IMPORTANCEAnnually in the United States, at least 3.5 million people seek medical attention for traumatic brain injury (TBI). The development of therapies for TBI is limited by the absence of diagnostic and prognostic biomarkers. Microtubule-associated protein tau is an axonal phosphoprotein. To date, the presence of the hypophosphorylated tau protein (P-tau) in plasma from patients with acute TBI and chronic TBI has not been investigated. OBJECTIVETo examine the associations between plasma P-tau and total-tau (T-tau) levels and injury presence, severity, type of pathoanatomic lesion (neuroimaging), and patient outcomes in acute and chronic TBI. DESIGN, SETTING, AND PARTICIPANTSIn the TRACK-TBI Pilot study, plasma was collected at a single time point from 196 patients with acute TBI admitted to 3 level I trauma centers (<24 hours after injury) and 21 patients with TBI admitted to inpatient rehabilitation units (mean [SD], 176.4 [44.5] days after injury). Control samples were purchased from a commercial vendor. The TRACK-TBI Pilot study was conducted from April 1, 2010, to June 30, 2012. Data analysis for the current investigation was performed from August 1, 2015, to March 13, 2017.MAIN OUTCOMES AND MEASURES Plasma samples were assayed for P-tau (using an antibody that specifically recognizes phosphothreonine-231) and T-tau using ultra-high sensitivity laser-based immunoassay multi-arrayed fiberoptics conjugated with rolling circle amplification. RESULTSIn the 217 patients with TBI, 161 (74.2%) were men; mean (SD) age was 42.5 (18.1) years. The P-tau and T-tau levels and P-tau-T-tau ratio in patients with acute TBI were higher than those in healthy controls. Receiver operating characteristic analysis for the 3 tau indices demonstrated accuracy with area under the curve (AUC) of 1.000, 0.916, and 1.000, respectively, for discriminating mild TBI (Glasgow Coma Scale [GCS] score, 13-15, n = 162) from healthy controls. The P-tau level and P-tau-T-tau ratio were higher in individuals with more severe TBI (GCS, Յ12 vs 13-15). The P-tau level and P-tau-T-tau ratio outperformed the T-tau level in distinguishing cranial computed tomography-positive from -negative cases (AUC = 0.921, 0.923, and 0.646, respectively). Acute P-tau levels and P-tau-T-tau ratio weakly distinguished patients with TBI who had good outcomes (Glasgow Outcome Scale-Extended GOS-E, 7-8) (AUC = 0.663 and 0.658, respectively) and identified those with poor outcomes (GOS-E, Յ4 vs >4) (AUC = 0.771 and 0.777, respectively). Plasma samples from patients with chronic TBI also showed elevated P-tau levels and a P-tau-T-tau ratio significantly higher than that of healthy controls, with both P-tau indices strongly discriminating patients with chronic TBI from healthy controls (AUC = 1.000 and 0.963, respectively).CONCLUSIONS AND RELEVANCE Plasma P-tau levels and P-tau-T-tau ratio outperformed T-tau level as diagnostic and prognostic biomarkers for acute TBI. Compared with T-tau levels alone, P-tau levels and P-tau-T-tau ratios show more robust and sustained el...

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Blast-induced traumatic brain injury (bTBI) is common in veterans of the Iraq- and Afghanistan-era conflicts. However, the typical subtlety of neural alterations and absence of definitive biomarkers impede clinical detection on conventional imaging. This preliminary study examined the structure and functional correlates of executive control network (ECN) white matter in veterans to investigate the clinical utility of using high-definition fiber tracking (HDFT) to detect chronic bTBI. Demographically similar male veterans (N = 38) with and without bTBI (ages 24 to 50 years) completed standardized neuropsychological testing and magnetic resonance imaging. Quantitative HDFT metrics of subcortical-dorsolateral prefrontal cortex (DLPFC) tracts were derived. Moderate-to-large group effects were observed on HDFT metrics. Relative to comparisons, bTBI demonstrated elevated quantitative anisotropy (QA) and reduced right hemisphere volume of all examined tracts, and reduced fiber count and increased generalized fractional anisotropy in the right DLPFC-putamen tract and DLPFC-thalamus, respectively. The Group × Age interaction effect on DLPFC-caudate tract volume was large; age negatively related to volume in the bTBI group, but not comparison group. Groups performed similarly on the response inhibition measure. Performance (reaction time and commission errors) robustly correlated with HDFT tract metrics (QA and tract volume) in the comparison group, but not bTBI group. Results support anomalous density and integrity of ECN connectivity, particularly of the right DLPFC-putamen pathway, in bTBI. Results also support exacerbated aging in veterans with bTBI. Similar ECN function despite anomalous microstructure could reflect functional compensation in bTBI, although alternate interpretations are explored.