Biochemical and clinical biomarkers in adult SMA 3–4 patients treated with nusinersen for 22 months

OBJECTIVE: To investigate biomarkers of disease progression in cerebrospinal fluid (CSF) and serum in adult patients with spinal muscular atrophy (SMA). Furthermore, we assess the clinical response to nusinersen treatment in adults with SMA over a longer follow‐up period than the previously reported 6–14 months. METHODS: We included 16 adults with SMA type 3–4 for nusinersen treatment over 22 months in this prospective study. We evaluated chitotriosidase‐1 (CHIT1) and chitinase‐3‐like protein 1 (YKL‐40) as neuroinflammatory biomarkers in CSF, and neurofilament light chain (NfL) and heavy chain (pNfH) as neurodegenerative markers in CSF and serum at baseline, month 6, 14 and 22, together with a wide range of clinical outcome measures. RESULTS: Levels of CHIT1 increased significantly (p = 0.048) throughout the 22‐month treatment period and pNfH decreased significantly (p = 0.022) in CSF, but both did not correlate with clinical outcome measures. YKL‐40 correlated strongly with neurofilaments in CSF (rho = 0.76) and decreased significantly (p = 0.037) in patients with improvements in the revised upper limb module (RULM). Finally, patients showed significant improvements in hand grip strength, hand motor function, medical research council (MRC) sum score, and peak expiratory flow (PEF) after 22 months of treatment. INTERPRETATION: YKL‐40 in CSF correlated with clinical improvements during nusinersen treatment. In contrast, CHIT1 and pNfH in CSF changed significantly during treatment but did not correlate with clinical outcomes. Finally, we demonstrated a sustained clinical effect of nusinersen treatment in adults after 22 months.