Signatures of altered free-water and cognition and associations with symptom severity in psychosis spectrum disorders

Evidence suggests extracellular free-water (FW) is a potential marker of neuroinflammation. In psychosis spectrum disorders (PSD), neuroinflammation has been associated with cognition deficits, but findings are heterogeneous. Thus, we derived FW and cognition-based subgroups in PSD. PSD (n = 166) and healthy (n = 50) individuals underwent diffusion magnetic resonance imaging, cognitive testing, and clinical assessments. Canonical correlation analysis (CCA) was performed using statistically significant measures, including 8 FW regions (anterior corona radiata, body, genu, and splenium of corpus callosum, fornix/stria terminalis, inferior and superior fronto-occipital fasciculus, and superior longitudinal fasciculus) and 13 cognitive measures. Permutation testing and cross validation quantified CCA significance and reliability. PSD subgroups were identified by hierarchical clustering of CCA projections. Random sampling and bootstrapping assessed clustering significance and reliability. Analysis of variance, general linear models, and Cohen's effect sizes tested for differences between groups. The false discovery rate corrected for multiple comparisons. The first latent variate (r = 0.45) identified two clusters: cluster 1 demonstrated lower FW (n = 110, 66%) while cluster 2 showed higher FW (n = 56, 34%). Both displayed cognitive deficits compared to controls. Cluster 2 showed greater FW in all regions tested (p < 0.05), exhibited cognitive impairment across multiple cognitive domains (p < 0.01), and higher depressive, manic, general and total psychosis symptoms (p < 0.05) compared to cluster 1. However, they did not differ with regard to medication, functioning, or potential inflammatory confounds. Results support previous research indicating that a high neuroinflammatory subgroup of PSD exists and is related to cognition and brain structure, but the translational impact remains to be determined.