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Effective treatments remain elusive due to the unclear pathophysiology of POD. To address the knowledge gap, we investigated DNA methylation profiles and gene expression changes in brain cells from POD and non-POD patients who underwent brain resection surgery for medication refractory epilepsy. DNA methylation analysis revealed alteration in epigenetic status of immune and inflammation-related genes. Single-nucleus RNA sequencing (snRNAseq) identified POD-specific glial cell alterations, particularly in microglia, where neuroinflammation was strongly enhanced, consistent with epigenetic findings. Astrocytes exhibited changes in synapse-related functions and migration. Furthermore, downstream analysis indicated similarities between POD-associated glial cell states and pathologies such as encephalitis and dementia. Overall, this study\u2014the first multi-omics analysis of brain tissue from POD patients\u2014provides direct evidence of glial cell contributions to POD pathogenesis, and highlights potential therapeutic targets.<\/jats:p>","DOI":"10.1101\/2025.03.13.643155","type":"posted-content","created":{"date-parts":[[2025,3,14]],"date-time":"2025-03-14T12:25:17Z","timestamp":1741955117000},"source":"Crossref","is-referenced-by-count":6,"title":["Glial Contribution to the Pathogenesis of Post-Operative Delirium Revealed by Multi-omic Analysis of Brain Tissue from Neurosurgery Patients"],"prefix":"10.64898","author":[{"given":"Takaya","family":"Ishii","sequence":"first","affiliation":[{"name":"Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto, California, USA"},{"name":"Regenerative & Cellular Medicine Kobe Center, Sumitomo Pharma Co., Ltd., Osaka, Osaka, Japan"},{"name":"RACTHERA Co., Ltd., Kobe, Hyogo, 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