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，估计仍有25%-32%的GW退伍军人 患有海湾战争病(GWI)，1这个术语用来描述困扰许多GW的症状 自退伍军人从部署归来以来，我们一直在为他们提供援助。尽管退伍军人的症状可能会因退伍军人而异 通常包括疲劳、疼痛、认知/情绪障碍、睡眠障碍和 自主神经障碍，如胃肠道(GI)、尿路和性功能障碍。流行病学数据 暗示化学物质暴露与帕金森氏病之间可能存在联系。 到目前为止，波斯湾战区的人员暴露在多种潜在危险的化学品中 关于退伍军人中帕金森病的发病率或患病率一直没有可靠的数据。1然而， 值得注意的是，GWI的许多症状与帕金森病的非运动症状(NMS)相似，7帕金森病患者可以 在临床诊断前几年到几十年占主导地位。9例如，帕金森病中一些常见的NMS包括 疲劳，疼痛，自主神经障碍，如胃肠道，排尿和性功能障碍，睡眠障碍， 焦虑、抑郁和认知功能障碍，如记忆力、注意力和文字方面的困难 找到了。我们有初步证据表明，退伍军人的自我报告频率与 暴露于与部署相关的化学品和类似PD的NMS的GWI症状。我们还发现了 退伍军人自述穿农药处理制服的频率呈负相关 以及衡量手工灵巧性的标准。最后，我们有初步证据表明， 退伍军人自我报告的GW相关化学品暴露频率和基底节体积和基底节体积 神经节N-乙酰天冬氨酸(NAA)，神经元完整性的标志。11因为NMS和显著的神经元丢失 在黑质中有两个特征在个体中反复被注意到，最终 开发临床PD，9基于这些初步发现，我们假设GW退伍军人过度 暴露在与部署相关的化学品中有帕金森病的前驱症状。虽然目前还没有治愈或疾病的方法- 修改阻止或减缓帕金森病进展的治疗，这是退伍军人帕金森病的早熟诊断 高暴露于与GW相关的毒物将有助于针对性地提供神经保护治疗 当它们最终变得可用时。此外，这些退伍军人可能会被建议收养 生活方式的改变，如增加体力活动，这与降低罹患糖尿病的风险有关 PD.13拟议的为期四年的研究将招募140名长期接触部署的GW退伍军人- 相关化学品(例如，GW杀虫剂施用器)。我们将获得临床和行为测量，并在体内 超高场(7特斯拉)和3特斯拉磁共振成像(MRI)测量铁、神经黑色素和 黑质中的游离水。我们提出了三个具体目标：(1)使用 国际帕金森和运动障碍协会(MDS)前驱帕金森病的研究标准；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- 相关化学物质和7特斯拉铁和神经黑色素测量与退伍军人的前驱症状概率 PD符合MDS研究标准；以及(3)比较实质中自由水的3个特斯拉度量 帕金森进展标记物计划(PPMI)的黑质和不同NMS量表的分数 年龄和性别匹配的GW退伍军人、PD患者和患有 PPMI队列中的前驱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，说明全球变暖在老龄化背景下的长期后果 和神经退行性疾病，尤其是帕金森病。

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.