Neuroinflammatory Biomarkers for Traumatic Brain Injury Diagnosis and Prognosis: A TRACK-TBI Pilot Study

Abstract

The relationship between systemic inflammation and secondary injury in traumatic brain injury (TBI) is complex. We investigated associations between inflammatory markers and clinical confirmation of TBI diagnosis and prognosis. The prospective TRACK-TBI Pilot (Transforming Research and Clinical Knowledge in Traumatic Brain Injury Pilot) study enrolled TBI patients triaged to head computed tomography (CT) and received blood draw within 24 h of injury. Healthy controls (HCs) and orthopedic controls (OCs) were included. Thirty-one inflammatory markers were analyzed from plasma. Area under the receiver operating characteristic curve (AUC) was used to evaluate discriminatory ability. AUC >0.7 was considered acceptable. Criteria included: TBI diagnosis (vs. OC/HC); moderate/severe vs. mild TBI (Glasgow Coma Scale; GCS); radiographic TBI (CT positive vs. CT negative); 3- and 6-month Glasgow Outcome Scale-Extended (GOSE) dichotomized to death/greater relative disability versus less relative disability (GOSE 1-4/5-8); and incomplete versus full recovery (GOSE <8/ = 8). One-hundred sixty TBI subjects, 28 OCs, and 18 HCs were included. Markers discriminating TBI/OC: HMGB-1 (AUC = 0.835), IL-1b (0.795), IL-16 (0.784), IL-7 (0.742), and TARC (0.731). Markers discriminating GCS 3-12/13-15: IL-6 (AUC = 0.747), CRP (0.726), IL-15 (0.720), and SAA (0.716). Markers discriminating CT positive/CT negative: SAA (AUC = 0.767), IL-6 (0.757), CRP (0.733), and IL-15 (0.724). At 3 months, IL-15 (AUC = 0.738) and IL-2 (0.705) discriminated GOSE 5-8/1-4. At 6 months, IL-15 discriminated GOSE 1-4/5-8 (AUC = 0.704) and GOSE <8/ = 8 (0.711); SAA discriminated GOSE 1-4/5-8 (0.704). We identified a profile of acute circulating inflammatory proteins with potential relevance for TBI diagnosis, severity differentiation, and prognosis. IL-15 and serum amyloid A are priority markers with acceptable discrimination across multiple diagnostic and outcome categories. Validation in larger prospective cohorts is needed. ClinicalTrials.gov Registration: NCT01565551.

Keywords: acute phase reactant; alarmin; cytokine; neuroinflammation; prognosis; traumatic brain injury.

FIG. 1.

Correlation matrix for 31 neuroinflammatory biomarkers after acute TBI. Spearman's correlation matrix is shown for the 31 biomarkers included in the current study. Correlation ranges from −1 to +1. Spearman's correlation was considered “moderate” in the 0.6–0.8 range and “strong” if >0.8. CRP, C-reactive protein; HMGB-1, biomarker high mobility group box 1; ICAM-1, intercellular adhesion molecule 1; IFN-γ, interferon-γ; IL, interleukin; IL-12/IL-23p40, IL-12/IL-23 p40 protein; IL-12 p70, IL-12 p70 protein; IP-10, interferon gamma-induced protein 10; MCP, monocyte chemoattractant protein; MDC, macrophage-derived chemokine; MIP-1a, macrophage inflammatory protein 1a; SAA, serum amyloid A; TARC, thymus- and activation-regulated chemokine; TBI, traumatic brain injury; TNF, tumor necrosis factor.