. There is a wealth of evidence suggesting hyperfunctioning of the hypothalamic-pituitary-adrenal (HPA) axis in affective disorders. Animal studies have shown that early matenal deprivation can lead to lasting changes in the reactivity of the HPA axis to stressful stimuli, providing another link from early experience to adult psychopathology. Continued studies of the effects of pre- and early post-natal events on the development of the nervous system and the relationships of these events to schizophrenia or affective disorder will provide new insights into the mechanisms underlying these common neuropsychiatric illnesses.