Neuroimaging to Assess the Effects of Therapy in Children with Acute Lymphoblasti

描述(申请人提供)：急性淋巴细胞白血病(ALL)儿童预后相对较好，但治疗可能会对生长发育产生巨大影响，包括对中枢神经系统(CNS)的影响。这反过来会影响学习成绩和神经认知功能，但所有治疗和认知缺陷之间的关系还没有被很好地理解。由于被诊断为ALL的儿童通常立即开始治疗，因此在治疗前往往很难评估认知功能。如果神经认知缺陷在生命后期被发现，目前还不清楚是否发生了与治疗相关的中枢神经系统损伤，而且往往为时已晚，无法采取适当的干预措施。这项建议旨在评估中枢神经系统的结构和化学；以及治疗开始后(6周)和12个月后的认知表现。这项研究填补了儿童肿瘤学小组(COG；www.Childrensoncologygroup.org)目前的一项研究AALL06N1(AALL06N1)(AALL06N1)，这是一项针对高危B细胞和T细胞ALL儿童的研究，但患有标准和中等风险ALL的幼儿(3-6岁)都被排除在研究之外。因此，拟议的项目通过研究患有标准和中等风险疾病的3-6岁儿童弥合了一个重要的差距，这些儿童面临中枢神经系统毒性的风险。使用高分辨率结构磁共振成像(HRS-MRI)、磁共振波谱(MRS)和扩散张量成像(DTI)可以在发现认知功能异常之前检测到中枢神经系统结构和代谢的早期变化。由Linda Chang博士和Thomas Ernst博士领导的研究正在成功地在患有其他疾病的3-6岁儿童中进行，使用非侵入性的先进磁共振技术，包括HRS-MRI、MRS和DTI，而无需有意识的镇静，这在这个时代很重要。我们的目标是确定ALL儿童早期结构、化学和功能方面的中枢神经系统变化，长期目标是开发干预措施来预防晚期神经认知后遗症和改善预后。我们的目标是：1)在开始化疗的6周内和首次扫描后12个月，使用高分辨率MRI、质子MRS和DTI来确定化疗对ALL儿童大脑的影响；2)表征ALL在基线和12个月时因化疗而发生的神经认知功能的变化；3)评估MR扫描异常与神经认知测试发现的认知缺陷的关系；以及4)测量儿童线粒体DNA水平，并评估其与微小残留病、神经认知测试和脑代谢物水平的关系。其意义在于，在注意到认知异常之前，使用敏感的工具(MRS和DTI)来检测早期中枢神经系统变化的可能性；并可能改善原本不符合开放COG研究条件的儿童的发病率。这项建议是创新的，因为该项目利用了Ernst和Chang博士在神经成像领域的专业知识，在不使用镇静的情况下捕获幼儿的数据，以进一步了解化疗对大脑发育的影响。公共卫生相关性：被诊断为急性淋巴细胞白血病(ALL)的儿童预后相对较好，但治疗可能会影响儿童未来的成长和发展，包括对中枢神经系统(CNS)的影响。这项建议旨在评估治疗开始后(6周)和12个月后(3-6岁)被诊断为标准和中等风险ALL的儿童的中枢神经系统结构和化学；以及认知表现。

DESCRIPTION (provided by applicant): Children with acute lymphoblastic leukemia (ALL) have a relatively good prognosis, but treatment can have tremendous impacts on growth and development, including effects on the central nervous system (CNS). This in turn affects school performance and neurocognitive function, but the relationship between ALL therapy and cognitive deficits is not well understood. Because children diagnosed with ALL typically begin treatment immediately, it is often difficult to evaluate cognitive function prior to therapy. If neurocognitive deficits are recognized later in life, it is unclear if therapy-associated CNS injury occurred, and often too late to institute appropriate interventions. This proposal aims to evaluate CNS structure and chemistry; and cognitive performance, after therapy begins (<6 weeks), and 12 months later. The study fills a void of a current study in the Children's Oncology Group (COG; www.childrensoncologygroup.org), AALL06N1 (Study of Neurocognitive Function in Children Treated for ALL), which is a study for children with high-risk B- lineage and T-cell ALL, but young children (3-6 year old) with ALL with standard- and intermediate-risk ALL are excluded from the study. Therefore, the proposed project bridges an important gap by studying 3-6 year old children with ALL with standard- and intermediate-risk disease who are at risk for CNS toxicity. Use of high resolution structural MRI (HRS-MRI), magnetic resonance spectroscopy (MRS), and diffusion tensor imaging (DTI) may allow detection of early changes in CNS structure and metabolism prior to detecting abnormal cognitive function. Studies led by Drs. Linda Chang and Thomas Ernst are successfully being conducted in 3-6 year old children with other diseases, using non-invasive advanced MR techniques, including HRS-MRI, MRS, and DTI without conscious sedation, which is important in this age. Our goal is to identify early structural, chemical, and functional CNS changes in children with ALL with the long term objectives to develop interventions to prevent late neurocognitive sequelae and improve prognosis. Our Aims are: 1) To determine the effect of chemotherapy on the brain in children with ALL using high resolution MRI, proton MRS, and DTI within 6 weeks of starting chemotherapy and at 12 months after the initial scans; 2) To characterize changes in neurocognitive function from chemotherapy exposure in children with ALL at baseline and at 12-months; 3) To assess the relationship of abnormalities on MR scans with cognitive deficits identified from neurocognitive tests; and 4) To measure mitochondrial DNA levels in children and evaluate its association with minimal residual disease, neurocognitive testing, and brain metabolite levels. The significance lies in the potential of using sensitive tools (MRS and DTI) to detect early CNS changes before cognitive abnormalities are noted; and possibly improve morbidity in children who otherwise are not eligible for the open COG study. The proposal is innovative because the project utilizes expertise of Drs. Ernst and Chang in the field of neuroimaging to capture data from young children without the use of sedation to further our understanding of chemotherapy effects on developing brains. PUBLIC HEALTH RELEVANCE: Children diagnosed with acute lymphoblastic leukemia (ALL) have a relatively good prognosis, however treatment can impact a child's future growth and development, including effects on the central nervous system (CNS). This proposal aims to evaluate CNS structure and chemistry; and cognitive performance, after treatment begins (<6 weeks), and 12 months later in children (3-6 year old) with ALL diagnosed with standard- and intermediate-risk ALL.