Blood neurofilament light chain as a biomarker of MS disease activity and treatment response

Abstract

ObjectiveTo assess the value of blood neurofilament light chain (NfL) as a biomarker of recent, ongoing, and future disease activity and tissue damage and its utility to monitor treatment response in relapsing-remitting multiple sclerosis.MethodsWe measured NfL in blood samples from 589 patients with relapsing-remitting multiple sclerosis (from phase 3 studies of fingolimod vs placebo, FREEDOMS and interferon [IFN]-β-1a, TRANSFORMS) and 35 healthy controls and compared NfL levels with clinical and MRI-related outcomes.ResultsAt baseline, NfL levels (pg/mL) were higher in patients than in healthy controls (30.5 and 27.0 vs 16.9, p = 0.0001) and correlated with T2 lesion load and number of gadolinium-enhancing T1 lesions (p < 0.0001, both). Baseline NfL levels, treatment, and number of new or enlarging T2 lesions during the studies predicted NfL levels at the end of study (all p < 0.01). High vs low baseline NfL levels were associated (estimate [95% confidence interval]) with an increased number of new or enlarging T2 lesions (ratio of mean: 2.64 [1.51–4.60]; p = 0.0006), relapses (rate ratio: 2.53 [1.67–3.83]; p < 0.0001), brain volume loss (difference in means: −0.78% [−1.02 to −0.54]; p < 0.0001), and risk of confirmed disability worsening (hazard ratio: 1.94 [0.97–3.87]; p = 0.0605). Fingolimod significantly reduced NfL levels already at 6 months (vs placebo 0.73 [0.656–0.813] and IFN 0.789 [0.704–0.884]), which was sustained until the end of the studies (vs placebo 0.628 [0.552–0.714] and IFN 0.794 [0.705–0.894]; p < 0.001, both studies at all assessments).ConclusionsBlood NfL levels are associated with clinical and MRI-related measures of disease activity and neuroaxonal damage and have prognostic value. Our results support the utility of blood NfL as an easily accessible biomarker of disease evolution and treatment response.

Serum neurofilament light chain levels associations with gray matter pathology: a 5‐year longitudinal study

“…A secondary, post hoc analysis employed a baseline sNfL cut‐off of 30 pg/mL . The PwMS were divided based on sNfL levels of <30 or ≥30 pg/mL and compared with previously described methods.…”

Blood neurofilament light as a potential endpoint in Phase 2 studies in MS

“…The association of the risk of 6‐month CDW with 6‐month measures (NfL and active lesions) was assessed by a Cox model with the independent covariates included in the model as continuous variables and displayed by Kaplan–Meier survival curves with the independent covariates as binary variables (comparing those with 6‐month NfL ≤ 30 pg/mL vs. those with 6‐month NfL > 30 pg/mL, and those with 6‐month active lesions = 0 vs. those with 6‐month active lesions > 0). The NfL cut‐off level of 30 pg/mL is close to the geometric mean observed in RRMS patients . The multivariate models for assessing the simultaneous impact of NfL and active T2 lesions at 6 months were a generalized Poisson model for 24‐month relapses, an ANOVA model for 24‐month PBVC and a Cox model for 6‐month CDW. What is the contribution of NfL and active lesions as surrogate markers to the treatment effect on other disease endpoints: For a quantitative assessment of this contribution, an additional measure ‐ the proportion of treatment effect (PTE) on Month 24 relapses, PBVC, and disability worsening that could be attributed to the effects on NfL and active lesions at Month 6 was calculated according to Lin, Fleming and De Gruttola (Table S1).…”

“…In a randomized controlled study, Kuhle et al found that over 24 months, changes in NfL levels positively correlated with changes in EDSS score and enhancing lesions, but not with brain atrophy or T2 lesion volume . Blood NfL levels also did not correlate with disease duration . A clear understanding of NfL homeostasis and clearing mechanisms and how NfL levels in blood relate to the progressive changes in MS disease pathology does not exist.…”

Brain atrophy in multiple sclerosis: mechanisms, clinical relevance and treatment options

“…It is an essential component of the axonal cytoskeleton, and reflects the axonal integrity and the stability of neurons. Under conditions of acute axonal transection, NfL are released and can be found as a result, in the cerebrospinal fluid (CSF) and blood of patients with MS. Of note, ultra high versus low blood NfL levels have been associated with MRI related (increased number of gadolinium enhancing or T2 lesion load, whole brain atrophy) and clinical measures (number of relapses, disability worsening) of disease activity and evolution and may, therefore, have prognostic value for patients and clinicians [59].…”