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

无认知症状老年人睡眠呼吸暂停、阿尔茨海默病生物标志物和记忆障碍的局部和整体机制之间的关系

• 批准号: 10224774
• 负责人: BRYCE A. MANDER
• 金额: $ 12.73万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10224774
• 关键词: Acoustic Stimulation; Address; Age; Age-associated memory impairment; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Amyloid; Amyloid beta-Protein; Apnea; Atrophic; Biological Markers; Brain; Breathing; Clinical; Clinical Research; Clinical Trials; Clinical Trials Design; Cognitive; Dementia; Development; Differential Diagnosis; Disease Progression; Elderly; Electroencephalography; Epidemiology; Episodic memory; Functional disorder; Funding; Future; Geriatric Psychiatry; Goals; Hippocampus (Brain); Human; Hypoxemia; Impaired cognition; Intervention; Intervention Studies; Knowledge; Link; Magnetic Resonance Imaging; Magnetism; Measures; Medial; Memory; Memory Loss; Memory impairment; Mentors; Methodology; Methods; Molecular; Monitor; Motor Skills; Nerve Degeneration; Neurodegenerative Disorders; Obstructive Sleep Apnea; Onset of illness; Parietal; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Pattern; Perforant Pathway; Pharmacology; Physiological; Play; Population; Positron-Emission Tomography; Postdoctoral Fellow; Prevalence; Preventive treatment; Process; Research; Research Activity; Research Personnel; Research Proposals; Research Training; Resolution; Resources; Risk; Role; Severities; Sleep; Sleep Apnea Syndromes; Sleep Deprivation; Sleep Disorders; Sleep Fragmentations; Sleep disturbances; Slow-Wave Sleep; Structure; Temporal Lobe; Training; Treatment Efficacy; Work; age related; base; career; certificate program; clinically relevant; density; entorhinal cortex; epidemiology study; indexing; memory consolidation; memory encoding; neuroimaging; novel; pre-clinical; pressure; procedural memory; programs; sleep spindle; standard of care; symptomatology; tau Proteins; β-amyloid burden

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.

项目概要/摘要 流行病学证据已确定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。 OSA 的特征包括严重的低氧血症、整体睡眠碎片化以及记忆相关的局部缺陷 睡眠振荡，即慢波和睡眠纺锤波，OSA 的这些临床特征是独立的。 与淀粉样蛋白和 tau 蛋白负荷和积累、内侧颞叶 (MTL) 变性以及 MTL- 依赖性记忆障碍——所有 AD 的标志性生物标志物。然而，目前尚不清楚其中每一个是如何发生的。 与 AD 病理生理学或 OSA 患者的 MTL 依赖性记忆衰退相关的特征。 本提案的研究目标是解决这些未知问题，并确定所提出的具体目标。 不同的整体和局部 OSA 特征是否与 1) 皮质淀粉样蛋白负荷、2) MTL tau 负荷相关， 3）特定 MTL 脑回路的退化，支持已知依赖的多种形式的记忆 睡眠和易受 AD 病理生理学影响将通过利用现有的支持来支持拟议的目标。 资源，并收集高密度脑电图（hdEEG，256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) 以评估淀粉样蛋白 和 tau 负载，以及 MTL 结构的超高分辨率磁共振成像 (uhr-MRI)。 因此，拟议的研究将利用这个机会来研究 OSA 与 AD 病理学之间的关系。 负担、MTL 结构和功能以及记忆的细节和广度达到了前所未有的程度。 具体来说，我计划提出与我的短期和长期职业目标一致的研究提案。 寻求资金来揭示不同形式的睡眠障碍对回路和分子机制的影响 这将支持我建立评估 i) 的临床研究计划的努力。 睡眠障碍对各种形式的神经退行性疾病的发生和进展的影响 跨临床阶段，ii) 基于睡眠的生物标志物在预测痴呆症发作和帮助鉴别方面的效用 痴呆症之间的诊断，以及 iii) 有针对性的基于睡眠的干预措施在阻止认知能力下降方面的效用 与 AD 和相关痴呆症相关的这项研究提案和我的长期职业目标得到了支持。 由我的指导团队监督的培训计划，其中包括 hdEEG、uhr-MRI、MTL 依赖方面的专家 记忆回路功能、衰老和 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方面以及临床试验设计和 拟议的培训计划包括结构化的培训计划。 对每个主题进行指导并参与临床研究证书计划以及课程 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。 降低痴呆症和与年龄相关的认知能力下降的风险、延迟发病和减缓进展。