Selective Continuous Positive Airway Pressure Withdrawal With Supplemental Oxygen During Slow-Wave Sleep as a Method of Dissociating Sleep Fragmentation and Intermittent Hypoxemia-Related Sleep Disruption in Obstructive Sleep Apnea.

Anna E Mullins,Daphne I Valencia,Jason Z Bronstein,Omar E Burschtin,Thomas M Tolbert,Korey Kam,Bresne Castillo,Andrew W Varga,Anne M Mooney,Indu Ayappa,Reagan Schoenholz,Ankit Parekh,David M Rapoport,Zachary J Roberts,Ahmad Fakhoury

doi:10.3389/fphys.2021.750516

Abstract

Obstructive sleep apnea (OSA) is considered to impair memory processing and increase the expression of amyloid-β (Aβ) and risk for Alzheimer’s disease (AD). Given the evidence that slow-wave sleep (SWS) is important in both memory and Aβ metabolism, a better understanding of the mechanisms by which OSA impacts memory and risk for AD can stem from evaluating the role of disruption of SWS specifically and, when such disruption occurs through OSA, from evaluating the individual contributions of sleep fragmentation (SF) and intermittent hypoxemia (IH). In this study, we used continuous positive airway pressure (CPAP) withdrawal to recapitulate SWS-specific OSA during polysomnography (PSG), creating conditions of both SF and IH in SWS only. During separate PSGs, we created the conditions of SWS fragmentation but used oxygen to attenuate IH. We studied 24 patients (average age of 55 years, 29% female) with moderate-to-severe OSA [Apnea-Hypopnea Index (AHI); AHI4% > 20/h], who were treated and adherent to CPAP. Participants spent three separate nights in the laboratory under three conditions as follows: (1) consolidated sleep with CPAP held at therapeutic pressure (CPAP); (2) CPAP withdrawn exclusively in SWS (OSASWS) breathing room air; and (3) CPAP withdrawn exclusively in SWS with the addition of oxygen during pressure withdrawal (OSASWS + O2). Multiple measures of SF (e.g., arousal index) and IH (e.g., hypoxic burden), during SWS, were compared according to condition. Arousal index in SWS during CPAP withdrawal was significantly greater compared to CPAP but not significantly different with and without oxygen (CPAP = 1.1/h, OSASWS + O2 = 10.7/h, OSASWS = 10.6/h). However, hypoxic burden during SWS was significantly reduced with oxygen compared to without oxygen [OSASWS + O2 = 23 (%min)/h, OSASWS = 37 (%min)/h]. No significant OSA was observed in non-rapid eye movement (REM) stage 1 (NREM 1), non-REM stage 2 (NREM 2), or REM sleep (e.g., non-SWS) in any condition. The SWS-specific CPAP withdrawal induces OSA with SF and IH. The addition of oxygen during CPAP withdrawal results in SF with significantly less severe hypoxemia during the induced respiratory events in SWS. This model of SWS-specific CPAP withdrawal disrupts SWS with a physiologically relevant stimulus and facilitates the differentiation of SF and IH in OSA.

Highlights

In obstructive sleep apnea (OSA), the cardinal polysomnographic (PSG) features following partial or complete closure of the airway are sleep fragmentation (SF) and intermittent hypoxemia (IH)
26 subjects with moderate-to-severe OSA (AHI4% ≥ 20), who were compliant with therapeutic continuous positive airway pressure (CPAP) (≥ 4 h/night for ≥ 70% of nights in the last month), were recruited as part of two studies as follows: first, a pilot study investigating the effect of slow-wave sleep (SWS) disruption on overnight spatial navigational memory processing, and a subsequent, ongoing study investigating the effects of this SWS intervention on overnight memory and Alzheimer’s disease (AD) fluid biomarkers
The PSG macrostructure variables were within the ageexpected range in all three PSG conditions. %SWS was significantly reduced during both CPAP withdrawal conditions [OSASWS = 13.8 (10.0)%, OSASWS + O2 = 13.1 (5.6)] compared to CPAP [16.2 (5.9)%]

Summary

Introduction

In obstructive sleep apnea (OSA), the cardinal polysomnographic (PSG) features following partial or complete closure of the airway are sleep fragmentation (SF) and intermittent hypoxemia (IH). There is a theorized bidirectional relationship between sleep disruption and neurodegeneration (Ju et al, 2014; Musiek et al, 2015; Andrade et al, 2018) with the magnitude of sleep changes in aging, electroencephalographic (EEG) slow-wave activity (SWA) by which SWS is defined, being associated with the degree of hippocampal-dependent memory impairments (Westerberg et al, 2012; Mander et al, 2013; Varga A.W. et al, 2016), and the severity of dementia risk assessed by Aβ (Mander et al, 2015; Varga A. et al, 2016). While the stage-specific sleep disruption has been achieved with auditory tones (Tasali et al, 2008; Van Der Werf et al, 2011), comparing the disruption of sleep from OSA while attenuating hypoxemia may represent a more physiological method of testing the withinsubject consequences of SWS disruption

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