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.

肌萎缩侧索硬化症（ALS）是一种破坏性的、快速致命的神经退行性疾病，病因不明。其临床特征为进行性骨骼肌麻痹和最终的呼吸衰竭，症状发作后平均存活约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，不同的环境和生活方式因素与ALS相关，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起作用，产生不同水平的OS，从而影响疾病进展。我们建议在来自美国11个ALS中心的420名新诊断的ALS患者中测试这一假设。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个月进行一次，持续24个月。在基线和随访时，我们将获得OS生物标志物（尿15-F2 t-异前列烷和8-氧代脱氧鸟苷，血浆对氧磷酶I [PON 1]水平和PON 1功能状态）的测量结果，并通过结构化访谈，获得与OS相关的当前环境，心理，饮食和生活方式因素的测量结果。检查OS生物标志物、OS指数和ALS患者生存率之间的相关性。将根据外部因素的总和开发OS指数（Goodman et al. 2007）。在资助期间，ALS中心将跟踪生存情况，此后将使用国家死亡指数数据。我们将测试通过指数和生物标志物测量的增加的和持续的OS是否影响生存; 3.确定各种环境、生活方式和心理因素是否与基线时OS生物标志物水平升高相关; 4.评估血脂谱与ALS进展（通过ALSFRS-R和生存率测量）之间的相关性。将在几个时间点分析脂质，以确定高胆固醇和LDL是否与较长的生存期相关，如最近报道的（Dupuis et al 2008）;和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，例如延髓或脊髓发作型ALS，以及伴或不伴额颞叶痴呆（FTD）的ALS。据我们所知，这是首次对ALS患者OS进行前瞻性、跨学科、深入的多中心流行病学调查。我们的项目将增加对疾病预后所涉及的疾病机制的理解，并可能是迈向新的治疗和预防方法的第一步，如多种抗氧化治疗，以靶向ALS中的氧化应激位点。公共卫生关系：据我们所知，这是第一个前瞻性的，深入的多中心，跨学科，分子流行病学调查氧化应激（OS）在ALS。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，以及各种因素和异常OS生物标志物是否与疾病进展相关。我们的研究将增加对疾病预后中涉及的疾病机制的理解，并可能是迈向新的治疗和预防方法的第一步，如多种抗氧化治疗，以靶向ALS中的OS。