Abstract
Long-COVID remains incompletely understood, particularly regarding the roles of peripheral systemic inflammation and neuroinflammation. The persistence and extent of these processes remain debated. We conducted a single-center, age- and sex-matched case–control study at Stavanger University Hospital, Norway, recruiting participants from the general population. Forty-eight long-COVID patients and 48 recovered controls were included at a median of 69 weeks post-SARS-CoV-2 infection. Exclusion criteria included autoimmune or chronic inflammatory diseases, cancer, and other conditions affecting fatigue. Plasma levels of neurofilament light (NfL), glial fibrillary acidic protein (GFAP), triggering receptor expressed on myeloid cells 2 (TREM2), C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) were measured using ultrasensitive NULISA™ technology. CRP, TNF-α, and IL-6 were additionally assessed by a standard hospital laboratory method (CRP) and MSD S-Plex chemiluminescence immunoassay (TNF-α and IL-6 MSD). No significant differences in NfL or GFAP were observed between groups, suggesting no ongoing neuronal injury or neuroinflammation. Routine immunoassays showed no differences for inflammatory markers. In unadjusted analyses using ultrasensitive assays, long-COVID patients showed nominally elevated levels of CRP (p = 0.04), TNF-α (p = 0.01), IL-6 (p = 0.02), and TREM2 (p = 0.02). However, these differences did not survive correction for multiple comparisons (all false discovery rate-adjusted p > 0.05). The absence of neuroinflammation markers is consistent with the hypothesis that persistent long-COVID symptoms are unlikely due to ongoing neuronal injury or central nervous system inflammation. Alternatively, persisting long-COVID symptoms may reflect a chronic, extremely low-level immune activation, that contributes to fatigue, pain, and other sickness phenomena through mechanisms such as pro-inflammatory signaling in the brain, or epigenetic mechanisms underlying the sickness behavior response. These findings should be considered preliminary and warrant validation in larger, longitudinal cohorts.
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Data availability
The data that support the findings of this study are not openly available due to reasons of sensitivity and are available from the corresponding author upon reasonable request.
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Acknowledgements
We are grateful to Anne Gro Larsen, Maombi Mirindi Mongane, Karina Fuglestein Bru, and Stina Kvalheim at the Clinical Research Unit at Stavanger University Hospital for their excellent assistance.
Funding
Open access funding provided by University of Bergen. The project is funded by Foundation Dam (Stiftelsen Dam) (grant number #SDAM_HEL45920) and The Norwegian Brain Council.
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Conception and design: O.B. Lenning, T. Grimstad, G.S. Braut, R. Omdal Analysis and interpretation of the data: G. Jonsson, G.D. Molfetta, K. Tan, A.L. Benedet, N.J. Ashton, H. Zetterberg, O.B. Lenning, T. Grimstad, G.S. Braut, R. Omdal Drafting of the article: O.B. Lenning, T. Grimstad, H. Zetterberg, R. Omdal Critical revision for important intellectual content: R. Omdal, O.B. Lenning, G. Jonsson, J.T. Kvaløy, G.D. Molfetta, K. Tan, A.L. Benedet, N.J. Ashton, G.S. Braut, H. Zetterberg, T. Grimstad Final approval of the article: R. Omdal, O.B. Lenning, G. Jonsson, J.T. Kvaløy, A.L. Benedet, N.J. Ashton, G.S. Braut, H. Zetterberg, T. Grimstad Provision of study materials or patients: O.B. Lenning Statistical expertise: J.T. Kvaløy. Obtaining of funding: R. Omdal Administrative, technical, or logistic support: G. Jonsson, G.D. Molfetta, K. Tan, A.L. Benedet, N.J. Ashton Collection and assembly of data: O.B. Lenning, T. Grimstad.
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RO, GDM, KT and ALB: None. HZ: HZ 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, Merck Sharp & Dohme, Merry Life, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Quanterix, Red Abbey Labs, reMYND, Roche, Samumed, ScandiBio Therapeutics AB, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures sponsored by Alzecure, BioArctic, Biogen, Cellectricon, Fujirebio, LabCorp, Lilly, Novo Nordisk, Oy Medix Biochemica AB, Roche, and WebMD, is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program, and is a shareholder of MicThera (outside submitted work). TG: TG has received unrestricted research grants from AbbVie, Tillotts Pharma AB, has served as speaker for AbbVie, Ferring Pharmaceuticals, Takeda AS, and has been advisory board member for Takeda AS, Johnson & Johnson, Tillotts Pharma AB and Galapagos.
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The study received ethical approval from the Regional Committee for Medical Research Ethics in Norway (REK vest 489162). All participants provided written informed consent to participate, and the study was conducted in accordance with the latest revision of the Helsinki Declaration.
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Omdal, R., Lenning, O.B., Jonsson, G. et al. Long-COVID: assessment of circulating markers suggests no cerebral neuronal damage, neuroinflammation or systemic inflammation–a controlled study. Sci Rep (2026). https://doi.org/10.1038/s41598-026-40142-0
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DOI: https://doi.org/10.1038/s41598-026-40142-0
