Multicenter ALS Cohort Study of Oxidative Stress and Disease Progression

氧化应激和疾病进展的多中心 ALS 队列研究

• 批准号: 7727882
• 负责人: HIROSHI MITSUMOTO
• 金额: $ 74.9万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-22 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7727882
• 关键词: 8-Oxo-2' -Deoxyguanosine; Accounting; Affect; Alcohol consumption; Amyotrophic Lateral Sclerosis; Animal Model; Antioxidants; Arts; Behavior; Benign; Biological; Biological Assay; Biological Markers; Blood; Cessation of life; Clinical; Clinical assessments; Cohort Studies; Consumption; Controlled Study; Coupled; DNA Adducts; Data; Dementia; Diagnosis; Diet; Dietary Factors; Disease; Disease Progression; Enrollment; Epidemiologic Methods; Epidemiologic Studies; Epidemiology; Exposure to; Food; Funding; Funding Mechanisms; Grant; Growth; Hazard Models; Hobbies; Human; Impaired cognition; Injury; Interview; Investigation; Isoprostanes; Knowledge; LDL Cholesterol Lipoproteins; Leisure Activities; Life Style; Link; Lipid Peroxidation; Lipids; Measures; Modeling; Molecular; Motor; Motor Neurons; Muscle; Nerve Degeneration; Neurodegenerative Disorders; Newly Diagnosed; Occupational Exposure; Onset of illness; Oral; Oxidative Stress; Paralysed; Paraoxonase 1; Pathway interactions; Patient Care; Patients; Physical activity; Plasma; Prevention approach; Principal Investigator; Process; Protocols documentation; Psychological Factors; Psychological Stress; Questionnaires; Recruitment Activity; Reporting; Respiratory Failure; Role; Site; Skeletal Muscle; Smoking; Spinal; Structure; Sum; Symptoms; Testing; Time; Urine; Visit; Vitamins; Wing; antioxidant therapy; aryldialkylphosphatase; base; clinical epidemiology; cohort; design; follow-up; functional status; hazard; indexing; isoprostaglandin F2alpha type-III; lifestyle factors; outcome forecast; prospective; psychologic; public health relevance; urinary

DESCRIPTION (provided by principal investigator): Amyotrophic lateral sclerosis (ALS) is a devastating, rapidly fatal neurodegenerative disease of largely unknown cause. It is clinically characterized by progressive skeletal muscle paralysis and eventual respiratory failure, with a mean survival of about 40 months after symptom onset. No prospective investigations have attempted to determine what factors accelerate or slow disease progression. Recent clinical and epidemiological studies suggest that diverse environmental and lifestyle factors are associated with ALS and that these generate oxidative stress (OS). We hypothesize that these extrinsic factors act throughout the disease course, generating varying levels of OS, and thus influence disease progression. We propose to test this hypothesis in 420 newly diagnosed ALS patients from 11 ALS centers across the US. We specifically aim: 1. To determine whether markers of increased exposure to OS, measured via questionnaire or biomarkers, are associated with the progression of ALS. ALS progression will be determined with a widely used and well-validated ALS functional scale (the ALSFRS-R) every 3 to 6 months for 24 months. At baseline and follow-up, we will obtain measures of OS biomarkers (urinary 15-F2t-isoprostane and 8- oxodeoxyguanosine, plasma paraoxonase I [PON1] levels, and PON1 functional status) and, through structured interviews, measures of current environmental, psychological, dietary, and lifestyle factors associated with OS. 2. To examine the associations between OS biomarkers, an OS index, and survival of patients with ALS. An OS index will be developed based on a sum of the external factors (Goodman et al. 2007). Survival will be followed at the ALS Centers during the grant period and thereafter by using National Death Index data. We will test whether increased and continuing OS as measured by the index and biomarkers affect survival; 3. To determine whether a variety of environmental, lifestyle, and psychological factors are associated with increased levels of OS biomarkers at baseline; 4. To evaluate associations between lipid profile and ALS progression, as measured by ALSFRS-R and survival. Lipids will be analyzed at several time points to determine whether high cholesterol and LDL are associated with longer survival, as recently reported (Dupuis et al 2008); and 5. In exploratory analyses, to determine whether OS markers and exposures are associated with distinct subtypes of ALS, such as bulbar- or spinal-onset ALS, and ALS with or without fronto-temporal dementia (FTD). To our knowledge, this is the first prospective, interdisciplinary, in-depth multicenter epidemiological investigation of OS in ALS. Our project will increase the understanding of the disease mechanisms involved in disease prognosis and may be the first step toward new treatment and prevention approaches, such as multiple anti- oxidant therapy, to target oxidative stress sites in ALS. PUBLIC HEALTH RELEVANCE: To our knowledge, this is the first prospective, in-depth multicenter, interdisciplinary, molecular epidemiological investigation of oxidative stress (OS) in ALS. We will investigate whether environmental, lifestyle, psychological, and dietary factors are linked to abnormal OS biomarkers and whether a variety of factors and abnormal OS biomarkers are associated with disease progression. Our study will increase the understanding of the disease mechanisms involved in disease prognosis and may be the first step toward new treatment and prevention approaches, such as multiple anti-oxidant therapy, to target OS in ALS.

描述（由首席研究员提供）：肌萎缩侧索硬化症 (ALS) 是一种毁灭性的、迅速致命的神经退行性疾病，其原因很大程度上未知。其临床特征为进行性骨骼肌麻痹和最终呼吸衰竭，症状出现后平均生存期约为 40 个月。没有前瞻性研究试图确定哪些因素加速或减缓疾病进展。最近的临床和流行病学研究表明，多种环境和生活方式因素与 ALS 相关，并且这些因素会产生氧化应激 (OS)。我们假设这些外在因素在整个疾病过程中发挥作用，产生不同水平的 OS，从而影响疾病进展。我们建议在美国 11 个 ALS 中心的 420 名新诊断的 ALS 患者中检验这一假设。我们的具体目标是： 1. 确定通过问卷或生物标志物测量的 OS 暴露增加的标志物是否与 ALS 的进展相关。 ALS 进展将使用广泛使用且经过充分验证的 ALS 功能量表 (ALSFRS-R) 每 3 至 6 个月一次确定，持续 24 个月。在基线和随访时，我们将获得 OS 生物标志物（尿液 15-F2t-异前列烷和 8-氧化脱氧鸟苷、血浆对氧磷酶 I [PON1] 水平和 PON1 功能状态）的测量值，并通过结构化访谈，测量与 OS 相关的当前环境、心理、饮食和生活方式因素。 2. 检查 OS 生物标志物、OS 指数与 ALS 患者生存率之间的关联。 OS 指数将根据外部因素的总和来制定（Goodman 等人，2007 年）。 ALS 中心将在拨款期间以及之后使用国家死亡指数数据来跟踪生存情况。我们将测试通过指数和生物标志物测量的增加和持续的 OS 是否会影响生存； 3. 确定各种环境、生活方式和心理因素是否与基线 OS 生物标志物水平升高相关； 4. 评估血脂谱与 ALS 进展之间的关联（通过 ALSFRS-R 测量）和生存率。正如最近报道的那样，将在几个时间点对脂质进行分析，以确定高胆固醇和低密度脂蛋白是否与更长的生存期相关（Dupuis et al 2008）； 5. 在探索性分析中，确定 OS 标志物和暴露是否与 ALS 的不同亚型相关，例如延髓或脊髓发病的 ALS，以及伴有或不伴有额颞叶痴呆 (FTD) 的 ALS。据我们所知，这是首次针对 ALS 的 OS 进行前瞻性、跨学科、深入的多中心流行病学调查。我们的项目将增进对疾病预后所涉及的疾病机制的了解，并且可能是迈向新的治疗和预防方法的第一步，例如针对 ALS 氧化应激位点的多重抗氧化疗法。公共卫生相关性：据我们所知，这是第一个针对 ALS 氧化应激 (OS) 的前瞻性、深入的多中心、跨学科、分子流行病学调查。我们将研究环境、生活方式、心理和饮食因素是否与异常 OS 生物标志物相关，以及多种因素和异常 OS 生物标志物是否与疾病进展相关。我们的研究将增进对疾病预后所涉及的疾病机制的了解，并且可能是迈向新的治疗和预防方法（例如针对 ALS 的 OS 的多重抗氧化疗法）的第一步。