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

海湾战争部署期间有毒物质暴露与前驱帕金森病之间关系的调查。

• 批准号: 10291784
• 负责人: Linda L Chao
• 金额: --
• 依托单位: VETERANS AFFAIRS MED CTR SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-10-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10291784
• 关键词: Adopted; Age; Aging; Anxiety; Basal Ganglia; Behavioral; Characteristics; Chemical Exposure; Chemicals; Clinical; Cognitive; Counseling; Data; Data Set; Department of Defense; Diagnosis; Disease; Enrollment; Environmental Exposure; Epidemiology; Exposure to; Fatigue; Frequencies; Gender; Gulf War; Gulf War veteran; Hazardous Chemicals; Hazardous Substances; Health; Human Resources; Image; Impaired cognition; Incidence; Individual; International; Investigation; Iron; Kansas; Life Style; Link; Magnetic Resonance; Magnetic Resonance Imaging; Manuals; Measures; Memory; Mental Depression; Military Personnel; Moods; Motor; Movement Disorder Society Unified Parkinson' s Disease Rating Scale; Movement Disorders; N-acetylaspartate; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Pain; Parkinson Disease; Participant; Patient Self-Report; Patients; Persian Gulf; Persian Gulf Syndrome; Pesticides; Physical activity; Pigments; Prevalence; Probability; Recording of previous events; Research; Risk; Severities; Sexual Dysfunction; Sleep disturbances; Societies; Substantia nigra structure; Symptoms; Testing; Time; Toxicant exposure; Veterans; War; Water; affective disturbance; associated symptom; base; behavior measurement; clinical Diagnosis; cohort; dexterity; dopaminergic neuron; epidemiologic data; epidemiology study; experience; experimental study; gastrointestinal; in vivo; motor symptom; neuromelanin; neuron loss; non-motor symptom; persistent symptom; progression marker; symptomatology; targeted delivery; toxicant; urinary

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.

1991 年海湾战争 (GW) 结束近 30 年后，估计 25-32% 的海湾战争退伍军人仍然 患有海湾战争疾病 (GWI)1，该术语用于描述困扰许多 GW 的症状 退伍军人从部署返回后。虽然不同退伍军人的症状可能有所不同，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，例如胃肠道（GI）、泌尿和性功能障碍。流行病学数据 表明化学品暴露与帕金森病 (PD) 之间可能存在联系。4 尽管 GW 军事 迄今为止，人员在波斯湾战区接触了多种潜在危险化学品 目前尚无关于 GW 退伍军人 PD 发生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 的非运动症状 (NMS) 相似，7 在临床诊断前数年至数十年占主导地位。9 例如，PD 中一些常见的 NMS 包括 疲劳、疼痛、自主神经紊乱，如胃肠道、泌尿和性功能障碍、睡眠障碍、 焦虑、抑郁和认知功能障碍，例如记忆力、注意力集中和言语困难 发现。我们有初步证据表明 GW 退伍军人的自我报告频率之间存在正相关 与部署相关的化学品的暴露量和与 PD 的 NMS 类似的 GWI 症状。我们还发现 乔治城退伍军人自我报告的穿着经过农药处理的制服的频率之间存在负相关关系 以及手动灵活性的测量。最后，我们有初步证据表明， 退伍军人自我报告的 GW 相关化学物质暴露频率以及基底神经节体积和基底神经节 神经节 N-乙酰天冬氨酸 (NAA)，神经元完整性的标志物。11 因为 NMS 和显着的神经元损失 在黑质中，有两个特征在个体中被反复注意到，最终 发展临床 PD，9 根据这些初步发现，我们假设 GW 退伍军人患有过度 暴露于与部署相关的化学品会导致前驱PD。虽然目前还没有治愈方法或疾病- 修改治疗方法以阻止或减缓 PD 的进展，这是 GW 退伍军人中 PD 的过早诊断 大量暴露于 GW 相关毒物将有助于神经保护治疗的针对性实施 当它们最终可用时。此外，这些 GW 退伍军人可能会被建议采用 生活方式的改变，例如增加体力活动，这与降低患病风险有关 PD.13 拟议的为期四年的研究将招募 140 名具有较高部署经验的 GW 退伍军人 - 相关化学品（例如 GW 农药喷洒器）。我们将获得临床和行为测量以及体内 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 黑质中的自由水。我们提出了三个具体目标：(1) 使用以下指标评估 GW 退伍军人： 国际帕金森和运动障碍协会 (MDS) 前驱帕金森病研究标准；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 - 相关化学物质和铁和神经黑色素的 7 特斯拉测量值以及退伍军人前驱的概率 根据MDS研究标准进行PD； (3) 比较物质中游离水的 3 个特斯拉测量值 黑质和帕金森病进展标记计划 (PPMI) 的各种 NMS 量表的分数15 具有年龄和性别匹配的健康对照的 GW 退伍军人、PD 患者和患有以下疾病的受试者的数据集 PPMI 队列中的前驱 PD。所提出的实验是及时且重要的，因为它是 预计将提供有关 GWI 在老龄化背景下的长期后果的急需信息 和神经退行性疾病，特别是帕金森病。