Assessing Neuroinflammation in GWI Using MRS

Assessing Neuroinflammation in Gulf War Illness With Whole-Brain Magnetic Resonance Spectroscopy

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.

Study Overview

• Status: Completed
• Conditions: Gulf War Syndrome
• Intervention / Treatment: Procedure: Magnetic Resonance Spectroscopic Imaging; Procedure: Blood draw

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.

• Study Type: Observational
• Enrollment (Actual): 54

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama at Birmingham

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 46 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

• 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.

Description

Inclusion Criteria:

• Between the ages of 46 and 70
• Veterans who meet the Kansas inclusion criteria .The Kansas Inclusion Criteria are a set of the most frequently reported symptoms experienced by Gulf War veterans. This frequency and severity of the symptoms reported by the participant indicate whether the person has Gulf War Illness or not. The Kansas Inclusion Criteria is the gold standard for identifying veterans with GWI in the field. The criteria are attached.
• Present in Persian Gulf between 1990 and August 1991
• Forward deployed (in Iraq or Kuwait)

Exclusion Criteria:

• Usage of experimental medications, opioid analgesics, psychostimulants (except caffeine), or benzodiazepines
• Uncontrolled diabetes, autoimmune disorders, and thyroid disorders.
• Major cardiovascular illness, cancer, or have any contraindications for MRI (including metallic implants or claustrophobia)

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Cross-Sectional

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Healthy Control; The healthy control group are men ages 46-70 who were present in the Persian Gulf War between 1990 and August 1991. This cohort do not experience any Gulf War Illness symptoms.	Procedure: Magnetic Resonance Spectroscopic Imaging; MRSI is a non invasive imaging technique used to detect neuroinflammation.; Other Names: MRSI; Procedure: Blood draw; Blood will be drawn to assess systemic inflammation in Gulf War verterans.
Gulf War Illness; The GWI cohort are men ages 46-70 who were present in the Persian Gulf War between 1990 and August 1991. The men in this cohort will also meet the Kansas Inclusion Criteria for GWI.	Procedure: Magnetic Resonance Spectroscopic Imaging; MRSI is a non invasive imaging technique used to detect neuroinflammation.; Other Names: MRSI; Procedure: Blood draw; Blood will be drawn to assess systemic inflammation in Gulf War verterans.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Concentration of myoinositol in the brain	The concentration of myoinositol will be measured in the brain using MRI as a measure of neuroinflammation. This will be measured in both the control and experimental groups.	20 minutes
Concentration of lactate in the brain	The concentration of lactate will be measured in the brain using MRI as a measure of neuroinflammation. The concentration will be expressed in water-normed "Institutional Units". This will be measured in both the control and experimental groups.	20 minutes
Concentration of choline in the brain	The concentration of choline will be measured in the brain using MRI as a measure of neuroinflammation. This will be measured in both the control and experimental groups.	20 minutes
Concentration of N-acetylaspartate in the brain	The concentration of N-acetylaspartate will be measured in the brain using MRI as a measure of neuroinflammation. This will be measured in both the control and experimental groups.	20 minutes
Temperature in the brain	The temperature of the brain will be measured using MRI as a measure of neuroinflammation. This will be measured in both the control and experimental groups.	20 minutes

Collaborators and Investigators

• Sponsor: University of Alabama at Birmingham
• Investigators: Principal Investigator: Jarred Younger, PhD, University of Alabama at Birmingham

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2020
• Primary Completion (Actual): September 29, 2023
• Study Completion (Actual): December 31, 2023

Study Registration Dates

• First Submitted: November 16, 2020
• First Submitted That Met QC Criteria: November 16, 2020
• First Posted (Actual): November 20, 2020

Study Record Updates

• Last Update Posted (Actual): January 5, 2024
• Last Update Submitted That Met QC Criteria: January 3, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Gulf War Illness; neuroinflammation
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Inflammation; Occupational Diseases; Persian Gulf Syndrome; Neuroinflammatory Diseases
• Other Study ID Numbers: IRB-3000004528

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No