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

项目摘要/摘要 开发有效的老年人妄想干预措施迫切需要更好地理解 早期生活中可改变的风险因素和潜在机制。有证据表明，~24区的变化- 一个小时的睡眠/清醒周期，即昼夜节律，与精神错乱的发展相吻合。骚乱发生在 昼夜节律和睡眠在老年人中更常见，在阿尔茨海默氏症等神经退行性疾病中更常见 痴呆症，并在危重疾病后变得更加明显。术后出现炎性改变 昼夜节律/睡眠紊乱，而与精神错乱相关的情况通常涉及高度炎症状态。这 该项目假设早年的昼夜节律/睡眠调节可以预测住院后出现的精神错乱，并且 这种系统性的炎症负担构成了这种联系的基础。我们建议分析从以下位置收集的休息/活动数据 可穿戴技术(动作记录表)、重复血清高敏感性(hs-CRP)和胰岛素样生长 来自英国生物库的中老年受试者的IGF-1测量和遗传数据 2006年至2010年招募的约500,000名年龄在40岁至69岁之间的受试者的数据库，以及 同意让他们的健康受到关注。归一化的24小时波幅，每日活动节律的顶相，每日间歇 稳定性(IS)、日内变异性(IV)和分形标度特性(α)将从活动图中获得作为度量 用于昼夜多尺度活动调节(CMAR)以及定量睡眠测量(睡眠碎片 指数、睡眠效率和总睡眠时间)，来自英国生物库的约96,600名受试者。在那些成为 住院/接受手术，我们将测试CMAR/睡眠指标是否独立预测事件 精神错乱，以及它们如何增强认知和衰老对精神错乱风险的影响(目标1)。两性关系 在CMAR/睡眠措施之间，全身炎症和精神错乱将通过检查 基线与两次就诊后hs-CRP和IGF-1的变化以及后来出现精神错乱的风险之间的关系，AS 以及CMAR/睡眠措施与基线炎症和(目标2)之间的联系。孟德尔式 随机化(MR)将被用来测试最近发现的昼夜节律/睡眠的遗传变异 CRP基因的紊乱和已建立的遗传变异与精神错乱有因果关系。遗传变异 将使用全基因组关联研究(GWAS)(探索性目标3)来探索与精神错乱有关的问题。 综上所述，拟议的三个目标可以提供可修改的、客观的精神错乱风险的衡量标准，扩大 基于我们对精神错乱病理生理学的知识，并导致对昼夜节律/睡眠如何的新的遗传学见解 调控和炎症会影响未来的精神错乱易感性。

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.