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

项目概要/摘要 肌萎缩侧索硬化症（ALS）是一种致命的、主要是散发性的神经退行性疾病， 上、下运动神经元死亡。这种疾病有无数的病理机制， 这使得识别用于治疗的单个目标成为一个巨大的挑战。人们普遍认为ALS是由 遗传易感性和环境因素的综合作用。环境因素的重要性在于 阿利亚是单卵双胞胎的不一致性，配偶ALS和特定的ALS风险增加支持 职业和有毒接触。虽然仍然迫切需要确定ALS的病理病因， 在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， 方法差异和评估方法不佳。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，铅代表了一个最强大的 与ALS相关的环境风险因素。然而，识别其他ALS相关元素 （1）报告测量结果的差异和（2）外周测量结果 很少反映中枢神经系统内的生理负荷。鉴于这些挑战，我们的初步 研究表明，在诊断为铅之前，有毒元素暴露与ALS之间存在关联， 汞和锰。我们进一步检测到ALS患者大脑中存在这些相同的元素， 组织.我们现在建议在马萨诸塞州验证这些和其他因素作为环境风险因素 (MA)是美国唯一一个有可报告（强制性）ALS登记的州。利用国家住宅 根据MA ALS登记研究参与者的病史，我们将估计受试者暴露于潜在毒性和持久性 在病例对照分析中确定与ALS风险增加相关的元素 利用时空地理信息系统（GIS）技术。同时，我们将评估 一组元素在疾病相关脑组织中的浓度、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研究结果相关联。 GIS研究。我们还将描述ALS病例中纳米颗粒的亚细胞分布和组成 相对于对照。总之，这项独特而新颖的研究将确定有根据的，与风险相关的风险暴露 并为这种疾病的病因学提供了新的见解。

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.