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After adjusting for confounders such as age and renal function, post-COVID syndrome patients show no evidence of widespread neuroaxonal injury via NfL levels, though they exhibit a subtle astroglial signal via modestly elevated GFAP. Novelty: ClaimNovelty.INCREMENTAL. Consensus alignment: ConsensusAlignment.NEUTRAL.

March 20, 2026Frontiers in Cellular Neuroscience2 citationsOpen Access

Serum NfL and GFAP in post-COVID syndrome: minimal evidence of CNS injury after adjusting for confounders

MWMichael Wunderle ARAndrea Ribeiro ILIsabelle Lethen

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Abstract

Background Post-COVID syndrome (PCS) often includes neurological symptoms, but evidence for persistent CNS injury remains inconsistent. Serum neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) are biomarkers of neuronal and astroglial injury. We investigated whether serum NfL and GFAP differ between PCS patients and recovered controls after adjusting for age and renal function. Methods In this prospective single-center case–control study, serum NfL and GFAP were quantified using Simoa® (Quanterix) in 102 PCS patients and 102 recovered controls. Group comparisons employed Mann–Whitney tests and ANCOVA-style multivariable linear regression of log-transformed biomarkers adjusted for age, sex, and eGFR. Associations with eGFR were examined in multivariable models, and findings were validated in an age- and sex-matched cohort. Results Age emerged as the primary determinant of NfL and GFAP concentrations. The inverse correlations with renal function (NfL ρ = −0.23; GFAP ρ = −0.33) and the initially higher GFAP in PCS (60.4 vs. 52.3 pg/mL; p = 0.002) were largely explained by age. After adjustment for age, sex, and eGFR, neither biomarker showed independent differences between groups (adjusted GMRs: NfL 1.04 0.91–1.18, p = 0.59; GFAP 1.10 0.96–1.26, p = 0.15). In an age- and sex-matched cohort (71 pairs), adjusted analyses confirmed no difference in NfL ( p = 0.48), while GFAP demonstrated a significant increase in PCS ( β = 0.15, p = 0.025). Conclusion GFAP concentrations were modestly elevated in PCS in an age- and sex-matched cohort and persisted after adjustment for kidney function, whereas NfL showed no group differences. These findings argue against widespread neuroaxonal injury in PCS and suggest only a subtle astroglial signal in a subset of patients. Rigorous adjustment for confounders—particularly age, sex, and renal function—is essential for valid interpretation of serum neuroinjury biomarkers in PCS.

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