Epigenetic Hypothesis of Delirium:Candidate gane approach and genome‐wide investigation

This article aims to outline the hypothetical framework and empirical evidence in the epigenetic investigation of delirium pathophysiology. Delirium, prevalent in the elderly, remains poorly understood in terms of pathophysiology. Our research investigates how aging‐related epigenetic changes, particularly in DNA methylation, influence the pathophysiological mechanism of delirium. We initially used blood samples from Grady Trauma Project to examine the correlation between cytokine gene methylation and age, discovering a negative correlation with the TNF‐alpha gene methylation, together with an increase in RNA expression with age. Subsequent analysis of brain tissue obtained from resected brain tissue through the treatment of medication refractory epilepsy patients revealed this trend in glial components, not neurons, indicating an age‐related decrease in TNF‐alpha gene methylation in glia, facilitating increased inflammation in older brain. Further, comparisons between delirious and non‐delirious patients showed maintained methylation decline in the delirious group, indicating a potential role in delirium onset. Additionally, we found increased DNA methylation of neurotrophic factor genes such as BDNF in the elderly, implying a vulnerability to delirium due to reduced neurotrophic support. Finally, a genome‐wide approach identified differences in DNA methylation between delirious and non‐delirious groups, with significant pathways related to immune response and cell activation. These findings suggest a crucial role for epigenetic changes, especially in DNA methylation, in the pathophysiology of delirium.