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.

项目概要 20 世纪 60 年代之前，儿童急性淋巴细胞白血病 (ALL) 都是致命的。今天的生存率 接近 95%，使 ALL 成为医学上最伟大的成功故事之一。随着美国各地的幸存者数量 增加，研究的重点已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。大多数患者会 在进入幼儿园之前得到治愈，这意味着这些神经认知问题可能会影响一生 负担。事实上，对 ALL 长期幸存者的研究表明，神经认知困难会影响学业和学习能力。 职业成功，给生活质量造成深刻而持久的负担。虽然生存问题是 尽管证据充分，但对接受治疗的年轻患者的研究却滞后。我们的评估计划 治疗期间患者神经发育的变化将有助于确定神经毒性的发生时间和程度 接受 ALL 治疗的儿童的暴露，为实施补救策略提供了切实的机会 和预防。该提案的总体目标是确定神经认知发展改变的标志物 在所有患者中。我们最近进行了一项前瞻性研究，其中年轻的 ALL 患者完成了神经认知 每隔 6 个月进行两次评估和非镇静神经影像检查。初步的 结果强调了评估生长轨迹对于深入了解疾病病因的重要性 神经认知疾病。在我们的试点研究中，观察到执行功能（EF）的下降。我们也 观察到 ALL 患者的额叶白质生长速度明显慢于同龄人。最后， 神经丝光浓度的增加（轴突损伤的标志）与 所有患者额叶白质体积变化速度较慢。根据我们的基础工作结果，我们 建议评估接受治疗的 ALL 患者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，其中新诊断的所有年龄段的患者 将 3-6 岁的儿童 (n=30) 与对照组 (n=30) 进行比较。利用主体内设计的力量， 参与者将在主要治疗里程碑时进行 3 次评估（180 次观察） 全部的）。使用经过验证的认知神经科学范式，我们将识别以下离散方面的变化 目标 1 的执行功能。工作中将使用非镇静结构和功能神经影像 根据目标 2 提出评估大脑体积、连通性和新陈代谢的变化。最后，我们将利用 用于量化所有患者脑损伤的神经化学标记物的超灵敏数字测定。结果来自 这项工作将对理解儿童早期神经发育变化产生重要影响 接受 ALL 治疗，为后续研究提供框架，将早期标记物与 生存中的神经认知结果。深入了解早期神经发育变化对于 未来的努力旨在遏制癌症治疗的神经毒性。