Increases of Plasma Levels of Glial Fibrillary Acidic Protein, Tau, and Amyloid β up to 90 Days after Traumatic Brain Injury

Abstract

Glial fibrillary acidic protein (GFAP), microtubule-associated protein tau, and amyloid β peptide (Aβ42) have been proposed as diagnostic and prognostic biomarkers in traumatic brain injury (TBI). Single molecule array (Simoa) is a novel technology that employs highly sensitive immunoassays for accurate measurements of candidate biomarkers found at low concentration in biological fluids. Our objective was to trace the trajectory of tau, GFAP, and Aβ42 levels in plasma from the acute through subacute stages after TBI, compared with controls. Samples from 34 TBI subjects enrolled in the Citicoline Brain Injury Treatment Trial (COBRIT) were studied. Injury severity was assessed by Glasgow Coma Scale (GCS) and admission CT. Glasgow Outcome Scale Extended (GOSE) was assessed 6 months after injury. Plasma was collected within 24 h (Day 0), and 30 and 90 days after the TBI. Plasma collected from 69 healthy volunteers was used for comparison. At every time point, increases were noted in plasma GFAP (p < 0.0001 for all comparisons), tau (p < 0.0001, p < 0.0001, and p = 0.0044, at Days 0, 30, and 90, respectively), and Aβ42 (p < 0.001, p < 0.0001, and p = 0.0203, respectively) in TBI cases compared with controls. The levels were maximal at Day 0 for GFAP and tau and at Day 30 for Aβ42. Area under curve (AUC) analyses for Day 0 GFAP and tau were excellent for discrimination of complicated mild TBI (cmTBI) from controls (0.936 and 0.901, correspondingly). Discriminant component analysis (DCA) for all three biomarkers at Days 0 and 30 differentiated controls from cmTBI (91.1% and 89.7% correctly classified, at each time point). Duration of post-traumatic amnesia (PTA) correlated weakly with tau levels at 30 days (Spearman's r = 0.40; 95% CI 0.0003-0.60, p = 0.044). The Marshall CT Grade on admission correlated weakly with Day 30 tau levels (Spearman's r = 0.41; 95% CI 0.04-0.68, p = 0.027). Day 30 Aβ42 correlated with GOSE (standardized β -0.486, p = 0.042). GFAP, tau and Aβ42 were increased up to 90 days after TBI compared with controls. Total tau levels correlated with clinical and radiological variables of TBI severity. Plasma Aβ42 correlated with clinical outcome. Combination of all three biomarkers at Days 0 and 30 can be used to differentiate controls from cmTBI populations, and may be useful as biomarkers of TBI in both acute and subacute phases.

Keywords: GFAP; TBI; diagnostic and prognostic biomarkers; highly sensitive immunoassays; total tau.

FIG. 1.

Median and interquartile rate for glial fibrillary acidic protein (GFAP) (A), tau (B), and amyloid β peptide (Aβ42) (C) for controls and for traumatic brain injury (TBI) patients at Days 0, 30, and 90. Color image is available online at www.liebertpub.com/neu

FIG. 2.

Temporal profiles (red represents complicated mild traumatic brain injury [TBI] patients and blue represents moderate to severe TBI for glial fibrillary acidic protein (GFAP) (A), tau (B), and amyloid β peptide (Aβ42) (C) at Days 0, 30, and 90. The Friedman test showed that biomarker levels changed significantly over 90 days for GFAP and tau (p < 0.0001) but not for Ab42 (p = 0.292). Aβ42 levels showed bimodal distribution at Day 90. Color image is available online at www.liebertpub.com/neu

FIG. 3.

Trajectory of plasma tau levels for complicated mild traumatic brain injury (TBI) (Glasgow Coma Scale [GCS] score 13–15 with abnormal CT), compared with moderate to severe TBI (GCS score 3–12) on 0, 30, and 90 days after injury. The difference between groups for day 30 tau was significant (Mann–Whitney test, p = 0.0031).