Elsevier

Experimental Neurology

Volume 275, Part 3, January 2016, Pages 334-352
Experimental Neurology

Current status of fluid biomarkers in mild traumatic brain injury

https://doi.org/10.1016/j.expneurol.2015.05.004Get rights and content

Highlights

  • Biomarkers of mild traumatic brain injury would aid in diagnosis, prognosis, return to play/duty assessments, and further elucidate pathophysiology.

  • The majority of biomarker research focuses on moderate to severe injury or uses a hypothesis-driven approach.

  • Summary of potential serum and cerebral spinal fluid biomarkers of mild traumatic brain injury.

  • Innovative and unbiased methods of discovery should be utilized in order to discover novel biomarkers of 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.

Section snippets

Biofluids for mTBI biomarkers

Blood (serum and plasma) is a preferred biofluid for biomarker discover because of the ease of access, ease of processing, relatively homogenous samples, and the large amount of normative data available (Lundblad, 2003). However, because it comes into contact with all tissues and organs, blood can present difficulties in identifying the source of a protein and can also present challenges in terms of sensitivity and dynamic range (Good et al., 2007).

Most mTBI studies have evaluated potential

The hypothesis-driven approach:

Based on the success of serum troponin-T as a biomarker for myocardial damage, (Mair et al., 1992), a search began for biomarkers of brain injury. Putative candidates were identified based on their relatively high abundance in cells or cellular compartments known to be affected in TBI, and protein concentrations in blood or CSF were evaluated.

Early TBI biomarker candidates were lactate dehydrogenase and creatine kinase BB. However, these did not have sufficient specificity, sensitivity, or

The unbiased approach

The above hypothesis-driven biomarkers have largely been evaluated in moderate to severe TBI. For mTBI, diagnosis is more challenging because of the less severe symptoms and typically negative conventional imaging results. As discussed above, evaluation of existing biomarkers reveals some promising candidates to assist in the diagnosis of mTBI, although many challenges remain. Several studies included multiple injury levels and did not analyze the mild injury data independently. Mild traumatic

Phage display

Phage display is a method to select peptides, proteins or antibodies with specific binding properties. It is most widely used to investigate protein-protein interactions, receptor- and antibody-binding sites, and for selecting antibodies against a range of antigens (Bradbury, 2010). It uses bacteriophages (viruses that infect bacteria) in which DNA encoding peptides or proteins is inserted into the gene encoding a coat protein of a filamentous phage such as M13 phage. Libraries of

Biomarkers in urine

Urine is easily obtained, particularly in the post-acute phase where it could be self-collected. However, quantitation of urinary biomarkers is problematic as they can very dependent upon flow rates. Urinary S100B measurement revealed elevations in children and adults with severe TBI and strong correlations with serum S100B levels (Berger and Kochanek, 2006, Hallen et al., 2010, Rodriguez-Rodriguez et al., 2012). However, a separate study of pediatric TBI found similar S100B levels in urine

Conclusions

Millions of people are affected by mTBI and its sequelae, but mTBI is difficult to diagnose. It lacks a consensus definition, relies on subjective self-reported symptoms, and is insensitive to commonly available imaging modalities. An objective and quantifiable measure of mTBI, such as a serum biomarker, is needed. Suitable biomarkers would aid in diagnosis, prognosis, return to play/duty assessments, therapeutic evaluations, and provide additional knowledge regarding mTBI pathophysiology. Most

Acknowledgements

The author’s research was supported by NIH grants R21 NS084088 and RO1 NS062993.

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