The genome‐wide DNA methylation profiles among neurosurgery patients with and without post‐operative delirium

Abstract

Aims: There is no previous study demonstrating the differences of genome-wide DNA methylation (DNAm) profiles between patients with and without postoperative delirium (POD). We aimed to discover epigenetic (DNAm) markers that are associated with POD in blood obtained from patients before and after neurosurgery.Methods: Pre-and post-surgical blood DNA samples from 37 patients, including 10 POD cases, were analyzed using the Illumina EPIC array genome-wide platform. We examined DNAm differences in blood from patients with and without POD. Enrichment analysis with Gene Ontology and Kyoto Encyclopedia of Genes and Genomes terms were also conducted.Results: When POD cases were tested for DNAm change before and after surgery, enrichment analyses showed many relevant signals with statistical significance in immune response related-pathways and inflammatory cytokine related-pathways such as "cellular response to cytokine stimulus", "regulation of immune system process", "regulation of cell activation", and "regulation of cytokine production". Furthermore, after excluding the potential effect of common factors related to surgery and anesthesia between POD cases and non-POD controls, the enrichment analyses showed significant signals such as "immune response" and "T cell activation", which are same pathways previously identified from an independent non-surgical inpatient cohort.Conclusions: Our first genome-wide DNAm investigation of POD showed promising signals related to immune response, inflammatory response and other relevant signals considered to be associated with delirium pathophysiology. Our data supports the hypothesis that epigenetics play an important role in the pathophysiological mechanism of delirium and suggest the potential usefulness of an epigenetics-based biomarker of POD.

Impact of intraoperative dexmedetomidine on postoperative delirium and pro-inflammatory cytokine levels in elderly patients undergoing thoracolumbar compression fracture surgery: A prospective, randomized, placebo-controlled clinical trial

“…[27] Furthermore, genome-wide DNA methylation profiles have been studied among neurosurgery patients with and without postoperative delirium, demonstrating heightened inflammatory cytokines such as IL-1β, IL-6, and TNF-α in the brain following surgical intervention. [28] These findings collectively emphasize the intricate relationship between inflammatory cytokines and the development of postoperative delirium, shedding light on the potential role of Dexmedetomidine in modulating the inflammatory response and its impact on POD. However, further research is warranted to elucidate the specific mechanisms through which Dexmedetomidine may influence the expression of inflammatory cytokines and subsequently affect the occurrence of postoperative delirium in surgical patients.…”

“…[ 27 ] Furthermore, genome-wide DNA methylation profiles have been studied among neurosurgery patients with and without postoperative delirium, demonstrating heightened inflammatory cytokines such as IL‐1β, IL‐6, and TNF-α in the brain following surgical intervention. [ 28 ]…”

The bispectral EEG (BSEEG) method quantifies post-operative delirium-like states in young and aged mice after head mount implantation surgery

“…Pro-inflammatory changes of microglia and macrophages in the immune system ( 43 ), inadequate blood flow and increased blood-brain barrier permeability in parenchymal vessels ( 44 ), decreased connectivity in nerve cell systems ( 45 ), and reduced mitochondrial efficiency ( 46 ) are among such mechanisms. In addition, our group has been focusing on the influence of age and investigating the potential role of epigenetic mechanisms, especially DNA methylation (DNAm), in the pathophysiological mechanism of delirium ( 47, 48 ). Our data clearly showed that DNAm in the TNF-alpha gene decreases along with age, together with the age associated increase of the gene expression.…”