{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,12]],"date-time":"2026-11-12T05:35:54Z","timestamp":1794461754427,"version":"4.9.1"},"reference-count":35,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T00:00:00Z","timestamp":1772496000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T00:00:00Z","timestamp":1775692800000},"content-version":"vor","delay-in-days":37,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"University of Bergen"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    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\u2013control 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\u00a0weeks 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-\u03b1 (TNF-\u03b1), and interleukin-6 (IL-6) were measured using ultrasensitive NULISA\u2122 technology. CRP, TNF-\u03b1, and IL-6 were additionally assessed by a standard hospital laboratory method (CRP) and MSD S-Plex chemiluminescence immunoassay (TNF-\u03b1 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 (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.04), TNF-\u03b1 (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.01), IL-6 (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.02), and TREM2 (\n                    <jats:italic>p<\/jats:italic>\n                    = \u20090.02). However, these differences did not survive correction for multiple comparisons (all false discovery rate-adjusted\u00a0\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&gt;\u20090.05). 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.\n                  <\/jats:p>","DOI":"10.1038\/s41598-026-40142-0","type":"journal-article","created":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T09:52:56Z","timestamp":1772531576000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Long-COVID: assessment of circulating markers suggests no cerebral neuronal damage, neuroinflammation or systemic inflammation\u2013a controlled study"],"prefix":"10.1038","volume":"16","author":[{"given":"Roald","family":"Omdal","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ole Bernt","family":"Lenning","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grete","family":"Jonsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan Terje","family":"Kval\u00f8y","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guglielmo","family":"Di Molfetta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kubra","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea L.","family":"Benedet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas J.","family":"Ashton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geir Sverre","family":"Braut","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henrik","family":"Zetterberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tore","family":"Grimstad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,3]]},"reference":[{"issue":"8","key":"40142_CR1","doi-asserted-by":"publisher","first-page":"2148","DOI":"10.1038\/s41591-024-03173-6","volume":"30","author":"Z Al-Aly","year":"2024","unstructured":"Al-Aly, Z. et al. Long COVID science, research and policy. Nat Med. 30(8), 2148\u20132164 (2024).","journal-title":"Nat Med."},{"key":"40142_CR2","doi-asserted-by":"publisher","DOI":"10.1016\/j.lanepe.2023.100756","volume":"35","author":"Q Shen","year":"2023","unstructured":"Shen, Q. et al. COVID-19 illness severity and 2-year prevalence of physical symptoms: an observational study in Iceland, Sweden, Norway and Denmark. Lancet Reg Health Eur. 35, 100756 (2023).","journal-title":"Lancet Reg Health Eur."},{"issue":"1","key":"40142_CR3","doi-asserted-by":"publisher","first-page":"1812","DOI":"10.1038\/s41467-022-29513-z","volume":"13","author":"VT Tran","year":"2022","unstructured":"Tran, V. T., Porcher, R., Pane, I. & Ravaud, P. Course of post COVID-19 disease symptoms over time in the ComPaRe long COVID prospective e-cohort. 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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.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"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.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}},{"value":"All authors have read the final version of the manuscript and have consented for publication.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}}],"article-number":"11856"}}