Hirokawa Daisuke, Tomiyasu Moyoko, Sonoda Masaki, Suenaga Jun, Goto Hiroaki, Aida Noriko, Yamamoto Tetsuya
Department of Neurosurgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Department of Radiology, Kanagawa Children's Medical Center, Yokohama, Japan.
Pediatr Blood Cancer. 2025 Oct;72(10):e31957. doi: 10.1002/pbc.31957. Epub 2025 Jul 31.
Methotrexate (MTX)-induced leukoencephalopathy is a significant neurological complication in pediatric acute lymphoblastic leukemia (ALL) treatment. Magnetic resonance spectroscopy (MRS) is a noninvasive method to assess metabolic changes associated with neurotoxicity. This study aimed to evaluate the diagnostic and prognostic value of MRS-derived metabolite levels, particularly N-acetylaspartate and N-acetylaspartylglutamate (tNAA), in MTX-induced leukoencephalopathy.
We retrospectively analyzed 89 pediatric patients with ALL who underwent brain magnetic resonance imaging (MRI) and MRS at Kanagawa Children's Medical Center between 2009 and 2022. A total of 261 MRS datasets were examined, focusing on metabolic changes in the centrum semiovale. Using mixed logistic regression, we evaluated the association between tNAA levels and leukoencephalopathy onset, as well as their correlation with clinical recovery after MTX discontinuation.
Patients with leukoencephalopathy had significantly lower tNAA levels than those of controls. A predictive model indicated that a 1.0-point decrease in pretreatment tNAA levels was associated with an approximately 3.22-fold increase in the odds of developing MTX-induced leukoencephalopathy. Furthermore, increasing tNAA levels over time were significantly correlated with clinical improvement.
This study suggests that tNAA levels measured using MRS may serve as a potential biomarker for diagnosing and monitoring MTX-induced leukoencephalopathy. Integrating MRS into clinical assessments may represent a promising future approach to facilitate earlier intervention, inform treatment strategies, and potentially improve patient outcomes, pending validation by future prospective studies. These findings highlight the importance of MRS in the real-time evaluation of disease progression and therapeutic responses in pediatric patients undergoing MTX treatment.
甲氨蝶呤（MTX）诱导的白质脑病是小儿急性淋巴细胞白血病（ALL）治疗中一种严重的神经并发症。磁共振波谱（MRS）是一种评估与神经毒性相关代谢变化的非侵入性方法。本研究旨在评估MRS衍生的代谢物水平，特别是N-乙酰天门冬氨酸和N-乙酰天门冬氨酰谷氨酸（总NAA，tNAA）在MTX诱导的白质脑病中的诊断和预后价值。
我们回顾性分析了2009年至2022年期间在神奈川儿童医疗中心接受脑磁共振成像（MRI）和MRS检查的89例小儿ALL患者。共检查了261个MRS数据集，重点关注半卵圆中心的代谢变化。使用混合逻辑回归，我们评估了tNAA水平与白质脑病发病之间的关联，以及它们与MTX停药后临床恢复的相关性。
白质脑病患者的tNAA水平显著低于对照组。一个预测模型表明，治疗前tNAA水平每降低1.0分，发生MTX诱导的白质脑病的几率增加约3.22倍。此外，tNAA水平随时间升高与临床改善显著相关。
本研究表明，使用MRS测量的tNAA水平可能作为诊断和监测MTX诱导的白质脑病的潜在生物标志物。将MRS纳入临床评估可能代表一种有前景的未来方法，以促进早期干预、为治疗策略提供信息并可能改善患者预后，有待未来前瞻性研究验证。这些发现突出了MRS在实时评估接受MTX治疗的小儿患者疾病进展和治疗反应中的重要性。
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