The neuropathology of mild traumatic brain injury in Alzheimer's disease

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Repetitive head impacts (RHI) are a form of mild traumatic brain injury that can 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. In addition, cerebrovascular disease is a well-known contributor to cognitive impairment; however, the role of vascular changes in the development of CTE and AD pathology are not well understood. Cerebrovascular integrity is critical for proper metabolism and perfusion of the brain. Compliance of large cerebral arteries allows these arteries to dampen the pulsatile pressure and protect the microcirculation and blood brain barrier from damage. Thus, cerebrovascular dysfunction can have detrimental impacts on the brain, including increased susceptibility to pulse pressure, blood brain barrier breakdown and ineffective clearance of tau pathology, beta-amyloid, and other toxic metabolites. The overall goal of this project is to determine whether RHI is associated with cerebrovascular remodeling and the progression of CTE and compare to the role of cerebrovascular remodeling in AD. Building upon our multidisciplinary expertise in vascular mechanobiology, precision mass spectrometry, advanced optical imaging, immunohistochemistry, vascular biology and neuropathology of CTE and AD, we will test this hypothesis in three aims: Aim 1) to determine cerebrovascular remodeling (biomechanical, structural, and compositional changes) in the frontal lobe in CTE; Aim 2) to determine the association between cerebrovascular remodeling and CTE and AD pathological changes; and Aim 3) to examine the association between cerebrovascular remodeling and RHI history and antemortem cognitive status. We will use no or low atherosclerotic cerebrovascular and brain tissue from 80 age- and sex-matched brain donors from the NIH and VA-funded BU Alzheimer Disease & CTE Research Center with 1) no RHI history and no pathology, 2) RHI history with no CTE, 3) low CTE pathology, and 4) high CTE pathology. These brain donors have undergone medical review and informants are given extensive structured interview/questionnaires using modified questions from the National Alzheimer’s Coordinating Center (NACC) Uniform Data Set (UDS), including postmortem assessments of cognitive functioning (including memory, language, attention, executive function and visuospatial function). This proposal is designed to leverage existing resources to make new discoveries. The matched and parallel studies of cerebral vessels and brain tissue will provide new understandings of the temporal development of cerebrovascular remodeling in CTE. Understanding the role of vascular remodeling in CTE may lead to the discovery of new treatment options and directions for interventions to stave off cognitive impairment in our military Veterans.