Lead And Other Neurotoxins As Risk Factors For Amyotrophic Lateral Sclerosis

铅和其他神经毒素是肌萎缩侧索硬化症的危险因素

• 批准号: 8734079
• 负责人: Dale P Sandler
• 金额: $ 4.23万
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8734079
• 关键词: 9p21; Academic Medical Centers; Accounting; Acute; Adult; Affect; Age; Air; Aircraft; Alcohols; Amyotrophic Lateral Sclerosis; Arsenic; Biological Assay; Biological Markers; Blood specimen; Bone Resorption; Brain Stem; C9ORF72; Cadmium; Caffeine; Case-Control Studies; Cessation of life; Chemical Exposure; Childhood; Chromium; Chromosomes; Chronic; Clinical; Comorbidity; Copper; Coupled; Craniocerebral Trauma; Cyclophosphamide; Data; Development; Diagnosis; Electromagnetic Fields; Enrollment; Environment; Environmental Exposure; Environmental Risk Factor; Environmental and Occupational Exposure; Etiology; Exposure to; Familial Amyotrophic Lateral Sclerosis; Family history of; Formaldehyde; General Population; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic Risk; Genotype; Goals; Gulf War; Heavy Metals; Hobbies; Home environment; Hospitalization; Hydrocarbons; Individual; Infection; Inflammation; Injury; Institutes; Interview; Introns; Lead; Life; Life Table Analyses; Malignant Neoplasms; Manganese; Mass Spectrum Analysis; Measures; Medical Records; Mercury; Metals; Methods; Military Personnel; Motor Neurons; Neurodegenerative Disorders; Neurologic; Neurologist; Neurotoxins; New England; Nickel; Occupational; Occupational Exposure; Occupations; Oils; Osteogenesis; Parkinson Disease; Participant; Patients; Pattern; Persian Gulf; Pesticides; Physical activity; Plasma; Play; Polychlorinated Biphenyls; Population Control; Prognostic Marker; Questionnaires; Recording of previous events; Registries; Reporting; Respiratory Failure; Respiratory physiology; Risk; Risk Factors; Role; Selenium; Sepsis; Services; Smoking; Solvents; Specialist; Spinal Cord; Stratification; Structure; Subgroup; Telephone Interviews; Tobacco use; Trauma; Tube; United States; Variant; Veterans; Viral; Vital Status; War; Whole Blood; Work; base; blood lead; bone turnover; cancer diagnosis; cancer risk; case control; cohort; demographics; experience; falls; follow-up; information gathering; inorganic phosphate; interest; lead exposure; mortality; population based

Swedish National Registers I have collaborated with Weimin Ye at the Karolinska Institute on studies based on the Swedish National Registers. ALS and Head Injury: Using 4,004 ALS cases from the Swedish Patient Register and 20,020 matched controls, we evaluated hospitalization for severe head injury before ALS diagnosis. Injury in the year preceding diagnosis was associated with ALS (OR 3.9, 95% CI 2.66.1). This relationship may be due to reverse causation, because individuals experience increased falls and injuries shortly before diagnosis of ALS. No association was observed for severe head injury 3 or more years before ALS diagnosis. These findings provide little support for an association of severe head injury in adulthood with ALS risk but do not exclude a relationship with less severe injury not requiring hospitalization or with injuries occurring in childhood. ALS and Sepsis: Severe infections may increase ALS risk by increasing inflammation. We studied 4,004 ALS cases from the Swedish Patient Register and 20,020 matched controls. Neither previous CNS infection nor sepsis was associated with ALS risk. Our results suggest that severe acute infections are unlikely to contribute to ALS risk. ALS and Cancer: We studied 5,481 ALS cases from the Swedish Patient Register and 27,405 population controls. Overall, a previous cancer diagnosis was not associated with ALS risk either for all cancers or for any specific cancer although increased risk of ALS was observed during the first year after cancer diagnosis (OR 1.5, 95% CI 1.2-1.9). In contrast, a lower risk of cancer was observed in ALS patients after diagnosis compared to ALS-free individuals (IRR 0.8; 95% CI 0.7-1.0). Our results provide little evidence for comorbidity of cancer and ALS; surveillance bias seems the most likely explanation for the limited associations previously detected. Occupational Cohorts Certain occupations and occupational exposures may be related to ALS, but data are sparse and inconsistent. Our results from the New England ALS study identified several associations with ALS. To extend this work, we collaborated with Lynne Pinkerton at NIOSH to study two cohorts. Formaldehyde: We studied ALS mortality in a cohort of 11,022 US garment workers exposed to formaldehyde. We ascertained vital status through 2008 and conducted life table analyses to obtain standardized mortality ratios. We observed 8 deaths from ALS. Compared to the US general population, ALS mortality was not elevated in the overall cohort or among subgroups with greater exposure based on exposure duration or year of first exposure. These results suggest that ALS is not associated with formaldehyde exposure but need confirmation in a larger study. Flight Attendants: Concern exists about the potential chronic neurological effects among flight crew of exposure to contaminants from engine oil in aircraft cabin air. We evaluated mortality from neurodegenerative diseases among 11,311 former US flight attendants. We ascertained vital status through 2007 and conducted life table analyses to obtain standardized mortality ratios. ALS mortality was elevated two-fold compared to the US population, based on 9 deaths. There was no clear pattern in risk related to exposure duration. Mortality from other neurodegenerative diseases was not elevated. Our findings are limited due to small numbers of observed deaths, but suggest that flight attendants may have an increased risk of ALS, possibly related to exposure to tricresyl phosphates in engine oil. GENEVA (Genes and Environment in Veterans with ALS) Reports that ALS risk might be increased among veterans deployed to the 19901991 Persian Gulf War prompted the Department of Veterans Affairs (VA) to establish a National Registry of Veterans with ALS. The registry, established in 2004, enrolled 1,573 US veterans with neurologist-confirmed ALS. Information in the VA Registry includes ALS diagnosis and other clinical details based on medical record review and information gathered during an initial screen and six-month follow-up interviews. Mortality has been ascertained through December 31, 2010. GENEVA is a case-control study comparing 631 ALS cases from the VA registry and 975 matched veteran controls. A structured telephone interview conducted collected information on demographics, lifetime occupational history, hobbies, home pesticide use, use of tobacco, caffeine, and alcohol, residential history, physical trauma, and family history of ALS or other neurodegenerative diseases. Extensive genotyping of cases and controls was also conducted. We conducted an add-on study, Veterans with ALS and Lead Exposure (VALE), to evaluate the relationship of blood lead to ALS. We collected whole blood samples in metal-free tubes from 200 ALS cases and 229 matched controls. We measured metals with inductively coupled plasma mass spectrometry, a highly sensitive assay, and evaluated bone turnover using biomarkers of bone formation and resorption. We found that age-adjusted blood lead levels were higher among cases compared with controls. Bone resorption was also greater in cases than controls, although bone formation was the same. ALS was associated with blood lead levels; the OR for each unit increase in log-transformed blood lead was 2.6 (1.9-3.7). The association persisted after adjustment for or stratification by bone turnover biomarkers. These results corroborate our earlier finding that elevated blood lead is associated with increased ALS risk and suggest that increased bone turnover in ALS cases does not fully explain this association. We are presently using VALE data to evaluate the relationship of blood lead to survival. Initial results suggest at best a weak association, consistent with that observed in the New England study. Of great interest is the fact that increased CTX, a marker of bone resorption, was associated with shorter survival, even after controlling for physical activity and respiratory function. Elevated CTX may be a clinically useful marker of prognosis. We are also using VALE data to evaluate the relationship of ALS to other metals. We measured several metals other than lead, including cadmium, chromium, copper, manganese, and nickel. We will evaluate the relationships of these metals to ALS risk. An interesting possibility is that combinations of metals will be related to ALS risk, as previously suggested for Parkinsons disease. GENEVA was initially developed by Silke Schmidt at Duke University Medical Center. Dr Schmidt was unable to continue work with the study, and consequently I have taken the lead in analyses of questionnaire data. We are planning several studies. Military Exposures: Studies suggesting increased ALS risk among veterans of the first Persian Gulf War and potentially all military veterans provided the impetus for development of the VA ALS registry on which GENEVA is based. Detailed data on military service (eg, war, if any, years of service, military branch, etc) and military-specific exposures was collected in the GENEVA interviews. We plan to evaluate associations of these military exposures with ALS risk and survival. We will investigate (i) military service by branch and war; (ii) deployment-specific exposures, including several unique to the first Persian Gulf War; (iii) specific exposures including pesticides. Occupational Exposures: A complete occupational history was collected from GENEVA participants. Susan Woskie, an industrial hygienist, and a team of specialists are evaluating these histories in order to assign exposures to several agents of interest, all of which have been implicated in ALS by one or more studies but none conclusively. These exposures include lead, mercury, selenium, arsenic, PCBs, hydrocarbon solvents, chlorinated solvents, formaldehyde, EMF, and viral agents.

瑞典国家名录 我与卡罗林斯卡学院的叶伟民合作进行了基于瑞典国家名录的研究。 ALS 和头部损伤：我们利用瑞典患者登记册中的 4,004 名 ALS 病例和 20,020 名匹配对照，评估了 ALS 诊断前因严重头部损伤而住院的情况。诊断前一年的损伤与 ALS 相关（OR 3.9，95% CI 2.66.1）。这种关系可能是由于反向因果关系造成的，因为在诊断 ALS 之前不久，个体跌倒和受伤的次数会增加。在 ALS 诊断前 3 年或以上，未观察到严重头部损伤与此相关。这些发现几乎没有支持成年期严重头部损伤与 ALS 风险之间的关联，但并不排除与不需要住院的较轻损伤或儿童时期发生的损伤之间的关系。 ALS 和脓毒症：严重感染可能会增加炎症，从而增加 ALS 风险。我们研究了瑞典患者登记处的 4,004 个 ALS 病例和 20,020 个匹配对照。既往中枢神经系统感染和败血症均与 ALS 风险无关。我们的结果表明，严重急性感染不太可能导致 ALS 风险。 ALS 和癌症：我们研究了瑞典患者登记处的 5,481 名 ALS 病例和 27,405 名对照人群。总体而言，尽管在癌症诊断后的第一年观察到 ALS 风险增加（OR 1.5，95% CI 1.2-1.9），但先前的癌症诊断与所有癌症或任何特定癌症的 ALS 风险均无关。相比之下，与无 ALS 的个体相比，诊断后 ALS 患者患癌症的风险较低（IRR 0.8；95% CI 0.7-1.0）。我们的结果几乎没有提供癌症和 ALS 共病的证据；监测偏差似乎是对先前发现的有限关联的最可能的解释。 职业群体 某些职业和职业暴露可能与 ALS 有关，但数据稀疏且不一致。我们的新英格兰 ALS 研究结果确定了与 ALS 的多种关联。为了扩展这项工作，我们与 NIOSH 的 Lynne Pinkerton 合作研究了两个队列。 甲醛：我们研究了 11,022 名接触甲醛的美国服装工人的 ALS 死亡率。我们确定了 2008 年的生命状况并进行了生命表分析以获得标准化死亡率。我们观察到 8 例死于 ALS。与美国一般人群相比，在整个队列中或在根据暴露持续时间或首次暴露年份而暴露较多的亚组中，ALS 死亡率并未升高。这些结果表明 ALS 与甲醛暴露无关，但需要更大规模的研究来证实。 空乘人员：人们担心机组人员接触飞机机舱空气中发动机油污染物可能会产生慢性神经系统影响。我们评估了 11,311 名美国前空乘人员因神经退行性疾病造成的死亡率。我们确定了 2007 年的生命状况并进行了生命表分析以获得标准化死亡率。根据 9 例死亡数据，ALS 死亡率比美国人口高出两倍。与暴露时间相关的风险没有明确的模式。其他神经退行性疾病的死亡率并未升高。由于观察到的死亡人数较少，我们的研究结果有限，但表明空乘人员患 ALS 的风险可能增加，这可能与接触发动机油中的磷酸三甲苯酯有关。 日内瓦（患有 ALS 的退伍军人的基因和环境） 有报道称，参加 19901991 波斯湾战争的退伍军人患 ALS 的风险可能会增加，促使退伍军人事务部 (VA) 建立了国家 ALS 退伍军人登记处。该登记处成立于 2004 年，登记了 1,573 名经神经科医生确诊患有 ALS 的美国退伍军人。 VA 登记处的信息包括 ALS 诊断和其他临床详细信息，这些信息基于医疗记录审查以及在初始筛选和六个月的后续访谈期间收集的信息。截至 2010 年 12 月 31 日，死亡率已确定。 GENEVA 是一项病例对照研究，对 VA 登记处的 631 例 ALS 病例和 975 例匹配的退伍军人对照进行比较。结构化电话访谈收集了有关人口统计、终生职业史、爱好、家庭杀虫剂使用、烟草、咖啡因和酒精使用、居住史、身体创伤以及 ALS 或其他神经退行性疾病家族史的信息。还对病例和对照进行了广泛的基因分型。 我们进行了一项附加研究，即患有 ALS 的退伍军人和铅暴露 (VALE)，以评估血铅与 ALS 的关系。我们从 200 名 ALS 病例和 229 名匹配对照者的无金属试管中收集了全血样本。我们使用电感耦合等离子体质谱法（一种高度灵敏的检测方法）测量金属，并使用骨形成和吸收的生物标志物评估骨转换。我们发现，与对照组相比，病例中经年龄调整的血铅水平较高。尽管骨形成相同，但病例中的骨吸收也比对照组更大。 ALS 与血铅水平有关；对数转换血铅每增加一个单位的 OR 为 2.6 (1.9-3.7)。在骨转换生物标志物调整或分层后，这种关联仍然存在。这些结果证实了我们之前的发现，即血铅升高与 ALS 风险增加相关，并表明 ALS 病例中骨转换增加并不能完全解释这种关联。 我们目前正在使用 VALE 数据来评估血铅与生存的关系。初步结果最多表明关联性较弱，与新英格兰研究中观察到的结果一致。令人感兴趣的是，即使在控制体力活动和呼吸功能后，骨吸收标志物 CTX 的增加也与较短的生存期相关。 CTX 升高可能是临床上有用的预后标志。我们还使用 VALE 数据来评估 ALS 与其他金属的关系。我们测量了除铅以外的几种金属，包括镉、铬、铜、锰和镍。我们将评估这些金属与 ALS 风险的关系。一个有趣的可能性是，金属的组合将与 ALS 风险相关，正如之前针对帕金森病所建议的那样。 GENEVA 最初由杜​​克大学医学中心的 Silke Schmidt 开发。施密特博士无法继续进行这项研究，因此我带头分析了问卷数据。我们正在计划进行几项研究。 军事暴露：研究表明，第一次波斯湾战争退伍军人以及可能所有退伍军人的 ALS 风险增加，这为日内瓦所依据的 VA ALS 登记册的发展提供了动力。在日内瓦采访中收集了有关兵役的详细数据（例如，战争，如果有的话，服役年限，军事部门等）和军事特定暴露。我们计划评估这些军事暴露与 ALS 风险和生存的关联。我们将调查（i）按兵种和战争划分的兵役情况； (ii) 部署特定的风险，包括第一次波斯湾战争特有的几种风险； (iii) 特定暴露，包括农药。 职业暴露：从日内瓦参与者收集了完整的职业史。工业卫生学家苏珊·沃斯基 (Susan Woskie) 和一组专家正在评估这些历史记录，以便将暴露情况分配给几种感兴趣的物质，一项或多项研究表明所有这些物质都与 ALS 有关，但还没有得出结论。这些暴露包括铅、汞、硒、砷、多氯联苯、碳氢化合物溶剂、氯化溶剂、甲醛、EMF 和病毒制剂。