Postoperative delirium in hip fracture patients linked to epigenetic alterations in inflammatory and immune pathways: a genome-wide DNA methylation study

Tomoteru Seki; Shota Nishitani; Yoshitaka Nishizawa; Kyosuke Yamanishi; Akiyoshi Shimura; Tsuyoshi Nishiguchi; Takaya Ishii; Bun Aoyama; Therese Anne Santiago; Nathan James Phuong; Nipun Gorantla; Hieu Dinh Nguyen; Ryo Takeda; Takashi Kameoka; Takeshi Inoue; Daisuke Sugiyama; Kenichi Ueda; Takehiko Yamanashi; Gen Shinozaki

doi:10.1038/s41398-026-04067-6

$Postoperative delirium in hip fracture patients linked to epigenetic alterations in inflammatory and immune pathways: a genome-wide DNA methylation study$

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Postoperative delirium in hip fracture patients linked to epigenetic alterations in inflammatory and immune pathways: a genome-wide DNA methylation study

Tomoteru Seki, Shota Nishitani, Yoshitaka Nishizawa, Kyosuke Yamanishi, Akiyoshi Shimura, Tsuyoshi Nishiguchi, Takaya Ishii, Bun Aoyama, Therese Anne Santiago, Nathan James Phuong, …

Translational psychiatry

05/16/2026

DOI: 10.1038/s41398-026-04067-6

PMID: 42143058

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Abstract

Delirium is a common yet underdiagnosed condition in elderly hospitalized patients. The lack of effective diagnostic and therapeutic methods can be attributed to the limited understanding of its pathophysiology. Delirium has recently been reported to be linked to neuroinflammation and epigenetic changes. The aim of this study was to validate the pathways in a larger cohort with a uniform type of surgery, while rigorously adjusting for potential covariates. This study primarily investigated DNA methylation (DNAm) changes before and after surgery in postoperative delirium (POD) among older adults having undergone femoral fracture surgery. After propensity analysis, 65 subjects were divided into 2 subgroups; one consisted of subjects who had blood samples collected preoperatively and on postoperative day 0, and the other consisted of those who had samples collected preoperatively and on postoperative day 3. We performed differential methylation analysis and enrichment analysis on each subgroup. Enrichment analysis using CpGs that exhibited substantial DNAm changes between pre- and postoperative day 0 samples in POD cases showed inflammation- and immunity-related pathways such as "leukocyte mediated immunity" and "NF-kappa B signaling pathway." Inflammation- and immunity-related pathways became less noticeable between pre- and postoperative day 3 samples. Inflammation- and immunity-related pathways showed in this study align with previous studies across diverse populations, reinforcing the role of inflammation- and immunity-related epigenetic mechanisms in delirium including POD. Notably, these DNAm changes were potentially transient, corresponding to the typical onset of delirium, suggesting their potential as biomarkers for early diagnosis.

Details

Title: Subtitle: Postoperative delirium in hip fracture patients linked to epigenetic alterations in inflammatory and immune pathways: a genome-wide DNA methylation study
Creators: Tomoteru Seki - Tokyo Medical University
Shota Nishitani - Kanazawa University
Yoshitaka Nishizawa - Osaka University of Pharmaceutical Sciences
Kyosuke Yamanishi - Stanford University
Akiyoshi Shimura - Tokyo Medical University
Tsuyoshi Nishiguchi - Tottori University
Takaya Ishii - Sumitomo Dainippon Pharma (Japan)
Bun Aoyama - National Hospital Organization Kochi National Hospital
Therese Anne Santiago - Stanford University
Nathan James Phuong - Stanford University
Nipun Gorantla - Stanford University
Hieu Dinh Nguyen - Stanford University
Ryo Takeda - Kameda Medical Center
Takashi Kameoka - Kameda Medical Center
Takeshi Inoue - Tokyo Medical University
Daisuke Sugiyama - University of Iowa
Kenichi Ueda - University of Iowa, Anesthesia
Takehiko Yamanashi - Tottori University
Gen Shinozaki - Stanford Medicine
Resource Type: Journal article
Publication Details: Translational psychiatry
DOI: 10.1038/s41398-026-04067-6
PMID: 42143058
NLM abbreviation: Transl Psychiatry
ISSN: 2158-3188
eISSN: 2158-3188
Publisher: Springer Nature
Grant note: R01 AG084710 / NIA NIH HHS R01 MH119165 / NIMH NIH HHS
Language: English
Electronic publication date: 05/16/2026
Academic Unit: Psychiatry; Anesthesia
Record Identifier: 9985164532302771

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