Linking Cerebral Hemodynamics and Neuroinflammation to Alzheimer s Pathology in Repetitive Mild Traumatic Brain Injury
Abstract
Concussions and subconcussive injuries are forms of mild traumatic brain injury (mTBI) that take a toll on a patient’s immediate physical and mental health. Moreover, patients exposed to repetitive mTBI, such as athletes and military personnel, are also at a greater risk of long-term neurological consequences, including Alzheimer’s disease and related dementias. Currently, it is difficult for clinicians to assess concussion severity, to determine when it is safe for a patient to resume the risk of concussion, and to predict which patients will have worse long-term outcomes. An objective measure that helps answer these questions, rather than relying solely on the current method of patient symptom reporting, would address this unmet clinical need. Our research group recently published data from mice exposed to multiple subconcussive impacts, which demonstrated that decreased blood flow in the brain immediately after injury might be one such objective measure. In particular, we found that low brain blood flow was a strong predictor of long-term cognitive outcome. In this proposal, we will build on this exciting result to ask several new questions: (1) WHAT early markers of long-term outcome can we find that may have a stronger predictive power of the molecular signs of Alzheimer’s disease in the brain, including plaques? and (2) WHY is reduced blood flow in the hours after injury a harbinger of worse outcome later on? To answer these questions, we have assembled an ideal team of investigators with expertise in blood flow (Buckley), traumatic brain injury (Sayeed/Stein), and Alzheimer’s disease (Wood). For these exploratory studies, we will work with a mouse model, wherein we can eliminate many of the confounding effects that limit human studies of concussion, including heterogeneity in patient age, sex, concussion history, mechanism of injury, and time of assessment. We will approach this work in two aims: Aim 1 - WHAT: To identify what early, non-invasively measured parameters strongly predict long-term formation of Alzheimer’s disease plaques found after repetitive mTBI, we will first thoroughly characterize how the brain changes with time immediately after repetitive concussions spaced one day apart. Specifically, we will quantify parameters related to brain blood flow, how much oxygen the brain uses, the reactivity of brain blood vessels, and inflammation. After a month, we will perform a post-mortem exam to look for evidence of Alzheimer’s disease, such as characteristic amyloid plaques. We hypothesize that alterations in the parameters we measure acutely after injury will strongly predict long-term evidence of Alzheimer’s disease in these animals. Aim 2 - WHY: To understand why blood flow is reduced in the brain after concussion and why this reduction correlates with worse outcome, we obtained pilot data looking at molecular markers of injury in specific cells in the brain. We found that mice with the lowest blood flow, and, by extension, the worst cognitive outcomes, had the highest amount of inflammation in the brain. Thus, based on this data, along with additional reports from literature, we hypothesize that inflammation is driving changes in blood flow and is ultimately causing worse outcomes after repetitive concussion. To test this hypothesis, we will administer drugs that block the inflammatory response seen after concussion. We expect that treated mice will not only have increased blood flow after multiple concussions, but also improved cognitive outcomes and less microscopic evidence of Alzheimer’s disease in their brains. Future studies will expand this work to the clinic. Promising measured parameters found in Aim 1 can be readily translated to controlled clinical studies, as many of the parameters we are studying can be quantified non-invasively in the emergency room, battlefield, or sideline setting. Further, successful drug treatments found in Aim 2 could represent easily translatable therapies
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810669
Entities
People
- Levi Wood
Organizations
- Georgia Tech Research Corporation
- United States Army