The role of serum brain injury biomarkers in individuals with a mild-to-moderate COVID infection and Long-COVID - results from the prospective population-based COVI-GAPP study

Abstract

Background: During and after mild (no hospitalization) or moderate (hospitalization without ICU) SARS-CoV-2 infections, a wide range of symptoms, including neurological disorders have been reported. It is, however, unknown if these neurological symptoms are associated with brain injury and whether brain injury and related symptoms also emerge in patients suffering from Long-COVID. Neuronal biomarkers such as serum neurofilament light chain and glial fibrillary acidic protein can be used to elucidate neuro-axonal and astroglial injuries. We therefore investigated whether these biomarkers are associated with the COVID-19 infection status (mild-to-moderate), the associated symptoms and Long-COVID. Methods: From 146 individuals of the general population with a post-acute, mild-to-moderate SARS-CoV-2 infection, serum neurofilament light chain (sNfL; marker of intra-axonal neuronal injury) and serum glial fibrillary acidic protein (sGFAP; marker of astrocytic activation/injury) were measured. Samples were taken before, during and after (five and ten months) a SARS-CoV-2 infection. Individual symptoms and Long-COVID status were assessed using questionnaires. Results: Neurological symptoms were described for individuals after a mild and moderate COVID-19 infection, however, serum markers of brain injury (sNfL/sGFAP) did not change after an infection (sNfL: P = 0.74; sGFAP: P = 0.24) and were not associated with headache (P = 0.51), fatigue (P = 0.93), anosmia (P = 0.77) and ageusia (P = 0.47). In participants with Long-COVID, sGFAP (P = 0.038), but not sNfL (P = 0.58) significantly increased but was not associated with neurological symptoms. Conclusion: Neurological symptoms in individuals after a mild-to-moderate SARS-CoV-2 infection with and without Long-COVID were not associated with brain injury, although there was some astroglial injury observed in Long-COVID patients. Funding: The COVI-GAPP study received grants from the Innovative Medicines Initiative (IMI grant agreement number 101005177), the Princely House of Liechtenstein, the government of the Principality of Liechtenstein, and the Hanela Foundation (Switzerland). None of the funders played a role in the study design, data collection, data analysis, data interpretation, writing of the report, or decision to publish.

Blood Biomarkers as Prognostic Indicators for Neurological Injury in COVID-19 Patients: A Systematic Review and Meta-Analysis

“…To determine the association of GFAP and NfL with COVID-19, we pooled the SMD from included studies. The majority of the studies included in our analysis showed significantly elevated GFAP levels in COVID-19 patients compared to healthy controls [17,20,35,37,62,65], while some studies demonstrated contradictory findings [31,53,60]. We included a total of 13 studies comprising 1896 participants in the meta-analysis of the association between GFAP and COVID-19 infection.…”

“…Taken together, previous studies have reported changes in NfL and GFAP levels in COVID-19 patients [18,19,21,26,27]. However, some studies have reported contradictory findings [30][31][32], which warrant a comprehensive analysis of the relationship between neurological biomarkers (GFAP and NfL) and COVID-19. Therefore, this systematic review and meta-analysis aimed to determine the pooled standardized mean differences (SMD) of GFAP and NfL between COVID-19 patients and healthy controls, generating evidence for the association between neurological injury-related biomarkers and COVID-19 prognosis.…”

“…The full texts of the remaining 47 studies were reviewed, and 26 studies were subsequently excluded based on the eligibility criteria. Among the excluded studies, 15 did not report outcomes of interest (NfL and GFAP) in both COVID-19 and healthy controls [30,31,[38][39][40][41][42][43][44][45][46][47][48][49][50], six did not include healthy controls [31,36,38,44,48,51], three were reviews [8,52,53], and two were editorial reports [54,55]; note that a few reports belonged to more than one category. Finally, 21 studies that reported mean (±SD) or median (±IQR) values for NfL and GFAP were included in the meta-analysis (Figure 1).…”

Neurological involvement among non-hospitalized adolescents and young adults 6 months after acute COVID-19

“…We have previously reported these biomarkers to be slightly elevated in the subacute phase of SARS-CoV-2 infection in adolescents and young adults with mildly symptomatic disease (11). Studies examining neuroinflammatory biomarkers during follow-up after COVID-19 infection yield varied outcomes, even when they are limited to mild initial cases (35,36).…”