Sleep, Circadian Rhythms, and Mechanisms of Cognitive Decline in the Human Brain

睡眠、昼夜节律和人脑认知能力下降的机制

• 批准号: 9235661
• 负责人: Andrew Lim
• 金额: $ 58.11万
• 依托单位: SUNNYBROOK RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-15 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9235661
• 关键词: Address; Adult; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease risk; American; Amyloid; Animal Model; Animals; Astrocytosis; Atherosclerosis; Autopsy; Brain; Brain Pathology; Cerebral Amyloid Angiopathy; Cerebrovascular Disorders; Cerebrum; Cessation of life; Circadian Rhythms; Clinical Data; Clinical Trials; Cognition; Cognitive; Communities; Data; Data Collection; Dementia; Devices; Elderly; Functional disorder; Genotype; Goals; Health; Histopathology; Human; Impaired cognition; Impairment; Individual; Infarction; Intervention; Joints; Knowledge; Lead; Left; Link; Magnetic Resonance Imaging; Measurement; Measures; Mediating; Memory; Methods; Modification; Movement; Myelin; Nerve Degeneration; Neurodegenerative Disorders; Observational Study; Oxygen saturation measurement; Pallor; Pathology; Patient Self-Report; Peripheral; Polysomnography; Proteins; Public Health; Relaxation; Reporting; Risk; Risk Factors; Severities; Sleep; Sleep Apnea Syndromes; Sleep Architecture; Sleep Disorders; Sleep Fragmentations; Stroke; Techniques; Testing; White Matter Hyperintensity; Work; actigraphy; apolipoprotein E-4; arterial tonometry; brain arteriolosclerosis; brain health; brain tissue; cognitive function; cognitive testing; community setting; experience; gray matter; high risk; hippocampal sclerosis; improved; indexing; novel; portability; prevent; programs; protein TDP-43; screening; secondary analysis; synuclein; targeted treatment; tau Proteins; therapy development; wearable technology; white matter

Sleep and circadian disruption, including sleep apnea, sleep fragmentation, and circadian rhythm irregularity, affect millions of Americans, and are associated with impaired cognition and Alzheimer’s disease (AD). Challenges in applying standard techniques (e.g. polysomnography) in ambulatory settings to quantify sleep and circadian disruption in large numbers of community-dwelling older adults, and in obtaining detailed cognitive assessments and brain tissue from the same individuals, have left knowledge gaps. Thus, although sleep and circadian rhythm disruption affect millions of older Americans, there are few data concerning the contribution of their different forms to the growing number of older adults with cognitive impairment and dementia, and associated brain mechanisms. This study aims to fill these gaps. The overall goal of this study is to quantify the contributions of, and identify brain mechanisms linking, sleep and circadian rhythm disruption to cognitive decline and incident AD in older adults. In compelling preliminary work, we developed and applied a new method of measuring sleep fragmentation in the community setting using actigraphy, the non-invasive continuous measurement of movement using a watch-like device. In older adults, we found that higher sleep fragmentation is associated with 1) a greater risk of incident AD, 2) more brain arteriolosclerosis and subcortical strokes at autopsy, and 3) a higher burden of AD pathology in APOE e4 carriers. However, sleep fragmentation is only one type of sleep disruption, and its impact cannot be understood without simultaneously examining the impact of common sleep disorders such as sleep apnea, which may affect up to half of older adults. To extend these findings, we propose to use a portable battery of 2 wearable devices measuring continuous peripheral arterial tonometry, oximetry, and actigraphy to simultaneously quantify 5 key forms of sleep and circadian disruption in 780 older adults in the Rush Memory and Aging Project (R01AG17911). These will include 1) sleep apnea, 2) sleep duration, 3) sleep architecture, 4) sleep fragmentation, and 5) circadian irregularity. These measurements will be combined with donated cognitive and other clinical data, as well as post-mortem histopathology and brain MRI indices from decedents, to elucidate the brain correlates of sleep and circadian disruption in community-dwelling adults, and their impact on cognitive impairment and incident AD dementia. By overcoming key translational barriers, this study will fill important gaps in our knowledge concerning the burden and brain correlates of 5 key forms of sleep and circadian disruption in old age. This offers the potential to leverage sleep and circadian interventions to decrease the growing burden of cognitive impairment and AD, and for targeted therapies to improve brain health for the millions of Americans who experience sleep or circadian rhythm dysfunction.

睡眠和昼夜节律紊乱，包括睡眠呼吸暂停、睡眠碎片化和昼夜节律不规律， 影响数百万美国人，并与认知受损和阿尔茨海默病 (AD) 相关。 在动态环境中应用标准技术（例如多导睡眠图）来量化睡眠的挑战 和大量社区居住老年人的昼夜节律紊乱，以及获取详细的 来自同一个人的认知评估和脑组织留下了知识空白。因此，虽然 睡眠和昼夜节律紊乱影响着数百万美国老年人，但关于这些问题的数据很少 其不同形式对越来越多患有认知障碍的老年人的贡献 痴呆症和相关的大脑机制。本研究旨在填补这些空白。本次活动的总体目标 研究的目的是量化睡眠和昼夜节律的贡献并确定连接睡眠和昼夜节律的大脑机制 节律紊乱会导致老年人认知能力下降和 AD 事件。在引人注目的前期工作中，我们 开发并应用了一种在社区环境中测量睡眠碎片的新方法 体动记录仪，使用类似手表的设备对运动进行非侵入性连续测量。在老年人中， 我们发现，较高的睡眠碎片化与 1) 发生 AD 的风险较高，2) 更多的大脑活动有关。 尸检时发现动脉硬化和皮质下中风，3) APOE e4 中 AD 病理负担较高 载体。然而，睡眠碎片化只是睡眠中断的一种类型，其影响尚不能确定。 在不同时检查睡眠呼吸暂停等常见睡眠障碍的影响的情况下理解， 这可能会影响多达一半的老年人。为了扩展这些发现，我们建议使用 2 的便携式电池 可穿戴设备测量连续外周动脉张力测定、血氧测定和体动记录仪 在 Rush Memory 中同时量化 780 名老年人的 5 种关键睡眠形式和昼夜节律紊乱 和老化项目（R01AG17911）。这些包括 1) 睡眠呼吸暂停，2) 睡眠持续时间，3) 睡眠结构， 4) 睡眠碎片化，以及 5) 昼夜节律不规律。这些测量结果将与捐赠的 死者的认知和其他临床数据，以及死后组织病理学和脑部 MRI 指数， 阐明社区居住成年人的睡眠和昼夜节律紊乱的大脑相关性及其 对认知障碍和 AD 痴呆症的影响。通过克服关键的转化障碍，本研究 将填补我们关于 5 种关键睡眠形式的负担和大脑相关性的知识空白 老年时昼夜节律紊乱。这提供了利用睡眠和昼夜节律干预的潜力 减轻认知障碍和 AD 日益增加的负担，并进行靶向治疗以改善大脑 数百万患有睡眠或昼夜节律功能障碍的美国人的健康。