Relationships between local and global mechanisms of sleep apnea, Alzheimer's disease biomarkers, and memory impairment in cognitively asymptomatic older adults

项目摘要/摘要 流行病学证据已证实阻塞性睡眠呼吸暂停(OSA)是阿尔茨海默病的危险因素 (Ad)。然而，AD风险增加的机制仍不清楚。三个可能与AD相关的临床病例 OSA的特征包括严重的低氧血症、整体睡眠片断和与记忆相关的局部缺陷 睡眠振荡，即慢波和睡眠纺锤波。阻塞性睡眠呼吸暂停综合征的这些临床特征是独立的 与淀粉样蛋白和tau的负荷和堆积、内侧颞叶(MTL)变性和MTL- 依赖性记忆障碍--AD的所有标志性生物标记物。然而，目前还不清楚这些因素是如何 这些特征与阻塞性睡眠呼吸暂停综合征患者的AD病理生理学或MTL依赖性记忆减退有关。最重要的是 这项提议的研究目标就是解决这些未知数。拟议的具体目标是确定 不同的全局和局部OSA特征是否与1)皮质淀粉样蛋白负荷，2)MTL tau负荷， 以及3)支持多种形式的记忆的特定MTL大脑回路的退化 睡眠不足，易受AD病理生理影响。拟议的目标将通过利用现有的 资源，并收集高密度脑电(hdEEG，256个通道)睡眠记录 认知正常的老年人(60-85岁)接受正电子发射断层扫描(PET)评估淀粉样蛋白 和tau负荷，以及MTL结构的超高分辨率磁共振成像(uhr-MRI)。这个 因此，拟议的研究将利用一个机会来研究阻塞性睡眠呼吸暂停综合征与AD病理的关系 负担、MTL结构和功能，以及前所未有的细节和广度的内存。这是 符合我的短期和长期职业目标。具体地说，我计划生成研究建议 寻求资金以揭示不同形式的睡眠障碍对电路和分子机制的影响 人类阿尔茨海默病发病机制的研究。这将支持我建立临床研究计划的努力，评估i) 睡眠障碍在各种形式的神经退行性疾病发生和发展中的作用 跨临床阶段，ii)以睡眠为基础的生物标记物预测痴呆发病和帮助区分的效用 痴呆症之间的诊断，以及iii)以睡眠为基础的有针对性的干预措施对阻止认知衰退的效用 与阿尔茨海默病和相关痴呆有关。这项研究建议和我的长期职业目标都得到了支持 由我的指导团队监督我的培训计划，该团队包括hdEEG、uhr-mri、MTL依赖方面的专家 记忆回路功能，老化和AD背景下的PET方法-包括淀粉样蛋白和tau PET，临床 睡眠障碍、老年精神病学和神经退行性疾病的方面，以及临床试验设计和 在睡眠障碍和阿尔茨海默病的背景下实施。拟议的培训计划包括结构化的 指导这些主题中的每一个，并参加临床研究证书计划和课程 专注于AD的临床试验。通过建立这个研究项目，我希望开发基于睡眠的方法 以降低风险，延迟发病，减缓痴呆症的进展和年龄相关的认知能力下降。

Project Summary/Abstract Epidemiologic evidence has established obstructive sleep apnea (OSA) as a risk factor for Alzheimer’s disease (AD). However, the mechanisms of this increase in AD risk remain unclear. Three potentially AD-relevant clinical features of OSA include severity of hypoxemia, global sleep fragmentation, and local deficits in memory-relevant sleep oscillations, i.e. slow waves and sleep spindles. These clinical features of OSA have been independently linked to amyloid and tau burden and accumulation, medial temporal lobe (MTL) degeneration, and MTL- dependent memory impairment—all hallmark biomarkers of AD. However, it remains unclear how each of these features relate to AD pathophysiology or MTL-dependent memory decline in patients with OSA. The overarching research objective of this proposal is to address these unknowns. The proposed specific aims are to determine whether distinct global and local OSA features are associated with 1) cortical amyloid burden, 2) MTL tau burden, and 3) degeneration of specific MTL brain circuits supporting multiple forms of memory known to depend on sleep and be vulnerable to AD pathophysiology. The proposed aims will be supported by leveraging existing resources, and collecting high density electroencephalography (hdEEG, 256 channels) sleep recordings in cognitively normal older adults (60-85 years) undergoing positron emission tomography (PET) to assess amyloid and tau burden, as well as ultrahigh resolution magnetic resonance imaging (uhr-MRI) of MTL structure. The proposed study will therefore capitalize on an opportunity to examine how OSA relates to AD pathological burden, MTL structure and function, and memory in an unprecedented level of detail and breadth. This is congruent with both my short and long-term career goals. Specifically, I plan to generate research proposals seeking funding to uncover the impact of distinct forms of sleep disturbance on circuit and molecular mechanisms of AD pathogenesis in humans. This will support my efforts to establish a clinical research program evaluating i) the contribution of sleep disturbance to the onset and progression of various forms of neurodegenerative disease across clinical stages, ii) the utility of sleep-based biomarkers to predict dementia onset and aid differential diagnosis between dementias, and iii) the utility of targeted sleep-based interventions to arrest cognitive decline associated with AD and related dementias. This research proposal and my long-term career goals are supported by my training plan overseen by my mentoring team which includes experts in hdEEG, uhr-MRI, MTL-dependent memory circuit function, PET methods in the context of aging and AD—including amyloid and tau PET, clinical aspects of sleep disorders, geriatric psychiatry, and neurodegenerative disease, and clinical trial design and implementation in the context of sleep disorders and AD. The proposed training plan includes structured mentoring on each of these topics and participation in a clinical research certificate program, as well as a course focused on clinical trials in AD. By establishing this research program, I hope to develop sleep-based approaches to reduce risk, delay onset, and slow progression of dementia and age-related cognitive decline.