Magnetic Resonance Spectroscopy as a Biomarker for Chronic Traumatic Encephalopathy

Michael L. Alosco, PhD; Johnny Jarnagin, BS; Benjamin Rowland, PhD; Huijun Liao, BS; Robert A. Stern, PhD; Alexander Lin, PhD


Semin Neurol. 2017;37(5):503-509. 

In This Article

Conclusions and Future Directions

MRS is a noninvasive neuroimaging assessment of brain tissue metabolism that may have key clinical applications in CTE. MRS neurometabolites (e.g., NAA, Cho, Glx) assess for the presence of neuropathological changes common (but not necessarily unique) in CTE, including neuronal loss, diffuse axonal injury, and neuroinflammation. Our review of MRS and RHI exposure studies shows that RHI exposure is associated with neurochemical changes consistent with CTE pathological changes. RHI was commonly found to lead to acute decreases in NAA, with evidence that such changes persist into later life, suggesting a possible link between RHI and neurodegeneration. RHI exposure was also associated with acute and chronic alterations in Cho, Glx, and mI metabolites that indicate the presence of diffuse axonal injury and neuroinflammation. Overall, the neuropathology of CTE combined with the in vivo literature provides preliminary support for MRS in the detection of later-life neurological impairment associated with RHI exposure.

Further research is needed to address the limitations of the literature to determine the utility of MRS in the setting of RHI exposure. Although all studies identified from this review included a diverse range of contact sport athletes, they were all small sample sizes (less than 30). We intend to examine MRS in large samples of former professional and college American football players, and additional study in other contact sports (e.g., soccer, ice hockey) and in military samples is needed. None of the studies reviewed included disease comparison groups. Regional MRS patterns can differentiate across neurodegenerative disorders, and comparison of regional neurochemical concentrations in subjects at high risk for CTE relative to other neurodegenerations (e.g., AD, Lewy body dementia) is warranted. Lin et al[22] used two-dimensional MRS methodology to show chronic neurochemical changes in former professional athletes, but examined only five individuals. Two-dimensional MRS provides a more robust examination of neurotransmitters, metabolites, lipids, and macromolecules at one time, and thus incorporation of L-COSY MRS in future work will improve understanding on the association between RHI and changes in brain chemistry.

Because CTE cannot be diagnosed during life, it is unclear whether the subjects from any of the in vivo studies reviewed have CTE. The direct relationship between MRS and CTE remains unknown. A critical next step is to correlate antemortem MRS with postmortem CTE pathology. It is likely that such data are not available in the short term. In the meantime, examination of MRS in subjects at high risk for CTE (e.g., symptomatic former professional football players) should investigate (1) the relationship between MRS and other theorized biomarkers of CTE pathology, particularly positron emission tomography imaging with tau-specific ligands (e.g., [F18] AV-1451) and (2) the association between MRS and proposed clinical research diagnostic criteria for CTE (e.g., TES).[8] TES classifies individuals into one of four symptom subtypes: cognitive, behavior/mood, mixed, or dementia. Cognitive decline is typical in the setting of neurodegeneration, and the extent to which the behavior/mood changes, specifically when they occur early and as the initial symptom, are a manifestation of CTE is unclear. MRS could shed insight into which TES subtypes and CTE symptoms may be specific to CTE-related neural degeneration versus chronic axonal injury/neuroinflammation due to prolonged RHI exposure. For example, alterations in mI, Cho, or GSH in the TES behavioral/mood subgroup, and reduced levels of NAA in the cognitive and dementia subgroups, would provide some support that behavioral/mood changes in CTE are a product of chronic axonal damage and neuroinflammation associated with concussion and subconcussive injury.

The existing literature provides a foundation for further exploration of MRS as a potential biomarker for CTE. The limitations and future research targets discussed earlier will be addressed by ongoing research, including a recently National Institute of Neurological Disorders and Stroke (NINDS)-funded, 7-year, multicenter study, entitled "Diagnostics, Imaging, and Genetics Network for the Objective Study and Evaluation of Chronic Traumatic Encephalopathy (DIAGNOSE CTE) Research Project." The primary goal of DIAGNOSE CTE is to develop and examine potential biomarkers for CTE, including MRS.