Long-Term Vascular-Related Cognitive Decline After Traumatic Brain Injury

Principal Investigator: SCHNEIDER, ANDREA L

Proposal Number: AZ200044

Award Number: W81XWH-21-1-0590

Period of Performance: 9/1/2021 - 8/31/2025

PUBLIC ABSTRACT

Background: Traumatic brain injury (TBI) in the United States is common, affecting approximately 23 million civilians and over 400,000 military active-duty and Veteran Service Members. It has become increasingly recognized that the consequences of TBI are long-lasting. Indeed, TBI has been associated with increased risk for the development of mild cognitive impairment and dementia. Vascular risk factors, such as diabetes and high blood pressure, are also associated with increased mild cognitive impairment and dementia risk. TBI is characterized by vascular injury, which may be a link between TBI and the later development of mild cognitive impairment and dementia. However, it remains unknown if vascular risk factors such as diabetes and high blood pressure are associated with poor cognition after TBI. Since vascular injury secondary to TBI and vascular risk factors are often preventable and treatable, it is critical to determine if TBI, in combination with vascular risk factors, is associated with poor cognition after TBI. It is important to note that studies of cognition are expensive and complex because of the long-term follow-up that is needed as well as loss to follow-up leading to incomplete data. In order to obtain unbiased results in studies of post-TBI related cognitive impairment, careful statistical techniques are needed.

Objectives/Hypotheses: The overall objective of this proposal is to use rigorously developed sophisticated statistical methods to unbiasedly determine if individuals with TBI and vascular risk factors have greater cognitive impairment compared to individuals with TBI without vascular risk factors and compared to controls. The overarching hypothesis of this proposal is that individuals with TBI and vascular risk factors will have greater decline in cognitive function over 5 years than individuals with TBI without vascular risk factors and controls. Further, we hypothesize that individuals with TBI and greater severity of vascular risk factors will have greater decline in cognitive function over 5 years than individuals with TBI and lower severity of vascular risk factors or no vascular risk factors and controls.

Research Strategy: This proposed project uses data from the Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) Study, which is one of the largest longitudinal studies of TBI and is funded by NIH/NINDS (2010-2011: RC2 NS069409; 2013-2019: U01 NS086090), DoD (2014-2019: W81XWH-14-0176), and multiple philanthropic sources, including the National Football League. The TRACK-TBI study was designed to characterize the acute and long-term clinical, neuroimaging, and blood biomarker features of TBI. The TRACK-TBI Study has nearly 2,700 participants with TBI and nearly 600 control participants without TBI that were enrolled from 18 Level 1 trauma centers in the United States. Participants are currently being followed up to 5 years for outcomes and have undergone cognitive testing at multiple time points over the course of the study. We propose to develop and validate statistical models to unbiasedly determine if participants with a combination of TBI and vascular risk factors such as diabetes and high blood pressure have greater decline in cognitive function after TBI compared to participants with TBI alone and to control participants without TBI. We will also investigate the role of the severity of vascular risk factors (e.g., uncontrolled versus controlled diabetes) on post-TBI cognitive function.

Impact/Innovation: The proposed project is clearly aligned with FY20 PRARP Convergence Science Research Award’s intent, vision, and mission. The proposal directly addresses the paucity of epidemiological and clinical research and focuses on vascular dementia. This proposed work has the potential to generate the following innovative deliverables: (1) identifying vascular risk factor reduction as a high-priority target for dementia prevention strategies and clinical trials in TBI populations and (2) developing statistical methods to model cognitive trajectories post-TBI that can be shared with other investigators and translated both within and across studies with the goal of collaboratively advancing research on post-TBI cognitive decline and dementia risk in both civilian and active-duty and Veteran military populations.

TECHNICAL ABSTRACT

Background: Traumatic brain injury (TBI) in the United States is common. It has become increasingly recognized that the sequelae from TBI are long-lasting, and several studies have reported increased cognitive impairment and higher rates of dementia among persons with TBI. TBI is characterized by both microvascular and macrovascular injury, which may be a mechanistic link between TBI and vascular dementia. Midlife vascular risk factors are independently associated with later-life cognitive decline and dementia. It remains unclear if these vascular risk factors are also associated with unfavorable cognitive outcomes after TBI. Since vascular dysfunction is often preventable and treatable, it is critical to determine if TBI, in combination with vascular risk factors, is associated with cognitive decline after TBI. However, studies of cognitive decline are expensive and complex, due to the length of follow-up needed and issues of study attrition. As a result, rigorous biostatistical methods are needed to model longitudinal cognitive trajectories and to account for missing data.

Objectives/Hypotheses: The overall objective of this proposal is to develop sophisticated biostatistical and epidemiological methods that account for study attrition to model cognitive trajectories assessed at multiple time points over 5 years of follow-up and to determine if individuals with TBI and vascular risk factors have greater cognitive decline compared to individuals with comparable TBI without vascular risk factors and compared to controls. Our proposal is based on the overarching hypothesis that when vascular injury secondary to TBI occurs in an individual with pre-existing vascular risk factors, there is a “multi-hit” vascular-mediated pathway that may lead to greater vascular-related cognitive decline and dementia risk after TBI.

Specific Aims:

Specific Aim 1. To collaboratively use cutting-edge, rigorous, biostatistical, and epidemiological methods to generate 5 years of analysis-ready cognitive trajectory models that account for study attrition. The methods developed will be readily translatable and able to be shared both among study investigators and across studies to facilitate advancing research on post-TBI cognitive decline.

Specific Aim 2: To investigate if vascular risk factors are associated with unfavorable cognitive outcomes after TBI. Specifically, we will examine the impact of the vascular risk factors of diabetes, hypertension, hyperlipidemia, smoking, and obesity on early (1 year post-TBI) and late (5 years post-TBI) cognitive impairment.

Specific Aim 3: To evaluate if markers of modifiable vascular risk severity are associated with unfavorable cognitive outcomes after TBI. Specifically, we will examine the impact of the markers of modifiable vascular risk severity of glucose, systolic and diastolic blood pressure, lipid profile, pack-years of smoking, and body mass index on early (1 year post-TBI) and late (5 years post-TBI) cognitive impairment. As an important step in achieving this aim, we propose to measure glucose and lipid profiles of participants from stored frozen plasma.

Research Strategy: We propose to use existing data from the Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) Study to develop and validate two approaches to account for missing cognitive outcome data due to study attrition: (1) inverse probability of attrition weighting and (2) multiple imputation using chained equations (MICE). We will use confirmatory factor analyses to create global and domain-specific factor scores and then with incorporation of the inverse probability of attrition weights and MICE methods developed above, and we will use models fit with generalized estimating equations (GEE) to model post-TBI cognitive trajectories (Aim 1). Using the statistical methods developed in Aim 1, we will model the associations between vascular risk factor burden and post-TBI cognitive trajectories (Aim 2) and vascular risk factor severity and post-TBI cognitive trajectories (Aim 3). To accomplish Aim 3, we propose to measure glucose and lipid profiles from stored frozen plasma samples from the 2-week post-TBI in-person visit (time of the first cognitive assessment).

Innovation and Impact: This proposed work has the potential to generate the following innovative and impactful deliverables: (1) identifying vascular risk factor reduction as a high-priority target for dementia prevention strategies and clinical trials in TBI populations (including military, Veteran, and civilian populations), and (2) developing biostatistical and epidemiological methods to model cognitive trajectories post-TBI that can be shared with other investigators and translated both within and across studies with the goal of collaboratively advancing research on post-TBI cognitive decline and dementia risk.