New Prognostic Biomarkers in Patients With Traumatic Brain Injury

Abstract

Context:Traumatic brain injury (TBI) is a leading cause of death, disability, and resource consumption per year. There are two kinds of brain injury in TBI, primary and secondary injuries. Primary injury refers to the initial physical forces applied to the brain at the moment of impact. Secondary injury occurs over a period of hours or days following the initial trauma and results from the activation of different pathways such as inflammation, coagulation, oxidation, and apoptosis.Evidence Acquisition:This review focuses on new prognostic biomarkers of mortality in TBI patients related to inflammation, coagulation, oxidation, and apoptosis.Results:Recently circulating levels of substance P (SP), soluble CD40 ligand (sCD40L), tissue inhibitor of matrix metalloproteinases (TIMP)-1, malondialdehyde (MDA), and cytokeratin (CK)-18 fragmented have been found to be associated with mortality in TBI patients. Substance P is a neuropeptide of the tachykinin family, mainly synthesized in the central and peripheral nervous system, with proinflammatory effects when binding to their neurokinin-1 receptor (NK1R). Soluble CD40 ligand, a member of the tumor necrosis factor (TNF) family that is released into circulation from activated platelets, exhibit proinflamatory, and procoagulant properties on binding to their cell surface receptor CD40. Matrix metalloproteinases (MMPs) are a family of zinc-containing endoproteinases involved neuroinflammation and TIMP-1 is the inhibitor of some of them. Malondialdehyde is an end-product formed during lipid peroxidation due to degradation of cellular membrane phospholipids, that is released into extracellular space and finally into the blood. Cytokeratin -18 is cleaved by the action of caspases during apoptosis, and CK-18 fragmented is released into the blood.Conclusions:Circulating levels of some biomarkers, such as SP, sCD40L, TIMP-1, MDA, and CK-18 fragmented, related to inflammation, coagulation, oxidation, and apoptosis have been recently associated with mortality in patients with TBI. These biomarkers could help in the prognostic classification of the patients and open new research lines in the treatment of patients with TBI.

Fluid biomarkers for mild traumatic brain injury and related conditions

“…More recently, blood concentrations of inflammatory molecules, such as substance P, soluble CD40 ligand, and tissue inhibitor of matrix metalloproteinases, have been associated with outcome in TBI patients. 131…”

Blood biomarkers for brain injury: What are we measuring?

“…However, additional analyses revealed that a combination of galectin-3 and occludin could distinguish mTBI patients from those with orthopedic injury, suggesting that this multi-marker approach may have diagnostic value for mTBI (Shan et al, 2016). Alternatively, a panel of inflammatory markers including substance P, soluble CD40 ligand, tissue inhibitor of matrix metalloproteinases-1, and malondialdehyde, albeit not specific to the brain, has also been proposed as candidate biomarkers for gauging the severity of brain damage in TBI (Lorente, 2015). Many of these markers have shown compelling associations between serum concentrations and the extent of brain injury; however, these reports are limited, as these inflammatory markers have only been evaluated in animal models and cases of severe TBI in humans.…”

“…The search for reliable serological markers of mTBI that are easily obtainable in the blood has yielded numerous promising candidates (Table 1). Although there are a number of excellent reviews, book chapters, and even a special issue summarizing current knowledge and identifying future directions in the field (Brody et al, 2015; Dashnaw et al, 2012; Di Battista et al, 2013; Giza and Difiori, 2011; Giza and Hovda, 2001, 2014; Jeter et al, 2013; Kovesdi et al, 2010; Ling et al, 2015; Lorente, 2015; Neher et al, 2014; Papa et al, 2015; Stoicea et al, 2016; Zetterberg and Blennow, 2015), rarely are potential blood biomarkers for mTBI discussed in terms of cellular origin and function. In continuing to validate existing serological biomarkers, it is important to understand their fundamental biological functions within the body and to explore the clinical implications of their increased presence in the blood.…”

High Mobility Group Box-1 and Pro-inflammatory Cytokines Are Increased in Dogs After Trauma but Do Not Predict Survival

“…In human trauma patients, biomarkers improve the ability of clinicians to identify occult injury (i.e., those not readily discernible via outward signs or symptoms such as myocardial injury), enable monitoring of response to therapy, and enhance prognostic accuracy ( 8 , 9 ). Few studies in human or in veterinary medicine have evaluated combinations of biomarkers in trauma.…”