In-vivo imaging of neuroinflammation in veterans with Gulf War illness

Abstract

Gulf War Illness (GWI) is a chronic disorder affecting approximately 30% of the veterans who served in the 1991 Gulf War. It is characterised by a constellation of symptoms including musculoskeletal pain, cognitive problems and fatigue. The cause of GWI is not definitively known but exposure to neurotoxicants, the prophylactic use of pyridostigmine bromide (PB) pills, and/or stressors during deployment have all been suspected to play some pathogenic role. Recent animal models of GWI have suggested that neuroinflammatory mechanisms may be implicated, including a dysregulated activation of microglia and astrocytes. However, neuroinflammation has not previously been directly observed in veterans with GWI. To measure GWI-related neuroinflammation in GW veterans, we conducted a Positron Emission Tomography (PET) study using [¹¹C]PBR28, which binds to the 18 kDa translocator protein (TSPO), a protein upregulated in activated microglia/macrophages and astrocytes. Veterans with GWI (n = 15) and healthy controls (HC, n = 33, including a subgroup of healthy GW veterans, HC_VET, n = 8), were examined using integrated [¹¹C]PBR28 PET/MRI. Standardized uptake values normalized by occipital cortex signal (SUVR) were compared across groups and against clinical variables and circulating inflammatory cytokines (TNF-α, IL-6 and IL-1β). SUVR were validated against volume of distribution ratio (n = 13). Whether compared to the whole HC group, or only the HC_VET subgroup, veterans with GWI demonstrated widespread cortical elevations in [¹¹C]PBR28 PET signal, in areas including precuneus, prefrontal, primary motor and somatosensory cortices. There were no significant group differences in the plasma levels of the inflammatory cytokines evaluated. There were also no significant correlations between [¹¹C]PBR28 PET signal and clinical variables or circulating inflammatory cytokines. Our study provides the first direct evidence of brain upregulation of the neuroinflammatory marker TSPO in veterans with GWI and supports the exploration of neuroinflammation as a therapeutic target for this disorder.

Figure 1:. ROI analyses.

Group differences in [¹¹C]PBR28 standardized volume uptake (SUVR) in a priori ROIs. These regions were selected as they demonstrated [¹¹C]PBR28 PET signal elevations in fibromyalgia patients. Top panel: Average ± standard deviation SUVR extracted showing differences between GWI and HC (adjusted for genotype and sex). Bottom panel: Average ± standard deviation SUVR extracted showing differences between GWI and HC_VET (adjusted for genotype). Surface projections of regions are displayed in red above the plots. * significant difference between groups (p < 0.05). M1 = primary motor cortex; S1 = primary somatosensory cortex; dlPFC = dorsolateral prefrontal cortex; aMCC = anterior mid cingulate cortex.

Figure 2:

Voxel-wise group difference in [¹¹C]PBR28 standardized volume uptake (SUVR). A. Surface projection maps displaying areas with significantly elevated [¹¹C]PBR28 SUVR in GWI (n=15) compared to HC (n=33), in voxel-wise analyses, data adjusted for sex and genotype. B. Surface projection maps displaying areas with significantly elevated [¹¹C]PBR28 SUVR in GWI (n=15) compared to HC_VET (n=8), in voxel-wise analyses, data adjusted for genotype. C. Average ± standard deviation SUVR extracted from several clusters identifies as statistically significant in the voxel-wise SUVR analysis from A. Data plots have been adjusted for sex and genotype. vmPFC = ventral medial prefrontal cortex; S1 = primary somatosensory cortex; M1 = primary motor cortex; ACC = anterior cingulate cortex; PCC = posterior cingulate cortex; dlPFC = dorsolateral prefrontal cortex; dmPFC = dorsomedial prefrontal cortex; mPFC = medial prefrontal cortex; aMCC = anterior mid cingulate cortex; SPL = superior parietal cortex; MCC = mid cingulate cortex; vlPFC = ventrolateral prefrontal cortex; S2 = secondary somatosensory cortex; cx = cortex.