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A number of biomarkers are being evaluated for or show promise in providing improved sensitivity for diagnosis, prognosis, and monitoring of traumatic brain injury (TBI). This appendix summarizes developments in this area.

NEUROIMAGING BIOMARKERS

Neuroimaging is an essential component in evaluating patients with a suspected TBI. Imaging is a critical tool in identifying TBI pathologies that increase a patient's risk of mortality or further neurologic deterioration and indicate the need for urgent medical intervention.

Current Options

Magnetic resonance imaging (MRI), the second common neuroimaging method for TBI, can better characterize the nature, locale, and extent of TBI pathology and track the course of pathologies over time relative to CT. Clinicians may use routine MRI when a patient exhibits persistent or worsening symptoms because MRI can provide enhanced anatomic detail compared with CT, giving clinicians greater diagnostic clarity. Currently, MRI is an adjunctive tool in the evaluation of patients whose clinical outcome appears more severe than what would be expected based on brain CT. 

Imaging methods for TBI can better characterize TBI pathology's nature, locale, and the extent and track the course of pathologies over time relative to CT. Clinicians may use routine MRI when a patient exhibits persistent or worsening symptoms because MRI can provide enhanced anatomic detail compared with CT, giving clinicians greater diagnostic clarity. Currently, MRI is an adjunctive tool in the evaluation of patients whose clinical outcome appears more severe than what would be expected based on brain CT. Susceptibility artifact-sensitive sequences (e.g., susceptibility-weighted imaging) are also available and provide information on the presence of microhemorrhages within the brain that are less visible on more conventional T2 sequences. 

Diffusion imaging (including diffusion tensor imaging, diffusion spectrum imaging, and diffusion kurtosis imaging) and volumetric analysis of three-dimensional anatomic imaging may provide insight into gross and microstructural changes following a TBI. These findings may have value in both the short- and longer-term phases of recovery in patients with a broad range of severity of injuries and time since injury. 

Magnetization transfer imaging (MTI) may also add sensitivity to the MRI evaluation of patients with all severities of TBI. MTI examines the presence or absence of macromolecules, which include proteins and phospholipids that coat axonal membranes or myelin sheaths within the white matter. MTI has been used to infer the degree of myelin integrity and Wallerian degeneration, inflammation, and edema in various disease processes, including TBI. 

Emerging research also suggests that cerebral blood flow dysregulation contributes to TBI pathophysiology and acute and chronic symptoms. Change in cerebral blood flow following a vasoactive stimulus is defined as cerebrovascular reactivity. It can be measured by imaging techniques, including CT, MRI, positron emission tomography (PET)/single photon emission computed tomography (SPECT) perfusion techniques, and transcranial Doppler. Cerebrovascular reactivity (CVR) imaging is used for diagnosing and managing many cerebrovascular diseases. Still, it has only recently been studied in TBI. Some work has begun to evaluate CVR as a neuroimaging biomarker of traumatic vascular injury in sports concussions and moderate to severe TBI. The aim is to improve TBI management by improving diagnosis and recovery prediction. 

Another method using MRI technology is the use of functional MRI (fMRI). In this method, blood oxygen level-dependent (BOLD)-based fMRI sequences are employed and involve interpretations of neurological activity related to the oxygenation state of blood and hemodynamic response to the activity-related metabolic task. Researchers have also used fMRI to establish connectivity patterns between brain regions and describe how these connections are altered during normal development and disease. In TBI, task-based fMRI studies have demonstrated alterations in brain activity across several cognitive tasks, including working memory, sustained attention, executive function, and language processing). Reduced connectivity has also been shown in brain regions following TBI.

PET is a neuroimaging technique that allows for the detection and localization of radioisotopes associated with biologically active radiopharmaceuticals that aggregate within the brain following the administration of the ligand. PET detects high-energy photons that result from positron decay. In TBI, much of the work conducted with PET has involved imaging glucose metabolism using 18F-fluorodeoxyglucose imaging. Postmortem examinations of chronic traumatic encephalopathy (CTE) report the pathological finding of abnormal tau aggregation.