Markers of Cognitive Decline During Treatment for Childhood ALL

 描述（由申请人提供）：急性淋巴细胞白血病（ALL）的长期存活者经常表现出可测量的认知功能缺陷，这是由于强化治疗性化疗的神经毒性所致。赤字的发生率超过兄弟姐妹和年龄匹配的对照组，对学校和职业表现产生负面影响，并降低生活质量。开发临床试验以测试保护性干预措施取决于首先确定那些最容易在白血病治疗期间和之后经历治疗诱导的认知功能障碍的受试者。该提案采取了一种新的方法来克服这一障碍。本研究的主要目的是确定特定治疗诱导的认知功能下降的标志物，以区分在完成治疗后几年中表现出认知缺陷的风险最大的儿童。为此，我们将使用基于计算机的非侵入性认知评估来记录治疗早期多个特定时间点（目标1）治疗诱导的神经认知功能变化，并将工作记忆、联想学习、和执行功能对从相同患者收集的脑脊液中生物标志物变化的影响（目的2）该项目的结果将使我们能够识别在治疗早期经历认知功能亚临床变化的患者，并将其与生物标志物联系起来，从而揭示潜在的病理生理学。这一贡献是重要的，因为如果神经认知功能的亚临床变化可以在治疗的早期阶段得到可靠的证明，并与治疗结束后的认知功能缺陷有关，那么就有可能测试专门针对治疗后持续认知缺陷风险增加的儿童的预防策略。因此，预计这些结果将产生积极的影响，因为它们将为改善癌症治疗的治疗指数提供基础，并可能指导旨在减少白血病治愈性治疗永久负担的保护性干预措施的临床试验。

 DESCRIPTION (provided by applicant): Long-term survivors of acute lymphoblastic leukemia(ALL) frequently demonstrate measurable deficits in cognitive functioning due to neurotoxicity of intensive, curative chemotherapy. Deficits occur at rates exceeding siblings and age-matched controls, negatively impacting school and occupational performance, and diminishing quality of life. Development of clinical trials to test protective interventions is dependent upon first identifying those subjects who are most vulnerable to experiencing treatment-induced cognitive dysfunction, both during and after treatment for leukemia. This proposal takes a novel approach to overcome this obstacle. The main objective of this research is to identify markers of specific treatment-induced decline in cognitive functions to differentiat children who are at greatest risk for exhibiting cognitive deficits in the years following completin of treatment. To do this, we will use non-invasive computer-based cognitive assessments to document treatment-induced changes in neurocognitive functioning at multiple specific time points during the early phases of therapy (Aim 1) and link the measured changes in working memory, associative learning, and executive functions to changes in biomarkers within cerebrospinal fluid collected from the same patients (Aim 2).The results of this project will enable us to identify patients experiencing subclinical changes in cognitive function early in therapy, and link them to biomarkers that will shed light on the underlying pathophysiology. This contribution is significant because if subclinical changes in neurocognitive function can be reliably demonstrated during the early stages of therapy, and linked to deficits in cognitive function after the conclusion of therapy, it would be possible to test preventive strategies specifically targeting those children at increased risk for persistent cognitive deficits post-treatment. The results are thus expected to have a positive impact because they will provide the foundation to improve the therapeutic index of cancer therapy, and potentially guide clinical trials of protective interventions aimed at reducing the permanent burdens of curative treatment for leukemia.