{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,6]],"date-time":"2026-11-06T19:37:59Z","timestamp":1793993879683,"version":"4.8.0"},"reference-count":44,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2019,10,30]],"date-time":"2019-10-30T00:00:00Z","timestamp":1572393600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Nusinersen is the first approved drug for the treatment of spinal muscular atrophy (SMA). Treatment of SMA with nusinersen is based on a fixed dosing regimen. For other motoneuron diseases, such as amyotrophic lateral sclerosis (ALS), biomarkers are available for clinical diagnostics; however, no such biomarkers have yet been found for SMA. Serum and cerebrospinal fluid (CSF) samples of 11 patients with adult SMA type 3 were prospectively collected and analyzed during loading with nusinersen. Neurofilament heavy chain, tau protein, S100B protein, and neuron-specific enolase were investigated as potential biomarkers of motor neuron destruction. No significant pathological alterations in levels of neurofilament heavy chain, tau protein, or S100B protein were detected in the CSF or blood samples under baseline conditions or during loading with nusinersen. Neuron-specific enolase was marginally elevated in CSF and blood samples without significant alteration during treatment. In a mixed cohort of adult patients with SMA type 3, neurofilament heavy chain, tau protein, S100B protein, and neuron-specific enolase do not serve as potential biomarkers during the loading phase of nusinersen. The slow progression rate of SMA type 3 may not lead to detectable elevation of levels of these common markers of axonal degradation.<\/jats:p>","DOI":"10.3390\/ijms20215397","type":"journal-article","created":{"date-parts":[[2019,10,31]],"date-time":"2019-10-31T05:18:26Z","timestamp":1572499106000},"page":"5397","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":49,"title":["Neurofilament Heavy Chain and Tau Protein Are Not Elevated in Cerebrospinal Fluid of Adult Patients with Spinal Muscular Atrophy during Loading with Nusinersen"],"prefix":"10.3390","volume":"20","author":[{"given":"Andreas","family":"Totzeck","sequence":"first","affiliation":[{"name":"Department of Neurology, University Hospital Essen, Hufelandstr. 55, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"Stolte","sequence":"additional","affiliation":[{"name":"Department of Neurology, University Hospital Essen, Hufelandstr. 55, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathrin","family":"Kizina","sequence":"additional","affiliation":[{"name":"Department of Neurology, University Hospital Essen, Hufelandstr. 55, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saskia","family":"Bolz","sequence":"additional","affiliation":[{"name":"Department of Neurology, University Hospital Essen, Hufelandstr. 55, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melina","family":"Schlag","sequence":"additional","affiliation":[{"name":"Department of Neurology, University Hospital Essen, Hufelandstr. 55, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Thimm","sequence":"additional","affiliation":[{"name":"Department of Neurology, University Hospital Essen, Hufelandstr. 55, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Kleinschnitz","sequence":"additional","affiliation":[{"name":"Department of Neurology, University Hospital Essen, Hufelandstr. 55, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tim","family":"Hagenacker","sequence":"additional","affiliation":[{"name":"Department of Neurology, University Hospital Essen, Hufelandstr. 55, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,10,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1712","DOI":"10.1016\/S0140-6736(95)92881-2","article-title":"SMN gene deletions in adult-onset spinal muscular atrophy","volume":"346","author":"Clermont","year":"1995","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/0092-8674(95)90460-3","article-title":"Identification and characterization of a spinal muscular atrophy-determining gene","volume":"80","author":"Lefebvre","year":"1995","journal-title":"Cell"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1055\/s-2001-15264","article-title":"Spinal muscular atrophy","volume":"21","author":"Talbot","year":"2001","journal-title":"Semin. Neurol."},{"key":"ref_4","first-page":"597","article-title":"Spinal muscular atrophy: Why do low levels of survival motor neuron protein make motor neurons sick? Nature reviews","volume":"10","author":"Burghes","year":"2009","journal-title":"Neuroscience"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.pediatrneurol.2011.09.001","article-title":"Spinal muscular atrophy: A clinical and research update","volume":"46","author":"Markowitz","year":"2012","journal-title":"Pediatric Neurol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1016\/S0960-8966(06)80015-5","article-title":"International SMA consortium meeting. (26\u201328 June 1992, Bonn, Germany)","volume":"2","author":"Munsat","year":"1992","journal-title":"Neuromuscul. Disord."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1159\/000052118","article-title":"The predictive value of achieved motor milestones assessed in 441 patients with infantile spinal muscular atrophy types II and III","volume":"45","author":"Borkowska","year":"2001","journal-title":"Eur. Neurol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1723","DOI":"10.1056\/NEJMoa1702752","article-title":"Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy","volume":"377","author":"Finkel","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1056\/NEJMoa1710504","article-title":"Nusinersen versus Sham Control in Later-Onset Spinal Muscular Atrophy","volume":"378","author":"Mercuri","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"932","DOI":"10.1002\/acn3.779","article-title":"Neurofilament as a potential biomarker for spinal muscular atrophy","volume":"6","author":"Darras","year":"2019","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2129","DOI":"10.1007\/s00415-019-09389-8","article-title":"NFL is a marker of treatment response in children with SMA treated with nusinersen","volume":"266","author":"Olsson","year":"2019","journal-title":"J. Neurol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1136\/jnnp-2012-303768","article-title":"Phosphorylated neurofilament heavy subunit (pNF-H) in peripheral blood and CSF as a potential prognostic biomarker in amyotrophic lateral sclerosis","volume":"84","author":"Boylan","year":"2013","journal-title":"J. Neurol. Neurosurg Psychiatry"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"852","DOI":"10.1212\/01.wnl.0000203120.85850.54","article-title":"Axonal damage markers in cerebrospinal fluid are increased in ALS","volume":"66","author":"Brettschneider","year":"2006","journal-title":"Neurology"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"146","DOI":"10.3109\/21678421.2012.729596","article-title":"pNfH is a promising biomarker for ALS","volume":"14","author":"Ganesalingam","year":"2013","journal-title":"Amyotroph. Lateral Scler. Front. Degener."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"144","DOI":"10.3109\/17482968.2010.542002","article-title":"Neurofilament heavy subunit in cerebrospinal fluid: A biomarker of amyotrophic lateral sclerosis?","volume":"12","author":"Mendonca","year":"2011","journal-title":"Amyotroph. Lateral Scler."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1007\/s00415-009-0131-z","article-title":"CSF neurofilament protein analysis in the differential diagnosis of ALS","volume":"256","author":"Reijn","year":"2009","journal-title":"J. Neurol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1007\/BF00308716","article-title":"Phosphorylated high molecular weight neurofilament protein in lower motor neurons in amyotrophic lateral sclerosis and other neurodegenerative diseases involving ventral horn cells","volume":"79","author":"Sobue","year":"1990","journal-title":"Acta Neuropathol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1111\/jnc.14574","article-title":"The S100B story: From biomarker to active factor in neural injury","volume":"148","author":"Michetti","year":"2018","journal-title":"J. Neurochem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1016\/S1474-4422(16)00070-3","article-title":"CSF and blood biomarkers for the diagnosis of Alzheimer\u2019s disease: A systematic review and meta-analysis","volume":"15","author":"Olsson","year":"2016","journal-title":"Lancet Neurol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1007\/s00381-018-3955-y","article-title":"Serial measurement of S100B and NSE in pediatric traumatic brain injury","volume":"35","author":"Park","year":"2018","journal-title":"Childs Nerv. Syst."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2353","DOI":"10.1007\/s00415-018-9008-3","article-title":"Diagnostic and prognostic power of CSF Tau in amyotrophic lateral sclerosis","volume":"265","author":"Scarafino","year":"2018","journal-title":"J. Neurol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1177\/37.4.2926122","article-title":"Immunocytochemical localization of S-100b protein in degenerating and regenerating rat sciatic nerves","volume":"37","author":"Spreca","year":"1989","journal-title":"J. Histochem. Cytochem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1640","DOI":"10.1016\/j.jalz.2018.06.2857","article-title":"Blood-brain barrier breakdown, neuroinflammation, and cognitive decline in older adults","volume":"14","author":"Bowman","year":"2018","journal-title":"Alzheimers Dement."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1212\/WNL.25.6.537","article-title":"Cerebrospinal fluid proteins in multiple sclerosis","volume":"25","author":"Lamoureux","year":"1975","journal-title":"Neurology"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1111\/j.1600-0404.1995.tb00450.x","article-title":"Cerebrospinal fluid levels of S-100b protein and neuron-specific enolase in chronic inflammatory demyelinating polyneuropathy","volume":"91","author":"Nagamatsu","year":"1995","journal-title":"Acta Neurol. Scand."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2247","DOI":"10.1212\/WNL.0000000000001642","article-title":"Neurofilament light chain: A prognostic biomarker in amyotrophic lateral sclerosis","volume":"84","author":"Lu","year":"2015","journal-title":"Neurology"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"748","DOI":"10.1002\/acn3.212","article-title":"CSF neurofilament light chain reflects corticospinal tract degeneration in ALS","volume":"2","author":"Menke","year":"2015","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1756286419846058","DOI":"10.1177\/1756286419846058","article-title":"Neurochemical markers in CSF of adolescent and adult SMA patients undergoing nusinersen treatment","volume":"12","author":"Wurster","year":"2019","journal-title":"Ther. Adv. Neurol. Disord."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Wurster, C.D., Steinacker, P., Gunther, R., Koch, J.C., Lingor, P., Uzelac, Z., Witzel, S., Wollinsky, K., Winter, B., and Osmanovic, A. (2019). Neurofilament light chain in serum of adolescent and adult SMA patients under treatment with nusinersen. J. Neurol., 1\u20139.","DOI":"10.1007\/s00415-019-09547-y"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1080\/15622970310029912","article-title":"CSF markers for Alzheimer\u2019s disease: Total tau, phospho-tau and Abeta42","volume":"4","author":"Andreasen","year":"2003","journal-title":"World J. Biol. Psychiatry"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1016\/S0304-3940(00)01697-9","article-title":"Transient increase in total tau but not phospho-tau in human cerebrospinal fluid after acute stroke","volume":"297","author":"Hesse","year":"2001","journal-title":"Neurosci. Lett."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.1001\/jamaneurol.2017.0655","article-title":"Comparing Plasma Phospho Tau, Total Tau, and Phospho Tau-Total Tau Ratio as Acute and Chronic Traumatic Brain Injury Biomarkers","volume":"74","author":"Rubenstein","year":"2017","journal-title":"JAMA Neurol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"300","DOI":"10.3389\/fneur.2017.00300","article-title":"Serial Sampling of Serum Protein Biomarkers for Monitoring Human Traumatic Brain Injury Dynamics: A Systematic Review","volume":"8","author":"Thelin","year":"2017","journal-title":"Front. Neurol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"779","DOI":"10.2174\/1566524016666161128113338","article-title":"Spinal Muscular Atrophy: More than a Disease of Motor Neurons?","volume":"16","author":"Nash","year":"2016","journal-title":"Curr. Mol. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1111\/joa.12083","article-title":"Spinal muscular atrophy: A motor neuron disorder or a multi-organ disease?","volume":"224","author":"Shababi","year":"2014","journal-title":"J. Anat."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1016\/j.cell.2004.12.020","article-title":"Thrombospondins are astrocyte-secreted proteins that promote CNS synaptogenesis","volume":"120","author":"Christopherson","year":"2005","journal-title":"Cell"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1016\/j.cell.2009.09.025","article-title":"Gabapentin receptor alpha2delta-1 is a neuronal thrombospondin receptor responsible for excitatory CNS synaptogenesis","volume":"139","author":"Eroglu","year":"2009","journal-title":"Cell"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Pera, M.C., Coratti, G., Forcina, N., Mazzone, E.S., Scoto, M., Montes, J., Pasternak, A., Mayhew, A., Messina, S., and Sframeli, M. (2017). Content validity and clinical meaningfulness of the HFMSE in spinal muscular atrophy. BMC Neurol., 17.","DOI":"10.1186\/s12883-017-0790-9"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1159\/000098441","article-title":"Performance characteristics of seven neuron-specific enolase assays","volume":"28","author":"Stern","year":"2007","journal-title":"Tumour. Biol."},{"key":"ref_40","first-page":"1230","article-title":"Serum neuron-specific enolase in children with neuroblastoma","volume":"57","author":"Zeltzer","year":"1986","journal-title":"Relationship to stage and disease course. Cancer"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.jflm.2018.02.016","article-title":"Post-mortem biochemistry of NSE and S100B: A supplemental tool for detecting a lethal traumatic brain injury?","volume":"55","author":"Sieber","year":"2018","journal-title":"J. Forensic Leg. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1097\/01.CCM.0000053644.16336.52","article-title":"S-100beta protein-serum levels in healthy children and its association with outcome in pediatric traumatic brain injury","volume":"31","author":"Spinella","year":"2003","journal-title":"Crit. Care Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.1001\/jamaneurol.2015.1285","article-title":"Longitudinal Cerebrospinal Fluid Biomarker Changes in Preclinical Alzheimer Disease During Middle Age","volume":"72","author":"Sutphen","year":"2015","journal-title":"JAMA Neurol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1136\/jnnp-2017-316605","article-title":"Comparison of elevated phosphorylated neurofilament heavy chains in serum and cerebrospinal fluid of patients with amyotrophic lateral sclerosis","volume":"89","author":"Jeromin","year":"2018","journal-title":"J. Neurol. Neurosurg. Psychiatry"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/21\/5397\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:30:23Z","timestamp":1760189423000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/21\/5397"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,10,30]]},"references-count":44,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2019,11]]}},"alternative-id":["ijms20215397"],"URL":"https:\/\/doi.org\/10.3390\/ijms20215397","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,10,30]]}}}