nature neuroscience • volume 2 no 12 • december 1999 1137 Cell transplantation in Parkinson’s disease (PD) aims at correct- ing the impairment of striatal dopaminergic neurotransmission caused by degeneration of substantia nigra neurons. In rodents and nonhuman primates with experimental parkinsonism, intrastriatal transplants of embryonic nigral neurons reinnervate the striatum, form synaptic connections, release dopamine and improve motor deficits 1,2 . Clinical trials have demonstrated that grafts of human embryonic nigral neurons can give rise to long- lasting symptomatic relief in patients with PD 3,4 . In the most suc- cessful cases, improvement after transplantation has been dramatic, and patients in an advanced stage of the disorder have been able to stop L-dopa treatment and resume an independent life. The gradual onset of clinical improvement over the first 6–24 months after transplantation is compatible with the protracted develop- ment, growth and maturation of new striatal dopaminergic inner- vation by the grafted neurons. Thus the magnitude of the transplant-induced effect probably reflects the capacity of the graft- ed neurons for regulated dopamine release at regenerated synaptic sites. Survival of the grafted dopamine neurons, reinnervation of the host striatum and formation of synaptic connections were shown in two autopsy cases with PD 5,6 . However, it has not yet been possible to demonstrate dopamine release from transplants in vivo in humans. Here we monitored synaptic dopamine release from intraputaminal nigral grafts in a PD patient using binding of the dopamine D 2 receptor antagonist [ 11 C]-raclopride (RAC) and positron emission tomography (PET) 7,8 . RESULTS Our 69-year-old patient had typical PD, which started with rigid- ity and tremor in the left arm in 1980. L-dopa treatment was suc- cessful until 1986, when he developed ‘on-off’ motor fluctuations (see ref. 9). In 1989, he was grafted with human embryonic mes- encephalic tissue in the right putamen 9 . During the first three postoperative years, the patient showed gradual, major clinical improvement (Fig. 1a). Rigidity and hypokinesia were marked- ly reduced bilaterally but predominantly contralaterally to the graft, ‘on-off’ fluctuations disappeared, and L-dopa could be withdrawn after 32 months 10 . Immunosuppressive treatment was stopped at 64 months 11 . Low-dose L-dopa (1/3 of preoperative dose) was reintroduced at 74 months due to progression of symp- toms axially and in the limbs ipsilateral to the graft. He respond- ed well to this medication, and motor function and L-dopa dose remained unchanged thereafter. Now, ten years after transplan- tation, he shows continuous marked benefit with virtually no rigidity, minor hypokinesia, intermittent, mild resting tremor and no ‘on-off ’ fluctuations (Fig. 1a). The regional [ 18 F]-dopa influx constant (K i o ) values in the grafted putamen increased up to 3 years post-surgery, by which time [ 18 F]-dopa uptake had reached normal levels. There were only minor additional changes by 6 and 10 years after trans- plantation (Fig. 1b). In contrast, [ 18 F]-dopa uptake values in the caudate nuclei and in the non-grafted putamen (Fig. 1b) decreased gradually. To monitor basal and drug-induced transmitter release from grafted dopaminergic neurons, the patient underwent two [ 11 C]- RAC PET scans ten years after grafting, one after a saline infusion and the other after a methamphetamine infusion. Binding of [ 11 C]-RAC to dopamine D 2 receptors was measured in the puta- men and caudate nucleus on each side. [ 11 C]-RAC binding was upregulated by 43.7% compared with normal subjects in the non-grafted putamen but was normal in the grafted putamen (Table 1 and Fig. 2). In the non-transplanted caudate nuclei of the PD patient, [ 11 C]-RAC binding was bilaterally increased with respect to binding in normal subjects. Following methampheta- articles Dopamine release from nigral transplants visualized in vivo in a Parkinson’s patient Paola Piccini 1 , David J. Brooks 1 , Anders Björklund 2 , Roger N. Gunn 1 , Paul M. Grasby 1 , Ornella Rimoldi 1 , Patrik Brundin 3 , Peter Hagell 4,5 , Stig Rehncrona 6 , Håkan Widner 3,5 and Olle Lindvall 4,5 1 MRC Cyclotron Unit, Imperial College School of Medicine, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK 2 Section for Neurobiology, 3 Section for Neuronal Survival and 4 Section of Restorative Neurology, Wallenberg Neuroscience Center, SE-223 62 Lund, Sweden 5 Division of Neurology and 6 Division of Neurosurgery, Department of Clinical Neuroscience, University Hospital, SE-221 85 Lund, Sweden Correspondence should be addressed to P.P. (paola@cu.rpms.ac.uk) Synaptic dopamine release from embryonic nigral transplants has been monitored in the striatum of a patient with Parkinson’s disease using [ 11 C]-raclopride positron emission tomography to measure dopamine D 2 receptor occupancy by the endogenous transmitter. In this patient, who had received a transplant in the right putamen 10 years earlier, grafts had restored both basal and drug-induced dopamine release to normal levels. This was associated with sustained, marked clinical benefit and normalized levels of dopamine storage in the grafted putamen. Despite an ongoing disease process, grafted neurons can thus continue for a decade to store and release dopamine and give rise to substantial symptomatic relief. © 1999 Nature America Inc. • http://neurosci.nature.com © 1999 Nature America Inc. • http://neurosci.nature.com