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

研究 ALS 病因中的有毒元素和纳米颗粒：对马萨诸塞州 ALS 登记患者的地理空间和毒理学评估

• 批准号: 10705574
• 负责人: ELIJAH W STOMMEL
• 金额: $ 40.89万
• 依托单位: DARTMOUTH-HITCHCOCK CLINIC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-19 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10705574
• 关键词: ALS patients; Age; Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Autopsy; Case/Control Studies; Central Nervous System; Cessation of life; Characteristics; Chemicals; Clinical; Clinical Research; Country; Data; Databases; Development; Diagnosis; Disease; Early Diagnosis; Elements; Environmental Exposure; Environmental Pollutants; Environmental Risk Factor; Etiology; Evaluation; Exhibits; Exposure to; Frontotemporal Dementia; Future; Genetic Predisposition to Disease; Geographic Information Systems; Human; Inductively Coupled Plasma Mass Spectrometry; Investigation; Lead; Light; Link; Location; Manganese; Maps; Massachusetts; Measurement; Measures; Mercury; Methodology; Methods; Monozygotic twins; Motor Neuron Disease; Motor Neurons; Nerve Degeneration; Neurodegenerative Disorders; Neurotoxins; Occupations; Parkinson Disease; Participant; Pathogenicity; Pathologic; Patients; Peripheral; Physiological; Population; Prevention; Recording of previous events; Registries; Reporting; Research; Risk; Risk Factors; Sampling; Shapes; Spatial Distribution; Symptoms; Techniques; Testing; Therapeutic; Tissues; Toxic effect; Toxicant exposure; Toxicology; Trace Elements; Transmission Electron Microscopy; United States; Work; X ray spectroscopy; brain tissue; case control; cell type; comparison control; disorder risk; drinking water; epidemiology study; experience; frontal lobe; insight; nanoparticle; neurotoxicity; novel; patient registry; prevent; residence; sex; spatiotemporal; targeted treatment; time interval

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.

项目概要/摘要 肌萎缩侧索硬化症 (ALS) 是一种致命且主要是散发性的神经退行性疾病，涉及 上、下运动神经元死亡。这种疾病有多种病理机制， 这使得确定单一治疗目标成为一项巨大的挑战。人们普遍认为 ALS 是由 由遗传易感性和环境因素共同作用。环境因素的重要性是 除其他外，单卵双胞胎、夫妻性 ALS 的不一致以及特定情况下 ALS 风险增加也支持这一观点。 职业和有毒物质暴露。虽然仍然迫切需要确定 ALS 的病理病因， 事实证明，在与病因相关的症状前时间间隔内进行暴露评估很困难，因为 方法论上的差异和不良的评估方法。在生理评估方面，某些 化学元素与神经毒性有关（例如铅）。迄今为止，铅代表了最强的之一 与 ALS 相关的环境风险因素。然而，其他 ALS 相关元素的识别 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 研究表明，在铅诊断之前的时期，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。我们现在建议将这些因素和其他因素验证为马萨诸塞州的环境风险因素 （马萨诸塞州），该国唯一拥有可报告（强制性）ALS 登记的州。利用国家住宅 MA ALS 注册参与者的历史，我们将估计受试者暴露于潜在毒性和持久性的环境 诊断前的要素，以在病例对照分析中识别与 ALS 风险增加相关的要素 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系列元素的浓度、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研究结果相关联 地理信息系统研究。我们还将描述 ALS 病例中纳米粒子的亚细胞分布和组成 相对于控件。总之，这项独特而新颖的研究将确定有根据的、与风险相关的敞口 为 ALS 提供新的见解，并对该疾病的病因学提供新的见解。