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

Magnetic Resonance Spectroscopy and Chronic Traumatic Encephalopathy Neuropathology

Magnetic Resonance Spectroscopy Neurometabolites

Using a standard magnetic resonance scanner, MRS depicts a spectrum of the type and concentration of various neurometabolic markers from a single cubic volume extracted from a brain region of interest (ROI), or other methods (e.g., chemical shift imaging) that quantify the spatial variations of metabolites within a large brain ROI. A peak spectrum of the chemical signals is generated and each chemical has a distinct resonance frequency, with the peak indicative of the chemical concentration in the brain (Figure 1).[22] Six neurometabolites are typically examined in the context of neurological disorders and neurodegeneration. These include N-acetyl aspartate (NAA), glutamate/glutamine (Glx), choline (Cho), myo-inositol (mI), creatine (Cr), and glutathione (GSH). Each of these neurometabolites has a different resonance frequency and suggests the presence of distinct neuropathology, specifically:

Figure 1.

Proton magnetic resonance spectroscopy spectrum (adapted from Lin et al22). Cho, choline; Cr, creatine; Glx, glutamine; mI, myo-inositol; NAA, N-acetyl aspartate.

  • NAA: NAA is an amino acid synthesized in neurons and transported along axons. It is a marker of neuronal viability and decreased NAA represents neuronal loss, thereby serving as a primary metabolic target in the detection of neurodegeneration.[22,23]

  • Glx: Glutamate is the most abundant excitatory neurotransmitter in the brain that is stored as glutamine in glial cells before being converted to glutamate contained in neurons.[24] Cycling between glutamate and glutamine accounts for 80% of brain metabolism,[25] and they are often examined together due to overlap on the MRS spectrum. Increased in Glx reflects immunoexcitotoxcity.[22,26]

  • Cho: Cho is a marker of membrane turnover, and elevated Cho represents diffuse axonal injury.[22,23,27,28]

  • mI: mI is an astrocyte marker and osmolyte, and increased concentrations can be interpreted as glial proliferation secondary to astrocytosis and microglial activation.[29,30]

  • Cr: Cr is involved in the storage and transfer of energy among neurons and astrocytes. Its concentrations are believed to be stable across individuals and often used as an internal reference to scale other metabolites and expressed as a ratio (e.g., NAA/Cr).[22]

  • GSH: GSH is an antioxidant, and increased concentrations of GSH suggests the presence of neuroinflammation.[31]

Chronic Traumatic Encephalopathy Neuropathology

The pathognomonic lesion of CTE is the deposition of hyperphosphorylated tau (p-tau) as neurofibrillary, astrocytic, and neuropil tangles around small blood vessels at the depths of the cortical sulci.[1] McKee et al[3] proposed a four-stage classification system to grade the progression and pathological severity of p-tau (stage I–IV, with IV being most severe). P-tau deposition begins in the superior, dorsolateral, and inferior frontal cortices and spreads throughout the cortex, and then into the medial temporal lobes (MTL), diencephalon, basal ganglia, brainstem, and spinal cord. In addition to the unique p-tau deposition of CTE, axonal injury, axonal degeneration, demyelination, and white matter atrophy can also be observed in some cases, but are not necessarily unique pathological features of CTE. Likewise, prominent gliosis throughout the cerebral cortex and TDP-43 inclusions are also common in CTE. Typical gross brain changes include cortical and subcortical shrinkage, thinning of the corpus callosum, septal abnormalities, and pallor of the locus coeruleus and substantia nigra. The neural mechanisms underlying RHI and CTE are unknown, but may involve chronic immunoexcitotoxicity due to recurrent traumatic axonal injury and neurometabolic changes (e.g., ionic flux and glutamate release, microglial activation) that occur during active RHI exposure.[32]

The neuropathology of CTE supports the utility of MRS in the detection of this disease, particularly NAA. Research in AD indeed shows lower antemortem NAA/CR and NAA/mI concentrations predict higher postmortem p-tau burden,[33] and antemortem decreases in NAA/Cr (and increases in mI/Cr) predict higher Braak's stage and neuritic plaque scores.[34] In addition to NAA, the chronic axonal pathology and neuroinflammatory processes associated with RHI that can be found in CTE suggest Cho, mI, Glx, and GSH and may also play a role in the detection of CTE-associated pathological changes.