Current status of fluid biomarkers in mild traumatic brain injury

Abstract

Mild traumatic brain injury (mTBI) affects millions of people annually and is difficult to diagnose. Mild injury is insensitive to conventional imaging techniques and diagnoses are often made using subjective criteria such as self-reported symptoms. Many people who sustain a mTBI develop persistent post-concussive symptoms. Athletes and military personnel are at great risk for repeat injury which can result in second impact syndrome or chronic traumatic encephalopathy. An objective and quantifiable measure, such as a serum biomarker, is needed to aid in mTBI diagnosis, prognosis, return to play/duty assessments, and would further elucidate mTBI pathophysiology. The majority of TBI biomarker research focuses on severe TBI with few studies specific to mild injury. Most studies use a hypothesis-driven approach, screening biofluids for markers known to be associated with TBI pathophysiology. This approach has yielded limited success in identifying markers that can be used clinically, additional candidate biomarkers are needed. Innovative and unbiased methods such as proteomics, microRNA arrays, urinary screens, autoantibody identification and phage display would complement more traditional approaches to aid in the discovery of novel mTBI biomarkers.

Sports-related brain injuries: connecting pathology to diagnosis

“…First, the detection of small amounts of biomarkers in blood is often difficult due to their dilution in the large fluid volume that comprises the systemic circulation. 71 Second, there exists a low signal-to-noise ratio because blood interfaces with most organ systems of the body and contains a complex, native cell population. Third, the BBB also remains a challenge because it prevents diffusion of CNS material into the systemic circulation.…”

“…71,148 Because axon injury is a widely described result of TBI, myelin basic protein, which is a component of the myelin sheaths of oligodendrocytes and Schwann cells, has also been investigated. Specifically, it has been proposed as a marker of TBI in children because serum levels have been found to reach a peak concentration 48-72 hours after injury and remain elevated for up to 2 weeks.…”

“…In an unbiased approach, high-throughput screens without preselected antibodies or pathophysiology-based designs are used to identify novel biomarkers. 71 Numerous methods for unbiased biomarker discovery include phage-linked-enzyme-linked immunosorbent assay, 151 miRNA modulation, 5 and high-throughput proteomics techniques combined with bioinformatics. In hypothesis-driven discovery, biomarker candidates are selected based on their abundance in cells known to be affected by TBI.…”

“…Despite inconclusive studies demonstrating its clinical value in adults, the use of NSE has been proposed as a marker of TBI in the pediatric population and has been shown to have a higher predictive value in this population. 71 Because NSE is also highly expressed in erythrocytes, care must be taken during sample processing because hemolysis may produce false-positive results. 120 MicroRNAs (miRNAs) have also emerged as biomarker candidates for TBI in early studies.…”

The current state of biomarkers of mild traumatic brain injury

“…The cytoskeletal protein αII-spectrin is present in axons and neuronal presynaptic terminals. During cellular injury it is cleaved to form spectrin breakdown products (SBDPs) (72). While studies in this area are limited, Siman et al identified a subset of mTBI patients with elevated plasma N-terminal αII-spectrin fragment (SNTF), which is an SBDP cleaved by calpain (73).…”