Association between neurofilament light chain concentrations and outcomes in patients with moderate to severe traumatic brain injury: a systematic review and meta-analysis

Abstract

Abstract Background Moderate to severe traumatic brain injury (TBI) is associated with high rates of mortality and long-term disability. Accurate biomarkers are needed to predict longterm neurological outcomes and guide decision-making early after TBI. Neurofilament light chain (NfL), a structural protein of neurons, has emerged as a promising candidate, but its association with outcomes in this population remains uncertain. Methods We conducted a systematic review and meta-analysis to assess the association between blood or cerebrospinal fluid NfL concentrations and outcomes in adults with moderate to severe TBI. We searched MEDLINE, Embase, Cochrane CENTRAL and Web of Science from inception to October 2025. Eligible studies included cohort studies or randomized controlled trials reporting NfL levels measured during the acute phase and reporting at least one outcome of interest. Our primary outcome was long-term neurological function, defined as the latest available Glasgow Outcome Scale (GOS) or Glasgow Outcome Scale–Extended (GOS-E) score, dichotomized into unfavorable (GOS ≤ 3 or GOS-E ≤ 4) and favorable (GOS > 3 or GOS-E > 4). Mortality, at any time point, was a secondary outcome. Risk of bias was assessed using an adapted scale from the QUADAS-2 tool, and certainty of evidence was evaluated using GRADE criteria. Results Fourteen studies (2,905 participants) were included, with ten (n = 1,648) contributing to the meta-analysis for our primary outcome. Higher NfL concentrations were associated with unfavorable neurological outcomes, with moderately higher levels in patients with poor outcomes compared with those with favorable outcomes (SMD 0.45, 95% CI 0.33–0.56; I² = 12%). Six studies (n = 483) assessed mortality; higher NfL concentrations were associated with increased mortality (SMD 0.71, 95% CI 0.04–1.39; I² = 82%), with a more consistent association when NfL was measured within 24 h after injury (I² = 0%). The certainty of evidence was graded as very low for both outcomes, reflecting risk of bias and, for mortality, additional inconsistency and imprecision. Conclusions Higher NfL concentrations were associated with unfavorable neurological outcomes after moderate-to-severe TBI. The association with mortality was more uncertain and should be interpreted with caution given the substantial heterogeneity across studies. Its incremental prognostic value beyond known predictors remains uncertain. Trial registration PROSPERO CRD42022332110, 22 May 2022.