Association between sleep microarchitecture and cognition in obstructive sleep apnea.

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) increases the risk of cognitive impairment. Measures of sleep microarchitecture from EEG may help identify patients at risk of this complication. METHODS: Participants with suspected OSA (n=1142) underwent in-laboratory polysomnography and completed sleep and medical history questionnaires, and tests of global cognition (Montreal Cognitive Assessment, MoCA), memory (Rey Auditory Verbal Learning Test, RAVLT) and information processing speed (Digit-Symbol Coding, DSC). Associations between cognitive scores and stage 2 NREM sleep spindle density, power, frequency and %-fast (12-16Hz), odds-ratio product (ORP), normalized EEG power (EEGNP) and the delta:alpha ratio were assessed using multivariable linear regression (MLR) adjusted for age, sex, education, and total sleep time. Mediation analyses were performed to determine if sleep microarchitecture indices mediate the negative effect of OSA on cognition. RESULTS: All spindle characteristics were lower in participants with moderate and severe OSA (p≤0.001, versus no/mild OSA) and positively associated with MoCA, RAVLT and DSC scores (false discovery rate corrected p-value, q≤0.026), except spindle power which was not associated with RAVLT (q=0.185). ORP during NREM sleep (ORPNREM) was highest in severe OSA participants (p≤0.001) but neither ORPNREM (q≥0.230) nor the delta:alpha ratio were associated with cognitive scores in MLR analyses (q≥0.166). In mediation analyses, spindle density and EEGNP (p≥0.048) mediated moderate-to-severe OSA's negative effect on MoCA scores while ORPNREM, spindle power and %-fast spindles mediated OSA's negative effect on DSC scores (p≤0.018). CONCLUSION: Altered spindle activity, ORP and normalized EEG power may be important contributors to cognitive deficits in patients with OSA.

All Obstructive Sleep Apnea Events Are Not Created Equal: The Relationship between Event-related Hypoxemia and Physiologic Response.

Rationale: Obstructive sleep apnea (OSA) severity is typically assessed by the apnea-hypopnea index (AHI), a frequency-based metric that allocates equal weight to all respiratory events. However, more severe events may have a greater physiologic impact. Objectives: The purpose of this study was to determine whether the degree of event-related hypoxemia would be associated with the postevent physiologic response. Methods: Patients with OSA (AHI, ⩾5/h) from the multicenter Canadian Sleep and Circadian Network cohort were studied. Using mixed-effect linear regression, we examined associations between event-related hypoxic burden (HBev) assessed by the area under the event-related oxygen saturation recording with heart rate changes (ΔHRev), vasoconstriction (vasoconstriction burden [VCBev] assessed with photoplethysmography), and electroencephalographic responses (power ratio before and after events). Results: Polysomnographic recordings from 658 patients (median [interquartile range] age, 55.00 [45.00, 64.00] yr; AHI, 27.15 [14.90, 64.05] events/h; 42% female) were included in the analyses. HBev was associated with an increase in all physiologic responses after controlling for age, sex, body mass index, sleep stage, total sleep time, and study centers; for example, 1 standard deviation increase in HBev was associated with 0.21 [95% confidence interval, 0.2, 0.22], 0.08 [0.08, 0.09], and 0.22 [0.21, 0.23] standard deviation increases in ΔHRev, VCBev, and ß-power ratio, respectively. Conclusions: Increased event-related hypoxic burden was associated with greater responses across a broad range of physiologic signals. Future metrics that incorporate information about the variability of these physiologic responses may have promise in providing a more nuanced assessment of OSA severity.

Contribution of obstructive sleep apnea to disrupted sleep in a large clinical cohort of patients with suspected obstructive sleep apnea.

STUDY OBJECTIVES: The response of sleep depth to CPAP in patients with OSA is unpredictable. The odds-ratio-product (ORP) is a continuous index of sleep depth and wake propensity that distinguishes different sleep depths within sleep stages, and different levels of vigilance during stage wake. When expressed as fractions of time spent in different ORP deciles, nine distinctive patterns are found. Only three of these are associated with OSA. We sought to determine whether sleep depth improves on CPAP exclusively in patients with these three ORP patterns. METHODS: ORP was measured during the diagnostic and therapeutic components of 576 split-night polysomnographic (PSG) studies. ORP architecture in the diagnostic section was classified into one of the nine possible ORP patterns and the changes in sleep architecture were determined on CPAP for each of these patterns. ORP architecture was similarly determined in the first half of 760 full-night diagnostic PSG studies and the changes in the second half were measured to control for differences in sleep architecture between the early and late portions of sleep time in the absence of CPAP. RESULTS: Frequency of the three ORP patterns increased progressively with the apnea-hypopnea index. Sleep depth improved significantly on CPAP only in the three ORP patterns associated with OSA. Changes in CPAP in the other six patterns, or in full diagnostic PSG studies, were insignificant or paradoxical. CONCLUSIONS: ORP architecture types can identify patients in whom OSA adversely affects sleep and whose sleep is expected to improve on CPAP therapy.

Adherence Index: sleep depth and nocturnal hypoventilation predict long-term adherence with positive airway pressure therapy in severe obstructive sleep apnea.

STUDY OBJECTIVES: Treatment of obstructive sleep apnea with positive airway pressure (PAP) devices is limited by poor long-term adherence. Early identification of individual patients' probability of long-term PAP adherence would help in their management. We determined whether conventional polysomnogram (PSG) scoring and measures of sleep depth based on the odds ratio product would predict adherence with PAP therapy 12 months after it was started. METHODS: Patients with obstructive sleep apnea referred to an academic sleep center had split-night PSG, arterial blood gases, and a sleep questionnaire. Multiple linear regression analysis of conventional PSG scoring and the odds ratio product both during diagnostic PSG and PAP titration provided an "Adherence Index," which was correlated with PAP use 12 months later. RESULTS: Patients with obstructive sleep apnea (n = 236, apnea-hypopnea index 72.2 ± 34.1 events/h) were prescribed PAP therapy (82% received continuous PAP, 18% received bilevel PAP). Each patient's adherence with PAP therapy 12 months later was categorized as "never used," "quit using," "poor adherence," and "good adherence." PSG measures that were most strongly correlated with PAP adherence were apnea-hypopnea index and odds ratio product during nonrapid eye movement sleep; the additional contribution of nocturnal hypoxemia to this correlation was confined to those with chronic hypoventilation treated with bilevel PAP. The Adherence Index derived from these measures, during both diagnostic PSG and PAP titration, was strongly correlated with PAP adherence 12 months later. CONCLUSIONS: Long-term adherence with PAP therapy can be predicted from diagnostic PSG in patients with severe obstructive sleep apnea, which may facilitate a precision-based approach to PAP management. CITATION: Younes MK, Beaudin AE, Raneri JK, Gerardy BJ, Hanly PJ. Adherence Index: sleep depth and nocturnal hypoventilation predict long-term adherence with positive airway pressure therapy in severe obstructive sleep apnea. J Clin Sleep Med. 2022:18(8):1933-1944.

Association of insomnia and short sleep duration, alone or with comorbid obstructive sleep apnea, and the risk of chronic kidney disease.

STUDY OBJECTIVES: Obstructive sleep apnea (OSA), sleep fragmentation, and short sleep duration (SD) have been associated with chronic kidney disease (CKD). However, these potential mechanisms for CKD have not been compared in the same cohort. This study investigated the independent and combined impact of OSA and insomnia with short sleep duration on the risk of CKD progression in a sleep clinic population. METHODS: In a cross-sectional study design, adults with suspected OSA completed an overnight sleep study and a questionnaire that included the Insomnia Severity Index (ISI) and Pittsburgh Sleep Quality Index (PSQI). They also provided blood and urine samples for measurement of the glomerular filtration rate and urine albumin:creatinine ratio, from which the risk of CKD progression was determined. RESULTS: Participants (n = 732, 41% female, 55 ± 13 years) were categorized into four groups: no/mild OSA without insomnia (NM-OSA, n = 203), insomnia with SD without OSA (Insomnia-SD, n = 104), moderate-to-severe OSA without insomnia (MS-OSA, n = 242), and comorbid insomnia and OSA with SD (COMISA-SD, n = 183). After stratification, 12.8% of NM-OSA, 15.4% of Insomnia-SD, 28.9% of MS-OSA, and 31.7% of the COMISA-SD participants had an increased risk of CKD progression. Compared to NM-OSA, the odds ratio (OR) for an increased risk of CKD progression was not increased in Insomnia-SD (OR 0.95, confidence interval [CI]: 0.45-1.99) and was increased to the same degree in MS-OSA (OR 2.79, CI: 1.60-4.85) and COMISA-SD (OR 3.04, CI: 1.69-5.47). However, the ORs were similar between the MS-OSA and COMISA-SD groups across all statistical models (p ≥ .883). CONCLUSIONS: In a sleep clinic population, insomnia with short sleep duration does not increase the risk of CKD progression; nor does it further increase the risk of CKD progression associated with moderate-to-severe OSA.

Risk of chronic kidney disease in patients with obstructive sleep apnea.

STUDY OBJECTIVES: Chronic kidney disease (CKD) is a global health concern and a major risk factor for cardiovascular morbidity and mortality. Obstructive sleep apnea (OSA) may exacerbate this risk by contributing to the development of CKD. This study investigated the prevalence and patient awareness of the risk of CKD progression in individuals with OSA. METHODS: Adults referred to five Canadian academic sleep centers for suspected OSA completed a questionnaire, a home sleep apnea test or in-lab polysomnography and provided blood and urine samples for measurement of estimated glomerular filtration rate (eGFR) and the albumin:creatinine ratio (ACR), respectively. The risk of CKD progression was estimated from a heat map incorporating both eGFR and ACR. RESULTS: 1295 adults (42% female, 54 ± 13 years) were categorized based on the oxygen desaturation index (4% desaturation): <15 (no/mild OSA, n = 552), 15-30 (moderate OSA, n = 322), and >30 (severe OSA, n = 421). After stratification, 13.6% of the no/mild OSA group, 28.9% of the moderate OSA group, and 30.9% of the severe OSA group had a moderate-to-very high risk of CKD progression (p < .001), which was defined as an eGFR <60 mL/min/1.73 m2, an ACR ≥3 mg/mmol, or both. Compared to those with no/mild OSA, the odds ratio for moderate-to-very high risk of CKD progression was 2.63 (95% CI: 1.79-3.85) for moderate OSA and 2.96 (2.04-4.30) for severe OSA after adjustment for CKD risk factors. Among patients at increased risk of CKD progression, 73% were unaware they had abnormal kidney function. CONCLUSION: Patients with moderate and severe OSA have an increased risk of CKD progression independent of other CKD risk factors; most patients are unaware of this increased risk.

Impact of intermittent hypoxia on human vascular responses during sleep.

Exposure to intermittent hypoxia (IH) ≥15 times per hour is believed to be the primary mechanism for the increased risk of cerebrovascular and cardiovascular disease in patients with moderate to severe sleep apnea. Human experimental models of IH used to investigate this link have been predominantly employed during wakefulness, which limits extrapolation of findings to sleep apnea where IH occurs during sleep. Moreover, how IH impacts vascular regulation during sleep has not been measured quantitatively. Therefore, the objective of this study was to assess the impact sleep accompanied by IH on vascular responses to hypoxia and hypercapnia during sleep. Ten males performed two randomly scheduled 6-h overnight sleep studies. One sleep study was performed in room air (normoxia) and the other sleep study was performed during isocapnic IH (60 s hypoxia-60 s normoxia). On each night, cerebrovascular (peak blood velocity through the middle cerebral artery (V¯P); transcranial Doppler ultrasound) and cardiovascular (blood pressure, heart rate) responses to hypoxia and hypercapnia were measured before sleep onset (PM-Awake), within the first 2 h of sleep (PM-Asleep), in the 5th (out of 6) hours of sleep (AM-Asleep) and after being awoken in the morning (AM-Awake). Sleep accompanied by IH had no impact on the V¯P and blood pressure responses to hypoxia and hypercapnic at any timepoint (p ≥ 0.103 for all responses). However, the AM-Awake heart rate response to hypoxia was greater following sleep in IH compared to sleep in normoxia. Independent of the sleep environment, the V¯P response to hypoxia and hypercapnia were reduced during sleep. In conclusion, cerebral blood flow responses are reduced during sleep compared to wakefulness, but 6 h of sleep accompanied by IH does not alter cerebrovascular and cardiovascular response to hypoxia and hypercapnia during wakefulness or sleep in healthy young humans. However, it is likely that longer exposure to IH during sleep (i.e., days-to-weeks) is required to better elucidate IH's impact on vascular regulation in humans.

Contribution of hypercapnia to cognitive impairment in severe sleep-disordered breathing.

STUDY OBJECTIVES: Although cognitive impairment in obstructive sleep apnea (OSA) is primarily attributed to intermittent hypoxemia and sleep fragmentation, hypercapnia may also play a role in patients whose OSA is complicated by hypoventilation. This study investigated the impact of hypercapnia on cognitive function in severe sleep-disordered breathing (OSA accompanied by hypoventilation). METHODS: Patients with severe OSA (apnea-hypopnea index >30 events/h; n = 246) underwent evaluation for accompanying hypoventilation with polysomnography that included continuous transcutaneous carbon dioxide (TcCO2) monitoring and awake arterial blood gas analysis. Patients were categorized as having no hypoventilation (n = 84), isolated sleep hypoventilation (n = 40), or awake hypoventilation (n = 122). Global cognitive function was evaluated using the Montreal Cognitive Assessment (MoCA), memory with the Rey Auditory Verbal Learning Test (RAVLT), and processing speed with the Wechsler Adult Intelligence Scale, Fourth Edition (WAIS-IV), Digit Symbol Coding subtest (DSC). RESULTS: Apnea-hypopnea index was similar across groups (P = .15), but the sleep and awake hypoventilation groups had greater nocturnal hypoxemia compared with the no-hypoventilation group (P < .01). Within all groups, mean MoCA scores were < 26, which is the validated threshold to indicate mild cognitive impairment; RAVLT scores were lower than age-matched norms only in the awake-hypoventilation group (P ≤ .01); and DSC scores were lower than age-matched norms within all groups (P < .01). In multivariable regression analyses, higher arterial partial pressure of carbon dioxide (PaCO2) and TcCO2 during wakefulness were associated with lower MoCA and DSC scores (P ≤ .03), independent of confounders including overlap syndrome (OSA + chronic obstructive pulmonary disease). CONCLUSIONS: Awake hypoventilation is associated with greater deficits in cognitive function in patients with severe sleep-disordered breathing. CITATION: Beaudin AE, Raneri JK, Ayas NT, Skomro RP, Smith EE, Hanly PJ; on behalf of Canadian Sleep and Circadian Network. Contribution of hypercapnia to cognitive impairment in severe sleep-disordered breathing. J Clin Sleep Med. 2022;18(1):245-254.

Impact of nocturnal oxygen and CPAP on the ventilatory response to hypoxia in OSA patients free of overt cardiovascular disease.

A primary characteristic of obstructive sleep apnea (OSA) is chronic exposure to intermittent hypoxia (IH) due to repeated upper airway obstruction. Chronic IH exposure is believed to increase OSA severity over time by enhancing the acute ventilatory response to hypoxia (AHVR), thus promoting ventilatory overshoot when apnea ends and perpetuation of apnea during sleep. Continuous positive airway pressure (CPAP), the gold-standard treatment of OSA, reduces the AHVR, believed to result from correction of IH. However, CPAP also corrects ancillary features of OSA such as intermittent hypercapnia, negative intrathoracic pressure and surges in sympathetic activity, which may also contribute to the reduction in AHVR. Therefore, the objective of this study was to investigate the impact of nocturnal oxygen therapy (to remove IH only) and CPAP (to correct IH and ancillary features of OSA) on AHVR in newly diagnosed OSA patients. Fifty-two OSA patients and twenty-two controls were recruited. The AHVR was assessed using a 5 min iscopanic-hypoxic challenge before, and after, treatment of OSA by nocturnal oxygen therapy and CPAP. Following baseline measurements, OSA patients were randomly assigned to nocturnal oxygen therapy (Oxygen, n = 26) or no treatment (Air; n = 26). The AHVR was re-assessed following two weeks of oxygen therapy or no treatment, after which all patients were treated with CPAP. The AHVR was quantified following ~4 weeks of adherent CPAP therapy (n = 40). Both nocturnal oxygen and CPAP treatments improved hypoxemia (p < 0.05), and, as expected, nocturnal oxygen therapy did not completely abolish respiratory events (i.e., apneas/hypopneas). Averaged across all OSA patients, nocturnal oxygen therapy did not change AHVR from baseline to post-oxygen therapy. Similarly, the AHVR was not altered pre- and post-CPAP (p > 0.05). However, there was a significant decrease in AHVR with both nocturnal oxygen therapy and CPAP in patients in the highest OSA severity quartile (p < 0.05). Nocturnal oxygen therapy and CPAP both reduce the AHVR in patients with the most severe OSA. Therefore, IH appears to be the primary mechanism producing ventilatory instability in patients with severe OSA via enhancement of the AHVR.

Recruitment of patients with chronic kidney disease and obstructive sleep apnoea for a clinical trial.

Obstructive sleep apnoea is common in chronic kidney disease (CKD) and may accelerate the decline in kidney function. Recruitment for a randomised controlled trial to address whether treatment of sleep apnoea with continuous positive airway pressure (CPAP) slows the progression of kidney failure may be challenging because sleep apnoea is often asymptomatic in this patient population. The present report outlines recruitment challenges and how to address them. Adult patients with CKD were recruited for a 12-month randomised, controlled, non-blinded, parallel clinical trial to evaluate the impact of CPAP therapy on kidney function. Patients completed a home sleep apnoea test and those that met pre-specified sleep apnoea and nocturnal hypoxaemia severity criteria were randomised to receive CPAP or no therapy. Although 1,665 patients were eligible to participate in the study over 3 years, only 57 (3.4%) were ultimately randomised. The sequential reasons (and number of patients) for recruitment failure were: no show at clinic appointment (137), insufficient recruiters to approach every eligible patient (461), on therapy for sleep apnoea (122), unable to provide informed consent (67), refused consent (645), home sleep apnoea test not completed (47) or inclusion criteria not met (116), and declined pre-randomisation education session (12). Many challenges limit effective recruitment, which may be addressed by hiring additional recruiters and increasing the awareness of sleep apnoea among patients with CKD. These findings can be used to improve recruitment strategies and the design of future studies.

Impact of obstructive sleep apnoea and intermittent hypoxia on blood rheology: a translational study.

BACKGROUND: Haemorheological alterations are reported in obstructive sleep apnoea (OSA) and reversed with continuous positive airway pressure (CPAP), observations potentially explained by intermittent hypoxia (IH)-induced oxidative stress. Our objective was to investigate whether IH causes haemorheological alterations via oxidative stress. METHODS: Wistar rats were exposed to normoxia (n=7) or IH (n=8) for 14 days. 23 moderate-to-severe OSA patients were assessed at three time-points: baseline, after randomisation to either 2 weeks of nocturnal oxygen (n=13) or no treatment (n=10) and after 1 month of CPAP treatment (n=17). Furthermore, an OSA-free control group (n=13) was assessed at baseline and after time-matched follow-up. We measured haemorheological parameters (haematocrit, blood viscosity, plasma viscosity (rats only), erythrocyte aggregation and deformability (humans only)) and redox balance (superoxide dismutase (SOD), glutathione peroxidase, protein oxidation (advanced oxidation protein products (AOPPs)) and lipid peroxidation (malondialdehyde)). We also tested the haemorheological sensitivity of erythrocytes to reactive oxygen species (ROS) in our human participants using the oxidant t-butyl hydroperoxide (TBHP). RESULTS: In rats, IH increased blood viscosity by increasing haematocrit without altering the haemorheological properties of erythrocytes. IH also reduced SOD activity and increased AOPPs. In humans, baseline haemorheological properties were similar between patients and control participants, and properties were unaltered following oxygen and CPAP, except erythrocyte deformability was reduced following oxygen therapy. Redox balance was comparable between patients and control participants. At baseline, TBHP induced a greater reduction of erythrocyte deformability in patients while CPAP reduced TBHP-induced increase in aggregation strength. CONCLUSIONS: IH and OSA per se do not cause haemorheological alterations despite the presence of oxidative stress or higher sensitivity to ROS, respectively.

Cognitive Function in a Sleep Clinic Cohort of Patients with Obstructive Sleep Apnea.

Rationale: Obstructive sleep apnea (OSA) is associated with an increased risk of mild cognitive impairment (MCI) within the general population. However, MCI risk in sleep-clinic populations of patients with OSA is poorly characterized.Objectives: To determine the prevalence of MCI in a sleep-clinic population of patients with OSA and which patients are at the greatest risk for this complication.Methods: Adults (n = 1,084) referred to three academic sleep centers for suspected OSA who had home sleep apnea testing or in-laboratory polysomnography were recruited. Patients completed sleep and medical history questionnaires, the Montreal Cognitive Assessment Test (MoCA) of global cognition, the Rey Auditory Verbal Learning Test of memory, and the Wechsler Adult Intelligence Scale-Fourth Edition Digit-Symbol Coding (DSC) subtest of information processing speed.Results: A MoCA score <26 (range 0-30) was operationally defined as MCI. MCI was present in 47.9% of our entire patient cohort, increasing to >55.3% in patients with moderate and severe OSA. Patients with a MoCA <26 were predominantly older males with more severe OSA, hypoxemia, and vascular comorbidities. Moderate and severe OSA were independently associated with >70% higher odds for MCI compared with patients with no OSA (P = 0.003). Memory and information processing speed was lower than age-matched normal values (P < 0.001), with lower MoCA and DSC scores associated with a higher oxygen desaturation index and nocturnal hypoxemia.Conclusions: Cognitive impairment is highly prevalent in patients referred to sleep clinics for suspected OSA, occurring predominantly in older males with moderate to severe OSA and concurrent vascular comorbidities. Moderate to severe OSA is an independent risk factor for MCI.

Effect of CPAP Therapy on Kidney Function in Patients With Chronic Kidney Disease: A Pilot Randomized Controlled Trial.

BACKGROUND: OSA is common in chronic kidney disease (CKD) and may accelerate a decline in kidney function. It is not clear whether treatment of OSA with CPAP improves kidney function. RESEARCH QUESTION: Does treatment with CPAP improve kidney function in patients with CKD and coexisting OSA? STUDY DESIGN AND METHODS: A randomized, controlled, nonblinded, parallel clinical trial was performed of patients with stages 3 and 4 CKD and coexisting OSA comparing the effect of CPAP vs usual care on the estimated glomerular filtration rate (eGFR) and the urine albumin to creatinine ratio (ACR) over 12 months. RESULTS: Fifty-seven patients were enrolled and 30 were randomized to CPAP. They had moderately severe CKD (eGFR, 38.4 ± 1.5 mL/min/1.73 m2) and significant OSA and nocturnal hypoxemia (oxygen desaturation index: 23.9 events/h; interquartile range [IQR], 20.3 events/h; mean peripheral capillary oxygen saturation: 89.5%; IQR, 1.7%); 60% had baseline albuminuria (ACR, > 3 mg/mmol). No significant difference was found between CPAP and usual care in the change in eGFR and ACR over 12 months. Although some improvement in eGFR occurred with CPAP therapy in patients with a lower risk of CKD progression, this did not reach statistical significance. INTERPRETATION: Although CPAP did not provide additional renal benefits over usual care in all CKD patients, some evidence suggested that CPAP slowed the decline in eGFR in CKD patients with a lower risk of CKD progression. These preliminary data support the need for larger clinical trials exploring the effects of CPAP on kidney function. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT02420184; URL: www.clinicaltrials.gov.

Symptom subtypes and cognitive function in a clinic-based OSA cohort: a multi-centre Canadian study.

BACKGROUND: Distinct symptom subtypes are found in patients with OSA. The association between these subtypes and neurocognitive function is unclear. OBJECTIVE: The purposes of this study were to assess whether OSA symptom subtypes are present in a cohort of Canadian patients with suspected OSA and evaluate the relationship between subtypes and neurocognitive function. METHODS: Patients with suspected OSA who completed a symptom questionnaire and underwent testing for OSA were included. Symptom subtypes were identified using latent class analysis. Associations between subtypes and neurocognitive outcomes (Montreal Cognitive Assessment [MoCA], Rey Auditory Verbal Learning Test [RAVLT], Wechsler Adult Intelligence Scale [WAIS-IV], Digit-Symbol Coding subtest [DSC]) were assessed using analysis of covariance (ANCOVA), controlling for relevant covariates. RESULTS: Four symptom subtypes were identified in patients with OSA (oxygen desaturation index ≥5 events/hour). Three were similar to prior studies, including the Excessively Sleepy (N=405), Disturbed Sleep (N=382) and Minimally Symptomatic (N=280), and one was a novel subtype in our sample defined as Excessively Sleepy with Disturbed Sleep (N=247). After covariate adjustment, statistically significant differences among subtypes (p=0.037) and among subtypes and patients without OSA (p=0.044) were observed in DSC scores; the Minimally Symptomatic subtype had evidence of higher DSC scores than all other groups, including non-OSA patients. No differences were seen in MoCA or RAVLT. CONCLUSIONS: Results support the existence of previously identified OSA symptom subtypes of excessively sleepy, disturbed sleep and minimally symptomatic in a clinical sample from Canada. Subtypes were not consistently associated with neurocognitive function across multiple instruments.

Effect of CPAP therapy on kidney function in patients with obstructive sleep apnoea and chronic kidney disease: a protocol for a randomised controlled clinical trial.

INTRODUCTION: Obstructive sleep apnoea (OSA) is common in patients with chronic kidney disease (CKD) and may contribute to the progression of kidney disease either through direct effects of hypoxia on the kidney or indirectly through hypoxaemia-induced oxidative stress, endothelial dysfunction, inflammation, activation of the renin-angiotensin and sympathetic nervous systems, and hypertension. Treatment of OSA with continuous positive airway pressure (CPAP) improves many of these physiological abnormalities in patients with normal renal function, though to date there are no trials evaluating the effect of OSA treatment on kidney function in patients with CKD. The purpose of this study is to test the feasibility and efficacy of CPAP therapy in CKD patients with OSA. METHODS AND ANALYSIS: The study is a randomised, controlled, non-blinded, parallel clinical trial in which patients with established CKD are screened for OSA. Patients with OSA are randomised to either conventional medical therapy (control group) or medical therapy and CPAP (CPAP group) and followed for 1 year. The primary outcome is the change in estimated glomerular filtration rate. Secondary outcomes are the change in the urinary albumin/creatinine ratio, the Epworth Sleepiness Scale , Pittsburgh Sleep Quality Index and Kidney Disease Quality of Life questionnaire. ETHICS AND DISSEMINATION: Ethics approval has been obtained from the Conjoint Health Research Ethics Board (ID: REB15-0055). Results from this study will be disseminated through presentations at scientific conferences and publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT02420184; Pre-results.

Vascular responses to hypoxia are not impaired in obstructive sleep apnoea patients free of overt cardiovascular disease.

NEW FINDINGS: What is the central question of this study? Does treatment of obstructive sleep apnoea (OSA) with nocturnal oxygen or continuous positive airway pressure (CPAP) improve hypoxic vascular responses, which are reportedly impaired in OSA? What is the main finding and its importance? Cerebrovascular and cardiovascular hypoxic responses were not impaired in OSA patients free of overt cardiovascular disease and known risk factors, and were not altered by nocturnal oxygen or CPAP treatment. We conclude that this OSA patient phenotype has normal vascular responses to hypoxia and is unlikely to obtain long term cardiovascular benefits from nocturnal oxygen or CPAP therapy. ABSTRACT: Cerebral blood flow (CBF) and cardiovascular responses to hypoxia are reportedly impaired in obstructive sleep apnoea (OSA) patients and corrected by continuous positive airway pressure (CPAP), beneficial effects that are ascribed to correction of OSA-related intermittent hypoxia (IH). However, CPAP corrects both IH and ancillary OSA features (i.e. intermittent hypercapnia, sympathetic activation, blood pressure surges, negative intrathoracic pressure swings and sleep fragmentation). Whether correction of these ancillary OSA features contribute to CPAP's beneficial effects on vascular hypoxic responses is unknown. Nocturnal oxygen corrects OSA-induced IH, but apnoeas and ancillary features persist. Thus, we examined the effects of nocturnal oxygen and CPAP on cerebrovascular and cardiovascular hypoxic responses in untreated OSA patients. Responses were assessed in 52 OSA patients free of overt cardiovascular disease and known risk factors at baseline, after 2 weeks of nocturnal oxygen (n = 26) or no treatment (n = 26), and after ∼4 weeks of CPAP treatment (n = 40). Twenty-two age-matched controls were assessed at baseline and follow-up visits. Resting, isocapnic euoxia mean blood pressure was decreased following nocturnal oxygen (-3.6 ± 6.0 mmHg; P = 0.006) and CPAP (-4.5 ± 7.5 mmHg; P < 0.001) while cerebrovascular conductance was increased with CPAP (P = 0.001). However, these changes were not different from controls. Unexpectedly, OSA patients and controls had similar hypoxic vascular responses at baseline that were not changed by either nocturnal oxygen or CPAP. We conclude that OSA patients free of overt cardiovascular disease and known risk factors did not have impaired cerebrovascular or cardiovascular responses to hypoxia and are unlikely to obtain long term cardiovascular benefits from nocturnal oxygen or CPAP therapy.

Effects of Six-Month Aerobic Exercise Intervention on Sleep in Healthy Older Adults in the Brain in Motion Study: A Pilot Study.

BACKGROUND: Sleep disturbances have been shown to be associated with the presence of the apolipoprotein (APOE) ɛ4 allele, the well-known genetic risk factor for late-onset sporadic Alzheimer's disease (AD). OBJECTIVE: This study quantifies the effects of a six-month aerobic exercise intervention on objective and subjective sleep quality in middle-aged to older individuals including those at increased genetic risk for late-onset sporadic Alzheimer's disease (AD), who carry the apolipoprotein (APOE) ɛ4 risk allele. METHODS: 199 sedentary men and women without significant cognitive impairments were enrolled in the Brain in Motion study, a quasi-experimental single group pre-test/post-test study with no control group. Participants completed a six-month aerobic exercise intervention and consented to genetic testing. Genotyping of APOE confirmed that 54 individuals were carriers of the ɛ4 allele. Participants' subjective quality of sleep was assessed with the Pittsburgh Sleep Quality Index (PSQI) pre- and post-intervention. A convenience sample of participants (n = 29, APOE ɛ4+ = 7) consented to undergo two nights of in-home polysomnography (PSG) pre- and post intervention. Sleep architecture and respiratory variables were assessed. RESULTS: The six-month aerobic exercise intervention significantly improved participants' total PSQI score, sleep efficiency, and sleep latency in the full sample (n = 199). PSG results showed that total sleep time and sleep onset latency significantly improved over the course of the exercise intervention only in individuals who carried the APOE ɛ4 allele. These results are, however, exploratory and need to be carefully interpreted due to the rather small number of APOE ɛ4+ in the PSG subgroup. CONCLUSIONS: The six-month aerobic exercise intervention significantly improved participants' sleep quality with beneficial effects on PSG shown in individuals at increased genetic risk for late-onset sporadic AD.

Evidence of association between sleep quality and APOE ε4 in healthy older adults: A pilot study.

BACKGROUND: It has been estimated that the prevalence of Alzheimer disease (AD) and related dementias will triple by 2035, unless effective interventions or treatments are found for the neurodegenerative disease. Understanding sleep changes as a marker for both AD risk and progression is a burgeoning area of investigation. Specifically, there is emerging evidence that both sleep disturbances and the APOE ε4 allele are associated with increased dementia risk. Previous research has suggested that in AD, individuals carrying the APOE ε4 allele have decreased sleep quality compared to individuals without the APOE ε4 allele. This observational trial aimed to determine if healthy older adults with the risk allele (APOE ε4+) have more sleep complaints or evidence of objective sleep disruption compared to healthy older adults without the risk allele (APOE ε4-). METHODS: Within the larger Brain in Motion study, a subset of participants completed at-home polysomnography (PSG) and actigraphy sleep assessment. Subjective sleep complaints were determined using the Pittsburgh Sleep Quality Index. RESULTS: This investigation found a significant relationship between presence of APOE ε4 allele and objective sleep disturbances measured by both actigraphy and PSG, but not subjective sleep complaints in a healthy population screened for dementia. CONCLUSIONS: These data suggest that the influence of APOE ε4 allele on objective sleep quality may precede subjective sleep complaints in individuals at increased risk for dementia.

Staging Sleep in Polysomnograms: Analysis of Inter-Scorer Variability.

STUDY OBJECTIVES: To determine the reasons for inter-scorer variability in sleep staging of polysomnograms (PSGs). METHODS: Fifty-six PSGs were scored (5-stage sleep scoring) by 2 experienced technologists, (first manual, M1). Months later, the technologists edited their own scoring (second manual, M2) based upon feedback from the investigators that highlighted differences between their scoring. The PSGs were then scored with an automatic system (Auto) and the technologists edited them, epoch-by-epoch (Edited-Auto). This resulted in 6 different manual scores for each PSG. Epochs were classified as scorer errors (one M1 score differed from the other 5 scores), scorer bias (all 3 scores of each technologist were similar, but differed from the other technologist) and equivocal (sleep scoring was inconsistent within and between technologists). RESULTS: Percent agreement after M1 was 78.9% ± 9.0% and was unchanged after M2 (78.1% ± 9.7%) despite numerous edits (≈40/PSG) by the scorers. Agreement in Edited-Auto was higher (86.5% ± 6.4%, p < 1E-9). Scorer errors (< 2% of epochs) and scorer bias (3.5% ± 2.3% of epochs) together accounted for < 20% of M1 disagreements. A large number of epochs (92 ± 44/PSG) with scoring agreement in M1 were subsequently changed in M2 and/or Edited-Auto. Equivocal epochs, which showed scoring inconsistency, accounted for 28% ± 12% of all epochs, and up to 76% of all epochs in individual patients. Disagreements were largely between awake/NREM, N1/N2, and N2/N3 sleep. CONCLUSION: Inter-scorer variability is largely due to epochs that are difficult to classify. Availability of digitally identified events (e.g., spindles) or calculated variables (e.g., depth of sleep, delta wave duration) during scoring may greatly reduce scoring variability.