Longitudinal Relationships Among Sleep, Cognition and Alzheimer's Disease Biomarkers: Discerning Causal Associations, Mediators and Susceptibility

随着人口老龄化，认知功能障碍的患病率和发病率惊人地增加， 损伤和阿尔茨海默病（AD）相关痴呆（ADRD）：到2050年，美国 ADRD将增加两倍，达到1380万，相关的医疗保健费用每年将超过1.1万亿美元。 遗传、生活方式和环境因素的结合似乎会增加ADRD的风险， 导致淀粉样蛋白-β（A β）和tau蛋白进行性积累的神经元过程的相关变化。而 越来越多的人认识到，睡眠紊乱和昼夜节律紊乱可能会加速羊水的积累， 和认知能力下降，关于特定睡眠的因果与非因果作用，文献尚无定论。 并且尚未解决夜间高血压（一个可修改的目标）是否介导睡眠相关的 认知结果。我们将利用许多睡眠测量中显著的个体间差异，以及 随着时间的推移，个体内部发生重大变化，以制定一个纵向框架，更好地解决问题 因果关系。我们建议利用2010-2013年进行的综合睡眠表型分析（梅萨- 睡眠;考试5），沿着正在进行的和新提出的数据收集在梅萨MIND研究， 包括对梅萨参与者样本的最先进的认知、神经精神和脑成像研究 在两个时间点间隔2.5年（2019-2023年）进行研究，以有效和独特地解决关键的研究差距。 虽然梅萨MIND研究解决了中年和晚年血管疾病作为ADRD风险因素的作用， 它没有涉及睡眠和昼夜节律紊乱的潜在促成或介导作用。因此我们 建议有效地扩大梅萨MIND研究第二次考试（2021-2023），以包括过夜状态， 艺术多导睡眠描记术，7天活动描记术，以及梅萨首次24小时血压记录， 我们的目标是从2000名参加者中招募1800名参加该考试。我们将产生高级定量 睡眠和昼夜节律的指标，以表征睡眠障碍在临界衰老过程中的演变 时期这些测量将被纳入认知的纵向评估，以确定 睡眠障碍和认知障碍之间的时间关联，从而确定哪些睡眠 干扰和度量是认知损害的先行因素。我们将评估睡眠是否 在大脑成像前8年测量，以及睡眠变化的轨迹，预测神经退行性疾病， 通过重复脑MRI和PET成像测量的脑血管疾病和AD脑生物标志物 （作为梅萨MIND研究的一部分进行）。我们还将评估血压变异性的作用， 夜间高血压是连接睡眠障碍和认知/AD易感性的介导途径。我们 将探讨男性和女性以及不同种族/民族的个体之间的关联差异 背景这项研究具有很大的潜在影响，因为睡眠障碍和夜间高血压是 可修改的目标该研究还将为适合性别的风险分层方法提供信息。

As the population has aged, there has been a staggering increase in the prevalence and morbidity of cognitive impairment and Alzheimer's disease (AD) related dementias (ADRD): by 2050 the number of people in the U.S. with ADRD will triple to 13.8 million, and associated health care costs will exceed $1.1 trillion annually. Combinations of genetic, lifestyle and environmental factors appear to increase risk for ADRD through age- related changes in neuronal processes that lead to progressive accumulation of amyloid-beta (Aß) and tau. While there is growing recognition that disturbed sleep and circadian disturbances may accelerate Aß accumulation and cognitive decline, the literature is inconclusive regarding the causal vs non-causal role of specific sleep disturbances and has not addressed whether nocturnal hypertension (a modifiable target) mediates sleep-related cognitive outcomes. We will exploit the marked inter-individual variability in many sleep measures, as well as substantial intra-individual changes over time to develop a longitudinal framework to better approach questions of causality. We propose to leverage the comprehensive sleep phenotyping performed from 2010-2013 (MESA- SLEEP; Exam 5), along with ongoing and newly proposed data to be collected in the MESA MIND study, which includes state-of-the-art cognitive, neuropsychiatric, and brain imaging studies in a sample of MESA participants studied at 2 time points 2.5 years apart (2019-2023) to efficiently and uniquely address critical research gaps. While the MESA MIND study addresses the role of mid- and later-life vascular disease as a risk factor for ADRD, it does not address the potential contributory or mediating roles of sleep and circadian disorders. We therefore propose to efficiently expand the MESA MIND study second exam (2021-2023) to include overnight state-of-the- art polysomnography, 7-day actigraphy, and for the first time in MESA, 24-hour blood pressure recordings, aiming to recruit 1800 of the 2000 participants targeted for that exam. We will generate advanced quantitative metrics of sleep and circadian rhythm to characterize the evolution of sleep disturbances over critical aging periods. These measurements will be incorporated into longitudinal assessments of cognition in order to define the temporal associations between sleep disturbances and cognitive impairment, and thus define which sleep disturbances and metrics are antecedent factors for cognitive impairment. We will evaluate whether sleep measured 8 years prior to brain imaging, as well as trajectories of sleep change, predict neurodegeneration, cerebral vascular disease and AD brain biomarkers as measured by repeated brain MRI and PET imaging (performed as part of the MESA MIND Study). We also will assess the role of blood pressure variability and nocturnal hypertension as a mediating pathway linking sleep disturbance and cognition/AD susceptibility. We will explore differences in associations between men and women and individuals of different race/ethnic backgrounds. The study has large potential impact given that sleep disturbances and nocturnal hypertension are modifiable targets. The study also will inform gender-appropriate risk stratification approaches.