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

睡眠老化和阿尔茨海默病风险-Resubmission-1

• 批准号: 9918202
• 负责人: Ricardo S Osorio
• 金额: $ 11.53万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-02 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9918202
• 关键词: Address; Affect; Age; Aging; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Amyloid; Amyloid beta-Protein; Amyloid deposition; Apnea; Atrophic; Benign; Blood Vessels; Body Weight Changes; Brain; Breathing; Carbon Dioxide; Cardiovascular system; Cerebrospinal Fluid; Cerebrum; Characteristics; Cognition; Cognitive; Collection; Development; Elderly; Enrollment; Evaluation; Event; Excessive Daytime Sleepiness; Experimental Models; Funding; Goals; High Prevalence; Home environment; Impaired cognition; Individual; Intervention; Lead; Lesion; Link; Longevity; Longitudinal Studies; MRI Scans; Magnetic Resonance Imaging; Measurement; Measures; Medial; Memory; Monitor; Morbidity - disease rate; Nature; Nerve Degeneration; Neuropsychological Tests; Obstructive Sleep Apnea; Outcome; Participant; Polysomnography; Positron-Emission Tomography; Prevalence; Prevention strategy; Preventive therapy; Recording of previous events; Risk Factors; Scanning; Severities; Sleep; Sleep Deprivation; Sleep Disorders; Sleep Stages; Sleep Wake Cycle; Sleep disturbances; Slow-Wave Sleep; Spinal Puncture; Structure; Study models; Testing; Therapeutic; Time; Visit; Work; abeta deposition; age related; cerebrovascular; cohort; dementia risk; follow-up; individual variation; insight; middle age; modifiable risk; new therapeutic target; novel; research clinical testing; sleep quality; uptake; way finding; white matter; white matter damage

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.

7.项目摘要 脑内淀粉样β肽沉积是阿尔茨海默病发生发展的关键机制 （AD）。实验模型显示，睡眠-觉醒周期可能调节淀粉样蛋白β水平，这表明， 睡眠质量差可能影响β淀粉样蛋白沉积的病理生理机制。睡眠变化 在整个生命周期中都是如此。随着年龄的增长，它变得更加分散，数量减少， 睡眠呼吸暂停综合征（OSA）是一种常见的睡眠呼吸暂停综合征。的目标 我们资助的R 01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。前4 我们目前的资金多年来，我们在实现这些目标方面取得了出色的进展。到目前为止我们已经 在一项为期2年的纵向研究中，招募了192名健康老年人，该研究包括家庭睡眠监测、脑MRI 并在基线和随访时进行腰椎穿刺（LP）。此外，我们获得了家庭睡眠 在一组具有可用PiB-PET扫描以及实验室内NPSG记录的受试者中进行测量， 具有可用CSF的子集。我们发现：a）较低的慢波睡眠（SWS）持续时间和较低的慢波活动 (SWA)与横截面处高脑脊液（CSF）Aβ42水平相关; B）OSA的高患病率 无日间过度嗜睡、心血管事件史或认知障碍;以及， c）与CSF Aβ42的纵向降低和PiB-PET SUVR摄取的增加相关的OSA的严重程度。 这种变化可能与脑淀粉样蛋白负荷的纵向增加一致，表明 睡眠中断，在我们的队列中很常见，有助于健康老年人的淀粉样蛋白沉积。在这 竞争性续约，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， 正常睡眠呼吸控制组和轻度至中度OSA受试者保留在队列中（计划 n=112，包括损耗率）。所有受试者将接受结构性3 T MRI、2晚NPSG和淀粉样蛋白检查 两次访视时进行18F-氟倍他本（FBB）PET-MR扫描。本研究的目的是：（1）研究直接 年龄相关的SWS损失对淀粉样蛋白沉积纵向变化的贡献; 2）检查 轻度至中度OSA对淀粉样蛋白沉积的纵向影响。这一新颖的建议可以确定： 睡眠障碍与淀粉样蛋白负荷纵向增加之间的关系; ii）SWS增强 和治疗OSA作为预防AD的新的治疗靶点。