Investigating Toxic Elements and Nanoparticles in ALS Etiology: A Geospatial and Toxicological Evaluation of Massachusetts ALS Registry Patients

项目摘要/摘要 肌萎缩侧索硬化症(ALS)是一种以散发性神经退行性疾病为主的致命性疾病，累及 上下运动神经元死亡。这种疾病背后有无数的病理机制， 这使得确定单一的治疗靶点成为一个巨大的挑战。人们普遍认为肌萎缩侧索硬化是由 这是遗传易感性和环境因素共同作用的结果。环境因素的重要性在于 除其他外，单卵双胞胎、夫妻ALS的不一致以及ALS与特定疾病的风险增加等因素支持 职业和接触有毒物质。尽管仍然迫切需要定义ALS的病理病因， 在与病因相关的症状前时间间隔内进行暴露评估已被证明是困难的，因为 方法上的差异和糟糕的评估方法。在生理评估方面，某些 化学元素与神经毒性有关(如铅)。到目前为止，铅代表着最强的 与肌萎缩侧索硬化有关的环境风险因素。然而，其他与ALS相关的元素的鉴定 受到以下因素的阻碍：(1)报告的测量结果存在差异；(2)外围测量结果 很少反映中枢神经系统内的生理负荷。鉴于这些挑战，我们初步的 研究表明，在被诊断为铅中毒之前，有毒元素暴露与ALS之间存在关联。 汞和锰。我们进一步在ALS患者的大脑中检测到这些相同成分的存在 组织。我们现在建议在马萨诸塞州验证这些因素和其他因素是否为环境风险因素 (马萨诸塞州)，该国唯一拥有可报告(强制性)ALS登记的州。利用民族住宅 MA ALS注册参与者的历史，我们将估计受试者暴露于潜在有毒和持续的 在病例对照分析中在诊断前确定与肌萎缩侧索硬化症风险增加相关的因素 使用时空地理信息系统(GIS)技术。同时，我们将评估 疾病相关脑组织中一组元素的浓度、组合和空间分布 MA ALS登记患者和非神经退行性MA尸检对照，并将这些发现与我们的 地理信息系统研究。我们还将表征ALS病例中纳米颗粒的亚细胞分布和组成 相对于控件。总而言之，这项独特而新颖的研究将确定有充分依据的、与风险相关的风险敞口 对于肌萎缩侧索硬化症，以及对这种疾病的病因提供了新的见解。

PROJECT SUMMARY/ABSTRACT Amyotrophic lateral sclerosis (ALS) is a fatal and primarily sporadic neurodegenerative disease involving the death of upper and lower motor neurons. There are a myriad of pathological mechanisms underlying this disease, which makes identifying a single target for treatment a great challenge. It is largely accepted that ALS is caused by a combination of genetic susceptibility and environmental factors. The importance of environmental factors is supported by inter alia discordance in monozygotic twins, conjugal ALS and increased risk of ALS with specific occupations and toxic exposures. While there remains an urgent need to define the pathological etiology of ALS, exposure assessments within etiologically-relevant, pre-symptom time intervals has proven difficult due to differences in methodology and poor assessment methods. In regards physiological assessments, certain chemical elements have been linked to neurotoxicity (e.g. lead). To date, lead represents one of the strongest environmental risk factors connected to ALS. The identification of additional ALS-associated elements however has been stymied by (1) discrepancies in reported measurements and (2) the fact that peripheral measurements rarely reflect the physiological load within the central nervous system. In light of these challenges, our preliminary work indicates an association between toxic element exposures and ALS in epochs prior to diagnosis for lead, mercury and manganese. We have further detected the presence of these same elements in ALS patient brain tissue. We now propose to validate these and other elements as environmental risk factors in Massachusetts (MA), the only state in the country with a reportable (mandatory) ALS registry. Utilizing the national residential history of MA ALS Registry participants, we will estimate subject exposure to potentially toxic and persistent elements prior to diagnosis to identify elements associated with increased ALS risk in a case-control analysis using spatiotemporal geographical information systems (GIS) techniques. In parallel, we will evaluate the concentrations, combinations and spatial distribution of a suite of elements in disease-relevant brain tissue from MA ALS Registry patients and non-neurodegenerative MA autopsy controls and correlate these findings to our GIS studies. We will also characterize the subcellular distribution and composition of nanoparticles in ALS cases relative to controls. Together, this unique and novel research will identify well-founded, risk-related exposures for ALS as well as provide novel insight into the etiology of this disease.