Detecting High-Dose Methotrexate-Induced Brain Changes in Pediatric and Young Adult Cancer Survivors Using [¹⁸F]FDG...

Significant improvements in treatments for children with cancer have resulted in a growing population of childhood cancer survivors who may face long-term adverse outcomes. Here, we aimed to diagnose high-dose methotrexate-induced brain injury on [¹⁸F]FDG PET/MRI and correlate the results with cognitive impairment identified by neurocognitive testing in pediatric cancer survivors. Methods: In this prospective, single-center pilot study, 10 children and young adults with sarcoma (n = 5), lymphoma (n = 4), or leukemia (n = 1) underwent dedicated brain [¹⁸F]FDG PET/MRI and a 2-h expert neuropsychologic evaluation on the same day, including the Wechsler Abbreviated Scale of Intelligence, second edition, for intellectual functioning; Delis-Kaplan Executive Function System (DKEFS) for executive functioning; and Wide Range Assessment of Memory and Learning, second edition (WRAML), for verbal and visual memory. Using PMOD software, we measured the SUV_mean, cortical thickness, mean cerebral blood flow (CBF_mean), and mean apparent diffusion coefficient of 3 different cortical regions (prefrontal cortex, cingulate gyrus, and hippocampus) that are routinely involved during the above-specified neurocognitive testing. Standardized scores of different measures were converted to z scores. Pairs of multivariable regression models (one for z scores < 0 and one for z scores > 0) were fitted for each brain region, imaging measure, and test score. Heteroscedasticity regression models were used to account for heterogeneity in variances between brain regions and to adjust for clustering within patients. Results: The regression analysis showed a significant correlation between the SUV_mean of the prefrontal cortex and cingulum and DKEFS-sequential tracking (DKEFS-TM4) z scores (P = 0.003 and P = 0.012, respectively). The SUV_mean of the hippocampus did not correlate with DKEFS-TM4 z scores (P = 0.111). The SUV_mean for any evaluated brain regions did not correlate significantly with WRAML-visual memory (WRAML-VIS) z scores. CBF_mean showed a positive correlation with SUV_mean (r = 0.56, P = 0.01). The CBF_mean of the cingulum, hippocampus, and prefrontal cortex correlated significantly with DKEFS-TM4 (all P < 0.001). In addition, the hippocampal CBF_mean correlated significantly with negative WRAML-VIS z scores (P = 0.003). Conclusion: High-dose methotrexate-induced brain injury can manifest as a reduction in glucose metabolism and blood flow in specific brain areas, which can be detected with [¹⁸F]FDG PET/MRI. The SUV_mean and CBF_mean of the prefrontal cortex and cingulum can serve as quantitative measures for detecting executive functioning problems. Hippocampal CBF_mean could also be useful for monitoring memory problems.