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

7.项目摘要 淀粉样β肽的脑沉积是阿尔茨海默病（AD）发展的关键机制。实验模型表明，睡眠-觉醒周期可能调节淀粉样蛋白β水平，这表明睡眠质量差可能影响淀粉样蛋白β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，它变得更加分散，深度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R 01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。在我们目前资助的前4年里，我们在实现这些目标方面取得了很大进展。到目前为止，我们已经招募了192名健康老年人参加了一项为期2年的纵向研究，包括家庭睡眠监测，脑MRI和基线和随访时进行的腰椎穿刺（LP）。此外，我们还获得了一组具有可用PiB-PET扫描的受试者的家庭睡眠测量结果，以及一个具有可用CSF的子集的实验室内NPSG记录。我们发现：a）慢波睡眠（SWS）持续时间较短和慢波活动（SWA）较低，与横断面脑脊液（CSF）Aβ42水平较高相关; B）在无过度日间嗜睡、心血管事件史或认知障碍的情况下，OSA患病率较高;以及，c）OSA严重程度与CSF Aβ42纵向降低和PiB-PET SUVR摄取增加相关。这种变化可能与大脑淀粉样蛋白负荷的纵向增加一致，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，我们将通过增加新的随访（基线和24个月）来扩展我们之前的工作，其中包括一组保留在队列中的正常睡眠呼吸控制和轻度至中度OSA受试者（计划n=112，包括脱落率）。所有受试者将在两次访视中接受结构性3 T MRI、2晚NPSG和淀粉样蛋白18 F-florbetaben（FBB）PET-MR扫描。本研究的目的是：1）检查与年龄相关的SWS损失对淀粉样蛋白沉积纵向变化的直接贡献; 2）检查轻度至中度OSA对淀粉样蛋白沉积的纵向影响。这种新的建议可以确定：i）睡眠障碍和淀粉样蛋白负荷的纵向增加之间的关系; ii）SWS的增强和OSA的治疗作为AD预防的新的治疗靶点。

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.