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 The need for traumatic brain injury (TBI) biomarkers

Significant scientific advances in the last decade have increased our understanding of the complex and heterogeneous pathophysiological processes associated with traumatic brain injury ^[6]. During the same period, numerous experimental drugs have been shown to be neuroprotective in animal models of brain injury. Unfortunately, none of these strategies have proven to be efficacious in TBI clinical trials [13–15]. The failure of clinical therapy trials has been attributed to the lack of therapeutic intervention-tracking CNS biomarkers complicated by the heterogeneity of TBI and poor translatability of preclinical TBI models. For example, it is now recognized that the pathophysiology of TBI is not only acute event, but is also a progressive and delayed neurodegenerative process made up of multiple, parallel, interacting, and interdependent cascades of biological reactions at the tissue, cellular, and subcellular levels. Due to the extended length of axonal fiber tracks, axons are particularly vulnerable to physical trauma to the brain. Thus, axonal injury is a common occurrence in both focal as well as diffuse brain trauma and can be found in TBI of all severities [16,17]. But in addition, neuronal body, dendrites, and synapses are also subjected to TBI-induced damage [18,19]. Similarly, not only are neurons at risk for injury, but also astroglia cells and the myelin-forming oligodendrocytes. For these reasons, a comprehensive understanding of these pathobiological processes at every cellular and subcellular level in greater detail is critical to bridging the knowledge gap that will allow new therapy development. Many agree that there is an unmet medical need for a rapid, simple biofluid-based diagnostic testing for the management of TBI patients, whether it is for monitoring severe TBI patients in the intensive care unit, or triaging mild and moderate TBI patients in the emergency room. Due to the multicomponent pathobiology in brain injury, it would be ideal to have a panel of neuroinjury biomarkers that closely match with the various pathological processes we described above. There are emerging data from many recent studies from multiple research teams showing that biofluid-based TBI biomarker tests have the potential to assess the extent of TBI severity and determine a patient prognosis even at times when correlation with other neurological measures (neuroimaging) may not always be informative such as for mild TBI.^[7]

TBI biomarker attributes   

In order for a biofluid-based TBI protein biomarker to be clinically useful, ideally it should have as many of the following attributes as possible (Table 2): (1) The protein biomarker levels should be readily measured in accessible biofluid such as cerebrospinal fluid (CSF), serum, plasma, and/or whole blood in TBI patients. [For severe TBI (i.e. those TBI patients in neurointensive care unit), the biofluid type where the biomarker can be detected should be biofluids such as CSF, serum, plasma, and/or whole blood. For moderate and mild TBI (e.g. those patients managed in Emergency Departments or admitted to non-ICU settings), the biofluid type should be serum, plasma, and/or whole blood for rapid accessibility and convenience. (2) The biomarker levels must be elevated in various forms and/or severities of human TBI in the acute phase (3–24 h post-injury), when compared to normal control counterparts. (3) The biomarker must have low background or basal biofluid levels in general noninjured healthy control population. (4) The biomarker detected in biofluid after TBI should be derived from or originated from the injured brain as the major source. (5) The biomarker levels in the above stated biofluids should be readily determined and quantified using sandwich ELISA or similar immunoassays with at least two assay formats or platforms. (6) There should be one or more available assay platform for such biomarker with test-retest reliability and reproducibility assay that meet assay analytical performance requirements acceptable to FDA. (7) The biomarker should be translational in nature with demonstrated evidence that there are similar to biofluid profiles in at least two different animal models of TBI (e.g. rodent control cortical impact [CCI], fluid percussion injury [FPI], close head injury [CHI], penetrating ballistic brain injury [PBBI], or blast overpressure wave brain injury [OBI]). (8) The biomarker should be sensitive to severity of TBI as defined by GCS, CT abnormality. (9) The biomarker should allow for repeated detections in one of the above-mentioned biofluids within a 48 h window following brain injury. (10) The biomarker should have initial acute levels (within first 48 h post-injury) that correlate with currently available and commonly accepted TBI patient outcome indices (such as Glasgow Outcome Scale [GOS] or GOS-extended [GOS-E]). (11) The post-TBI biofluid levels of the biomarker are responsive to therapeutic treatments.Based on cumulative evidence on a number of existing neuroinjury biomarkers and the discovery of additional biomarkers, we derived a TBI biofluid-based biomarker panel .

Current biomarker candidates

Graphic representation of major TBI protein biomarkers linked to different pathophysiologic processes in TBI.

Mirroring the different pathophysiologic processes occurring in TBI, a panel of TBI biofluid-based protein biomarkers has now been identified. The processes covered by these biomarkers thus far include axonal injury, dendritic injury, neuronal cell body injury, demyelination, synaptic injury and astroglia injury, and microglia responses. Neuronal cell body injury markers include Neuron-specific enolase (NSE), Ubiquitin C-terminal hydrolase-L1 (UCH-L1), Astroglial biomarkers include S100B protein and glial fibrillary acidic protein (GFAP), There are also αII-spectrin breakdown products/fragments as cell death markers. Delayed axonal injury and demyelination markers include Neurofilament proteins (NF) – heavy, medium and light and Myelin basic protein (MBP).  Subacute, chronic TBI biomarkers can include neuroinflammatory markers. Post-injury neurodegeneration/tauopathy such as Tau protein and phospho-tau protein. There are also autoantibodies as autoimmune response. They can target brain protein such as GFAP.  Other biomarker candidates with biofluid evidence from animal models of TBI from severe to mTBI in human. These include dendritic protein microtubule-associated protein-2 (MAP-2) [137,138], brain-derived nerve growth factor (BDNF) [139], and postsynaptic protein neurogranin. Other  emerging biomarkers include MicroRNA (miRNA), Circulating nucleic acids, and Exosome/micro-vesicles biomarkers.