Brain Connectivity and Cognitive Flexibility in Nonirradiated Adult Survivors of Childhood Leukemia

Background: This study aimed to assess functional and structural brain connectivity in adult childhood leukemia survivors and the link with cognitive functioning and previously identified risk factors such as intrathecal methotrexate dose and age at start of therapy. Methods: Thirty-one nonirradiated adult childhood leukemia survivors and 35 controls underwent cognitive testing and multimodal magnetic resonance imaging (resting state functional MRI, T1-weighted, diffusion-weighted, and myelin water imaging [MWI]). Analyses included dual regression, voxel-based morphometry, advanced diffusion, and MWI modeling techniques besides stepwise discriminant function analysis to identify the most affected executive cognitive domain. Correlations with discrete intrathecal MTX doses and (semi)continuous variables were calculated using Spearman's rank and Pearson's correlation, respectively. All correlation tests were two-sided. Positive and negative T-contrasts in functional and structural MRI analysis were one-sided. Results: Survivors demonstrated lower functional connectivity between the default mode network (DMN) and inferior temporal gyrus (ITG; P < .008). Additionally, we observed higher fractional anisotropy (FA; P = .04) and lower orientation dispersion index (ODI; P = .008) at the left centrum semiovale, which could-given that several fiber bundles cross this region-suggest selective reduced integrity of the respective white matter tracts. Set shifting reaction time, a measure of cognitive flexibility, was mostly impaired and correlated with lower FA (r = -0.53, P = .003) and higher ODI (r = 0.40, P = .04) in survivors but not with DMN-ITG connectivity. There were no statistically significant differences between survivors and controls in WM or GM volume, nor was there a statistically significant correlation between imaging measurements and age at start of therapy or intrathecal methotrexate dose. Conclusions: Adult, nonirradiated childhood leukemia survivors show altered brain connectivity, which is linked with cognitive flexibility.