甲氨蝶呤相关神经毒性和认知障碍的脑基础和进展仍然未知。我们测试了脑异常恶化是否与鞘内甲氨蝶呤 (IT-MTX) 剂量成比例。在这项前瞻性纵向研究中，我们招募了 19 名新诊断的 4 至 20 岁急性淋巴细胞白血病患者和 20 名匹配的对照者。我们收集了甲氨蝶呤治疗前基线以及治疗期间第 9 周、第 22 周和第 1 年的 MRI 和神经心理学评估。患者的皮质和皮质下灰质 (GM)、白质 (WM) 体积和微观结构、区域性基线异常。脑血流量和神经元密度。 GM、血流和代谢物的异常恶化与 IT-MTX 剂量成正比。 WM 异常持续到第 22 周，但到第 1 年就恢复正常。脑损伤局限于背侧和腹侧注意力以及额顶认知网络。患者在基线时存在认知缺陷，并在 1 年随访中持续存在。基线异常可能是神经炎症和氧化应激的结果。 WM 微观结构和体积以及血流的基线异常持续到第 22 周，但到第 1 年就恢复正常，这可能是由于治疗及其对减少炎症的影响。然而，IT-MTX 的细胞毒性作用可能导致皮层持续、进行性变薄和神经元密度减少，从而导致持久的认知缺陷。甲氨蝶呤治疗前基线的大脑异常可能是由于急性疾病所致。鞘内注射 MTX 的细胞毒性作用会导致皮层逐渐变薄、神经元密度降低和持久的认知缺陷。通过甲氨蝶呤治疗和减少神经炎症，基线白质异常可能已正常化。皮质类固醇和亚叶酸具有神经保护作用。我们的研究结果表明，神经保护剂和抗炎剂的施用甚至应该比目前的施用更早考虑。亚叶酸的神经保护作用表明，可以制定策略来延长这种干预的持续时间或调整其用于标准风险患者。© 2024。作者。

Brain bases and progression of methotrexate-associated neurotoxicity and cognitive disturbances remain unknown. We tested whether brain abnormalities worsen in proportion to intrathecal methotrexate(IT-MTX) doses.In this prospective, longitudinal study, we recruited 19 patients with newly diagnosed acute lymphoblastic leukemia 4-to-20 years of age and 20 matched controls. We collected MRI and neuropsychological assessments at a pre-methotrexate baseline and at week 9, week 22, and year 1 during treatment.Patients had baseline abnormalities in cortical and subcortical gray matter(GM), white matter(WM) volumes and microstructure, regional cerebral blood flow, and neuronal density. Abnormalities of GM, blood flow, and metabolites worsened in direct proportions to IT-MTX doses. WM abnormalities persisted until week 22 but normalized by year 1. Brain injuries were localized to dorsal and ventral attentional and frontoparietal cognitive networks. Patients had cognitive deficits at baseline that persisted at 1-year follow-up.Baseline abnormalities are likely a consequence of neuroinflammation and oxidative stress. Baseline abnormalities in WM microstructure and volumes, and blood flow persisted until week 22 but normalized by year 1, likely due to treatment and its effects on reducing inflammation. The cytotoxic effects of IT-MTX, however, likely contributed to continued, progressive cortical thinning and reductions in neuronal density, thereby contributing to enduring cognitive deficits.Brain abnormalities at a pre-methotrexate baseline likely are due to acute illness. The cytotoxic effects of intrathecal MTX contribute to progressive cortical thinning, reductions in neuronal density, and enduring cognitive deficits. Baseline white matter abnormalities may have normalized via methotrexate treatment and decreasing neuroinflammation. Corticosteroid and leucovorin conferred neuroprotective effects. Our findings suggest that the administration of neuroprotective and anti-inflammatory agents should be considered even earlier than they are currently administered. The neuroprotective effects of leucovorin suggest that strategies may be developed that extend the duration of this intervention or adapt it for use in standard risk patients.© 2024. The Author(s).