A frontotemporal free water signature associated to interleukin-8 and cognitive impairment in schizophrenia with comorbidity of metabolic syndrome

Neuroimmune hypothesis posits that inflammation plays a key role in shared neurobiological substrate responsible for the comorbidity between schizophrenia and metabolic syndrome (MS). However, the specific neural mechanisms by which inflammation contributes to this comorbidity remain elusive. This study investigated whether inflammation-related brain microstructural alterations were associated with this comorbidity and its concomitant cognitive deficits. We utilized multi-site data from independent centers. Applying the two-factor experimental design, a total of 398 participants were included and categorized into four groups based on diagnoses of schizophrenia and MS: schizophrenia patients with/without metabolic syndrome (SZ-wMS and SZ-nMS), and healthy controls with/without metabolic syndrome (HC-wMS and HC-nMS). By leveraging diffusion and structural magnetic resonance imaging, free water (FW) was estimated to quantify the microstructure in cerebral gray matter. Clinical assessments included peripheral inflammatory cytokines and cognitive function tests. Interaction effects of schizophrenia and MS on brain microstructural FW were revealed, with SZ-wMS exhibiting exacerbated microstructural alterations in frontotemporal lobes compared with SZ-nMS, HC-wMS and HC-nMS groups. More pronounced cognitive deficits in multiple cognitive domains were also observed in SZ-wMS group. In SZ-wMS group, correlations between elevated FW within frontotemporal lobes and both peripheral level of interleukin-8 and scores of multiple cognitive functions were revealed. In addition, an indirect effect of interleukin-8 on delayed recall via FW of right middle frontal gyrus was revealed. Several findings were validated within each independent dataset. These results suggest that inflammation-related microstructural FW alterations within frontotemporal lobes may be associated with the comorbidity of schizophrenia and MS and the associated long-term memory decline. • Frontotemporal microstructural FW alterations are associated with comorbidity between schizophrenia and MS. • Frontotemporal microstructural FW alterations are associated with IL-8 in comorbid schizophrenia patients . • Inflammation-related FW alterations are associated with memory decline in comorbid schizophrenia patients.