Childhood Leukemia: Oxidative Stress, Cognitive Changes & Academic Outcomes

儿童白血病：氧化应激、认知变化

• 批准号: 7652094
• 负责人: Ida Marie, DNSc Moore
• 金额: $ 55.94万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-15 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7652094
• 关键词: 12 year old; 15 year old; 5 year old; Acute Lymphocytic Leukemia; Acute leukemia; Address; Adolescent; Adverse effects; Age; Antioxidants; Area; Biological; Brain; Cancer Survivorship; Cells; Central Nervous System Diseases; Ceramides; Child; Childhood Acute Lymphocytic Leukemia; Childhood Leukemia; Children' s Oncology Group; Clinical Trials Cooperative Group; Cognitive; Cognitive deficits; Diagnosis; Diagnostic; Disease-Free Survival; Dose; Education; Employment Opportunities; Enrollment; F2-Isoprostanes; Funding; Future; Gender; Goals; Hippocampus (Brain); Impaired cognition; Impairment; Incidence; Injury; Intervention; Intravenous; Knowledge; Lead; Learning; Lecithin; Life; Literature; Long-Term Survivors; Malignant Childhood Neoplasm; Malignant Neoplasms; Maternal Age; Measures; Methotrexate; Modeling; Motor Skills; NIH Program Announcements; Neuraxis; Organ; Outcome; Oxidative Stress; Pathology; Pattern; Persons; Pharmaceutical Preparations; Reading; Reporting; Research; Sampling; Short-Term Memory; Site; Spinal Puncture; Survivors; Testing; Therapeutic; Time; Tissues; Treatment Protocols; United States; Visuospatial; Vocabulary; base; brain tissue; cancer diagnosis; central nervous system injury; chemotherapy; cognitive change; comparative efficacy; experience; improved; leukemia; longitudinal design; motor learning; neuropsychological; prevent; programs; prospective; public health relevance; response; standardize measure; therapy design; visual motor; white matter

DESCRIPTION (provided by applicant): Acute lymphoblastic leukemia (ALL) is the most prevalent cancer among children and adolescents less than 15 years of age. Central nervous system (CNS) treatment with intrathecal and intravenous methotrexate is an essential part of ALL therapy because the brain is a sanctuary site for leukemia cells. Despite the importance of CNS treatment for long-term disease-free survival, declines in academic abilities, especially math and reading have been reported. Our preliminary findings demonstrate declines in specific cognitive abilities during the first two years of CNS treatment, while declines in academic abilities are evident after 3 years of treatment. Early changes in specific cognitive abilities may be important predictors of academic outcomes. Methotrexate increases oxidative stress in several organs, including the brain. White matter and the hippocampus are known to be vulnerable to oxidative stress, and are important for cognitive abilities, such as working memory, learning, visual-spatial and visual-motor skills. Oxidative stress as a mechanism of methotrexate-induced CNS injury that may lead to cognitive declines and academic outcomes has not been studied. The long-term goal is to increase knowledge about mechanisms of methotrexate-induced CNS injury, and to develop interventions that will prevent or minimize tissue damage, cognitive declines, and academic problems that are significant challenges for long-term survivors of childhood ALL. The purpose is to explicate relationships among oxidative stress, cognitive abilities, and academic outcomes among children with ALL who receive aggressive CNS treatment with methotrexate. Specific Aims are to: 1. Describe changes in oxidative stress during CNS treatment with methotrexate. 2. Describe changes in cognitive abilities during CNS treatment with methotrexate. 3. Describe relationships among oxidative stress, cognitive abilities, and academic outcomes. A prospective longitudinal design enrolling 80 children with ALL between 3 and 12 years of age will be used. Verbal and non-verbal cognitive abilities will be assessed within 1 month after diagnosis, and then annually for 3 years. Academic abilities will be assessed 3 years after ALL diagnosis. CSF samples will be obtained during diagnostic and therapeutic lumbar punctures for measuring oxidative stress. Aims 1 and 2 will be addressed using mixed model ANOVAs. Aim 3 will be addressed using correlations and multiple regression. Ancillary analyses will be conducted to describe the potential influence of covariates (total amount of methotrexate received, subject gender and age, and maternal education) on oxidative stress, cognitive abilities, and academic outcomes. This is the first study of oxidative stress as a mechanism of methotrexate-induced CNS injury that could be associated with early declines in cognitive abilities and academic outcomes among children with ALL. Findings will provide the basis for future studies of biological and cognitive interventions designed to prevent or minimize CNS tissue injury, and improve cognitive abilities and academic outcomes among the ever increasing number of long-term survivors of childhood leukemia. Public Health Relevance: Acute leukemia is the most common cancer among children in the United States. Curative therapy requires treating the brain with chemotherapy which frequently results in devastating effects on learning, academic abilities and employment opportunities for leukemia survivors. This study will increase knowledge about how chemotherapy damages normal brain tissue, and determine if this damage leads to the cognitive and academic problems experienced by children with leukemia.

描述（由申请人提供）：急性淋巴细胞性白血病（全）是小于15岁的儿童和青少年中最普遍的癌症。中枢神经系统（CNS）用鞘内和静脉内甲氨蝶呤治疗是所有疗法的重要组成部分，因为大脑是白血病细胞的避难所。尽管中枢神经系统治疗对于长期无疾病生存至关重要，但据报道，学术能力的下降，尤其是数学和阅读。我们的初步发现表明，在中枢神经系统治疗的头两年中，特定的认知能力下降，而经过3年的治疗后，学术能力的下降是显而易见的。特定认知能力的早期变化可能是学术成果的重要预测指标。甲氨蝶呤会增加包括大脑在内的多个器官中的氧化应激。已知白质和海马容易受到氧化应激的影响，并且对于认知能力，例如工作记忆，学习，视觉空间和视觉运动技能很重要。氧化应激作为甲氨蝶呤诱导的中枢神经系统损伤的机制，可能导致认知能力下降，并且尚未研究学术结果。长期的目标是增加有关甲氨蝶呤诱导的中枢神经系统损伤机制的知识，并开发干预措施，以防止或最大程度地减少组织损害，认知能力下降以及对童年长期幸存者的重大挑战的学术问题。目的是说明所有接受甲氨蝶呤的侵略性中枢神经系统治疗的儿童之间氧化应激，认知能力和学术成果之间的关系。具体目的是：1。描述用甲氨蝶呤处理中CNS治疗期间氧化应激的变化。 2。描述甲氨蝶呤治疗中枢神经系统治疗期间认知能力的变化。 3。描述氧化压力，认知能力和学术成果之间的关系。将使用一个预期的纵向设计，其中包括80名年龄在3至12岁之间的儿童。口头和非语言认知能力将在诊断后的1个月内进行评估，然后每年3年。所有诊断后3年将评估学术能力。在测量氧化应激的诊断和治疗性腰椎穿刺期间，将获得CSF样品。目标1和2将使用混合模型方差分析来解决。 AIM 3将使用相关和多重回归解决。将进行辅助分析，以描述协变量（甲氨蝶呤总数，受试者性别和年龄以及孕产妇教育）对氧化压力，认知能力和学术成果的潜在影响。这是氧化应激作为甲氨蝶呤诱导的中枢神经系统损伤机制的首次研究，可能与所有人的认知能力和学术成果的早期下降有关。研究结果将为未来研究旨在预防或最大程度减少中枢神经系统组织损伤的生物学和认知干预措施的研究提供基础，并在不断增加的儿童白血病长期幸存者中提高认知能力和学术成果。公共卫生相关性：急性白血病是美国儿童中最常见的癌症。治疗疗法需要对大脑进行化学疗法治疗，这通常会对白血病幸存者的学习，学术能力和就业机会产生毁灭性影响。这项研究将增加有关化学疗法如何损害正常脑组织的知识，并确定这种损害是否导致白血病儿童遇到的认知和学术问题。