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 (?) 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.
The goal of this project is to identify and quantify earlier-life risk factors for delirium in the elderly by using actigraphy data from wearable devices alongside self-report, hospital records, serum biomarkers, and genetic data from the UK Biobank of ~500,000 middle-aged to elderly subjects. We will use novel nonlinear dynamics alongside traditional methods to test how circadian/sleep regulation affects later-life delirium risk, how systemic inflammation state may contribute to this relationship, and explore causal links using recently discovered genetic variants. The results will potentially establish modifiable measures of delirium risk, expand on our knowledge of delirium pathophysiology, and lead to novel genetic insights into how circadian/sleep health and inflammation influence the development of delirium in the elderly.
