TBI Exosomal Activity in Military Personnel: Perivascular Space and Role of Indicators of Sleep Metrics TEAM-PRISM
Abstract
Background: Traumatic brain injuries (TBIs) are common in Service Members (SMs) and often result in long- term disability, yet we do not understand the reasons for the development of chronic symptoms. Proteins in the blood allow early identification of those at risk for long-term disability after TBI are not well identified. Our group’s research focuses on the early identification of SMs at risk of disability after TBIs and who could benefit from preventive interventions. To address this critical issue, we have developed the ability to examine central processes through examination of exosomal vesicles (EVs). EVs are secreted from the brain and cross the blood brain barrier and into the blood, where they can be isolated and their activity can be determined. Brain-derived exosomal vesicles (BDEVs) contain cytokines, inflammatory-related proteins. Cytokines within BDEVs can increases neuroinflammation. BDEVs also participate in the clearance of proteins from the brain, including tau, whose aggregation is linked to neurodegenerative disorders, such as dementias. It is likely that BDEVs, glymphatic function, and disturbed sleep are all related and are also associated with chronic symptoms following TBI. We need more research to determine these relationships. Proteins that increase neurodegeneration, including amyloid beta (Aß), tau, and other markers of brain injury, are removed from the brain via the glymphatic pathway. These proteins can be measured within BDEVs and in total blood through plasma. The glymphatic pathway is a network of perivascular spaces that supports the clearance of proteins from the brain, and is active primarily during sleep. In humans, work from our group and others suggests that way that it works efficiently is measured by its number and volume of perivascular spaces (PVS) seen on magnetic resonance imaging (MRI). Poor sleep is present in more than half of SMs with a TBI. Our team has shown that sufficient sleep as a key factor in recovery TBIs and that disturbed sleep in a preclinical leads to increased levels of Aß24 and tau in the brain. Objective: In this proposal, we will establish the relationship between objective sleep measurements, PVS burden, and protein levels. Specifically, we expect to observe an association between poor sleep and increased PVS burden. We believe that PVS burden will be associated with increased BDEV levels of injury proteins. Understanding the reasons why proteins are not cleared from the brain after a TBI and their clinical consequences is a critical step in the prevention of long-term symptoms. Design: We will utilize clinical data, MRIs, sleep studies and blood samples collected within an ongoing study at the National Intrepid Center of Excellence (NICoE) in SMs within the intensive outpatient program (IOP). We will determine plasma and BDEV concentrations of neuronal injury (i.e., tau, phosphorylated tau p-tau, and neurofilament light chain NfL), neuroinflammation (i.e., interleukin IL- IL-1ß, IL-6, IL-8, IL-10, IL-12, tumor necrosis factor-alpha TNF-, vascular endothelial growth factor VEGF), and markers of clearance and blood- brain barrier function (i.e., amyloid-beta Aß 40/42, alpha-synuclein, aquaporin-4, occludin). We assert that proteins in BDEVs reflect the central mechanisms that underlie chronic symptoms and deficits following TBI in SMs. Accordingly, the measurement of peripheral blood levels of BDEVs may provide insights into the link between brain injury and neurobehavioral impairment and allow us to identify those at risk of poor outcomes. Specific Aims: 1. In SMs with TBIs and controls without TBIs, examine the effects of TBI status and poor sleep on levels of BDEV and plasma proteins of neural, brain barrier function, inflammation, and clearance. 2. In SM with TBIs, determine the relationship between slow-wave sleep and PVS burden and the relationship between PVS burden and BDEV and plasma proteins of neural, brain barr
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210650
Entities
People
- Juan Piantino
Organizations
- Oregon Health & Science University
- United States Army