Assessing Neuroinflammation in GWI Using MRS
Condition: Gulf War Syndrome
MeSH terms: Neuroinflammatory Diseases; Persian Gulf Syndrome
Study type: Observational

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Magnetic Resonance Spectroscopic Imaging; Blood draw
Intervention type(s): Procedure; Procedure
Intervention description(s): MRSI is a non invasive imaging technique used to detect neuroinflammation.; Blood will be drawn to assess systemic inflammation in Gulf War verterans.
Other intervention name(s): MRSI
Observational model: Case-Control
Time perspective: Cross-Sectional
Sampling method: Non-Probability Sample
Study population: 
        This study requires the recruitment of Gulf War Veterans who were present in the Persian
        Gulf between 1990 and August 1991 and who were forward deployed to either Iraq or Kuwait.
        Of the approximate 650,000 service members who served in the Gulf War, only around 50,000
        were women. As the number of female veterans who fit the study criteria wanes in comparison
        to that of the male veterans, it would prove extremely difficult to recruit both GWI and
        age-matched, healthy control female veterans. To circumvent this issue, the investigators
        chose to use only male Gulf War veterans for our study.
      
Biospecimen description: 
      Plasma samples
    
Keywords: neuroinflammation; Gulf War Illness