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Intrathecal therapy with the antisense oligonucleotide nusinersen modifies the disease course. However, biomarkers for understanding underlying molecular pathomechanisms and monitoring therapy are not yet known.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>A total of 130 cerebrospinal fluid (CSF) samples from 24 adult patients with SMA type 2 or 3 were collected over 3.5\u00a0years, and CSF proteome was analyzed using mass spectrometry (MS). By applying two complementary MS protein quantification methods, label-free quantification (LFQ) and tandem mass tag (TMT) isotopic labeling, specific protein patterns reflecting changes in the CSF in response to nusinersen therapy were identified. These results were combined with cellular and metabolic profiles.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>Nusinersen therapy led to a median motor function improvement of 2.2 Hammersmith Functional Motor Scale-Expanded points after 10\u00a0months and 2.6 points after 34\u00a0months. CSF macrophages increased in number and showed an altered morphology. Albumin quotient (qAlb), glucose, and lactate concentrations were inversely correlated with clinical improvement. MS analysis of CSF identified 1,674 (TMT) and 441 (LFQ) proteins. Protein profiles reflected reduced inhibition of \u201cnervous system development\u201d and \u201caxogenesis\u201d pathways under therapy. In addition, clinical improvement was associated with upregulation of the interacting proteins \u03b1-dystroglycan and beta-1,4-glucuronyltransferase 1, reduction of complement factors, negative correlation in immunoglobulin- and B cell-related pathways, and reduction of cellular mediators such as lymphocytes.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusion<\/jats:title>\n            <jats:p>The present multi-proteomic analysis contributes to the understanding of the molecular mechanisms underlying nusinersen\u2019s therapeutic effects and offers potential biomarkers for monitoring treatment response in SMA.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1007\/s00415-025-12984-7","type":"journal-article","created":{"date-parts":[[2025,3,14]],"date-time":"2025-03-14T13:09:25Z","timestamp":1741957765000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Long-term CSF responses in adult patients with spinal muscular atrophy type 2 or 3 on treatment with nusinersen"],"prefix":"10.1007","volume":"272","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-3091-259X","authenticated-orcid":false,"given":"Gina","family":"Cebulla","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Hai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Uwe","family":"Warnken","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cansu","family":"G\u00fcng\u00f6r","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dirk C.","family":"Hoffmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mirjam","family":"Korporal-Kuhnke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brigitte","family":"Wildemann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6171-634X","authenticated-orcid":false,"given":"Wolfgang","family":"Wick","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8350-7074","authenticated-orcid":false,"given":"Tobias","family":"Kessler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8942-7662","authenticated-orcid":false,"given":"Markus","family":"Weiler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,3,14]]},"reference":[{"issue":"4","key":"12984_CR1","doi-asserted-by":"publisher","first-page":"306","DOI":"10.1016\/j.tins.2020.11.009","volume":"44","author":"B Wirth","year":"2021","unstructured":"Wirth B (2021) Spinal muscular atrophy: in the challenge lies a solution. 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Cebulla, L. Hai, U. Warnken, C. G\u00fcng\u00f6r, and D.C. Hoffmann report no disclosures.M. Korporal-Kuhnke reports speaker honoraria from Novartis, BMS and Merck, all outside the present work. B. Wildemann reports research support from DFG, BMBF, Dietmar-Hopp-Stiftung, Klaus-Tschita-Stiftung, Merck, Novartis, Roche, and speaker honoraria form Alexion, Merck, INSTAND, Novartis, and Roche, all outside the present work. W. Wick reports consulting honoraria outside the present work from Enterome, Roche, and Servier. T. Kessler reports no disclosures. M. Weiler reports consultant honoraria from Biogen and Roche, and speaker honoraria and travel support for conference attendance from Biogen, all outside the present work.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"This prospective exploratory monocentric study was approved by the institutional ethics board (University of Heidelberg; S-554\/2018). 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