The goal of this project is to examine the clinical presentation and biomarkers that accompany chronic traumatic encephalopathy (CTE), a neurodegenerative disease associated with exposure to repetitive head impacts. A history of repetitive head impacts is a necessary factor in the development of CTE, though it is not a sufficient cause of the disease. The specific head impact exposures, other modifying risk factors (e.g., genetics), and incidence and prevalence of CTE remain unknown. To be able to address these critical issues, as well as to begin clinical trials, it is necessary to develop methods of detecting and diagnosing CTE during life and distinguish it from other clinically similar presentations. This proposed investigation is a continuation of the Diagnosing and Evaluating Traumatic Encephalopathy with Clinical Tests (DETECT) project. Our study population will include 110 former NFL players (high exposure to head impacts;HE) and 30 former elite non- contact sport athletes (low exposure to head impacts;LE). The HE group includes symptomatic and asymptomatic subjects;the LE group includes only asymptomatic subjects. All subjects will undergo a two-day evaluation, including clinical examinations (neurological, motor, cognitive, mood and behavioral evaluations), blood draw (for genetic sequencing and genotyping of APOE, MAPT, and MAO-A), EEG, lumbar puncture (CSF tau, p-tau, and Abeta42;monoamine metabolites), and neuroimaging (including volumetrics, cortical thickness, diffusion tensor imaging, free water imaging, and magnetic resonance spectroscopy). Specific tests were chosen to maximize the ability to share and compare data through datasets such as the Federal Interagency Traumatic Brain Injury Research (FITBIR) informatics system and the National Alzheimer's Coordinating Center. For the 80 subjects (60 HE and 20 LE) who previously participated in the initial DETECT study, this evaluation will serve as a 3-yr follow-up. The remaining former HE and LE subjects will return for a 3-yr follow-up evaluation within this study cycle. We will also examine 20 individuals with mild cognitive impairment (MCI) due to Alzheimer's disease and 20 individuals with Alzheimer's disease dementia (AD). AD and MCI subjects will have no contact sport or TBI history and will only receive a single evaluation for ths study;their data are only for cross-sectional comparison purposes. This project will utilize a multi-modal approach evaluating the relationship between head impact exposure and later-life clinical and biomarker outcomes, taking into account potential modifying variables. Additionally, expanding the cohort to include individuals with AD and MCI as well as older and asymptomatic HE and LE subjects will provide a more comprehensive picture of the repercussions of repetitive head impacts, and the factors that differentiate CTE from other disease processes. Furthermore, longitudinal evaluation will allow for important examination of the progression of clinical course and biomarker outcomes. Given the millions of Americans who participate in contact sports at all levels of play this study has the potential to have a tremendous impact on public health.

Public Health Relevance

Chronic Traumatic Encephalopathy (CTE) is a neurodegenerative disease caused in part by repetitive head impacts, such as those experienced by contact sport athletes and military personnel. Results of this study will improve our understanding of the long-term outcomes of repetitive head impacts, including CTE, experienced by contact sport athletes at all levels of play, and may provide insights relevant to other groups exposed to brain trauma such as combat military personnel. This investigation may also provide knowledge regarding the pathogenesis, early detection, and eventual treatment and prevention of other diseases such as Alzheimer's disease and other tauopathies.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
High Priority, Short Term Project Award (R56)
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Special Emphasis Panel (ZRG1-BDCN-N (02))
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Bellgowan, Patrick S F
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Boston University
Schools of Medicine
United States
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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
Cherry, Jonathan D; Mez, Jesse; Crary, John F et al. (2018) Variation in TMEM106B in chronic traumatic encephalopathy. Acta Neuropathol Commun 6:115
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; 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
Alosco, Michael L; Duskin, Jonathan; Besser, Lilah M et al. (2017) Modeling the Relationships Among Late-Life Body Mass Index, Cerebrovascular Disease, and Alzheimer's Disease Neuropathology in an Autopsy Sample of 1,421 Subjects from the National Alzheimer's Coordinating Center Data Set. J Alzheimers Dis 57:953-968
Alosco, Michael L; Jarnagin, Johnny; Tripodis, Yorghos et al. (2017) Olfactory Function and Associated Clinical Correlates in Former National Football League Players. J Neurotrauma 34:772-780
McKee, Ann C; Cairns, Nigel J; Dickson, Dennis W et al. (2016) The first NINDS/NIBIB consensus meeting to define neuropathological criteria for the diagnosis of chronic traumatic encephalopathy. Acta Neuropathol 131:75-86
Stern, Robert A; Tripodis, Yorghos; Baugh, Christine M et al. (2016) Preliminary Study of Plasma Exosomal Tau as a Potential Biomarker for Chronic Traumatic Encephalopathy. J Alzheimers Dis 51:1099-109
Mez, Jesse; Solomon, Todd M; Daneshvar, Daniel H et al. (2016) Pathologically Confirmed Chronic Traumatic Encephalopathy in a 25-Year-Old Former College Football Player. JAMA Neurol 73:353-5

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