Case-Control Studies Nested in National ALS Registry to Evaluate Environmental Risks

 描述(申请人提供)：肌萎缩侧索硬化症(ALS)被认为是最具破坏性的神经退行性疾病。患者出现进行性功能丧失，包括言语丧失、吞咽、行动不便和呼吸，平均在确诊后2至4年内导致死亡。除了积极的对症治疗，没有有效的治疗方法。除了利鲁唑，50多项基于看似合理的疾病机制假说的临床试验都失败了。已确认的遗传性致病突变约占所有ALS病例的10%；大多数散发性病例的原因尚不清楚。肌萎缩侧索硬化症现在被认为是遗传和环境风险因素共同作用的潜在原因。我们的总体假设是，据报道与ALS相关的个别环境风险因素通过共同的机制发挥作用，特别是氧化应激(OS)。我们由NIEHS资助的ALS前瞻性多中心队列研究(ALS COSMOS)调查了与OS相关的多种风险因素与ALS进展相关的程度，该研究已进入最后阶段。我们目前的逮捕肌萎缩侧索硬化症项目通过全国肌萎缩侧索硬化症登记处，使用结构化的电话采访和一次性的尿液和唾液收集，在国家层面上扩大了肌萎缩侧索硬化症的范围。现在，我们提出了一套设计良好、高质量的病例对照研究，嵌套在逮捕ALS中。我们的具体目标是：1.在国家肌萎缩侧索硬化症注册中心逮捕肌萎缩侧索硬化症研究的人群病例对照研究中，评估环境和其他危险因素。这些病例(150名患者)将在正在进行的逮捕肌萎缩侧索硬化症项目中确定。我们将根据性别、年龄(±5岁)、种族/民族和居住地为每个病例匹配2个对照。我们将进行经过充分验证的结构化访谈，以确定认知功能，并获取有关早期生活事件和环境、居住、职业、饮食、生活方式和心理因素的数据。将收集饮食问卷数据、首次检测OS标志物的无效尿样和唾液DNA；2.在一项以兄弟姐妹为基础的病例对照研究中，评估早年和晚年的环境和其他危险因素。我们将确定同意参与并在年龄上最接近病例的同性兄弟姐妹。我们估计，80%的病例将有符合这些标准的兄弟姐妹。他们将接受与人群对照相同的风险因素评估，并提供唾液和尿液样本。3.评估不同生命阶段患者和对照组之间的个体或总体环境危险因素，并探讨尿OS生物标记物与ALS和环境危险因素的关系。我们将结合病例分析两个对照组不同生命阶段的危险因素，并进一步分析OS生物标记物与危险因素的关系。总之，精心设计的基于人群和兄弟姐妹的病例对照研究嵌套在逮捕的ALS中，将揭示关于环境风险因素、疾病进展和ALS的潜在原因(S)的全新和独特的数据。

 DESCRIPTION (provided by applicant): Amyotrophic lateral sclerosis (ALS) is considered the most devastating neurodegenerative disease. Patients suffer progressive functional loss, including loss of speech, swallowing, mobility, and respiration that leads to death on average 2 to 4 years after diagnosis. Except for aggressive symptomatic care, there are no effective treatments. More than 50 clinical trials based on plausible hypotheses of disease mechanisms have failed except for riluzole. Identified inherited pathogenic mutations account for ~10% of all ALS cases; the cause of most sporadic cases is unknown. ALS is now considered to be potentially caused by a combination of both genetic and environmental risk factors. Our overall hypothesis is that individual environmental risk factors reported to be associated with ALS act via a common mechanism, specifically oxidative stress (OS). Our NIEHS-funded prospective multicenter cohort study of ALS (ALS COSMOS), which investigates the extent to which multiple risk factors associated with OS are also associated with ALS progression, is in its final stages. Our current ARREST ALS project expands ALS COSMOS at a national level through the National ALS Registry, using structured telephone interviews and one-time urine and saliva collection. Now, we propose a set of well-designed, high-quality, case-control studies nested within ARREST ALS. We specifically aim: 1. To evaluate environmental and other risk factors in a population-based case-control study nested within the ARREST ALS study of the National ALS Registry. The cases (150 patients) will be identified in the on- going ARREST ALS project. We will match 2 controls to each case based on sex, age (± 5 years), race/ethnicity, and geographic area of residence. We will administer our well-validated, structured interview to determine cognitive function and obtain data on early life events and environmental, residential, occupational, dietary, lifestyle, and psychological factors. Dietary questionnaire data, first-void urine samples to measure OS markers, and saliva DNA will be collected; 2. To evaluate early life and late life environmental and other risk factors in a sibling-based, case-control study. We will identify a same-sex sibling who agrees to participate and is closest in age to the case. We estimate that 80% of cases will have a sibling who meets these criteria. They will receive the same risk factor assessment and provide saliva and urine samples as the population controls. 3. To evaluate individual or aggregate environmental risk factors between cases and controls at different stages of life and to investigate the significance of the urinary OS biomarker in relation to ALS and environmental risk factors. We will analyze risk factors at different stages of life in the two control groups combined in comparison to the cases and further analyze OS biomarkers in relation to risk factors. In summary, carefully designed population-based and sibling-based case-control studies nested within ARREST ALS will reveal entirely new and unique data concerning environmental risk factors, disease progression, and the potential cause(s) of ALS.