Multimodal white matter imaging to investigate reduced fractional anisotropy and its age-related decline in schizophrenia

We hypothesized that reduced fractional anisotropy (FA) of water diffusion and its elevated aging-related decline in schizophrenia patients may be caused by elevated hyperintensive white matter (HWM) lesions, by reduced permeability-diffusivity index (PDI), or both. We tested this hypothesis in 40/30 control/patient participants. FA values for the corpus callosum were calculated from high angular resolution diffusion tensor imaging (DTI). Whole-brain volume of HWM lesions was quantified by 3D-T2w-fluid-attenuated inversion recovery (FLAIR) imaging. PDI for corpus callosum was ascertained using multi b-value diffusion imaging (15 b-shells with 30 directions per shell). Patients had significantly lower corpus callosum FA values, and there was a significant age-by-diagnosis interaction. Patients also had significantly reduced PDI but no difference in HWM volume. PDI and HWM volume were significant predictors of FA and captured the diagnosis-related variance. Separately, PDI robustly explained FA variance in schizophrenia patients, but not in controls. Conversely, HWM volume made equally significant contributions to variability in FA in both groups. The diagnosis-by-age effect of FA was explained by a PDI-by-diagnosis interaction. Post hoc testing showed a similar trend for PDI of gray mater. Our study demonstrated that reduced FA and its accelerated decline with age in schizophrenia were explained by pathophysiology indexed by PDI, rather than HWM volume.