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Multicenter Study
. 2025 Mar 11;104(5):e213371.
doi: 10.1212/WNL.0000000000213371. Epub 2025 Feb 13.

Long-Term Dynamics of CSF and Serum Neurofilament Light Chain in Adult Patients With 5q Spinal Muscular Atrophy Treated With Nusinersen

Isabell Cordts  1 , Cornelia Fuetterer  2 , Annika Wachinger  1 , Ricarda von Heynitz  1 , Tobias Kessler  3   4 , Maren Freigang  5 , Anna Lisa Quinten  6 , Bogdan Bjelica  7 , Svenja Brakemeier  8 , Elke Hobbiebrunken  9 , Tim Hagenacker  8 , Susanne Petri  7 , Jan Christoph Koch  10 , Andreas Hahn  6 , Paul Lingor  1 , Marcus Deschauer  1 , Rene Günther  5 , Markus Weiler  3 , Bernhard Haller  2 , Emily Feneberg  1
Affiliations
Multicenter Study

Long-Term Dynamics of CSF and Serum Neurofilament Light Chain in Adult Patients With 5q Spinal Muscular Atrophy Treated With Nusinersen

Isabell Cordts et al. Neurology. .

Abstract

Background and objectives: The availability of disease-modifying therapies for 5q-associated spinal muscular atrophy (SMA) has heightened the need to identify suitable biomarkers. This study investigates neurofilament light chain (NfL) concentrations during long-term nusinersen treatment in adult SMA.

Methods: In a retrospective study of prospectively collected data, NfL concentrations in the CSF (cNfL) and serum (sNfL) were measured in patients with SMA from 8 German centers and in neurologic controls using a single-molecule array (Simoa) assay. NfL concentrations and clinical characteristics, including the clinical scores Hammersmith Functional Motor Scale Expanded (HFMSE), Revised Upper Limb Module (RULM), and Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R), were analyzed for defined treatment intervals (T1-T4 [loading phase until 4 months], T5-T8 [until 23 months], T9-T12 [until 37 months], and T13-T19 [until 60 months]). Linear mixed models with a random intercept were used to assess the changes in NfL levels during treatment, considering time and covariates as fixed effects.

Results: One hundred thirteen adult patients with SMA (median age 35, 46% female), with a treatment duration of maximum 60 months, and 52 controls were included. At baseline, NfL concentrations were significantly higher in SMA {cNfL median, 585 (interquartile range [IQR] 428-787) pg/mL; sNfL, 11 (IQR 8-14) pg/mL} than in controls (cNfL, 420 [IQR 323-662] pg/mL; sNfL, 8 [IQR 6-12] pg/mL) (cNfL, p = 0.021; sNfL, p = 0.030). Median differences for all clinical scores were the highest for T5-T8 compared with the loading phase (Δ HFMSE, 0.6 [IQR 0.1-1.4], p = 0.017; Δ RULM, 0.9 [IQR 0.4-1.3], p < 0.001; Δ ALSFRS-R, 0.7 [IQR 0.4-1.0], p < 0.001), but not for subsequent intervals. Longitudinal analysis revealed a significant decrease of NfL concentrations during each treatment interval compared with the loading phase (p < 0.05, respectively) except for sNfL in T13-T19. Even among patients with no measurable clinical improvement (Δ HFMSE ≤ 0), more than 50% showed declining cNfL and sNfL levels up to T13-T19.

Discussion: NfL decreased during nusinersen treatment, suggesting its potential as a pharmacodynamic response marker in adult SMA. However, in patients without detectable clinical improvement, our study cannot determine whether they represent a more sensitive outcome measure or are not clinically meaningful.

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Conflict of interest statement

I. Cordts received speaker fees from Biogen and Hoffmann-La Roche outside of the submitted work and a research grant from Biogen. C. Fuetterer, A. Wachinger, R. von Heynitz, and T. Kessler report no disclosures relevant to the manuscript. M. Freigang received a speaker honorarium and nonfinancial support from Biogen outside the submitted work. A.L. Quinten, B. Bjelica, S. Brakemeier, and E. Hobbiebrunken report no disclosures relevant to the manuscript. T. Hagenacker received advisory board, speaker, and consultant honoraria from Biogen and Hoffmann-La Roche, Amylyx, Argenx, and Alexion and research support from Biogen, Hoffmann-La Roche, and Novartis outside of the submitted work. S. Petri received honoraria as a speaker/consultant from Biogen GmbH, Roche, Novartis, Teva, Cytokinetics Inc., Desitin, Italfarmaco, Amylyx, and Zambon and grants from DGM e.V, Federal Ministry of Education and Research, German Israeli Foundation for Scientific Research and Development, EU Joint Program for Neurodegenerative Disease Research, and Neurodegenerative Research, Inc., outside of the submitted work. J.C. Koch has received advisory board, speaker, and consultant honoraria from Biogen, Hoffmann-La Roche, Zambon, Merz, Ipsen, and AbbVie outside of the submitted work. A. Hahn reports no disclosures relevant to the manuscript. P. Lingor received honoraria for advisory boards and/or consultancies from Stada Pharm, Abbvie, Alexion, Bial, ITF Pharma, Desitin, Novartis, and Woolsey Pharma outside the scope of the submitted work. M. Deschauer received honoraria as a speaker/consultant from Biogen, Roche, and Sanofi outside the submitted work. R. Günther received personal honoraria as a speaker/consultant, personal fees from Biogen, Hofmann-La Roche, Zambon, and Sanofi ITF Pharma and research support from Biogen. All support was received outside the scope of the submitted work. M. Weiler received an advisory board and consultant honoraria from Biogen and Hoffmann-La Roche and speaker honoraria and travel support for conference attendance from Biogen outside the submitted work. M. Weiler is a member of the European Reference Network for Neuromuscular Diseases. B. Haller reports no disclosures relevant to the manuscript. E. Feneberg has applied for a US patent no. 17916203 outside of the submitted work and has received a research grant from Biogen. Go to Neurology.org/N for full disclosures.

Figures

Figure 1
Figure 1. Baseline NfL Levels in Patients With SMA and Controls
cNfL and sNfL concentrations at baseline in all patients with SMA, as well as categorized by SMA types (A) and functional status (B) on a logarithmic scale. Paired t test of subgroups compared with controls, adjusted for multiple testing with the Holm procedure. Spearman correlation (ρ, CI and p value) of cNfL and sNfL levels at baseline for CON (n = 52) and SMA (n = 68) (C). Between-subject correlation of logarithmized cNfL and sNfL levels for all included treatment time points (D). CON = controls; cNfL = neurofilament light chain in the cerebrospinal fluid; SMA = spinal muscular atrophy; sNfL = neurofilament light chain in the serum.
Figure 2
Figure 2. NfL Levels in SMA Patients at Different Time Points and Intervals of Nusinersen Treatment
(A) Comparison of NfL levels during nusinersen treatment in patients with SMA at individual treatment time points (T5, T9, and T13) compared with baseline (T1) on a logarithmic scale, differences tested using a paired Wilcoxon signed rank test. (B) Comparison of averaged logarithmized NfL levels for each treatment interval (T5–T8, T8–T12, and T13–T19) compared with the loading phase (T1–T4) using paired t tests. Averaged logarithmized NfL levels for each treatment interval, for the different SMA types (C) and functional status (D) using paired t tests. cNfL = neurofilament light chain in cerebrospinal fluid; SMA = spinal muscular atrophy; sNfL = neurofilament light chain in serum.
Figure 3
Figure 3. Longitudinal Trends of NfL Levels Across Nusinersen Treatment Intervals for SMA Types 1-3
Changes in cNfL (A) and sNfL (B) levels over time based on categorized treatment intervals for SMA types 1–3. Color lines represent the linear trend of NfL levels for CSF (blue) and serum (yellow) over time in each interval using a random intercept linear mixed-effects model. cNfL = neurofilament light chain in cerebrospinal fluid; SMA = spinal muscular atrophy; sNfL = neurofilament light chain in serum.
Figure 4
Figure 4. Changes in NfL Levels in Relation to HFMSE Scores in SMA Patients Treated With Nusinersen
Visualization of the changes in cNfL (A) and sNfL (B) levels along with the changes in HFMSE scores for each individual patient and each treatment interval compared with the loading phase. For patients without a measurable clinical improvement (Δ HFMSE ≤0, yellow) and patients with a clinical improvement (Δ HFMSE >0, green), the percentages of individuals with decreasing NfL levels are displayed. cNfL = neurofilament light chain in cerebrospinal fluid; HFMSE = Hammersmith Functional Motor Scale Expanded; SMA = spinal muscular atrophy; sNfL = neurofilament light chain in serum.
See this image and copyright information in PMC

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