Apnea and local sleep: Mechanism and intervention in preclinical Alzheimer's

 描述（由申请人提供）：阿尔茨海默病（AD）正在达到流行病的比例，在缺乏有效治疗的情况下，需要预防策略。越来越多的证据表明，睡眠在调节淀粉样蛋白沉积中起着重要作用，淀粉样蛋白沉积是AD病理学的标志。睡眠障碍和阻塞性睡眠呼吸暂停（OSA）（一种特征为睡眠期间呼吸频繁暂停并导致低氧血症和睡眠片段化的疾病）在AD中非常普遍，并与AD病理学进展相关。我们小组和其他人的工作表明，睡眠中断与临床前AD中淀粉样蛋白沉积增加有关。我们的团队率先使用高密度脑电图（hdEEG，256通道）来证明睡眠在整个大脑中并不均匀，而是局部调节并与清醒期间的可塑性变化有关;大脑的不同部分在不同时间“入睡”，因此某些大脑区域可能会在局部睡眠中经历慢性缺陷。此外，我们的研究小组已经证明，这种现象发生在各种神经精神疾病中。重要的是，我们最近发现OSA与后扣带回区域睡眠脑活动的局部缺陷相关，该区域恰好是AD中淀粉样蛋白沉积峰值发生的区域，这表明OSA加剧AD病理的机制。我们的总体研究目标是确定AD风险因素和机制，可以在中年进行修改，以防止或延迟进展为AD。睡眠提供了这样一个目标。本研究的3个具体目的是在2年时间内确定（1）OSA与淀粉样蛋白沉积和神经损伤的相关性;（2）OSA治疗是否降低AD病理学和记忆丧失的进展;以及（3）扣带皮层中局部睡眠缺陷对AD病理学和记忆丧失的影响。这项研究将阐明OSA的哪些方面--呼吸暂停/低通气指数、低氧血症或睡眠片段--对AD病理学有贡献，并检验OSA相关的局部睡眠剥夺介导AD进展的新假设。这项研究将在威斯康星州阿尔茨海默病研究中心招募的参与者中收集的大量数据中添加全面的成像、睡眠和活动记录，包括hdEEG和淀粉样蛋白-PET收集，该研究包括一组基于父母家族史有AD风险的无症状中年受试者（50-65岁）。拟议的研究提供了一个前所未有的机会，以评估OSA，睡眠特征和治疗的影响，在一个良好的特征和纵向跟踪组的参与者在增加风险的AD。结果还将为大规模实用的临床试验提供有价值的初步数据，以测试OSA筛查和治疗的价值，以防止高危人群中AD病理学的进展。

 DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is reaching epidemic proportions, and in the absence of effective treatments, prevention strategies are needed. Accumulating evidence suggests that sleep plays an important role in regulating amyloid deposition, a hallmark of AD pathology. Both sleep disturbance and obstructive sleep apnea (OSA), a disorder characterized by frequent pauses in breathing during sleep and leading to hypoxemia and sleep fragmentation, are highly prevalent in AD and are associated with progression of AD pathology. Work from our group and others has shown that sleep disruption is associated with increased amyloid deposition in preclinical AD. Our group has pioneered the use of high density EEG (hdEEG, 256 channels) to demonstrate that sleep is not uniform throughout the brain, but is locally regulated and related to plastic changes during waking; different parts of the brain "fall asleep" at different times, such that certain brain regions may experience chronic deficits in local sleep. Further, this phenomenon has been shown by our group to occur in a variety of neuropsychiatric disorders. Importantly, we have recently shown that OSA is associated with a local deficit in sleeping brain activity in the posterior cingulate region, in precisely the same area where peak amyloid deposition occurs in AD, suggesting a mechanism by which OSA exacerbates AD pathology. Our overarching research objective is to identify AD risk factors and mechanisms that can be modified in midlife to prevent or delay progression to AD. Sleep provides such a target. The 3 Specific Aims of this study are to determine over a 2 year period (1) the association of OSA with amyloid deposition and neural damage; (2) whether OSA treatment decreases progression of AD pathology and memory loss; and (3) the effect of local sleep deficits in the cingulate cortex on AD pathology and memory loss. The proposed study will clarify which aspects of OSA-apnea/hypopnea index, hypoxemia or sleep fragmentation-contribute to AD pathology and tests the novel hypothesis that OSA-related local sleep deprivation mediates AD progression. This study will add comprehensive imaging, sleep and activity recordings including hdEEG and amyloid-PET collection to the extensive battery of data already being collected in participants enrolled in the Wisconsin Alzheimer's Disease Research Center, comprising a cohort of asymptomatic, middle-aged subjects (50-65 yrs) at risk for AD based on parental family history. The proposed study provides an unprecedented opportunity to assess the effects of OSA, sleep features, and treatment in a well characterized and longitudinally followed group of participants at increased risk for AD. Results will also provide valuable preliminary data for a large-scale pragmatic clinical trial to test the value of OSA screening and treatment to prevent progression of AD pathology in at-risk individuals.