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Unraveling the role of polyamine metabolism in postoperative delirium: insights into biochemical mechanisms and biomarker potential
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  • Published: 21 February 2026

Unraveling the role of polyamine metabolism in postoperative delirium: insights into biochemical mechanisms and biomarker potential

  • Nazia Saiyed1,2 na1,
  • Vaibhav Pandya3 na1,
  • Xiaobei Pan3,
  • Miroslava Cuperlovic-Culf4 na1,
  • Nadia Ashrafi1,2,
  • Shiva Kant5,6,
  • Marie Migaud7,
  • Jyothi Dhuguru8,
  • Henrik Zetterberg9,10,11,12,13,14,15,
  • Bernadette McGuinness16,
  • Anthony P. Passmore16,
  • Leiv Otto Watne17,18,
  • Brian D. Green3,
  • Emma L. Cunningham16 &
  • …
  • Stewart F. Graham1,2,19 

npj Aging , Article number:  (2026) Cite this article

We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.

Subjects

  • Biomarkers
  • Diseases
  • Neurology
  • Neuroscience

Abstract

Postoperative delirium (POD) is a common complication in older surgical patients, linked to long-term cognitive decline and progression to dementia, yet its mechanisms remain unclear. We investigated arginine-related metabolites (ARMs) in cerebrospinal fluid (CSF) from 248 patients undergoing elective-surgery: 25 developed POD. Targeted mass spectrometry, gene expression profiling, and machine learning were applied to identify metabolic predictors. POD patients showed significant correlations with citrulline, ornithine, and glutamine, while models highlighted glutamine, glutamic acid, putrescine, N1-acetylspermidine, and spermidine as key biomarkers, achieving >77% predictive accuracy. Cluster and pathway analyses revealed POD-specific shifts in GABA synthesis and polyamine metabolism, contrasting with urea cycle dominance in non-POD cases. Associations persisted after adjusting for age and CSF Aβ42. Preoperative profiles in polyamine metabolism, ammonia detoxification, and neurotransmitter regulation suggest underlying neuroinflammatory and oxidative stress vulnerabilities that reduce resilience. Targeting polyamine biosynthesis may offer novel preventative and therapeutic strategies to mitigate POD and dementia risk.

Data availability

This study is registered and archived at the NIH Common Fund’s National Metabolomics Data Repository (Metabolomics Workbench, Study ID ST004212; https://doi.org/10.21228/M8G55V). Data are available through the Metabolomics Workbench portal (https://www.metabolomicsworkbench.org), supported by NIH grant U2C-DK119886 and OT2-OD030544.

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Acknowledgements

This work was funded by NIH/NIA grants (NIA/R21/R21AG067083) and (NIA/R33/R33AG067083) under the program: Clarifying the Relationship between Delirium and Alzheimer's Disease and Related Dementias’, Belfast Trust Charitable funds and Belfast Arthroplasty Research Trust. L.O.W. is funded by the South-Eastern Norway Regional Health Authorities (# 2017095), the Norwegian Health Association (#19536, #1513) and by Wellcome Leap’s Dynamic Resilience Program (jointly funded by Temasek Trust) (#104617). We express our gratitude to the John and Marilyn Bishop Charitable Foundation for their generous contributions. Their support has been invaluable in making this work possible.

Author information

Author notes

  1. These authors contributed equally: Nazia Saiyed, Vaibhav Pandya, Miroslava Cuperlovic-Culf.

Authors and Affiliations

  1. Corewell Health East William Beaumont University Hospital, Royal Oak, MI, USA

    Nazia Saiyed, Nadia Ashrafi & Stewart F. Graham

  2. Corewell Health Research Institute, Metabolomics Department, Royal Oak, MI, USA

    Nazia Saiyed, Nadia Ashrafi & Stewart F. Graham

  3. Institute for Global Food Security, School of Biological Sciences, Queen’s University Belfast, Belfast, Northern Ireland, UK

    Vaibhav Pandya, Xiaobei Pan & Brian D. Green

  4. Digital Technologies Research Centre, National Research Council of Canada, Ottawa, ON, Canada

    Miroslava Cuperlovic-Culf

  5. Department of Radiation Oncology, Corewell Health, Royal Oak, MI, USA

    Shiva Kant

  6. Department of Biology and Environmental Science, Auburn University of Montgomery, Montgomery, AL, USA

    Shiva Kant

  7. Mitchell Cancer Institute, Department of Pharmacology, Frederick P. Whiddon College of Medicine, University of South Alabama, Mobile, AL, USA

    Marie Migaud

  8. Aragen Life Sciences, Hyderabad, Telangana, India

    Jyothi Dhuguru

  9. Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden

    Henrik Zetterberg

  10. Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK

    Henrik Zetterberg

  11. UK Dementia Research Institute at UCL, London, UK

    Henrik Zetterberg

  12. Hong Kong Center for Neurodegenerative Diseases, InnoHK, Hong Kong, China

    Henrik Zetterberg

  13. Wisconsin Alzheimer’s Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA

    Henrik Zetterberg

  14. Centre for Brain Research, Indian Institute of Science, Bangalore, India

    Henrik Zetterberg

  15. Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden

    Henrik Zetterberg

  16. Centre for Public Health, Queen’s University Belfast, Block B, Institute of Clinical Sciences, Royal Victoria Hospital site, Belfast, Northern Ireland, UK

    Bernadette McGuinness, Anthony P. Passmore & Emma L. Cunningham

  17. Department of Geriatric Medicine, Akershus University Hospital, Lørenskog, Norway

    Leiv Otto Watne

  18. Oslo Delirium Research Group, Institute of Clinical Medicine, Campus Ahus, University of Oslo, Oslo, Norway

    Leiv Otto Watne

  19. Oakland University-William Beaumont School of Medicine, Rochester, MI, USA

    Stewart F. Graham

Authors
  1. Nazia Saiyed
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  2. Vaibhav Pandya
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Contributions

The authors contributed to the study as follows: S.F.G., E.L.C., B.D.G., and L.O.W. contributed to conceptualization, study design, supervision, project administration, funding acquisition, and critical manuscript review. N.S. was responsible for conceptualization, manuscript drafting, data collection, statistical analysis, experimental work, data analysis, data interpretation, manuscript revision, methodology development, visualization, and critical manuscript review. V.P. participated in data collection, experimental work, methodology development, and review. M.C.C. contributed to statistical analysis, data analysis, data interpretation, visualization, and review. H.Z., B.M., A.P.P., and X.P. contributed to data analysis and visualization. N.A. contributed to visualization and review. S.K. was involved in experimental work, data interpretation, and review. M.M. and J.D. contributed to data curation and review. All authors have read, reviewed and agreed to the published version of the manuscript.

Corresponding authors

Correspondence to Nazia Saiyed or Stewart F. Graham.

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Competing interests

H.Z. has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZpath, Amylyx, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, Enigma, LabCorp, Merry Life, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Quanterix, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures sponsored by Alzecure, BioArctic, Biogen, Cellectricon, Fujirebio, Lilly, Novo Nordisk, Roche, and WebMD, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). Declaration. H.Z. is a Wallenberg Scholar and a Distinguished Professor at the Swedish Research Council supported by grants from the Swedish Research Council (#2023-00356, #2022-01018 and #2019-02397), the European Union’s Horizon Europe research and innovation program under grant agreement No 101053962, Swedish State Support for Clinical Research (#ALFGBG-71320), the National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre, the UK Dementia Research Institute at UCL (UKDRI-1003), and an anonymous donor.

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Saiyed, N., Pandya, V., Pan, X. et al. Unraveling the role of polyamine metabolism in postoperative delirium: insights into biochemical mechanisms and biomarker potential. npj Aging (2026). https://doi.org/10.1038/s41514-025-00324-y

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  • Received: 19 September 2025

  • Accepted: 24 December 2025

  • Published: 21 February 2026

  • DOI: https://doi.org/10.1038/s41514-025-00324-y

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