Lower fractional anisotropy without evidence for neuro-inflammation in patients with early-phase schizophrenia spectrum disorders

Various lines of research suggest immune dysregulation as a potential therapeutic target for negative and cognitive symptoms in schizophrenia spectrum disorders (SSD). Immune dysregulation would lead to higher extracellular free -water (EFW) in cerebral white matter (WM), which may partially underlie the frequently reported lower fractional anisotropy (FA) in SSD. We aim to investigate differences in EFW concentrations - a presumed proxy for neuro-inflammation - between early-phase SSD patients (n = 55) and healthy controls (HC; n = 37), and to explore immunological and cognitive correlates. To increase specificity for EFW, we study several complementary magnetic resonance imaging contrasts that are sensitive to EFW. FA, mean diffusivity (MD), magnetization transfer ratio (MTR), myelin water fraction (MWF) and quantitative T1 and T2 were calculated from diffusion-weighted imaging (DWI), magnetization transfer imaging (MTI) and multicomponent driven equilibrium single -pulse observation of T1/T2 (mcDESPOT). For each measure, WM skeletons were constructed with tract-based spatial statistics. Multivariate SSD-HC comparisons with WM skeletons and their average values (i.e. global WM) were not statistically significant. In voxel-wise analyses, FA was significantly lower in SSD in the genu of the corpus callosum and in the left superior longitudinal fasciculus (p < 0.04). Global WM measures did not correlate with immunological markers (i.e. IL1-RA, IL -6, IL -8, IL -10 and CRP) or cognition in HC and SSD after corrections for multiple comparisons. We confirmed lower FA in early-phase SSD patients. However, non-FA measures did not provide additional evidence for immune dysregulation or for higher EFW as the primary mechanism underlying the reported lower FA values in SSD.