Elevated Extracellular Free-Water in a Multicentric First-Episode Psychosis Sample, Decrease During the First 2 Years of Illness

Recent diffusion imaging studies using free-water (FW) elimination have shown increased FW in gray matter (GM) and white matter (WM) in first-episode psychosis (FEP) and lower corrected fractional anisotropy (FAt) in WM in chronic schizophrenia. However, little is known about the longitudinal stability and clinical significance of these findings.To determine tissue-specific FW and FAt abnormalities in FEP, as part of a multicenter Spanish study, 132 FEP and 108 healthy controls (HC) were clinically characterized and underwent structural and diffusion-weighted MRI scanning. FEP subjects were classified as schizophrenia spectrum disorder (SSD) or non-SSD. Of these subjects, 45 FEP and 41 HC were longitudinally assessed and rescanned after 2 years. FA and FW tissue-specific measurements were cross-sectional and longitudinally compared between groups using voxel-wise analyses in the skeletonized WM and vertex-wise analyses in the GM surface.SSD and non-SSD subjects showed (a) higher baseline FW in temporal regions and in whole GM average (P.adj((SSD vs HC)) =.003, P.adj((Non-SSD vs HC)) =.040) and (b) lower baseline FAt in several WM tracts. SSD, but not non-SSD, showed (a) higher FW in several WM tracts and in whole WM (P.adj((SSD vs HC))=.049) and (b) a significant FW decrease over time in temporal cortical regions and in whole GM average (P.adj =.011). Increased extracellular FW in the brain is a reliable finding in FEP, and in SSD appears to decrease over the early course of the illness. FAt abnormalities are stable during the first years of psychosis.