Longitudinal assessment of Gulf War veterans with suspected Sarin exposure

描述(由申请人提供)： 尽管在第一次海湾战争(GW)期间伊拉克Khamisiyah的伊拉克弹药储存设施被摧毁后，国防部(DOD)对沙林(GB；o-异丙基甲基氟膦)和环沙林(GF；环己基甲基氟膦)暴露的模型假设存在不确定性，但我们和其他人在事件发生8-19年后的三个不同的GW退伍军人队列中发现了脑萎缩的证据。[1-3]我们认为这使其成为迄今为止在GW退伍军人中重复最多的生物学发现，值得进一步研究。然而，在过去的研究中，疑似接触GW的退伍军人总数(N=130)仅占100,000多名疑似接触GB/GF的GW退伍军人的一小部分。因此，重要的是确认和扩展在更大的非重叠样本中暴露于GB/GF的GW退伍军人的大脑结构和功能变化的发现。这项研究的目标是在150 GB/GF暴露的新样本中复制和扩展我们之前关于脑萎缩和认知障碍的发现，相对于150名匹配的非GB/GF暴露的GW退伍军人。第一个目标是复制我们之前的发现，即暴露于GB/GF的退伍军人脑体积减少。目的2将通过研究GB/GF暴露对海马亚区的影响来扩展我们先前在GB/GF暴露的退伍军人中发现的海马区萎缩。目的3利用弥散张量成像(DTI)研究GB/GF暴露对脑白质微结构完整性的影响，扩展我们先前发现的GB/GF暴露老兵脑白质总体积减少的结果。AIM 4将复制和扩展我们之前在暴露于GB/GF的GW退伍军人中发现的认知功能受损(即注意力和记忆力)。探索性分析将：1)检验估计的累积GB/GF暴露水平之间的关系，基于国防部使用改进的气象模拟对2000个羽流模型进行的再分析，以及通过测量脑和海马子场体积、DTI指数和认知表现更准确地估计含有GB/GF的火箭总数；2)使用Lea Steele博士的堪萨斯海湾战争军事与健康问卷[4，5]评估暴露组和非暴露组战时经历的潜在差异[4，5]，以及通过脑和海马亚场体积、DTI值和认知表现的测量来评估这些战时经历之间的关系。暴露和未暴露的GW退伍军人将是年龄、性别和海湾战争疾病状况相匹配的先验者。我们将考虑其他潜在的混杂变量，如教育年限、创伤后应激障碍和抑郁症状严重程度、吸烟、酒精和非酒精物质使用、载脂蛋白�4基因，并在统计分析中将脑体积、颅内体积作为协变量进行分析。有证据表明，大脑体积减少和认知功能受损可能会增加对神经退行性疾病(如阿尔茨海默病)病理影响的易感性。因此，如果我们在另一组暴露于GB/GF的GW退伍军人中发现神经变性和认知障碍的确凿证据，这可能会对退伍军人管理局产生影响，当这些措施可用时，退伍军人管理局将采用非药理学和药理学的痴呆症预防措施来治疗可疑暴露于GB/GF的GW退伍军人，因为这些退伍军人即将步入老年。

DESCRIPTION (provided by applicant): Despite uncertainty in the Department of Defense (DOD) ''plume'' model assumptions of sarin (GB; o-isopropyl methylphosphonoflouridate) and cyclosarin (GF; cyclohexyl methylphosphonoflouridate) exposure following the destruction of an Iraqi munitions storage complex at Khamisiyah, Iraq during the first Gulf War (GW), we and others have found evidence of brain atrophy in three separate cohorts of GW veterans with suspected exposure at 8-19 years after the incident.[1-3] We believe this makes it the most replicated biological finding in GW veterans to date and worthy of additional research. However, the combined total number of GW veterans with suspected exposure in the past studies (N=130) represents only a tiny fraction of the more than 100,000 GW veterans with suspected GB/GF exposure. Therefore, it is important to confirm and extend the findings of structural and functional brain changes in a larger, non-overlapping sample of GB/GF exposed GW veterans. The goal of this study is to replicate and extend our previous findings of brain atrophy and cognitive impairment in a new sample of 150 GB/GF exposed relative to a new sample of 150 matched non-GB/GF exposed GW veterans. The first aim is to replicate our previous findings of reduced brain volume in GB/GF exposed veterans. Aim 2 will expand our previous finding of hippocampal atrophy in GB/GF exposed veterans by examining the effect of GB/GF exposure on hippocampal subfields. Aim 3 will expand our previous finding of reduced total brain white matter volume in GB/GF-exposed veterans by using diffusion tensor imaging (DTI) to examine the effects of GB/GF exposure on white matter microstructure integrity. Aim 4 will replicate and extend our previous finding of impaired cognitive function (i.e., attention and memory) in GB/GF exposed GW veterans. Exploratory analyses will: 1) examine the relationship between estimated cumulative GB/GF exposure levels, based on the DOD reanalysis of the 2000 plume models using improved meteorological modeling and more accurate estimates of the total number of GB/GF-containing rockets destroyed with measures of brain and hippocampal subfield volumes, DTI indices, and cognitive performance; 2) assess potential differences in wartime experiences between exposed and non-exposed groups using Dr. Lea Steele's Kansas Gulf War Military and Health Questionnaire [4,5] and the relationship between these wartime experiences with measures of brain and hippocampal subfield volumes, DTI values, and cognitive performance. The exposed and unexposed GW veterans will be a priori matched for age, sex, and Gulf War Illness status. We will account for other potentially confounding variables such as years of education, posttraumatic stress disorder and depression symptom severity, smoking, alcohol and non-alcohol substance use, apolipoprotein � 4 genotype, and for analyses of brain volume, intracranial volume as covariates in the statistical analyses. Evidence suggests that reduced brain volume and impaired cognitive function may increase vulnerability to the pathological effects of neurodegenerative disease, such as Alzheimer's disease. Therefore, if we find confirmatory evidence of neurodegeneration and cognitive impairment in yet another cohort of GB/GF exposed GW veterans, this could have implications for the VA to employ non-pharmacological, and pharmacological, when they become available, dementia preventive measures in the treatment of GW veterans with suspected GB/GF exposure as these veterans approach old age.