Trajectories of Neuroimaging and Blood-Based Biomarkers After Remote Traumatic Brain Injury and Associations with Dementia Risk

Principal Investigator: SCHNEIDER, ANDREA L

Proposal Number: TP220129P1

Award Number: HT9425-23-1-0981

Partnering Awards: TP220129

Period of Performance: 9/1/2023 - 8/31/2026

PUBLIC ABSTRACT

Background/Rationale: Traumatic brain injury (TBI) is common, affecting both civilians and military Service Members, and is a major public health burden. The consequences from TBI can have long-lasting effects and multiple studies have identified that TBI is associated with an increased risk of later-life development of dementia. After TBI, there are measurable changes that indicate that, if the health of the brain is affected, two useful tools to identify these changes are blood-based biomarkers and brain magnetic resonance imaging (MRI). Blood-based biomarkers can be obtained from a simple blood draw where concentrations of certain biomarkers of brain health can be measured. MRI allows both a structural and functional look at the brain post- injury and there are a variety of sequences that can be used, each with their own strengths, that reveal different properties of brain health. Using these two tools, a significant amount of previous research has focused on the effects of TBI in the short-term time frame after injury (days to months post-injury) and the trajectory of neuroimaging and blood-based biomarkers is clearly established in this time period. However, there is limited research studying these two tools in the long-term post-injury time period, (i.e., decades after a TBI).

Additionally, the relationship between these biomarkers over time and the risk of developing dementia among older individuals with prior TBI is not well established.

Objectives: The overall objective of this proposal is to identify biomarkers of TBI-related dementia. Using existing data from one of the largest and most well characterized community-based prospective studies, the Atherosclerosis Risk in Communities (ARIC) Study, we will characterize trajectories of neuroimaging and blood-based biomarkers in the remote post-injury time-period (>5 years to decades) and investigate associations of biomarker trajectories with dementia risk among individuals with a history of TBI. The ARIC Study is comprised of nearly 16,000 community dwelling black and white adults (27% military veterans, 31% with prior head injury occurring approximately 32 years prior to the first biomarker assessment).

Types of Patients That Will Be Helped by This Research and Clinical Applications, Benefits, and Risk: The work generated from this proposal has the potential to help anyone who has suffered from a TBI. There is limited information about the brain decades after a brain injury and this proposal will help to determine if the brain remains impacted by the TBI or if there is some improvement over time. Additionally, the work generated from this proposal has the ability to help develop clinical tools that can be used for more accurate diagnosis or treatment of TBI-related dementia. The potential risks of this proposal are minimal because only existing data will be used (no new participant recruitment). There will be no direct identifying information in the data used in order to minimize and breach of confidentiality risks. There is no anticipated direct benefit of this proposal to the ARIC Study participants, but there is potential to help the greater population at large and future generations in the prevention of TBI-related dementia.

Timeline: The projected 3-year timeline for this award is feasible because we propose three aims using existing data from the ARIC Study. No new data will be collected, and no new participants will be recruited as part of this proposed project. Our study team has the expertise needed to carry out the proposed work, including expertise in TBI, dementia, MRI/neuroimaging biomarkers, blood-based biomarkers, and biostatistics.

Alignment with FY22 TBIPHRP IIRA Focus Areas: This proposal is clearly aligned with the FY22 TBIPHRP IIRA’s intent, vision, mission, and focus areas as we propose to use existing data from the community-based ARIC cohort to identify trajectories of neuroimaging and blood-based biomarkers as predictors of dementia risk after remote TBI. It is aligned with focus area 1a (understand): understanding of risk, protective, and biological factors contributing to an individual’s vulnerability to, response to, and long- term outcomes of psychological health conditions and/or TBI. Our proposal also aligns with focus area 2a (prevent and assess): identification and validation of biomarkers or other objective markers for diagnosis, prognosis, or monitoring of psychological health conditions and/or TBI.

Impact and Relevance to Military Health: TBI in military populations is common and often occurs at younger ages compared to the general population, thus TBI-related dementia is an important military health problem. Both TBI and dementia are associated with significant long-lasting patient and caregiver burden. This proposed work has the potential to generate the innovative deliverables of (1) defining long-term trajectories of neuroimaging and blood-based biomarkers in the remote post-TBI time period and (2) identifying trajectories of neuroimaging and blood-based biomarkers as high-priority targets for future clinical trials of therapeutics to reduce TBI-related dementia risk.

TECHNICAL ABSTRACT

Background/Rationale: Traumatic brain injury (TBI) is common and represents a major public health burden in the United States. The sequelae from TBI are long-lasting, and multiple studies have reported an increased risk of dementia years and decades after TBI. Based on this accumulated evidence, the 2020 Lancet Commission on Dementia added TBI as one of 12 potentially modifiable risk factors for dementia, and the 2019 NINDS Alzheimer’s Disease-Related Dementias (ADRD) Summit formally recommended further study into the role of TBI in dementia, including a specific emphasis on studying mechanism and identifying TBI-AD/ADRD-related biomarkers. There has been a significant amount of prior work done in the acute and subacute post-injury time period (within 6 months of injury) and the trajectory of neuroimaging and blood-based biomarkers, including GFAP, NfL, and others is clearly established in this time period. More recently, these observations have been extended to the chronic post-injury period, but this has largely been limited to within the first 5 years post-injury. The relationship of the trajectories of these biomarkers in relation to dementia risk among older individuals with prior head injury is not well established.

Objective/Hypothesis/Specific Aims: The overall objective of this proposal is to identify biomarkers of TBI-related neurodegeneration in the remote post-injury time period. Using data from one of the largest and deeply phenotyped community-based prospective cohort studies, the Atherosclerosis Risk in Communities (ARIC) Study, we will characterize trajectories of neuroimaging and blood-based biomarkers in the remote post-injury time-period (>5 years to decades) and investigate associations of biomarker trajectories with dementia risk among individuals with a history of TBI. The overarching hypothesis of this proposal is that individuals with TBI will have greater slopes over time in the direction of worse brain health for both neuroimaging and blood-based biomarkers and that among individuals with prior TBI, individuals with the greatest slopes over time in the direction of worse brain health will have greater dementia risk compared to individuals with lesser slopes in biomarkers over time.

Specific Aim 1. To investigate whether remote head injury is associated with longitudinal changes in brain magnetic resonance imaging (MRI) metrics. Specifically, we will examine trajectories of the MRI metrics of volumetrics, cortical thickness, predicted brain age, fractional anisotropy, and mean diffusivity over an 8-year period (2011- 2019), comparing individuals with and without a history of head injury. Importantly, the metric of predicted brain age will be newly derived for the ARIC cohort and will be shared widely with other investigators as part of this proposed work.

Specific Aim 2. To determine whether remote head injury is associated with increased levels of neurodegenerative blood-based biomarkers, both cross-sectionally and longitudinally. Specifically, we will investigate levels and trajectories of NfL, GFAP, p-tau181, and the Aß40/Aß42 ratio among individuals with and without head injury over a 26-year period (1993-2019). Recent non-overlapping funding from other federal sources have added the NfL, GFAP, p-tau181, Aß40, and Aß42 measurements to ARIC.

Specific Aim 3. To evaluate associations of blood-based biomarker and neuroimaging biomarker trajectories with incident dementia risk over time among individuals with a history of prior head injury.

Study Design: We will utilize existing data from the ARIC Study, one of the largest, most comprehensively phenotyped community-based cohort studies. The ARIC study contains over 30 years of follow-up data collected on 15,792 white and black participants (27% military veterans, 31% with prior head injury occurring a median of 32 years prior to first biomarker assessment). We will leverage the rich ARIC phenotypic data as well as the neuroimaging and blood-based biomarker assessments obtained prior to onset of mild cognitive impairment or dementia, to assess the long-term relationships between TBI, neurodegenerative imaging and blood-based biomarkers, and dementia risk.

Impact: This proposal clearly aligns with the FY22 TBIPHRP IIRA’s focus area 1a (understand): understanding of risk, protective, and biological factors contributing to an individual’s vulnerability to, response to, and long- term outcomes of psychological health conditions and/or TBI. Our proposal also aligns with focus area 2a (prevent and assess): identification and validation of biomarkers or other objective markers for diagnosis, prognosis, or monitoring of psychological health conditions and/or TBI. This proposed work has the potential to generate the innovative deliverables of (1) defining long-term trajectories of neuroimaging and blood-based biomarkers in the remote post-TBI time period and (2) identifying trajectories of neuroimaging and blood-based biomarkers as high-priority surrogate endpoints/targets for future clinical trials of therapeutics to reduce TBI-related dementia risk.

Relevance to Military Health: The prevalence of TBI in military populations is significant and TBI often occurs at younger ages compared to the general population, thus TBI-related dementia is an important military health problem. Both TBI and dementia are associated with significant long-lasting patient and caregiver burden. The ability to better understand the trajectories of biomarkers and their role in TBI-related dementia risk has the potential to identify high-priority surrogate endpoints/targets for future clinical trials of therapeutics to reduce TBI-related dementia risk.