CTE is a progressive neurodegenerative disease defined by p-tau lesions in characteristic locations of the brain, leading to cognitive impairment as well as mood and behavioral dysfunction. Exposure to repetitive head impacts is a major risk factor for developing CTE; however, additional risk factors and secondary modulating factors, which may expand available treatment and prevention options, are still being elucidated. Studies into the glymphatic system, a system of waste clearance in the brain thought to be activated during sleep, have implicated glymphatic dysfunction in the clearance of toxic proteins like amyloid-beta and hyperphosphorylated tau, as well as in cognitive decline in neurodegenerative disorders like Alzheimer’s Disease, bringing into question whether sleep, through impacting glymphatic clearance, may act as a modulating factor in the development of CTE. In the present study, we began to characterize the presence of sleep disorders and their co-morbid conditions in a cohort of former college football players to gain better insight into their prevalence and the health outcomes of those with sleep conditions. Our results found higher rates of sleep apnea in the study sample, as well as an association between diagnosis with sleep apnea and diagnosis with dementia, AD, MCI, CTE, and similar disorders. Sleep apnea was significantly associated with depression, anxiety, high cholesterol, and diabetes. Further research into whether sleep disorders exacerbate CTE pathology or clinical symptoms, and whether treatment of sleep symptoms leads to better outcomes for patients with CTE, is necessary to further elucidate a potential connection.

As people age they are more likely to develop chronic conditions and will tend to be on multiple medications for long periods of time to manage those conditions. Some of these medications have side effects that are anticholinergic in nature. These side effects can impact different parts of the body including the central nervous system. As people enter their later years the permeability of the blood brain barrier increases, increasing their risk of these kinds of side effects.

Adhesion G-protein coupled receptors (GPCRs) are the second largest class of GPCRs, yet their functions and ligands remain predominantly unidentified. Polymorphisms in the gene encoding the adhesion GPCR latrophilin 3 (ADGRL3) have been associated with an increased risk for attention deficit hyperactivity disorder (ADHD) and substance use disorder (SUD) in various linkage and association studies. Disrupting the function of ADGRL3 homologs across mammalian and invertebrate model systems leads to changes in various dopaminergic phenotypes such as hyperactivity, sleep impairment, and changes in sensitivity to psychostimulants, suggesting that ADGRL3 contributes to behavior by modulating dopamine signaling. Here, I use behavioral and imaging studies to delineate an important role for Cirl, the Drosophila homolog of ADGRL3, in a recently characterized dopaminergic sleep circuit. Sleep impairment is a common symptom in both SUD and ADHD, and sleep studies are well established in Drosophila. Our work shows that fruit flies that carry a null mutation for Cirl are hyperactive and display a deficit in sleep that is enhanced by adult thermogenetic activation of dopamine neurons. Though Cirl displays high expression within dopamine neurons, conditional knockout of Cirl in dopamine neurons does not recapitulate sleep deficits seen in Cirl null flies, and specific rescue of Cirl in a knockout background does not ameliorate them. Intriguingly, activating dopamine neurons in Cirl null flies throughout development rescued the sleep deficits, indicating that this dopaminergic intervention induces lasting changes that can ameliorate lack of Cirl function. Imaging studies reveal that Cirl shows high expression in the central complex, which is involved in sleep and receives dense dopaminergic input. I demonstrate that Cirl functions within different populations of the central complex downstream of dopaminergic innervation to differentially affect night and daytime sleep through both dopaminergic and non-dopaminergic mechanisms. This work delineates a novel role for an adhesion GPCR in modulating sleep behavior, and further characterizes ADGRL3 as a potential therapeutic target for disorders characterized by dysregulation of dopaminergic neurotransmission.

A Clinic for the study of Sleep Disorders The proposal for a clinic for sleep disorders sited on the edge of Dupont Circle within the District of Columbia. This thesis is a reference to time and movement as it relates to our individual perception. We each experience our environments differently and architecture should be prescribed to the fit the needs of the individual. It is the study of design evolution along a time-line. The science of effect. As we move along a line how does our environment and influence shape the final outcome? In architecture, process is the task of understanding. The following documentation is my personal time-line along that undefined path. / Master of Architecture

Sleep-disordered breathing and insomnia are common sleep disorders and associated with an increased risk of morbidity. The aim of this thesis was to study the contribution of a behavioural sleep medicine perspective on sleep-disordered breathing and insomnia. More specific, factors considered important for changing eating behaviour and the impact of physical activity were studied. Methods: In study I, semi-structured interviews of participants with obstructive sleep apnoea and obesity (n = 15) were analysed using a qualitative content analysis. A population-based female cohort was followed prospectively over ten years in study II and III using a postal questionnaire on two occasions (n = 4,851 and n = 5062, respectively). In study IV, a series of five experimental single-case studies was conducted testing how an aerobic exercise intervention affected selected typical snores, following an A1B1A2B2A3 design over nine days and nights (n = 5). Results:  Facilitators and barriers towards eating behaviour change were identified. A low level of self-reported leisure-time physical activity was a risk factor among women for future habitual snoring complaints, independent of weight, weight gain alcohol dependence or smoking. Maintaining higher levels or increasing levels of leisure-time physical activity over the ten-year period partly protected from snoring complaints (study II). Further, a low level of self-reported leisure-time physical activity is a risk factor for future insomnia among women. Maintaining higher levels or increasing levels of leisure-time physical activity over the ten-year period partly protect against self-reported insomnia, independent of psychological distress, age, change in body mass index, smoking, alcohol dependence, snoring status or level of education (study III). Single bouts of aerobic exercise did not produce an acute effect on snoring the following nights in the studied individuals. A pronounced night-to-night variation in snoring was identified (study IV). Conclusion: Women with sleep disorders would benefit from a behavioural sleep medicine perspective targeting their physical activity in the prevention and management of snoring and insomnia. This is motivated by the protective effects of physical activity confirmed by this thesis. Knowledge was added about facilitators and barriers for future eating behaviour change interventions.

Cardiovascular disease is the leading cause of death in the United States. Chronic short sleep duration is also a significant public health problem and has been linked to several markers and outcomes of cardiovascular disease. To date, inconsistency of assessments of sleep duration and insufficiency, use of covariates, and cardiovascular disease measurement across studies limits strong conclusions about the relationship between sleep duration, sleep insufficiency, and cardiovascular disease. The current study examined the association between sleep duration, sleep insufficiency, and a marker of preclinical coronary heart disease (i.e., carotid intima-media thickness) in a community sample using a cross-sectional design. Some evidence for a relationship between sleep duration and cIMT was found, with longer sleep duration predicting higher cIMT in some segments. Additionally, the interaction between sleep duration and sleep insufficiency was significant. However, neither of these effects were significant after adjusting for age and in some cases race/ethnicity, suggesting demographics may explain this association. Actigraphy and sleep diary duration assessments demonstrated significantly different correlations with cIMT in some segments, suggesting the nature of the assessment method may impact the strength or direction of the relationship between sleep duration and cIMT. Limitations and future directions are discussed.

Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Biological and Medicinal Sciences Student: Bc. Eva Hepnerová Supervisor: Doc. MUDr. Josef Herink, DrSc. Title: Temporolimbic dysfunction in persons with sleep disorders Background: The aim is to demonstrate the occurrence of symptoms of the temporolimbic dysfunction in person with sleep disorders using standard psychosocial questionnaires. Methods: The occurrence of symptoms of the temporolimbic dysfunction was detected by means of CPSI and LSCL-33 questionnaires. Correlation of both questionnaires' results was evaluated by Spearman's coefficient. Results: According to CPSI 11 % patients have abnormal score and they have higher occurrence of symptoms of the temporolimbic dysfunction. According to LSCL-33 achieve 32 % of respondents abnormal score and 7 % respondents have pathologic score, which means the presence of the temporolimbic dysfunction. Conclusions: The occurrence of the temporolimbic dysfunction in persons with sleep disorders have been shown, but it haven't been higher in comparison with healthy population. Keywords: mood disorders, sleep disorders, psychosocial questionnaire, sleep, temporolimbic region

Introdução: A apnéia central do sono e a apnéia obstrutiva do sono (ACS e AOS, respectivamente) são comuns em pacientes com insuficiência cardíaca com disfunção sistólica (ICC). No entanto, vários fatores que levam a instabilidade respiratória incluindo baixo débito cardíaco, congestão pulmonar e hipocapnia coexistem nestes pacientes. Pacientes com valvopatias (VAL) com alta pressão de capilar pulmonar (PCP) e com fração de ejeção (FE) de ventrículo esquerdo normal representam um modelo adequado para elucidar a gênese da apnéia do sono. Objetivos: Comparar as características dos distúrbios respiratórios do sono em pacientes com VAL e pacientes com ICC. Métodos: Pacientes com VAL com PCP > 12 mmHg e pacientes com ICC foram avaliados por, gasometria arterial, ecocardiograma e polissonografia. Resultados: Pacientes com VAL (n=17, PCP 24 ± 9 mmHg e FE 61 ± 6 %) e ICC (n=17, FE 31 ± 10 %) eram semelhantes quanto as características demográficas e gases arteriais (idade: 46 ± 10 versus 47 ± 9, sexo feminino: 11 em ambos os grupos, índice de massa corporal: 26 ± 5 vs 26 ± 6 Kg/m2, PaCO2: 34 ± 3 vs 35 ± 4 mmHg, respectivamente). Pacientes com VAL apresentaram índice de apnéia-hipopnéia (IAH) significativamente menor do que pacientes com ICC (10 ± 8 e 26 ± 25 eventos/hora, p=0,0179) e uma menor prevalência de apnéia do sono (IAH > 15 eventos/hora, 29% e 53%, p=0,0009). Dentre os pacientes com apnéia do sono, os pacientes com VAL apresentaram predominantemente AOS (60%) enquanto os pacientes com ICC apresentaram predominantemente ACS (89%, p < 0,0001). Conclusões: Pacientes com VAL e alta PCP e FE normal apresentam apnéia do sono menos grave e com excesso de eventos de origem obstrutiva quando comparados com pacientes com ICC. Congestão pulmonar e hipocapnia não explicam completamente a presença de ACS em pacientes com doenças cardíacas / Introduction: Central and obstructive sleep apnea (CSA and OSA, respectively) are common in patients with systolic congestive heart failure (ICC). However, several factors leading to respiratory instability, including low cardiac output, pulmonary congestion and hypocapnia co-exist in these patients. Patients with valvular heart disease (VAL) with high pulmonary capillary wedge pressure (PCWP) but normal resting left ventricular ejection fraction (LVEF) may provide insights into the genesis of sleep apnea. Objectives: Compare sleep disordered breathing characteristics in patients with VAL and patients with ICC. Methods: Patients with VAL and PCWP > 12 mmHg and ICC were evaluated by awake arterial blood gas analysis, echocardiogram and overnight polysomnography. Results: Patients with VAL (n=17, PCP=24 ± 9 mmHg and LVEF=61 ± 6 %) and ICC (n=17, LVEF=31 ± 10 %) were similar for demographics and blood gases (age: 46 ± 10 vs 47 ± 9, females: 11 in both groups, body mass index: 26 ± 5 Kg/m2 vs 26 ± 6, PaCO2: 34 ± 3 vs 35 ± 4 mmHg, respectively). Patients with VAL as compared to patients with ICC presented significantly lower apnea hypopnea index (10 ± 8 vs 26 ± 25 events/hour, p=0.0179), a lower prevalence of sleep apnea (apnea-hypopnea index > 15 events/hour) 29% vs 53%, p=0.0009, and among patients with sleep apnea the nature was predominantly OSA (60%) while patients with ICC had predominantly CSA (89%, p < 0.0001). Conclusion: Patients with VAL and high PCWP had a less severe sleep apnea and an excess of obstructive events when compared to patients ICC. Pulmonary congestion and hypocapnia do not completely explain CSA in patients with heart diseases

Avaliou-se a arquitetura do sono e distúrbios respiratórios do sono (DRS) em crianças (6 a 12 meses) portadoras de doenças cardíacas congênitas (DCC) sem (DCC-NH) e com presença hipoxemia (DCC-H) durante a vigília. Foram estudadas 21 crianças através de polissonografia noturna (7 DCC-NH, 7 DCC-H e 7 controles). O índice de distúrbios respiratórios (eventos/hora de sono) foi de 2,2, 2,5 e 0,7 nos grupos DCC-NH, DCC-H e controle, respectivamente, p < 0,05. A saturação de oxigênio mínima foi de 79%, 73% e 90% nos grupos DCC-NH, DCC-H e controle, respetivamente, p < 0,05. Apesar do alto índice de DRS nas crianças com DCC, a arquitetura do sono mostrou-se preservada / This study has investigated the sleep architecture and sleep breathing disorders (SBD) in infants (6 to 12 months) with congenital cardiac disease (CCD). Nocturnal polysomnography was performed in 21 infants: 7 non-hypoxemic, 7 hypoxemic and 7 healthy infants (control group). The respiratory disturbance index (events/hour) was 2.2, 2.5 and 0.7 in the non-hypoxemic, hypoxemic and control group (p < 0.05). The minimum oxygen saturation was 79% for the non-hypoxemic group, 73% for the hypoxemic group and 90% for the control group. Despite the high respiratory disturbance index the sleep architecture was preserved in infants with CCD

Fundamento. A frequente associação da síndrome metabólica (SMet) com a apneia obstrutiva do sono (AOS) prejudica o balanço simpato-vagal, cujos mecanismos não são totalmente conhecidos. Alterações metabólicas e inflamatórias podem explicar, pelo menos em parte, esta disfunção autonômica. Dieta hipocalórica associada ao treinamento físico (D+TF) é a terapia de primeira escolha no tratamento da SMet e pode impactar na melhora desses parâmetros. Objetivos. Investigar se a sobreposição da AOS na SMet tem um efeito aditivo nas alterações metabólicas e inflamatórias e se essas alterações estão associadas com o desbalanço simpato-vagal. Adicionalmente, investigar o efeito da D+TF nos fatores de risco da SMet, na severidade da AOS, na recuperação da frequência cardíaca pós-esforço máximo (FCrec), no balanço simpato-vagal e nos marcadores metabólicos e inflamatórios. Métodos. Foram estudados 67 pacientes recém-diagnosticados com SMet (ATP-III), não diabéticos e sem uso de medicamentos. Um grupo controle saudável (CS, n=19) também foi recrutado no estudo. A AOS foi definida pelo índice de apneia/hipopneia (IAH) > 15eventos/hora (polissonografia, PSG). Os grupos SMet com AOS (SMet+AOS, n=36) e SMet sem AOS (SMet-AOS, n=31) foram subdivididos consecutivamente em dois grupos:D+TF (D, decréscimo de 500 kcal/dia; e TF, 50-70% VO2pico, 3x/sem, 1h) ou seguimento clínico sem intervenção (C), compondo, assim, os seguintes 4 grupos: SMet+AOS/D+TF (n=19), SMet+AOS/C (n=10), SMet-AOS/D+TF (n=14) e SMet-AOS/C (n=13). No período pré e pós 4 meses de D+TF ou período C, foram realizadas as seguintes avaliações: PSG; microneurografia (atividade nervosa simpática muscular, ANSM); teste esforço cardiopulmonar (TECP) para avaliar o consumo de oxigênio (VO2pico) e o comportamento da FC; glicose e insulina de jejum (índice HOMA-IR e índice QUICKI); teste de tolerância oral à glicose para avaliação da área sobre a curva (ASCglicose e ASCinsulina); leptina; adiponectina; TNF-alfa; PCR; IL1-beta ; e IL-6. Adicionalmente, foi realizado o estudo da variabilidade da FC (banda de alta frequência, AF; banda de baixa frequência, BF e o balanço simpato-vagal cardíaco, AF/BF). Resultados. No período pré-intervenção, exceto pela glicemia de jejum, ambos os grupos com SMet foram semelhantes entre si e diferentes do grupo CS nas variáveis peso, fatores de risco da SMet e na BF e AF/BF. SMet+AOS e SMet-AOS apresentaram prejuízo na ANSM e AF comparados ao CS, enquanto que SMet+AOS apresentou prejuízo na ANSM e AF comparado ao SMet-AOS. Comparado com o CS, somente SMet+AOS apresentou prejuízo na glicemia de jejum (P < 0,001), leptina (P=0,03), ASC glicose (P=0,001), ASCinsulina (P=0,02), HOMA-IR (P < 0,001), QUICKI (P < 0,001) e TNF-alfa (P < 0,05). Adicionalmente, ASCglicose (P=0,004) e QUICKI (P=0,04) foram piores no SMet+AOS que SMet-AOS. AANSM se correlacionou positivamente com leptina (R=0,27; P=0,03), ASCglicose (R=0,38; P=0,002), ASCinsulina (R=0,26; P=0,04) e QUICK (R=-0,30; P=0,02). Após a intervenção por D+TF, os grupos SMet+AOS e SMet-AOS apresentaram redução na ANSM e melhora na recuperação da FC após o TECP. Somente o grupo SMet+AOS submetido à D+TF apresentou redução no IAH (37±3,5 vs. 23±3,4 eventos/h, P=0,003), na insulina de jejum (13±1,3 vs. 9±1, ?UI/mL,P=0,02) no HOMA-IR (3,4±0,4 vs. 2,2±0,3 P=0,03) e no QUICKI (0,32±0,01 vs. 0,35±0,01, P=0,04). Os grupos C para a intervenção não apresentaram alterações no período pós-seguimento clínico. Conclusão. Em pacientes com SMet não diabéticos, a presença da AOS leva a um estado inflamatório e prejudica o controle metabólico e autonômico. A AOS também leva uma exacerbação simpática que pode ser explicada, em parte, pelo prejuízo metabólico da glicemia, insulinemia e leptinemia. Nos pacientes com AOS, a intervenção por D+TF diminuiu a IAH e a resistência à insulina. Independente da AOS, D+TF diminuiu o número de pacientes com SMet e melhorou o controle autonômico / Background. The frequent association between metabolic syndrome (MetS) and obstructive sleep apnea (OSA) impairs the sympathovagal balance, which mechanisms are not fully known. Metabolic and inflammatory alterations could be explain, at least in part, this autonomic dysfunction. Hypocaloric diet and exercise training (D+ET) the first choice therapy in the treatment of SMet and may impact the improvement of these parameters. Objectives. Verify whether the overlap of OSA and MetS has an additive effect on metabolic and inflammatory markers and if these alterations are associated with sympathovagal unbalance. Additionally, to investigate the effect of D+ET over MetS risk factors, OSA severity, heart rate recovery after maximal exercise, the sympathovagal balance and metabolic and inflammatory markers. Methods. We studied 67 patients newly diagnosed with MetS (ATP-III), non-diabetic, without medication. A healthy control group (CS, n=19) was also recruited for the study. OSA was defined by the apnea-hypopnea index (AHI) >15 events/hour (polysomnography, PSG). The groups MetS with OSA (MetS+OSA, n=36) and without OSA (MetS-OSA, n=31) were divided in two groups. The intervention by D+ET (D was decrease of 500 kcal/day, and ET, 50-70% of peakVO2, 3x/week, 1h) or control group (C, follow up without intervention): MetS+OSA/D+ET (n=19), MetS+OSA/C (n=10), MetS-OSA/D+ET (n=14) and MetS + OSA/C (n=13). The pre and post period of 4 months of D+ET or C, were measured: PSG; microneurography (muscular sympathetic nerve activity, MSNA); cardiopulmonary exercise test (CPET) for evaluated the oxygen uptake (peakVO2) and heart rate (HR) response; glucose and insulin (HOMA-IR, QUICKI); oral glucose tolerance test for evaluate the area under the curve (AUCglucose and AUCinsulin); leptin; adiponectin; TNF-alpha; PCR; IL1-beta; IL-6. In addition, HR variability (LF=low frequency, HF=high frequency, LF/HF=sympathovagal balance). Results. In pre-intervention, except for fasting glucose, both MetS groups were similar and different from CS group in the weight, MetS risk factors and LF and HF/LF. MetS+OSA and MetS-OSA showed impairment in ANSM and HF compared to CS. In addition, MetS+OSA impairment in ANSM and HF compared to MetS-OSA. Compared to CS, only the MetS+OSA showed differences in fasting glucose (P < 0.001), leptin (P=0.03), glucose ASC (P=0.001), insulin ASC (P=0.02), HOMA-IR (P < 0.001), QUICKI (P < 0.001), TNF-alpha (P < 0.05). In addition, glycemia ASC (P = 0.004) and QUICKI (P = 0.04) were worse in MetS+OSA than to MetS-OSA. The ANSM correlated with leptin (R=0.27, P=0.03), ASC (R=0.38, P=0.002), ASC insulin; (R=0.26; P=0.04) and QUICK (R=-0.30; P=0.02). After intervention by D+TF, the MetS+OSA and MetS-OSA groups showed a reduction in the ANSM and improvement in the recovery of the HR after the TECP.Only the MetS+OSA group submitted to D+ET showed a diminished in AHI (37±3.5 vs. 23±3.4 events/h, P=0.003), fasting insulin (13±1.3 vs. 9±1, P=0.02), HOMA-IR (3.4±0.4 vs. 2.2±0.3 ?UI/mL, P=0.03) and QUICKI (0.32±0.01 vs. 0.35±0.01, P=0.04). The C groups did not change for intervention. Conclusion. In patients with non-diabetic MetS, the OSA leads to an inflammatory state and impairs in metabolic and autonomic control. The OSA also carries a sympathetic exacerbation that can be explained in part by the metabolic glucose, insulin, and leptin impairment. In patients with OSA, D+ET decreased the AHI and insulin resistance. Independently of AOS, D+ET decreased SMet number and improved autonomic control