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Reactivity to neural tissue epitopes, aquaporin 4 and heat shock protein 60 is associated with activated immune–inflammatory pathways and the onset of delirium following hip fracture surgery

  • Research Paper
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European Geriatric Medicine Aims and scope Submit manuscript

Key summary points

AbstractSection Aim

Is IgA/IgG reactivity against neural tissue epitopes associated with delirium severity and activation of the immune response system?

AbstractSection Findings

IgA antibody levels against neurofilament protein, glial fibrillary acidic protein, myelin basic protein, metabotropic glutamate receptors 1 and 5, N-Methyl-D-Aspartate receptor GLU1 (NR1) and GLU2 (NR2), and heat shock protein 60 strongly predict severity of delirium and are associated with activation of the cytokine network.

AbstractSection Message

Polyreactive antibody-associated breakdown of immune tolerance, cytokine network activation and neuronal injuries are involved in delirium.

Abstract

Objectives

Activation of the immune–inflammatory response system (IRS) and a deficiency in the compensatory immunoregulatory system (CIRS), neuronal injuries, and alterations in the glutamate receptor (GlutaR), aquaporin-4 (AQP4) and heat shock protein 60 (HSP60) are involved in delirium. Increased serum levels of neurofilament protein (NFP), glial fibrillary acidic protein (GFAP) and myelin basic protein (MBP) are biomarkers of neuronal injury. This investigation delineates whether elevated IgA/IgG reactivity against those self-antigens is associated with delirium severity and IRS activation.

Methods

We measured peak Delirium Rating Scale (DRS) scores on days 2 and 3 following surgery in 59 hip fractured older adults, and IgA and IgG antibody levels against MBP, NFP, GFAP and myelin oligodendrocyte glycoprotein (MOG), metabotropic glutamate receptors mGluRs 1 and 5, N-Methyl-D-Aspartate receptor (NMDAR) GLU1 (NR1) and GLU2 (NR2), APQ4 and HSP60.

Results

The IgA antibody levels against those self-antigens, especially GFAP, MBP and HSP60, strongly predict peak DRS scores on days 2 and 3 post-surgery. IgA reactivity against NMDAR and baseline DRS scores explained 40.6% of the variance in peak DRS scores, while IgA against NMDAR, IgG against MBP and age explained 29.1% of the variance in the IRS/CIRS ratio. There was no correlation between DRS scores and IgG directed against other self-antigens.

Conclusions

Increased IgA levels against neuronal self-antigens, AQP4 and HSP60 are risk factors for delirium. Polyreactive antibody-associated breakdown of immune tolerance, IRS activation and injuries in the neuronal cytoskeleton, oligodendrocytes, astrocytes, glial cells, and myelin sheath are involved in the pathophysiology of delirium.

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Availability of data and materials

The dataset generated during and/or analyzed during the current study will be available from Prof. Dr. Michael Maes upon reasonable request and once the dataset has been fully exploited by the authors.

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Acknowledgements

We gratefully acknowledge the help of all psychiatry/orthopedic/anesthesiology nursing staff and residents involved in the execution of this study.

Funding

This study was supported by a Ratchadapisek Sompoch Endowment Fund of the Faculty of Medicine, Chulalongkorn University (RA62/014).

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Authors and Affiliations

  1. Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand

    Michael Maes & Yanin Thipakorn

  2. Department of Psychiatry, Medical University of Plovdiv, Plovdiv, Bulgaria

    Michael Maes

  3. IMPACT Strategic Research Center, Deakin University, Geelong, Australia

    Michael Maes

  4. Department of Psychiatry, Hip Fracture Research Unit, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand

    Paul Thisayakorn

  5. Department of Orthopedics, Hip Fracture Research Unit, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand

    Saran Tantavisut

  6. Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand

    Sunee Sirivichayakul

  7. Immunosciences Lab. Inc, Los Angeles, CA, USA

    Aristo Vojdani

  8. Cyrex Labs LLC, Phoeniz, AZ, USA

    Aristo Vojdani

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  1. Michael Maes
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Contributions

PT: designed the conception, planned, and collected the data, provided a delirium care, interpreted the results, drafted and revised the manuscript. YT: planned and collected the data, provided a delirium care, revised the manuscript. ST: planned and collected the data, provided an orthopedic care, revised the manuscript. SS: prepared, analyzed, and interpreted the laboratory specimens, revised the manuscript. MM: designed the conception, analyzed, and interpreted the data, drafted and revised the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Michael Maes or Paul Thisayakorn.

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Conflict of interest

The authors declare that they have no competing interests.

Ethical approval and consent to participate

Approval for the study was obtained from the Institutional Review Board of the Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand (registration number 528/61), in compliance with the International Guideline for Human Research protection, as required by the Declaration of Helsinki, conducted according to Thai and international ethics and privacy laws. Written informed consent was obtained before the study from the patients or their guardians (first-degree family members).

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Maes, M., Thisayakorn, P., Thipakorn, Y. et al. Reactivity to neural tissue epitopes, aquaporin 4 and heat shock protein 60 is associated with activated immune–inflammatory pathways and the onset of delirium following hip fracture surgery. Eur Geriatr Med 14, 99–112 (2023). https://doi.org/10.1007/s41999-022-00729-y

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  • DOI: https://doi.org/10.1007/s41999-022-00729-y

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