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The main pathology underlying the motor symptoms in Parkinson's disease (PD) is a rather selective degeneration of the nigrostriatal dopamine (DA) neuron system. The experimental strategies to restore brain function in PD patients have all been based on a very simple principle, namely, to replace the dead dopaminergic neurons by new, transplanted DA-producing cells. The interest in cell replacement dates back to the late 1970s when it was demonstrated that intrastriatal grafts of embryonic mesencephalic tissue, rich in DA neuroblasts, induced functional recovery in rats with neurotoxin-induced lesions of the nigrostriatal DA system. There is now a solid experimental basis showing functional efficacy of such transplantation to the striatum in animal models of PD, and a biological mechanism underlying the observed improvement, that is, restoration of striatal DA transmission.1,2 Extensive animal studies have shown that the grafted DA neurons display many of the morphological and functional characteristics of the intrinsic mesencephalic DA neurons: they reinnervate the denervated striatum and form synaptic contacts with host neurons, are spontaneously active and release DA, and receive afferent inputs from the host. Reinnervation by the grafts ameliorates several aspects of the DA deficiency syndrome in rodents and monkeys.

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Based on these animal experimental data, clinical trials with transplantation of human embryonic mesencephalic tissue to the striatum in patients with PD were started in 1987. At that time, it was unknown whether cell replacement could work at all in the human brain. Therefore, the first phase of clinical transplantation research aimed at answering several basic scientific questions: first, can the grafted DA neurons survive and form connections? Second, can the patient's brain integrate and use the grafted DA neurons? Third, can the grafts induce a measurable clinical improvement in PD patients? So far, 300–400 patients with PD have been grafted with human embryonic mesencephalic tissue. The results have provided proof-of-principle that cell replacement can work in the PD patient's brain.

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Besides transplantation of embryonic mesencephalic tissue, several other sources of cells secreting catecholamines have been tested clinically in PD patients. Intrastriatal implantation of tissue from the patient's own adrenal medulla was pioneered by Backlund and coworkers already in the early 1980s.3 These trials were the first attempts to apply the cell transplantation strategy to the human brain. The main interest in this approach arose in 1987, when dramatic improvements were described after adrenal medulla transplantation in PD patients using a new surgical technique.4 This report led to a large number of clinical trials. When the outcome in these studies had been evaluated, it was concluded that adrenal medulla transplantation can lead to modest improvement but with a serious level of mortality and morbidity5 and poor graft survival.6 Another approach has used autotransplantation of dopaminergic glomus cells from carotid body into the striatum of PD patients. An open-label trial showed modest mean improvement in operated patients and no direct positron emission tomography (PET) evidence for graft survival.7 Finally, ...

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