Inflammatory Cytokines Associate With Neuroimaging After Acute Mild Traumatic Brain Injury

Abstract

Introduction: Elevated levels of blood-based proinflammatory cytokines are linked to acute moderate to severe traumatic brain injuries (TBIs), yet less is known in acute mild (m)TBI cohorts. The current study examined whether blood-based cytokines can differentiate patients with mTBI, with and without neuroimaging findings (CT and MRI). Material and Methods: Within 24 h of a mTBI, determined by a Glasgow Coma Scale (GCS) between 13 and 15, participants (n = 250) underwent a computed tomography (CT) and magnetic resonance imaging (MRI) scan and provided a blood sample. Participants were classified into three groups according to imaging findings; (1) CT+, (2) MRI+ (CT-), (3) Controls (CT- MRI-). Plasma levels of circulating cytokines (IL-6, IL-10, TNFα), and vascular endothelial growth factor (VEGF) were measured using an ultra-sensitive immunoassay. Results: Concentrations of inflammatory cytokines (IL-6, TNFα) and VEGF were elevated in CT+, as well as MRI+ groups (p < 0.001), compared to controls, even after controlling for age, sex and cardiovascular disease (CVD)-related risk factors; hypertension, and hyperlipidemia. Post-concussive symptoms were associated with imaging groupings, but not inflammatory cytokines in this cohort. Levels of VEGF, IL-6, and TNFα differentiated patients with CT+ findings from controls, with the combined biomarker model (VEGF, IL-6, TNFα, and IL-10) showing good discriminatory power (AUC 0.92, 95% CI 0.87-0.97). IL-6 was a fair predictor of MRI+ findings compared to controls (AUC 0.70, 95% CI 0.60-0.78). Finally, the combined biomarker model discriminated patients with MRI+ from CT+ with an AUC of 0.71 (95% CI 0.62-0.80). Conclusions: When combined, IL-6, TNFα, and VEGF may provide a promising biomarker cytokine panel to differentiate mTBI patients with CT+ imaging vs. controls. Singularly, IL-6 was a fair discriminator between each of the imaging groups. Future research directions may help elucidate mechanisms related to injury severity and potentially, recovery following an mTBI.

Keywords: cardiovascular disease risk; cytokines; inflammation; mild traumatic brain injury; neuroimaging.

Figure 1

Inflammatory cytokines are associated with neuroimaging. Dot plots showing (A) VEGF, (B) IL-6, (C) TNFα, and (D) IL-10 concentrations in the CT+, MRI+, and control groups. Significant differences are indicated with *p < 0.05, **p < 0.01, and ***p < 0.001. VEGF, vascular endothelial growth factor; IL-6, interleukin 6; TNFα, tumor necrosis factor alpha; IL-10, interleukin 10.

Figure 2

Sensitivity of Acute Cytokines to Predict Imaging Group. Receiver operating characteristic (ROC) curves for VEGF, IL-6, IL-10, and TNFα and combined model which includes all biomarkers (VEGF, IL-6, IL-10, TNFα). (A) ROC stratifying CT+ patients vs. controls (CT– and MRI–) [VEGF (AUC 0.86, 95% CI 0.80–0.92); IL-6 (AUC 0.87, 95% CI 0.81–0.93); TNFα (AUC 0.75, 95% CI 0.67–0.84); model (AUC 0.92, 95% CI 0.87–0.97)], (B) ROC stratifying MRI+ patients vs. controls [VEGF (AUC 0.59, 95% CI 0.49–0.69); IL-6 (AUC 0.70, 95% CI 0.60–0.78); and TNFα (AUC 0.60, 95% CI 0.50–0.73)] (C) ROC stratifying MRI+ patients vs. CT+ [VEGF (AUC 0.63, 95% CI 0.53–0.72), IL-6 (AUC 0.69, 95% CI 0.60–0.78), TNFα (AUC 0.61, 95% CI 0.51–0.71); model (AUC 0.71, 95% CI 0.62–0.80)].