Serum neurofilament is associated with progression of brain atrophy and disability in early MS

Abstract

Objective: To investigate a potential effect of riluzole on serum neurofilaments (Nf) compared to placebo and the relationship between longitudinal clinical and MRI outcomes and serum Nf levels.

Methods: Serum samples were obtained from participants enrolled in a randomized double-blind trial of neuroprotection with riluzole vs placebo as an add-on to weekly interferon-β (IFN-β)-1a IM initiated 3 months after randomization. Nf measurements were performed by ELISA and electrochemiluminescence immunoassay.

Results: Longitudinal serum samples were available from 22 riluzole and 20 placebo participants over 24 months. There was no observed treatment effect with riluzole. Nf light chain (NfL) levels decreased over time (p = 0.007 at 24 months), whereas the Nf heavy chain was unchanged (p = 0.997). Changes in NfL were correlated with EDSS change (p = 0.009) and neuropsychological outcomes. Brain volume decreased more rapidly in patients with high baseline NfL (p = 0.05 at 12 months and p = 0.008 at 24 months) and this relationship became stronger at 24 months (p = 0.024 for interaction). Higher and increasing NfL predicted higher number of gadolinium-enhancing lesions (p < 0.001 for both).

Conclusions: Our findings support the potential value of serum NfL as a marker of neuroaxonal injury in early multiple sclerosis. Its reduction over time could represent regression to the mean, or a possible treatment effect of IFN-β-1a. The association with whole brain atrophy and the formation of acute white matter lesions has relevant implications to use serum NfL as a noninvasive biomarker of the overall consequences of brain damage and ongoing disease activity.

Clinicaltrialsgov identifier: NCT00501943.

Figure. Associations between serum neurofilament light chain (NfL) and clinical and MRI parameters

(A) Changes in NfL levels over the study period were positively correlated with changes in Expanded Disability Status Scale (EDSS) score (p = 0.009) (blue circles: change in EDSS and serum NfL between baseline and month 12; red circles: changes in EDSS and serum NfL between baseline and month 24). (B) Brain volume decreased more rapidly in patients with high baseline NfL (regression coefficient β −0.85, 95% confidence interval [CI] −0.04 to −1.66, p = 0.050 at month 12, and −1.29, 95% CI −0.42 to −2.15, p = 0.008 at 24 months), and the negative relationship between brain volume and NfL at 12 months became stronger at 24 months (p = 0.024 for the difference). (C) Patients with higher NfL levels at baseline had more enhancing lesions with 10-fold higher NfL baseline levels being associated with 2.9-fold (95% CI 2.2 to 3.8, p < 0.001) more enhancing lesions over time. (D) Patients with increasing NfL had a higher number of gadolinium (Gd)-enhancing lesions, with a 10-fold increase in NfL being associated with a 4.7-fold (95% CI 3.3 to 6.9, p < 0.001) increase in new enhancing lesions over the study period.