Defining and Characterizing GWI Pathobiology Using Longitudinal Brain Imaging Biomarkers of White Matter Integrity and Hemodynamic Response
Abstract
Gulf War Illness (GWI) is a chronic debilitating disorder characterized by symptoms including fatigue, joint pain, memory and concentration problems, headaches, and gastrointestinal problems. It is thought to affect approximately 30% of the 697,000 Veterans who served in the 1991 Gulf War. Despite significant research over the years, GWI remains a disorder primarily diagnosed by self-report of symptoms. This makes clear diagnosis, treatment development, and access to benefits and care difficult for many GW Veterans. However, our recent research and that of others have shown important preliminary evidence for objective brain imaging and blood markers that have been associated with the chronic symptoms of GWI. The brain is made up of neurons and glia. Glia make up the white matter (WM) of the brain and allow for fast information processing. Although the finding that cerebral WM injury has been reported multiple times in GWI research, until now there have not been mechanistic hypotheses for these findings. Neither have studies shown if these changes are static or are getting worse over time. In addition, there have been very few studies assessing cerebrovascular health, including the cerebral blood flow changes and blood–brain barrier integrity in Veterans with GWI. Our recent brain imaging and blood biomarker study results suggest that GW Veterans are showing clear changes in the brain WM that we believe may be associated with cerebral blood flow changes. These WM changes have also been associated with circulating levels of phosphate and the excitatory neurotransmitter glutamate. Importantly, recent reports suggest that microstructural WM changes are detected before noticeable small-vessel cerebrovascular disease (SVD), which can result in stroke and increased mortality rates. Thus, the ability to detect these early changes before they become severe and perhaps in time to intervene in Veterans at risk for SVD is pertinent. Our research group has taken a team approach to solving the mystery of GWI, and we have begun to implement an important and necessary GWI Biorepository Network of experienced and dedicated GWI researchers to tackle and solve this problem of devising more definitive diagnostic markers of GWI. The “Boston Biorepository, Recruitment and Integrative Network (BBRAIN) for GWI” is based on the infrastructure of our extremely productive Boston GWI consortium (GWIC). The current advanced brain imaging study will be considered a call-back study to BBRAIN and GWIC. One hundred GW Veterans (50 GWI cases, 50 healthy GW controls) will be asked to return to complete the planned brain imaging protocol to provide a second longitudinal brain scan to compare with their prior scans. This will allow us to determine if the important brain changes that we have seen in the GWIC study is still found (validated) in this second brain imaging protocol and if is it progressing/worsening over time. This second brain imaging data will also be added to BBRAIN repository to be shared with other GWI researchers to hasten biomarker and treatment trial research efforts. Determining the association between cerebral blood flow patterns, blood–brain barrier permeability (leakage), and WM health (microstructural integrity) will allow for better understanding of the exact pathobiology of GWI. If successful, this study will have a tremendous impact on GW Veterans because it can then be utilized to assess disease severity and progression, perhaps in time before clinically significant cerebrovascular disease results. These markers can also be used for planning targeted GWI treatments and to measure treatment trial effectiveness. Our ongoing work with machine learning technology will allow us to utilize advanced data reduction measures to identify a “GWI” magnetic resonance imaging (MRI)-based signature of GWI case/control status and clinically relevant subgroups that will aid in developing more personalized medicine treatment
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910767
Entities
People
- Kimberly Sullivan
Organizations
- Boston University Medical Campus
- United States Army