Neurofilament light chain: A prognostic biomarker in amyotrophic lateral sclerosis

Abstract

Objective: To test blood and CSF neurofilament light chain (NfL) levels in relation to disease progression and survival in amyotrophic lateral sclerosis (ALS).

Methods: Using an electrochemiluminescence immunoassay, NfL levels were measured in samples from 2 cohorts of patients with sporadic ALS and healthy controls, recruited in London (ALS/control, plasma: n = 103/42) and Oxford (ALS/control, serum: n = 64/36; paired CSF: n = 38/20). NfL levels in patients were measured at regular intervals for up to 3 years. Change in ALS Functional Rating Scale-Revised score was used to assess disease progression. Survival was evaluated using Cox regression and Kaplan-Meier analysis.

Results: CSF, serum, and plasma NfL discriminated patients with ALS from healthy controls with high sensitivity (97%, 89%, 90%, respectively) and specificity (95%, 75%, 71%, respectively). CSF NfL was highly correlated with serum levels (r = 0.78, p < 0.0001). Blood NfL levels were approximately 4 times as high in patients with ALS compared with controls in both cohorts, and maintained a relatively constant expression during follow-up. Blood NfL levels at recruitment were strong, independent predictors of survival. The highest tertile of blood NfL at baseline had a mortality hazard ratio of 3.91 (95% confidence interval 1.98-7.94, p < 0.001).

Conclusion: Blood-derived NfL level is an easily accessible biomarker with prognostic value in ALS. The individually relatively stable levels longitudinally offer potential for NfL as a pharmacodynamic biomarker in future therapeutic trials.

Classification of evidence: This report provides Class III evidence that the NfL electrochemiluminescence immunoassay accurately distinguishes patients with sporadic ALS from healthy controls.

Figure 1. Summary of the cross-sectional analyses of NfL levels in the Oxford and London cohorts

NfL levels (median [interquartile range]) in patients with amyotrophic lateral sclerosis and controls in the cross-sectional analysis using (A) CSF, (B) serum, and (C) plasma (Mann–Whitney U test). Results of receiver operating characteristic analysis are shown in the right panel. (D) Matched CSF and serum NfL levels are strongly correlated in controls and in patients with ALS. (E) Blood NfL levels are strongly correlated with progression rate at baseline in both London and Oxford cohorts. AUC = area under the curve; NfL = neurofilament light chain.

Figure 2. Summary of the longitudinal analyses of NfL levels in the London and Oxford cohorts

Observed trajectories of log NfL levels in the 15-month follow-up period for individual patients with ALS (dashed lines) and the predicted average trajectories (solid lines) are shown for ALS-fast (red), ALS-intermediate (green), and ALS-slow (blue) patients in the London cohort (plasma, panel A) and Oxford cohort (serum, panel B; CSF, panel C). ALS-fast: progression rate at last visit (PRL) >1.0; ALS-intermediate: PRL 0.5–1.0; ALS-slow: PRL <0.5. ALS = amyotrophic lateral sclerosis; NfL = neurofilament light chain.

Figure 3. Summary of survival analyses in patients with ALS from London and Oxford cohorts separately and combined

(A) Distinct curves representing cumulative survivals in patients with ALS with different baseline plasma NfL and serum NfL levels in the London cohort (A.a), Oxford cohort (A.b), and combined cohort (A.c). All 3 cohorts were divided by cohort-specific tertile cutoff values. (B) Kaplan–Meier curve of patients with ALS treated with riluzole or untreated in the London cohort (B.a), Oxford cohort (B.b), and combined cohort (B.c).