Fluid Biomarkers of Traumatic Brain Injury and Intended Context of Use.

diagnostics Review Fluid Biomarkers of Traumatic Brain Injury and Intended Context of Use Tanya Bogoslovsky 1, *, Jessica Gill 2 , Andreas Jeromin 3 , Cora Davis 1 and Ramon Diaz-Arrastia 4 1 2 3 4 * Center for Neuroscience and Regenerative Medicine, Uniformed Services University of the Health Sciences, Rockville, MD 20856, USA; National Institute of Nursing Research, National Institutes of Health, Bethesda, MD 20814, USA; Quanterix Inc., Lexington, MA 02421, USA; Director, Traumatic Brain Injury Clinical Research Center, Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Correspondence: ; Tel.: +1-319061262 Academic Editor: Ludmilla A. Morozova-Roche Received: 27 July 2016; Accepted: 30 September 2016; Published: 18 October 2016 Abstract: Traumatic brain injury (TBI) is one of the leading causes of death and disability around the world. The lack of validated biomarkers for TBI is a major impediment to developing effective therapies and improving clinical practice, as well as stimulating much work in this area. In this review, we focus on different settings of TBI management where blood or cerebrospinal fluid (CSF) biomarkers could be utilized for predicting clinically-relevant consequences and guiding management decisions. Requirements that the biomarker must fulfill differ based on the intended context of use (CoU). Specifically, we focus on fluid biomarkers in order to: (1) identify patients who may require acute neuroimaging (cranial computerized tomography (CT) or magnetic resonance imaging (MRI); (2) select patients at risk for secondary brain injury processes; (3) aid in counseling patients about their symptoms at discharge; (4) identify patients at risk for developing postconcussive syndrome (PCS), posttraumatic epilepsy (PTE) or chronic traumatic encephalopathy (CTE); (5) predict outcomes with respect to poor or good recovery; (6) inform counseling as to return to work (RTW) or to play. Despite significant advances already made from biomarker-based studies of TBI, there is an immediate need for further large-scale studies focused on identifying and innovating sensitive and reliable TBI biomarkers. These studies should be designed with the intended CoU in mind. Keywords: traumatic brain injury (TBI); biomarkers; TBI management 1. Introduction TBI is an important public health concern, as it is one of the leading causes of death and disability around the world [1]. Recent epidemiological studies indicate that around 5.3 million people in the United States and nearly 7.7 million people in Europe live with a TBI-related disability [2]. Mild TBI (mTBI) accounts for 70%–90% of all cases [3]. Importantly, mTBI may be associated with persistent symptoms and prolonged disability in approximately 10%–20% of cases [4]. This indicates a significant public health issue due to the prevalence of TBI among civilians in the U.S. and around the world. The ultimate challenge in the clinical practice of TBI resides in three major factors: (1) Ambiguity in determining the clinical severity of TBI based on clinical variables, such as the Glasgow Coma Scale (GCS) [5], loss of consciousness (LOC) and posttraumatic amnesia (PTA). It is widely recognized that assessing TBI severity from GCS, LOC and PTA is imprecise [6]. Scores may be compromised in patients who are intubated or sedated, and GCS in acute settings has a low Diagnostics 2016, 6, 37; doi:10.3390/diagnostics6040037 www.mdpi.com/journal/diagnostics Diagnostics 2016, 6, 37 2 of 22 inter-rater reliability [7]. mTBI can especially be a challenge to diagnose, as the symptoms are often vague, inconsistent and overlap with other conditions that frequently confound the clinical picture, such as intoxication, delirium and functional disorders, like post-traumatic stress disorder (PTSD) [8]. The Abbreviated Injury Scale (AIS) is an anatomically-based, consensus-derived, global severity scoring system that classifies each injury by body region according to its relative importance on a six-point ordinal scale. Demetriades et al. evaluated the prognostic value of AIS by correlating head AIS with GCS using 7764 patients with head injuries. However, the study found that there was no good correlation (with correlation coefficient −0.31) between GCS and AIS [9]. (2) Relatively low sensitivity of the primary brain imaging modality used in the emergency department (ED), i.e., head computed tomography (CT) to identify subtle brain injuries, such as diffuse axonal injury (DAI) or microhemorrhages, which may significantly contribute to prolonged post-concussive symptoms and disability. Various studies have shown that only 10% of CT scans detect abnormalities in mTBI subjects [10,11]; whereas conventional MRI lacks the sensitivity to detect DAI (identifying approximately 32% of all DAI lesions) [12] and diffuse traumatic vascular injury (DVI), the most common abnormalities in mTBI [13,14]. Up to 30% of mTBI subjects had abnormalities in research MRI, including: microhemorrhages (identified by susceptibility weighted imaging (SWI) sequences), small contusions and edema (identified by diffuse weighted imaging (DWI) sequences) and meningeal enhancement (identified after intravenous contrast gadolinium administration on postcontrast fluid attenuated inversion recovery (FLAIR) images) [15]. These subtle and previously underdiagnosed types of brain injury have an important impact on the rate of recovery. The presence of DAI is associated with poor outcome after brain injury [16]. One study showed that DAI identified by MRI in the genu of the corpus callosum after TBI was associated with worse outcome after adjustment for age (p = 0.0051) [17]. Likewise, a large multicenter study demonstrated that the presence of ≥4 microhemorrhages after mTBI was associated with poorer three-month outcome with an odds ratio (O.R.) of 3.2 (p = 0.03) [15]. The visualization of DAI and DVI will likely require advanced methods, such as diffusion tensor imaging (DTI) and arterial spin labelling (ASL) (by demonstrating a decrease of cerebral flow in mTBI) [18], which are not routinely used in clinical practice. While MRI is safe, its application is limited for patients who are pregnant, claustrophobic, anxious, sedated, have cardiac pacemakers or retained metal shrapnel. MRI is also expensive, requires lying for a prolonged time in the scanner during image acquisition and cannot be tolerated by a subset of patients. Fluid biomarkers will likely be complementary to imaging and provide important tools for making progress in the management of TBI, particularly mTBI. (3) Augmentation of pathophysiological changes in the chronic period, especially after repetitive TBI. Emerging evidence suggests that axonal loss and unique glial scarring after blast TBI [19] may be present for years post-injury. Furthermore, the consequences of repetitive injuries may not be accurately diagnosed by neuroimaging and may (...truncated)