Sleep Aging and Risk for Alzheimer's disease-Resubmission-1

7.项目总结 脑内淀粉样β蛋白沉积是阿尔茨海默病(AD)发生发展的关键机制之一。实验模型表明，睡眠-觉醒周期可能调节淀粉样β蛋白水平，这表明睡眠质量差可能会影响淀粉样β蛋白沉积的病理生理机制。睡眠在人的一生中会发生巨大的变化。随着年龄的增长，它变得更加支离破碎，深部阶段的数量和质量下降，阻塞性睡眠呼吸暂停(OSA)的患病率增加。我们资助的R01的目标是测试睡眠质量和OSA的严重程度如何导致淀粉样蛋白沉积。在我们目前资金的头4年里，我们在实现这些目标方面取得了很好的进展。到目前为止，我们已经招募了192名健康的老年人参加了一项为期两年的纵向研究，包括家庭睡眠监测、脑MRI和在基线和随访时进行的腰椎穿刺术(LP)。此外，我们获得了一组受试者的家庭睡眠测量数据，这些受试者使用了可用的PIB-PET扫描，以及实验室内使用可用的脑脊液的NPSG记录。我们发现：a)较低的慢波睡眠时间和较低的慢波活动与横断面脑脊液Aβ42水平升高相关；b)无日间过度嗜睡、心血管事件史或认知损害的阻塞性睡眠呼吸暂停的高患病率；以及c)阻塞性睡眠呼吸暂停的严重程度与脑脊液Aβ42纵向降低和PIB-PET SUVR摄取增加有关。这些变化可能与大脑淀粉样蛋白负荷的纵向增加一致，这表明睡眠中断，在我们的队列中非常常见，有助于健康老年人的淀粉样蛋白沉积。在这次竞争性更新中，我们将通过为队列中保留的一组正常睡眠呼吸控制和轻中度OSA受试者(计划n=112，包括自然减少率)增加新的随访(基线和24个月)来扩展我们之前的工作。在两次访问中，所有受试者都将接受结构性3T磁共振、两晚NPSG和淀粉样蛋白18F-氟倍他滨(FBB)PET-MR扫描。这项研究的目标是：1)研究年龄相关的SWS缺失对淀粉样蛋白沉积纵向变化的直接贡献；以及2)检测轻中度阻塞性睡眠呼吸暂停综合征对淀粉样蛋白沉积的纵向影响。这一新的建议可能确定：i)睡眠障碍与淀粉样蛋白负荷纵向增加之间的关系；ii)增强SWS和治疗OSA作为预防AD的新的治疗靶点。

7. PROJECT SUMMARY Cerebral deposition of amyloid-beta peptides is a key mechanism in the development of Alzheimer's disease (AD). Experimental models show that the sleep-wake cycle may regulate amyloid-beta levels, suggesting that poor sleep quality may affect the pathophysiological mechanisms of amyloid-beta deposition. Sleep changes dramatically throughout the lifespan. With age, it becomes more fragmented, declines in the quantity and quality of deep stages and there is an increase in the prevalence of obstructive sleep apnea (OSA). The goals of our funded R01 are to test how sleep quality and severity of OSA lead to amyloid deposition. In the first 4 years of our current funding we have made excellent progress in addressing these goals. So far, we have enrolled 192 healthy elderly in a 2-year longitudinal study that includes home sleep-monitoring, brain MRIs and a lumbar puncture (LP) done at baseline and follow-up. In addition, we obtained home sleep measurements in a group of subjects with available PiB-PET scans as well as in-lab NPSG recordings in a subset with available CSF. We found: a) lower slow wave sleep (SWS) duration and lower slow wave activity (SWA) associated with high cerebrospinal fluid (CSF) Aβ42 levels at cross-section; b) a high prevalence of OSA in the absence of excessive daytime sleepiness, history of cardiovascular events or cognitive impairment; and, c) severity of OSA associated with longitudinal decreases in CSF Aβ42 and increases in PiB-PET SUVR uptake. Such changes are potentially consistent with longitudinal increases in brain amyloid burden, suggesting that disrupted sleep, very common in our cohort, contributes to amyloid deposition in healthy elderly. In this competitive renewal, we will extend our prior work by adding new follow-ups (baseline and 24 months) to a group of normal sleep breathing controls and mild-to-moderate OSA subjects retained in the cohort (planned n=112 including attrition rates). All subjects will receive a structural 3T MRI, 2 nights of NPSGs and an amyloid 18F-florbetaben (FBB) PET-MR scan in both visits. The goals of this study are: 1) to examine the direct contribution of age-related SWS loss on longitudinal changes in amyloid deposition; and, 2) to examine the longitudinal effects of mild-to-moderate OSA on amyloid deposition. This novel proposal may identify: i) a relationship between sleep disturbances and longitudinal increase in amyloid burden; ii) enhancement of SWS and treatment of OSA as novel therapeutic targets for AD prevention.