{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T20:27:47Z","timestamp":1792009667866,"version":"4.4.0"},"reference-count":34,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2025,11,12]],"date-time":"2025-11-12T00:00:00Z","timestamp":1762905600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NanoSomiX, Inc."},{"DOI":"10.13039\/100000001","name":"National Science Foundation through the UC Irvine Materials Research Science and Engineering Center","doi-asserted-by":"publisher","award":["DMR-2011967"],"award-info":[{"award-number":["DMR-2011967"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["1R01NS113950"],"award-info":[{"award-number":["1R01NS113950"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Indiana State Department of Health","award":["ISCBIRF 0019939"],"award-info":[{"award-number":["ISCBIRF 0019939"]}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"crossref","award":["1U10NS086513"],"award-info":[{"award-number":["1U10NS086513"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100006108","name":"National Center for Advancing Translational Sciences","doi-asserted-by":"crossref","award":["KL2TR001432"],"award-info":[{"award-number":["KL2TR001432"]}],"id":[{"id":"10.13039\/100006108","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>White matter, comprising 60% of the human brain, is formed by axonal fibers supported by oligodendrocytes. It is essential for brain communication, yet damage can accumulate silently leading to severe neurological problems. Current diagnostics detect changes only after symptoms appear. To enable earlier detection damage, we developed a blood test monitoring changes in oligodendrocyte-derived extracellular vesicles (ODEs) released from the brain into circulation. After validating the assay, we have shown that ODE levels vary from different individuals. However, ODE levels remain stable under mild head impacts in soccer heading practice (n = 15) and boxing\/mixed martial arts (n = 10), whereas change markedly following neurological insults such as hemorrhagic (n = 7) and ischemic stroke (n = 14), or gynecological cancer after chemotherapy (n = 11). ODE measurement can potentially provide a minimally invasive window into white matter health and support early diagnosis, personalized assessment, and new insights into human brain biology.<\/jats:p>","DOI":"10.3390\/cells14221771","type":"journal-article","created":{"date-parts":[[2025,11,12]],"date-time":"2025-11-12T10:56:47Z","timestamp":1762945007000},"page":"1771","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["WHITE MATTER MATTERS: New Approach to the Brain\u2019s Hidden Half Using Circulating Oligodendrocyte-Derived Extracellular Vesicles"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3392-140X","authenticated-orcid":false,"given":"Masato","family":"Mitsuhashi","sequence":"first","affiliation":[{"name":"NanoSomiX, Inc., Irvine, CA 92618, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dennis","family":"Van Epps","sequence":"additional","affiliation":[{"name":"NanoSomiX, Inc., Irvine, CA 92618, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-5328-7342","authenticated-orcid":false,"given":"Haiping","family":"Sun","sequence":"additional","affiliation":[{"name":"Irvine Materials Research Institute, University of California\u2014Irvine, Irvine, CA 92697, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7612-602X","authenticated-orcid":false,"given":"Li","family":"Xing","sequence":"additional","affiliation":[{"name":"Irvine Materials Research Institute, University of California\u2014Irvine, Irvine, CA 92697, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4135-9311","authenticated-orcid":false,"given":"Keisuke","family":"Kawata","sequence":"additional","affiliation":[{"name":"Kinesiology, School of Public Health, Indiana University, Bloomington, IN 47405, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viviana","family":"Jimenez","sequence":"additional","affiliation":[{"name":"Center for Sports Neurology & Pain Medicine, Cedars-Sinai Kerlan-Jobe Institute, Los Angeles, CA 90045, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-8648-2628","authenticated-orcid":false,"given":"Vernon B.","family":"Williams","sequence":"additional","affiliation":[{"name":"Center for Sports Neurology & Pain Medicine, Cedars-Sinai Kerlan-Jobe Institute, Los Angeles, CA 90045, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6617-567X","authenticated-orcid":false,"given":"Cina","family":"Sasannejad","sequence":"additional","affiliation":[{"name":"Department of Neurology, Duke University, Durham, NC 27710, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8715-5210","authenticated-orcid":false,"given":"Michael L.","family":"James","sequence":"additional","affiliation":[{"name":"Duke Clinical Research Institute, Duke University, Durham, NC 27710, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0327-5531","authenticated-orcid":false,"given":"Matthew A.","family":"Edwardson","sequence":"additional","affiliation":[{"name":"Neurology & Rehabilitation Medicine, Georgetown University, Washington, DC 20007, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8449-9053","authenticated-orcid":false,"given":"Takuya","family":"Murata","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Kawasaki Medical School General Medical Center, Okayama 700-8505, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Grieb, P., \u015awi\u0105tkiewicz, M., Kami\u0144ska, A., J\u00fcnemann, A., Rejdak, R.R., and Rejdak, K. (2021). Citicoline: A Candidate for Adjunct Treatment of Multiple Sclerosis. Pharmaceuticals, 14.","DOI":"10.3390\/ph14040326"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2481","DOI":"10.1016\/S0140-6736(17)32346-2","article-title":"Clemastine Fumarate as a Remyelinating Therapy for Multiple Sclerosis (ReBUILD): A Randomised, Controlled, Double-Blind, Crossover Trial","volume":"390","author":"Green","year":"2017","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"12079","DOI":"10.1038\/srep12079","article-title":"Treatment of Minocycline Alleviates White Matter and Cognitive Impairments After Chronic Cerebral Hypoperfusion","volume":"5","author":"Ma","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"112533","DOI":"10.1016\/j.exger.2024.112533","article-title":"Pegylated Chitosan Nanoparticles of Fluoxetine Enhance Cognitive Performance and Hippocampal Brain Derived Neurotrophic Factor Levels in a Rat Model of Local Demyelination","volume":"195","author":"Dadkhah","year":"2024","journal-title":"Exp. Gerontol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1186\/s13287-015-0111-4","article-title":"White Matter Injury Restoration After Stem Cell Administration in Subcortical Ischemic Stroke","volume":"6","author":"Fuentes","year":"2015","journal-title":"Stem Cell Res. Ther."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"113895","DOI":"10.1016\/j.expneurol.2021.113895","article-title":"Exosomes Derived From Bone Marrow Mesenchymal Stromal Cells Promote Remyelination and Reduce Neuroinflammation in the Demyelinating Central Nervous System","volume":"347","author":"Zhang","year":"2022","journal-title":"Exp. Neurol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"557","DOI":"10.2174\/1871527320666210809121922","article-title":"Mechanisms Involved in Neuroprotective Effects of Transcranial Magnetic Stimulation","volume":"21","author":"Medina","year":"2022","journal-title":"CNS Neurol. Disord. Drug Targets"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.wneu.2024.06.003","article-title":"Applications of Functional Magnetic Resonance Imaging to the Study of Functional Connectivity and Activation in Neurological Disease: A Scoping Review of the Literature","volume":"189","author":"Leskinen","year":"2024","journal-title":"World Neurosurg."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1016\/j.neulet.2018.12.007","article-title":"Review of Diffusion MRI Studies in Chronic White Matter Diseases","volume":"694","author":"Raja","year":"2019","journal-title":"Neurosci. Lett."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1177\/000456320203900610","article-title":"Detection of Myelin Basic Protein in Cerebrospinal Fluid and Serum From Patients with HTLV-1-associated Myelopathy\/Tropical Spastic Paraparesis","volume":"39","author":"Ohta","year":"2002","journal-title":"Ann. Clin. Biochem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1065","DOI":"10.1089\/neu.2024.0581","article-title":"Blood-Based Biomarkers for Improved Characterization of Traumatic Brain Injury: Recommendations From the 2024 National Institute for Neurological Disorders and Stroke Traumatic Brain Injury Classification and Nomenclature Initiative Blood-Based Biomarkers Working Group","volume":"42","author":"Bazarian","year":"2025","journal-title":"J. Neurotrauma"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.parkreldis.2018.11.021","article-title":"Quantification of brain-derived extracellular vesicles in plasma as a biomarker to diagnose Parkinson\u2019s and related diseases","volume":"61","author":"Ohmichi","year":"2019","journal-title":"Park. Relat. Disord."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"5272","DOI":"10.1038\/s41598-024-55983-w","article-title":"Elevation of astrocyte-derived extracellular vesicles over the first month post-stroke in humans","volume":"14","author":"Edwardson","year":"2024","journal-title":"Sci. Rep."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"239","DOI":"10.3389\/fneur.2018.00239","article-title":"A preliminary report on brain-derived extracellular vesicle as novel blood biomarkers for sport-related concussions","volume":"9","author":"Kawata","year":"2018","journal-title":"Front. Neurol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"11772719221128145","DOI":"10.1177\/11772719221128145","article-title":"Monitoring of Post-Brain Injuries By Measuring Plasma Levels of Neuron-Derived Extracellular Vesicles","volume":"17","author":"Hotta","year":"2022","journal-title":"Biomark. Insights"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e0239507","DOI":"10.1371\/journal.pone.0239507","article-title":"Does acute soccer heading cause an increase in plasma S100B? A randomized controlled trial","volume":"15","author":"Huibregtse","year":"2020","journal-title":"PLoS ONE"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e12451","DOI":"10.1002\/jev2.12404","article-title":"Minimal information for studies of extracellular vesicles (MISEV2023): From basic to advanced approaches","volume":"13","author":"Welsh","year":"2024","journal-title":"J. Extracell. Vesicles"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"11059","DOI":"10.1073\/pnas.1833158100","article-title":"The Crystal Structure of Myelin Oligodendrocyte Glycoprotein, a Key Autoantigen in Multiple Sclerosis","volume":"100","author":"Clements","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/j.ctrv.2017.09.010","article-title":"Chemotherapy-Induced Cognitive Impairments: White Matter Pathologies","volume":"61","author":"Matsos","year":"2017","journal-title":"Cancer Treat. Rev."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"600","DOI":"10.1016\/j.jalz.2014.06.008","article-title":"Identification of preclinical Alzheimer\u2019s disease by a profile of pathogenic proteins in neurally derived blood exosomes: A case-control study","volume":"11","author":"Fiandaca","year":"2015","journal-title":"Alzheimers Dement."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1124\/pharmrev.122.000788","article-title":"Emergence of Extracellular Vesicles as \u201cLiquid Biopsy\u201d for Neurological Disorders: Boom or Bust","volume":"76","author":"Kumar","year":"2024","journal-title":"Pharmacol. Rev."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1194210","DOI":"10.3389\/fnmol.2023.1194210","article-title":"A New Diagnostic Tool for Brain Disorders: Extracellular Vesicles Derived from Neuron, Astrocyte, and Oligodendrocyte","volume":"16","author":"Wang","year":"2023","journal-title":"Front. Mol. Neurosci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1038\/s41582-025-01080-z","article-title":"Extracellular Vesicles: Translational Research and Applications in Neurology","volume":"21","author":"Manolopoulos","year":"2025","journal-title":"Nat. Rev. Neurol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Agliardi, C., Guerini, F.R., Zanzottera, M., Bolognesi, E., Picciolini, S., Caputo, D., Rovaris, M., Pasanisi, M.B., and Clerici, M. (2023). Myelin Basic Protein in Oligodendrocyte-Derived Extracellular Vesicles as a Diagnostic and Prognostic Biomarker in Multiple Sclerosis: A Pilot Study. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24010894"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1780","DOI":"10.1093\/brain\/awaa110","article-title":"Reduced Oligodendrocyte Exosome Secretion in Multiple System Atrophy Involves SNARE Dysfunction","volume":"143","author":"Yu","year":"2020","journal-title":"Brain J. Neurol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Banks, W.A., Sharma, P., Bullock, K.M., Hansen, K.M., Ludwig, N., and Whiteside, T.L. (2020). Transport of Extracellular Vesicles across the Blood-Brain Barrier: Brain Pharmacokinetics and Effects of Inflammation. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21124407"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"24436","DOI":"10.1038\/srep24436","article-title":"Lymphatic transport of exosomes as a rapid route of information dissemination to the lymph node","volume":"6","author":"Srinivasan","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Banks, W.A., Sharma, P., Hansen, K.M., Ludwig, N., and Whiteside, T.L. (2022). Characteristics of Exosomes and the Vascular Landscape Regulate Exosome Sequestration by Peripheral Tissues and Brain. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232012513"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1696517","DOI":"10.1080\/20013078.2019.1696517","article-title":"Blood Concentrations of Small Extracellular Vesicles Are Determined by a Balance Between Abundant Secretion and Rapid Clearance","volume":"9","author":"Matsumoto","year":"2020","journal-title":"J. Extracell. Vesicles"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"7589","DOI":"10.1007\/s00018-021-03969-6","article-title":"Extracellular Vesicle Release and Uptake by the Liver Under Normo-And Hyperlipidemia","volume":"78","author":"Varga","year":"2021","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"14265","DOI":"10.1038\/s41598-022-16431-9","article-title":"Unveiling Trail Making Test: Visual and Manual Trajectories Indexing Multiple Executive Processes","volume":"12","author":"Linari","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1016\/j.humov.2010.11.009","article-title":"Review of First Trial Responses in Balance Control: Influence of Vestibular Loss and Parkinson\u2019s Disease","volume":"30","author":"Allum","year":"2011","journal-title":"Hum. Mov. Sci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"109212","DOI":"10.1016\/j.neuropsychologia.2025.109212","article-title":"Gait Disorientation as a Proxy for Impaired Spatial Navigation: Associations Between the Gait Disorientation Test and Vestibular-Mediated Functions","volume":"217","author":"Batts","year":"2025","journal-title":"Neuropsychologia"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Peksa, J., and Mamchur, D. (2023). State-of-the-Art on Brain-Computer Interface Technology. Sensors, 23.","DOI":"10.3390\/s23136001"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/22\/1771\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,14]],"date-time":"2025-11-14T05:24:35Z","timestamp":1763097875000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/22\/1771"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,12]]},"references-count":34,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2025,11]]}},"alternative-id":["cells14221771"],"URL":"https:\/\/doi.org\/10.3390\/cells14221771","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,12]]}}}