Mount Sinai Integrative Sleep Center, Division of Pulmonary, Critical Care, and Sleep Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Center for Brain Health, Department of Psychiatry, NYU Langone Medical Center, New York, NY 10016, USA.
Neurobiol Dis. 2020 Nov;145:105054. doi: 10.1016/j.nbd.2020.105054. Epub 2020 Aug 27.
Here we review the impact of obstructive sleep apnea (OSA) on biomarkers of Alzheimer's disease (AD) pathogenesis, neuroanatomy, cognition and neurophysiology, and present the research investigating the effects of continuous positive airway pressure (CPAP) therapy. OSA is associated with an increase in AD markers amyloid-β and tau measured in cerebrospinal fluid (CSF), by Positron Emission Tomography (PET) and in blood serum. There is some evidence suggesting CPAP therapy normalizes AD biomarkers in CSF but since mechanisms for amyloid-β and tau production/clearance in humans are not completely understood, these findings remain preliminary. Deficits in the cognitive domains of attention, vigilance, memory and executive functioning are observed in OSA patients with the magnitude of impairment appearing stronger in younger people from clinical settings than in older community samples. Cognition improves with varying degrees after CPAP use, with the greatest effect seen for attention in middle age adults with more severe OSA and sleepiness. Paradigms in which encoding and retrieval of information are separated by periods of sleep with or without OSA have been done only rarely, but perhaps offer a better chance to understand cognitive effects of OSA than isolated daytime testing. In cognitively normal individuals, changes in EEG microstructure during sleep, particularly slow oscillations and spindles, are associated with biomarkers of AD, and measures of cognition and memory. Similar changes in EEG activity are reported in AD and OSA, such as "EEG slowing" during wake and REM sleep, and a degradation of NREM EEG microstructure. There is evidence that CPAP therapy partially reverses these changes but large longitudinal studies demonstrating this are lacking. A diagnostic definition of OSA relying solely on the Apnea Hypopnea Index (AHI) does not assist in understanding the high degree of inter-individual variation in daytime impairments related to OSA or response to CPAP therapy. We conclude by discussing conceptual challenges to a clinical trial of OSA treatment for AD prevention, including inclusion criteria for age, OSA severity, and associated symptoms, the need for a potentially long trial, defining relevant primary outcomes, and which treatments to target to optimize treatment adherence.
在这里，我们回顾了阻塞性睡眠呼吸暂停（OSA）对阿尔茨海默病（AD）发病机制的生物标志物、神经解剖结构、认知和神经生理学的影响，并介绍了研究持续气道正压通气（CPAP）治疗效果的研究。OSA 与脑脊液（CSF）中淀粉样蛋白-β和 tau 的 AD 标志物的增加有关，这些标志物可以通过正电子发射断层扫描（PET）和血清测量到。有一些证据表明 CPAP 治疗可以使 CSF 中的 AD 生物标志物正常化，但由于人类中淀粉样蛋白-β和 tau 产生/清除的机制尚未完全了解，因此这些发现仍处于初步阶段。在 OSA 患者中观察到注意力、警觉、记忆和执行功能等认知领域的缺陷，在来自临床环境的年轻人中，这种损害的程度比老年社区样本更强。使用 CPAP 后，认知能力会在不同程度上得到改善，在中年有更严重 OSA 和嗜睡的成年人中，注意力的改善效果最大。在有或没有 OSA 的情况下，信息编码和检索之间通过睡眠期分离的范式仅很少进行，但也许比单独的日间测试更有机会了解 OSA 的认知影响。在认知正常的个体中，睡眠期间 EEG 微观结构的变化，特别是慢波和纺锤波，与 AD 的生物标志物以及认知和记忆的测量值有关。在 AD 和 OSA 中也报告了类似的 EEG 活动变化，例如在清醒和 REM 睡眠期间的“EEG 减慢”，以及 NREM EEG 微观结构的退化。有证据表明 CPAP 治疗可以部分逆转这些变化，但缺乏证明这一点的大型纵向研究。仅依靠呼吸暂停低通气指数（AHI）的 OSA 诊断定义并不能帮助我们理解与 OSA 相关的日间损伤或对 CPAP 治疗的反应的个体差异程度。最后，我们讨论了对 OSA 治疗 AD 预防的临床试验的概念挑战，包括年龄、OSA 严重程度和相关症状的纳入标准、需要潜在的长期试验、定义相关的主要结局，以及针对哪些治疗方法来优化治疗依从性。
