Downstate Medical Center, College of Medicine, State University of New York, Brooklyn, New York.
Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.
Neuro Oncol. 2020 Aug 17;22(8):1126-1137. doi: 10.1093/neuonc/noaa086.
With the enhanced use of chemotherapy and the advent of increased patient survival rates, there are an increasing number of cancer survivors living with chemotherapy-induced cognitive impairment. A growing number of clinical studies have brought to light the association of agents like methotrexate in generating these neurological sequelae, although mechanisms remain unclear.
Here, we use a clinically relevant regimen of several cycles of methotrexate and leucovorin rescue to develop a model of chemotherapy-induced cognitive impairment, and investigate the in vivo long-term (16 mo) impact of high-dose systemic methotrexate on white matter cellular dynamics as assessed by stereology, animal behavior, and diffusion tensor imaging.
Our results indicate that at 6 and 16 months post-chemotherapy, methotrexate-treated rats exhibit a significant and permanent decrease in the number of oligodendrocytes and their progenitors in the white matter, in corpus callosum volumes, and myelin basic protein. These findings are associated with mostly delayed deficits in performance on Morris Water Maze and Novel Object Recognition tasks. Diffusion tensor imaging demonstrates significantly decreased fractional anisotropy values in the callosum genu, body, and splenium, as well as previously unassessed areas like the fimbria. Interestingly, these white matter changes are preceded by an earlier, transient decrement in white matter microglia at 3 months, and hippocampal neural progenitors at 3 and 6 months.
These results demonstrate a significant negative impact of methotrexate on the oligodendrocyte compartment and white matter, associated with cognitive impairment. The data also support the use of diffusion tensor imaging in monitoring white matter integrity in this context.
随着化疗的广泛应用和患者生存率的提高，越来越多的癌症幸存者患有化疗引起的认知障碍。越来越多的临床研究揭示了甲氨蝶呤等药物在产生这些神经后遗症方面的作用，尽管其机制尚不清楚。
在这里，我们使用几轮甲氨蝶呤和亚叶酸钙解救的临床相关方案来开发化疗诱导的认知障碍模型，并通过体视学、动物行为和弥散张量成像来研究高剂量全身甲氨蝶呤对 16 个月的体内（16 个月）白质细胞动力学的长期影响。
我们的结果表明，在化疗后 6 个月和 16 个月，甲氨蝶呤治疗的大鼠在白质、胼胝体体积和髓鞘碱性蛋白中表现出少突胶质细胞及其前体细胞数量的显著和永久性减少。这些发现与水迷宫和新物体识别任务表现的延迟缺陷有关。弥散张量成像显示胼胝体膝部、体部和压部的分数各向异性值显著降低，以及以前未评估的区域，如穹窿。有趣的是，这些白质变化之前是 3 个月时白质小胶质细胞的早期、短暂减少，以及 3 个月和 6 个月时海马神经祖细胞的减少。
这些结果表明，甲氨蝶呤对少突胶质细胞区室和白质有显著的负面影响，与认知障碍有关。这些数据还支持在这种情况下使用弥散张量成像来监测白质完整性。
