{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T05:53:32Z","timestamp":1789192412334,"version":"build-2803163510"},"reference-count":30,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2024,7,10]],"date-time":"2024-07-10T00:00:00Z","timestamp":1720569600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"OCTAVE Biosciences"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Increased choroid plexus (CP) volume has been recently implicated as a potential predictor of worse multiple sclerosis (MS) outcomes. The biomarker signature of CP changes in MS are currently unknown. To determine the blood-based biomarker characteristics of the cross-sectional and longitudinal MRI-based CP changes in a heterogeneous group of people with MS (pwMS), a total of 202 pwMS (148 pwRRMS and 54 pwPMS) underwent MRI examination at baseline and at a 5-year follow-up. The CP was automatically segmented and subsequently refined manually in order to obtain a normalized CP volume. Serum samples were collected at both timepoints, and the concentration of 21 protein measures relevant to MS pathophysiology were determined using the Olink\u2122 platform. Age-, sex-, and BMI-adjusted linear regression models explored the cross-sectional and longitudinal relationships between MRI CP outcomes and blood-based biomarkers. At baseline, there were no significant proteomic predictors of CP volume, while at follow-up, greater CP volume was significantly associated with higher neurofilament light chain levels, NfL (standardized \u03b2 = 0.373, p = 0.001), and lower osteopontin levels (standardized \u03b2 = \u22120.23, p = 0.02). Higher baseline GFAP and lower FLRT2 levels were associated with future 5-year CP % volume expansion (standardized \u03b2 = 0.277, p = 0.004 and standardized \u03b2 = \u22120.226, p = 0.014, respectively). The CP volume in pwMS is associated with inflammatory blood-based biomarkers of neuronal injury (neurofilament light chain; NfL) and glial activation such as GFAP, osteopontin, and FLRT2. The expansion of the CP may play a central role in chronic and compartmentalized inflammation and may be driven by glial changes.<\/jats:p>","DOI":"10.3390\/biom14070824","type":"journal-article","created":{"date-parts":[[2024,7,12]],"date-time":"2024-07-12T11:28:03Z","timestamp":1720783683000},"page":"824","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Serum Biomarker Signatures of Choroid Plexus Volume Changes in Multiple Sclerosis"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7114-4958","authenticated-orcid":false,"given":"Dejan","family":"Jakimovski","sequence":"first","affiliation":[{"name":"Buffalo Neuroimaging Analysis Center, Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY 14203, USA"},{"name":"Wynn Hospital, Mohawk Valley Health System (MVHS), Utica, NY 13502, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7799-1485","authenticated-orcid":false,"given":"Robert","family":"Zivadinov","sequence":"additional","affiliation":[{"name":"Buffalo Neuroimaging Analysis Center, Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY 14203, USA"},{"name":"Center for Biomedical Imaging at the Clinical Translational Science Institute, University at Buffalo, State University of New York, Buffalo, NY 14203, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ferhan","family":"Qureshi","sequence":"additional","affiliation":[{"name":"Octave Bioscience, Menlo Park, CA 94025, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Murali","family":"Ramanathan","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY 14214, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6732-151X","authenticated-orcid":false,"given":"Bianca","family":"Weinstock-Guttman","sequence":"additional","affiliation":[{"name":"Department of Neurology, Jacobs Comprehensive MS Treatment and Research Center, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY 14203, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleonora","family":"Tavazzi","sequence":"additional","affiliation":[{"name":"Multiple Sclerosis Centre, IRCCS Mondino Foundation, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4684-4658","authenticated-orcid":false,"given":"Michael G.","family":"Dwyer","sequence":"additional","affiliation":[{"name":"Buffalo Neuroimaging Analysis Center, Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY 14203, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7792-0433","authenticated-orcid":false,"given":"Niels","family":"Bergsland","sequence":"additional","affiliation":[{"name":"Buffalo Neuroimaging Analysis Center, Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY 14203, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,7,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/S0140-6736(23)01473-3","article-title":"Multiple sclerosis","volume":"403","author":"Jakimovski","year":"2024","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2066","DOI":"10.1093\/brain\/awy151","article-title":"The compartmentalized inflammatory response in the multiple sclerosis brain is composed of tissue-resident CD8+ T lymphocytes and B cells","volume":"141","author":"Saji","year":"2018","journal-title":"Brain"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"E911","DOI":"10.1212\/WNL.0000000000201608","article-title":"Association of Choroid Plexus Inflammation on MRI with Clinical Disability Progression over 5 Years in Patients with Multiple Sclerosis","volume":"100","author":"Bergsland","year":"2023","journal-title":"Neurology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1368","DOI":"10.1172\/JCI41911","article-title":"Trafficking of immune cells in the central nervous system","volume":"120","author":"Wilson","year":"2010","journal-title":"J. Clin. Investig."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1186\/s12987-023-00441-4","article-title":"The choroid plexus acts as an immune cell reservoir and brain entry site in experimental autoimmune encephalomyelitis","volume":"20","author":"Lazarevic","year":"2023","journal-title":"Fluids Barriers CNS"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1186\/s40478-020-00903-y","article-title":"Altered secretory and neuroprotective function of the choroid plexus in progressive multiple sclerosis","volume":"8","author":"Francisco","year":"2020","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1646","DOI":"10.1093\/brain\/awab025","article-title":"Surface-in pathology in multiple sclerosis: A new view on pathogenesis?","volume":"144","author":"Pardini","year":"2021","journal-title":"Brain"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1528","DOI":"10.1002\/acn3.51644","article-title":"Choroid plexus volume in multiple sclerosis predicts expansion of chronic lesions and brain atrophy","volume":"9","author":"Klistorner","year":"2022","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1655","DOI":"10.1515\/cclm-2015-1195","article-title":"Comparison of three analytical platforms for quantification of the neurofilament light chain in blood samples: ELISA, electrochemiluminescence immunoassay and Simoa","volume":"54","author":"Kuhle","year":"2016","journal-title":"Clin. Chem. Lab. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"329","DOI":"10.2217\/nmt-2020-0058","article-title":"Disease biomarkers in multiple sclerosis: Current serum neurofilament light chain perspectives","volume":"11","author":"Jakimovski","year":"2021","journal-title":"Neurodegener. Dis. Manag."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2200018","DOI":"10.1002\/prca.202200018","article-title":"Analytical validation of a multi-protein, serum-based assay for disease activity assessments in multiple sclerosis","volume":"17","author":"Qureshi","year":"2023","journal-title":"Proteom. Clin. Appl."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1670","DOI":"10.1177\/1352458519881428","article-title":"Serum neurofilament light chain level associations with clinical and cognitive performance in multiple sclerosis: A longitudinal retrospective 5-year study","volume":"26","author":"Jakimovski","year":"2019","journal-title":"Mult. Scler. J."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1757","DOI":"10.1002\/acn3.50872","article-title":"Serum neurofilament light chain levels associations with gray matter pathology: A 5-year longitudinal study","volume":"6","author":"Jakimovski","year":"2019","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"fcad183","DOI":"10.1093\/braincomms\/fcad183","article-title":"Proteomics and relationship with axonal pathology in multiple sclerosis: 5-year diffusion tensor imaging study","volume":"5","author":"Jakimovski","year":"2023","journal-title":"Brain Commun."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1002\/acn3.51996","article-title":"Proteomic signatures of physical, cognitive, and imaging outcomes in multiple sclerosis","volume":"11","author":"Jalaleddini","year":"2024","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1016\/S1474-4422(17)30470-2","article-title":"Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria","volume":"17","author":"Thompson","year":"2018","journal-title":"Lancet Neurol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1444","DOI":"10.1212\/WNL.33.11.1444","article-title":"Rating neurologic impairment in multiple sclerosis: An expanded disability status scale (EDSS)","volume":"33","author":"Kurtzke","year":"1983","journal-title":"Neurology"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1212\/WNL.0000000000000560","article-title":"Defining the clinical course of multiple sclerosis: The 2013 revisions","volume":"83","author":"Lublin","year":"2014","journal-title":"Neurology"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1016\/S0896-6273(02)00569-X","article-title":"Whole brain segmentation: Automated labeling of neuroanatomical structures in the human brain","volume":"33","author":"Fischl","year":"2002","journal-title":"Neuron"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.3233\/JAD-190706","article-title":"Improving Choroid Plexus Segmentation in the Healthy and Diseased Brain: Relevance for Tau-PET Imaging in Dementia","volume":"74","author":"Tadayon","year":"2020","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_21","first-page":"2","article-title":"Association of Plasma Markers of Alzheimer\u2019s Disease, Neurodegeneration, and Neuroinflammation with the Choroid Plexus Integrity in Aging","volume":"15","author":"Bouhrara","year":"2024","journal-title":"Aging Dis."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1148\/radiol.2021204426","article-title":"Choroid Plexus Enlargement in Inflammatory Multiple Sclerosis: 3.0-T MRI and Translocator Protein PET Evaluation","volume":"301","author":"Ricigliano","year":"2021","journal-title":"Radiology"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e200026","DOI":"10.1212\/NXI.0000000000200026","article-title":"Imaging Characteristics of Choroid Plexuses in Presymptomatic Multiple Sclerosis a Retrospective Study","volume":"9","author":"Ricigliano","year":"2022","journal-title":"Neurol. Neuroimmunol. Neuroinflamm."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3056","DOI":"10.1016\/j.cell.2021.04.003","article-title":"A cellular and spatial map of the choroid plexus across brain ventricles and ages","volume":"184","author":"Dani","year":"2021","journal-title":"Cell"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Chunder, R., Schropp, V., Marzin, M., Amor, S., and Kuerten, S. (2023). A Dual Role of Osteopontin in Modifying B Cell Responses. Biomedicines, 11.","DOI":"10.21203\/rs.3.rs-2559156\/v1"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"102653","DOI":"10.1016\/j.msard.2020.102653","article-title":"Leptomeningeal, dura mater and meningeal vessel wall enhancements in multiple sclerosis","volume":"47","author":"Hildesheim","year":"2020","journal-title":"Mult. Scler. Relat. Disord."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e1083","DOI":"10.1212\/NXI.0000000000001083","article-title":"CSF Levels of CXCL12 and Osteopontin as Early Markers of Primary Progressive Multiple Sclerosis","volume":"8","author":"Marastoni","year":"2021","journal-title":"Neurol. Neuroimmunol. Neuroinflamm."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Li, J., Shinoda, Y., Ogawa, S., Ikegaya, S., Li, S., Matsuyama, Y., Sato, K., and Yamagishi, S. (2021). Expression of FLRT2 in Postnatal Central Nervous System Development and After Spinal Cord Injury. Front. Mol. Neurosci., 14.","DOI":"10.3389\/fnmol.2021.756264"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e2025000118","DOI":"10.1073\/pnas.2025000118","article-title":"Translational value of choroid plexus imaging for tracking neuroinflammation in mice and humans","volume":"118","author":"Fleischer","year":"2021","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"103406","DOI":"10.1016\/j.msard.2021.103406","article-title":"Discontinuation of disease modifying therapies is associated with disability progression regardless of prior stable disease and age","volume":"57","author":"Jakimovski","year":"2021","journal-title":"Mult. Scler. Relat. Disord."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/14\/7\/824\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:12:42Z","timestamp":1760109162000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/14\/7\/824"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,7,10]]},"references-count":30,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2024,7]]}},"alternative-id":["biom14070824"],"URL":"https:\/\/doi.org\/10.3390\/biom14070824","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,7,10]]}}}