Head trauma is a risk factor for both Alzheimer disease (AD) and Chronic Traumatic Encephalopathy (CTE), a progressive neurodegenerative disease that occurs as a consequence of repetitive mild traumatic brain injury (mTBI). CTE causes personality and behavioral changes, executive dysfunction, and memory loss and is characterized by the accumulation of phosphorylated tau protein in the brain. We have shown that CTE can develop following a single explosive blast injury. Thus, veterans are at particular risk for developing CTE as well as AD. Presently, CTE can only be diagnosed at autopsy and there are no known clinical biomarkers. We propose a translational approach to systematically address neurodegeneration in the largest neuropathologically-confirmed autopsy cohort of CTE and CTE with AD (CTE-AD) patients in the world on the protein, DNA, and RNA levels, with the goal of identifying biomarkers, genetic risk factors, and mechanisms that can be targeted for drug discovery. We hypothesize that head trauma leads to the pathologies of AD and CTE through independent mechanisms involving different tau haplotypes and isoforms. Because head trauma and the resulting early pathology of CTE can affect different regions of the brain, we will correlate histological, biochemical, and genetic measures with a tissue microarray demonstrating affected and non-affected regions in human brain. We will use plate-based ELISA to quantitate levels of A (1-40, 1-42, oligomeric) and tau (total and phosphorylated). In addition, we will determine the apolipoprotein E (APOE) genotypes and tau haplotypes of our subjects and correlate with clinical and pathological measures. Our preliminary data demonstrate that the APOE 4 allele and H1 tau haplotype are enriched in subjects with CTE and suggests that tau isoform expression differs between CTE and AD. Thus, genomic variation in APOE and MAPT may predict risk for developing trauma-induced neurodegenerations. Furthermore, we will recruit 105 subjects with AD and with and without a history of mTBI as well as controls to measure tau and A biomarkers in the CSF. We expect that trauma will exacerbate the changes seen in AD, leading to greater tau and less A. Our preliminary data shows that tau and A levels in CSF can be used to discriminate subjects with CTE and A plaques from subjects with AD or FTLD. Overall, we propose a two-pronged approach of 1) uncovering the progression of AD pathologies in subjects with repetitive mTBI and the mechanisms involved in CTE and AD tauopathy and 2) discovering genetic risk factors and biomarkers based on these pathologies in living subjects. A basic understanding of the mechanisms underlying the neuropathology of mTBI will facilitate rational drug design; and the development of reliable biomarkers to detect the long-term effects of mTBI will enable the diagnosis and monitoring of CTE and CTE-AD during life and will be crucial for assessing the efficacy of potential therapies as they are developed.
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. There is a critical need to understand the mechanisms underlying this injury to facilitate rational drug design. In addition, biomarkers are needed to identify those individuals at risk so that potential treatments can be tested before damage to the brain is advanced. 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.
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