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

描述(申请人提供)：在美国，每年约有2400名儿童和青少年被诊断为急性淋巴细胞白血病(ALL)。5年总存活的概率现在为90%，因此迫切需要将神经毒性降至最低，并提高儿童所有幸存者的生活质量。即使消除了放射治疗作为大多数治疗的一个组成部分，幸存者仍然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作为一个整体看起来是正常的，但不成比例的幸存者在注意力(44%)和工作记忆(66%)方面的表现受到了损害。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注意力和记忆的神经认知障碍。我们证明，甲氨蝶呤暴露会导致1)白质损害，优先发生在额叶，2)与额叶功能相关的特定神经认知缺陷。仅靠成像无法准确预测以后的神经认知缺陷。我们现在假设，关键叶酸途径酶编码的遗传多态介导了接受ALL治疗的患者对甲氨蝶呤神经毒性的易感性。我们将前瞻性地测试这一假设，即叶酸途径中的基因多态将导致治疗早期的神经成像表型(不同程度的髓鞘破坏)，该表型可以被纳入一个模型，以识别那些在治疗完成时在额叶功能中发展特定神经认知缺陷的风险最大的患者(目标1)。甲氨蝶呤毒性与甲氨蝶呤代谢的遗传差异有关，在治疗过程中导致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(目标2)。髓鞘紊乱和皮质异常厚度降低神经处理的效率，特别是在前额叶皮质，这最终导致大脑活动模式的改变和治疗导致的认知障碍(目标3)。我们在前一项研究的基础上，通过开发神经认知后效风险模型来建议研究范式的转变，这将通过建立叶酸途径的遗传多态与额叶皮质结构和功能之间的关系，极大地促进当前的研究，并潜在地促进临床实践。

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.