联合多模态MRI及叶酸通路多态性分析在儿童白血病化疗后认知损害的研究

Individual difference of neurocognitive problems in survivors of childhood acute lymphoblastic leukemia (ALL) is a clinically important issue to be solved. Folate pathway gene polymorphism has been believed to play an important role in the action of chemotherapy drugs. Based on works we have done, this project focuses on the convergence of multimodal imaging phenotype and their gene polymorphism presentations, breaks through the bottleneck of multimodal imaging bio-markers and individual variability, and revolves around multimodal connectomics, brain network dynamics, structure-functional convergences and their associations with folate pathway polymorphism. Sixty childhood ALL who had finished chemotherapy more than one year, and gender-, age-, education- and socioeconomic status matched healthy controls were included. With the combination of multi-scale neurocognitive estimates, multimodal MRI brain parameters and SNPs, we will analyze the folate pathway polymorphism and its representations of multiple brain MRI parameters; explore the underlying anatomic and functional bases of the survivals of childhood ALL under the genetic risk, which will promote for individualized chemotherapy and more effective ways to deduce delayed cognitive impairments, and provide theoretical underpinnings for cognitive impairment in children with chemotherapy for other malignant tumors.

儿童期急性淋巴细胞白血病（ALL）化疗后认知损害的个体差异性机制是当前临床亟待解决的难题。已有研究提示叶酸代谢通路基因多态性与化疗药物作用的个体差异密切相关。本项目在前期研究基础上，聚焦于多模态影像表型与基因多态性表征的儿童期ALL“化疗脑”脑损害模型构建，突破多模态MR影像标记、个体差异性的研究方法瓶颈，围绕多模态MR脑连接组、网络动力学、结构-功能共变性模型的建构及叶酸通路基因多态性关联进行研究。选择儿童期ALL化疗治愈一年以上的患儿60例及性别、年龄、教育和社会经济学地位匹配的健康对照60例，联合多维度神经认知评估、多模态MR脑参数及多个单核苷酸多态性，分析叶酸通路基因多态性下多模态MR脑参数及其表征，探寻遗传风险因素影响下儿童ALL化疗后迟发认知损害的脑结构和功能基础，为推动其临床个体化治疗、有效降低化疗后认知功能的损害，为儿童因其他恶性肿瘤化疗后认知功能损害机制提供理论基础。

急性淋巴细胞白血病是儿童期最常见的恶性肿瘤。目前常用的化疗方案损伤了处于发育期的儿童的神经环路，据报道，所有儿童期急淋患者都遭受不同程度的化疗相关认知障碍。我们针对如何用多模态功能磁共振研究儿童期急淋患者化疗相关认知障碍这个热点问题进行了深入的研究。首先我们同时招募了儿童期ALL化疗治愈一年以上的患儿及性别、年龄、利手相匹配的健康对照组儿童，所有被试接受磁共振检查和神经认知功能量表检查。我们发现了 ALL经治儿童的大脑网络节点重要性和异常脑区与全脑功能连接的改变，体现局部脑区对化疗相关的各 种病理因素的易感性。随后发现ALL组存在背侧默认模式网络和腹侧默认模式网络的不同的网络内功能连接异常。上述的静息态脑网络的改变与神经认知功能量表结果相关，提示静息态磁共振可以作为一种客观的无创的检查方法为 ALL 经治儿童的脑功能变化提供更多的信息，也为预防和治疗ALL经治儿童化疗相关认知损害提供了新的思路。