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treatment, sma, nfl, children, nusinersen, motor, levels, csf, article, tau, disease, age, function, study, dose, google, scholar, change, baseline, gfap, cas, pubmed, biomarker, smn, chop, intend, onset, clinical, patient, zetterberg, spinal, type, patients, marker, treated, points, protein, hospital, university, analysis, access, muscular, atrophy, effects, increased, received, olsson, blennow, gene, included,

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         headline:NFL is a marker of treatment response in children with SMA treated with nusinersen
         description: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. 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. 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. 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.
         datePublished:2019-05-23T00:00:00Z
         dateModified:2019-05-23T00:00:00Z
         pageStart:2129
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            Cerebrospinal fluid
            Biomarkers
            Neurofilament
            Tau
            Neurology
            Neurosciences
            Neuroradiology
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      headline:NFL is a marker of treatment response in children with SMA treated with nusinersen
      description: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. 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. 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. 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.
      datePublished:2019-05-23T00:00:00Z
      dateModified:2019-05-23T00:00:00Z
      pageStart:2129
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         SMA
         Cerebrospinal fluid
         Biomarkers
         Neurofilament
         Tau
         Neurology
         Neurosciences
         Neuroradiology
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               type:PostalAddress
            type:Organization
            name:University of Pennsylvania
            address:
               name:Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA
               type:PostalAddress
            type:Organization
      name:Eva Michael
      affiliation:
            name:Sahlgrenska University Hospital
            address:
               name:Queen Silvia Children’S Hospital, Sahlgrenska University Hospital, Gothenburg, Sweden
               type:PostalAddress
            type:Organization
            name:Sahlgrenska Academy at the University of Gothenburg
            address:
               name:Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
               type:PostalAddress
            type:Organization
      name:Lisa Wahlgren
      affiliation:
            name:Sahlgrenska University Hospital
            address:
               name:Queen Silvia Children’S Hospital, Sahlgrenska University Hospital, Gothenburg, Sweden
               type:PostalAddress
            type:Organization
            name:Sahlgrenska Academy at the University of Gothenburg
            address:
               name:Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
               type:PostalAddress
            type:Organization
      name:Anna-Karin Kroksmark
      affiliation:
            name:Sahlgrenska University Hospital
            address:
               name:Queen Silvia Children’S Hospital, Sahlgrenska University Hospital, Gothenburg, Sweden
               type:PostalAddress
            type:Organization
            name:Sahlgrenska Academy at the University of Gothenburg
            address:
               name:Institute of Health and Care Sciences, Sahlgrenska Academy at the University of Gothenburg, Gothenburgs, Sweden
               type:PostalAddress
            type:Organization
      name:Kevin Rostasy
      affiliation:
            name:Witten/Herdecke University
            address:
               name:Pediatric Neurology, Children’S Hospital Datteln, Witten/Herdecke University, Datteln, Germany
               type:PostalAddress
            type:Organization
      name:Kaj Blennow
      affiliation:
            name:Sahlgrenska Academy at the University of Gothenburg
            address:
               name:Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden
               type:PostalAddress
            type:Organization
            name:Sahlgrenska University Hospital
            address:
               name:Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
               type:PostalAddress
            type:Organization
      name:Henrik Zetterberg
      affiliation:
            name:Sahlgrenska Academy at the University of Gothenburg
            address:
               name:Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden
               type:PostalAddress
            type:Organization
            name:Sahlgrenska University Hospital
            address:
               name:Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
               type:PostalAddress
            type:Organization
            name:UCL Institute of Neurology, Queen Square
            address:
               name:Department of Neurodegeneration, UCL Institute of Neurology, Queen Square, London, UK
               type:PostalAddress
            type:Organization
            name:UK Dementia Research Institute at UCL
            address:
               name:UK Dementia Research Institute at UCL, London, UK
               type:PostalAddress
            type:Organization
      name:Már Tulinius
      affiliation:
            name:Sahlgrenska University Hospital
            address:
               name:Queen Silvia Children’S Hospital, Sahlgrenska University Hospital, Gothenburg, Sweden
               type:PostalAddress
            type:Organization
            name:Sahlgrenska Academy at the University of Gothenburg
            address:
               name:Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
               type:PostalAddress
            type:Organization
PostalAddress:
      name:Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden
      name:Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
      name:Queen Silvia Children’S Hospital, Sahlgrenska University Hospital, Gothenburg, Sweden
      name:Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden
      name:Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA
      name:Queen Silvia Children’S Hospital, Sahlgrenska University Hospital, Gothenburg, Sweden
      name:Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
      name:Queen Silvia Children’S Hospital, Sahlgrenska University Hospital, Gothenburg, Sweden
      name:Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
      name:Queen Silvia Children’S Hospital, Sahlgrenska University Hospital, Gothenburg, Sweden
      name:Institute of Health and Care Sciences, Sahlgrenska Academy at the University of Gothenburg, Gothenburgs, Sweden
      name:Pediatric Neurology, Children’S Hospital Datteln, Witten/Herdecke University, Datteln, Germany
      name:Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden
      name:Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
      name:Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden
      name:Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
      name:Department of Neurodegeneration, UCL Institute of Neurology, Queen Square, London, UK
      name:UK Dementia Research Institute at UCL, London, UK
      name:Queen Silvia Children’S Hospital, Sahlgrenska University Hospital, Gothenburg, Sweden
      name:Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden

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