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

Abstract and Introduction


Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with exposure to repetitive head impacts (RHI). Currently, CTE can only be diagnosed after death by postmortem, as validated in vivo biomarkers of CTE do not yet exist. Proton magnetic resonance spectroscopy (MRS) measures brain tissue metabolism in vivo and could facilitate a "probable CTE" diagnosis during life. Here, we propose MRS as one potential biomarker for CTE through a review of CTE neuropathology, and the extant literature that has examined the acute and long-term effects of RHI exposure on brain chemistry. There is preliminary empirical support for MRS in the detection of later-life neurological impairment associated with RHI exposure, but further ante- and postmortem research is needed before MRS can be considered a diagnostic biomarker for CTE.


Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with exposure to repetitive head impacts (RHI), or recurrent concussion and subconcussive head trauma.[1,2] RHI exposure plays a prominent role in the development of CTE, though not all individuals exposed to RHI develop CTE.[3] Notably, 16% of CTE cases were without a reported concussion history, supporting subconcussive head trauma as a primary contributor to CTE.[3,4] CTE was originally described in boxers, but has more recently been documented in former professional American football players, as well as other contact sport athletes (e.g., rugby and soccer players), and military veterans.[3,5,6]

Currently, CTE can only be diagnosed after death by postmortem using defined neuropathological criteria.[1] Clinically, CTE presents with a constellation of cognitive, behavior, and mood impairments[7] that serve as core symptom constituents of proposed clinical research diagnostic criteria for CTE (i.e., traumatic encephalopathy syndrome [TES]).[8] The course of symptoms of CTE is variable and can be influenced by factors such as cognitive reserve (CR).[9] To designate a "probable CTE" diagnosis during life, there must be an in vivo biomarker that suggests the positive presence of CTE pathology. Unfortunately, validated biomarkers of CTE do not yet exist. The diagnosis of CTE during life is critical to facilitate research on its epidemiology and risk factors and to ultimately identify and conduct prevention strategies and treatment interventions.

Proton magnetic resonance spectroscopy (MRS) may be one tool to support an in-life diagnosis of CTE. MRS is a safe and noninvasive neuroimaging method often referred to as a "virtual biopsy," as it examines physiological metabolism of brain tissue in vivo. The clinical diagnostic utility of MRS is widely supported in many different neurological disorders, including neurodegenerative diseases such as Alzheimer's disease (AD),[10] Lewy body disease,[11] and frontotemporal lobar degeneration.[12,13] Griffith et al[14] provided a review on MRS findings across the common neurodegenerative diseases.

The objective of this article is to propose MRS as a potential in vivo biomarker for CTE through a review of the literature examining MRS in the setting of RHI exposure, with emphasis on subconcussive head trauma. There have been previous reviews on the utility of MRS in sports-related symptomatic concussion[15] and on neuroimaging findings in the context of traumatic brain injury and RHI exposure,[16,17] but none have been devoted to MRS and CTE. We first provide a brief overview of MRS and discuss the characteristic neuropathology of CTE that could potentially be detected by MRS neurometabolites. The literature on the acute and chronic effects of exposure to RHI on brain chemistry is then reviewed. We conclude with a discussion on current knowledge gaps and future research targets.