Increased blood–brain barrier leakage in schizophrenia spectrum disorders compared to healthy controls in dynamic contrast-enhanced magnetic resonance imaging

Background There is growing evidence for inflammatory mechanisms in schizophrenia spectrum disorders (SSD) that have been associated with blood-brain barrier (BBB) disruption. Previous studies investigating the BBB in SSD focused on cerebrospinal fluid (CSF) markers, that cannot adequately assess BBB integrity. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) represents a sensitive method for investigating subtle barrier breakdown in vivo. So far, only one pilot study has investigated BBB breakdown in SSD with DCE-MRI, in a relatively small cohort. We hypothesized higher leakage in SSD compared to HC, indicative of a clinical sub-phenotype of SSD. Methods Forty-one people with SSD and 40 age- and sex-matched healthy controls (HC) were included in the final analyses of the cross-sectional study. DCE-MRI, clinical characterization, cognitive assessments, blood and CSF analyses were conducted. The volume transfer constant K trans was calculated with pharmacokinetic modelling (Patlak method), to estimate the rate of contrast agent transfer between blood and the brain’s extravascular space. K trans maps were compared between the groups to detect group differences in BBB leakage. Within the SSD cohort, the association between leakage and clinical characteristics was investigated with linear regression analyses. Results Group comparisons of K trans maps showed higher leakage in SSD compared to HC on a whole brain level. The effect was more pronounced in first episode compared to multiple episode psychosis. No association was detected between leakage and measures of cognition, psychopathology, peripheral inflammation and albumin CSF/serum ratio. Discussion This is the largest study to date investigating the BBB in SSD with DCE-MRI in a multimodal approach, allowing direct exploration of the BBB, compared to a HC group. The integrity of the BBB is crucial for maintaining the brain’s microenvironment, and its disruption could be associated with potential immune system abnormalities. The results of this study provide the first in vivo evidence of higher BBB leakage on a whole brain level compared to HC. The disruption of the BBB in SSD, as detected through DCE-MRI, may provide insights into the disease’s mechanisms and potential for targeted treatments. Further research in this area may clarify specific biological disease mechanisms and identify new therapeutic targets.