Assessing Neuroinflammation in GWI Using MRS

NCT ID: NCT04638998

Last Updated: 2025-01-13

Basic Information

• Recruitment Status: COMPLETED
• Total Enrollment: 49 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2020-12-01
• Study Completion Date: 2023-12-31

Brief 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.

Conditions

Gulf War Syndrome

Study Design

• Observational Model Type: CASE_CONTROL
• Study Time Perspective: CROSS_SECTIONAL

Study Groups

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.

Magnetic Resonance Spectroscopic Imaging

Intervention Type: PROCEDURE

MRSI is a non invasive imaging technique used to detect neuroinflammation.

Blood draw

Intervention Type: PROCEDURE

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.

Magnetic Resonance Spectroscopic Imaging

Intervention Type: PROCEDURE

MRSI is a non invasive imaging technique used to detect neuroinflammation.

Blood draw

Intervention Type: PROCEDURE

Blood will be drawn to assess systemic inflammation in Gulf War verterans.

Interventions

Magnetic Resonance Spectroscopic Imaging

MRSI is a non invasive imaging technique used to detect neuroinflammation.

Intervention Type: PROCEDURE

Blood draw

Blood will be drawn to assess systemic inflammation in Gulf War verterans.

Intervention Type: PROCEDURE

Other Intervention Names

MRSI

Eligibility Criteria

Inclusion Criteria

• Between the ages of 46 and 70
• 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)

• Minimum Eligible Age: 46 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: MALE
• Accepts Healthy Volunteers: Yes

Sponsors

United States Department of Defense

FED

Sponsor Role: collaborator

University of Alabama at Birmingham

OTHER

Sponsor Role: lead

Responsible Party

Jarred Younger

Assistant Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Jarred Younger, PhD

Role: PRINCIPAL_INVESTIGATOR

University of Alabama at Birmingham

Locations

University of Alabama at Birmingham

Birmingham, Alabama, United States

Countries

United States

References

Jones C, Haskin O, Younger J. Neurometabolite alterations in Gulf War Illness: a whole-brain magnetic resonance spectroscopy study. Exp Brain Res. 2025 Oct 25;243(11):237. doi: 10.1007/s00221-025-07174-w.

Reference Type: DERIVED

PMID: 41137912 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

W81XWH-19-1-0725

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

IRB-3000004528

Identifier Type: -

Identifier Source: org_study_id