Neuroinflammation as molecular landscape of post-operative delirium revealed by live human brain multi-omics profiling

Takaya Ishii; Tao Wang; Kazuki Shibata; Shota Nishitani; Takehiko Yamanashi; Nadia E Wahba; Tomoteru Seki; Kaitlyn J Thompson; Kyosuke Yamanishi; Tsuyoshi Nishiguchi; Akiyoshi Shimura; Bun Aoyama; Nipun Gorantla; Nathan J Phuong; Hieu D Nguyen; Therese A Santiago; Yoshitaka Nishizawa; Takaaki Nagao; Mathew A Howard III; Hiroto Kawasaki; Kyosuke Hino; Atsushi Ikeda; Michael P Snyder; Gen Shinozaki

doi:10.1038/s41380-026-03804-z

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Neuroinflammation as molecular landscape of post-operative delirium revealed by live human brain multi-omics profiling

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Neuroinflammation as molecular landscape of post-operative delirium revealed by live human brain multi-omics profiling

Takaya Ishii, Tao Wang, Kazuki Shibata, Shota Nishitani, Takehiko Yamanashi, Nadia E Wahba, Tomoteru Seki, Kaitlyn J Thompson, Kyosuke Yamanishi, Tsuyoshi Nishiguchi, …

Molecular psychiatry

08/05/2026

DOI: 10.1038/s41380-026-03804-z

PMID: 42557393

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Abstract

Post-operative delirium (POD) is a serious complication of surgery particularly in older adults, characterized by acute disturbances in consciousness and cognition and associated with increased mortality and long-term cognitive impairment. Despite its clinical relevance, the underlying pathophysiology remains poorly understood. To address this, we performed multi-omics profiling of live brain tissue from patients undergoing neurosurgery. Single-nucleus RNA sequencing revealed POD-specific transcriptional alterations in glial cells, especially microglia, characterized by enhanced neuroinflammatory signatures. Astrocytes also exhibited changes in synaptic and migratory pathways. Upstream analysis implicated external cytokines as potential drivers of glial responses, while downstream analysis linked POD to encephalitis and dementia. DNA methylation profiling identified immune-related epigenetic alterations, suggesting a regulatory role in POD-associated neuroinflammation. Integration of bulk methylation and cell type-specific transcriptomic data suggested that epigenetic changes may influence gene expression during POD pathogenesis. These findings provide the convincing evidence of neuroinflammation and glial involvement as the pathophysiological mechanism of POD based on the first multi-omics analysis using patient brain tissue.

Details

Title: Subtitle: Neuroinflammation as molecular landscape of post-operative delirium revealed by live human brain multi-omics profiling
Creators: Takaya Ishii - Sumitomo Dainippon Pharma (Japan)
Tao Wang - Stanford University
Kazuki Shibata - Sumitomo Dainippon Pharma (Japan)
Shota Nishitani - Stanford University
Takehiko Yamanashi - Tottori University
Nadia E Wahba - University of Iowa
Tomoteru Seki - Tokyo Medical University
Kaitlyn J Thompson - University of Iowa
Kyosuke Yamanishi - Stanford University
Tsuyoshi Nishiguchi - Stanford University
Akiyoshi Shimura - Tokyo Medical University
Bun Aoyama - National Hospital Organization Kochi National Hospital
Nipun Gorantla - Stanford University
Nathan J Phuong - Stanford University
Hieu D Nguyen - Stanford University
Therese A Santiago - Stanford University
Yoshitaka Nishizawa - Osaka University of Pharmaceutical Sciences
Takaaki Nagao - Toho University
Mathew A Howard III - University of Iowa, Iowa Neuroscience Institute
Hiroto Kawasaki - University of Iowa
Kyosuke Hino - Sumitomo Dainippon Pharma (Japan)
Atsushi Ikeda - Sumitomo Dainippon Pharma (Japan)
Michael P Snyder - Stanford University
Gen Shinozaki - University of Iowa
Resource Type: Journal article
Publication Details: Molecular psychiatry
DOI: 10.1038/s41380-026-03804-z
PMID: 42557393
NLM abbreviation: Mol Psychiatry
ISSN: 1476-5578
eISSN: 1476-5578
Publisher: Springer Nature; LONDON
Grant note: R01 MH119165 / U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH) AG084710 / U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH)
Language: English
Electronic publication date: 08/05/2026
Academic Unit: Neurology; Psychiatry; Iowa Neuroscience Institute; Neurosurgery; Otolaryngology
Record Identifier: 9985217066302771

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