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: 8463181
• 负责人: HIROSHI MITSUMOTO
• 金额: $ 62.48万
• 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 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8463181
• 关键词: 8-Oxo-2' -Deoxyguanosine; Accounting; Affect; Alcohol consumption; Amyotrophic Lateral Sclerosis; Animal Model; Antioxidants; Behavior; Benign; Biological; Biological Assay; Biological Markers; Blood; Cessation of life; Clinical; Clinical Research; Clinical assessments; Cohort Studies; Consumption; Controlled Study; Coupled; DNA Adducts; Data; Diagnosis; Diet; Dietary Factors; Disease; Disease Progression; Enrollment; Environmental Risk Factor; Epidemiologic Methods; Epidemiologic Studies; Epidemiology; Exposure to; Food; Frontotemporal Dementia; Funding; Funding Mechanisms; Grant; Growth; Hazard Models; High Density Lipoproteins; Hobbies; Human; Impaired cognition; Injury; Interview; Investigation; Isoprostanes; LDL Cholesterol Lipoproteins; Leisure Activities; Link; Lipid Peroxidation; Lipids; Low-Density Lipoproteins; 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; disorder subtype; follow-up; functional status; hazard; indexing; isoprostaglandin F2alpha type-III; lifestyle factors; outcome forecast; prospective; 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.

描述（由首席研究者提供）：肌萎缩性侧索硬化症（ALS）是一种毁灭性的，迅速致命的神经退行性疾病，这在很大程度上未知原因。它的特征是进行性骨骼肌瘫痪和最终的呼吸衰竭，症状发作后的平均存活约为40个月。没有前瞻性调查试图确定哪些因素加速或缓慢的疾病进展。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有关，并且这些因素会产生氧化应激（OS）。我们假设这些外部因素在整个疾病过程中起作用，从而产生不同水平的OS，从而影响疾病的进展。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。我们特别针对：1。确定通过问卷或生物标志物测量的增加OS的标记是否与ALS的进展有关。 ALS的进展将通过每3至6个月的广泛使用且验证良好的ALS功能量表（ALSFRS-R）确定24个月。在基线和随访中，我们将获得OS生物标志物（尿尿15-F2T-异丙烷和8-氧氧化鸟苷，血浆寄生虫I [PON1]水平和PON1功能状态）以及结构化的访谈，与当前环境，心理，饮食，饮食和生物因素相关的措施。 2。检查OS生物标志物，OS指数和ALS患者存活之间的关联。将根据外部因素的总和制定OS指数（Goodman等，2007）。在赠款期间，通过使用国家死亡指数数据，将在ALS中心进行生存。我们将测试由指数和生物标志物衡量的增加和继续OS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有关； 4。通过ALSFRS-R和存活率衡量脂质谱与ALS进展之间的关联。正如最近报道的那样，将在几个时间点分析脂质，以确定高胆固醇和LDL是否与更长的生存有关（Dupuis等人，2008年）。 5。在探索性分析中，确定OS标记和暴露是否与ALS的不同亚型相关，例如Bulbar-或脊柱发作的ALS，以及具有或没有额叶痴呆症（FTD）的ALS。据我们所知，这是对ALS中OS的第一个前瞻性，跨学科，深入的多中心流行病学研究。我们的项目将增加对疾病预后涉及的疾病机制的理解，并且可能是迈向新的治疗方法和预防方法的第一步，例如多种抗氧化剂治疗，以靶向ALS中的氧化应激部位。

项目成果

Nuclear localization of SMN and FUS is not altered in fibroblasts from patients with sporadic ALS.

• DOI: 10.3109/21678421.2014.907319
• 发表时间: 2014-12
• 期刊: Amyotrophic lateral sclerosis & frontotemporal degeneration
• 影响因子: 2.8
• 作者: Kariya S;Sampson JB;Northrop LE;Luccarelli CM;Naini AB;Re DB;Hirano M;Mitsumoto H
• 通讯作者: Mitsumoto H

Lipidomics study of plasma from patients suggest that ALS and PLS are part of a continuum of motor neuron disorders.

• DOI: 10.1038/s41598-021-92112-3
• 发表时间: 2021-06-30
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Area-Gomez E;Larrea D;Yun T;Xu Y;Hupf J;Zandkarimi F;Chan RB;Mitsumoto H
• 通讯作者: Mitsumoto H

Corrigendum to "Longitudinal Screening Detects Cognitive Stability and Behavioral Deterioration in ALS Patients".

“纵向筛查检测 ALS 患者认知稳定性和行为恶化”的勘误表。

• DOI: 10.1155/2019/6704740
• 发表时间: 2019
• 期刊: Behavioural neurology
• 影响因子: 2.8
• 作者: Woolley,Susan;Goetz,Ray;Factor-Litvak,Pam;Murphy,Jennifer;Hupf,Jonathan;Garofalo,DianaC;Lomen-Hoerth,Catherine;Andrews,Howard;Heitzman,Daragh;Bedlack,Richard;Katz,Jonathan;Barohn,Richard;Sorenson,Eric;Oskarsson,Bjorn;Filho,Am
• 通讯作者: Filho,Am