Sleep apnoea and the hypothalamic-pituitary-adrenal axis in men and women: effects of continuous positive airway pressure.

Previous findings on the association of obstructive sleep apnoea (OSA) and the hypothalamic-pituitary-adrenal (HPA) axis are inconsistent, partly due to the confounding effect of obesity and infrequent sampling. Our goal was to examine whether in a relatively nonobese population, OSA is associated with elevated cortisol levels and to assess the effects of a 2-month placebo-controlled continuous positive airway pressure (sham-CPAP) use.72 subjects (35 middle-aged males and post-menopausal females with OSA, and 37 male and female controls) were studied in the sleep laboratory for four nights. 24-h blood sampling was performed every hour on the fourth day and night in the sleep laboratory at baseline, after sham-CPAP and after CPAP treatment.In both apnoeic men and women, OSA was associated with significantly higher 24-h cortisol levels compared with controls, whereas CPAP lowered cortisol levels significantly, close to those of controls.These results suggest that OSA in nonobese men and slightly obese women is associated with HPA axis activation, similar albeit stronger compared with obese individuals with sleep apnoea. Short-term CPAP use decreased cortisol levels significantly compared with baseline, indicating that CPAP may have a protective effect against comorbidities frequently associated with chronic activation of the HPA axis, e.g. hypertension.

Gender differences in the association of sleep apnea and inflammation.

Over the last 15years, many studies have established an association of sleep apnea with inflammation and metabolic aberrations. However, no controlled studies have examined potential gender effects in this association. We recruited 120 middle-aged, predominantly non-obese mild-to-moderate sleep apneics and controls (62 males, 58 females). All participants underwent a clinical history, physical examination, and 1-night 8-h polysomnography recording and provided a single fasting blood sample for assessment of interleukin-6 (IL-6), tumor necrosis factor receptor 1 (TNFR1), C-reactive protein (CRP), leptin, and adiponectin levels. Among non-sleep apneics, females had higher levels of TNFR1 (p=0.01), CRP (p=0.005), leptin (p<0.001), and adiponectin (p<0.001) compared to males, independent of age and body mass index. When analyzed separately by gender, sleep apneic men had elevated TNFR1 (p=0.04), CRP (p=0.06) and IL-6 (p=0.11) relative to control men; in sleep apneic females, only CRP was elevated (p=0.04). Furthermore, CRP was associated with apnea severity in a dose-response manner (p-linear=0.04 in both genders) and was independently associated with comorbid hypertension in apnea (p-linear=0.005 for women; p-linear=0.09 for men). In conclusion, although women have naturally higher levels of inflammatory and metabolic markers than men, sleep apneic men appear to have a more severe inflammatory profile compared to women. Our findings suggest that these markers should be analyzed and interpreted separately in men and women, and that a single measure of plasma CRP appears to be a clinically-useful marker of apnea severity and comorbid cardiovascular morbidity.

Sleep apnoea, sleepiness, inflammation and insulin resistance in middle-aged males and females.

In obese males obstructive sleep apnoea (OSA) is associated with inflammation and insulin resistance; however, findings are confounded by adipose tissue, a hormone- and cytokine-secreting organ. Our goal was to examine whether in a relatively nonobese population, OSA is associated with sleepiness and inflammation/insulin resistance, and to assess the effects of a 2-month placebo-controlled continuous positive airway pressure (CPAP) use. 77 subjects, 38 middle-aged males and post-menopausal females with OSA and 39 male and female controls, were studied in the sleep laboratory for 4 nights. Measures of sleepiness (objective and subjective), performance, serial 24-h blood samples for interleukin (IL)-6, tumour necrosis factor receptor (TNFR)-1, leptin and adiponectin, and single samples for high-sensitivity C-reactive protein (hsCRP), fasting glucose and insulin levels were obtained. Apnoeic males were significantly sleepier and had significantly higher hsCRP, IL-6, leptin and insulin resistance than controls. Apnoeic females had significantly higher hsCRP; however, objective sleepiness, IL-6, TNFR-1, insulin resistance (Homeostatic Model Assessment index), leptin and adiponectin were similar to controls. CPAP improved subjective sleepiness, but no changes were observed in any of the biomarkers. In conclusion, OSA is associated with sleepiness, inflammation and insulin resistance, even in nonobese males, and this association is stronger in males than in females. Short-term CPAP does not improve the inflammatory/metabolic aberrations in OSA.

Effects of recovery sleep after one work week of mild sleep restriction on interleukin-6 and cortisol secretion and daytime sleepiness and performance.

One workweek of mild sleep restriction adversely impacts sleepiness, performance, and proinflammatory cytokines. Many individuals try to overcome these adverse effects by extending their sleep on weekends. To assess whether extended recovery sleep reverses the effects of mild sleep restriction on sleepiness/alertness, inflammation, and stress hormones, 30 healthy young men and women (mean age ± SD, 24.7 ± 3.5 yr; mean body mass index ± SD, 23.6 ± 2.4 kg/m(2)) participated in a sleep laboratory experiment of 13 nights [4 baseline nights (8 h/night), followed by 6 sleep restriction nights (6 h/night) and 3 recovery nights (10 h/night)]. Twenty-four-hour profiles of circulating IL-6 and cortisol, objective and subjective daytime sleepiness (Multiple Sleep Latency Test and Stanford Sleepiness Scale), and performance (Psychomotor Vigilance Task) were assessed on days 4 (baseline), 10 (after 1 wk of sleep restriction), and 13 (after 2 nights of recovery sleep). Serial 24-h IL-6 plasma levels increased significantly during sleep restriction and returned to baseline after recovery sleep. Serial 24-h cortisol levels during restriction did not change compared with baseline, but after recovery they were significantly lower. Subjective and objective sleepiness increased significantly after restriction and returned to baseline after recovery. In contrast, performance deteriorated significantly after restriction and did not improve after recovery. Extended recovery sleep over the weekend reverses the impact of one work week of mild sleep restriction on daytime sleepiness, fatigue, and IL-6 levels, reduces cortisol levels, but does not correct performance deficits. The long-term effects of a repeated sleep restriction/sleep recovery weekly cycle in humans remain unknown.

Sleep apnoea and visceral adiposity in middle-aged male and female subjects.

In obese male subjects, visceral adiposity has been associated with obstructive sleep apnoea (OSA), while studies in overweight males and females are limited. Our goal was to examine the association between OSA and visceral fat in a relatively nonobese population and assess the effects of 2 months placebo-controlled continuous positive airway pressure (CPAP) use on abdominal fat. 81 subjects, 22 middle-aged males and 20 post-menopausal females with OSA, and 19 male and 20 female controls were studied in the sleep laboratory for four nights. Abdominal (visceral (VAT) and subcutaneous (SAT) adipose tissue) and liver fat were assessed with computed tomography. OSA patients were re-assessed post-CPAP and post sham-CPAP. Apnoeic males had significantly higher VAT than controls, while apnoeic females had higher SAT than controls. In both sexes, OSA was associated with increased liver fat. In males, apnoea was associated with VAT whereas in females it was associated with subcutaneous, visceral and total fat. CPAP did not affect abdominal and liver fat. In overweight males, visceral adiposity is associated with OSA whereas in females it is associated with global adiposity. In overweight males, our therapeutic goal should be the reduction of visceral adiposity and its metabolic correlates, whereas, in females, weight loss may be sufficient. Short-term CPAP treatment does not affect general, abdominal or intra-hepatic adiposity.

Psychomotor Vigilance Test and Its Association With Daytime Sleepiness and Inflammation in Sleep Apnea: Clinical Implications.

STUDY OBJECTIVES: Excessive daytime sleepiness (EDS) is a key symptom of obstructive sleep apnea (OSA). The Psychomotor Vigilance Task (PVT) has been suggested as an objective easy-to-use, inexpensive alternative to the Multiple Sleep Latency Test (MSLT) to measure EDS. In patients with OSA, physiological sleepiness, but not subjective EDS (Epworth Sleepiness Scale [ESS]), has been associated with increased levels of the sleep- inducing proinflammatory cytokine interleukin-6 (IL-6). The goal of this study was to assess the association of PVT with objectively measured sleepiness (MSLT) and subjectively measured sleepiness (ESS) and IL-6 levels in patients with OSA. METHODS: We studied 58 untreated patients with OSA who underwent an 8-hour in-laboratory polysomnography for 4 consecutive nights. MSLT, PVT, and 24-hour serial profiles of IL-6 were assessed on the fourth day. PVT variables included number of lapses, mean reciprocal of the fastest 10% and slowest 10% reaction times, and median of 1/reaction time. ESS was assessed on day 1 of the study. RESULTS: Higher ESS scores were significantly associated with greater number of lapses (ß = .34, P = .02) and lower values of 1/RT (ß = -.36, P = .01) and slowest 10% RTs (ß = -.30, P = .04). No significant association was observed between PVT and MSLT, nor PVT and IL-6 levels. CONCLUSIONS: Our findings suggest that PVT is associated with subjectively assessed daytime sleepiness, but not with physiological sleepiness nor IL-6 levels in patients with OSA. It appears that ESS and PVT may be useful in predicting risks associated with impaired performance, such as traffic accidents, in patients with OSA.

Objective, but Not Subjective, Sleepiness is Associated With Inflammation in Sleep Apnea.

Study objectives: Objective and subjective measures of excessive daytime sleepiness (EDS) are only weakly associated. No study, however, has examined whether these two measures of EDS differ in terms of underlying mechanisms and prognostic value. Pro-inflammatory cytokines, that is, interleukin-6 (IL-6) appear to promote sleepiness/fatigue, while the stress hormone cortisol promotes vigilance. We hypothesized that objective sleepiness is associated with increased levels of IL-6 and decreased levels of cortisol. Methods: We studied 58 obstructive sleep apnea (OSA) patients with clinical EDS and/or cardiovascular comorbidities who underwent 8-hour in-lab polysomnography for four consecutive nights. Objective and subjective daytime sleepiness were measured by Multiple Sleep Latency Test (MSLT), Epworth Sleepiness Scale (ESS), and Stanford Sleepiness Scale (SSS), respectively. Twenty-four-hour profiles of IL-6 and cortisol levels were assessed on the fourth day. Results: The agreement between objective and subjective EDS in OSA patients was fair (kappa = 0.22). Objective EDS (lower MSLT) in OSA patients was associated with significantly elevated 24-hour (ß = -0.34, p = .01), daytime (ß = -0.30, p = .02) and nighttime (ß = -0.38, p < .01) IL-6 levels, and significantly decreased daytime (ß = 0.35, p = .01) cortisol levels. In contrast, subjective EDS (higher ESS/SSS) was not associated with either elevated IL-6 levels or decreased cortisol levels. Conclusions: Our findings suggest that OSA with objective EDS is the more severe phenotype of the disorder associated with low-grade inflammation, a link to cardiometabolic morbidity and mortality. Compared to subjective EDS, objective EDS is a stronger predictor of OSA severity and may be useful in the clinical management of the disorder.

Natural history of excessive daytime sleepiness: role of obesity, weight loss, depression, and sleep propensity.

STUDY OBJECTIVES: Excessive daytime sleepiness (EDS) is highly prevalent in the general population and is associated with occupational and public safety hazards. However, no study has examined the clinical and polysomnographic (PSG) predictors of the natural history of EDS. DESIGN: Representative longitudinal study. SETTING: Sleep laboratory. PARTICIPANTS: From a random, general population sample of 1,741 individuals of the Penn State Adult Cohort, 1,395 were followed up after 7.5 years. MEASUREMENTS AND RESULTS: Full medical evaluation and 1-night PSG at baseline and standardized telephone interview at follow-up. The incidence of EDS was 8.2%, while its persistence and remission were 38% and 62%, respectively. Obesity and weight gain were associated with the incidence and persistence of EDS, while weight loss was associated with its remission. Significant interactions between depression and PSG parameters on incident EDS showed that, in depressed individuals, incident EDS was associated with sleep disturbances, while in non-depressed individuals, incident EDS was associated with increased physiologic sleep propensity. Diabetes, allergy/ asthma, anemia, and sleep complaints also predicted the natural history of EDS. CONCLUSIONS: Obesity, a disorder of epidemic proportions, is a major risk factor for the incidence and chronicity of EDS, while weight loss is associated with its remission. Interestingly, objective sleep disturbances predict incident EDS in depressed individuals, whereas physiologic sleep propensity predicts incident EDS in those without depression. Weight management and treatment of depression and sleep disorders should be part of our public health policies.

Performance evaluation of an Artificial Neural Network automatic spindle detection system.

Sleep spindles are transient waveforms found in the electroencephalogram (EEG) of non-rapid eye movement (NREM) sleep. Sleep spindles are used for the classification of sleep stages and have been studied in the context of various psychiatric and neurological disorders, such as Alzheimer's disease (AD) and the so-called Mild Cognitive Impairment (MCI), which is considered to be a transitional stage between normal aging and dementia. The visual processing of whole-night sleep EEG recordings is tedious. Therefore, various techniques have been proposed for automatically detecting sleep spindles. In the present work an automatic sleep spindle detection system, that has been previously proposed, using a Multi-Layer Perceptron (MLP) Artificial Neural Network (ANN), is evaluated in detecting spindles of both healthy controls, as well as MCI and AD patients. An investigation is carried also concerning the visual detection process, taking into consideration the feedback information provided by the automatic detection system. Results indicate that the sensitivity of the detector was 81.4%, 62.2%, and 83.3% and the false positive rate was 34%, 11.5%, and 33.3%, for the control, MCI, and AD groups, respectively. The visual detection process had a sensitivity rate ranging from 46.5% to 60% and a false positive rate ranging from 4.8% to 19.2%.