Dopamine cell transplantation for Parkinson's disease: the importance of controlled clinical trials

Abstract

Transplantation of human fetal dopamine neurons into the brain of Parkinson's disease patients started in the late 1980s, less than 10 years after experiments in rats showed that embryonic dopamine neurons from a narrow window of development are suitable for transplantation. For human transplantation, the critical stage of development is 6 to 8 weeks after conception. Because putamen is the basal ganglia structure most depleted of dopamine in Parkinson's disease and because it is the structure most closely mapped to the motor cortex, it has been the primary target for neurotransplantation. The double blind trial conducted at the University of Colorado, Columbia University, and North Shore University is the first controlled surgical trial performed in the field of neurosurgery. Results have shown that transplants of fetal dopamine neurons can survive transplantation without immunosuppression and without regard to the age of the patients. Transplants improved objective signs of Parkinson's disease to the best effects of L-DOPA seen preoperatively. Placebo surgery produced no clinical changes. In subjects in whom transplants replaced the need for L-DOPA, the implants replicated the preoperative effects of L-DOPA, including dyskinesias in susceptible patients. Our trial has provided the first controlled evidence that dopamine cell transplants can improve the clinical state of patients with Parkinson's disease.

Fig. 1

Changes in Unified Parkinson’s Disease Rating Scale (UPDRS) motor “off” scores in the first 12 months after transplant during the double-blind phase. Results show significant improvement for the transplant group as a whole and for the younger transplant patients, as compared to the sham surgery group

Fig. 2

Fluorodopa (FDOPA) positron emission tomography (PET) scans before and after transplantation adapted from Freed et al. [7]. The left panel shows the FDOPA PET signal of a normal person scanned in a horizontal plane that includes caudate and putamen. Stored 18F-fluorodopamine is shown in the false color red. The 2 upper right panels show PET scans in a patient before and 12 months after implantation with embryonic dopamine neurons. The preoperative panel demonstrates the profound depletion of putamenal signal. The caudate signal is relatively higher. Twelve months after transplant, the FDOPA PET signal in putamen has increased toward the normal range. The 2 lower right panels show PET signals in a sham surgery patient before and 12 months after transplant. As shown, there is no improvement in putamenal dopamine. The caudate dopamine is further depleted. Reproduced with permission of The New England Journal of Medicine