Characterization of Extracellular Free Water Pathologies in Schizophrenia Using Multi-Site Diffusion MRI Harmonization

Abstract Studies applying Free Water Imaging have consistently reported significant global increases in extracellular FW in populations of individuals with early psychosis. However, these published studies focused on homogenous clinical participant groups (e.g., only first episode or chronic), thereby limiting our understanding of the time course of free water (FW) elevations across illness stages. Moreover, the relationship between FW and duration of illness has yet to be directly tested. Leveraging our multi-site diffusion magnetic resonance imaging(dMRI) harmonization approach, we analyzed dMRI scans collected by 12 international sites from 441 healthy controls and 434 individuals diagnosed with schizophrenia-spectrum disorders who represent different illness stages and ages (15–58 years). We characterized the pattern of age-related FW changes by assessing whole brain white matter in individuals with schizophrenia and healthy controls. Quadratic and non-parametric curves were used to model between-group FW differences in averaged whole brain white matter. In individuals with schizophrenia, whole brain FW was higher than in controls across all ages, with the greatest FW values observed from 15 to 23 years of age (effect size range= [0.70-0.87]). Following this peak, FW exhibited a monotonic decrease until reaching a minima at the age of 39 years. After 39 years of age, an attenuated monotonic increase in FW was observed, but with markedly lower effect sizes when compared to younger patients (effect size range = [0.32-0.43]). Importantly, FW was found to be negatively associated with duration of illness in schizophrenia (p=0.006), independent of the effects of age. In summary, our study finds in a large, age-diverse sample that participants with schizophrenia with a shorter duration of illness showed higher FW values compared to participants with more prolonged illness. Our findings indicate that FW might be a reliable imaging marker of acute, extracellular processes which appear to occur predominantly in the early stages of schizophrenia.