Abstract
Major depressive disorder (MDD) is a common non-motor symptom in Parkinson’s disease (PD), affecting one third of patients. Dopaminergic deficits have been hypothesised to contribute to PD-MDD, but direct molecular evidence is limited. In this cross-sectional study, we compared striatal dopamine transporter (DAT) binding between 22 depressed (DSM-5) and 34 well-matched non-depressed PD patients using [18F]FE-PE2I PET. The striatum was segmented into ventral striatum, medial caudate, anterior putamen and posterior putamen. Mixed-effect models included region, hemisphere, and group as fixed effects, and subject ID as random effect. PD-MDD patients showed lower DAT binding in the ventral striatum (P = 0.016), but not in caudate or putamen, driving a significant group × region interaction (P = 0.012). Within the depressed group, greater depression severity was paradoxically associated with higher ventral striatal DAT binding (P = 0.039). These findings provide in vivo evidence linking ventral striatal dopaminergic dysfunction to PD-MDD, advancing mechanistic understanding relevant for treatment development.
Acknowledgements
The AnHedonic dEpression and Alterations in the Dopaminergic neurocircuitry in Parkinson’s disease (AHEAD) study was funded by the U.S. Army Medical Research and Development Command through a Parkinson’s Research Program Early Investigator Research Award (W81XWH-19-1-0713) awarded to dr. van Beek. The sponsor had no role in the design, data collection, analysis, interpretation, or writing of this manuscript.We thank all participants who volunteered for the AHEAD study, and the supporting staff of the Psychiatry and Medical Imaging departments of the Radboudumc and the Donders Institute, particularly Jon Matthews. We also thank Jan Axelsson for his input on the PET reconstruction.
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J.D., F.G., N.D. and M.v.B. declare no competing financial or non-financial interests. R.C. is funded by an ERC Advanced Grant CHEMCONTROL #101054532, and acts as a consultant with Roche Ltd, but has no shares. J.B. is a consultant with GE Healthcare (all related payments to the institute). B.B. serves as the co-Editor in Chief for the Journal of Parkinson’s disease and serves on the editorial board of Practical Neurology and Digital Biomarkers. B.B. was not involved in the journal’s review of, or decisions related to, this manuscript. B.B. has received fees from serving on the scientific advisory board for the Critical Path Institute, Gyenno Science, MedRhythms, UCB, Kyowa Kirin and Zambon (paid to the institute), has received fees for speaking at conferences from AbbVie, Bial, Biogen, GE Healthcare, Oruen, Roche, UCB and Zambon (paid to the Institute), has received research support from Biogen, Cure Parkinson’s, Davis Phinney Foundation, Edmond J. Safra Foundation, Fred Foundation, Gatsby Foundation, Hersenstichting Nederland, Horizon 2020, IRLAB Therapeutics, Maag Lever Darm Stichting, Michael J Fox Foundation, Ministry of Agriculture, Ministry of Economic Affairs & Climate Policy, Ministry of Health, Welfare and Sport, Netherlands Organization for Scientific Research (ZonMw), Not Impossible, Parkinson Vereniging, Parkinson’s Foundation, Parkinson’s UK, Stichting Alkemade-Keuls, Stichting Parkinson NL, Stichting Woelse Waard, Health Holland/Topsector Life Sciences and Health, UCB, Verily Life Sciences, Roche and Zambon, and does not hold any stocks or stock options with any companies that are connected to Parkinson’s disease or any of his clinical or research activities. R.H. serves on the Scientific Advisory Board of ParkinsonNL, has received consulting fees from Neurocrine Biosciences (payments to the institute), and has received research support from The Netherlands Organisation for Health Research and Development, Dutch Brain Foundation, ParkinsonNL, and Michal J Fox Foundation. HR has received speaking fees from J&J, Lundbeck, Prelum, Benecke, E-Wise, Fagron, SCEM, has received grants from Hersenstichting, Horizon 2020 (EU), Janssen/Johnson & Johnson (Educational Grant), Kwaliteitsnetwerk Geestelijke Gezondheidszorg, Parkinson Foundation, and Zorgonderzoek en Medische Wetenschappen (ZonMw)/Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO).
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Dirkx, J.E.M.C., Grill, F., Dijk, N. et al. Depression in Parkinson’s disease is associated with reduced ventral striatal dopamine transporter binding. npj Parkinsons Dis. (2026). https://doi.org/10.1038/s41531-026-01363-2
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DOI: https://doi.org/10.1038/s41531-026-01363-2
