Inflammation and Immunogenetic Influences on Epileptogenesis, Seizure Development, and Epilepsy-Associated Comorbidities After Moderate to Severe TBI
Abstract
Background and Rationale: Epilepsy affects 1 in 26 Americans and is often a result of traumatic brain injury (TBI). Despite these numbers, we are the only research group that has generated clinical prediction models that quantify risk for post-traumatic epilepsy (PTE) in the civilian population. In addition to the public health burden associated with civilian TBI, epilepsy is a significant concern for the Department of Defense and Department of Veterans Affairs given the high number of Service Members who have suffered a TBI while deployed in Iraq and Afghanistan (post-9/11). Roughly, 20% of Veteran-related TBI is moderate to severe in nature, with ~60,000 cases identified between September 2001 and June 2015. However, prognostic longitudinal PTE risk models are lacking for this population, potentially due to difficulty tracking seizure development from acute to chronic phases of recovery for Veterans with TBI. Our proposed civilian population is among the largest available cohorts with an accompanying biorepository of longitudinal samples with the potential to provide quantitative information to elucidate the driving role of personal biology and inflammation have in PTE risk over time post-injury. Currently, there are no established genetic tests or blood-based biomarkers reflective of epileptogenesis or PTE risk. We have conducted pioneering work identifying candidate gene variants within inflammatory genes such as the IL-1ß gene, and assessing systemic IL-1ß levels as companion markers for capturing PTE risk and accelerated epileptogenesis after TBI. In this application, we also provide substantial evidence, from serum samples of individuals with moderate-to-severe TBI, that there is ongoing immune dysregulation that likely impacts risk for PTE and other conditions that can commonly co-occur with epilepsy. Health-related quality of life is often poor among individuals living with epilepsy, in part due to comorbid disease burden, including diseases related to mental health. Currently, there is virtually no literature evaluating the combined effects of epilepsy and co-occurring conditions on outcome after TBI. The most common co-occurring conditions associated with epilepsy in the general population are depression and anxiety. We have published work on a sizeable civilian cohort enrolled into a large longitudinal database, which shows higher rates of depression and anxiety among individuals with PTE when compared to individuals without PTE. Our previously published work also suggests that TBI survivors have significant barriers to recovery and limitations in multiple measures of outcome, including employment and participation in other life roles. Together, these findings suggest a need to study how (1) the added burden of PTE couples with mental health and cognitive symptoms and (2) how inflammation following TBI affects these processes. Scientific Goals: Based on our work presented in this application, we want to study if/how inflammatory markers and genetic variation within genes that contribute to inflammation will significantly influence PTE risk. Further, we want to see if inflammation (genes and levels) associated with PTE will have a shared influence on other co-occurring TBI-associated conditions, like depression, anxiety, and cognition, as well as overall recovery. We will build on previous work generated from our prospective longitudinal cohort of individuals with moderate-to-severe TBI by utilizing this well-characterized cohort of ~800 civilians with moderate-to-severe TBI and a ~20% PTE rate over 3 years (1) to understand how chronic serum inflammatory profiles influence epileptogenesis and time to first seizure, (2) to understand how both genetic variation in inflammatory genes and corresponding serum inflammatory expression influence seizure risk and epileptogenesis (as measured by time to first seizure), (3) to understand the shared influence of serum inflammation and immunogenetics on PTE-associate
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110913
Entities
People
- Amy K Wagner
Organizations
- United States Army
- University of Pittsburgh