Assessing Neuroinflammation in GWI Using MRS

The primary aim of this study is to determine if Gulf War Illness (GWI) likely involves neuroinflammation. The investigators hypothesize that GWI involves neuroinflammation. By assessing the five neuroinflammatory outcomes across the brain, the investigators can determine if there are focal or global signs of one or more neuroinflammatory markers in the brains of individuals with GWI. This neuroimaging technique may allow investigators and others to detect cases of GWI neuroinflammation, which would improve treatment decisions as well as the development of new targeted therapies. It is an ideal diagnostic tool because it has low patient risk, is noninvasive, can be used repeatedly in longitudinal studies, provides whole-brain coverage, yields multiple independent markers of inflammation, and can be employed at most hospitals and research neuroimaging suites.

This proposal is for a Tier 1 (Discovery) study that uses a human, cross-sectional, observational neuroimaging approach to measure neuroinflammation in Gulf War Illness (GWI). A whole-brain magnetic resonance spectroscopic imaging (MRSI) scan will be used to detect multiple markers of neuroinflammation in 30 individuals with GWI and 30 healthy veteran controls. The investigators have fully tested the MRSI scan in several patient groups, and have found strong evidence of neuroinflammation in fibromyalgia and chronic fatigue syndrome - conditions the investigators believe involve abnormal central immune system processing. The investigators have not, however, performed the scan on individuals with GWI. The discovery study will allow investigators to transfer this existing technology to the GWI field. This project meets the core Special Interest of investigating dysregulation between the immune and neurological systems in the brain. The investigators' central hypothesis is that GWI involves chronic neuroinflammation. The symptoms of GWI (e.g. fatigue, musculoskeletal pain, sleep disturbances, and cognitive dysfunction) overlap heavily with classic cytokine-induced sickness responses. In the case of GWI, microglial cells in the brain can be pushed into a hypersensitized state by toxins or abnormal immune challenges, leading to chronic overproduction of pro-inflammatory factors that result in the primary symptoms of GWI. To test the central hypothesis, it is necessary to measure neuroinflammation in humans in vivo. However, most techniques are too invasive for use in living individuals. To address that problem, the investigators use an MRSI scan which provides metabolite concentrations in 4,000 separate voxels, giving whole-brain coverage. The scan yields measurements for: Myo-inositol (a marker of glial cell proliferation), lactate (a product of anaerobic metabolism), choline (a sign of cellular breakdown), and N-acetylaspartate (a marker of neuronal health). The scan also provides absolute brain temperature, which is shown to be elevated with severe neuroinflammation. The five main outcomes are as follows: Myo-inositol (MI): Higher values represent greater microglia proliferation or gliosis. Lactate (Lac): Higher values represent more severe inflammatory activity. Choline (Cho): Higher values indicate greater cell turnover (inflammation, gliosis, or demyelination). NAA: Lower values represent neurodegeneration. Temperature: Higher values represent greater neuroinflammation. Metabolite and water-reference data will be analyzed using the MIDAS package and thermometry extension41. Absolute brain temperatures (in °C) within each voxel will be calculated by measuring the distance of the temperature-invariant NAA peak from the temperature-variant water peak using the formula: Tbrain = -102.76 × Δwater-NAA + 310.5°C, which has been validated in our scanner to produce reliable readings. Temperature will be expressed on absolute values in °C.