Early Cerebrospinal Fluid Elevations of pTau-217 in Severe Traumatic Brain Injury Subjects

Hamad A. Yadikar^1*Firas Kobeissy^2,3,4,5,6Claudia Robertson⁷Spyridoula Tsetsou⁷John B Williamson^4,5Damon G Lamb^4,5Amy Kathleen Wagner^10,11,12,8,9Todd Justen Kilbaugh^13,14Shih-Han Kao^13,15Zhifeng Kou¹⁶Robert D. Welch¹⁶Jose-Miguel Yamal¹⁷Luis Leon Novelo¹⁷Richard Rubenstein¹⁸Kevin K W Wang^19,2,4,5,6

• ¹Biological Sciences, Kuwait University, Kuwait City, Kuwait
• ²Morehouse School of Medicine, Atlanta, United States
• ³American University of Beirut, Beirut, Lebanon
• ⁴University of Florida, Gainesville, United States
• ⁵VA Medical Center Malcom Randall, Gainesville, United States
• ⁶Atlanta VA Center for Visual & Neurocognitive Rehabilitation, Decatur, United States
• ⁷Baylor College of Medicine, Houston, United States
• ⁸University of Pittsburgh Department of Physical Medicine and Rehabilitation, Pittsburgh, United States
• ⁹Safar Center for Resuscitation Research, University of Pittsburgh,, Pittsburgh, United States
• ¹⁰University of Pittsburgh Department of Neuroscience, Pittsburgh, United States
• ¹¹Center for Neuroscience, University of Pittsburgh, Pittsburgh, United States
• ¹²University of Pittsburgh Clinical and Translational Science Institute, Pittsburgh, United States
• ¹³The Children's Hospital of Philadelphia Research Institute, Philadelphia, United States
• ¹⁴University of Pennsylvania, Philadelphia, United States
• ¹⁵University of Pittsburgh, Pittsburgh, United States
• ¹⁶Wayne State University School of Medicine, Detroit, United States
• ¹⁷Department of Biostatistics and Data Science, School of Public Health, The University of Texas Health Science Center at Houston, USA., Texas, United States
• ¹⁸Departments of Neurology and Physiology SUNY Downstate Health Sciences University,, Brooklyn, United States
• ¹⁹Department of Emergency Medicine, University of Florida,, Gainesville, United States

Tauopathies, including Alzheimer's disease (AD), feature abnormal accumulations of hyperphosphorylated Tau protein; however, their biomarker potential in traumatic brain injury (TBI) is not well-defined. This study investigated whether cerebrospinal fluid (CSF) phosphorylated Tau at threonine-217 (pTau-217) could serve as an early biomarker for severe TBI (sTBI). CSF samples from 26 sTBI patients, collected between 6 and 240 hours post-injury, and 19 healthy controls were analyzed using an optimized direct enzyme-linked immunosorbent assay (ELISA; sensitivity <4.7 pg/mL) for pTau-217 detection, complemented by Western blot validation. CSF pTau-217 levels were significantly elevated in sTBI patients at 6, 12, 18, 24, and 48 hours post-injury compared to controls (p<0.05-p<0.001), peaking around 18 hours (~65 ng/mL) before declining to near-control levels by 120 hours. Individual trajectories showed notable variability. Receiver operating characteristic (ROC) analyses demonstrated robust diagnostic performance of pTau-217, with areas under the curve (AUC) of 0.78 (95% CI: 0.63-0.93) at 6-12 hours and 0.83 (95% CI: 0.70-0.96) at 24-48 hours. These findings indicate that CSF pTau-217 could be a sensitive early biomarker for acute tau pathology in sTBI. However, further longitudinal validation in larger cohorts must is needed to confirm clinical utility.