{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T22:58:01Z","timestamp":1791932281754,"version":"4.3.4"},"reference-count":51,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2023,12,27]],"date-time":"2023-12-27T00:00:00Z","timestamp":1703635200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JPM"],"abstract":"<jats:p>Background: Alongside their long-term effects, post-concussion syndrome (PCS) and mild traumatic brain injuries (mTBI) are significant public health concerns. Currently, there is a lack of reliable biomarkers for diagnosing and monitoring mTBI and PCS. Exosomes are small extracellular vesicles secreted by cells that have recently emerged as a potential source of biomarkers for mTBI and PCS due to their ability to cross the blood\u2013brain barrier and reflect the pathophysiology of brain injury. In this study, we aimed to investigate the role of salivary exosomal biomarkers in mTBI and PCS. Methods: A systematic review using the PRISMA guidelines was conducted, and studies were selected based on their relevance to the topic. Results: The analyzed studies have shown that exosomal tau, phosphorylated tau (p-tau), amyloid beta (A\u03b2), and microRNAs (miRNAs) are potential biomarkers for mTBI and PCS. Specifically, elevated levels of exosomal tau and p-tau have been associated with mTBI and PCS as well as repetitive mTBI. Dysregulated exosomal miRNAs have also been observed in individuals with mTBI and PCS. Additionally, exosomal Prion cellular protein (PRPc), coagulation factor XIII (XIIIa), synaptogyrin-3, IL-6, and aquaporins have been identified as promising biomarkers for mTBI and PCS. Conclusion: Salivary exosomal biomarkers have the potential to serve as non-invasive and easily accessible diagnostic and prognostic tools for mTBI and PCS. Further studies are needed to validate these biomarkers and develop standardized protocols for their use in clinical settings. Salivary exosomal biomarkers can improve the diagnosis, monitoring, and treatment of mTBI and PCS, leading to improved patient outcomes.<\/jats:p>","DOI":"10.3390\/jpm14010035","type":"journal-article","created":{"date-parts":[[2023,12,27]],"date-time":"2023-12-27T05:43:15Z","timestamp":1703655795000},"page":"35","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Exploring the Potential of Exosomal Biomarkers in Mild Traumatic Brain Injury and Post-Concussion Syndrome: A Systematic Review"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9844-4010","authenticated-orcid":false,"given":"Ioannis","family":"Mavroudis","sequence":"first","affiliation":[{"name":"Department of Neuroscience, Leeds Teaching Hospitals, NHS Trust, Leeds LS2 9JT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sidra","family":"Jabeen","sequence":"additional","affiliation":[{"name":"Liaquat National Hospital and Medical College, Karachi 74800, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ioana Miruna","family":"Balmus","sequence":"additional","affiliation":[{"name":"Department of Exact Sciences and Natural Sciences, Institute of Interdisciplinary Research, \u201cAlexandru Ioan Cuza\u201d University of Iasi, 26th Alexandru Lapusneanu Street, 700057 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alin","family":"Ciobica","sequence":"additional","affiliation":[{"name":"Department of Biology, Faculty of Biology, Alexandru Ioan Cuza University of Iasi, 20th Carol I Avenue, 700506 Ia\u0219i, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vasile","family":"Burlui","sequence":"additional","affiliation":[{"name":"Preclinical Department, Apollonia University, P\u0103curari Street 11, 700511 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Romila","sequence":"additional","affiliation":[{"name":"Preclinical Department, Apollonia University, P\u0103curari Street 11, 700511 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3933-3393","authenticated-orcid":false,"given":"Alin","family":"Iordache","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, University of Medicine and Pharmacy \u201cGrigore T. Popa\u201d, 700115 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,12,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.spen.2019.03.003","article-title":"Definition, Classification, and Epidemiology of Concussion","volume":"30","author":"Kazl","year":"2019","journal-title":"Semin. Pediatr. Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Mavroudis, I., Kazis, D., Chowdhury, R., Petridis, F., Costa, V., Balmus, I.M., Ciobica, A., Luca, A.C., Radu, I., and Dobrin, R.P. (2022). Post-Concussion Syndrome and Chronic Traumatic Encephalopathy: Narrative Review on the Neuropathology, Neuroimaging and Fluid Biomarkers. Diagnostics, 12.","DOI":"10.3390\/diagnostics12030740"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1016\/j.mcn.2005.12.003","article-title":"Exosomes are released by cultured cortical neurones","volume":"31","author":"Lachenal","year":"2006","journal-title":"Mol. Cell. Neurosci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"79","DOI":"10.3389\/fnmol.2020.00079","article-title":"Brain Derived Exosomes Are a Double-Edged Sword in Alzheimer\u2019s Disease","volume":"13","author":"Song","year":"2020","journal-title":"Front. Mol. Neurosci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1007\/s11481-017-9768-z","article-title":"Extracellular vesicle biology in Alzheimer\u2019s disease and related tauopathy","volume":"13","author":"DeLeo","year":"2018","journal-title":"J. Neuroimmune Pharmacol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"9412","DOI":"10.1016\/S0021-9258(18)48095-7","article-title":"Vesicle formation during reticulocyte maturation. Association of plasma membrane activities with released vesicles (exosomes)","volume":"262","author":"Johnstone","year":"1987","journal-title":"J. Biol. Chem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"6917","DOI":"10.2147\/IJN.S264498","article-title":"Exosome: A review of its classification, isolation techniques, storage, diagnostic and targeted therapy applications","volume":"15","author":"Zhang","year":"2020","journal-title":"Int. J. Nanomed."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3126","DOI":"10.1038\/s41375-020-01041-z","article-title":"Extracellular microvesicles\/exosomes: Discovery, disbelief, acceptance, and the future?","volume":"34","author":"Ratajczak","year":"2020","journal-title":"Leukemia"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"26913","DOI":"10.3402\/jev.v3.26913","article-title":"Minimal experimental requirements for definition of extracellular vesicles and their functions: A position statement from the International Society for Extracellular Vesicles","volume":"3","author":"Hill","year":"2014","journal-title":"J. Extracell. Vesicles"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"McKelvey, K.J., Powell, K.L., Ashton, A.W., Morris, J.M., and McCracken, S.A. (2015). Exosomes: Mechanisms of uptake. J. Circ. Biomark, 4.","DOI":"10.33393\/jcb.2015.2057"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Fr\u00fchbeis, C., Fr\u00f6hlich, D., Kuo, W.P., Amphornrat, J., Thilemann, S., Saab, A.S., Kirchhoff, F., M\u00f6bius, W., Goebbels, S., and Nave, K.-A. (2013). Neurotransmitter-triggered transfer of exosomes mediates oligodendrocyte-neuron communication. PLoS Biol., 11.","DOI":"10.1371\/journal.pbio.1001604"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Manek, R., Moghieb, A., Yang, Z., Kumar, D., Kobeissy, F., Sarkis, G.A., Raghavan, V., and Wang, K.K.W. (2018). Correction to: Protein biomarkers and neuroproteomics characterization of microvesicles\/exosomes from human cerebrospinal fluid following traumatic brain injury. Mol. Neurobiol., 55.","DOI":"10.1007\/s12035-018-0909-z"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e1126","DOI":"10.1212\/WNL.0000000000010087","article-title":"Blood biomarkers of traumatic brain injury and cognitive impairment in older veterans","volume":"95","author":"Peltz","year":"2020","journal-title":"Neurology"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"5082","DOI":"10.1096\/fj.201802319R","article-title":"Altered levels of plasma neuron-derived exosomes and their cargo proteins characterize acute and chronic mild traumatic brain injury","volume":"33","author":"Goetzl","year":"2019","journal-title":"FASEB J."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e2412","DOI":"10.1212\/WNL.0000000000009577","article-title":"Exosomal neurofilament light: A prognostic biomarker for remote symptoms after mild traumatic brain injury?","volume":"94","author":"Guedes","year":"2020","journal-title":"Neurology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1038\/s41582-018-0126-4","article-title":"Exosomes\u2014Beyond stem cells for restorative therapy in stroke and neurological injury","volume":"15","author":"Zhang","year":"2019","journal-title":"Nat. Rev. Neurol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1096\/fj.201700673r","article-title":"Increased miR-124-3p in microglial exosomes following traumatic brain injury inhibits neuronal inflammation and contributes to neurite outgrowth via their transfer into neurons","volume":"32","author":"Huang","year":"2018","journal-title":"FASEB J."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1903","DOI":"10.1007\/s11064-019-02825-1","article-title":"Increases in miR-124-3p in Microglial Exosomes Confer Neuroprotective Effects by Targeting FIP200-Mediated Neuronal Autophagy Following Traumatic Brain Injury","volume":"44","author":"Li","year":"2019","journal-title":"Neurochem. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1276","DOI":"10.1080\/02699052.2018.1483530","article-title":"Higher exosomal phosphorylated tau and total tau among veterans with combat-related repetitive chronic mild traumatic brain injury","volume":"32","author":"Kenney","year":"2018","journal-title":"Brain Inj."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1038\/s41378-021-00244-3","article-title":"Acoustofluidic separation enables early diagnosis of traumatic brain injury based on circulating exosomes","volume":"7","author":"Wang","year":"2021","journal-title":"Microsyst. Nanoeng."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2482","DOI":"10.1089\/neu.2019.6933","article-title":"Exosomal MicroRNAs in Military Personnel with Mild Traumatic Brain Injury: Preliminary Results from the Chronic Effects of Neurotrauma Consortium Biomarker Discovery Project","volume":"37","author":"Devoto","year":"2020","journal-title":"J. Neurotrauma"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"652","DOI":"10.1080\/02699052.2022.2042854","article-title":"Remote blast-related mild traumatic brain injury is associated with differential expression of exosomal microRNAs identified in neurodegenerative and immunological processes","volume":"36","author":"Devoto","year":"2022","journal-title":"Brain Inj."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1359","DOI":"10.1080\/02699052.2018.1471738","article-title":"Higher exosomal tau, amyloid-beta 42 and IL-10 are associated with mild TBIs and chronic symptoms in military personnel","volume":"32","author":"Gill","year":"2018","journal-title":"Brain Inj."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"452","DOI":"10.3389\/fnins.2019.00452","article-title":"Neuron-Derived Exosome Proteins May Contribute to Progression from Repetitive Mild Traumatic Brain Injuries to Chronic Traumatic Encephalopathy","volume":"13","author":"Goetzl","year":"2019","journal-title":"Front. Neurosci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.3389\/fnins.2019.01005","article-title":"Assessing Neuronal and Astrocyte Derived Exosomes from Individuals With Mild Traumatic Brain Injury for Markers of Neurodegeneration and Cytotoxic Activity","volume":"13","author":"Winston","year":"2019","journal-title":"Front. Neurosci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.bbi.2021.11.015","article-title":"Extracellular vesicle-associated cytokines in sport-related concussion","volume":"100","author":"Meier","year":"2022","journal-title":"Brain Behav. Immun."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"745348","DOI":"10.3389\/fphar.2021.745348","article-title":"Extracellular Vesicle Proteins and MicroRNAs Are Linked to Chronic Post-Traumatic Stress Disorder Symptoms in Service Members and Veterans With Mild Traumatic Brain Injury","volume":"12","author":"Guedes","year":"2021","journal-title":"Front. Pharmacol."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Mavroudis, I., Chatzikonstantinou, S., Petridis, F., Palade, O.D., Ciobica, A., and Balmus, I.-M. (2023). Functional Overlay Model of Persistent Post-Concussion Syndrome. Brain Sci., 13.","DOI":"10.3390\/brainsci13071028"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Mavroudis, I., Chatzikonstantinou, S., Ciobica, A., Balmus, I.-M., Iordache, A., Kazis, D., Chowdhury, R., and Luca, A.-C. (2022). A Systematic Review and Meta-Analysis of the Grey Matter Volumetric Changes in Mild Traumatic Brain Injuries. Appl. Sci., 12.","DOI":"10.3390\/app12199954"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Mavroudis, I., Petridis, F., Balmus, I.-M., Ciobica, A., Gorgan, D.L., and Luca, A.C. (2023). Review on the Role of Salivary Biomarkers in the Diagnosis of Mild Traumatic Brain Injury and Post-Concussion Syndrome. Diagnostics, 13.","DOI":"10.3390\/diagnostics13081367"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"904295","DOI":"10.3389\/fmed.2022.904295","article-title":"Cargo and Functional Profile of Saliva-Derived Exosomes Reveal Biomarkers Specific for Head and Neck Cancer","volume":"9","author":"Hofmann","year":"2022","journal-title":"Front. Med."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Mavroudis, I., Balmus, I.-M., Ciobica, A., Nicoara, M.N., Luca, A.C., and Palade, D.O. (2023). The Role of Microglial Exosomes and miR-124-3p in Neuroinflammation and Neuronal Repair after Traumatic Brain Injury. Life, 13.","DOI":"10.20944\/preprints202307.1850.v1"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"743353","DOI":"10.3389\/fncel.2021.743353","article-title":"Role of Exosomes in Brain Diseases","volume":"15","author":"Zhang","year":"2021","journal-title":"Front. Cell. Neurosci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1038\/s41398-019-0459-9","article-title":"The emerging role of exosomes in mental disorders","volume":"9","author":"Saeedi","year":"2019","journal-title":"Transl. Psychiatry"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1186\/s12967-022-03493-6","article-title":"Role of exosomes in the pathogenesis, diagnosis, and treatment of central nervous system diseases","volume":"20","author":"Fan","year":"2022","journal-title":"J. Transl. Med."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Xu, X., Xu, L., Wen, C., Xia, J., Zhang, Y., and Liang, Y. (2023). Programming assembly of biomimetic exosomes: An emerging theranostic nanomedicine platform. Mater. Today Bio, 22.","DOI":"10.1016\/j.mtbio.2023.100760"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"608","DOI":"10.1038\/s44222-023-00064-2","article-title":"Stem cell-derived exosome versus stem cell therapy","volume":"1","author":"Zhang","year":"2023","journal-title":"Nat. Rev. Bioeng."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"7","DOI":"10.21037\/sci-2020-037","article-title":"Exosomal therapy-a new frontier in regenerative medicine","volume":"8","author":"Muthu","year":"2021","journal-title":"Stem. Cell Investig."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Dehmelt, L., and Halpain, S. (2004). The MAP2\/Tau family of microtubule-associated proteins. Genome Biol., 6.","DOI":"10.1186\/gb-2004-6-1-204"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1089\/neu.2018.6348","article-title":"Traumatic Brain Injury Induces Tau Aggregation and Spreading","volume":"37","author":"Edwards","year":"2020","journal-title":"J. Neurotrauma"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"CNC98","DOI":"10.2217\/cnc-2022-0004","article-title":"Tau as a fluid biomarker of concussion and neurodegeneration","volume":"7","author":"Hossain","year":"2022","journal-title":"Concussion"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.1001\/jamaneurol.2017.0655","article-title":"Comparing Plasma Phospho Tau, Total Tau, and Phospho Tau-Total Tau Ratio as Acute and Chronic Traumatic Brain Injury Biomarkers","volume":"74","author":"Rubenstein","year":"2017","journal-title":"JAMA Neurol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"299","DOI":"10.3233\/JAD-2011-110731","article-title":"Salivary tau species are potential biomarkers of Alzheimer\u2019s disease","volume":"27","author":"Shi","year":"2011","journal-title":"J. Alzheimers Dis."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/j.archoralbio.2019.06.004","article-title":"Salivary biological biomarkers for Alzheimer\u2019s disease","volume":"105","author":"Liang","year":"2019","journal-title":"Arch. Oral. Biol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1049","DOI":"10.3233\/JAD-220159","article-title":"Traumatic Brain Injury and Risk of Alzheimer\u2019s Disease and Related Dementias in the Population","volume":"88","author":"Mielke","year":"2022","journal-title":"J. Alzheimers Dis."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1159\/000520966","article-title":"Traumatic Brain Injury and Risk of Dementia and Alzheimer\u2019s Disease: A Systematic Review and Meta-Analysis","volume":"56","author":"Gu","year":"2022","journal-title":"Neuroepidemiology"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2398212820979802","DOI":"10.1177\/2398212820979802","article-title":"The role of cytokines in modulating learning and memory and brain plasticity","volume":"4","author":"Bourgognon","year":"2020","journal-title":"Brain Neurosci. Adv."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1186\/s12974-020-02005-x","article-title":"Cellular infiltration in traumatic brain injury","volume":"17","author":"Alam","year":"2020","journal-title":"J. Neuroinflammation"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"3644","DOI":"10.7150\/ijms.46834","article-title":"The Peripheral Immune System and Traumatic Brain Injury: Insight into the role of T-helper cells","volume":"18","author":"Bao","year":"2021","journal-title":"Int. J. Med. Sci."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"eabb6260","DOI":"10.1126\/sciadv.abb6260","article-title":"M-CSF, IL-6, and TGF-\u03b2 promote generation of a new subset of tissue repair macrophage for traumatic brain injury recovery","volume":"7","author":"Li","year":"2021","journal-title":"Sci. Adv."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"n71","DOI":"10.1136\/bmj.n71","article-title":"The PRISMA 2020 statement: An updated guideline for reporting systematic reviews","volume":"372","author":"Page","year":"2021","journal-title":"BMJ"}],"container-title":["Journal of Personalized Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-4426\/14\/1\/35\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:42:41Z","timestamp":1760132561000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-4426\/14\/1\/35"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,12,27]]},"references-count":51,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,1]]}},"alternative-id":["jpm14010035"],"URL":"https:\/\/doi.org\/10.3390\/jpm14010035","relation":{},"ISSN":["2075-4426"],"issn-type":[{"value":"2075-4426","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,12,27]]}}}