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Salivary Biomarkers as Indicators of TBI Diagnosis and Prognosis: A Systematic Review

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Abstract

Background and Objective

Traumatic brain injuries are physical injuries to the head that result in disruptions to normal brain function. Diagnostic tools such as computed tomography scans have commonly been used to detect traumatic brain injuries but are costly and not ubiquitously available. Recent research on diagnostic alternatives has focused on using salivary biomarkers, but there is no consensus on the utility of these methods.  The objective of this manuscript is to address the gap in the literature pertaining to the effectiveness of salivary biomarkers for TBI diagnosis and prognosis.

Methods

A systematic review was conducted between November 2020 and October 2021 using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Six databases were searched using the terms “traumatic brain injury,” “TBI,” “saliva,” and “biomarkers.” Literature published prior to 2010 was excluded, and two authors reviewed each full-text article to ensure its relevance.

Results

A total of 18 articles were included in this review, with nine articles on salivary microRNA, three on salivary hormones, three on salivary extracellular vesicles, and three on salivary proteins.

Conclusions

Studies reported changes in salivary biomarkers after traumatic brain injuries and indicated a possible link between salivary biomarker expression and traumatic brain injury severity. However, it is unclear the degree to which salivary biomarkers accurately predict traumatic brain injury diagnosis and prognosis; some studies reported significant associations while others reported weaker associations. More research into the robustness of salivary biomarkers is needed to fully elucidate their utility for the traumatic brain injury population.

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References

  1. National Institute of Neurological Disorders and Stroke. Traumatic brain injury information. https://www.ninds.nih.gov/Disorders/All-Disorders/Traumatic-Brain-Injury-Information-Page. Accessed 26 Jun 2021.

  2. CDC Injury Center. Traumatic brain injury/concussion/concussion. https://www.cdc.gov/traumaticbraininjury/index.html. Accessed 2 Jul 2021.

  3. McAllister TW. Neurobehavioral sequelae of traumatic brain injury: evaluation and management. World Psychiatry. 2008;7:3–10. https://doi.org/10.1002/j.2051-5545.2008.tb00139.x.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Gaddam SSK, Buell T, Robertson CS. Systemic manifestations of traumatic brain injury. Handb Clin Neurol. 2015;127:205–18. https://doi.org/10.1016/B978-0-444-52892-6.00014-3.

    Article  PubMed  Google Scholar 

  5. Dang B, Chen W, He W, Chen G. Rehabilitation treatment and progress of traumatic brain injury dysfunction. Neural Plast. 2017;2017:1582182. https://doi.org/10.1155/2017/1582182.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Su YRS, Schuster JM, Smith DH, Stein SC. Cost-effectiveness of biomarker screening for traumatic brain injury. J Neurotrauma. 2019;36:2083–91. https://doi.org/10.1089/neu.2018.6020.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Katz DI, Cohen SI, Alexander MP. Mild traumatic brain injury. Handb Clin Neurol. 2015;127:131–56. https://doi.org/10.1016/B978-0-444-52892-6.00009-X.

    Article  PubMed  Google Scholar 

  8. Silverberg ND, Iverson GL, Brubacher JR, Holland E, Hoshino LC, Aquino A, et al. The nature and clinical significance of preinjury recall bias following mild traumatic brain injury. J Head Trauma Rehabil. 2016;31:388–96. https://doi.org/10.1097/HTR.0000000000000198.

    Article  PubMed  Google Scholar 

  9. Wang KK, Yang Z, Zhu T, Shi Y, Rubenstein R, Tyndall JA, et al. An update on diagnostic and prognostic biomarkers for traumatic brain injury. Expert Rev Mol Diagn. 2018;18:165–80. https://doi.org/10.1080/14737159.2018.1428089.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Dadas A, Washington J, Diaz-Arrastia R, Janigro D. Biomarkers in traumatic brain injury (TBI): a review. Neuropsychiatr Dis Treat. 2018;14:2989–3000. https://doi.org/10.2147/NDT.S125620.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Teunissen CE, Petzold A, Bennett JL, Berven FS, Brundin L, Comabella M, et al. A consensus protocol for the standardization of cerebrospinal fluid collection and biobanking. Neurology. 2009;73:1914–22. https://doi.org/10.1212/WNL.0b013e3181c47cc2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Migdal VL, Wu WK, Long D, McNaughton CD, Ward MJ, Self WH. Risk-benefit analysis of lumbar puncture to evaluate for nontraumatic subarachnoid hemorrhage in adult ED patients. Am J Emerg Med. 2015;33:1597–601. https://doi.org/10.1016/j.ajem.2015.06.048.

  13. Yoshizawa JM, Schafer CA, Schafer JJ, Farrell JJ, Paster BJ, Wong DTW. Salivary biomarkers: toward future clinical and diagnostic utilities. Clin Microbiol Rev. 2013;26:781–91. https://doi.org/10.1128/CMR.00021-13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Ng WH, Drake JM. Symptomatic spinal epidural CSF collection after lumbar puncture in a young adult: case report and review of literature. Child Nerv Syst. 2010;26:259–62. https://doi.org/10.1007/s00381-009-0998-0.

    Article  Google Scholar 

  15. Lindsay A, Costello JT. Realising the potential of urine and saliva as diagnostic tools in sport and exercise medicine. Sports Med. 2017;47:11–31. https://doi.org/10.1007/s40279-016-0558-1.

    Article  PubMed  Google Scholar 

  16. Gorodischer R, Burtin P, Hwang P, Levine M, Koren G. Saliva versus blood sampling for therapeutic drug monitoring in children: patient and parental preferences and an economic analysis. Ther Drug Monit. 1994;16:437–43. https://doi.org/10.1097/00007691-199410000-00001.

    Article  CAS  PubMed  Google Scholar 

  17. Pinchi E, Luigi C, Paola S, Gianpietro V, Raoul T, Mauro A, et al. MicroRNAs: the new challenge for traumatic brain injury diagnosis. Curr Neuropharmacol. 2019;18:319–31. https://doi.org/10.2174/1570159x17666191113100808.

    Article  CAS  Google Scholar 

  18. Guedes VA, Devoto C, Leete J, Sass D, Acott JD, Mithani S, et al. Extracellular vesicle proteins and microRNAs as biomarkers for traumatic brain injury. Front Neurol. 2020;11:663. https://doi.org/10.3389/fneur.2020.00663.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Cheng Y, Pereira M, Raukar N, Reagan J, Quesenberry M, Goldberg L, et al. Inflammation-related gene expression profiles of salivary extracellular vesicles in patients with head trauma. Neural Regen Res. 2020;15:676–81. https://doi.org/10.4103/1673-5374.266924.

    Article  PubMed  Google Scholar 

  20. Cheng Y, Pereira M, Raukar N, Reagan JL, Queseneberry M, Goldberg L, et al. Potential biomarkers to detect traumatic brain injury by the profiling of salivary extracellular vesicles. J Cell Physiol. 2019;234:14377–88. https://doi.org/10.1002/jcp.28139.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Janigro D, Kawata K, Silverman E, Marchi N, Diaz-Arrastia R. Is salivary S100B a biomarker of traumatic brain injury? A pilot study. Front Neurol. 2020;11:528. https://doi.org/10.3389/fneur.2020.00528.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Yeung C, Bhatia R, Bhattarai B, Sinha M. Role of salivary biomarkers in predicting significant traumatic brain injury. Pediatr Emerg Care. 2020. https://doi.org/10.1097/PEC.0000000000002050.

    Article  Google Scholar 

  23. Hicks SD, Johnson J, Carney MC, Bramley H, Olympia RP, Loeffert AC, et al. Overlapping microRNA expression in saliva and cerebrospinal fluid accurately identifies pediatric traumatic brain injury. J Neurotrauma. 2018;35:64–72. https://doi.org/10.1089/neu.2017.5111.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Johnson JJ, Loeffert AC, Stokes J, Olympia RP, Bramley H, Hicks SD. Association of salivary microRNA changes with prolonged concussion symptoms. JAMA Pediatr. 2018;172:65–73. https://doi.org/10.1001/jamapediatrics.2017.3884.

    Article  PubMed  Google Scholar 

  25. LaRocca D, Barns S, Hicks SD, Brindle A, Williams J, Uhlig R, et al. Comparison of serum and saliva miRNAs for identification and characterization of mTBI in adult mixed martial arts fighters. PLoS One. 2019;14: e0207785. https://doi.org/10.1371/journal.pone.0207785.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. di Pietro V, Porto E, Ragusa M, Barbagallo C, Davies D, Forcione M, et al. Salivary microRNAs: diagnostic markers of mild traumatic brain injury in contact-sport. Front Mol Neurosci. 2018;11:290. https://doi.org/10.3389/fnmol.2018.00290.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Ewing-Cobbs L, Prasad MR, Cox CS, Granger DA, Duque G, Swank PR. Altered stress system reactivity after pediatric injury: relation with post-traumatic stress symptoms. Psychoneuroendocrinology. 2017;84:66–75. https://doi.org/10.1016/j.psyneuen.2017.06.003.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Hicks SD, Onks C, Kim RY, Zhen KJ, Loeffert J, Loeffert AC, et al. Refinement of saliva microRNA biomarkers for sports-related concussion. J Sport Health Sci. 2021. https://doi.org/10.1016/J.JSHS.2021.08.003.

    Article  PubMed  Google Scholar 

  29. Hicks SD, Olympia RP, Onks C, Kim RY, Zhen KJ, Fedorchak G, et al. Saliva microRNA biomarkers of cumulative concussion. Int J Mol Sci. 2020;21:7758. https://doi.org/10.3390/IJMS21207758.

    Article  CAS  PubMed Central  Google Scholar 

  30. Fedorchak G, Rangnekar A, Onks C, Loeffert AC, Loeffert J, Olympia RP, et al. Saliva RNA biomarkers predict concussion duration and detect symptom recovery: a comparison with balance and cognitive testing. J Neurol. 2021;268:4349–61. https://doi.org/10.1007/S00415-021-10566-X.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Hicks SD, Onks C, Kim RY, Zhen KJ, Loeffert J, Loeffert AC, et al. Diagnosing mild traumatic brain injury using saliva RNA compared to cognitive and balance testing. Clin Transl Med. 2020;10: e197. https://doi.org/10.1002/CTM2.197.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Matuk R, Pereira M, Baird J, Dooner M, Cheng Y, Wen S, et al. The role of salivary vesicles as a potential inflammatory biomarker to detect traumatic brain injury in mixed martial artists. Sci Rep. 2021;11:1–10. https://doi.org/10.1038/s41598-021-87180-4.

    Article  CAS  Google Scholar 

  33. Shekleton JA, Parcell DL, Redman JR, Phipps-Nelson J, Ponsford JL, Rajaratnam SMW. Sleep disturbance and melatonin levels following traumatic brain injury. Neurology. 2010;74:1732–8. https://doi.org/10.1212/WNL.0b013e3181e0438b.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Seeger TA, Tabor J, Sick S, Schneider KJ, Jenne C, La P, et al. The association of saliva cytokines and pediatric sports-related concussion outcomes. J Head Trauma Rehabil. 2020;35:354–62. https://doi.org/10.1097/HTR.0000000000000605.

    Article  PubMed  Google Scholar 

  35. Di Pietro V, O’Halloran P, Watson CN, Begun G, Acharjee A, Yakoub KM, et al. Unique diagnostic signatures of concussion in the saliva of male athletes: the Study of Concussion in Rugby Union through MicroRNAs (SCRUM). Br J Sports Med. 2021. https://doi.org/10.1136/BJSPORTS-2020-103274.

    Article  PubMed  Google Scholar 

  36. Grima NA, Ponsford JL, St Hilaire MA, Mansfield D, Rajaratnam SM. Circadian melatonin rhythm following traumatic brain injury. Neurorehabil Neural Repair. 2016;30:972–7. https://doi.org/10.1177/1545968316650279.

    Article  PubMed  Google Scholar 

  37. Ma C, Wu X, Shen X, Yang Y, Chen Z, Sun X, et al. Sex differences in traumatic brain injury: a multi-dimensional exploration in genes, hormones, cells, individuals, and society. Chin Neurosurg J. 2019;5:1–9. https://doi.org/10.1186/s41016-019-0173-8.

    Article  Google Scholar 

  38. Critical Appraisal Skills Programme (CASP). CASP checklists. https://casp-uk.net/casp-tools-checklists/. Accessed 2 Jul 2021.

  39. von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Lancet. 2007;370:1453–7. https://doi.org/10.1016/S0140-6736(07)61602-X.

    Article  Google Scholar 

  40. Thelin EP, Nelson DW, Bellander BM. A review of the clinical utility of serum S100B protein levels in the assessment of traumatic brain injury. Acta Neurochir (Wien). 2017;159:209–25. https://doi.org/10.1007/s00701-016-3046-3.

    Article  Google Scholar 

  41. Araki T, Yokota H, Morita A. Pediatric traumatic brain injury: characteristic features, diagnosis, and management. Neurol Med Chir (Tokyo). 2017;57:82–93. https://doi.org/10.2176/nmc.ra.2016-0191.

    Article  Google Scholar 

  42. Seifman MA, Gomes K, Nguyen PN, Bailey M, Rosenfeld JV, Cooper DJ, et al. Measurement of serum melatonin in intensive care unit patients: changes in traumatic brain injury, trauma and medical conditions. Front Neurol. 2014;5:237. https://doi.org/10.3389/fneur.2014.00237.

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

The authors thank Marilyn K. Farmer for her continued editorial support.

Author information

Authors and Affiliations

  1. The University of Texas at Austin College of Liberal Arts, Austin, TX, USA

    Jacqueline Porteny

  2. The University of Texas at Austin College of Natural Sciences, Austin, TX, USA

    Elicenda Tovar, Samuel Lin & Afifa Anwar

  3. Dell Medical School, Austin, TX, USA

    Samuel Lin

  4. The University of Texas Health Science Center at San Antonio School of Dentistry, San Antonio, TX, USA

    Afifa Anwar

  5. The University of Texas at Austin School of Nursing, Austin, TX, USA

    Nico Osier

  6. Department of Neurology, Dell Medical School, Austin, TX, USA

    Nico Osier

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  1. Jacqueline Porteny
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  5. Nico Osier
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Corresponding author

Correspondence to Nico Osier.

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Funding

Funding for this project comes from a pilot grant from the University of Texas at Austin St. David’s Center for Health Promotion and Disease Prevention Research in Underserved Populations and a pilot grant from the Heilbrunn Family Center for Nursing Research.

Conflicts of interest/competing interests

To the authors’ best knowledge, there is no conflict of interest in this literature review. This is the first systematic review to exclusively investigate multiple types of salivary biomarkers in the context of TBI.

Ethics approval

No human subjects are involved in this study.

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No human subjects are involved in this study.

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Not applicable.

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Additional information

Jacqueline Porteny and Elicenda Tovar are co-first authors.

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Porteny, J., Tovar, E., Lin, S. et al. Salivary Biomarkers as Indicators of TBI Diagnosis and Prognosis: A Systematic Review. Mol Diagn Ther 26, 169–187 (2022). https://doi.org/10.1007/s40291-021-00569-9

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