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.

Peripheral Blood and Salivary Biomarkers of Blood–Brain Barrier Permeability and Neuronal Damage: Clinical and Applied Concepts

“…S100B has proven its high NPV to rule out intracranial bleeding in patients after mTBI. However, its specificity for brain parenchyma structural lesions remains debated, and MRI is required for a specific explanation of clinical symptoms ( 76 , 126 , 127 ). Positron emission tomography (PET) and radiolabeled biomarkers were tested along with blood biomarkers.…”

“…Elevated levels of Nfl were also reported in plasma ( 43 ). Finally, TBI is associated with inflammation as blood levels of IL6, TNFα, and VEGF were increased in CT- and MRI-positive patients as compared to controls ( 126 ).…”

miRNA-92a-3p regulates osteoblast differentiation in patients with concomitant limb fractures and TBI via IBSP/PI3K-AKT inhibition

“…41,42 Currently, research on the increased fracture healing and bone callus formation seen in concomitant brain trauma has largely focused on investigating the effect of cytokines and other proteins, while research on the regulation of miRNAs is still lacking. [43][44][45] However, our study found that the expression level of miRNAs-92a-3p was significantly increased in patients with concomitant fractures and brain trauma, as well as in the mouse model. miRNAs-92a-3p can promote the mineralization and maturation of osteoblast precursor cells in vitro, and local injection of agomiR-92a-3p can significantly promote scab formation at the fracture site in mice.…”

Assessment of the Effects of Stretch-Injury on Primary Rat Microglia

“…Cell culture media was assessed for lactate dehydrogenase (LDH) at 1,6,12,18,24,48, and 72 hours post-injury using the Cytotox 96 assay (Promega) according to the manufacturer's instructions. Absorbance at 496nm was measured using a ChroMate microplate reader (Awareness Technology Inc., Palm City, FL).…”

“…Nitric oxide (NO) measurement NO was measured in primary microglia exposed to stretch-injury at 1,6,12,18,24,48, and 72 hours postinjury. NO content in the media was quanti ed using a Griess reagent assay kit (Invitrogen).…”