ALL therapy and developing brains: MRI measures, genetic factors and cognition

描述（由申请人提供）：在美国，每年约有2，400名儿童和青少年被诊断患有急性淋巴细胞白血病（ALL）。目前5年总生存率为90%，因此迫切需要最大限度地减少神经毒性并改善儿童ALL幸存者的生活质量。即使消除了作为大多数ALL治疗组成部分的放射治疗，幸存者仍然受到继发于疾病和治疗的认知障碍增加的影响。虽然ALL幸存者的神经认知表现总体上似乎正常，但不成比例的幸存者在注意力（44%）和工作记忆（66%）方面表现受损。在我们先前资助的研究中，我们确定了白质脑病的患病率，并仔细描述了治疗期间MRI上明显的结构变化以及后来注意力和记忆力的神经认知缺陷。我们证明，甲氨蝶呤暴露导致1）白色损害优先在额叶和2）特定的神经认知功能障碍与额叶功能。单独的成像无法准确预测以后的神经认知缺陷。 我们现在假设，编码关键叶酸途径酶的遗传多态性介导了接受甲氨蝶呤神经毒性治疗的ALL患者的易感性。我们将前瞻性地测试以下假设：叶酸途径中的遗传多态性将在治疗早期导致神经成像表型（不同程度的髓鞘破坏），该表型可以纳入模型中，以识别那些在治疗完成时出现特定神经认知缺陷的风险最大的患者（目标1）。与甲氨蝶呤代谢的遗传差异相关的可变甲氨蝶呤毒性导致治疗过程中额叶皮质变薄的速率改变，这将导致额叶功能的神经认知测量缺陷（目的2）。髓鞘破坏和异常皮质厚度降低神经处理的效率，特别是在前额叶皮质，最终导致脑活动模式的改变和治疗诱导的认知缺陷（目的3）。我们建立在以前的研究经验，提出了一个转变的研究范式，通过发展神经认知迟发效应的风险模型，这将大大推进目前的研究，并可能临床实践，通过建立叶酸途径和额叶皮质结构和功能的遗传多态性之间的关系。

DESCRIPTION (provided by applicant): Approximately 2,400 children and adolescents are diagnosed with acute lymphoblastic leukemia (ALL) each year in the United States. The probability of 5-year overall survival is now at 90%, so there is a compelling need to minimize neurotoxicity and improve the quality of life for childhood ALL survivors. Even with the elimination of radiation therapy as a component of most ALL therapies, survivors remain subject to increased cognitive impairments secondary to disease and treatment. While neurocognitive performance for ALL survivors as a whole appears normal, a disproportionate number of survivors have impaired performance in attention (44%) and working memory (66%). In our previously funded study, we determined the prevalence of leukoencephalopathy and carefully characterized the structural changes apparent on MRI during treatment and later neurocognitive deficits in attention and memory. We demonstrated that methotrexate exposure results in 1) white matter damage preferentially in the frontal lobes and 2) specific neurocognitive deficits associated with frontal lobe functioning. Imaging alone was unable to accurately predict later neurocognitive deficits. We now hypothesize that genetic polymorphisms in the coding of key folate pathway enzymes mediate the vulnerability of patients treated for ALL to methotrexate neurotoxicity. We will prospectively test the hypothesis that genetic polymorphisms in the folate pathway will result in a neuroimaging phenotype (differing degrees of myelin disruption) early in therapy which can be incorporated into a model to identify those patients at greatest risk of developing specific neurocognitive deficits in frontal lobe functioning at completion of therapy (Aim 1). Variable methotrexate toxicity related to genetic differences in methotrexate metabolism causes altered rates of cortical thinning in frontal cortex over the course of therapy which will result in deficits in neurocognitive measures of frontal lobe functioning (Aim 2).Disrupted myelin and abnormal cortical thickness diminish the efficiency of neural processing, especially in prefrontal cortex, which leads ultimately to altered patterns of brain activity and therapy-induced cognitive deficits (Aim 3). We build upon the experience of the previous study to propose a shift in the research paradigm through development of a neurocognitive late effects risk model, which will greatly advance current research, and potentially clinical practice, by establishing the relationship between genetic polymorphisms in the folate pathway and frontal cortex structure and function.