Repairing Myelin After Irradiated Pediatric Brain Tumor: A Magnetization Transfer Imaging Analysis

BACKGROUND: While exercise training and metformin treatment have demonstrated preliminary cognitive improvements in pediatric brain tumor (PBT) survivors, the neuronal mechanisms underlying their cognitive improvements are unclear. Diffusion-weighted metrics (e.g., fractional anisotropy [FA]) are commonly used to evaluate remyelination, but magnetization transfer imaging is thought to be more sensitive to myelin plasticity. METHODS: We compared white matter changes after exercise and metformin interventions by evaluating magnetization transfer ratio (MTR) and FA changes in irradiated PBT survivors who completed either an exercise (NCT01944761) or metformin pilot trial (NCT02040376) (30 participants: exercise n = 11, metformin n = 12, and control n = 7). Then, we explored correlations between MTR and cognitive outcomes. RESULTS: There were significant MTR changes in three brain regions (right forceps minor in both interventions, right inferior and superior longitudinal fasciculi in the exercise group), but no significant FA changes. MTR increases occurred in the right forceps minor in the exercise and metformin groups compared with the control group (p < 0.033), and in the superior longitudinal fasciculus in the exercise group compared with the control group (p = 0.016). Preliminary correlations between MTR and cognitive changes were not significant after correcting for multiple comparisons. CONCLUSIONS: Our results suggest that 12 weeks of exercise or metformin intervention may promote remyelination in PBT survivors in brain regions involved in memory and executive function, and there may be differences in the brain regions affected by each intervention. This work sets the stage for larger clinical trials to identify definitive differences in MTR and validate their association with cognition.