Traumatic brain injury (TBI) is a global health challenge, impacting more than 50 million annually^1,2. TBI can be classified as mild or severe depending on the extent of the injury³, with severe TBI (sTBI) associated with lower rates of survival².  Despite the effectiveness of neuroimaging techniques in detecting sTBI, there remains a critical need for precise and accessible blood-based biomarkers. These biomarkers are essential for monitoring biochemical brain-related changes within a few hours of trauma, assessing TBI severity, predicting outcomes, and guiding therapeutic interventions. In this context, an exciting new study, “Association of Serum Brain-Derived Tau With Clinical Outcome and Longitudinal Change in Patients With Severe Traumatic Brain Injury,” authored by Dr. Fernando Gonzalez-Ortiz and colleagues, demonstrates that serum brain-derived tau (BD-tau) can serve as a useful biomarker to monitor sTBI outcomes and provide valuable insights into neuronal damage⁴.  

The Question: Are Levels of Serum BD-Tau at Admission Associated with Clinical Outcome and Long-Term Change in Patients with sTBI?

Serum total T-tau (T-tau) is a well-established biomarker for sTBI^3,5, however, current assays for T-tau quantify cannot differentiate between central nervous system (CNS) and peripheral derived tau^5,6. The researchers hypothesized that a blood-based biomarker selectively targeting CNS tau would provide more accurate reflections of brain-associated tau released into the bloodstream, while minimizing potential influences from peripheral tau. To this end, they aimed to evaluate the association of BD-tau with clinical severity at admission and longitudinal outcome in patients with sTBI. They also examined changes in serum phosphorylated tau231 (p-Tau 231) and neurofilament light chain (NfL) concentrations as additional markers of neuronal injury.

The Approach

This prospective study included 42 participants from Swedish TBI Neurointensivvårdsavdelning cohort of patients with sTBI who were receiving clinical care at the Sahlgrenska University Hospital, Gothenburg, Sweden and were followed for 1 year. Serum samples were collected from the patients at admission (day 0), on day 7, and day 365.

Both BD-tau and p-Tau 231 were measured on the Simoa® HD-X platform using validated in-house assays^7,8 developed using Quanterix’s Homebrew Assay Kit. T-tau was measured using the Simoa® Tau Advantage Kit and NfL was measured using the Simoa® NfL V2 Advantage Kit. Simoa® technology has delivered the gold standard for earlier blood-based biomarker detection, with the ability to quantify proteins as low as femtogram (fg/ml) levels that are far lower than the typical lower limit of quantification. The Simoa® bead-bead immunoassays lead to a higher sensitivity using microwells, 4.25 µm in diameter. Paramagnetic particles coupled with antibodies designed to bind the specific target, fluorescent detection antibodies, and an enzyme are added to the sample. The specific target is captured on the paramagnetic beads and single antibody–antigen complexes along with a substrate which forms a fluorescent product in the presence of the enzyme are dispersed to 216,000 microwells, thus requiring a much smaller number of target molecules to emit a detectable signal than previous technologies.

BD-tau Levels at Admission and 7 Days Later Are Associated with Unfavorable sTBI Clinical Outcomes

On both the day 0 and day 7, individuals with unfavorable sTBI clinical outcomes exhibited significantly higher serum BD-tau concentrations compared to those with favorable outcomes. However, this association was not observed for the other biomarkers, serum T-Tau, p-Tau 231, and NfL. This discovery underscores the potential of serum BD-tau as a blood-based biomarker to help predict clinical outcome in sTBI, both at admissions and 7 days later.

Longitudinal Changes in BD-tau Level Differ from Other Biomarkers

When looking at the whole cohort, serum BD-tau levels decreased by 42.2% at day 7 and 93.0% at day 365. However, a smaller decrease in BD-tau level was observed in the unfavorable clinical outcome group (35.1% decrease by day 7) vs the favorable group (41.8% decrease by day 7). Nevertheless, despite the smaller decrease, the mean differences between the two outcome groups were similar. Serum T-tau and p-Tau 231 levels also decreased over time however, the decreases were considerably larger compared with BD-tau levels. As a whole cohort, T-tau levels decreased by 81.5% at day 7 and 99% at day 365, while p-Tau 231 levels decreased by 92.5% at day 7 and 95.0% at day 365. Additionally, the decreases in serum T-tau and p-Tau 231 were similar across clinical outcome groups. The results suggest BD-tau is not cleared as quickly as T-tau and p-Tau 231 and substantial levels of BD-tau remain for in the blood for up to 1 year post sTBI. This slow clearance of BD-tau has the potential to be useful for the clinical monitoring of outcomes and recovery for sTBI patients.

The longitudinal trajectory of serum NfL differed from that of the tau blood-based biomarkers. Instead of decreasing from day 0 to day 7, serum NfL increased by 255.5% in the whole cohort. Furthermore, NfL increased by 156.0% by day 7 in the favorable outcome groups and by 343.5% in unfavorable outcome groups. By day 365, serum NfL levels decreased by 97.0%.  This data suggests that NfL is released more slowly into the bloodstream compared with the tau markers following sTBI. However, the peaking of the signal at day 7 and its difference from day 365 does indicate potential value for monitoring outcomes following sTBI and further research studies are needed.

Implications for sTBI Research and Clinical Care

These findings highlight the potential of serum BD-tau as a promising biomarker for assessing injury severity, predicting clinical outcomes, and monitoring recovery in sTBI injury cases. Its ability to differentiate between CNS-derived tau and peripheral tau positions it as a potentially transformative tool in TBI assessment. However, these findings necessitate further validation across larger and more diverse patient populations. Furthermore, while this study focuses on sTBI, the potential utility of serum BD-tau in mild and moderate TBI contexts warrants exploration to uncover potential variations in dynamics and prognostic utility within these contexts.

References

1. Maas AIR, Menon DK, Adelson PD, et al. Traumatic brain injury: integrated approaches to improve prevention, clinical care, and research. Lancet Neurol. 2017;16(12):987-1048. doi:10.1016/S1474-4422(17)30371-X
2. Bruns J Jr, Hauser WA. The epidemiology of traumatic brain injury: a review. Epilepsia. 2003;44(s10):2-10. doi:10.1046/j.1528-1157.44.s10.3.x
3. Dadas A, Washington J, Diaz-Arrastia R, Janigro D. Biomarkers in traumatic brain injury (TBI): a review. Neuropsychiatr Dis Treat. 2018;14:2989-3000. Published 2018 Nov 8. doi:10.2147/NDT.S125620
4. Gonzalez-Ortiz F, Dulewicz M, Ashton NJ, et al. Association of Serum Brain-Derived Tau With Clinical Outcome and Longitudinal Change in Patients With Severe Traumatic Brain Injury. JAMA Netw Open. 2023;6(7):e2321554. Published 2023 Jul 3. doi:10.1001/jamanetworkopen.2023.21554
5. Zetterberg H, Morris HR, Hardy J, Blennow K. Update on fluid biomarkers for concussion. Concussion. 2016;1(3):CNC12. Published 2016 Feb 18. doi:10.2217/cnc-2015-0002
6. Dugger BN, Whiteside CM, Maarouf CL, et al. The Presence of Select Tau Species in Human Peripheral Tissues and Their Relation to Alzheimer’s Disease [published correction appears in J Alzheimers Dis. 2016 Oct 4;54(3):1249]. J Alzheimers Dis. 2016;51(2):345-356. doi:10.3233/JAD-150859
7. Gonzalez-Ortiz F, Turton M, Kac PR, et al. Brain-derived tau: a novel blood-based biomarker for Alzheimer’s disease-type neurodegeneration [published correction appears in Brain. 2023 Jun 27;:]. Brain. 2023;146(3):1152-1165. doi:10.1093/brain/awac407
8. Ashton NJ, Pascoal TA, Karikari TK, et al. Plasma p-tau231: a new biomarker for incipient Alzheimer’s disease pathology. Acta Neuropathol. 2021;141(5):709-724. doi:10.1007/s00401-021-02275-6