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NFL is a marker of treatment response in children with SMA treated with nusinersen.
J Neurol 2019; 266(9):2129-2136JN

Abstract

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.

Authors+Show Affiliations

Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, V-house, Sahlgrenska University Hospital Mölndal, 431 80, Mölndal, Sweden. bob.olsson@neuro.gu.se. Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden. bob.olsson@neuro.gu.se.Queen Silvia Children'S Hospital, Sahlgrenska University Hospital, Gothenburg, Sweden.Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, V-house, Sahlgrenska University Hospital Mölndal, 431 80, Mölndal, Sweden. Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.Queen Silvia Children'S Hospital, Sahlgrenska University Hospital, Gothenburg, Sweden. Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.Queen Silvia Children'S Hospital, Sahlgrenska University Hospital, Gothenburg, Sweden. Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.Queen Silvia Children'S Hospital, Sahlgrenska University Hospital, Gothenburg, Sweden. Institute of Health and Care Sciences, Sahlgrenska Academy at the University of Gothenburg, Gothenburgs, Sweden.Pediatric Neurology, Children'S Hospital Datteln, Witten/Herdecke University, Datteln, Germany.Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, V-house, Sahlgrenska University Hospital Mölndal, 431 80, Mölndal, Sweden. Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, V-house, Sahlgrenska University Hospital Mölndal, 431 80, Mölndal, Sweden. Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden. Department of Neurodegeneration, UCL Institute of Neurology, Queen Square, London, UK. UK Dementia Research Institute at UCL, London, UK.Queen Silvia Children'S Hospital, Sahlgrenska University Hospital, Gothenburg, Sweden. Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31123861

Citation

Olsson, Bob, et al. "NFL Is a Marker of Treatment Response in Children With SMA Treated With Nusinersen." Journal of Neurology, vol. 266, no. 9, 2019, pp. 2129-2136.
Olsson B, Alberg L, Cullen NC, et al. NFL is a marker of treatment response in children with SMA treated with nusinersen. J Neurol. 2019;266(9):2129-2136.
Olsson, B., Alberg, L., Cullen, N. C., Michael, E., Wahlgren, L., Kroksmark, A. K., ... Tulinius, M. (2019). NFL is a marker of treatment response in children with SMA treated with nusinersen. Journal of Neurology, 266(9), pp. 2129-2136. doi:10.1007/s00415-019-09389-8.
Olsson B, et al. NFL Is a Marker of Treatment Response in Children With SMA Treated With Nusinersen. J Neurol. 2019;266(9):2129-2136. PubMed PMID: 31123861.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - NFL is a marker of treatment response in children with SMA treated with nusinersen. AU - Olsson,Bob, AU - Alberg,Lars, AU - Cullen,Nicholas C, AU - Michael,Eva, AU - Wahlgren,Lisa, AU - Kroksmark,Anna-Karin, AU - Rostasy,Kevin, AU - Blennow,Kaj, AU - Zetterberg,Henrik, AU - Tulinius,Már, Y1 - 2019/05/23/ PY - 2019/01/07/received PY - 2019/05/17/accepted PY - 2019/04/11/revised PY - 2019/5/28/pubmed PY - 2019/5/28/medline PY - 2019/5/25/entrez KW - Biomarkers KW - Cerebrospinal fluid KW - Neurofilament KW - SMA KW - Tau SP - 2129 EP - 2136 JF - Journal of neurology JO - J. Neurol. VL - 266 IS - 9 N2 - 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. SN - 1432-1459 UR - https://www.unboundmedicine.com/medline/citation/31123861/NFL_is_a_marker_of_treatment_response_in_children_with_SMA_treated_with_nusinersen_ L2 - https://dx.doi.org/10.1007/s00415-019-09389-8 DB - PRIME DP - Unbound Medicine ER -