Exploring Serum Biomarkers for Mild Traumatic Brain Injury

Review
In: Brain Neurotrauma: Molecular, Neuropsychological, and Rehabilitation Aspects. Boca Raton (FL): CRC Press/Taylor & Francis; 2015. Chapter 22.

Excerpt

The diagnosis of traumatic brain injury (TBI) in the acute setting is based on neurological examination and neuroimaging tools such as CT scanning and MRI. However, CT scanning has low sensitivity to diffuse brain damage and confers exposure to radiation. On the other hand, MRI can provide information on the extent of diffuse injuries but its widespread application is restricted by cost, the limited availability of MRI in many centers, and the difficulty of performing it in physiologically unstable patients. Although some patients with Mild traumatic brain injury (mTBI) may be admitted to the hospital overnight, the vast majority are treated and released from emergency departments with basic discharge instructions. This group of TBI patients represents the greatest challenges to accurate diagnosis and outcome prediction. The lack of clinical tools to detect the deficits that affect daily function, have left these individuals with little or no treatment options. The injury is often seen as “not severe” and subsequently therapies have not been aggressively sought for MTBI. The diagnostic and prognostic tools for risk stratification of TBI patients are therefore limited in the early stages after injury. Unlike other organ-based diseases where rapid diagnosis employing biomarkers from blood tests are clinically essential to guide diagnosis and treatment, there are no rapid, definitive diagnostic blood tests for TBI. Over the last decade there has been a myriad of studies exploring many promising biomarkers. Despite the large number of published studies there is still a lack of any FDA-approved biomarkers for clinical use in adults and children. There is now an important need to validate and introduce them into the clinical setting. This chapter will review some of the most widely studied biomarkers for TBI in the clinical setting, with an emphasis on those that have been evaluated in MTBI.

Mild traumatic brain injury is also known as a concussion and is a traumatic force to the brain leading to a disruption of brain function. This disruption may seem transient, but could have long-lasting effects. It can manifest as an alteration in mental status such as confusion, amnesia, or loss of consciousness. There is a misconception among many that loss of consciousness must occur to have mTBI or concussion. As a result, many people with mTBI do not seek help, and many health care professionals do not recognize that an mTBI has occurred. There are an estimated 10 million people affected annually by TBI across the globe (Hyder et al., 2007). However, this is likely an underestimate given that many patients sustain mTBI but do not seek medical care. According to the World Health Organization, TBI will surpass many diseases as the major cause of death and disability by the year 2020 (Hyder et al., 2007).

Although TBI is often categorized into mild, moderate, and severe based on the Glasgow Coma Scale (GCS) score, it really represents a spectrum of injury. The GCS is a 15-point neurological scale used to characterize severity of TBI and was originally intended to provide an easy-to-use assessment tool and to facilitate communication between care providers on rotating shifts (Teasdale and Jennett, 1974). A GCS equal to or less than 8 is considered a “severe” TBI, a GCS of 9–12 is a “moderate” TBI, and a GCS of 13–15 is considered mTBI. The term “mild TBI” is actually a misnomer. Individuals who incur a TBI and have an initial GCS score of 13–15 are acutely at risk for intracranial bleeding and diffuse axonal injury (Stein et al., 2009). Additionally, a significant proportion is at risk for impairment of physical, cognitive, and psychosocial functioning (Alexander, 1995; Alves et al., 1993; Barth et al., 1983; Millis et al., 2001; Rimel et al., 1981).

An important neuropathological consequence of TBI is axonal injury, termed diffuse axonal injury (DAI) and more recently called traumatic axonal injury (TAI) (Povlishock, 1992). DAI/TAI can be found after severe, moderate, and mild TBI, and can occur after rapid acceleration and deceleration forces that can occur following motor vehicle accidents. DAI/TAI involves a number of abnormalities from direct damage to the axonal cytoskeleton to secondary damage from disruption of transport, proteolysis, and swelling (Johnson et al., 2012). For instance, ionic imbalances, through an efflux of potassium and influx of sodium, lead to calcium influx into cells, creating mitochondrial damage and impaired oxidative metabolism with lactate production (Buki et al., 2003; Maxwell et al., 2003).

The diagnosis of TBI in the acute setting is based on neurological examination and neuroimaging tools such as computed tomography (CT) scanning and magnetic resonance imaging (MRI). However, CT scanning has low sensitivity to diffuse brain damage and confers exposure to radiation. MRI can provide information on the extent of diffuse injuries, but its widespread application is restricted by cost, the limited availability of MRI in many centers, and the difficulty of performing it in physiologically unstable patients. In particular, the recognition of DAI/TAI is even more difficult and standard neuroimaging techniques may not detect TBI (Metting et al., 2012). Diffusion tensor imaging (DTI) is a promising neuroimaging technique that may help to identify axonal injury after mTBI (Bazarian et al., 2007; Huang et al., 2009). However, the role of MRI and DTI in the acute clinical management of TBI patients has not been established (Jagoda et al., 2008; Kesler, 2000). Although some patients with mTBI may be admitted to the hospital overnight, the vast majority are treated and released from emergency departments with basic discharge instructions. This group of TBI patients represents the greatest challenge to accurate diagnosis and outcome prediction. The lack of clinical tools to detect the deficits that affect daily function have left these individuals with little or no treatment options. The injury is often seen as “not severe” and subsequently therapies have not been aggressively sought for mTBI.

The diagnostic and prognostic tools for risk stratification of TBI patients are therefore limited in the early stages after injury. Unlike other organ-based diseases in which rapid diagnosis employing biomarkers from blood tests are clinically essential to guide diagnosis and treatment, such as for myocardial ischemia or kidney and liver dysfunction, there are no rapid, definitive diagnostic blood tests for TBI. Over the past decade, there have been myriad studies exploring many promising biomarkers. Despite the large number of published studies (Kochanek et al., 2008; Papa, 2012), there is still a lack of any Food and Drug Administration–approved biomarkers for clinical use in adults and children (Papa, 2012; Papa et al., 2013). There is now a strong need to validate and introduce them into the clinical setting.

This chapter will review some of the most widely studied biomarkers for TBI in the clinical setting, with an emphasis on those that have been evaluated with mTBI. Figure 22.1 shows the neuroanatomical locations of the biomarkers that will be reviewed.

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