Subcortical brain atrophy in Gulf War Illness

Abstract

Gulf War Illness (GWI) is a multisystem disorder that has affected a substantial number of veterans who served in the 1990-1991 Gulf War. The brain is prominently affected, as manifested by the presence of neurological, cognitive and mood symptoms. Although brain dysfunction in GWI has been well documented (EBioMedicine 12:127-32, 2016), abnormalities in brain structure have been debated. Here we report a substantial (~10%) subcortical brain atrophy in GWI comprising mainly the brainstem, cerebellum and thalamus, and, to a lesser extent, basal ganglia, amygdala and diencephalon. The highest atrophy was observed in the brainstem, followed by left cerebellum and right thalamus, then by right cerebellum and left thalamus. These findings indicate graded atrophy of regions anatomically connected through the brainstem via the crossed superior cerebellar peduncle (left cerebellum → right thalamus, right cerebellum → left thalamus). This distribution of atrophy, together with the observed systematic reduction in volume of other subcortical areas (basal ganglia, amygdala and diencephalon), resemble the distribution of atrophy seen in toxic encephalopathy (Am J Neuroradiol 13:747-760, 1992) caused by a variety of substances, including organic solvents. Given the potential exposure of Gulf War veterans to "a wide range of biological and chemical agents including sand, smoke from oil-well fires, paints, solvents, insecticides, petroleum fuels and their combustion products, organophosphate nerve agents, pyridostigmine bromide, …" (Institute of Medicine National Research Council. Gulf War and Health: Volume 1. Depleted uranium, pyridostigmine bromide, sarin, and vaccines. National Academies Press, Washington DC, 2000), it is reasonable to suppose that such exposures, alone or in combination, could underlie the subcortical atrophy observed.

Human Leukocyte Antigen (HLA) and Gulf War Illness (GWI): HLA-DRB1*13:02 Spares Subcortical Atrophy in Gulf War Veterans

“…In this study we investigated possible protection conferred by HLA DRB1*13:02 in GW veterans based on the facts that (a) DRB1*13:02 is protective for GWI ( Georgopoulos et al, 2016 ), (b) DRB1*13:02 is broadly protective for immune-related disorders ( Bettencourt et al, 2015 , Furukawa et al, 2017 , Hov et al, 2011 ), and (c) GWI is a neuroimmune disorder ( James et al, 2016 , Georgopoulos et al, 2017 ). Unlike typical studies based on analysis of relative frequencies of occurrence of DRB1*13:02 in various healthy and disease populations ( Bettencourt et al, 2015 , Furukawa et al, 2017 ), we, additionally, assessed its effect on subcortical brain volumes found previously to be reduced in GWI ( Christova et al, 2017 ); indeed, we found here that DRB1*13:02 exerted a protective effect on these volumes and spared their atrophy. Specifically, the subcortical volume was significantly higher in carriers of DRB1*13:02 than in non-carriers ( Fig.…”

“…Either or both of these mechanisms (i.e. protracted low-grade inflammation and/or autoimmunity) could be involved in subcortical brain atrophy observed in GWI ( Christova et al, 2017 ), as discussed in detail in that publication. Given the considerations above, it is possible that the protective role of DRB1*13:02 may be primarily due to preventing infection by providing “matches” ( Fig.…”

“…Many symptoms of GWI involve the central nervous system; consequently, several studies have investigated brain structure and function as it relates to GWI, with mixed findings ( White et al, 2016 ). We have recently identified functional ( Engdahl et al, 2016 ) and structural ( Christova et al, 2017 ) brain anomalies in GWI, both of which prominently involved subcortical regions. For example, compared to healthy control veterans, veterans with GWI showed an average of 10.4% reduction in cerebellar volume and 2 × the rate of reduction of cerebellar gray matter volume with age (− 14%/decade in GWI vs. − 6.9%/decade in controls).…”

“…Given the reported protective role of DRB1*13:02 for immune-related diseases and the evidence that GWI is closely related to such disorders ( Georgopoulos et al, 2016 , 217), we investigated the effect of DRB1*13:02 on the volumes of subcortical brain regions found to be reduced in GWI ( Christova et al, 2017 ) to test the hypothesis that HLA DRB1*13:02 prevents subcortical brain atrophy in GW veterans, thus exerting a protective role in GWI too.…”

Trauma, Traumatization and Adverse Environments in War and Armed- Conflict

“…These linkages of maternal stress and BDNF methylation were associated with high tissue specificity with significant associations observed in the putative transcription factor binding regions of these individuals; a notable demonstration of detrimental epigenetic changes with long-lasting, trans-generational consequences. A substantial (greater than10%) subcortical brain atrophy in Gulf war combatants that consisted of the brainstem, highest level of atrophy, followed by the left cerebellum and right thalamus, then right cerebellum and left thalamus for the most part, with to a lesser extent, basal ganglia, amygdala and diencephalon loss [30]. The particular pattern and distribution of cerebral atrophy of atrophy, together with the observed systematic reduction in volume of other subcortical areas (basal ganglia, amygdala and diencephalon), corresponds to the distribution of atrophy observed in toxic encephalopathy.…”