Epigenetics Biomarker of Post Operative Delirium and Long Term Cognitive Decline among Elderly Dementia Patients

PROJECT SUMMARY/ABSTRACT Delirium exposes patients to a greater risk of developing Alzheimer’s disease and dementia, and patients with Alzheimer’s disease and dementia are more likely to develop delirium. Delirium among elderly patients is dangerous and common, yet it is underdiagnosed and undertreated. Especially common in patients with

Alzheimer’s disease, delirium is a strong predictor of poor outcomes including post-operative cognitive decline (POCD) and mortality. The key to reducing the burden associated with delirium is early identification of those at

high risk for it, especially prior to surgery, which is known to be a major risk factor for delirium. However, currently, there are no reliable tools available to predict the risk of post-operative delirium (POD). Also, there is no clear understanding of the pathophysiological mechanism of delirium. The long-term goal of this project is to

investigate the role of epigenetics to better understand the molecular mechanism of pathogenesis of POD and to identify potential biomarkers associated with POD and POCD. We will test for a specific type of epigenetic modification, DNA methylation (DNAm), which is known to be induced by environmental factors. Previous

searches for biomarkers of delirium in humans led to the proposal that inflammation and pro-inflammatory cytokines play a key role in the pathophysiology of delirium. Yet, how the aging process enhances cytokine release remains unclear. Aging is known to have a strong effect on gene expression, and such changes in gene

expression are tightly controlled by DNAm. Thus, it is suspected that DNAm changes over the course of aging, leading to enhanced cytokine release due to altered control of gene expression, and that such DNAm modification contributes to delirium. This project will be the first to investigate the role of epigenetics associated

with POD in humans, and the objective of the project is to identify potential biomarkers for elevated risk of POD and subsequent patient outcomes related to delirium such as POCD and dementia. The proposed research will accomplish its objective by following a large sample of elderly patients going through hip fracture surgery

throughout their hospital stay, comparing differences in genome-wide DNAm between those who develop POD and those who do not. Lastly, the project will test if DNAm is predictive of patient outcomes including survival and long-term memory problem after surgery. This research will enhance our understanding of the epigenetic

mechanisms in the pathogenesis of delirium and its interplay with the progression of dementia, and may identify biomarkers predictive of their risk. The identification of epigenetic markers of delirium would hopefully lead to improvement in medical and surgical practice.