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 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. GWI (n=15) and healthy controls (HC, n=33, including a subgroup of healthy Gulf War veterans, HCVET, 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 HCVET 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.

中文翻译：

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海湾战争疾病退伍军人神经炎症的体内成像

海湾战争疾病 (GWI) 是一种慢性疾病，影响了 1991 年海湾战争中服役的大约 30% 的退伍军人。它的特点是一系列症状，包括肌肉骨骼疼痛、认知问题和疲劳。GWI 的原因尚不清楚，但暴露于神经毒物、预防性使用溴化吡啶斯的明 (PB) 药丸和/或部署期间的压力源都被怀疑起某些致病作用。最近的 GWI 动物模型表明可能涉及神经炎症机制，包括小胶质细胞和星形胶质细胞的失调激活。然而，以前没有在 GWI 退伍军人中直接观察到神经炎症。为了测量 GW 退伍军人的 GWI 相关神经炎症，我们使用 [11C]PBR28 进行了正电子发射断层扫描 (PET) 研究，它与 18 kDa 转运蛋白 (TSPO) 结合，这是一种在活化的小胶质细胞/巨噬细胞和星形胶质细胞中上调的蛋白质。使用整合的 [11C]PBR28 PET/MRI 检查 GWI (n=15) 和健康对照 (HC, n=33，包括健康的海湾战争退伍军人亚组 HCVET, n=8)。通过枕叶皮层信号 (SUVR) 标准化的标准化摄取值在各组之间进行比较，并与临床变量和循环炎性细胞因子 (TNF-α、IL-6 和 IL-1β) 进行比较。SUVR 针对分布体积比 (n=13) 进行了验证。无论与整个 HC 组还是仅 HCVET 亚组相比，GWI 退伍军人在楔前叶、前额叶、初级运动和体感皮层等区域的 [11C]PBR28 PET 信号中表现出广泛的皮层升高。所评估的炎性细胞因子的血浆水平没有显着的组间差异。[11C]PBR28 PET 信号与临床变量或循环炎性细胞因子之间也没有显着相关性。我们的研究提供了 GWI 退伍军人大脑中神经炎症标志物 TSPO 上调的第一个直接证据，并支持探索神经炎症作为这种疾病的治疗靶点。