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

Background: Previous studies investigating disruptions in central nervous system (CNS) barriers in schizophrenia spectrum disorders (SSD) mainly focused on cerebrospinal fluid (CSF) markers, that cannot adequately assess blood-brain barrier (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, pathognomonic for a clinical sub-phenotype of SSD. Methods: Forty-five people with SSD and 42 age- and sex-matched healthy controls (HC) were included in the cross-sectional study and 41 SSD and 40 HC were included in the final analyses. Clinical characterization, cognitive assessments, blood and CSF analyses were conducted. Pharmacokinetic modelling (Patlak method) was implemented. The volume transfer constant Ktrans was calculated and Ktrans 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. Results: Group comparisons of Ktrans 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, allowing direct exploration of the BBB, compared to a healthy control group and the first study to implement this modality in a multimodal approach, with CSF, blood, clinical and cognitive assessments. The results provide the first in vivo evidence of higher BBB leakage on a whole brain level compared to HC. ### Competing Interest Statement The authors have declared that there are no conflicts of interest in relation to the subject of this study. General declaration of potential conflict of interests: EW has been invited to advisory boards from Recordati and Boehringer Ingelheim. PF received speaker fees by Boehringer Ingelheim, Janssen, Otsuka, Lundbeck, Recordati, and Richter and was member of advisory boards of these companies and Rovi. All other authors report no potential conflicts of interest. AH was member of advisory boards of Boehringer-Ingelheim, Lundbeck, Janssen, Otsuka, Rovi and Recordati and received paid speakership by these companies as well as by AbbVie and Advanz. He is editor of the German schizophrenia guideline. ### Funding Statement This research was not supported by any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. JM was supported by the research funding program "Foerderprogramm fuer Forschung und Lehre (FoeFoLe)", University Hospital, LMU Munich (project number 1167). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee of the Ludwig-Maximilian University gave ethical approval for this work I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors.