Diagnosing Sport-related Concussion Using Urine Metabolomics: A 1H NMR-Based Analysis

Background:

Sport concussion or sport-related mild traumatic brain injury (mTBI) affects patients across the spectrum of age, race and gender. It is a medical problem that if not treated appropriately can have devastating outcomes to patients and families. MTBI or concussion (terminology used interchangeably in this proposal) more recently has been a hot topic in the media with high profile politicians and athletes having career altering outcomes following a concussion. According to the Canadian Institute for Health Information, sports and recreational activities were the third leading cause of TBI admissions in Canadian hospitals in 2003-2004. In the United States, the Center for Disease Control and Prevention estimates that 1.6 to 3.8 million concussions occur in sports and recreational activities annually. In Calgary, approximately 10,000 patients were seen in the emergency departments with a head injury in 2013, 80% of which were diagnosed as mTBI and a vast majority of these were sport related (unpublished data).

Currently, there is no single "gold standard" assessment or diagnostic marker to objectively determine if a patient has suffered a sport concussion and if so, how long it will take to recover. As such, concussion remains a clinical diagnosis based on post-traumatic symptoms, physical signs, and impairment in cognitive function, which at best is done by a trained and experienced medical professional. But, this is primarily a qualitative, individualized approach to diagnosing and is typically clouded by a lack of objective clinical findings. Other assessment tools can aid a clinician in diagnosing a concussion such as the Sport Concussion Assessment Tool 3 (SCAT3) (Appendix 1), but unfortunately this has not been validated and was developed based on expert consensus. As well, computerized neuropsychological testing may help with the assessment of concussion recovery; however it is expensive, time consuming and has recently been criticized as lacking specificity and sensitivity for head injury.

Over the past 20 years researchers have studied biomarkers such as S100B and neuron-specific enolase in hopes of finding a quantitative approach to diagnosing and prognosticating concussion. This unfortunately, has met with much disappointment as none of these markers, in and of themselves, has adequate specificity or sensitivity to be used as a single biomarker in clinical practice.

Metabolomics is defined as "the quantitative measurement of the metabolic response of living systems to pathophysiological stimuli or genetic modification" and is based on analytical platforms such as proton nuclear magnetic resonance spectroscopy (1H NMR) and/or mass spectrometry. Metabolomic studies of clinically accessible bio-fluids, such as blood and urine, provides an intricate and relatively non-invasive snapshot into this response. To date, metabolomics has been shown to be a useful biomarker tool in amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, neonatal hypoxic ischemic encephalopathy, brain cancer, multiple sclerosis, aging and neurodegenerative disease, epilepsy, stroke, severe traumatic brain injury and pediatric septic shock. To the best of our knowledge, no study has assessed quantitative metabolomic profiling as a diagnostic and prognosticating tool in sport concussion.