DOI: https://doi.org/10.14710/jai.v0i0.82593

DNA Methylation Analysis in Predicting Postoperative Delirium in Head Surgery Patients: A Systematic Review

Faculty of Medicine, Universitas Islam Al-Azhar, Mataram, Nusa Tenggara Barat, Indonesia

Received: 20 Feb 2026; Revised: 16 Jun 2026; Accepted: 9 Jul 2026; Available online: 9 Jul 2026; Published: 31 Jul 2026.
Open Access Copyright 2026 JAI (Jurnal Anestesiologi Indonesia)
Creative Commons License This work is licensed under a Creative Commons Attribution 4.0 International License.

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Abstract

Objectives: To assess whether DNA methylation (DNAm) analysis can serve as a predictive biomarker for postoperative delirium (POD) in patients undergoing head surgery, and to synthesize current evidence linking perioperative epigenetic alterations with POD incidence.

Study design: Systematic review of prospective observational studies conducted in accordance with PRISMA guidelines. Eligible studies included cohort designs evaluating DNAm profiles in relation to POD. Risk of bias was assessed using the ROBINS-E tool. Due to methodological heterogeneity and limited sample size, meta-analysis was not performed.

Data sources: A comprehensive search of PubMed, Google Scholar, and ScienceDirect was conducted for studies published between January 2020 and December 2025. Reference lists of included articles were also screened to identify additional relevant studies.

Data synthesis: Four prospective cohort studies met the inclusion criteria. Across studies, POD was associated with differential DNAm in immune- and inflammation-related pathways, including cytokine signaling and immune system regulation. Epigenetic alterations were identified in both central nervous system tissue and peripheral samples. Dysregulation of glial cell–related pathways and surgery-induced methylation changes in proinflammatory genes were consistently reported. Although no individual CpG site achieved genome-wide significance, pathway-level analyses and composite methylation indices demonstrated moderate discriminatory potential for POD.

Conclusions: DNAm alterations are associated with POD following head surgery, particularly through immune and neuroinflammatory mechanisms. Current evidence remains exploratory and limited by small sample sizes and heterogeneity. Larger, well-designed longitudinal studies are required to validate the clinical utility of epigenetic biomarkers for POD prediction.

Registration: This review was not prospectively registered.

Note: This article has supplementary file(s).

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Keywords: biomarker; DNA methylation; epigenetics; head surgery; postoperative delirium

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Section: Systematic Reviews
Language : EN
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  2. Meza Monge, Kenneth, et al. "From Bench to Bedside: New Frontiers in Understanding and Treating Postoperative Delirium." Journal of Clinical Medicine 14.23 (2025): 8418
  3. Xu, Yinuo, et al. "Postoperative delirium in neurosurgical patients: recent insights into the pathogenesis." Brain Sciences 12.10 (2022): 1371
  4. Wang, Xue-Jian. “Research progress of postoperative delirium in neurosurgery.” World journal of psychiatry vol. 15,4 104708. 19 Apr. 2025, doi: 10.5498/wjp.v15.i4.104708
  5. Li, Weiqing et al. “Advances in research on the pathogenesis and signaling pathways associated with postoperative delirium (Review).” Molecular medicine reports vol. 32,2 (2025): 220. doi: 10.3892/mmr.2025.13585
  6. Ishii, Takaya, et al. "Glial Contribution to the Pathogenesis of Post-Operative Delirium Revealed by Multi-omic Analysis of Brain Tissue from Neurosurgery Patients." bioRxiv (2025)
  7. Wahba, Nadia E., et al. "Genome-wide DNA methylation analysis of post-operative delirium with brain, blood, saliva, and buccal samples from neurosurgery patients." Journal of psychiatric research 156 (2022): 245-251
  8. Yamanashi, Takehiko, et al. "The genome‐wide DNA methylation profiles among neurosurgery patients with and without post‐operative delirium." Psychiatry and clinical neurosciences 77.1 (2022): 48-55
  9. Yamanashi, Takehiko, et al. "DNA methylation in the inflammatory genes after neurosurgery and diagnostic ability of post-operative delirium." Translational psychiatry 11.1 (2021): 627
  10. Kappen, P R et al. “Delirium in neurosurgery: a systematic review and meta-analysis.” Neurosurgical review vol. 45,1 (2022): 329-341. doi: 10.1007/s10143-021-01619-w
  11. Saito, Taku et al. “Epigenetics of neuroinflammation: Immune response, inflammatory response and cholinergic synaptic involvement evidenced by genome-wide DNA methylation analysis of delirious inpatients.” Journal of psychiatric research vol. 129 (2020): 61-65. doi: 10.1016/j.jpsychires.2020.06.005
  12. Yamanashi T, Nagao T, Wahba NE, Marra PS, Crutchley KJ, Meyer AA, Andreasen AJ, Hellman MM, Jellison SS, Hughes CG, Pandharipande PP, Howard Iii MA, Kawasaki H, Iwata M, Hefti MM, Shinozaki G. DNA methylation in the inflammatory genes after neurosurgery and diagnostic ability of post-operative delirium. Transl Psychiatry. 2021 Dec 9;11(1):627. doi: 10.1038/s41398-021-01752-6.PMID:34887385;PMCID:PMC8660911
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  15. Nishizawa Y, Yamanashi T, Nishiguchi T, Kajitani N, Miura A, Matsuo R, Tanio A, Yamamoto M, Sakamoto T, Fujiwara Y, Thompson K, Malicoat J, Yamanishi K, Seki T, Kanazawa T, Iwata M, Shinozaki G. The Genome-wide DNA methylation changes in gastrointestinal surgery patients with and without postoperative delirium: Evidence of immune process in its pathophysiology. J Psychiatr Res. 2024 Sep;177:249-255. doi: 10.1016/j.jpsychires.2024.07.013.Epub2024Jul20.PMID:39043004
  16. Thisayakorn P, Thipakorn Y, Tantavisut S, Sirivichayakul S, Maes M. Delirium due to hip fracture is associated with activated immune-inflammatory pathways and a reduction in negative immunoregulatory mechanisms. BMC Psychiatry. 2022 May 31;22(1):369. doi: 10.1186/s12888-022-04021-y.PMID:35641947;PMCID:PMC9158285
  17. Nishizawa Y, Thompson KC, Yamanashi T, Wahba NE, Saito T, Marra PS, Nagao T, Nishiguchi T, Shibata K, Yamanishi K, Hughes CG, Pandharipande P, Cho H, Howard MA 3rd, Kawasaki H, Toda H, Kanazawa T, Iwata M, Shinozaki G. Epigenetic signals associated with delirium replicated across four independent cohorts. Transl Psychiatry. 2024 Jul 4;14(1):275. doi: 10.1038/s41398-024-02986-w.PMID:38965205;PMCID:PMC11224347
  18. Jin Z, Hu J, Ma D. Postoperative delirium: perioperative assessment, risk reduction, and management. Br J Anaesth. 2020 Oct;125(4):492-504. doi: 10.1016/j.bja.2020.06.063.Epub2020Aug11.PMID:32798069

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