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The lack of a single specific test, and the similarity to other inflammatory diseases of the central nervous system, makes it difficult to have a clear diagnosis of multiple sclerosis. Therefore, laboratory tests that allows a clear and definite diagnosis, as well as to predict the different clinical courses of the disease are of utmost importance. Herein, we compared the cerebrospinal fluid (CSF) proteome of patients with multiple sclerosis (in the relapse\u2013remitting phase of the disease) and other diseases of the CNS (inflammatory and non-inflammatory) aiming at identifying reliable biomarkers of multiple sclerosis.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>CSF samples from the discovery group were resolved by 2D-gel electrophoresis followed by identification of the protein spots by mass spectrometry. The results were analyzed using univariate (Student\u2019s <jats:italic>t<\/jats:italic> test) and multivariate (Hierarchical Cluster Analysis, Principal Component Analysis, Linear Discriminant Analysis) statistical and numerical techniques, to identify a set of protein spots that were differentially expressed in CSF samples from patients with multiple sclerosis when compared with other two groups. Validation of the results was performed in samples from a different set of patients using quantitative (e.g., ELISA) and semi-quantitative (e.g., Western Blot) experimental approaches.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Analysis of the 2D-gels showed 13 protein spots that were differentially expressed in the three groups of patients: Alpha-1-antichymotrypsin, Prostaglandin-H2-isomerase, Retinol binding protein 4, Transthyretin (TTR), Apolipoprotein E, Gelsolin, Angiotensinogen, Agrin, Serum albumin, Myosin-15, Apolipoprotein B-100 and EF-hand calcium-binding domain\u2014containing protein. ELISA experiments allowed validating part of the results obtained in the proteomics analysis and showed that some of the alterations in the CSF proteome are also mirrored in serum samples from multiple sclerosis patients. CSF of multiple sclerosis patients was characterized by TTR oligomerization, thus highlighting the importance of analyzing posttranslational modifications of the proteome in the identification of novel biomarkers of the disease.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>The model built based on the results obtained upon analysis of the 2D-gels and in the validation phase attained an accuracy of about 80% in distinguishing multiple sclerosis patients and the other two groups.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12974-022-02404-2","type":"journal-article","created":{"date-parts":[[2022,2,8]],"date-time":"2022-02-08T12:02:35Z","timestamp":1644321755000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Posttranslational modifications of proteins are key features in the identification of CSF biomarkers of multiple sclerosis"],"prefix":"10.1186","volume":"19","author":[{"given":"Ivan L.","family":"Salazar","sequence":"first","affiliation":[]},{"given":"Ana S. T.","family":"Louren\u00e7o","sequence":"additional","affiliation":[]},{"given":"Bruno","family":"Manadas","sequence":"additional","affiliation":[]},{"given":"In\u00eas","family":"Baldeiras","sequence":"additional","affiliation":[]},{"given":"Cl\u00e1udia","family":"Ferreira","sequence":"additional","affiliation":[]},{"given":"Anabela Claro","family":"Teixeira","sequence":"additional","affiliation":[]},{"given":"Vera M.","family":"Mendes","sequence":"additional","affiliation":[]},{"given":"Ana Margarida","family":"Novo","sequence":"additional","affiliation":[]},{"given":"Rita","family":"Machado","sequence":"additional","affiliation":[]},{"given":"S\u00f3nia","family":"Batista","sequence":"additional","affiliation":[]},{"given":"Maria do Carmo","family":"Mac\u00e1rio","sequence":"additional","affiliation":[]},{"given":"M\u00e1rio","family":"Gr\u00e3os","sequence":"additional","affiliation":[]},{"given":"L\u00edvia","family":"Sousa","sequence":"additional","affiliation":[]},{"given":"Maria Jo\u00e3o","family":"Saraiva","sequence":"additional","affiliation":[]},{"given":"Alberto A. C. C.","family":"Pais","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1474-0208","authenticated-orcid":false,"given":"Carlos B.","family":"Duarte","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2022,2,8]]},"reference":[{"key":"2404_CR1","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1038\/s41572-018-0041-4","volume":"4","author":"M Filippi","year":"2018","unstructured":"Filippi M, Bar-Or A, Piehl F, Preziosa P, Solari A, Vukusic S, Rocca MA. Multiple sclerosis. Nat Rev Dis Primers. 2018;4:43.","journal-title":"Nat Rev Dis Primers"},{"key":"2404_CR2","doi-asserted-by":"crossref","first-page":"a028928","DOI":"10.1101\/cshperspect.a028928","volume":"8","author":"S Klineova","year":"2018","unstructured":"Klineova S, Lublin FD. Clinical course of multiple sclerosis. 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This study was approved by the Ethics Board of the Faculty of Medicine, University of Coimbra (Ref. 084-CE-2016), and all subjects or responsible caregivers, whichever appropriate, gave their informed consent.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"The authors declare that no consent for publication was necessary.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors have declared that no conflict of interest exists.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"44"}}