Repetitive head impacts (RHI) lead to severe cognitive and behavioral symptoms and the progressive neurodegeneration of chronic traumatic encephalopathy (CTE). Trauma is also a known risk factor for Alzheimer disease (AD) and we hypothesize that a prolonged period of RHI can play a causative role in the development of AD as well as CTE. Currently, there are no disease modifying treatments for CTE or AD, and diagnosis of CTE can only be made at autopsy. Furthermore, little is known about the genetic and molecular changes in CTE or in AD in the setting of RHI exposure. This is largely because there has not been a systematic collection of more than a handful of cases of CTE, until now. Our translational approach is to systematically address neurodegeneration in the world's largest neuropathologically-confirmed autopsy cohort of CTE and CTE with AD (CTE-AD) subjects on the DNA, RNA, and protein levels, with the goal of identifying novel genetic risk factors, biomarkers, and mechanisms that can be targeted for drug discovery. We have shown that in CTE subjects beta-amyloid deposition is accelerated, related to areas where mechanical stresses are greatest, and influenced by APOE allele status. Furthermore, genomic variation can play an important role in disease progression, and stratification based on APOE allele ?4 status uncovers additional risk alleles and predicts altered pathologies based on the underlying genetics. Our preliminary data shows that variation in TMEM106B is associated with microglia activation, tau pathology, and clinical symptoms in CTE in APOE ?4-negative subjects. Variation in TMEM106B is related to the development of FTLD-TDP and to progranulin (PRGN) levels and modulation of inflammatory pathways. Many other genes implicated in AD genetic risk are also involved in the brain's inflammatory response/immune system. We have shown that microglial activation is an early change in CTE and have demonstrated that altered neuroinflammatory cytokines are related to the development of tau pathologies disparately in CTE versus AD. Our hypothesis, based on our preliminary data, is that variants of APOE and TMEM106B are enriched in CTE and CTE-AD subjects and are associated with altered cytokines and increased levels of beta-amyloid and tau and progression of disease. We further hypothesize that genomic variation in known AD genes will predict risk or progression of CTE and CTE-AD following RHI exposure and that levels of beta-amyloid, tau, and neuroinflammatory cytokines may serve as biomarkers for trauma-induced neurodegenerations. Our long-term goal is to uncover genetic and molecular mechanisms underlying the development of AD in the setting of multiple mild traumatic brain injuries. The immediate goal of this research project is to discover differences in genomic variation and neuroinflammatory markers that may serve as biomarkers to identify those individuals at risk for developing AD in the setting of trauma. This research will be critical for understanding how trauma may cause or accelerate AD, developing ways to assess risk in contact sports play and military service, and for informing rational drug design. Here we propose a cross-disciplinary approach that combines expertise and novel techniques in neuropathology, genetics, and data analysis to discover new pathogenic pathways for risk assessment, biomarker development, and therapeutics.

Public Health Relevance

This proposal addresses a critical need for both our older and younger populations of veterans. Head trauma is a risk factor for both Alzheimer disease and Chronic Traumatic Encephalopathy, a neurodegenerative disease caused by repetitive mild traumatic brain injury. Soldiers have always been at risk for head injury and this is particularly the case for OEF/OIF veterans, many of who have experienced explosive blast injury and participated in contact sports. There is a critical need to understand the mechanisms and genetic risk factors underlying this injury to facilitate prevention, diagnosis, and treatment. The aging veteran population and high rate of head injury will lead to daunting costs and responsibilities for the VA if research aimed at translating mechanisms into biomarkers and treatments is not developed.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Neurobiology D (NURD)
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Edith Nourse Rogers Memorial Veterans Hospital
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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; 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
Armstrong, R A; McKee, A C; Stein, T D et al. (2017) A quantitative study of tau pathology in 11 cases of chronic traumatic encephalopathy. Neuropathol Appl Neurobiol 43:154-166
Cherry, Jonathan D; Stein, Thor D; Tripodis, Yorghos et al. (2017) CCL11 is increased in the CNS in chronic traumatic encephalopathy but not in Alzheimer's disease. PLoS One 12:e0185541
Kanaan, Nicholas M; Cox, Kristine; Alvarez, Victor E et al. (2016) Characterization of Early Pathological Tau Conformations and Phosphorylation in Chronic Traumatic Encephalopathy. J Neuropathol Exp Neurol 75:19-34
Cherry, Jonathan D; Tripodis, Yorghos; Alvarez, Victor E et al. (2016) Microglial neuroinflammation contributes to tau accumulation in chronic traumatic encephalopathy. Acta Neuropathol Commun 4:112
Mez, Jesse; Solomon, Todd M; Daneshvar, Daniel H et al. (2015) Assessing clinicopathological correlation in chronic traumatic encephalopathy: rationale and methods for the UNITE study. Alzheimers Res Ther 7:62
Daneshvar, Daniel H; Goldstein, Lee E; Kiernan, Patrick T et al. (2015) Post-traumatic neurodegeneration and chronic traumatic encephalopathy. Mol Cell Neurosci 66:81-90
Martinez-Ramirez, Sergi; Romero, Jose-Rafael; Shoamanesh, Ashkan et al. (2015) Diagnostic value of lobar microbleeds in individuals without intracerebral hemorrhage. Alzheimers Dement 11:1480-1488
McKee, Ann C; Stein, Thor D; Kiernan, Patrick T et al. (2015) The neuropathology of chronic traumatic encephalopathy. Brain Pathol 25:350-64

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