The proposed study will use magnetic resonance spectroscopy (MRS) to examine the relationship between neurochemistry and clinical features in individuals at high-risk for chronic traumatic encephalopathy (CTE). CTE is a neurodegenerative tauopathy believed to be caused, in part, by repetitive head impacts (RHI) that currently can only be diagnosed by neuropathological examination. Investigators at the Boston University Alzheimer's Disease and CTE Center published research diagnostic criteria for the clinical presentation of CTE, known as Traumatic Encephalopathy Syndrome (TES), to be used in conjunction with biomarkers (when they become available) for in vivo diagnosis of CTE. Based on past work on the clinical presentation of neuropathologically-confirmed CTE cases, TES criteria include four variants: Behavioral/Mood, Cognitive, Mixed, and Dementia. A goal of the proposed research is to investigate MRS-based neurochemical profiles that may serve as potential biomarkers for CTE and help differentiate the TES phenotypic subtypes. CTE has been proposed to involve prolonged neurometabolic alterations due to RHI exposure. Neuropathological research supports neurometabolic disruption in CTE, such as axonal and neuronal loss, and neuroinflammation. MRS, an advanced neuroimaging tool, measures neurometabolic function and has strong clinical utility in other neurodegenerative illnesses (e.g., Alzheimer's disease). Pilot work by proposed mentors has linked RHI with long-term neurochemical changes in former professional athletes, suggesting MRS may serve as a biomarker for CTE. To test this possibility, the proposed study will examine the relationship between MRS and TES in individuals at high-risk for CTE. The proposed investigation will examine data collected in the NIH-funded DETECT study. Subjects will include 100 former NFL players, aged 40-69 years, presumably at high risk for CTE due to a history of high exposure to RHI based on positions played and active cognitive, mood, and behavioral complaints. There will be a control group of 30 same-aged males without history of brain trauma or contact sport involvement, and are asymptomatic. All subjects will be classified into the TES variants using the extensive neuropsychological, neurological, and psychiatric evaluations conducted for DETECT. MRS will quantify neurochemical concentrations for all subjects. We will test the hypothesis that the former NFL group will exhibit abnormal neurochemical levels relative to controls that will present in a distinct pattern for each TES variant. We will also investigate the association between neurochemistry and the various individual cognitive, behavioral, and mood symptoms that accompany CTE. Findings from this study will expand the limited knowledge of CTE and may support MRS as a potential biomarker for CTE. Given the millions of Americans involved in contact sports, as well as military personnel who experience RHI, a better understanding of CTE and identification of biomarkers that detect this disease during life will have a major public health impact and facilitate research into risk factors, epidemiology, prevention, and treatment of CTE.

Public Health Relevance

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease that is caused, in part, by repetitive head impacts, such as those experience by contact sport athletes, and leads to impairments in thinking, mood, and behavior, as well as dementia. Millions of Americans participate in contact sports and the ability to detect CTE during life is imperative in order to diagnose, treat, and prevent this progressive brain disease. The proposed study will be part of a larger NIH-funded investigation, which is the first to address these issues, and examine the role of sophisticated neuroimaging in the detection of CTE.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1)
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Bellgowan, Patrick S F
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Boston University
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Alosco, Michael L; Tripodis, Yorghos; Fritts, Nathan G et al. (2018) Cerebrospinal fluid tau, A?, and sTREM2 in Former National Football League Players: Modeling the relationship between repetitive head impacts, microglial activation, and neurodegeneration. Alzheimers Dement 14:1159-1170
Alosco, Michael L; Sugarman, Michael A; Besser, Lilah M et al. (2018) A Clinicopathological Investigation of White Matter Hyperintensities and Alzheimer's Disease Neuropathology. J Alzheimers Dis 63:1347-1360
Guenette, Jeffrey P; Stern, Robert A; Tripodis, Yorghos et al. (2018) Automated versus manual segmentation of brain region volumes in former football players. Neuroimage Clin 18:888-896
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Alosco, M L; Kasimis, A B; Stamm, J M et al. (2017) Age of first exposure to American football and long-term neuropsychiatric and cognitive outcomes. Transl Psychiatry 7:e1236
Alosco, Michael L; Tripodis, Yorghos; Jarnagin, Johnny et al. (2017) Repetitive head impact exposure and later-life plasma total tau in former National Football League players. Alzheimers Dement (Amst) 7:33-40
Alosco, Michael L; Mez, Jesse; Kowall, Neil W et al. (2017) Cognitive Reserve as a Modifier of Clinical Expression in Chronic Traumatic Encephalopathy: A Preliminary Examination. J Neuropsychiatry Clin Neurosci 29:6-12
Alosco, Michael L; Jarnagin, Johnny; Rowland, Benjamin et al. (2017) Magnetic Resonance Spectroscopy as a Biomarker for Chronic Traumatic Encephalopathy. Semin Neurol 37:503-509
Alosco, Michael L; Jarnagin, Johnny; Tripodis, Yorghos et al. (2017) Utility of providing a concussion definition in the assessment of concussion history in former NFL players. Brain Inj 31:1116-1123

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