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Identified candidate proteins were validated in CSF samples of SMA patients by Western blot and enzyme\u2010linked immunosorbent assay. Furthermore, levels of peripheral neurofilament heavy and light chain were determined.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Untargeted proteomic analysis of CSF samples of three SMA type 1 patients revealed the lysosomal protease cathepsin D as a candidate biomarker. Subsequent validation analysis in a larger cohort of 31 pediatric SMA patients (type 1, <jats:italic>n<\/jats:italic>\u00a0=\u00a012; type 2, <jats:italic>n<\/jats:italic>\u00a0=\u00a09; type 3, <jats:italic>n<\/jats:italic>\u00a0=\u00a06; presymptomatically treated, <jats:italic>n<\/jats:italic>\u00a0=\u00a04; age = 0\u201316\u00a0years) revealed a significant decline of cathepsin D levels in SMA patients aged \u22652\u00a0months at the start of treatment. Although evident in all older age categories, this decline was only significant in the group of patients who showed a positive motor response. Moreover, downregulation of cathepsin D was evident in muscle biopsies of SMA patients.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>We identified a decline of cathepsin D levels in CSF samples of SMA patients under nusinersen treatment that was more pronounced in the group of \"treatment responders\" than in \"nonresponders.\" We believe that our results indicate a suitability of cathepsin D levels as a possible biomarker in SMA also in older patients, in combination with analysis of peripheral neurofilament light chain in adolescents or alone in adult patients.<\/jats:p><\/jats:sec>","DOI":"10.1111\/ene.15331","type":"journal-article","created":{"date-parts":[[2022,3,23]],"date-time":"2022-03-23T07:35:22Z","timestamp":1648020922000},"page":"2084-2096","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Cathepsin D as biomarker in cerebrospinal fluid of nusinersen\u2010treated patients with spinal muscular atrophy"],"prefix":"10.1111","volume":"29","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4277-4891","authenticated-orcid":false,"given":"David C.","family":"Schorling","sequence":"first","affiliation":[{"name":"Department of Neuropediatrics and Muscle Disorders Medical Center, University of Freiburg Faculty of Medicine University of Freiburg  Freiburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heike","family":"K\u00f6lbel","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neurology, Developmental Neurology, and Social Pediatrics Center for Neuromuscular Disorders in Children and Adolescents University of Duisburg\u2010Essen  Essen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Hentschel","sequence":"additional","affiliation":[{"name":"Leibniz Institute of Analytical Sciences, ISAS  Dortmund 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Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roman","family":"Rombo","sequence":"additional","affiliation":[{"name":"Center for Molecular Medicine Cologne Institute of Human Genetics Institute of Genetics, and Center for Rare Disorders University of Cologne  Cologne Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"the SMArtCARE consortium","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albert","family":"Sickmann","sequence":"additional","affiliation":[{"name":"Leibniz Institute of Analytical Sciences, ISAS  Dortmund Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1618-7386","authenticated-orcid":false,"given":"Janbernd","family":"Kirschner","sequence":"additional","affiliation":[{"name":"Department of Neuropediatrics and Muscle Disorders Medical Center, University of Freiburg Faculty of Medicine University of Freiburg  Freiburg Germany"},{"name":"Department of Neuropediatrics Faculty of Medicine University Hospital Bonn  Bonn Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrike","family":"Schara\u2010Schmidt","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neurology, Developmental Neurology, and Social Pediatrics Center for Neuromuscular Disorders in Children and Adolescents University of Duisburg\u2010Essen  Essen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanns","family":"Lochm\u00fcller","sequence":"additional","affiliation":[{"name":"Department of Neuropediatrics and Muscle Disorders Medical Center, University of Freiburg Faculty of Medicine University of Freiburg  Freiburg Germany"},{"name":"Division of Neurology Department of Medicine Children's Hospital of Eastern Ontario Research Institute Ottawa Hospital and Brain and Mind Research Institute University of Ottawa  Ottawa Ontario Canada"},{"name":"National Center 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