• Richard Rubenstein, Leah McQuillan, WangKevin K WKKWDepartment of Emergency Medicine, McKnight Brain Institute, University of Florida, Gainesville, Florida, USA., Claudia Robertson, Binggong Chang, Zhihui Yang, Haiyan Xu, John Williamson, and Amy K Wagner.
• Department of Neurology, SUNY Downstate Health Sciences University, Brooklyn, New York, USA.
• J. Neurotrauma. 2024 Feb 1; 41 (3-4): 369392369-392.

AbstractTraumatic brain injury (TBI) can initiate progressive injury responses, which are linked to increased risk of 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 the cerebrospinal fluid (CSF) and serum and their 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 with those in healthy controls (n = 89 for both CSF and serum), and univariate/multivariable associations are made with global outcome, including the Disability Rating Scale (DRS) and the Glasgow Outcome Scale-Extended (GOS-E) scores at 3 and 6 months post-TBI (BCM cohort) and at 6 and 12 months post-TBI (UPitt cohort). For both the UPitt and BCM cohorts, 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 toward tau hyperphosphorylation. BCM analyses showed that 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 (months 1-6) 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.

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