Serum Neurofilament light: A biomarker of neuronal damage in multiple sclerosis

Abstract

ObjectiveNeurofilament light chains (NfL) are unique to neuronal cells, are shed to the cerebrospinal fluid (CSF), and are detectable at low concentrations in peripheral blood. Various diseases causing neuronal damage have resulted in elevated CSF concentrations. We explored the value of an ultrasensitive single‐molecule array (Simoa) serum NfL (sNfL) assay in multiple sclerosis (MS).MethodssNfL levels were measured in healthy controls (HC, n = 254) and two independent MS cohorts: (1) cross‐sectional with paired serum and CSF samples (n = 142), and (2) longitudinal with repeated serum sampling (n = 246, median follow‐up = 3.1 years, interquartile range [IQR] = 2.0–4.0). We assessed their relation to concurrent clinical, imaging, and treatment parameters and to future clinical outcomes.ResultssNfL levels were higher in both MS cohorts than in HC (p < 0.001). We found a strong association between CSF NfL and sNfL (β = 0.589, p < 0.001). Patients with either brain or spinal (43.4pg/ml, IQR = 25.2–65.3) or both brain and spinal gadolinium‐enhancing lesions (62.5pg/ml, IQR = 42.7–71.4) had higher sNfL than those without (29.6pg/ml, IQR = 20.9–41.8; β = 1.461, p = 0.005 and β = 1.902, p = 0.002, respectively). sNfL was independently associated with Expanded Disability Status Scale (EDSS) assessments (β = 1.105, p < 0.001) and presence of relapses (β = 1.430, p < 0.001). sNfL levels were lower under disease‐modifying treatment (β = 0.818, p = 0.003). Patients with sNfL levels above the 80th, 90th, 95th, 97.5th, and 99th HC‐based percentiles had higher risk of relapses (97.5th percentile: incidence rate ratio = 1.94, 95% confidence interval [CI] = 1.21–3.10, p = 0.006) and EDSS worsening (97.5th percentile: OR = 2.41, 95% CI = 1.07–5.42, p = 0.034).InterpretationThese results support the value of sNfL as a sensitive and clinically meaningful blood biomarker to monitor tissue damage and the effects of therapies in MS. Ann Neurol 2017;81:857–870

Neurofilament light chain serum levels correlate with 10‐year MRI outcomes in multiple sclerosis

“…In a cohort of 42 MS patients followed in a trial of riluzole over 24 months which included MS patients with high disability scores, serum NfL levels were correlated with EDSS change ( P = 0.009)15. In a study following subjects for a mean of 3.1 years, serum NfL levels were associated with EDSS assessments (beta = 1.105, P < 0.001) 13. As discussed above, NfL increases are closely correlated with new T2 lesions, and thus the short‐term correlations may reflect the effect of relapses and new lesion formation, which has limited impact on longer term outcomes.…”

“…Shorter term studies have found correlations between new gadolinium‐enhancing lesions and serum NfL values 13, 15, 31. Patients with either brain, spinal, or both brain and spinal gadolinium‐enhancing lesions had higher serum NfL than those without 13.…”

“…Shorter term studies have found correlations between new gadolinium‐enhancing lesions and serum NfL values 13, 15, 31. Patients with either brain, spinal, or both brain and spinal gadolinium‐enhancing lesions had higher serum NfL than those without 13. Our study found associations between averaged NfL values up to year 9 with T2LV measured at or close to year 10, however, the strongest associations was with averaged values from years 1 through 5 with little gain beyond that timepoint.…”

“…The NfL serum samples were shipped on dry ice from Boston to Basel in a temperature controlled container and were measured by SIMOA assay as previously described 13. Inter‐assay coefficients of variation (CV) for three native serum samples were 10.8%, 8.3%, and 5.7% for control samples with mean concentrations of 9.2 pg/mL, 24.4 pg/mL, and 101.4 pg/mL, respectively.…”

Are neurofilaments valuable biomarkers for long-term disease prognostication in MS?

“…This has now changed with the introduction of a highly sensitive single molecule array (Simoa) technology, 5 allowing reliable detection of blood NfL levels. 6 Several studies have proven that NfL in CSF and serum are very well correlated to each other, supporting the notion that serum NfL may be used as a bloodderived marker for neuro-axonal damage. [7][8][9] There is evidence showing that both CSF and serum Nfs levels are associated with disease activity, physical disability, and magnetic resonance imaging (MRI) changes in MS; however, clinical follow-up time was relatively short in most of these studies.…”