Independent lines of research have demonstrated that GWI is associated with elevated inflammatory markers, metabolic disruptions, and alterations in brain morphometry. Possessing specific Class II human leukocyte antigen (HLA) alleles, on the other hand, has been shown to protect against GWI and to be inversely associated with symptom severity in a dose-dependent manner. The aim of the present study was to evaluate the association between C-reactive protein (CRP), a marker of inflammation, body mass index (BMI), and brain morphometry in GWI veterans with and without a protective HLA allele. Sixty-three veterans with GWI provided blood samples for evaluation of CRP and HLA, height and weight for calculating BMI, and underwent a 3T magnetic resonance imaging scan from which the volume, surface area, and cortical thickness of 68 cortical regions of interest (ROI) were determined. Results demonstrated that the CRP was highly significantly associated with BMI and cortical thinning in veterans lacking protective HLA alleles but not in those possessing a protective HLA allele. Given the role of HLA in antibody production against foreign antigens, the findings suggest that persistent foreign antigens stemming from lack of immunogenetic protection against them contribute to inflammation, metabolic disruption, and cortical thinning in GWI. The findings are discussed in terms of GW-related exposures that are known to result in inflammation.
GWI has affected a substantial number of Gulf War (GW) veterans. The disease involves several organ systems among which the brain is most prominent. Neurological, cognitive and mood-related (NCM) symptoms frequently dominate and are at the root of chronic ill-health and disability in veterans suffering from GWI. In addition, such symptoms frequently co-occur with diagnosable mental health disorders, predominantly posttraumatic stress disorder (PTSD). Here we investigated the possibility that increased GWI severity leads, above a threshold, to a diagnosable mental health disorder (excluding psychosis). For this purpose, we used, in separate analyses, symptom severity scores and resting-state brain functional connectivity patterns, as determined by magnetoencephalography (MEG). Two-hundred-thirty GW-era veterans participated in this study. They completed diagnostic interviews to establish the presence of GWI and assess mental health status. This distinguished 3 groups: healthy controls (N = 41), veterans with GWI and no mental illness (GWI group, N = 91), and veterans with both GWI and mental health disorder (GWI+MH, N = 98). For each veteran, symptom severity scores in the 6 GWI domains (fatigue, pain, NCM, skin, gastrointestinal, respiratory) were available as well as 9 summary measures of the distribution of Synchronous Neural Interactions (SNI) derived from the MEG recordings. We tested the hypothesis that, in the presence of GWI, the appearance of a diagnosable mental health disorder may depend on GWI symptom severity. For that purpose, we performed a logistic regression on the GWI population, where the presence (or absence) of the MH disorder was the dependent variable and the age- and gender-adjusted GWI severity in the 6-symptom domains were the predictors. The outcome was the probability that a participant will have MH disorder or not. Similarly, we tested the hypothesis that the presence of the MH disorder can be predicted by the SNI distribution patterns by performing a second logistic regression as above but with the 9 SNI measures as predictors. We found GWI symptom severity differed significantly across groups (GWI+MH > GWI > Control). SNI distributions of the GWI group also differed significantly from the other groups in a systematic hemispheric pattern, such that the presence of GWI involved predominantly the left hemisphere, and presence of mental health disorders involved, in addition, the right hemisphere. Both logistic regressions yielded highly significant outcomes, demonstrating that both GWI symptom severity and SNI distribution measures can predict the presence of MH disorder in GWI. Remarkably, the prediction probabilities for MH presence derived from the symptom-based and SNI-based logistic regressions were positively and highly statistically significantly correlated. Taken together, both objective (neural) and subjective (symptoms) indices suggest that GWI is distinct from healthy controls and varies in severity in

