Temporal Profiles of P-tau, T-tau and P-tau:T-tau Ratios in CSF and Blood from Moderate-Severe TBI Patients and Relationship to 6-12 Months Global Outcomes.

TBI can initiate progressive injury responses which are linked to increased risks for neurodegenerative diseases known as tauopathies. Increased post-TBI tau hyperphosphorylation has been reported in brain tissue and biofluids. Acute to chronic TBI total (T)-tau and phosphorylated (P)-tau temporal profiles in CSF and serum and relationship to global outcome is unknown. Our multi-site longitudinal study examines these concurrent profiles acutely (CSF and serum) and also characterizes the acute to chronic serum patterns. Serial serum and CSF samples from individuals with moderate-to-severe TBI were obtained from two cohorts [acute, subacute and chronic samples from University of Pittsburgh (UPitt) (N=286 unique subjects) and acute samples from Baylor College of Medicine (BCM) (N=114 unique subjects)] and assayed for T-tau and P-tau using the Rolling Circle Amplification-Surround Optical Fiber ImmunoAssay platform. Biokinetic analyses described serum T-tau and P-tau temporal patterns. T-tau and P-tau levels are compared to healthy controls (N=89 for both CSF and serum), and univariate/multivariable associations made with global outcome, including Disability Rating Scale (DRS) and Glasgow Outcome Scale-Extended (GOS-E) scores at 3- and 6-months post-TBI (BCM cohort) and 6- and 12-months (UPitt cohort). For both UPitt and BCM, temporal increases in median serum and CSF T-tau and P-tau levels occurred over the first 5 days post-injury, while the initial increases of P-tau:T-tau ratio plateaued by day 4 post-injury (UPitt: N=99, BCM: N=48). Biokinetic analyses with UPitt data showed novel findings that T-tau (N=74) and P-tau (N=87) reached delayed maximum levels at 4.5 and 5.1 days, while exhibiting long serum half-lives (152 and 123 days), respectively. The post-TBI rise in acute (days 2-6) serum P-tau (up to 276-fold) far outpaced that of T-tau (7.3-fold), leading to a P-tau:T-tau increase of up to 267-fold, suggesting a shift towards tau hyperphosphorylation. BCM analyses showed days 0-6 mean CSF T-tau and P-tau levels and P-tau:T-tau ratios were associated with greater disability (DRS) (N=48) and worse global outcome (GOS-E) (N=48) 6-months post-injury. Days 0-6 mean serum T-tau, P-tau, and P-tau:T-tau ratio were not associated with outcome in either cohort (UPitt: N=145 (DRS), N=154 (GOS-E), BCM: N=99 (DRS and GOS-E)). UPitt multivariate models showed that higher chronic (1-6 months) mean P-tau levels and P-tau:T-tau ratio, but not T-tau levels, are associated with greater disability (DRS: N=119) and worse global outcomes (GOS-E: N=117) 12-months post-injury. This work shows the potential importance of monitoring post-TBI T-tau and P-tau levels over time. This multi-site longitudinal study features concurrent acute TBI T-tau and P-tau profiles in CSF and serum, and also characterizes acute to chronic serum profiles. Longitudinal profiles, along with no temporal concordance between trajectory groups over time, imply a sustained post-TBI shift in tau phosphorylation dynamics that may favor tauopathy development chronically.