Imaging of human stem cell-derived dopamine grafts correlates with behavioural recovery and reveals microstructural brain changes

Paisey, Stephen J. ORCID: https://orcid.org/0000-0002-2274-3708, Jones, Lucy R. ORCID: https://orcid.org/0000-0002-3872-4376, Harrison, David J., Drummond, Nicola J., Edwards, Olivia Z., Canham, Maurice A., Roberton, Victoria H., Marshall, Christopher ORCID: https://orcid.org/0000-0002-2228-883X, Parker, Greg, Hills, Rachel, Rosser, Anne E. ORCID: https://orcid.org/0000-0002-4716-4753, Lane, Emma L. ORCID: https://orcid.org/0000-0001-8800-3764, Dunnett, Stephen B. ORCID: https://orcid.org/0000-0003-1826-1578, Kunath, Tilo, Assaf, Yaniv and Lelos, Mariah J. ORCID: https://orcid.org/0000-0001-7102-055X 2025. Imaging of human stem cell-derived dopamine grafts correlates with behavioural recovery and reveals microstructural brain changes. Neurobiology of Disease 209 , 106910. 10.1016/j.nbd.2025.106910

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Abstract

Cell therapy is a promising therapeutic intervention for Parkinson's disease (PD) and is currently undergoing safety and efficacy testing in clinical trials worldwide. The goals of this project were (1) to determine whether [ F]Fluorodopa or [ F]Fallypride imaging correlates robustly with functional recovery; and (2) to explore whether diffusion-weighted MR imaging (DWI) could detect graft-induced cytoarchitectural changes in the host brain. hfVM and hESC-derived dopamine precursor cells were transplanted into the 6-OHDA lesioned rat striatum. Tests of motor function and PET and MR imaging were conducted up to 6 months post-transplantation. Our data demonstrate that [ F]Fluorodopa imaging identified presynaptic DA synthesis from hfVM and hESC-derived dopaminergic grafts and [ F]Fallypride imaging confirmed occupancy and normalisation of D /D receptor expression in the grafted hemisphere. In hfVM grafted rats, [ F]Fluorodopa binding correlated robustly with motor recovery on a range of drug-induced and drug-free behavioural tasks. In hESC-DA grafted rats, improvements in [ F]Fluorodopa PET imaging signals preceded recovery of naturalistic motor behaviours. DWI revealed widespread graft-mediated microstructural changes in the rodent brain, which did not identify graft placement, but instead may reflect remodelling of neuroglia. These data further our understanding of the impact of dopaminergic grafts on brain cytoarchitecture and the potential of these radioligands to predict graft efficacy may aid in the translation of therapeutics from preclinical to clinical settings. [Abstract copyright: Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.]

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Schools > Medicine Schools > Pharmacy Schools > Biosciences
Publisher:	Elsevier
ISSN:	0969-9961
Date of First Compliant Deposit:	7 May 2025
Date of Acceptance:	11 April 2025
Last Modified:	07 May 2025 10:00
URI:	https://orca.cardiff.ac.uk/id/eprint/178112

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