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、睡眠碎片和昼夜节律紊乱， 影响数以百万计的美国人，并与认知受损和阿尔茨海默病(AD)有关。 在非卧床环境中应用标准技术(如多导睡眠图)量化睡眠面临的挑战 以及大量居住在社区的老年人的昼夜节律紊乱，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着数百万美国老年人，但关于睡眠和昼夜节律紊乱的数据很少 他们的不同形式对越来越多的老年人认知障碍和 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之间的联系，并确定大脑机制。 老年人认知功能减退和阿尔茨海默病事件的节律紊乱。在紧迫的前期工作中，我们 开发并应用了一种新的方法来测量社区环境中的睡眠碎片 动作记录仪，使用类似手表的设备对运动进行非侵入性的连续测量。在老年人中， 我们发现，更高的睡眠碎片与1)发生AD的风险更大，2)大脑更多相关 尸检中的动脉硬化和皮质下卒中，以及3)载脂蛋白E e4的AD病理负担较高 承运人。然而，睡眠碎片只是睡眠中断的一种类型，其影响不能 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， 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个电池的便携式电池 可穿戴设备测量连续的外周动脉血压、血氧和肌动描记，以 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 和老龄化工程(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)睡眠片断，5)昼夜节律不规律。这些测量结果将与捐赠的 认知和其他临床数据，以及死者的死后组织病理学和脑MRI指标， 为了阐明居住在社区的成年人睡眠和昼夜节律紊乱的大脑相关性，以及他们的 对认知损害和阿尔茨海默病事件的影响。通过克服关键的翻译障碍，这项研究 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的重要空白 老年昼夜节律紊乱。这提供了利用睡眠和昼夜节律干预来 减轻认知障碍和阿尔茨海默病日益增长的负担，并进行有针对性的治疗以改善大脑 为数百万睡眠或昼夜节律紊乱的美国人提供健康保障。

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.