{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T09:28:31Z","timestamp":1790501311022,"version":"4.1.0"},"reference-count":47,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2021,1,23]],"date-time":"2021-01-23T00:00:00Z","timestamp":1611360000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100007366","name":"Fondazione Italiana Sclerosi Multipla","doi-asserted-by":"publisher","award":["FISM 16\/17\/F14"],"award-info":[{"award-number":["FISM 16\/17\/F14"]}],"id":[{"id":"10.13039\/100007366","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Ann Clin Transl Neurol"],"published-print":{"date-parts":[[2021,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Introduction and methods<\/jats:title><jats:p>In order to verify whether parvalbumin (PVALB), a protein specifically expressed by GABAergic interneurons, could be a MS\u2010specific marker of grey matter neurodegeneration, we performed neuropathology\/molecular analysis of PVALB expression in motor cortex of 40 post\u2010mortem progressive MS cases, with\/without meningeal inflammation, and 10 control cases, in combination with cerebrospinal fluid (CSF) assessment. Analysis of CSF PVALB and neurofilaments (Nf\u2010L) levels combined with physical\/cognitive\/3TMRI assessment was performed in 110 na\u00efve MS patients and in 32 controls at time of diagnosis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>PVALB gene expression was downregulated in MS (fold change\u00a0=\u00a03.7\u00a0\u00b1\u00a01.2, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001 compared to controls) reflecting the significant reduction of PVALB+ cell density in cortical lesions, to a greater extent in MS patients with high meningeal inflammation (51.8, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001). Likewise, post\u2010mortem CSF\u2010PVALB levels were higher in MS compared to controls (fold change\u00a0=\u00a0196\u00a0\u00b1\u00a036, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001) and correlated with decreased PVALB+ cell density (<jats:italic>r<\/jats:italic>\u00a0=\u00a0\u22120.64, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001) and increased MHC\u2010II+ microglia density (<jats:italic>r<\/jats:italic>\u00a0=\u00a00.74, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01), as well as with early age of onset (<jats:italic>r<\/jats:italic>\u00a0=\u00a0\u22120.69, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05), shorter time to wheelchair (<jats:italic>r<\/jats:italic>\u00a0=\u00a0\u22120.49, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05) and early age of death (<jats:italic>r<\/jats:italic>\u00a0=\u00a0\u22120.65, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01). Increased CSF\u2010PVALB levels were detected in MS patients at diagnosis compared to controls (<jats:italic>P<\/jats:italic>\u00a0=\u00a00.002). Significant correlation was found between CSF\u2010PVALB levels and cortical lesion number on MRI (<jats:italic>R<\/jats:italic>\u00a0=\u00a00.28, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.006) and global cortical thickness (<jats:italic>R<\/jats:italic>\u00a0=\u00a0\u22120.46, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001), better than Nf\u2010L levels. CSF\u2010PVALB levels increased in MS patients with severe cognitive impairment (mean\u00a0\u00b1\u00a0SEM:25.2\u00a0\u00b1\u00a07.5\u00a0ng\/mL) compared to both cognitively normal (10.9\u00a0\u00b1\u00a02.4, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.049) and mild cognitive impaired (10.1\u00a0\u00b1\u00a02.9, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.024) patients.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>CSF\u2010PVALB levels reflect loss of cortical interneurons in MS patients with more severe disease course and might represent an early, new MS\u2010specific biomarker of cortical neurodegeneration, atrophy, and cognitive decline.<\/jats:p><\/jats:sec>","DOI":"10.1002\/acn3.51298","type":"journal-article","created":{"date-parts":[[2021,1,23]],"date-time":"2021-01-23T15:41:35Z","timestamp":1611416495000},"page":"534-547","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["CSF parvalbumin levels reflect interneuron loss linked with cortical pathology in multiple sclerosis"],"prefix":"10.1002","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8284-7763","authenticated-orcid":false,"given":"Roberta","family":"Magliozzi","sequence":"first","affiliation":[{"name":"Neurology Section Department of Neurosciences, Biomedicine and Movement Sciences University of Verona Verona Italy"},{"name":"Division of Neuroscience Department of Brain Sciences Imperial College London London United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8093-4548","authenticated-orcid":false,"given":"Marco","family":"Pitteri","sequence":"additional","affiliation":[{"name":"Neurology Section Department of Neurosciences, Biomedicine and Movement Sciences University of Verona Verona Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Ziccardi","sequence":"additional","affiliation":[{"name":"Neurology Section Department of Neurosciences, Biomedicine and Movement Sciences University of Verona Verona Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna Isabella","family":"Pisani","sequence":"additional","affiliation":[{"name":"Neurology Section Department of Neurosciences, Biomedicine and Movement Sciences University of Verona Verona Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luigi","family":"Montibeller","sequence":"additional","affiliation":[{"name":"Neurology Section Department of Neurosciences, Biomedicine and Movement Sciences University of Verona Verona Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Damiano","family":"Marastoni","sequence":"additional","affiliation":[{"name":"Neurology Section Department of Neurosciences, Biomedicine and Movement Sciences University of Verona Verona Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefania","family":"Rossi","sequence":"additional","affiliation":[{"name":"Department of Oncology and Molecular Oncology Istituto Superiore di Sanit\u00e0 Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Mazziotti","sequence":"additional","affiliation":[{"name":"Neurology Section Department of Neurosciences, Biomedicine and Movement Sciences University of Verona Verona Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maddalena","family":"Guandalini","sequence":"additional","affiliation":[{"name":"Neurology Section Department of Neurosciences, Biomedicine and Movement Sciences University of Verona Verona Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caterina","family":"Dapor","sequence":"additional","affiliation":[{"name":"Neurology Section Department of Neurosciences, Biomedicine and Movement Sciences University of Verona Verona Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gianmarco","family":"Schiavi","sequence":"additional","affiliation":[{"name":"Neurology Section Department of Neurosciences, Biomedicine and Movement Sciences University of Verona Verona Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agnese","family":"Tamanti","sequence":"additional","affiliation":[{"name":"Neurology Section Department of Neurosciences, Biomedicine and Movement Sciences University of Verona Verona Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0414-1225","authenticated-orcid":false,"given":"Richard","family":"Nicholas","sequence":"additional","affiliation":[{"name":"Division of Neuroscience Department of Brain Sciences Imperial College London London United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Reynolds","sequence":"additional","affiliation":[{"name":"Division of Neuroscience Department of Brain Sciences Imperial College London London United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimiliano","family":"Calabrese","sequence":"additional","affiliation":[{"name":"Neurology Section Department of Neurosciences, Biomedicine and Movement Sciences University of Verona Verona Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,1,23]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-011-0840-0"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-444-52001-2.00002-9"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM200009283431307"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn3900"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1100648"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.25365"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0135428"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1590\/0004-282X20160015"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/aws246"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(12)70230-2"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(08)70259-X"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10072-018-3427-x"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2006.10.006"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.22230"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awr182"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.1123"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1097\/NEN.0000000000000189"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1404-z"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-017-0812-y"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.25197"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1177\/1352458509359725"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000006282"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000004761"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1002\/acn3.325"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-019-1650-x"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1255263"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471-4159.2001.00582.x"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2003.07.013"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.20736"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00221-008-1317-9"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awm038"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.33.11.1444"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e31820a0cc4"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.200033797"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1177\/1352458506070933"},{"key":"e_1_2_10_37_1","first-page":"111","article-title":"Una versione abbreviata del test di Stroop: dati normativi nella popolazione italiana","volume":"12","author":"Caffarra P","year":"2002","journal-title":"Nuova Rivista di Neurologia"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1177\/1352458516665496"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1177\/1352458519871818"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1212\/01.wnl.0000237551.26858.39"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awh641"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awp070"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awv398"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.25145"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneuroim.2017.02.011"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(14)70250-9"},{"key":"e_1_2_10_47_1","doi-asserted-by":"publisher","DOI":"10.1111\/ene.13687"},{"key":"e_1_2_10_48_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00415-019-09398-7"}],"container-title":["Annals of Clinical and Translational Neurology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/acn3.51298","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/acn3.51298","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/acn3.51298","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,1]],"date-time":"2023-09-01T07:06:07Z","timestamp":1693551967000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/acn3.51298"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1,23]]},"references-count":47,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2021,3]]}},"alternative-id":["10.1002\/acn3.51298"],"URL":"https:\/\/doi.org\/10.1002\/acn3.51298","archive":["Portico"],"relation":{},"ISSN":["2328-9503","2328-9503"],"issn-type":[{"value":"2328-9503","type":"print"},{"value":"2328-9503","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,1,23]]},"assertion":[{"value":"2020-06-17","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-11-11","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-01-23","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}