Human embryonic dopamine-neuron transplants survive in patients with severe Parkinson's disease and result in some clinical benefit in younger but not in older patients.

Fetal-tissue implants appear to offer long-term clinical benefit to some patients with advanced Parkinson's disease.

We have previously reported the results of a 1-y double-blind, placebo-controlled study of embryonic dopamine cell implantation for Parkinson's disease. At the end of the blinded phase, we found a significant increase in putamen uptake on 18 F-fluorodopa ( 18 F-FDOPA) PET reflecting the viability of the grafts. Nonetheless, clinical improvement was significant only in younger (age # 60 y) transplant recipients, as indicated by a reduction in Unified Parkinson's Disease Rating Scale (UPDRS) motor scores. Methods: We now report long-term clinical and PET outcomes from 33 of the original trial participants who were followed for 2 y after transplantation and 15 of these subjects who were followed for 2 additional years. Longitudinal changes in UPDRS motor ratings and caudate and putamen 18 F-FDOPA uptake were assessed with repeated-measures ANOVA. Relationships between these changes over time were evaluated by the analysis of within-subject correlations. Results: We found that UPDRS motor ratings declined over time after transplantation (P , 0.001). Clinical improvement at 1 y was relatively better for the younger transplant recipients and for men, but these age and sex differences were not evident at longer-term follow-up. Significant increases in putamen 18 F-FDOPA uptake were evident at all posttransplantation time points (P , 0.001) and were not influenced by either age or sex. Posttransplantation changes in putamen PET signal and clinical outcome were significantly intercorrelated (P , 0.02) over the course of the study. Image analysis at the voxel level revealed significant bilateral increases in 18 F-FDOPA uptake at 1 y (P , 0.001) in the posterior putamen engraftment sites. PET signal in this region increased further at 2 and 4 y after engraftment. Concurrently, this analysis disclosed progressive declines in radiotracer uptake in the nonengrafted caudate and ventrorostral putamen. Clinical improvement after transplantation correlated with the retention of PET signal in this region at the preoperative baseline. Conclusion: These results suggest that clinical benefit and graft viability are sustained up to 4 y after transplantation. Moreover, the dependence of clinical (but not imaging) outcomes on subject age and sex at 1 y may not persist over the long term. Last, the imaging changes reliably correlate with clinical outcome over the entire posttransplantation time course.

Persistent dyskinesias in the absence of or with only minimal amounts of dopaminergic medication have been reported after dopamine cell implantation for Parkinson's disease. In this study, we used [(18)F]fluorodopa (FDOPA) and positron emission tomography to determine whether this complication resulted from specific alterations in dopamine function after transplantation. Caudate and putamen FDOPA uptake values in these patients (DYS+, n = 5) were compared with those obtained in a cohort of age- and disease duration-matched transplant recipients who did not develop this complication (DYS-, n = 12). PET signal for both groups was compared at baseline and at 12 and 24 months after transplantation. We found that putamen FDOPA uptake was significantly increased (p < 0.005) in DYS+ transplant recipients. These increases were predominantly localized to two zones within the left putamen. In addition to the posterodorsal zone in which a prominent reduction in FDOPA uptake was present at baseline, the DYS+ group also displayed a relative increase ventrally, in which preoperative dopaminergic input was relatively preserved. Postoperative FDOPA uptake did not reach supranormal values over the 24-month follow-up period. These findings suggest that unbalanced increases in dopaminergic function can complicate the outcome of neuronal transplantation for parkinsonism.

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