Discovery of Blood-based Biomarkers of Concussion from Metabolic Profiling of Plasma

Although concussion affects an estimated 1.8-3.6 million persons each year, no diagnostic tools exist for evaluating this injury.1 Evaluation of concussion relies on accurate history taking (which is dependent on patient’s recollection and willingness to provide accurate answers) and physical examination (which is not always reliable). The majority of concussed persons achieve full recovery within 7 days, however, approximately 25% have persistent cognitive deficits that last more than 30 days.2, 3 Unfortunately, clinicians have no objective tools for predicting how long it will take for a concussed person to recover. Current efforts to identify blood-based biomarkers for predicting protracted recovery from concussion are focused on examining circulating proteins (proteomics). However, the existence of the blood brain barrier (BBB) limits the ability of brain-enriched proteins (which are typically large) to enter the circulatory system. Despite this limitation, a number of brain-enriched proteins including Tau,4, 5 αII-spectrin N-terminal fragment (SNTF),6, 7 and neurofilament light chain (NFL)8 have been reported to have prognostic significance in concussion. However, the prognostic accuracy of these proteins reported in published studies are modest. Therefore innovative approaches are needed for identifying novel blood-based biomarkers of concussion.

Metabolomics is a newly emerging scientific field focused on the identification and measurement of metabolites in biological samples by either high-throughput mass spectroscopy or nuclear magnetic resonance NMR spectroscopy. Metabolites are small molecule intermediates and products of cellular metabolism. Recent advances in biotechnology fused with “big data” analytics now allow the measurement of large numbers of metabolites over a short period of time. This advance has helped unravel mechanisms underlining different diseases and has led to the identification of blood-based biomarkers of cardiovascular disease9, 10 and oncology,11, 12 among others. Since metabolites are smaller than proteins they are more likely to cross the BBB and thus can provide a window into pathological processes occurring in the brain. We hypothesize that differences between the metabolome of concussed persons achieving full recovery and those with protracted recovery will provide insights into the biology of recovery and yield novel biomarkers for predicting protracted recovery. 

To test our hypothesis, we will perform a pilot case-control study examining the metabolic profile of concussed persons between the age of 18 and 40 years with full recovery from concussion symptoms (n=50) and those with persistent post-concussive symptoms at 1 month after injury (n=50). Subjects will be selected from an ongoing study of traumatic brain injury (Head Injury Serum Markers for Assessing Response to Trauma, HeadSMART, PI: Korley, Applicant). Subjects included in this sub-study will meet the American Congress of Rehabilitation Medicine’s criteria for having brain injury13 but have no evidence of brain injury on head CT scan. We will utilize banked plasma samples obtained on the day of injury (a median of 4 hours after injury). Untargeted metabolomics and lipidomic assays will performed by the University of Michigan Metabolomics Core. 

Principal Investigator: 
Frederick Korley
Assistant Professor
Emergency Medicine
2016 - 2017
Abstract Text: 
PI Title: 
Assistant Professor