Biomarkers in Traumatic Brain Injury

Introduction

Traumatic brain injury (TBI) induces a complex array of immunological/inflammatory cellular responses. Primary and secondary insults activate the release of cellular mediators including proinflammatory cytokines, prostaglandins, free radicals, and complement activators. These processes induce chemokines and adhesion molecules, which in turn mobilize immune and glial cells in a parallel and synergistic fashion. The progression of tissue damage relates to direct release of neurotoxic mediators or indirectly to the release of nitric oxide and cytokines.

TBI can be diagnosed and classified by neurological examinations [Glasgow Coma Scale (GCS)] and neuroimaging [computed tomography (CT) and magnetic resonance]. The use of the GCS as a diagnostic tool has a number of important limitations. Neuroimaging techniques are used to provide objective information on injury magnitude and location. However, CT has low sensitivity to diffuse brain damage and the availability and utility of magnetic resonance acutely is limited. Monitoring the brain may provide more information about pathophysiological disturbances after TBI but has limited sensitivity and specificity. These include monitoring for intracranial pressure (ICP), cerebral perfusion pressure, brain oxygenation, cerebral metabolism, and cerebral hemodynamics.

In medicine today, several specialties uses biomarker blood tests to diagnose, direct treatment, and prognosis.

A biomarker is an indicator of a specific biological or disease state that can be measured using samples taken from either the affected tissue or peripheral body fluids. These markers can be altered enzymatic activity, changes in protein expression, posttranslational modification, altered gene expression of proteins, or lipid metabolites, or a combination of these changes. As a consequence, a variety of strategies have been used for biomarker discovery including transcriptional profiling and proteomic and metabolomic approaches. The majority of TBI biomarker research has focused on protein profiling.

The brain biomarker should show clinical significance. The ideal biomarker has several potential benefits in the management of patients with mild and severe TBI. In mild TBI, particularly when there is little clinical or radiological evidence of injury, biomarker levels may more accurately predict the degree of brain injury and identify patients who are most likely to develop long-term sequelae. These patients may benefit the most by being targeted for rehabilitation therapy. High biomarker levels may also identify patients who are at highest risk for secondary deterioration and who would benefit from repeat imaging, monitoring, and increased surveillance.

For patients with severe TBI, a biomarker may be helpful to predict which patients are likely to experience secondary insults, such as raised ICP, and help prognosticate. For these reasons, the past decade and, in particular, the past few years have witnessed an increasing interest in biomarkers for TBI. Finding such a biomarker, though, has proved difficult for several reasons. The brain is a hugely complex organ and is protected by a selective blood–brain barrier. Its functions are both qualitative and quantitative, while most biomarkers are purely quantitative. For example, lobar injury has different consequences for outcome compared with the same volume of tissue injury in the brainstem. Furthermore, several factors, including secondary brain insults, may occur independently of the primary brain injury and contribute to outcome, thereby reducing the sensitivity of biomarkers to predict outcome.

Extracranial sources of the biomarker also may limit its specificity. The level of a biomarker in the serum may also reflect both the degree of cellular injury and/or the degree of blood–brain barrier disruption.