Biomarkers Associated with OSA Phenotypes

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The cyclic alternating pattern demonstrates increased sleep instability and correlates with fatigue and sleepiness in adults with upper airway resistance syndrome
Christian Guilleminault, M Cecilia Lopes, Chad C Hagen, Agostinho da Rosa
https://www.researchgate.net/public..._Adults_with_Upper_Airway_Resistance_Syndrome (PDF available)

Objective: To clarify the relationship between sleep instability and subjective complaints in patients with upper airway resistance syndrome (UARS).

Methods: Thirty subjects (15 women) with UARS and 30 age- and sex-matched controls in a prospective, single-blind, case-control study. Blinded cyclic alternating pattern (CAP) electroencephalogram analysis and scales of fatigue and sleepiness were completed.

Analysis: Mann-Whitney U tests for independent, nonparametric variables between groups and chi2 tests for nonparametric variables with defined standard values.

Results: Patients with UARS had significantly more complaints of fatigue and sleepiness, compared with controls, demonstrated on their Fatigue Severity Scale (P < 0.001) and Epworth Sleepiness Scale (P < 0.001). By design, the mean apnea-hypopnea index was normal in both groups, whereas the respiratory disturbance index was greater in patients with UARS than in those without (14.5 +/- 3.0 vs 9 +/- 5.2, respectively [P < 0.001]). CAP analysis demonstrated abnormal non-rapid eye movement sleep with abnormally increased CAP rate, electroencephalogram arousals, A2 index, and A3 index. Decreased A1 index in controls was consistent with their more normal progression of sleep. CAP rate correlated with both the Epworth Sleepiness Scale (r = 0.38, P < 0.01) and the Fatigue Severity Scale (r = 0.51, P < 0.0001), and there was a positive trend between the Fatigue Severity Scale and phase A2 index (r = 0.29, P < 0.05).

Conclusion: Compared with age- and sex-matched controls, patients with UARS have higher electroencephalogram arousal indexes and important non-rapid eye movement sleep disturbances that correlate with subjective symptoms of sleepiness and fatigue. These disturbances are identifiable with sensitive measures such as CAP analysis but not with traditional diagnostic scoring systems.

 

[nataliezzz]

Re: the Epworth Sleepiness Scale, it has been shown to measure an uninterpretable mix of objective sleepiness and fatigue (which are uncorrelated symptoms in OSA patients), so the Epworth Sleepiness Scale may just be capturing fatigue (more poorly than the Fatigue Severity Scale) here.

However, it does appear that some UARS patients can be objectively sleepy (with their objective sleepiness improved by CPAP), as this was demonstrated in the first group of UARS patients identified by Dr. Guilleminault and colleagues: A cause of excessive daytime sleepiness. The upper airway resistance syndrome (1993).

The CAP framework offers a plausible mechanism for this via interference with slow-wave/deep sleep: the UARS patients in that study had a mean of 31 arousals per hour and virtually absent slow wave sleep (mean 1.2%), with CPAP restoring both slow wave sleep (to 9.7%) and MSLT (to 13.5 minutes). The 31 arousals per hour were almost certainly embedded within a much larger burden of sub-threshold CAP activity, with IFL-triggered A2 and A3 activations collectively preventing the A1-mediated EEG synchronization that normally builds and sustains slow wave sleep.

 

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Altered K-complex morphology during sustained inspiratory airflow limitation is associated with next-day lapses in vigilance in obstructive sleep apnea
Ankit Parekh, Korey Kam, Anna E Mullins, Bresne Castillo, Asem Berkalieva, Madhu Mazumdar, Andrew W Varga, Danny J Eckert, David M Rapoport, Indu Ayappa
https://pmc.ncbi.nlm.nih.gov/articles/PMC8271137/ (PDF available)

Study objectives: Determine if changes in K-complexes associated with sustained inspiratory airflow limitation (SIFL) during N2 sleep are associated with next-day vigilance and objective sleepiness.

Methods: Data from thirty subjects with moderate-to-severe obstructive sleep apnea who completed three in-lab polysomnograms: diagnostic, on therapeutic continuous positive airway pressure (CPAP), and on suboptimal CPAP (4 cmH2O below optimal titrated CPAP level) were analyzed. Four 20-min psychomotor vigilance tests (PVT) were performed after each PSG, every 2 h. Changes in the proportion of spontaneous K-complexes and spectral characteristics surrounding K-complexes were evaluated for K-complexes associated with both delta (∆SWAK), alpha (∆αK) frequencies.

Results: Suboptimal CPAP induced SIFL (14.7 (20.9) vs 2.9 (9.2); % total sleep time, p < 0.001) with a small increase in apnea-hypopnea index (AHI3A: 6.5 (7.7) vs 1.9 (2.3); p < 0.01) versus optimal CPAP. K-complex density (num./min of stage N2) was higher on suboptimal CPAP (0.97 ± 0.7 vs 0.65±0.5, #/min, mean ± SD, p < 0.01) above and beyond the effect of age, sex, AHI3A, and duration of SIFL. A decrease in ∆SWAK with suboptimal CPAP was associated with increased PVT lapses and explained 17% of additional variance in PVT lapses. Within-night during suboptimal CPAP K-complexes appeared to alternate between promoting sleep and as arousal surrogates. Electroencephalographic changes were not associated with objective sleepiness.

Conclusions: Sustained inspiratory airflow limitation is associated with altered K-complex morphology including the increased occurrence of K-complexes with bursts of alpha as arousal surrogates. These findings suggest that sustained inspiratory flow limitation may be associated with nonvisible sleep fragmentation and contribute to increased lapses in vigilance.

Other relevant S4ME threads:

• Increased Flow Limitation During Sleep Is Associated With Increased Psychomotor Vigilance Task Lapses in...Suspected OSA, 2024, Staykov et al.
• Psychomotor Vigilance Test and Its Association With Daytime Sleepiness and Inflammation in Sleep Apnea: Clinical Implications, 2017, Li et al.

 

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Characteristics of quantitative arousal intensity and its association with cognitive function and sleepiness in sleep apnea patients
Xiang Gao, Yunhan Shi, Rongcui Sui, Shenglong Xu, Mengyu Xu, Jianhong Liao, Yanru Li, Demin Ha

https://www.sciencedirect.com/science/article/abs/pii/S138994572500317X

Study objectives: Obstructive sleep apnea (OSA) disrupts sleep, leading to cognitive impairment and sleepiness, but risk stratification remains unclear. We developed an EEG-based arousal marker to quantify sleep fragmentation and assessed its associations with neurocognitive function and daytime sleepiness.

Methods: Arousal intensity was derived from EEG signals in 1070 APPLES (Apnea Positive Pressure Long-term Efficacy Study) study participants. We analyzed its associations with PSG parameters, cognitive function (Wechsler Abbreviated Scale of Intelligence, WASI), and sleepiness (Multiple Sleep Latency Test, MSLT; Epworth Sleepiness Scale, ESS). Stepwise regression identified predictors of cognitive function. Sensitivity analysis examined arousal intensity's link to 6-month CPAP outcomes (N = 419).

Results: Among OSA individuals, the AHI ranged from 10 to 130.7/h, the average arousal index was 26.75/h and a total of 235,835 arousal events were extracted. The arousal intensity was significantly greater for hypoxia-associated and desaturation-related events compared to hypopnea-associated or spontaneous arousals (p<0.001). It correlated negatively with age, PSG measures, and cognitive function. Adjusted models showed Delta-band arousal intensity negatively predicted WASI-Full scores (β = -3.24, p = 0.019). Higher Gamma-band intensity was associated with both greater subjective sleepiness (ESS: β = 0.03, p = 0.028) and increased CPAP-induced MSLT improvement (β = 0.12, p = 0.020).

Conclusions: Arousal intensity is a novel EEG marker for cognitive impairment and sleepiness in OSA, with potential clinical utility in predicting CPAP response. This EEG-based marker could be integrated into standard sleep analysis platforms to identify OSA patients at risk of cognitive impairment, enabling early intervention.

 

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Objective, but Not Subjective, Sleepiness is Associated With Inflammation in Sleep Apnea
Yun Li, Alexandros N Vgontzas, Julio Fernandez-Mendoza, Ilia Kritikou, Maria Basta, Slobodanka Pejovic, Jordan Gaines, Edward O Bixler
https://pmc.ncbi.nlm.nih.gov/articles/PMC6251609/ (PDF available)

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 (β = -0.34, p = .01), daytime (β = -0.30, p = .02) and nighttime (β = -0.38, p < .01) IL-6 levels, and significantly decreased daytime (β = 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.

 

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Review paper on the cyclic alternating pattern:

Cyclic alternating pattern (CAP): The marker of sleep instability
Liborio Parrino, Raffaele Ferri, Oliviero Bruni, Mario G. Terzano
https://www.sciencedirect.com/science/article/abs/pii/S108707921100027X
Sci-Hub full-text link: https://sci-hub.st/10.1016/j.smrv.2011.02.003

Abstract
Cyclic alternating pattern CAP is the EEG marker of unstable sleep, a concept which is poorly appreciated among the metrics of sleep physiology. Besides, duration, depth and continuity, sleep restorative properties depend on the capacity of the brain to create periods of sustained stable sleep. This issue is not confined only to the EEG activities but reverberates upon the ongoing autonomic activity and behavioral functions, which are mutually entrained in a synchronized oscillation. CAP can be identified both in adult and children sleep and therefore represents a sensitive tool for the investigation of sleep disorders across the lifespan. The present review illustrates the story of CAP in the last 25 years, the standardized scoring criteria, the basic physiological properties and how the dimension of sleep instability has provided new insight into pathophysiology and management of sleep disorders.