Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2025 May 28;15(6):581.
doi: 10.3390/brainsci15060581.

The Diagnostic and Prognostic Role of Biomarkers in Mild Traumatic Brain Injury: An Umbrella Meta-Analysis

Ioannis Mavroudis  1   2 , Foivos Petridis  2 , Dimitrios Kazis  2 , Alin Ciobica  3   4   5   6 , Gabriel Dăscălescu  3   4 , Antoneta Dacia Petroaie  7 , Irina Dobrin  7 , Otilia Novac  7 , Ioana Vata  8 , Bogdan Novac  7
Affiliations
Review

The Diagnostic and Prognostic Role of Biomarkers in Mild Traumatic Brain Injury: An Umbrella Meta-Analysis

Ioannis Mavroudis et al. Brain Sci. .

Abstract

Background: Mild traumatic brain injury (mTBI), commonly known as concussion, is a major public health issue characterized by subtle neuronal damage that traditional imaging techniques such as computed tomography (CT) and magnetic resonance imaging (MRI) often fail to detect. Fluid biomarkers have emerged as promising diagnostic and prognostic tools for mTBI.

Objectives: This umbrella meta-analysis aims to evaluate the diagnostic accuracy and clinical utility of the key fluid biomarkers, S100B, glial fibrillary acidic protein (GFAP), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1, neurofilament light chain (NfL)) and tau protein, in detecting mTBI and to clarify their roles as screening, confirmatory, and complementary indicators.

Methods: A systematic review was performed using PubMed, Web of Science, Scopus, and Cochrane to identify the published meta-analyses that assessed the biomarkers in mTBI. Sensitivity, specificity, and diagnostic odds ratios were then calculated using random-effects models. Heterogeneity was evaluated with the I2 statistic, and publication bias was assessed via funnel plots. The results of S100B demonstrated high sensitivity (91.6%) but low specificity (42.4%), making it an effective rule-out biomarker to minimize unnecessary CT scans. In contrast, GFAP exhibited moderate sensitivity (84.5%) with improved specificity (61.0%), supporting its role in confirming mTBI diagnoses. UCH-L1 revealed a sensitivity of 86.7% alongside low specificity (37.3%), indicating its potential as a complementary marker. Additionally, the NfL levels were notably elevated in sports-related concussions, while the diagnostic utility of tau protein remains inconclusive due to limited available data.

Conclusions: The findings underscore the clinical promise of fluid biomarkers in the management of mTBI. S100B and GFAP are particularly valuable as screening and confirmatory markers, respectively. Nonetheless, further standardization of biomarker thresholds and additional longitudinal studies are necessary to validate the roles of UCH-L1, NfL, and Tau protein. The integration of these biomarkers into a multimodal diagnostic panel may enhance mTBI detection accuracy and facilitate improved patient stratification and management.

Keywords: GFAP; S100B; Tau protein; UCH-L1; biomarkers; concussion; diagnostic accuracy; meta-analysis; mild traumatic brain injury; neurofilament light chain; traumatic brain injury detection.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Figures

Figure 1
Figure 1
PRISMA flowchart (designed according to the guidelines from [21] and the PRISMA 2020 statement website).
Figure 2
Figure 2
Summary ROC curve for GFAP.
Figure 3
Figure 3
Summary ROC curve for UCH-L1.
Figure 4
Figure 4
Summary ROC curve for S100B.
Figure 5
Figure 5
Summary ROC curve for tau protein.
Figure 6
Figure 6
Summary ROC curve for NfL.
See this image and copyright information in PMC

References

    1. McInnes K., Friesen C.L., MacKenzie D.E., Westwood D.A., Boe S.G. Mild traumatic brain injury (mTBI) and chronic cognitive impairment: A scoping review. PLoS ONE. 2017;12:e0174847. doi: 10.1371/journal.pone.0174847. - DOI - PMC - PubMed
    1. Centers for Disease Control and Prevention (CDC) Surveillance Report on Traumatic Brain Injury-Related Hospitalizations and Deaths. [(accessed on 11 April 2025)];2021 Available online: https://www.cdc.gov/traumatic-brain-injury/data-research/index.html.
    1. Maas A.I., Menon D.K., Adelson P.D., Andelic N., Bell M.J., Belli A., Bragge P., Brazinova A., Büki A., Chesnut R.M., et al. Traumatic brain injury: Integrated approaches to improve prevention, clinical care, and research. Lancet Neurol. 2017;16:987–1048. doi: 10.1016/S1474-4422(17)30371-X. - DOI - PubMed
    1. Giza C.C., Kutcher J.S., Ashwal S., Barth J., Getchius T.S., Gioia G.A., Gronseth G.S., Guskiewicz K., Mandel S., Manley G., et al. Summary of evidence-based guideline update: Evaluation and management of concussion in sports. Neurology. 2014;82:2250–2255. doi: 10.1212/WNL.0b013e31828d57dd. - DOI - PMC - PubMed
    1. Laker S.R. Return to play decisions. Phys. Med. Rehabil. Clin. N. Am. 2011;22:619–634. doi: 10.1016/j.pmr.2011.08.004. - DOI - PubMed

LinkOut - more resources