Development of Blood-Based Biomarker of Blood-Brain Barrier Dysfunction in Traumatic Brain Injury
Abstract
The underlying hypothesis of this proposed work is that impairment of the blood-brain barrier is a critical early event triggering the brain pathology that ultimately causes clinical dementia. The blood-brain barrier protects the brain from toxins, inflammatory cells, metals, and other circulating particles in the bloodstream that can damage the brain. Recent evidence suggests that disruption of the blood-brain barrier may be an early event in cognitive decline in Alzheimer s Disease as well as other disorders. We have found that the blood-brain barrier is disrupted following traumatic injuries of the brain and that this dysfunction persists over time. We and others hypothesize that persistent disruption of the blood-brain barrier contributes to cognitive decline and dementia in some survivors of traumatic brain injuries. Currently, injury to the blood-brain barrier can only be measured using highly specialized magnetic resonance imaging (MRI) scans only available at a few research institutions in the world. Recently, a protein found in the cells of the blood-brain barrier (platelet derived growth factor receptor-beta) was found in the spinal fluid of individuals with early cognitive decline. The level of this protein corresponded to the level of blood-brain barrier injury detected by MRI. However, spinal fluid is difficult to sample, making this marker impractical for clinical use. Our group has recently found that this protein can be measured in the blood and, critically, these blood levels correspond to the level of blood-brain barrier injury by MRI. In this study, we aim to build upon these findings to develop a blood-based biomarker of blood-brain barrier dysfunction. While this study will focus on early age-related cognitive impairment and traumatic brain injuries, the work we propose has broad implications for a wide variety of neurological and psychiatric disorders in which blood-brain barrier disruption may play a role in cognitive decline. In this proposal, we seek to study healthy individuals with normal cognition, those with early age-related cognitive decline (the earliest form of dementia), and those with traumatic brain injuries to investigate if platelet derived growth factor receptor-beta measured in the blood can be used as a marker of blood brain barrier disruption and serve as a marker of present or future cognitive impairment. In this work we will (1) determine if blood and cerebrospinal fluid levels of this protein are related, (2) determine if this biomarker is increased in those with mild cognitive decline, traumatic brain injuries, or both compared to individuals with normal cognition, (3) determine if the level of this biomarker corresponds to evidence of blood brain barrier dysfunction detected using a specialized MRI technique to examine the blood brain barrier, and (4) determine if the level of platelet derived growth factor receptor-beta measured in the blood near the time of injury corresponds with later cognitive decline. The work that we propose will be the first to use a protein detected in the blood to measure blood-brain barrier disruption. These studies will form the basis to define the normal population ranges of this protein, a critical step in making this a clinically available test. We have a plan established to complete this next phase of analysis, ensuring that this will become a clinically usable test in the relatively short term. We will leverage existing biospecimens and neuroimaging, in addition to enrolling new participants.; This will ensure that we can make rapid progress and convert this research project into a clinically useful test in a reasonable time frame. The overall goal of this work is to develop easily measurable markers that would allow us to measure blood brain barrier disruption and use this to help predict future cognitive difficulties. This would help us to better care for these individuals, as well as design more targeted clinical tria
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310399
Entities
People
- Danielle Sandsmark
Organizations
- United States Army
- University of Pennsylvania