DEPARTMENT OF DEFENSE - CONGRESSIONALLY DIRECTED MEDICAL RESEARCH PROGRAMS

TGF-beta Signaling in Post-Traumatic Epileptogenesis: Novel Mechanisms and Therapeutic Target

Principal Investigator: FRIEDMAN, ALON
Institution Receiving Award: DALHOUSIE UNIVERSITY
Program: ERP
Proposal Number: EP160053
Award Number: W81XWH-17-1-0684
Funding Mechanism: Idea Development Award - Funding Level 1
Partnering Awards:
Award Amount: $573,554.00


PUBLIC ABSTRACT

A single traumatic brain injury (TBI) can lead to later appearance of chronic neurological disease that plagues patients for the rest of their lives. The most well-known of these secondary diseases is post-traumatic epilepsy (PTE), likely because its symptoms are so salient and devastating. Approximately 10%-40% of TBI patients go on to develop epilepsy, which typically manifests months to years after the original injury. Combat personnel are particularly impacted, with a high incidence of severe TBI, resulting in PTE in up to 50% of cases. Because PTE seizures are frequently resistant to anti-epileptic drugs, patients suffer lifelong disability, and the enormous financial costs are shouldered by both patient and care providers such as the Department of Veterans Affairs (VA). However, TBI also increases risk for other secondary pathologies that are less well known and understood. These outcomes include neurodegenerative disease (dementia, Alzheimer’s, Parkinson’s, and mild cognitive impairment) and affective disorders (depression and post-traumatic stress disorder).

There are two major reasons that current clinical approaches have failed to solve the problem of chronic diseases caused by TBI. The first is that there are currently no diagnostic methods to predict which TBI patients are at risk for developing delayed complications such as PTE. As such, current TBI patients are treated for acute injury until recovery, and then released into looming uncertainty. Though we know the risk for subsequent complication is high, no one can say whether the patient will develop symptoms or not; rather, the patient must wait until it is too late, returning to his or her doctor when symptoms appear (for example, seizures in the case of PTE). The chance for prevention is lost, and the treatments available for managing end-stage symptoms are often ineffective. The second problem is that there has been a poor understanding of the mechanisms that are triggered by TBI to cause later disease, and so there are no preventative drugs to treat the early stages of pathology that cause later disease.

We believe that both of these problems can be solved with a single approach. In a research program culminating over 10 years, we have identified that microvascular pathology, and specifically dysfunction of the blood-brain barrier is frequently observed in TBI patients, even years after the acute trauma. We also demonstrated that when blood proteins, specifically the common protein albumin, gains access into the brains, it activates inflammatory TGFß receptors signaling, which initiates an epileptogenic process, culminating in the development of epilepsy. We hypothesize that a similar process occurs following TBI to promote PTE, and propose here to test a novel diagnostic method for the quantitative assessment of blood-brain barrier integrity by contrast-enhanced MR imaging, to identify which patients are at risk to develop post-traumatic epilepsy (and associated pathologies). We have demonstrated previously that blocking TGFß signaling can block the development of epilepsy, and hence has the clinically coveted potential to act by modifying the disease process and prevent seizures and other delayed complications. Thus, we seek to develop a mechanism-based diagnostic and a comprehensive therapeutic approach for PTE prevention.