Neurofilament light as a biomarker in traumatic brain injury

Abstract

Objective: To determine whether serum neurofilament light (NfL) correlates with CSF NfL, traumatic brain injury (TBI) diagnosis, injury severity, brain volume, and diffusion tensor imaging (DTI) estimates of traumatic axonal injury (TAI).

Methods: Participants were prospectively enrolled in Sweden and the United States between 2011 and 2019. The Swedish cohort included 45 hockey players with acute concussion sampled at 6 days, 31 with repetitive concussion with persistent postconcussive symptoms (PCS) assessed with paired CSF and serum (median 1.3 years after concussion), 28 preseason controls, and 14 nonathletic controls. Our second cohort included 230 clinic-based participants (162 with TBI and 68 controls). Patients with TBI also underwent serum, functional outcome, and imaging assessments at 30 (n = 30), 90 (n = 48), and 180 (n = 59) days and 1 (n = 84), 2 (n = 57), 3 (n = 46), 4 (n = 38), and 5 (n = 29) years after injury.

Results: In athletes with paired specimens, CSF NfL and serum NfL were correlated (r = 0.71, p < 0.0001). CSF and serum NfL distinguished players with PCS >1 year from PCS ≤1 year (area under the receiver operating characteristic curve [AUROC] 0.81 and 0.80). The AUROC for PCS >1 year vs preseason controls was 0.97. In the clinic-based cohort, NfL at enrollment distinguished patients with mild from those with moderate and severe TBI (p < 0.001 and p = 0.048). Serum NfL decreased over the course of 5 years (ß = -0.09 log pg/mL, p < 0.0001) but remained significantly elevated compared to controls. Serum NfL correlated with measures of functional outcome, MRI brain atrophy, and DTI estimates of TAI.

Conclusions: Serum NfL shows promise as a biomarker for acute and repetitive sports-related concussion and patients with subacute and chronic TBI.

Classification of evidence: This study provides Class III evidence that increased concentrations of NfL distinguish patients with TBI from controls.

Figure 1. Flowchart of study participants

Flowchart shows study participants in the 2 study cohorts. The first cohort included 45 professional ice hockey players with acute concussion sampled at 6 days after a sports-related concussion, 31 professional hockey players with postconcussion symptoms (PCS) due to repetitive concussions, 28 ice hockey players who underwent blood sampling at preseason, and 14 healthy controls. The players with persistent PCS due to repetitive concussions and healthy controls also underwent paired CSF and serum assessment. The second cohort includes 162 clinic-based patients with subacute and chronic traumatic brain injury (TBI) and 68 healthy controls after the exclusion 17 participants due to screen failure. Of 162, 102 underwent repeated blood, imaging, and functional assessments up to 5 years.

Figure 2. Serum NfL shows diagnostic and prognostic utility for both AC and chronic repetitive concussion

(A) Association between CSF and serum neurofilament light (NfL) obtained from players with postconcussion symptoms (PCS) due to repetitive mild concussion (n = 28) and healthy controls (n = 14). (B) Serum NfL concentrations in players who contributed blood samples during preseason, players with acute concussion (AC), and players with PCS. (C) Serum concentrations in relation to return to play (RTP) and duration of PCS. (D) Individual areas under the receiver operating characteristics curve (AUROCs) (error bars indicate the mean and 95% confidence interval) for how well serum NfL distinguishes players with AC from preseason controls, those with RTP ≥10 days from those with RTP <10 days, those with PCS >1 year from those with PCS ≤1 year, and players with PCS >1 year from preseason controls. (E) Higher concentration of CSF or serum NfL is associated with the number of concussions. (F) NfL increases with symptom severity score. Preseason samples are from professional hockey players who contributed samples during the preseason. The p values are from Kruskal-Wallis test, adjusted for multiple comparisons with the Benjamini-Hochberg procedure. Fitted lines are from the linear regression model (overlaid for visual clarity). The y-axes of plots E and F are normalized for comparison between CSF and serum values. RPQ = Rivermead Post-Concussion Questionnaire.

Figure 3. Serum NfL shows diagnostic utility in patients with subacute and chronic TBI

(A) Serum concentrations of neurofilament light (NfL) measured at enrollment (median 7 months after injury) across traumatic brain injury (TBI) severity and controls. The p values are from the Kruskal-Wallis test, adjusted for multiple comparisons with the Benjamin-Hochberg procedure. (B) Serum NfL over time in patients with longitudinal data. The y-axes of plots A and B are log-transformed for visual clarity. (C) Diagnostic accuracy (area under the receiver operating characteristic curve [AUROC], error bars indicate 95% confidence interval) of serum NfL measured at different time points after injury vs controls. Boxplots show the median and interquartile range.

Figure 4. Association between serum NfL at enrollment and cross-sectional measures of GM, WM, and CC volumes

(A–F) Association between serum neurofilament light (NfL) measured at enrollment and gray matter (GM), white matter (WM), and corpus callosum (CC) volumes assessed at enrollment (all patients with traumatic brain injury). The ß estimates and p values are from regression models, covaried for age, education, sex, and total intracranial volume. We also assessed the relationship with univariate Spearman rank correlation (ρ). Brain regions were normalized to total intracranial volume before analysis with ρ.

Figure 5. Serum NfL concentration at enrollment shows association with cross-sectional DTI white matter integrity

(A–C) Association between serum neurofilament light (NfL) measured at enrollment and diffusion tensor imaging (DTI) measures of corpus callosum (CC) integrity measured at enrollment (all traumatic brain injury severities). The ß estimates and p values are from regression models, covaried for age, education, and sex. We also assessed the relationship with univariate Spearman rank correlation (ρ). FA = fractional anisotropy; MD = mean diffusivity; RD = radial diffusivity.