Utility of Acute and Subacute Blood Biomarkers to Assist Diagnosis in CT-Negative Isolated Mild Traumatic Brain Injury
Jonathan Reyes, Gershon Spitz, Brendan P. Major, William T. O’Brien, Lauren P. Giesler, Jesse Bain, Becca Xie, Jeffrey V. Rosenfeld, Meng Law, Jennie Ponsford, Terence J. O’Brien, Sandy R. Shultz, Catherine Willmott, Biswadev Mitra, Stuart J. McDonald
Abstract
<h3>Objectives</h3> : Blood biomarkers GFAP and UCH-L1 have recently been FDA approved as predictors of intracranial lesions on CT after mild traumatic brain injury (mTBI). However, the vast majority of mTBI cases are CT negative, and no biomarkers are approved to assist diagnosis in these individuals. Here we aimed to determine the optimal combination of blood biomarkers to assist mTBI diagnosis in otherwise healthy adults aged under 50 presenting to an ED within 6h of injury. To further understand the utility of biomarkers, we assessed how biological sex, presence or absence of loss of consciousness and/or post traumatic amnesia (LOC/PTA), and delayed presentation, affected classification performance. <h3>Methods</h3> : Blood samples, symptom questionnaires and cognitive tests were conducted prospectively for mTBI participants recruited from The Alfred Hospital Level 1 Emergency & Trauma Centre and uninjured controls. Follow-up testing was conducted at 7 days. Simoa® quantified plasma GFAP, UCH-L1, Tau, NfL, IL-6 and IL-1β. AUC analysis assessed classification accuracy for diagnosed mTBI and logistic regression models identified optimal biomarker combinations. <h3>Results</h3> : Plasma IL-6 (AUC=0.91, 95%CI=0.86-0.96), GFAP (AUC=0.85, 95%CI=0.78-0.93) and UCH-L1 (AUC=0.79, 95%CI=0.70-0.88) best differentiated mTBI (n=74) from controls (n=44) acutely (<6h), with NfL (AUC=0.81, 95%CI=0.72-0.90) the only marker to have such utility sub-acutely (7 days). Biomarker performance was similar between sexes and for participants with and without LOC/PTA, with the exception at 7 days, where GFAP and IL-6 retained some utility in female participants (GFAP AUC=0.71, 95%CI=0.55-0.88; IL-6 AUC=0.71, 95%CI=0.55-0.87) and those with LOC/PTA (GFAP AUC=0.73, 95%CI=0.59-0.86; IL-6 AUC=0.71, 95%CI=0.57-0.84). Acute IL-6 (R<sup>2</sup>=0.50, 95%CI=0.34-0.64) outperformed GFAP and UCH-L1 combined (R<sup>2</sup>=0.35, 95%CI=0.17-0.50), with the best acute model featuring GFAP and IL-6 (R<sup>2</sup>=0.54, 95%CI=0.34-0.68). <h3>Discussion</h3> <b>:</b> These findings indicate that adding IL-6 to a panel of brain-specific proteins such as GFAP and UCH-L1 might assist in the acute diagnosis of mTBI in adults under 50. Multiple markers had high classification accuracy in participants without LOC/PTA. When compared with the best performing acute markers, sub-acute measures of plasma NfL resulted in minimal reduction in classification accuracy. Future studies will investigate the optimal time frame over which plasma IL-6 might assist diagnostic decisions and how extracranial trauma affects utility.