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NFL is a marker of treatment response in children with SMA treated with nusinersen

Journal article
Authors Bob Olsson
L. Alberg
Nicholas C Cullen
Eva Michael
Lisa Wahlgren
Anna-Karin Kroksmark
K. Rostasy
Kaj Blennow
Henrik Zetterberg
Mar Tulinius
Published in Journal of Neurology
Volume 266
Issue 9
Pages 2129-2136
ISSN 0340-5354
Publication year 2019
Published at Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry
Institute of Clinical Sciences, Department of Pediatrics
Institute of Health and Care Sciences
Pages 2129-2136
Language en
Keywords SMA, Cerebrospinal fluid, Biomarkers, Neurofilament, Tau, neurofilament light-chain, fibrillary acidic protein, cerebrospinal-fluid, sham control, biomarkers, disease, csf, blood, Neurosciences & Neurology
Subject categories Neurology, Neurosciences


Background Recently, the anti-sense oligonucleotide drug nusinersen was approved for spinal muscular atrophy (SMA) and our aim was to find a response marker for this treatment. Methods Twelve children with SMA type 1 and two copies of the SMN2 gene were included in a consecutive single-center study. The children were sampled for CSF at baseline and every time nusinersen was given intrathecally. The neuronal biomarkers NFL and tau and the glial biomarker GFAP were measured. Motor function was assessed using CHOP INTEND. Eleven similarly aged children, who were investigated to rule out neurological or infectious disease, were used as controls. Results Baseline levels of NFL (4598 +/- 981 vs 148 +/- 39, P = 0.001), tau (939 +/- 159 vs 404 +/- 86, P = 0.02), and GFAP (236 +/- 44 vs 108 +/- 26, P = 0.02) were significantly higher in SMA children than controls. Motor function improved by nusinersen treatment in median 13 points corresponding to 5.4 points per month of treatment (P = 0.001). NFL levels typically normalized ( < 380 pg/ml) between the fourth and fifth doses [- 879.5 pg/mL/dose, 95% CI (- 1243.4, - 415.6), P = 0.0001], tau levels decreased [- 112.6 pg/mL/dose, 95% CI (- 206-7, - 18.6), P = 0.01], and minor decreases in GFAP were observed [- 16.9 pg/mL/dose, 95% CI (- 22.8, - 11.2), P = 0.02] by nusinersen treatment. Improvement in motor function correlated with reduced concentrations of NFL (rho = - 0.64, P = 0.03) and tau (rho = - 0.85, P = 0.0008) but not GFAP. Conclusions Nusinersen normalized the axonal damage marker NFL and correlated with motor improvement in children with SMA. NFL may, therefore, be a novel biomarker to monitor treatment response early in the disease course.

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