Circadian Multiscale Activity Regulation and the Risk for Delirium in Elderly Hospitalized Patients

昼夜节律多尺度活动调节和老年住院患者谵妄的风险

基本信息

批准号：
10027773
负责人：
Lei Gao
金额：
$ 13.4万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10027773
关键词：
Accounting Address Adherence Affect Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease related dementia Animal Model Biological Markers C-reactive protein Cessation of life Chronic Circadian Dysregulation Circadian Rhythms Cognition Complex Critical Illness Data Databases Delirium Development Disease Elderly Etiology Fractals Functional disorder Future Genetic Genetic Predisposition to Disease Goals Health Hospital Records Hospitalization Hour Impaired cognition Inflammation Inflammatory Insulin-Like Growth Factor I Knowledge Lead Life Life Expectancy Link Measurement Measures Methods Morbidity - disease rate Neurodegenerative Disorders Nonlinear Dynamics Operative Surgical Procedures Pathway interactions Patient Self-Report Patients Physiological Property Randomized Regulation Rest Risk Risk Factors Role Sampling Serum Sleep Sleep Deprivation Sleep Fragmentations Sleep Wake Cycle Sleep disturbances Slow-Wave Sleep Testing Visit actigraphy aged biobank causal variant circadian cohort disability effective intervention genetic approach genetic variant genome wide association study genomic locus healthy aging human model indexing insight middle age modifiable risk mortality neuroinflammation normal aging novel older patient postoperative delirium recruit sleep health sleep quality sleep regulation trait wearable device

项目摘要

PROJECT SUMMARY/ABSTRACT Developing effective interventions for delirium in the elderly urgently requires a better understanding of modifiable risk factors and underlying mechanisms in earlier life. There is evidence that alterations in the ~24- hour sleep/wake cycle, known as circadian rhythms, coincide with the development of delirium. Disturbances in circadian rhythm and sleep are more common in the elderly, in neurodegenerative diseases such as Alzheimer’s dementia, and become more pronounced after critical illness. Inflammatory changes have been shown after circadian/sleep disruption, while conditions associated with delirium often involve high inflammatory states. This project hypothesizes that earlier life circadian/sleep regulation predicts incident delirium after hospitalization, and that systemic inflammatory burden underlies this link. We propose the analysis of rest/activity data collected from wearable technology (actigraphy watches), repeated serum high-sensitivity (hs-CRP) and insulin-like growth factor-1 (IGF-1) measurements and genetic data in middle/elderly age subjects from the UK Biobank, a unique database of ~500,000 subjects aged between 40-69 years who were recruited between 2006 and 2010, and agreed to have their health followed. Normalized 24h amplitude, acrophase of daily activity rhythm, inter-daily stability (IS), intra-daily variability (IV) and fractal scaling property (α) will be derived from actigraphy as measures for circadian multiscale activity regulation (CMAR), as well as quantitative sleep measures (sleep fragmentation index, sleep efficiency and total sleep duration), in ~96,600 subjects from the UK Biobank. In those who become hospitalized/undergo surgery, we will test whether CMAR/sleep measures independently predict incident delirium, and how they augment the effects of cognition and aging on delirium risk (Aim 1). Relationships between CMAR/sleep measures, systemic inflammation and delirium will be studied by examining the associations between baseline and change in hs-CRP and IGF-1 over two visits, and later risk for delirium, as well as the associations between CMAR/sleep measures and baseline inflammation and (Aim 2). Mendelian randomization (MR) will be used to test whether recently discovered genetic variants of circadian/sleep disturbances and established genetic variants of the CRP gene are causally related to delirium. Genetic variants associated with delirium will be explored using a Genome-wide association study (GWAS) (Exploratory Aim 3). Taken together, the proposed three aims may provide modifiable, objective measures of delirium risk, expand on our knowledge of delirium pathophysiology, and lead to novel genetic insights into how circadian/sleep regulation and inflammation influence future delirium vulnerability.

项目概要/摘要制定针对老年人谵妄的有效干预措施迫切需要更好地了解早期生活中可改变的风险因素和潜在机制有证据表明〜24-的改变。小时睡眠/觉醒周期，称为昼夜节律，与谵妄的发展相一致。昼夜节律和睡眠在老年人以及阿尔茨海默病等神经退行性疾病中更为常见痴呆，并在危重病后表现出炎症改变。昼夜节律/睡眠中断，而与谵妄相关的病症通常涉及高炎症状态。项目发现早期的昼夜节律/睡眠调节可以预测住院后发生的谵妄事件，以及我们建议对从其中收集的休息/活动数据进行分析。可穿戴技术（体动记录手表）、重复血清高敏度 (hs-CRP) 和胰岛素样生长来自英国生物银行的中老年受试者的因子 1 (IGF-1) 测量和遗传数据，这是一个独特的 2006 年至 2010 年间招募的约 500,000 名年龄在 40-69 岁之间的受试者的数据库，以及同意跟踪他们的健康状况，包括标准化的 24 小时振幅、每日活动节律的顶峰期、日间活动。稳定性（IS）、日内变异性（IV）和分形标度特性（α）将从体动记录仪中导出作为衡量标准用于昼夜节律多尺度活动调节 (CMAR) 以及定量睡眠测量（睡眠碎片化）指数、睡眠效率和总睡眠时间），来自英国生物银行的约 96,600 名受试者。住院/接受手术，我们将测试 CMAR/睡眠测量是否独立预测事件谵妄，以及它们如何增强认知和衰老对谵妄风险的影响（目标 1）。将通过检查 CMAR/睡眠测量、全身炎症和谵妄之间的关系来研究两次就诊期间基线与 hs-CRP 和 IGF-1 变化之间的关联，以及随后发生谵妄的风险，如以及 CMAR/睡眠测量与基线炎症之间的关联（目标 2）。随机化（MR）将用于测试最近发现的昼夜节律/睡眠遗传变异是否存在 CRP 基因的紊乱和已确定的遗传变异与谵妄有因果关系。将使用全基因组关联研究 (GWAS) 来探索与谵妄的相关性（探索性目标 3）。综上所述，拟议的三个目标可以提供可修改的、客观的谵妄风险衡量标准，扩大基于我们对谵妄病理生理学的了解，并对昼夜节律/睡眠如何产生新的遗传学见解调节和炎症会影响未来的谵妄脆弱性。