Neuroimaging evaluation of high dose methotrexate-induced neurotoxicity in pediatric and young adults: a PET/MRI study

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Introduction High-dose Methotrexate (HDMTX) can induce neurotoxicity, yet its impact on brain metabolism remains underexplored. This study aimed to assess short- and long-term brain metabolic changes post-HDMTX on 18F-FDG PET/MRI relative to baseline (pre-HDMTX) scans. Methods In this IRB approved, retrospective study, we included 19 children and young adults (3 females and 16 males; age 17.9 ± 4.3 years), with lymphoma ( n = 13) or osteosarcoma ( n = 6). All patients underwent 18F-FDG PET/MRI before (baseline) and after HDMTX (>1000 mg/m 2 ). Post-treatment scans were conducted ≤3 months (short-term group, n = 11) or >3 months (long-term group, n = 8) after completion of HDMTX and were compared with baseline scans. SUVmean and SUVmax of the whole brain cortex and six subregions were measured with PMOD software. A generalized linear regression model was used to evaluate post-pre-HDMTX SUV values differences in whole cortex with p < 0.05 and for with of different brain subregions, with p < 0.008 after Bonferroni correction. Results In the short-term group, compared with baseline, both SUVmean (pre-HDMTX vs. post-HDMTX: 5.06 ± 1.62 vs. 6.31 ± 1.71, p < 0.001) and SUVmax (9.16 ± 3.33 vs. 13.25 ± 3.35, p < 0.001) significantly increased in the whole cortex following HDMTX. In contrast, the long-term group showed no significant changes in SUVmean (6.31 ± 1.71 vs. 6.30 ± 1.54, p = 0.1) or SUVmax (12.01 ± 3.53 vs. 11.58 ± 3.07, p = 0.1) after HDMTX. Discussion 18 F-FDG PET/MRI revealed short-term increases in brain metabolism post-HDMTX compared with baseline, possibly reflecting neuroinflammation. Long-term follow up scans revealed normalization of brain metabolism or decreased brain metabolism compared to baseline, the latter possibly indicating neurotoxicity.

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