Long-Term Dynamics of CSF and Serum Neurofilament Light Chain in Adult Patients With 5q Spinal Muscular Atrophy Treated With Nusinersen
Isabell Cordts, Cornelia Fuetterer, Annika Wachinger, Ricarda von Heynitz, Tobias Keßler, Maren Freigang, Anna Lisa Quinten, Bogdan Bjelica, Svenja Brakemeier, Elke Hobbiebrunken, Tim Hagenacker, Susanne Petri, Jan Christoph Koch, Andreas Hahn, Paul Lingor, Marcus Deschauer, René Günther, Markus Weiler, Bernhard Haller, Emily Feneberg
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: < 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.