Many studies have shown that short sleep duration and/or poor sleep quality is associated with increasing rates of cardiovascular (CVD) mortality and morbidity. One hypothesized explanation for this association has been that sleep loss is a type of chronic stress that induces dysregulation of biological systems that ultimately increase the risk of CVD. One biological system that has been thought to link sleep loss and CVD is the hypothalamus-pituitary-adrenal (HPA) axis. A number of studies using small or convenience samples have addressed the effects of sleep deprivation on cortisol. Only a few studies have examined the association of habitual short sleep duration and/or poor sleep quality with changes in the diurnal cortisol in population based-samples; those studies vary in their methodology and in findings. Another biological system that has been thought to link sleep loss and CVD is the autonomic nervous system (ANS), through overactivation of the sympathetic nervous system (SNS) and/or probably a withdrawal of the parasympathetic nervous system. Experimental studies have shown an association between the sleep stages and markers of the sympathetic system. However, very few studies of habitual sleep duration/sleep quality and ANS markers have been conducted. Even fewer studies have examined the association of habitual sleep duration and/or sleep quality and ANS responses to a stress challenge in a population-based sample. The findings again have been inconsistent probably due to the use of different methodology and different samples. This dissertation used measures of salivary diurnal cortisol as well as cortisol responses to a stress challenge protocol to assess the relationship of habitual sleep duration and/or sleep quality with diurnal cortisol profile in natural conditions and in response to a stress challenge protocol in a laboratory setting. Diurnal cortisol was assessed from up to 16 samples of salivary cortisol for two days. Cortisol responses to a stress challenge were assessed from four salivary samples taken during the stress challenge that was performed in a different day than the diurnal cortisol collection. To examine the relationship of habitual sleep duration and/or sleep quality and markers of the ANS, this dissertation used continuous cardiovascular measures (heart rate and heart rate variability) and four salivary amylase samples obtained during the stress challenge. The stress challenge included mental stress and orthostatic stress. Sleep duration and sleep efficiency (an objective measure of sleep quality) were assessed from 7-day actigraphy and sleep diaries. Insomnia symptoms (a subjective measure of sleep quality) were also assessed using a questionnaire that included the Women’s Health Initiative Insomnia rating scale (WHIIRS). We used mixed models so as to account for the repeated measures of diurnal salivary cortisol levels as well as the responses (reactivity and recovery) to the stress challenge tests. Chapter 1 presents an introduction to this dissertation discussing the relationship between short sleep duration and/or poor sleep quality and CVD morbidity and mortality. Chapter 2 presents a systematic literature review of studies of the association between habitual sleep duration and/or sleep efficiency and markers of neuro-endocrine systems: HPA and ANS. These are plausible mechanisms that link short and/or poor sleep to CVD morbidity and mortality. Chapter 3 presents our analyses of the relationship between short sleep duration and/or poor sleep quality and features of the diurnal cortisol. We hypothesized that those participants whose slept < 6 hours per night or whose sleep efficiency was < 85% would have higher cortisol levels on awakening, flatter cortisol awakening responses (CAR), and higher evening cortisol levels than participants who slept longer or slept better. We found that short sleepers had higher evening cortisol than the longer sleepers and that this association persisted after the adjustment for several known confounders. In chapter 4, we examined how the same groups of participants responded in terms of hormones (cortisol and amylase) and cardiovascular indices (heart rate (HR) and HR variability (HRV)) to a stress challenge test. We hypothesized that those participants who slept for a shorter time or whose sleep was of poorer quality would have more exaggerated responses to and less recovery from a stress challenge test than participants who slept longer or slept better. We found that participants with insomnia had exaggerated high frequency-HRV (HF-HRV) orthostatic reactivity. In an extended analysis, we found that participants who slept less than 7 hours/night had exaggerated heart rate reactivity to a mental stress test compared to participants who slept 7 or more hours/night, but this association was attenuated after adjustment for naps. Paradoxically, we also found that participants who slept less than 7 hours had higher HF-HRV recovery from mental stress compared to longer sleepers (≥7 hours). Short sleep duration or low sleep efficiency was not associated with cortisol or amylase responses to the stress challenge protocol. These findings suggest that sustained high evening cortisol levels and cardiovascular responses to a stress challenge may be among the mechanisms linking short/poor sleep and CV disease.

Introdução: Adrenomedulina, peptídeo recentemente identificado, atua como mediador em diversos estados fisiológicos e patológicos, sendo expresso em inúmeros tecidos. Níveis elevados de adrenomedulina foram observados em quadros inflamatórios e sépticos, além de atividade inibitória da adrenomedulina sobre a liberação de insulina, o que poderia contribuir para a gênese e manutenção dos quadros hipeglicêmicos, situação comum em pacientes pediátricos internados em unidades de terapia intensiva, tendo sido comprovado que o controle glicêmico melhora o prognóstico nesses pacientes. O objetivo do estudo foi relacionar as concentrações de adrenomedulina com alterações de hormônios do eixo hipófise-adrenal e o controle glicêmico de crianças submetidas à cirurgia cardíaca com circulação extracorpórea (CEC) representando modelo de síndrome da resposta inflamatória sistêmica. Material e métodos: Foram incluídas 20 crianças com idade entre 11-84 meses submetidas à cirurgia cardíaca com CEC. Foram avaliadas concentrações sangüíneas de glicose, insulina, peptídeo-C, cortisol, ACTH, interleucina-6 e adrenomedulina nos tempos pré-CEC, pós-CEC, 1ºPO, 2ºPO e 3ºPO. Os resultados foram expressos em medianas e inter-quartis. Todas crianças receberam antibioticoterapia profilática (Cefuroxima 150mg/kg) e metilprednisolona (30mg/kg) na indução anestésica. Resultados: Adrenomedulina aumentou de 1,13 ng/mL (0.83 1.81) pré- CEC a 3,28 ng/mL (1.82 4.25) no 1ºPO (p=0,0005). A insulina e o peptídeo-C apresentaram queda do tempo pré-CEC ao 1ºPO: 10,9 U/mL (10.5 13.6) a 2,88 U/mL (1.68 3.46) (p= 0,0001) e 1,44 (0.93 2.08) a 0.89 ng/mL (0.58 2.06) (p=0,076), respectivamente. Houve aumento da glicemia de 86,5 mg/dL (67 88) pré-CEC a 169 mg/dL (153 201) no 1ºPO (p=0,0001). Não houve alterações significativas das concentrações de cortisol e ACTH. Após a CEC todas as concentrações de interleucina-6 encontravam-se elevadas retornando aos valores normais no 3ºPO. Houve correlação negativa entre as concentrações de peptídeo-C e de adrenomedulina no 1ºPO (R= - 0,70 - p< 0,0009). Conclusão: os resultados deste estudo indicam que a adrenomedulina possa ter contribuído para a gênese e manutenção da hiperglicemia em pacientes pediátricos com SRIS, agindo por intermédio da redução das concentrações de insulina e do peptídeo-C / Background: Adrenomedullin (AM), a recently identified vasoactive peptide, is expressed in a large number of tissues and was found to be increased in some pathophysiologic conditions such as sepsis and Systemic Inflammatory Response Syndrome (SIRS). It has been shown that AM inhibits insulin secretion by means of a direct action on pancreatic -cells thus contributing to the genesis and sustaining of hypeglicemia, a common condition in critically ill pediatric patients. Therefore, the strict control of glucose concentrations has proved beneficial and associated to decrement of morbimortality rates in adults and children. The aim of the present study was to monitor serum adrenomedullin concentration in parallel with interleukin-6, plasma glucose, insulin and C-peptide, as well as ACTH and cortisol in pediatric patients submitted to cardiac surgery and cardiopulmonary bypass (CPB) representing a SIRS model. Methods: Twenty children aged 11-84 months who underwent cardiac surgery requiring cardiopulmonary bypass were prospective studied. Blood glucose, insulin, C-peptide, adrenocorticotropic hormone, cortisol, interleukin- 6 and AM were measured immediately before cardiopulmonary bypass (BCPB), immediately after CPB, on the first (POD1), second (POD2) and third days (POD3) after surgery. Data were expressed by median values and inter quartile range. All children received profilatic antibiotic (cefuroxime 150mg/kg) and methylprednisolone (30mg/kg) during induction of anesthesia. Results: Adrenomedullin increased from 1.13 ng/mL (0.83 1.81) BCPB to 3.28 ng/mL (1.82 4.25) in POD1 (p=0.0005). Insulin dropped from 10.9 U/mL (10.5 13.6) BCPB to 2.88 U/mL (1.68 3.46) in POD1 (p=0.0000). C-peptide decreased from 1.44 (0.93 2.08) BCPB to 0.89 ng/mL (0.58 2.06) in POD1 (p=0.076). Glucose increased from 86.5 mg/dL (67 88) BCPB to 169 mg/dL (153 201) in POD1 (p=0.0000). No significant changes were observed in ACTH and cortisol levels. After CPB, IL-6 concentrations of all patients were significantly increased and returned to basal values in POD3 (p=0.0009). There was a negative correlation between C-peptide an adrenomedullin in POD1 (R= - 0.70 - p< 0.0009). Conclusion: Our results indicate that adrenomedullin might be partly responsible for the genesis and sustaining of hyperglycemia in pediatric SIRS patients, by means of the decrement of insulin and C- peptide levels

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 &lt; .05). Further, this study gives preliminary support indicating that remission of insomnia in patients with chronic fatigue can significantly reduce levels of fatigue (p &lt; .05), and furthermore improve the physiological stress-response (p &lt; .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.)--University of Oklahoma. / Includes bibliographical references.

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

Conselho Nacional de Desenvolvimento Científico e Tecnológico / "Response to stress" is the designation for the set of metabolic and hormonal changes that take place after any traumatic situation. The stress response is intended to maintain and / or restore the homeostasis of the body injured. The major endocrine response to stress is characterized as the increased secretion of pituitary hormones and activation of the sympathetic nervous system. Among the pituitary hormones is ACTH, which will sensitize the cells of the adrenal gland to secrete cortisol. The biochemical measurements, especially cortisol and glucose has been shown to be important references for the evaluation of pain and stress by indirect means. Therefore, the objective of this research is to measure cortisol, the glucose and triglyceride metabolic energy, in evaluating the neuroendocrine response of dogs with tibial fractures. For the present study, we used 12 dogs with tibial fractures. Were colected five venous blood samples, at the time of patient care, during the surgical procedure after induction of anesthesia, five minutes after stimulation by periosteal implant, 24 hours after the first collection during surgery and after seven days of the surgery. There were no statistically significant differences between times and between the values of cortisol, glucose and triglycerides, but there was a numerical difference between the mean times analyzed, we observed that the cortisol showed an average decrease between times. The mean glucose values had increased in the pre and trans-surgical times, and with a decrease in mean postoperative periods. Mean triglyceride values varied widely between periods. It is possible to conclude that cortisol is an important mediator in the neuroendocrine response of dogs with acute tibial fractures, the mean values of glucose did not respond similarly to cortisol during surgical procedures and that the triglyceride is not a good parameter for evaluating the neuroendocrine stress dogs with acute tibial fractures. / Resposta ao estresse é a designação para o conjunto de alterações hormonais e metabólicas que decorrem após qualquer situação de trauma. A resposta ao estresse tem como finalidade manter e/ou restaurar a homeostase do organismo lesado. A principal resposta endócrina ao estresse é caracterizada como o aumento da secreção de hormônios pituitário e ativação do sistema nervoso simpático. Dentre os hormônios pituitários está o ACTH, que irá sensibilizar as células da adrenal para secretar cortisol. As mensurações bioquímicas, especialmente o cortisol e a glicose tem se mostrado importantes referencias para a avaliação da dor e do estresse por meio indireto. Sendo assim, o objetivo desta pesquisa é medir o cortisol, os metabólicos energéticos glicose e triglicerídeo, na avaliação da resposta neuroendócrina de cães com fratura tibial. Para o presente estudo, foram utilizados 12 cães com fratura tibial. Foram realizadas cinco coletas de sangue venoso, no momento do atendimento do paciente, durante o procedimento cirúrgico logo após a indução anestésica, cinco minutos após a estimulação periosteal pelo implante, 24 horas após a primeira coleta durante o procedimento cirúrgico e após sete dias do procedimento cirúrgico. Não foram observadas diferenças estatísticas significativas entre os tempos e entre os valores de cortisol, glicose e triglicerídeo, porém houve diferença numérica entre as médias dos tempos analisados, sendo observado que o cortisol apresentou uma média decrescente entre os tempos. As médias dos valores de glicose apresentaram acréscimo nos períodos pré e trans cirúrgicos com decréscimo das médias nos períodos pós-cirúrgicos. As médias dos valores de triglicerídeo apresentaram grande variação entre os períodos. É possível concluir que o cortisol é um importante mediador na resposta neuroendócrina aguda de cães com fratura tibial, os valores médios de glicose não responderam de forma similar ao cortisol durante os procedimentos cirúrgicos e que o triglicerídeo não é um bom parâmetro de avaliação do estresse neuroendócrino agudo de cães com fratura tibial.

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.