The future of mesencephalic cell transplantation for PD is uncertain at this time. Laboratory studies have demonstrated that transplanted dopamine cells can survive, release dopamine, reinnervate the striatum and provide benefit in animal models of PD. Open label studies of fetal nigral transplantation showed positive clinical benefits associated with increased striatal FD uptake on PET. Post-mortem studies reveal histologic evidence of robust graft survival with extensive and organotypic striatal reinnervation. However, two double-blind studies failed to demonstrate that transplanted patients were superior to placebo with respect to their primary endpoints. Further, transplantation of fetal mesen-cephalic dopamine neurons was associated with a potentially disabling off-medication dyskinesia. Thus, fetal nigral transplantation can not be currently recommended as a treatment for PD. It is still possible that transplantation using different transplant protocols or different dopaminergic cells will prove helpful for PD patients. Post hoc analyses in the double-blind transplant studies suggest that improved clinical results might be obtained with protocols that employ younger patients with milder disease and long-term use of immunosuppression. It remains to be determined if transplantation of larger numbers of cells or co-administration of agents that enhance cell survival will influence outcome. It is also possible that enhanced benefit can be derived by transplantation of other dopaminergic cell types such as stem cells.
It is also important to question whether transplantation of dopaminergic cells can provide benefits any greater than can be achieved with levodopa (Lang and Obeso, 2004b). Levodopa does not improve potentially disabling features of PD such as sleep disturbances, autonomic dysfunction, freezing of gait, postural instability, and dementia presumably because they result from degeneration of non-dopaminergic neurons. It is not clear that transplanted dopamine cells will provide better results. Indeed, Lindvall et al. report the best results in patients whose clinical features can be best controlled with levodopa, and suggest that these are the optimal candidates for a transplant procedure. It is possible that early replacement of dopaminergic tone will have downstream effects that prevent damage to non-dopaminergic regions. For example, it has been postulated that dopamine depletion-induced increased firing of glutamatergic neurons in the STN could cause excitotoxic damage in target neurons such as the globus pallidus, substantia nigra pars reticulata, the pedunculopontine nucleus, as well as the SNc (Rodriguez et al., 1998). Early restoration of dopamine might prevent these non-dopaminergic consequences. It is also possible that degeneration of dopaminergic pathways to cerebral cortex and other brain regions might contribute to the gait, auto-nomic, and cognitive dysfunction that occurs in PD. It is by no means clear, however, that transplantation of dopamine neurons into the striatum will have any effect on these non-dopaminergic systems and that these types of disability that occur in PD will persist despite complete restoration of the nigrostri-atal dopamine system. For additional discussion of transplantation therapies in Parkinson's and other neurodegenerative disease, see Volume I, Chapter 34.
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