Neurometabolite alterations in Gulf War Illness: a whole-brain magnetic resonance spectroscopy study

Gulf War Illness (GWI) affects approximately 30% of veterans who served in the 1991 Persian Gulf War and is characterized by chronic pain and fatigue, as well as cognitive, mood, gastrointestinal, and respiratory symptoms. Animal research has suggested that GWI is caused by a combination of neurotoxicants such as nerve gas, anti-nerve agent pills, and pesticides, though a definitive pathophysiological model has not been established. In this human observational study, 20 veterans with GWI and 20 healthy Gulf War veterans (HV) underwent whole-brain magnetic resonance spectroscopy to non-invasively measure several metabolites associated with neuroinflammation. Veterans also completed an arterial spin labeling scan to assess cerebral perfusion. Compared to HV, veterans with GWI demonstrated widespread decreases in brain choline, N-acetylaspartate, and creatine, and regional elevations in lactate and brain temperature. No group difference was observed in cerebral perfusion. Exploratory analyses revealed brain metabolites were associated with self-reported neurotoxicant exposures in theater. These findings support a role of cholinergic alterations and neuroinflammatory processes in GWI. Trial registration: The study was registered in ClinicalTrials.gov, ID NCT04638998. Registered November 16, 2020, https://clinicaltrials.gov/study/NCT04638998 .