Grey matter morphometric biomarkers for classifying early schizophrenia and PD psychosis: a multicentre study

Psychotic symptoms occur in a majority of schizophrenia patients, and in approximately 50% of all Parkinson’s disease (PD) patients. Altered grey matter (GM) structure within several brain areas and networks may contribute to their pathogenesis. Little, however, is known about transdiagnostic similarities when psychotic symptoms occur in different disorders, such as schizophrenia and PD. The present study investigated a large, multicenter sample containing 722 participants: 146 patients with first episode psychosis, FEP; 106 individuals at-risk mental state for developing psychosis, ARMS; 145 healthy controls matching FEP and ARMS, Con-Psy; 92 PD patients with psychotic symptoms, PDP; 145 PD patients without psychotic symptoms, PDN; 88 healthy controls matching PDN and PDP, Con-PD. We applied source-based morphometry in association with receiver operating curves (ROC) analyses to identify common GM structural covariance networks (SCN) and investigated their accuracy in identifying the different patient groups. We assessed group-specific homogeneity and variability across the different networks and potential associations with clinical symptoms. SCN-extracted GM values differed significantly between FEP and Con-Psy, PDP and Con-PD as well as PDN and Con-PD, indicating significant overall grey matter reductions in PD and early schizophrenia. ROC analyses showed that SCN-based classification algorithms allow good classification (AUC∼0.80) of FEP and Con-Psy, and fair performance (AUC∼0.72) when differentiating PDP from Con-PD. Importantly, best performance was found in partly the same networks including the precuneus. Finally, reduced GM volume in SCN with increased variability was linked to increased psychotic symptoms in both FEP and PDP. Alterations within selected SCNs may be related to the presence of psychotic symptoms in both early schizophrenia and PD psychosis, indicating some commonality of underlying mechanisms. Furthermore, results provide first evidence that GM volume within specific SCNs may serve as a biomarker for identifying FEP and PDP. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement Funding: FK received funding from the European Union s Horizon 2020 [Grant number 754462]. Subjects recruited at the National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India were part of a project funded by the Indian Council of Medical research (ICMR). [ICMR/003/304/2013/00694]. SJGL is supported by a National Health and Medical Research Council Leadership Fellowship (1195830). The Singapore Translational and Clinical Research in Psychosis is supported by the National Research Foundation Singapore under the National Medical Research Council Translational and Clinical Research Flagship Program (NMRC/TCR/003/2008). This study is also supported by Agency for Science, Technology, and Research (A STAR) Singapore under the Biomedical Research Council (13/1/96/19/ 687), National Medical Research Council (CBRG/0088/2015), and Duke-NUS Medical School Signature Research Program funded by Ministry of Health and Yong Loo Lin School of Medicine Research fund, National University of Singapore. SSA is supported by DBT/Wellcome Trust India Alliance Intermediate Clinical and Public Health Fellowship grant (IA/CPHI/18/1/50393). ### 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: Ethical approval was obtained from local ethical committees for each original studies: The studies were approved by the Cambridgeshire 3 National Health Service research ethics committee (Garofalo et al., 2017; Knolle et al., 2020); by the ethics review board of the Singaporean National Healthcare Group (Dandash et al., 2014); by the ethical commitee of the University of Sydney (Shine et al., 2015); and by the Institute Ethics Committee of NIMHANS, Bangalore (Lenka et al., 2018). Furthermore, freely available data was used from the Human Connectome Projects (https://www.humanconnectome.org/study/human-connectome-project-for-early-psychosis), for which ethical approval was waived by the Ethical Commission Board of the Technical University Munich. All subjects gave written informed consent in accordance with the Declaration of Helsinki. 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 and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Data availability: All data produced in the present study are available upon reasonable request to the authors.