Contributions of mild traumatic brain injury to neurodegeneration due to chronic traumatic encephalopathy and alzheimer's disease

Understanding the risks mild traumatic brain injury (mTBI) poses for neurodegeneration is critically important for Veterans. Single and repetitive mTBI is common in Veterans, with as many as 17% reporting mTBI during deployment. TBI has been reported as one of the strongest environmental risk factors associated with late-onset Alzheimer’s disease (AD), and repetitive mTBI has been associated

with chronic traumatic encephalopathy (CTE). However, there is ongoing debate as to whether mTBI outside of sports, which represents the vast majority of brain injuries, results in neurodegenerative changes. Studies investigating the overlap of AD and CTE, two potentially co-occurring neurodegenerative conditions, are few and more are needed. This proposal examines the contribution

of mTBI to neurodegeneration with the intent of detecting behavioral and biomarker evidence of neurodegeneration due AD and CTE in Veterans. Our hypothesis is that, after correcting for age, it is possible to separate the hallmarks of brain trauma related to TBI itself, from deficits related to neurodegeneration. [We will examine recognition memory, separating recollection and familiarity as a

model of the cognitive changes underlying potential neurodegeneration in mTBI. As measures of recognition memory, recollection and familiarity are ideal for use in the mTBI population—at risk for neurodegeneration—as they have previously been used to detect neurodegeneration in AD. Our hypothesis is that subjects with more mTBIs and more time since their mTBIs will be more likely to

develop neurodegeneration due to AD or CTE, leading to relative decreases in recollection and, eventually, decreases in familiarity as well once the disease reaches the mild dementia stage. In addition to these behavioral techniques, complimentary data regarding the underpinnings of these cognitive processes provided by event-related potentials (ERPs), MRI, and cerebrospinal fluid (CSF)

will allow further separation of possible AD and CTE. A total of 220 veterans will be recruited consisting of 65 younger adult veterans with a history of mTBI, 65 older adult veterans with mTBI, 30 older veterans with mild cognitive impairment (MCI) but lacking a history of mTBI to act as cognitive controls,

as well as 30 younger healthy control veterans without a history of mTBI and 30 older healthy control veterans without a history of mTBI.] The primary aims will be explored within the mTBI cohort using regression analyses for the relations between [total number of life time mTBIs], time since [first lifetime]

mTBI, and outcomes of interest including behavioral, ERP, MRI measures and CSF measures. Multivariate linear mixed-effects models will be used to examine differences between mTBI subjects and non-mTBI controls for all outcomes measures. The models will be adjusted for age, [education, APOE status] and other potential confounding factors. The research and career development activities

proposed will prepare Dr. Turk for her long-term goal of a research career in neurodegeneration in veterans following mTBI and will allow her to eventually study this well-characterized population of veterans with mTBI longitudinally. She proposes focused coursework, study and mentoring from a group of well-established investigators who are leaders in their fields, as well as practical research

experience completing the project proposed. The proposed training plan focuses on three objectives: (1) training in experimental psychology and experimental design including counterbalancing and data analytic techniques, (2) training in quantitative imaging techniques and data analytic techniques, and

(3) training in cerebrospinal fluid biomarker measurements in neurodegeneration. The knowledge, techniques, and experience gained through this proposal will allow Dr. Turk to gain skills needed to compete successfully for a Merit Review Award and become an independent investigator.