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

Giulio Disanto, Christian Barro, Pascal Benkert, Yvonne Naegelin, Sabine Schädelin, Antonella Giardiello, Chiara Zecca, Kaj Blennow, Henrik Zetterberg, David Leppert, Ludwig Kappos, Claudio Gobbi, Jens Kuhle, Swiss Multiple Sclerosis Cohort Study Group, Jens Kuhle, Johannes Lorscheider, Özgür Yaldizli, Tobias Derfuss, Ludwig Kappos, Giulio Disanto, Chiara Zecca, Claudio Gobbi, Pascal Benkert, Lutz Achtnichts, Krassen Nedeltchev, Christian P Kamm, Anke Salmen, Andrew Chan, Patrice H Lalive, Caroline Pot, Myriam Schluep, Cristina Granziera, Renaud Du Pasquier, Stefanie Müller, Jochen Vehoff, Giulio Disanto, Christian Barro, Pascal Benkert, Yvonne Naegelin, Sabine Schädelin, Antonella Giardiello, Chiara Zecca, Kaj Blennow, Henrik Zetterberg, David Leppert, Ludwig Kappos, Claudio Gobbi, Jens Kuhle, Swiss Multiple Sclerosis Cohort Study Group, Jens Kuhle, Johannes Lorscheider, Özgür Yaldizli, Tobias Derfuss, Ludwig Kappos, Giulio Disanto, Chiara Zecca, Claudio Gobbi, Pascal Benkert, Lutz Achtnichts, Krassen Nedeltchev, Christian P Kamm, Anke Salmen, Andrew Chan, Patrice H Lalive, Caroline Pot, Myriam Schluep, Cristina Granziera, Renaud Du Pasquier, Stefanie Müller, Jochen Vehoff

Abstract

Objective: Neurofilament 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).

Methods: sNfL 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.

Results: sNfL 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).

Interpretation: These 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.

© 2017 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.

Figures

Figure 1
Figure 1
(A) Association between cerebrospinal fluid (CSF) neurofilament light chain (NfL) and serum neurofilament light chain (sNfL) levels in the Lugano cohort. A 10% increase in CSF NfL corresponds to an increase of approximately 5.9% in sNfL (β = 0.589, p < 0.001). Gray band: 95% confidence interval. (B) Association between brain T2 lesion load and sNfL levels in the Lugano cohort (2–9 vs 0–1: β = 1.849, p = 0.001; >9 vs 0–1: β = 2.524, p < 0.001). (C) Association between number of brain gadolinium‐enhancing (GE) lesions and sNfL levels in the Lugano cohort (1 vs 0: β = 1.077, p = 0.630; 2 vs 0: β = 1.551, p = 0.024; ≥3 vs 0: β = 2.138, p = 0.001). (D) Association between brain and spinal cord GE lesions and sNfL levels in the Lugano cohort (either brain or spinal vs neither: β = 1.461, p = 0.005; both brain and spinal vs neither: β = 1.902, p = 0.002).
Figure 2
Figure 2
(A) Association between age and serum neurofilament light chain (sNfL) levels in healthy controls (HC), clinically isolated syndrome (CIS)/relapsing–remitting multiple sclerosis (RRMS) patients, and primary progressive multiple sclerosis (PPMS)/secondary progressive multiple sclerosis (SPMS) patients from the Swiss Multiple Sclerosis Cohort Study (SMSC) cohort. An increase of 1 year in age corresponds to an increase of approximately 2.2%, 1.5%, and 1.5% in sNfL in the 3 groups, respectively. Gray band: 95% confidence interval (CI). (B) sNfL in HC versus CIS/RRMS and SPMS/PPMS from the SMSC cohort. (C) Association between Expanded Disability Status Scale (EDSS) and sNfL levels in the SMSC cohort. A 1‐point EDSS increase corresponds to an sNfL increase of approximately 14.1%. Gray band: 95% CI. (D) Significant interaction between EDSS and disease course (CIS/RRMS vs PPMS/SPMS) in the association with sNfL in the SMSC cohort (interaction β = 0.904, interaction p = 0.021). Gray shading: 95% CI.
Figure 3
Figure 3
Baseline serum neurofilament light chain (sNfL) was higher in patients starting natalizumab (50.8pg/ml) and rituximab (51.0pg/ml) than in those initiating fingolimod (29.8pg/ml) and injectable disease‐modifying treatments (DMTs; 28.1pg/ml). sNfL levels decreased in patients starting injectable DMTs, fingolimod, natalizumab, or rituximab over time. HC = healthy controls.
Figure 4
Figure 4
Model‐predicted means (marginal means) and model estimates including 95% confidence intervals from generalized estimating equation models. (A) Probability of a recent relapse (within 60 days before sampling), annualized relapse rate (ARR) in the 1 year before sampling, and probability of Expanded Disability Status Scale (EDSS) worsening since 6 to 12 months before sampling according to serum neurofilament light chain (sNfL) percentiles. (B) ARR in the 1 year after sampling, ARR in the 2 years after sampling, and probability of EDSS worsening within 1 year after sampling according to sNfL percentiles. There were 287 samples (49.4%) with sNfL values above the 80th percentile, 228 samples (39.2%) above the 90% percentile, 171 samples (29.4%) above the 95th percentile, 135 samples (23.2%) above the 97.5th percentile, and 105 (18.1%) above the 99th percentile.

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