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

描述（由申请人提供）：在美国，每年大约有2400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。即使消除了放射治疗作为大多数ALL治疗的一个组成部分，幸存者仍然会受到继发于疾病和治疗的认知障碍的增加。虽然所有幸存者的神经认知表现总体上是正常的，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。在我们之前资助的研究中，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的注意力和记忆神经认知缺陷。我们证明，甲氨蝶呤暴露导致1)白质损伤优先发生在额叶，2)与额叶功能相关的特定神经认知缺陷。单纯的成像并不能准确预测以后的神经认知缺陷。我们现在假设，关键叶酸通路酶编码的遗传多态性介导了ALL治疗患者对甲氨蝶呤神经毒性的脆弱性。我们将前瞻性地测试叶酸通路的遗传多态性将导致治疗早期的神经影像学表型（不同程度的髓磷脂破坏）的假设，该假设可以纳入一个模型，以确定那些在治疗完成时在额叶功能中发生特定神经认知缺陷风险最大的患者（目的1）。甲氨蝶呤代谢的遗传差异导致治疗过程中额叶皮质变薄率的改变，这将导致额叶功能的神经认知测量缺陷（目的2）。髓磷脂的破坏和皮质厚度的异常降低了神经处理的效率，尤其是在前额皮质，这最终导致大脑活动模式的改变和治疗引起的认知缺陷（目的3）。我们在先前研究的基础上，提出了一种研究范式的转变，通过建立神经认知晚期效应风险模型，通过建立叶酸通路遗传多态性与额叶皮质结构和功能之间的关系，将极大地推进当前的研究，并可能促进临床实践。

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.