1. Investigating dopaminergic abnormalities in schizophrenia and first-episode psychosis with normative modelling and multisite molecular neuroimaging.
- Author
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Giacomel A, Martins D, Nordio G, Easmin R, Howes O, Selvaggi P, Williams SCR, Turkheimer F, De Groot M, Dipasquale O, and Veronese M
- Abstract
Molecular neuroimaging techniques, like PET and SPECT, offer invaluable insights into the brain's in-vivo biology and its dysfunction in neuropsychiatric patients. However, the transition of molecular neuroimaging into diagnostics and precision medicine has been limited to a few clinical applications, hindered by issues like practical feasibility, high costs, and high between-subject heterogeneity of neuroimaging measures. In this study, we explore the use of normative modelling (NM) to identify individual patient alterations by describing the physiological variability of molecular functions. NM potentially addresses challenges such as small sample sizes and diverse acquisition protocols typical of molecular neuroimaging studies. We applied NM to two PET radiotracers targeting the dopaminergic system ([
11 C]-(+)-PHNO and [18 F]FDOPA) to create a reference-cohort model of healthy controls. The models were subsequently utilized on different independent cohorts of patients with psychosis in different disease stages and treatment outcomes. Our results showed that patients with psychosis exhibited a higher degree of extreme deviations (~3-fold increase) than controls, although this pattern was heterogeneous, with minimal overlap of extreme deviations topology (max 20%). We also confirmed that striatal [18 F]FDOPA signal, when referenced to a normative distribution, can predict treatment response (striatal AUC ROC: 0.77-0.83). In conclusion, our results indicate that normative modelling can be effectively applied to molecular neuroimaging after proper harmonization, enabling insights into disease mechanisms and advancing precision medicine. In addition, the method is valuable in understanding the heterogeneity of patient populations and can contribute to maximising cost efficiency in studies aimed at comparing cases and controls., Competing Interests: Competing interests: M.d.G. is an employee of GSK, GSK had no role in the design of this study. R.A.M. has received speaker/consultancy fees from Karuna, Janssen, Boehringer Ingelheim, and Otsuka, and co-directs a company that designs digital resources to support treatment of mental illness. F.B. has received consulting fees from Petalouda Therapeutics and has been an employee at Compass Pathways. AE has received consulting fees from Leal Therapeutics. O.H. and M.V. hold a patent application for the use of dopamine imaging as a prognostic tool in mental health (WO2021111116). The other authors do not report any conflict of interest in relation to this article. Ethics: All the research protocols for data acquisitions were approved by local ethics committees and local institutional revision boards. Full details on approval protocol numbers are reported on original references [7, 13, 14, 40–48]. Informed written consent was obtained for all the participants and the studies were conducted following the Declaration of Helsinki and Good Clinical Practice., (© 2025. Crown.)- Published
- 2025
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