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发生的关键机制 (Ad)。实验模型显示，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。睡眠变化 戏剧性地贯穿了整个生命周期。随着年龄的增长，它变得更加碎片化，数量减少， 深度阶段的质量和阻塞性睡眠呼吸暂停(OSA)的患病率增加。的目标 我们资助的R01是为了测试睡眠质量和OSA的严重程度如何导致淀粉样蛋白沉积。在前4个月 多年来，在我们目前的资金支持下，我们在实现这些目标方面取得了巨大进展。到目前为止，我们已经 在一项为期两年的纵向研究中，招募了192名健康的老年人，其中包括家庭睡眠监测、大脑核磁共振 在基线和随访时进行腰椎穿刺术(LP)。此外，我们还可以在家里睡觉。 在一组受试者中使用可用的PIB-PET扫描以及实验室中的NPSG记录进行测量 具有可用的CSF的子集。我们发现：a)慢波睡眠(SWS)持续时间和慢波活动减少 (B)阻塞性睡眠呼吸暂停低通气综合征的高患病率；b)与高脑脊液相关的β42水平 在没有白天过度嗜睡、心血管事件史或认知障碍的情况下； 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-PETSUVR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相一致，这表明 睡眠障碍，在我们的队列中非常常见，导致健康老年人的淀粉样蛋白沉积。在这 竞争续订，我们将通过将新的后续工作(基线和24个月)添加到 队列中保留的正常睡眠呼吸控制组和轻中度OSA受试者(计划 N=112(包括流失率)。所有受试者将接受结构性3T核磁共振，2晚NPSG和淀粉样蛋白 两次检查均行18F-氟倍他滨(FBB)PET-MR扫描。本研究的目的是：1)直接考察 年龄相关的SWS丢失对淀粉样蛋白沉积的纵向变化的贡献；以及，2)检查 轻至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。这一新颖的提议可以确定：i) 睡眠障碍与淀粉样蛋白负荷纵向增加的关系：II)SWS增强 阻塞性睡眠呼吸暂停综合征的治疗是预防AD的新靶点。

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.