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

• 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
• 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' s Disease; Alzheimer' 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

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.

项目摘要/摘要 在古老的急切中制定有效的干预措施，需要更好地理解 早期生活中的可修改风险因素和基本机制。有证据表明〜24-的变化 小时睡眠/唤醒周期，称为昼夜节律，与del妄的发展相吻合。干扰 在神经退行性疾病（例如阿尔茨海默氏症）中，昼夜节律的节奏和睡眠更常见 痴呆症，在危重疾病后变得更加明显。炎症发生了变化 昼夜节律/睡眠中断，而与ir妄有关的疾病通常涉及高炎症状态。这 项目假设较早的生命昼夜节律/睡眠调节预测住院后发生了del妄的事件， 这种系统性的炎症烧伤奠定了这一联系。我们提出了从 可穿戴技术（行动手表），重复的血清高敏性（HS-CRP）和类似胰岛素的生长 来自英国生物库中的中/老年年龄受试者的因子1（IGF-1）的测量和遗传数据，这是一个独特的 在2006年至2010年之间招募的40-69岁之间的约500,000名受试者的数据库， 同意遵循他们的健康。标准化的24小时振幅，每日活动节奏的杂音，每日 稳定性（IS），每日内变异性（IV）和分形缩放特性（α）将源自行动学作为测量值 昼夜节律活动调节（CMAR）以及定量睡眠测量（睡眠碎片） 索引，睡眠效率和总睡眠持续时间），来自英国生物库的约9600名受试者。在那些成为的人 住院/接受手术，我们将测试CMAR/睡眠措施是否独立预测事件 del妄，以及它们如何增加认知和衰老对ir妄风险的影响（AIM 1）。关系 在CMAR/睡眠测量值之间，全身性炎症和del妄将研究通过检查 两次访问中HS-CRP和IGF-1的基线与变化之间的关联，后来犯了ir妄的风险， 以及CMAR/睡眠测量结果与基线注入和（AIM 2）之间的关联。门德利安 随机化（MR）将用于测试最近发现的昼夜节律/睡眠的遗传变异 CRP基因的干扰和已建立的遗传变异有时与del妄有关。遗传变异 将使用全基因组关联研究（GWAS）探索与del妄相关的（探索目标3）。 综上所述，拟议的三个目标可能会提供可修改的，客观的ir妄风险，扩大 关于我们对del妄的病理生理学的了解，并导致对昼夜节律/睡眠的新遗传见解 监管和影响未来的ir妄脆弱性。