Brain Advance Access originally published online on October 24, 2005
Brain 2005 128(12):2977-2986; doi:10.1093/brain/awh649
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Factors affecting the clinical outcome after neural transplantation in Parkinson's disease
1 MRC Clinical Sciences Centre and Division of Neuroscience, Faculty of Medicine, Imperial College, Hammersmith Hospital, 2 Sobell Department of Motor Neuroscience and Movement Disorders, London, UK, 3 Section of Restorative Neurology, University Hospital, 4 Department of Health Sciences and 5 Division of Neurobiology, Lund University, Lund, Sweden and 6 Department of Neurology, University of Marburg, Marburg, Germany
Correspondence to: Olle Lindvall, MD, PhD, Laboratory of Neurogenesis and Cell Therapy, Section of Restorative Neurology, Lund Strategic Research Center for Stem Cell Biology and Cell Therapy, University Hospital BMC A-11, SE-221 84 Lund, Sweden E-mail: Olle.Lindvall{at}neurol.lu.se
Intrastriatal grafts of embryonic mesencephalic tissue can survive in the brains of patients with Parkinson's disease, but the degree of symptomatic relief is highly variable and some cases develop troublesome dyskinesias. Here we explored, using clinical assessment and 18F-dopa and 11C-raclopride PET, factors which may influence the functional outcome after transplantation. We observed increased 18F-dopa uptake in the grafted putamen, signifying continued survival of the transplanted dopaminergic neurons, in parallel with a progressive reduction of 18F-dopa uptake in non-grafted regions for the whole patient group. The patients with the best functional outcome after transplantation exhibited no dopaminergic denervation in areas outside the grafted areas either preoperatively or at 1 or 2 years post-operatively. In contrast, patients with no or modest clinical benefit showed reduction of 18F-dopa in ventral striatum prior to or following transplantation, which may have limited graft-induced improvement. We obtained no evidence that dyskinesias were caused by abnormal dopamine (DA) release from the grafts. As has been observed for intrinsic dopaminergic neurons, there was a significant correlation between 18F-dopa uptake and methamphetamine-induced change of 11C-raclopride binding (as a measure of DA release) in the putamen containing the graft. Furthermore, we observed no correlation between 11C-raclopride binding in anterior, posterior or entire putamen under basal conditions or after methamphetamine, and dyskinesia severity scores in the contralateral side of the body. Withdrawal of immunosuppression at 29 months after transplantation caused no reduction of 18F-dopa uptake or worsening of UPDRS motor score, indicating continued survival and function of the graft. However, patients showed increased dyskinesia scores, which might have been caused either by growth of the graft or worsening of a low-grade inflammation around the graft. These findings indicate that poor outcome after transplantation is associated with progressive dopaminergic denervation in areas outside the grafts, a process which may have started already before surgery. Also, that the development of dyskinesias after transplantation is not associated with excessive DA release from the grafts. Finally, our data provide evidence that long-term immunosuppression can be withdrawn without interfering with graft survival or the motor recovery induced by transplantation.
Key Words: Parkinson's disease; neural transplantation; dopamine; dyskinesias; positron emission tomography
Abbreviations: CDRS = Clinical Dyskinesia Rating Scale; DA = dopamine; GID = graft-induced dyskinesias; SNpc = substantia nigra pars compacta; SPM = statistical parametric mapping; UPDRS = Unified Parkinson's Disease Rating Scale; VTA = ventral tegmental area
Received March 10, 2005. Revised May 20, 2005. Accepted September 5, 2005.
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