Slow-wave sleep enhancement in those at risk for Alzheimer's disease: Links with memory, excitotoxicity, and plasma A-beta

慢波睡眠可增强阿尔茨海默病风险人群：与记忆、兴奋性毒性和血浆 A-β 的联系

• 批准号: 10207060
• 负责人: Kristine Ann Wilckens
• 金额: $ 72.04万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10207060
• 关键词: Address; Adult; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease risk; Amyloid beta-Protein; Apolipoprotein E; Beds; Behavior Therapy; Behavioral; Biological; Biological Assay; Cognition; Cognitive; Dementia; Disease; Education; Elderly; Exhibits; Functional Magnetic Resonance Imaging; Functional disorder; Glutamate Receptor; Gold; Health behavior; Hippocampus (Brain); Home; Impaired cognition; Intervention; Link; Mass Spectrum Analysis; Measures; Mediating; Memory; Nerve Degeneration; Neurons; Nonpharmacologic Therapy; Pathway interactions; Pharmacology; Pittsburgh Compound-B; Plasma; Play; Positron-Emission Tomography; Process; Proteins; Race; Research; Retirement; Role; Sleep; Sleep Apnea Syndromes; Sleeplessness; Slow-Wave Sleep; Synapses; Therapeutic Intervention; Time; abeta accumulation; abeta deposition; behavioral study; cognitive change; cognitive function; cognitive performance; cognitive testing; cost; excitotoxicity; executive function; human old age (65+); improved; indexing; intervention effect; memory retention; neuroimaging; neuroimaging marker; neurotoxic; non rapid eye movement; normal aging; pre-clinical; preservation; sex; sleep behavior; sleep difficulty; uptake

Dementia caused by Alzheimer’s disease affects approximately 5.6M adults over age 65, with costs expected to rise from $307B to $1.5T over the next 30 years. Behavioral interventions have shown promise for mitigating neurodegeneration and cognitive impairments. Sleep is a modifiable health behavior that is critical for cognition and deteriorates with advancing age and Alzheimer’s disease. Thus, it is a priority to examine whether improving sleep modifies Alzheimer’s disease pathophysiology and cognitive function. Our research suggests that deeper, more consolidated sleep is positively associated with memory and executive functions and networks that underlie these processes. Our preliminary studies confirm that time-in-bed restriction interventions increase sleep efficiency and non-rapid eye movement slow-wave activity (SWA) and suggest that increases in SWA are associated with improved cognitive function. SWA reflects synaptic downscaling predominantly among prefrontal connections. Downscaling of prefrontal connections with the hippocampus during sleep may help to preserve the long-range connections that support memory and cognitive function. In pre-clinical Alzheimer’s disease, hyperactivation of the hippocampus is thought to be excitotoxic and is shown to leave neurons vulnerable to further Aβ deposition. Synaptic downscaling through SWA may mitigate the progression of Alzheimer’s disease through these pathways. The proposed study will behaviorally increase sleep depth (SWA) through four weeks of time-in-bed restriction in older adults characterized on Aβ deposition and multiple factors associated with Alzheimer’s disease risk. We will examine whether behaviorally enhanced SWA reduces hippocampal hyperactivation, leading to improved task-related prefrontal-hippocampal connectivity, plasma Aβ levels, and cognitive function. This research addresses whether a simple, feasible, and scalable behavioral sleep intervention improves functional neuroimaging indices of excitotoxicity, Alzheimer’s pathophysiology, and cognitive performance.

阿尔茨海默氏病引起的痴呆症影响约560万年龄段65岁以上，预计成本 在未来30年内，从307B上涨到$ 1.5T。行为干预措施显示了减轻的希望 神经变性和认知障碍。睡眠是一种可修改的健康行为，对认知至关重要 并确定年龄和阿尔茨海默氏病。这是优先检查是否优先考虑 改善睡眠修饰剂阿尔茨海默氏病的病理生理学和认知功能。我们的研究表明 更深，更整合的睡眠与记忆和执行功能和行政功能正相关， 这些过程的基础的网络。我们的初步研究证实了时间限制的限制 干预措施提高了睡眠效率和非比式眼动慢波活动（SWA），并建议 SWA的增加与改善的认知功能有关。 SWA反映合成的降尺度 主要在额叶连接之间。与海马的前额叶连接的缩小 在睡眠期间，可能有助于保留支持记忆和认知功能的远程连接。在 临床前阿尔茨海默氏病，海马过度激活被认为是兴奋的，显示出 使神经元容易受到进一步的Aβ沉积。通过SWA进行突触降尺度可能会减轻 阿尔茨海默氏病的进展通过这些途径。拟议的研究将在行为上增加 在Aβ沉积中的老年人中，到四个星期的床床限制，睡眠深度（SWA） 以及与阿尔茨海默氏病风险相关的多种因素。我们将检查行为是否增强 SWA减少了海马过度活化，从而改善了与任务相关的前额叶海马 连通性，血浆Aβ水平和认知功能。这项研究解决了一个简单，可行的， 可扩展的行为睡眠干预改善了兴奋性毒性的功能性神经影像学指标， 阿尔茨海默氏症的病理生理学和认知表现。