Decoding the effects of neural transplantation in patients with Parkinson's disease: a multimodal imaging study

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Parkinson's disease (PD) is a common incurable neurodegenerative disease, clinically characterised by the development of bradykinesia, rigidity and tremor. These clinical features are linked to progressive loss of the dopaminergic input from the substantia nigra to the striatum. Thus the management of PD can initially be highly successful using dopaminergic drugs, however these agents do not re-establish normal tonic /phasic signalling, and with time lead to disabling side-effects, such as "ON-OFF" fluctuations and uncontrollable involuntary movements (dyskinesias). These side effects relate not only to the non physiological delivery of dopamine (DA), but also to drug actions that are off target. One way to combat these problems is using targeted DA cell based therapies placed in the putamen, the site of the brain with greatest DA loss in PD. This has been done with greatest success when the grafted tissue is derived from the developing human ventral mesencephalon. Over the last 25 years it has been shown (including by our group) that this approach can lead to long term survival of cells, with physiological DA release and re-activation of relevant cortical motor areas. However, while some patients have responded extremely well to this intervention with significant relief of symptoms to the extent that they could come off their anti-PD medications, others showed only modest clinical improvements while some developed severe, off-state graft-induced dyskinesias (GID). Nonetheless, the potential for this therapy to provide considerable benefit is clear and led to a gathering of international experts to examine the reasons behind the variable outcomes. This resulted in a successful application to the EU, and a new trial (Transeuro) in which patient selection, immunosuppressive regime, method of transplant and tissue dissection were re-appraised and optimized (including new pre-clinical studies) to increase the rate of success. This project has now evolved to the point that by the end of this year 15 patients will have been grafted out of an observational cohort of 150 patients, who have had extensive imaging pre transplantation. From November 2015 to date we have performed 13 surgeries, and we aim to complete 15 patients by December 2016. We now wish to follow up this unique cohort of grafted patients using the same extensive multimodal battery of neuroimaging techniques that we have already employed pre transplantation. This study that we are now proposing will: 1. Accurately quantify any changes to the metabolism and transport of DA, particularly in the putamen at the graft site. 2. Examine whether the grafted tissue contains significant serotonin neurons which in the past have been linked to the development of GIDs.3. Identify which brain alterations are most important at predicting a positive clinical outcome post grafting, as well as those associated with any side effects such as GIDs. 4. Define the degree to which functional activation in cortical motor regions is restored, and whether there are improvements in specific frontostriatal circuits which are impacted on by the transplant.5. Combine imaging analysis with the extensive motor, cognitive, neuropsychological and quality of life data, in order to ascertain the direct links between brain and behaviour.6. Define those imaging parameters pre and post grafting that best predict clinical response to dopamine cell transplants.While human fetal mesencephalic tissue transplants will never become a mainline therapy for PD given the logistical and ethical problems that they engender, they will lay the foundations for the next generation of stem cell derived dopamine therapies for PD. STEM-PD is currently is in the final stages of pre clinical development, with a projected time to a first in human trial in 2019. As such the outcome of this study will inform us as to how to deliver the best imaging protocol for this first in human clinical trial with stem cells.