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

 描述(申请人提供)：阿尔茨海默病(AD)正在达到流行的程度，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方面发挥着重要作用，淀粉样蛋白沉积是AD病理的一个标志。睡眠障碍和阻塞性睡眠呼吸暂停(OSA)是一种以睡眠中频繁的呼吸暂停为特征的疾病，导致低氧血症和睡眠碎片，在AD中非常普遍，并与AD的病理进展有关。我们小组和其他人的工作表明，睡眠障碍与临床前阿尔茨海默病患者淀粉样蛋白沉积增加有关。我们小组率先使用高密度脑电(hdEEG，256个通道)来证明睡眠在整个大脑中并不是统一的，而是局部调节的，与清醒过程中的可塑性变化有关；大脑的不同部分在不同的时间入睡，从而使某些大脑区域可能在局部睡眠中经历慢性缺陷。此外，我们的团队已经证明，这种现象发生在各种神经精神障碍中。重要的是，我们最近发现OSA与后扣带区睡眠脑活动的局部缺陷有关，该区域恰好是AD中淀粉样蛋白沉积峰值的同一区域，这表明OSA加重AD病理的机制。我们的主要研究目标是确定AD风险因素和机制，这些因素和机制可以在中年进行修改，以防止或延缓进展为AD。睡眠就是这样一个靶子。这项研究的三个具体目标是在两年的时间里确定(1)OSA与淀粉样蛋白沉积和神经损伤的关系；(2)OSA治疗是否减缓AD病理和记忆丧失的进展；以及(3)扣带皮质局部睡眠缺陷对AD病理和记忆丧失的影响。这项拟议的研究将阐明OSA的哪些方面-呼吸暂停/低通气指数、低氧血症或睡眠碎片-与AD病理有关，并测试与OSA相关的局部睡眠剥夺介导AD进展的新假说。这项研究将在威斯康星州阿尔茨海默病研究中心登记的参与者中已经收集的大量数据中增加全面的成像、睡眠和活动记录，包括hdEEG和淀粉样蛋白-PET收集，包括一组基于父母家族史的无症状的中年AD风险受试者(50-65岁)。这项拟议的研究提供了一个前所未有的机会来评估阻塞性睡眠呼吸暂停、睡眠特征和治疗对具有良好特征的、纵向跟踪的AD风险增加的参与者组的影响。研究结果还将为大规模实用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，以防止高危个体的AD病理进展。

 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.