Personal Biology and Comorbidity Impact on Post-TBI Cognitive Dysfunction and Neurodegenerative Disease
Abstract
Background: Over 2 million troops have deployed in support of the Afghanistan and Iraq wars. Over the course of these conflicts, the majority of TBIs (80-85%) are mild (mTBI), many (reported ranges 72-88%), and associated with blast or repeated blast exposures, the neurological effects of which have not been fully evaluated and may differ from other causes of TBI. Given the deployed population and estimates that 15-20% have experienced at least one mTBI, these findings raise significant concern regarding long-term outcomes for post-9/11 Veterans with mTBI. Cognitive impairment can be an enduring consequence of TBI that lasts months to years post-injury. Chronic cognitive complaints are cited by as many as 65% of those with moderate to severe TBI, yet less is known about the prevalence or scope of these issues in those who have suffered a mTBI or repetitive TBI and whether these injuries lead to more serious dysfunction or neurodegenerative disease later in life. Reports do suggest that some individuals with mTBI continue to exhibit persistent symptoms. Age-related cognitive decline is a growing concern in general due to increasing life expectancy in the United States. Dementia is currently rare among post-9/11 Veterans (mean age, about 36 years), but it remains a significant concern due to the high prevalence of mTBI in this population. Supporting this concern is that there are more than 9 million Veterans among the 46 million people over age 65 living in the United States. In about 20 years, Veterans of recent military conflicts will reach the age of increased dementia risk. As such, there is great urgency to determine the late-life impact of TBI and military service. In our currently funded work, we have used a multidisciplinary team of experts to clinically adjudicate EOD status among post-9/11 Veterans identified through Veterans Health Administration and Department of Defense Trauma Registry data. We have also used a civilian population with TBI to identify biologically vetted candidate genes within the dopamine system that are strongly related to cognitive performance and whose effects may be influenced by comorbid conditions like depression. In addition, we show strong evidence that inflammation influences cognition and mood, and variations within these pathway genes are strongly linked to risk for dementia. Scientific Goals: Based on these needs and our preliminary data, the primary goal of this application is to develop and validate gene risk scores (GRS) that inform EOD status among Veterans with TBI and can predict cognitive performance deficits in both civilians and Veterans with TBI. The Fiscal Year 2017/1018 Psychological Health/Traumatic Brain Injury Research Program Complex Traumatic Brain Injury Rehabilitation Research Clinical Research Award seeks research on mechanisms of conditions that inform potential interventions relevant to TBI rehabilitation. As such, our primary goal in this proposal is to assess TBI-related EOD and cognitive impairments using a biomarker (genetics/proteomics)-defined evaluation reflecting hypothesized mechanisms of cognitive impairment (hypodopaminergia/chronic inflammation) that are relevant to developing rehabilitation interventions aimed at prevention, mitigation, and recovery from cognitive deficits. Our models will address genetic markers/mechanisms associated with EOD risk stratification. These points of stratification will help guide treatment and gauge long-term cognitive performance and prognosis. Our work also will support future studies leveraging these databases to obtain DNA for large-scale prognostic models that incorporate personal biology, clinical, and other personal factors when assessing individualized EOD risk and the risk for cognitive dysfunction. Research Team: We have assembled a multi-disciplinary research team with expertise in neurorehabilitation, military TBI, neuroepidemiology, neuropsychology, biostatistics, and genetic,
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810803
Entities
People
- Amy K Wagner
Organizations
- United States Army
- University of Pittsburgh