Altered brain activation during response inhibition in obstructive sleep apnea

This study examined response inhibition during a Go–NoGo task in individuals with obstructive sleep apnea (OSA). Fourteen OSA patients and 14 controls were studied with functional magnetic resonance imaging. Compared to controls, the OSA group showed more false positives (error of commission) during the NoGo trials with decreased brain activation in the left postcentral gyrus, cingulate gyrus and inferior parietal lobe, as well as right insula and putamen. This is consistent with previous findings of impaired performance and decreased brain activation in OSA patients during a working memory task, suggesting that compromised brain function in response to cognitive challenges may underlie some of the cognitive deficits seen in patients with OSA.     

成年阻塞性睡眠呼吸暂停患者多导睡眠图及临床特征分析性差异

目的:分析成年男性阻塞性睡眠呼吸暂停(OSA)患者多导睡眠图及临床特征,明确年龄对OSA严重程度的影响。方法:回顾性研究包括836名成年男性OSA患者,按年龄分为三组:青年组312人(平均年龄37.07岁),中年组359人(平均年龄52.14岁),老年组165人(平均年龄69.43岁)。分析其多导睡眠图和临床特征,并进行相关性分析。结果:中年组和老年组呼吸暂停低通气指数(AHI)、阻塞性呼吸暂停指数(OAI)、AHI-NREM和AHI-REM均无显著统计学意义(P>0.05),但均低于青年组(P<0.01);中年组和老年组的最低血氧饱和度(SaO2)均高于青年组;中枢性呼吸暂停指数(CAI)随年龄增长而升高(P<0.05)。在睡眠结构方面,老年组总睡眠时间、非快速眼动(NREM)睡眠时间和快速眼动期(REM)睡眠时间均缩短,睡眠效率亦低于青年组(P<0.01),但睡眠潜伏期和入睡后觉醒时间(WASO)明显延长(P<0.01)。年龄与以下各项均呈现显著的相关性:AHI(P<0.01),OAI(P<0.01),CAI(P<0.01),最低SaO2(P<0.01)。多重回归分析表明年龄作为独立变量分别与AHI,OAI,CAI具有相关性。结论:在成年OSA患者中,年龄与OSA严重程度具有显著的相关性,表现为OSA随年龄增长而降低。本研究为研究年龄与OSA严重程度的关系提供了新的证据。     

Association between polysomnographic sleep measures and health-related quality of life in obstructive sleep apnea

Many facets of health-related quality of life are diminished in obstructive sleep apnea (OSA) as they are in other chronic medical conditions. We speculated that impairment in health-related quality of life (HRQoL) might result from the fatigue and daytime somnolence associated with the sleep disorder, as an indirect result from the fragmentation of night-time sleep in OSA. Our hypothesis was that sleep fragmentation measures would correlate with poorer HRQoL measured by medical outcomes study (MOS) subscales. Thirty-nine patients with polysomnographically-confirmed OSA participated in this study. Pearson's correlations were performed with the following sleep architecture variables: wake after sleep onset, the total number of brief arousals, the number of respiratory-related arousals, the rate of respiratory events per hour, and total sleep time. To our surprise, although the total number of arousals was associated with health distress (r=-0.481, P < 0.005), it did not correlate with any other subscales indicating poorer physical and mental health. The relatively insensitive measure of total sleep time (TST) correlated in the expected direction with most subscales. However, after controlling for age and gender, respiratory disturbance indices (RDI) and/or number of arousals emerged as significantly associated with mobility, cognitive functioning, social functioning, energy and fatigue, and health distress. Our findings suggest that polysomnographic indicators of sleep quality and sleep continuity may be an important influence determining many aspects of HRQoL in OSA patients.     

No relation between apolipoprotein E alleles and obstructive sleep apnea

Apolipoprotein E (ApoE) is a genetic risk factor influencing the development of cardiovascular diseases and Alzheimer's disease. Patients with obstructive sleep apnea (OSA) suffer an excess mortality and morbidity from cardiovascular diseases. The frequencies of ApoE alleles were determined in 291 patients with OSA and 728 controls. The distribution of ApoE alleles and genotypes showed no difference between OSA and controls.     

Association between left atrial enlargement and obstructive sleep apnea in a general population of 71‐year‐old men

Left atrial enlargement has been shown to be associated with obstructive sleep apnea in patients with coronary artery disease and in sleep clinic cohorts. However, data from the general population are limited. The aim of this study was to investigate whether there is an association between obstructive sleep apnea and left atrial enlargement in a random sample from a general population of 71‐year‐old men. As part of the longitudinal population study The Study of Men Born in 1943, we analysed cross‐sectional data for 411 men, all 71 years old, who had participated in an overnight home sleep study and a standardized echocardiographic examination. Of the 411 men, 29.4% had moderate to severe obstructive sleep apnea [apnea–hypopnea index score of ≥15 (n = 121)]. These participants showed a significantly higher frequency of systolic heart failure, hypertension, overweight, had greater waist circumference as well as higher left atrial areas compared with men with no or mild obstructive sleep apnea (23.7 ± 5.5 cm² versus 21.6 ± 4.5 cm², P < 0.001). In a linear regression analysis, obstructive sleep apnea was significantly associated with left atrial enlargement after adjusting for overweight, atrial fibrillation, heart failure with reduced ejection fraction, hypertension and mitral regurgitation. Compared with individuals without obstructive sleep apnea, the mean left atrial area was 1.7 ± 1.5 cm² larger in men with severe obstructive sleep apnea (P < 0.05) and 1.3 ± 1.1 cm² larger among men with moderate obstructive sleep apnea (P < 0.05). In this cross‐sectional study of 71‐year‐old men from the general population, left atrial area was independently associated with prevalence and severity of obstructive sleep apnea.     

Noninvasive determination of brain tissue oxygenation during sleep in obstructive sleep apnea: a near-infrared spectroscopic approach

STUDY OBJECTIVES: Recurrent apneas and hypoxemia during sleep in obstructive sleep apnea (OSA) are associated with profound changes in cerebral blood flow to the extent that cerebral autoregulation may be insufficient to protect the brain. Since the brain is sensitive to hypoxia, the cerebrovascular morbidity seen in OSA could be due to chronic, cumulative effects of intermittent hypoxia. Near-infrared spectroscopy (NIRS) has the potential to noninvasively monitor brain tissue oxygen saturation (SO2), and changes in concentration of oxyhemoglobin [O2Hb], deoxyhemoglobin [HHb] and total hemoglobin [tHb] with real-time resolution. We hypothesized that brain tissue oxygenation would be worse during sleep in OSA relative to controls and sought to determine the practical use of NIRS in the sleep laboratory. DESIGN: We evaluated changes in brain tissue oxygenation using NIRS during overnight polysomnography. SETTING: Studies were conducted at University of Illinois, Chicago and Carle Hospital, Urbana, Illinois. PATIENTS: Nineteen subjects with OSA and 14 healthy controls underwent continuous NIRS monitoring during polysomnography. MEASUREMENTS AND RESULTS: We observed significantly lower indexes of brain tissue oxygenation (SO2: 57.1 +/- 4.9 vs. 61.5 +/- 6.1), [O2Hb]: 22.8 +/- 7.7 vs. 31.5 +/- 9.1, and [tHb]: 38.6 +/- 11.2 vs. 48.6 +/- 11.4 micromol/L) in OSA than controls (all P < 0.05). However, multivariate analysis showed that the differences might be due to age disparity between the two groups. CONCLUSIONS: NIRS is an effective tool to evaluate brain tissue oxygenation in OSA. It provides valuable data in OSA assessment and has the potential to bridge current knowledge gap in OSA.     

Morphometric and functional connectivity changes in the brain of patients with obstructive sleep apnea: A meta‐analysis

Existing evidence for brain morphometric changes and functional connectivity alterations in patients with obstructive sleep apnea is mixed. The current study aimed to meta‐analyse the neuroimaging data, and thus synthesize a brain map showing locations with morphometric and functional connectivity differences between patients with obstructive sleep apnea and controls. Published studies to 2018 were retrieved and included into the analysis if they reported such between‐group differences using voxel‐based morphometry or resting‐state functional magnetic resonance imaging, and reported the results in the form of brain coordinates based on whole‐brain analysis. Twelve voxel‐based morphometry and seven resting‐state functional magnetic resonance imaging studies that comprised a total of 1,113 participants fulfilled the inclusion criteria. Compared with healthy controls, patients with obstructive sleep apnea had reduced resting‐state connectivity in the right anterior cingulate and larger grey matter volume in the right insula. Patients with obstructive sleep apnea do have morphometric and resting‐state connectivity alterations in the brain. These neural correlates may help explain the effects of obstructive sleep apnea on the emotion, cognition and quality of life of patients, and may be used in future for evaluating its treatment outcome.     

Genomic approaches to understanding obstructive sleep apnea

Obstructive sleep apnea (OSA) is an increasingly recognized, common chronic disease in the developed nations and is a complex disease that has high social and economic costs. OSA and its associated 'intermediate' phenotypes-craniofacial structure, body fat distribution and metabolism, and neurological control of the upper airway muscles and of sleep and circadian rhythm-are under a substantial degree of genetic control. Investigating the genetic aetiology of OSA offers a means of better understanding its pathogenesis, with the goal of improving preventive strategies, diagnostic tools and therapies. Molecular studies of OSA itself are in their infancy, but considerable effort and expense has already been expended in attempts to detect genetic loci contributing to OSA-associated intermediate phenotypes, such as obesity. However, many of the fundamental questions relating to the genetic epidemiology of OSA and associated factors remain unanswered. This chapter reviews the current state of knowledge of the genetics of OSA, with a focus on genomic approaches to understanding sleep disorders.     

Associations of self-reported obstructive sleep apnea with total and site-specific cancer risk in older women: a prospective study

Background and ObjectivesChronic intermittent hypoxia resulting from obstructive sleep apnea (OSA) may activate multiple carcinogenic pathways and lead to cancer development.MethodsWe prospectively examined the association between OSA and cancer risk among 65,330 women in the Nurses’ Health Study who were free of cancer in 2008 (mean age: 73.3 years). Incident cancer diagnoses were collected until 2016 and confirmed by pathology reports. Clinically diagnosed OSA was self-reported in 2008 and updated in 2012. We used time-dependent Cox regression to estimate hazard ratios (HR) for the associations of OSA with total and site-specific cancer risk.ResultsWe documented 5,257 incident cancer diagnoses during follow-up. In the age-adjusted model, OSA was associated with a 15% (95% CI: 1.03, 1.29) increase in total cancer risk. The association became nonsignificant after adjustment for multiple cancer risk factors (HR: 1.08; 95% CI: 0.96, 1.21). When examining cancer risk by site, OSA was associated with significantly increased risk for lung (fully adjusted HR: 1.52; 95% CI: 1.07, 2.17), bladder (fully adjusted HR: 1.94; 95% CI: 1.12, 3.35), and thyroid cancer (fully adjusted HR: 2.06; 95% CI: 1.01, 4.22) and possibly increased risk for kidney cancer (fully adjusted HR: 1.59; 95% CI: 0.84, 3.01). When grouping cancer sites by risk factor profiles, OSA was positively associated with smoking-related cancers (fully adjusted HR: 1.37; 95% CI: 1.11, 1.67), and this association was stronger in never smokers than ever smokers.ConclusionWhile OSA was not independently associated with overall cancer risk in older women, significant associations were observed for smoking-related cancers, especially in nonsmokers.     

Dry mouth upon awakening in obstructive sleep apnea

The aim was to assess the significance of dry mouth upon awakening as a symptom of obstructive sleep apnea (OSA). The participants were 668 consecutive adults referred for polysomnographic evaluation (PSG) because of snoring and suspected OSA, and 582 adults who were attending a general health check‐up. Data were obtained from self‐administered questionnaires and PSG evaluation. The participants were asked to answer the following question: ‘During the last month, did you experience waking up in the morning with a dry mouth?’. The response scale consisted of five categories: ‘never’, ‘rarely’, ‘sometimes’, often’, or ‘almost always’. We classified patients as having dry mouth upon awakening complaint only if they reported experiencing the symptom ‘almost always’. The prevalence of dry mouth upon awakening was twofold higher in patients with OSA (31.4%) than in primary snorers (16.4%, P < 0.001), and increased linearly from 22.4%, to 34.5%, and 40.7% in mild, moderate, and severe OSA respectively (P < 0.001). The prevalence of dry mouth upon awakening in the control group was 3.2%. Logistic regression results indicated that this symptom significantly differentiated OSA patients from primary snorers after adjusting for age, BMI, gender, hypertension, and other classical OSA symptoms (OR 2.33, 95% CI 1.34–4.07). Dry mouth upon awakening appears as a significant symptom of OSA. We suggest that increased sleep time spent with an open mouth is a likely explanation for these findings.     

Association between proteomics and obstructive sleep apnea phenotypes in a community‐based cohort of women

Proteomic‐based technologies offer new opportunities to identify proteins that might reflect the cardiometabolic stress caused by different aspects of sleep‐disordered breathing. We aimed to investigate whether severe obstructive sleep apnea and severe obstructive sleep apnea during rapid eye movement sleep are associated with changed levels of inflammatory and cardiac disease‐related proteins in a population‐based cohort of women. In the community‐based “Sleep and Health in Women” (SHE) cohort study, 400 women underwent polysomnography, anthropometric measurements and blood sampling. Two proteomic assays (Olink Proseek^® Inflammation panel and Olink Proseek^® Cardiovascular II panel), each measuring 92 proteins, were analysed in a subsample of 253 women. p‐Values were adjusted for multiple testing, with false discovery rate set at 10%. In unadjusted models, 57 proteins were associated with apnea?hypopnea index, 56 proteins with oxygen desaturation index and 64 proteins with rapid eye movement?apnea?hypopnea index. After adjustment for age, body mass index and plate, there were no significant associations between apnea?hypopnea index or oxygen desaturation index and any of the proteins. Severe obstructive sleep apnea during rapid eye movement sleep (rapid eye movement?apnea?hypopnea index ≥ 30) was associated with decreased levels of two anti‐inflammatory proteins; Sirt2 (q‐value .016) and LAP‐TGF‐β₁ (q‐value .016). There was also a negative association between rapid eye movement?apnea?hypopnea index of ≥ 30 and Axin1 (q‐value .095), a protein thought to facilitate TGF‐β‐signalling. We conclude that severe obstructive sleep apnea during rapid eye movement sleep is associated with low levels of Sirt2, LAP‐TGF‐β₁ and Axin1, anti‐inflammatory proteins involved in metabolic regulation and in the atherosclerotic process. For obstructive sleep apnea based on a whole night, the associations with cardiac and inflammatory proteins are weaker, and explained to a large extent by age and body mass index.     

阻塞型睡眠呼吸暂停综合征与动脉粥样硬化

阻塞型睡眠呼吸暂停综合征（obstructive sleep apnea syndrome，OSAS）是临床上常见的重要慢性睡眠呼吸疾病。近年来的研究已证实，OSAS是动脉粥样硬化性疾病的独立危险因素。OSAS患者在睡眠时由于上气道阻塞或部分阻塞导致反复发作的慢性间歇性缺氧，这可能是其诱发动脉粥样硬化性疾病的重要原因，此过程中可能的分子机制包括：I-κB复合物和P38激酶激活调控NF-κB信号通路；端粒酶和Fas死亡配体依赖性细胞凋亡调控途径；间歇性缺氧诱发肝脏损伤导致高胆固醇血症和脂质过氧化反应代谢紊乱，引起不可逆的血管和周围组织重塑，伴有平滑肌增生和纤维化，导致动脉粥样硬化。     

Sleepiness and residual sleepiness in adults with obstructive sleep apnea

Sleepiness is a common, but not necessary symptom of the obstructive sleep apnea syndrome (OSA) and is a frequent chief complaint of patients with OSA who seek medical attention. While sleepiness may seem simple in nature, the underlying mechanisms producing daytime sleepiness in OSA are complex and poorly characterized. Moreover, the meaningful assessment of pathological sleepiness is frequently far from straightforward. Effective treatment of OSA is generally expected to resolve or ameliorate daytime sleepiness. An unknown percentage of treated OSA patients, however, remain sleepy during waking hours. The assessment and treatment of residual sleepiness in treated OSA can range from simple to difficult, depending on the nature and causes of the continued sleepiness. Recently, however, data from clinical trials have been generated which provide direction in the evaluation and management of the OSA patient suffering residual daytime sleepiness.     

Cortical processing of respiratory afferent stimuli during sleep in children with the obstructive sleep apnea syndrome

STUDY OBJECTIVES: Children with the obstructive sleep apnea syndrome (OSAS) have blunted upper airway responses to negative pressure, but the underlying cause remains unknown. Cortical processing of respiratory afferent information can be tested by measuring respiratory-related evoked potentials (RREPs). We hypothesized that children with OSAS have blunted RREP responses compared to normal children during sleep. DESIGN: During sleep, RREPs were obtained from EEG electrodes Fz, Cz, Pz during stage 2 sleep, slow wave sleep (SWS), and REM sleep. RREPs were produced with multiple short occlusions of the upper airway. SETTING: Sleep laboratory. PARTICIPANTS: 9 children with OSAS and 12 normal controls. MEASUREMENTS AND RESULTS: Children with OSAS had significantly decreased evoked K-complex production in stage 2 sleep and slow wave sleep and significantly reduced RREP N350 and P900 components in slow wave sleep. There were no significant differences in any of the measured RREP components in stage 2 sleep, and the only REM difference was decreased P2 amplitude. CONCLUSIONS: Results indicate that in children with OSAS, cortical processing of respiratory-related information measured with RREPs persists throughout sleep; however, RREPs during SWS are blunted compared to those seen in control children. Possible causes for this difference include a congenital deficit in neural processing reflective of a predisposition to develop OSAS, or changes in the upper airway rendering the airway less capable of transducing pressure changes following occlusion. Further research is required to evaluate RREPs after effective surgical treatment of OSAS in children, in order to distinguish between these alternatives.     

Low‐grade albuminuria in children with obstructive sleep apnea

Small urinary protein loss (low‐grade albuminuria or microalbuminuria) may reflect altered permeability of the glomerular filtration barrier. In the present study, it was hypothesized that children with obstructive sleep apnea have an increased risk of microalbuminuria compared with control subjects without sleep‐disordered breathing. Albumin‐to‐creatinine ratio was measured in morning spot urine specimens collected from consecutive children with or without snoring who were referred for polysomnography. Three groups were studied: (i) control subjects (no snoring, apnea–hypopnea index < 1 episode h^?1; n = 31); (ii) mild obstructive sleep apnea (snoring, apnea–hypopnea index = 1–5 episodes h^?1; n = 71); and (iii) moderate‐to‐severe obstructive sleep apnea (snoring, apnea–hypopnea index > 5 episodes?h^?1; n = 27). Indications for polysomnography in control subjects included nightmares, somnambulism and morning headaches. An albumin‐to‐creatinine ratio > median value in the control group (1.85 mg of albumin per g of creatinine) was defined as elevated. Logistic regression analysis revealed that children with moderate‐to‐severe obstructive sleep apnea, but not those with mild obstructive sleep apnea, had increased risk of elevated albumin‐to‐creatinine ratio relative to controls (reference) after adjustment for age, gender and presence of obesity: odds ratio 3.8 (95% confidence interval 1.1–12.6); P = 0.04 and 1.5 (0.6–3.7); P > 0.05, respectively. Oxygen desaturation of hemoglobin and respiratory arousal indices were significant predictors of albumin‐to‐creatinine ratio (r = 0.31, P = 0.01; and r = 0.43, P < 0.01, respectively). In conclusion, children with moderate‐to‐severe obstructive sleep apnea are at significantly higher risk of increased low‐grade excretion of albumin in the morning urine as compared with control subjects without obstructive sleep apnea. These findings may reflect altered permeability of the glomerular filtration barrier related to nocturnal hypoxemia and sympathetic activation which are induced by obstructive sleep apnea.     

Intact implicit probabilistic sequence learning in obstructive sleep apnea

Obstructive sleep apnea (OSA) belongs to the sleep-related breathing disorders and is associated with cognitive impairments in learning and memory functions. The impairments in attention-demanding cognitive functions such as working memory and executive functions are well established in OSA; however, it remains unknown if less attention-demanding implicit sequence learning is affected. In the present study, we examined implicit sequence learning in OSA to probe the functional integrity of this fundamental learning mechanism. We used listening span to measure complex working memory capacity and the alternating serial reaction time (ASRT) task, which enables us to measure general skill learning and sequence-specific learning separately. Twenty OSA patients and 20 healthy controls participated in this study. Our data show dissociation between working memory and implicit sequence learning in OSA. Surprisingly, OSA patients showed preserved general skill and sequence-specific learning in spite of the possible hypoxia and sleep restriction. In contrast, working memory performance measured by listening span task was impaired in the OSA group. This finding suggests selective susceptibility of more attention-demanding cognitive functions in this patient population, while implicit learning remains intact. Our findings draw attention the fact that disordered sleep may have less impact on the integrity of structures connected to implicit sequence learning.     

Validation of a predictive model for obstructive sleep apnea in people with Down syndrome

Detecting obstructive sleep apnea (OSA) is important to both prevent significant comorbidities in people with Down syndrome (DS) and untangle contributions to other behavioral and mental health diagnoses. However, laboratory-based polysomnograms are often poorly tolerated, unavailable, or not covered by health insurance for this population. In previous work, our team developed a prediction model that seemed to hold promise in identifying which people with DS might not have significant apnea and, consequently, might be able to forgo a diagnostic polysomnogram. In this study, we sought to validate these findings in a novel set of participants with DS. We recruited an additional 64 participants with DS, ages 3–35 years. Caregivers completed the same validated questionnaires, and our study team collected vital signs, physical exam findings, and medical histories that were previously shown to be predictive. Patients then had a laboratory-based polysomnogram. The best modeling had a validated negative predictive value of 50% for an apnea–hypopnea index (AHI) > 1/hTST and 73.7% for AHI >5/hTST. The positive predictive values were 60% and 39.1%, respectively. As such, a clinically reliable screening tool for OSA in people with DS was not achieved. Patients with DS should continue to be monitored for OSA according to current healthcare guidelines.     

A Sleep Position Trainer for positional sleep apnea: a randomized,controlled trial

We tested the effect of the Sleep Position Trainer, a vibrational device, for positional sleep apnea in an open, randomized controlled trial with 101 patients, where 52 patients were allocated to Sleep Position Trainer and 49 patients to a non‐treatment control group for 2 months (Part 1). All patients were then followed as a cohort for a period of 6 months with use of the Sleep Position Trainer (Part 2). The participants were assessed with polygraphy at entry, and after 2 and 6 months. The mean apnea–hypopnea index supine was 35 per h (SD, 18) in the Sleep Position Trainer group and 38 per h (SD, 15) in the control group at entry. In a per protocol analysis, the mean total apnea–hypopnea index at entry and after 2 months in the Sleep Position Trainer group was 18 per h (SD, 10) and 10 per h (SD, 9; P < 0.001) versus 20 per h (SD, 9) and 18 per h (SD, 10; NS) in the control group. The mean supine sleep time decreased from 47% (SD, 22) to 17% (SD, 18; P < 0.001) in the Sleep Position Trainer group after 2 months. In the control group, the mean supine sleep time was 48% (SD, 20) at entry and 39% (SD, 21; NS) after 2 months. The positive effect of Sleep Position Trainer was maintained in all patients treated with Sleep Position Trainer after 6 months. Daytime sleepiness improved after 6 months. Compliance with the Sleep Position Trainer device during the first 2 months, defined as use of Sleep Position Trainer >4 h per night for all weekdays, was 75.5% (SD 21.2). The discontinuation rate was 28.8 and 49.4% after 2 and 6 months, respectively.