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

Mrs and Rhi Exposure: In Vivo Studies

Below, we review the extant evidence that has investigated the acute and chronic effects of RHI exposure on neurochemistry. Table 1 provides a summary of the identified studies.

Acute Effects of Subconcussive Head Trauma on Neurochemistry

Emerging research has examined the association between recurrent subconcussive head trauma (i.e., head trauma with enough force to result in neuronal injury, but below threshold to cause overt symptoms) exposure and brain chemistry. Poole et al[43] examined the neurochemistry of the left dorsolateral prefrontal cortex (DLPFC) and primary motor cortex in 34 active high school American football players without a concussion history at pre-season and at least once in season. Relative to 10 non–contact sport controls, football players exhibited decreases in Cr and inositol (Ins) in the DLPFC throughout the season. Reductions in Glx, Cr, and Cho were observed in the primary motor cortex. A follow-up study from the same author group investigated the direct relationship between RHI exposure and neurochemistry using the Head Impact Telemetry System (HITS).[42] Single voxel spectra were collected from the left DLPFC and dominant primary motor cortex at the beginning of the season and at least once during the season among 25 active male high school football players without a history of concussion. In the primary motor cortex, duration of exposure was the strongest predictor of Glx, and Glx negatively correlated with percentage of 60 g (gravitational force) hits. Cr positively correlated with total number of hits experienced in the previous week. In the DLPFC, the number of 60 g hits inversely correlated with Cr and mI concentrations, and hit metrics predicted NAA and Cho changes.

Subconcussive head trauma has been linked with acute NAA changes in other RHI exposure populations. A sample of mixed martial art fighters exhibited decreased concentrations of white matter NAA concentrations (sampled from above the lateral ventricles) throughout the course of 1 year (3 of 13 had a confirmed concussion during the year), and no such relationship was present in a matched healthy control group without contact sport participation.[41] Chamard et al[36] also found significant decreases in NAA/Cr in the corpus callosum over the course of a season in female ice hockey players without a history of concussion, but not in male ice hockey players. Taken together, RHI exposure appears to lead to acute changes in neurochemistry, particularly reduced NAA.

Chronic Effects of RHI Exposure on Neurochemistry

Research has also begun to examine chronic changes in neurochemistry. Alosco et al used MRS to compare the neurochemistry of 79 symptomatic former National Football League (NFL) players to 23 same-age controls without a history of head trauma or contact sport participation.[35] The former NFL players exhibited lower NAA concentrations in the parietal white matter compared with controls. In the former NFL players, there was an inverse relationship between RHI exposure and levels of parietal white matter Cr, such that greater exposure to RHI was associated with lower levels of Cr. A recent study examined brain chemistry of 11 former professional soccer players (mean age: 52 years) without a history of a clinically diagnosed concussion relative to age- and gender-matched former non–contact sport controls. The former soccer players showed increased Cho and mI in the PCG, and mI and GSH concentrations correlated with lifetime subconcussive head trauma exposure.[39] Tremblay and colleagues[44] examined 30 former male college athletes (70% former ice hockey players, 30% former American football players) between the ages of 51 and 75 years who were clinically intact and underwent clinical (e.g., neuropsychological testing) and neuroimaging evaluations, including MRS. Among the formerly concussed athletes, there were elevations of mI/H2O in the left MTL that negatively correlated with episodic memory test performance. There were reductions in Cho in the MTL, and the right prefrontal cortex had increased Cho/H2O. A more remote study demonstrated reductions of NAA in the lentiform nucleus in former professional boxers with parkinsonian syndrome relative to patients with idiopathic Parkinson's disease and a control group.[37]

The aforementioned studies all used one-dimensional MRS. Recently, more novel MRS technology has been developed, known as Localized Correlated SpectroscopY (L-COSY).[45,46] One-dimensional MRS can be problematic due to neurochemical overlap on the spectra and signal-to-noise ratio (SNR). L-COSY utilizes a three-pulse MR sequence to provide a two-dimensional MRS spectrum, limiting SNR and sampling a larger number of brain molecules. A recent study examined L-COSY in five former professional male athletes (three football players, one professional wrestler, and one baseball player) with a history of multiple symptomatic concussions, and repetitive subconcussive head trauma.[40] Relative to controls, former athletes had >30% Glx increases, and 65% higher levels of Cho in the PCG. Spectral regions that contain threonine, fucose, lactate, and phenylalanine—metabolites not measured by one-dimensional MRS—were higher in the former athletes.

All MRS and RHI exposure studies have been in contact sport athletes, with the exception of one. Military veterans with multiple blast exposures have been shown to exhibit decreased in NAA/Cho and NAA/Cr along the hippocampal formations.[38] This, however, is the only study to date that examined MRS in military veterans, despite their high exposure to subconcussive trauma.