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

随着人口老龄化，认知障碍的患病率和发病率出现了惊人的增长 损害和阿尔茨海默病(AD)相关痴呆(ADRD)：到2050年，美国的人口数量。 与ADRD相关的费用将增加两倍，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组合似乎会随着年龄的增长增加ADRD的风险。 神经元突起的相关变化导致淀粉样β蛋白(A？)和tau的进行性积累。而当 越来越多的人认识到，睡眠障碍和昼夜节律紊乱可能会加速A？的积累 和认知能力下降，关于特定睡眠的因果作用和非因果作用，文献没有定论。 并且没有解决夜间高血压(一个可改变的目标)是否调节与睡眠相关的问题 认知结果。我们将在许多睡眠测量中利用显著的个体间可变性，以及 随着时间的推移，个人内部的重大变化，以开发更好地处理问题的纵向框架 因果关系。我们建议利用2010-2013年进行的全面睡眠表型分析(MESA- 睡眠；检查5)，以及正在进行的和新提出的数据将在台地精神研究中收集，其中 包括对MESA参与者样本的最先进的认知、神经精神病学和脑成像研究 在相隔2.5年的两个时间点(2019-2023年)进行研究，以有效和独特地解决关键研究差距。 虽然MESA Mind研究解决了中老年血管疾病作为ADRD风险因素的作用， 它没有解决睡眠和昼夜节律紊乱的潜在贡献或中介作用。因此，我们 建议有效地扩大MESA心智研究第二次考试(2021-2023)，将过夜状况包括在内- 艺术多导睡眠监测，7天动态监测，并首次在梅萨，24小时血压记录， 目标是招募2000名参加该考试的人中的1800人。我们将产生高级量化 睡眠和昼夜节律的指标来表征临界衰老期间睡眠障碍的演变 句号。这些测量将被合并到认知的纵向评估中，以便定义 睡眠障碍和认知障碍之间的时间联系，从而定义了哪种睡眠 干扰和测量是认知障碍的先行因素。我们将评估是否有睡眠 在大脑成像前8年进行测量，以及睡眠变化的轨迹，可以预测神经退化， 重复脑MRI和PET成像检测脑血管疾病和AD脑生物标志物 (作为梅萨思维研究的一部分进行)。我们还将评估血压变异性和 夜间高血压作为联系睡眠障碍和认知/AD易感性的中介途径。我们 将探索不同种族/民族的男性和女性以及个人之间的联系差异 背景。这项研究有很大的潜在影响，因为睡眠障碍和夜间高血压 可修改的目标。这项研究还将提供适合性别的风险分层方法。

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.