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

睡眠和昼夜节律紊乱，包括睡眠呼吸暂停、睡眠片段化和昼夜节律不规则， 影响数百万美国人，并与认知受损和阿尔茨海默病（AD）有关。 在门诊环境中应用标准技术（例如多导睡眠图）量化睡眠的挑战 和昼夜节律中断在大量的社区居住的老年人，并在获得详细的 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了数百万美国老年人，但很少有数据表明， 他们的不同形式的贡献越来越多的老年人有认知障碍， 痴呆症和相关的大脑机制。本研究旨在填补这些空白。这个项目的总体目标是 这项研究旨在量化睡眠和昼夜节律的贡献，并确定联系睡眠和昼夜节律的大脑机制 节律紊乱导致老年人认知能力下降和AD事件。在引人注目的初步工作中，我们 开发并应用了一种在社区环境中测量睡眠片段的新方法， 体动记录仪，使用类似手表的设备对运动进行无创连续测量。在老年人中， 我们发现，较高的睡眠碎片与1）更大的AD发病风险，2）更多的大脑 尸检时小动脉硬化和皮质下卒中，3）APOE e4中AD病理学负荷较高 载波然而，睡眠碎片化只是睡眠中断的一种类型，其影响不能被忽视。 如果不同时检查常见的睡眠障碍如睡眠呼吸暂停的影响， 这可能会影响多达一半的老年人。为了扩展这些发现，我们建议使用便携式电池2 测量连续外周动脉张力测定、血氧测定和体动记录的可穿戴设备， 在Rush Memory中同时量化780名老年人的5种关键形式的睡眠和昼夜节律紊乱 和老化项目（R01AG17911）。这些将包括1）睡眠呼吸暂停，2）睡眠持续时间，3）睡眠结构， 4)睡眠片段化和5）昼夜节律不规则。这些测量结果将与捐赠的 认知和其他临床数据，以及死后组织病理学和死者的脑MRI指数， 为了阐明社区居住成年人睡眠和昼夜节律紊乱的大脑相关性， 对认知障碍和AD痴呆事件的影响。通过克服关键的翻译障碍，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中的重要空白， 老年人的昼夜节律紊乱这提供了利用睡眠和昼夜节律干预的潜力， 减少认知障碍和AD日益增长的负担，并用于靶向治疗，以改善大脑 数百万经历睡眠或昼夜节律功能障碍的美国人的健康。

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.