Identifying markers of abnormal neurocognitive trajectories during chemotherapy treatment of childhood acute lymphoblastic leukemia

识别儿童急性淋巴细胞白血病化疗期间异常神经认知轨迹的标志物

• 批准号: 10516474
• 负责人: Ellen van der Plas
• 金额: $ 47.53万
• 依托单位: ARKANSAS CHILDREN'S HOSPITAL RES INST
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10516474
• 关键词: 6 year old; Acute Lymphocytic Leukemia; Address; Affect; Age; Anterior; Behavior; Biological Assay; Brain; Brain Injuries; Cerebrospinal Fluid; Child; Childhood Acute Lymphocytic Leukemia; Clinical; Continuance of life; Data; Development; Diagnosis; Diffusion Magnetic Resonance Imaging; Etiology; Evaluation; Executive Dysfunction; Exhibits; Exposure to; Functional Magnetic Resonance Imaging; Future; Glial Fibrillary Acidic Protein; Growth; Life; Light; Link; Long-Term Survivors; Longitudinal Studies; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Malignant Childhood Neoplasm; Malignant Neoplasms; Measures; Medicine; Mental Processes; Metabolic; Metabolism; Methotrexate; Morbidity - disease rate; Myelin; Neurocognitive; Neurocognitive Deficit; Neuroglia; Neuropsychology; Neurosciences; Newly Diagnosed; Nursery Schools; Oligodendroglia; Outcome; Parents; Participant; Patients; Phenotype; Pilot Projects; Population; Prevention; Process; Prospective Studies; Quality of life; Reporting; Research; Rest; Sampling; Survival Rate; Survivors; Technology; Ubiquitin; Work; active method; axon injury; base; brain abnormalities; brain volume; cancer therapy; chemotherapy; cognitive neuroscience; design; digital; early childhood; efficacious intervention; executive function; frontal lobe; high risk; insight; kindergarten; leukemia; leukemia treatment; longitudinal design; mental function; myelination; neurochemistry; neurodevelopment; neurofilament; neuroimaging; neuroprotection; neurotoxic; neurotoxicity; peer; prospective; rate of change; remediation; screening; single molecule; stressor; success; survivorship; tau Proteins; white matter

PROJECT SUMMARY Childhood acute lymphoblastic leukemia (ALL) was uniformly fatal prior to the 1960s. Survival rates today approach 95%, making ALL one of medicine's great success stories. As the number of survivors across the US has increased, the focus of research has shifted to life after cancer. Research in ALL survivors has highlighted problems in executive functions, representing mental functions governed by the frontal lobes. Most patients will be cured prior to entering kindergarten, meaning that these neurocognitive problems potentially create a lifetime burden. Indeed, research in long-term survivors of ALL show that neurocognitive difficulties affect scholastic and vocational success, creating a profound and long-lasting burden on quality of life. While survivorship issues are well-documented, research in young patients undergoing treatment is lagging. Our plan to assess neurodevelopmental changes in patients during treatment will help pinpoint the timing and extent of neurotoxic exposures in children treated for ALL, providing tangible opportunities to implement strategies of remediation and prevention. The overall objective of this proposal is to identify markers of altered neurocognitive development in ALL patients. We recently piloted a prospective study where young ALL patients completed neurocognitive evaluations and non-sedated neuroimaging on two occasions occurring at a 6-month interval. Preliminary outcomes highlighted the importance of evaluating growth trajectories in gaining insights into the etiology of neurocognitive morbidity. In our pilot study decrements in executive functions (EF) were observed. We also observed that frontal white matter growth was substantially slower in ALL patients relative to peers. And finally, increased concentrations of neurofilament light, which is a marker of axonal damage, was associated with a slower rate of change in frontal white matter volume in ALL patients. Based on our groundwork results, we propose to evaluate early markers of abnormal neurodevelopmental trajectories in ALL patients undergoing active treatment. We will employ a longitudinal design where newly diagnosed ALL patients between the ages of 3-6 years old (n=30) will be compared to controls (n=30). Leveraging the power of a within-subject design, participants will be assessed on three occasions occurring at major treatment milestones (180 observations total). Using validated cognitive neuroscience paradigms, we will identify changes in discrete aspects of executive function for aim 1. Non-sedated structural and functional neuroimaging will be used for the work proposed under aim 2 to evaluate changes in brain volume, connectivity, and metabolism. Lastly, we will utilize ultrasensitive digital assays for quantifying neurochemical markers of brain injury in ALL patients. Results from this work will have impactful implications for understanding early neurodevelopmental changes in children undergoing treatment for ALL, providing a framework for subsequent studies linking early markers to neurocognitive outcomes in survivorship. Gaining insight into early neurodevelopmental change is invaluable for future efforts aimed at curbing neurotoxicity of cancer treatment.

项目摘要 儿童急性淋巴细胞白血病（ALL）在20世纪60年代之前是一致致命的。今天的存活率 接近95%，使所有的医学的伟大的成功故事之一。美国各地的幸存者人数 随着癌症的增加，研究的重点已经转移到癌症后的生活。对所有幸存者的研究强调， 执行功能的问题，代表由额叶控制的心理功能。大多数患者将 在进入幼儿园之前被治愈，这意味着这些神经认知问题可能会造成一生的痛苦。 负担事实上，对ALL长期幸存者的研究表明，神经认知障碍影响学业和心理健康。 职业成功，对生活质量造成深刻而持久的负担。虽然生存问题是 对接受治疗的年轻患者进行的研究记录良好，但却滞后了。我们的评估计划 治疗期间患者的神经发育变化将有助于确定神经毒性的时间和程度， 接受ALL治疗的儿童暴露，为实施补救战略提供切实机会 和预防这项建议的总体目标是确定改变神经认知发展的标志物 全组我们最近进行了一项前瞻性研究，年轻的ALL患者完成了神经认知 评价和非镇静神经成像两次发生在6个月的时间间隔。初步 结果强调了评估生长轨迹在深入了解疾病病因方面的重要性。 神经认知疾病在我们的初步研究中，观察到执行功能（EF）的下降。我们也 观察到ALL患者的额叶白色物质生长相对于同龄人明显较慢。最后， 神经丝光的浓度增加，这是轴突损伤的标志， ALL患者额叶白色体积变化速率较慢。根据我们的基础研究结果，我们 建议评估接受ALL治疗的患者中异常神经发育轨迹的早期标志物， 积极治疗。我们将采用纵向设计，其中年龄段之间的新诊断ALL患者 将3-6岁儿童（n=30）与对照组（n=30）进行比较。利用主题内设计的力量， 将在主要治疗里程碑发生的三个场合对参与者进行评估（180个观察结果 共计）。使用经过验证的认知神经科学范式，我们将识别 目标1的执行职能。非镇静结构和功能神经成像将用于这项工作 在目标2下提议评估脑容量、连通性和新陈代谢的变化。最后，我们将利用 用于定量ALL患者脑损伤的神经化学标志物的超灵敏数字分析。结果 这项工作将对理解儿童早期神经发育变化产生重要影响。 正在接受ALL治疗，为随后的研究提供了一个框架， 神经认知结果的影响。对早期神经发育变化的深入了解对于 未来的努力旨在遏制癌症治疗的神经毒性。