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

呼吸暂停和局部睡眠：临床前阿尔茨海默病的机制和干预

• 批准号: 9348885
• 负责人: RUTH M BENCA
• 金额: $ 74.76万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-30 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9348885
• 关键词: Accounting; Adult; Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid; Amyloid deposition; Apnea; Area; Biological; Brain; Brain Injuries; Brain imaging; Brain region; Breathing; Chronic; Clinical; Clinical Data; Cohort Studies; Collection; Data; Development; Diagnosis; Disease; Disease Progression; Early treatment; Electroencephalography; Enrollment; Epidemic; Family; Funding; Goals; Health; Hypoxemia; Hypoxia; Image; Individual; Intervention; Laboratories; Link; Measures; Mediating; Mediation; Medicine; Memory; Memory Loss; Memory impairment; Monitor; Nerve Degeneration; Observational Study; Obstructive Sleep Apnea; Participant; Pathology; Patients; Pattern; Phase; Pilot Projects; Play; Positron-Emission Tomography; Pragmatic clinical trial; Prevalence; Prevention strategy; Preventive measure; Recording of previous events; Recruitment Activity; Research; Resources; Rest; Risk; Risk Factors; Role; Sleep; Sleep Apnea Syndromes; Sleep Deprivation; Sleep Fragmentations; Sleep disturbances; Specimen; Staging; Symptoms; TNFRSF5 gene; Testing; Time; Wisconsin; Work; base; brain health; cingulate cortex; cohort; compliance behavior; density; design; effective therapy; experience; falls; high risk; imaging biomarker; improved; in vivo; indexing; insight; middle age; neurogranin; neuropathology; neuropsychiatric disorder; novel; outcome forecast; pre-clinical; pre-clinical research; pressure; prevent; prospective; relating to nervous system; screening; tau Proteins; treatment strategy

 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.

 描述（由申请人提供）：阿尔茨海默病 (AD) 已达到流行程度，在缺乏有效治疗的情况下，需要采取策略，越来越多的证据表明睡眠在调节淀粉样蛋白沉积（AD 病理学的标志）方面发挥着重要作用。睡眠障碍和阻塞性睡眠呼吸暂停 (OSA) 是一种以睡眠期间呼吸频繁暂停为特征并导致低氧血症和睡眠碎片化的疾病，在 AD 中非常普遍，并且与 AD 病理进展相关。我们的团队和其他人已经证明，睡眠中断与临床前 AD 中淀粉样蛋白沉积的增加有关。我们的团队率先使用高密度脑电图（hdEEG，256 个通道）来证明整个大脑的睡眠并不均匀，而是受到局部调节。与清醒时的可塑性变化有关；大脑的不同部分在不同的时间“入睡”，因此某些大脑区域可能会经历局部睡眠的慢性缺陷。此外，我们的研究小组已经证明这种现象发生在各种情况中。重要的是，我们最近发现 OSA 与后扣带区睡眠大脑活动的局部缺陷有关，该区域正是 AD 中淀粉样蛋白沉积高峰的区域，这表明 OSA 加剧 AD 病理的机制。我们的总体研究目标是确定可在中年改变的 AD 风险因素和机制，以预防或延缓 AD 进展，本研究的 3 个具体目标是确定 2 年以上的时间 (1)。 OSA 与淀粉样蛋白沉积和神经损伤的关系；(2) OSA 治疗是否会减缓 AD 病理学和记忆丧失的进展；(3) 扣带皮层局部睡眠缺陷对 AD 病理学和记忆丧失的影响。将阐明 OSA 的哪些方面（呼吸暂停/呼吸不足指数、低氧血症或睡眠碎片）导致 AD 病理学，并测试 OSA 相关的局部睡眠剥夺介导 AD 进展的新假设。该研究将增加综合成像、睡眠和活动。记录包括 hdEEG 和淀粉样蛋白 PET 收集，以及已经在威斯康星州阿尔茨海默氏病研究中心注册的参与者中收集的大量数据，其中包括一组有 AD 风险的无症状中年受试者（50-65 岁），基于拟议的研究提供了一个前所未有的机会来评估 OSA、睡眠特征和治疗对 AD 风险增加的参与者群体的明确特征和治疗结果。大规模实用临床试验，旨在测试 OSA 筛查和治疗对于预防高危个体 AD 病理进展的价值。