Tracking Neuroinflammation in GWI from Brain-Derived Extracellular Vesicles in the Blood
Abstract
Overarching Challenges: The proposed studies in this application are highly relevant to several overarching problems listed for the Gulf War Illness Research Program (GWIRP). One is to understand why the severity of GWI is higher in some Veterans than others. The second is diagnosing the extent of central nervous system inflammation in Veterans with GWI. The third challenge is determining whether GWI puts a higher risk of developing neurodegenerative diseases. Rationale: Gulf War Illness (GWI) affects nearly 40% of military personnel who served in the 1990-1991 GW. Altered function of the brain is one of the most bothering health issues in Veterans with GWI. The symptoms include difficulties for memory formation and memory recall, concentration issues, mood swings, and chronic pain. Although the precise cause of different symptoms in GWI remains unclear, studies have suggested that the environmental and chemical exposures during the GW underlie this illness. Epidemiological studies indicate that significant exposure to one or more GW-related chemicals during the war or interaction of these chemicals with war-related stress is the cause of GWI in a substantial percentage of Veterans. In the 29 years after the GW, progress has been made in diagnosing unrelenting symptoms that are linked to changes in the function of multiple organ systems, including the brain. Also, the pathology underlying the persistent brain-related impairments have been identified in animal models. Such studies have shown that combined exposure to low doses of GWI-related chemicals is detrimental to the central nervous system function. Furthermore, neuroinflammation and elevated levels of free radicals have been identified as the most significant changes observed at chronic time points after the exposure to GWI-related chemicals. However, it is unknown whether pathological changes found in animal models of GWI or alterations that are unique to the human brain manifest in Veterans afflicted with chronic GWI. Currently, there are no efficient treatments that ease the symptoms of this debilitating chronic illness. A major hurdle to improving the treatment of GWI is the lack of peripheral biomarkers that can be measured to assess the extent of inflammation in the brain. Also, due to the possible differences in the extent of brain pathology in different subsets of Veterans with GWI, it is difficult for any single biomarker to sufficiently characterize inflammation in the brain of GW Veterans. Thus, there is a substantial unmet need for blood-based biomarkers to make a clear assessment of the extent of neuroinflammation in Veterans with GWI. Routine magnetic resonance imaging (MRI) techniques are not efficient for providing information on the status of inflammation in the human brain. A combination of MRI and magnetic resonance spectroscopy (MRS) methods are evolving and providing useful information on several aspects of pathology in the central nervous system. However, these approaches are expensive, not accessible to a large number of Veterans, and not efficient for providing information on specific mediators of inflammation. Non-invasive techniques, as simple as blood tests, are needed for repeated tracking of inflammation in the brain of Veterans with GWI. Scientific Objectives and Approach: Recent studies have shown that nanosized vesicles shed by brain cells into the blood carry specific biomarkers. Examination of the composition of these vesicles, therefore, would offer information on changes that occur in brain cells in disease conditions. For example, in our animal model study, we found that chronic inflammation in the brain of GWI rats could also be tracked via analyses of markers of inflammation in vesicles shed by neurons and astrocytes into the circulating blood. This liquid biopsy approach is currently also helping the diagnosis of several other neurodegenerative diseases. Therefore, we propose to investigate the ex
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010568
Entities
People
- Ashok Shetty
Organizations
- Texas A&M Health Science Center
- United States Army