An investigation of the relationship between toxicant exposures during Gulf War deployment and prodromal Parkinson's disease.

在1991年波斯湾战争（GW）结束近30年后，估计有25-32%的GW退伍军人仍然 患有海湾战争病（GWI），该术语用于描述困扰许多GW的症状 退伍军人从部署回来后。虽然退伍军人的症状可能各不相同，但GWI 通常包括疲劳、疼痛、认知/情绪功能障碍、睡眠障碍和 自主神经紊乱，如胃肠道（GI）、泌尿系统和性功能障碍。流行病学数据 表明化学暴露与帕金森病（PD）之间可能存在联系。 迄今为止，在波斯湾战区，人员暴露于多种潜在危险的化学品 一直没有关于GW退伍军人中PD发病率或患病率的可靠数据。1然而， 值得注意的是，GWI的许多症状与PD中的非运动症状（NMS）相似， 在临床诊断前的几年到几十年中占主导地位。9例如，PD中的一些常见NMS包括 疲劳、疼痛、自主神经障碍，例如胃肠道、泌尿系统和性功能障碍、睡眠障碍， 焦虑、抑郁和认知功能障碍，如记忆、注意力和文字困难 发现我们有初步的证据表明，GW退伍军人自我报告的频率之间存在积极的关联， 暴露于部署相关的化学物质和GWI症状类似于PD的NMS。我们还发现 GW退伍军人自我报告的穿着杀虫剂处理过的制服的频率 和手工灵巧度的测量。最后，我们有初步证据表明， 退伍军人自我报告的接触GW相关化学物质的频率和基底神经节体积和基底 神经节N-乙酰天冬氨酸（NAA），神经元完整性的标志物。11由于NMS和显著的神经元损失 在黑质中有两个特征，这两个特征在最终 根据这些初步发现，我们假设GW退伍军人患有过多的PD，9 暴露于与部署相关的化学物质有前驱PD。尽管目前还没有治愈或疾病- 修改治疗，停止或减缓PD进展，GW退伍军人中PD的早熟诊断 高暴露于GW相关毒物将有助于神经保护治疗的靶向递送 当它们最终变得可用时。此外，这些GW退伍军人可能会被建议采用 生活方式的改变，如增加体育活动，这与降低风险有关。 PD.13拟议的四年期研究将招募140名GW退伍军人，这些退伍军人具有高水平的部署暴露- 相关化学品（例如，GW农药施用器）。我们将获得临床和行为指标， 超高场（7特斯拉）和3特斯拉磁共振成像（MRI）测量铁，神经黑色素， 黑质中的游离水我们提出了三个具体目标，将：（1）评估GW退伍军人使用 国际帕金森和运动障碍学会（MDS）前驱期PD的研究标准;14（2） 检查退伍军人自我报告的GW部署暴露频率之间的关联- 相关的化学物质和7特斯拉铁和神经黑色素的措施和退伍军人的前驱症状的概率 根据MDS研究标准的PD;和（3）比较3个特斯拉测量的物质中的游离水， 黑质和帕金森氏进展标志物倡议（PPMI）15的各种NMS量表评分 GW退伍军人与年龄和性别匹配的健康对照、PD患者和 PPMI队列的前驱PD。拟议的实验是及时和重要的，因为它是 预计将提供急需的信息，在老龄化的背景下，GWI的长期后果 和神经退行性疾病，特别是PD。

Nearly 30 years after the end of the 1991 Persian Gulf War (GW), an estimated 25-32% of GW veterans still suffer from Gulf War illness (GWI),1 the term used to describe the symptoms that have plagued many GW veterans since their return from deployment. Although symptoms may vary from veteran to veteran, GWI typically includes some combination of fatigue, pain, cognitive/mood dysfunction, sleep disturbances, and autonomic disturbances such as gastrointestinal (GI), urinary, and sexual dysfunction. Epidemiological data suggest a possible link between chemical exposures and Parkinson’s disease (PD).4 Although GW military personnel were exposed to multiple, potentially hazardous chemicals in the Persian Gulf theater, to date there has been no reliable data on the incidence or prevalence of PD among GW veterans.1 However, it is noteworthy that many of the symptoms of GWI are similar to non-motor symptoms (NMS) in PD,7 which can predominate years to decades prior to clinical diagnosis.9 For example, some common NMS in PD include fatigue, pain, autonomic disturbances, such as GI, urinary, and sexual dysfunction, sleep disturbances, anxiety, depression, and cognitive dysfunction such as difficulties with memory, concentration, and word finding. We have preliminary evidence of positive associations between GW veterans’ self-reported frequency of exposures to deployment-related chemicals and GWI symptoms similar to PD’s NMS. We have also found an inverse relationship between GW veterans’ self-reported frequency of wearing pesticide-treated uniforms and measures of manual dexterity. Finally, we have preliminary evidence of negative associations between the veterans’ self-reported frequency of exposures to GW-related chemicals and basal ganglia volume and basal ganglia N-acetylaspartate (NAA), a marker of neuronal integrity.11 Because NMS and significant neuronal loss in the substantia nigra are two characteristics that have been repeatedly noted in individuals who eventually develop clinical PD,9 based on these preliminary findings, we hypothesize that GW veterans with excessive exposures to deployment-related chemicals have prodromal PD. While there is presently no cure or disease- modifying treatment that halts or slows the progression PD, the precocious diagnosis of PD in GW veterans with high exposures to GW-related toxicants would facilitate the targeted delivery of neuroprotective therapies when they eventually do become available. Furthermore, these GW veterans may be counseled to adopt lifestyle changes, such as increasing physical activity, which have been associated with lowering the risk of PD.13 The proposed four-year study will enroll 140 GW veterans with high levels of exposure to deployment- related chemicals (e.g., GW pesticide applicators). We will obtain clinical and behavioral measures and in vivo ultra-high field (7 Tesla) and 3 Tesla magnetic resonance imaging (MRI) measures of iron, neuromelanin, and free water in the substantia nigra. We propose three specific aims that will: (1) evaluate GW veterans using the International Parkinson and Movement Disorder Society (MDS) research criteria for prodromal PD;14 (2) examine the association between the veterans’ self-reported frequency of exposures to GW deployment- related chemicals and 7 Tesla measures of iron and neuromelanin and the veterans’ probability of prodromal PD according to the MDS research criteria; and (3) compare 3 Tesla measures of free water in the substantia nigra and scores from various NMS scales from the Parkinson's Progression Markers Initiative (PPMI)15 dataset in GW veterans with age- and gender-matched healthy controls, PD patients, and subjects with prodromal PD from the PPMI cohort. The proposed experiments are timely and important because it is expected to provide much needed information on the long-term consequences of GWI in the context of aging and neurodegenerative diseases, particularly PD.