Association of Serum Brain-Derived Tau With Clinical Outcome and Longitudinal Change in Patients With Severe Traumatic Brain Injury

Abstract

ImportanceBlood-based measurements of total tau (T-tau) are commonly used to examine neuronal injury in patients with traumatic brain injury (TBI), but current assays do not differentiate between brain-derived tau (BD-tau) and tau produced in peripheral tissues. A novel assay for BD-tau has recently been reported that selectively quantifies nonphosphorylated tau of central nervous system origin in blood samples.ObjectivesTo examine the association of serum BD-tau with clinical outcomes in patients with severe TBI (sTBI) and its longitudinal changes over 1 year.Design, Setting, and ParticipantsThis prospective cohort study was conducted at the neurointensive unit at the Sahlgrenska University Hospital, Gothenburg, Sweden, between September 1, 2006, and July 1, 2015. The study included 39 patients with sTBI followed up for up to 1 year. Statistical analysis was performed between October and November 2021.ExposuresSerum BD-tau, T-tau, phosphorylated tau231 (p-tau231), and neurofilament light chain (NfL) measured on days 0, 7, and 365 after injury.Main Outcomes and MeasuresAssociations of serum biomarkers with clinical outcome and longitudinal change in sTBI. Severity of sTBI was evaluated using the Glasgow Coma Scale at hospital admission, while clinical outcome was assessed with the Glasgow Outcome Scale (GOS) at 1-year follow-up. Participants were classified as having a favorable outcome (GOS score, 4-5) or unfavorable outcome (GOS score, 1-3).ResultsAmong the 39 patients (median age at admission, 36 years [IQR, 22-54 years]; 26 men [66.7%]) in the study on day 0, the mean (SD) serum BD-tau level was higher among patients with unfavorable outcomes vs those with favorable outcomes (191.4 [190.8] pg/mL vs 75.6 [60.3] pg/mL; mean difference, 115.9 pg/mL [95% CI, 25.7-206.1 pg/mL]), while the other markers had smaller between-group mean differences (serum T-tau, 60.3 pg/mL [95% CI, −22.0 to 142.7 pg/mL]; serum p-tau231, 8.3 pg/mL [95% CI, −6.4 to 23.0 pg/mL]; serum NfL, −5.4 pg/mL [95% CI, −99.0 to 88.3 pg/mL]). Similar results were recorded on day 7. Longitudinally, baseline serum BD-tau concentrations showed slower decreases in the whole cohort (42.2% on day 7 [from 138.6 to 80.1 pg/mL] and 93.0% on day 365 [from 138.6 to 9.7 pg/mL]) compared with serum T-tau (81.5% on day 7 [from 57.3 to 10.6 pg/mL] and 99.0% on day 365 [from 57.3 to 0.6 pg/mL]) and p-tau231 (92.5% on day 7 [from 20.1 to 1.5 pg/mL] and 95.0% on day 365 [from 20.1 to 1.0 pg/mL]). These results did not change when considering clinical outcome, where T-tau decreased twice as fast as BD-tau in both groups. Similar results were obtained for p-tau231. Furthermore, the biomarker levels on day 365 were lower, compared with day 7, for BD-tau but not T-tau or p-tau231. Serum NfL had a different trajectory to the tau biomarkers, with levels increasing by 255.9% on day 7 compared with day 0 (from 86.8 to 308.9 pg/mL) but decreasing by 97.0% by day 365 vs day 7 (from 308.9 to 9.2 pg/mL).Conclusions and RelevanceThis study suggests that serum BD-tau, T-tau, and p-tau231 have differential associations with clinical outcome and 1-year longitudinal change in patients with sTBI. Serum BD-tau demonstrated utility as a biomarker to monitor outcomes in sTBI and can provide valuable information regarding acute neuronal damage.

Levels of plasma brain‐derived tau and p‐tau181 in Alzheimer's disease and rapidly progressive dementias

“…19,20 Moreover, CSF surrogate markers of neurodegeneration, including proteins t-tau and 14-3-3, remain fundamental and widely used to support the diagnosis of CJD in patients with RPDs despite the recent introduction of the prion RT-QuIC, a specific CSF assay for the detection of PrP Sc . 20 Since plasma p-tau is strongly associated with amyloid pathology, 11,21 and plasma BD-tau with the intensity of neurodegeneration and cortical injury, 17,22 we hypothesized that the combined use of plasma BD-tau and p-tau181 may also provide valuable information in patients with RPD. Here, we have investigated the value of these novel tau-specific plasma biomarkers in the RPD diagnosis compared to established CSF markers.…”

Brain-derived Tau for Monitoring Brain Injury in Acute Ischemic Stroke

“…This observation aligns with prior data on the delayed response of NfL to brain injury 13 and its earlier detection by BD-tau. 24 It remains speculative to assume that this difference might be rooted in the dynamic interaction of tau with microtubules 20,21 primarily in dendrites 40,41 as opposed to NfL’s more static role as a core filament in axons. 42 Notably, while axons start to fully degrade only 72 hours after injury, 23 dendrites are among the first structural components to retract and degrade upon ischemia.…”

“…18 Unlike NfL, which serves as a core structural protein within axons, 19 Tau dynamically binds to microtubules, mainly in dendrites and distal axons, 20,21 and may thus be released into the extracellular space more quickly upon neuronal death. 22,23 Indeed, in recent studies on neurodegenerative diseases 18 and traumatic brain injury 24 , BD-tau outperformed established biomarkers of brain injury including NfL in the early detection of CNS pathology.…”

Association of Plasma Brain-Derived Tau With Functional Outcome After Ischemic Stroke

“… 2 We found that plasma/serum BD-tau outperforms T-tau as a biomarker for Alzheimer disease–type neurodegeneration 2 and that increased BD-tau concentrations associated with unfavorable outcome after traumatic brain injury. 3 Based on these findings, we hypothesize that circulating acute-phase BD-tau concentrations are associated with functional outcome after ischemic stroke.…”