Dopamine cell implantation in Parkinson's disease: long-term clinical and (18)F-FDOPA PET outcomes

Abstract

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 < or = 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.

Figures

FIGURE 1

Off-state UPDRS motor ratings and striatal 18F-FDOPA uptake (mean ± SE) at baseline (pre) and at 1 (post 1 y), 2 (post 2 y), and 4 (post 4 y) years after bilateral implantation of fetal dopaminergic cells into putamen of PD patients. Significant treatment effect was noted over 2 y (A) (P < 0.0001; RMANOVA) in whole group and over 4 y (B) (P < 0.001) in 15 participants who were evaluated at all 4 time points. 18F-FDOPA uptake in putamen increased significantly (P < 0.0001) over 2 y in whole group (C) and over 4 y in 15 transplant recipients scanned at all 4 time points (D). These graphs indicated progressive postoperative clinical improvement and increases in 18F-FDOPA uptake relative to baseline. By contrast, no significant changes were evident (P > 0.4) in nongrafted caudate after implantation in whole group (E) and subgroup (F) analyses. 18F-FDOPA uptake was measured in anatomic VOIs and plotted as percentages of normal mean. Dotted lines represent lower limit of striatal 18F-FDOPA uptake (mean − 2 SDs) in 15 healthy control subjects. Asterisks represent P values with respect to baseline. *P < 0.05; †P < 0.005; ‡P < 0.001.

FIGURE 2

Maps of mean 18F-FDOPA uptake in transplant recipients scanned at baseline (pre) and at 1 (post 1 y), 2 (post 2 y), and 4 (post 4 y) years after surgery. Postoperative scans showed sustained increases in putamen 18F-FDOPA uptake after transplantation. Maps were created on voxel basis from spatially normalized images of 18F-FDOPA uptake ratio, presented as percentage of normal value in 15 healthy subjects and displayed on standard MRI brain template. Color stripe represents normalized values of 18F-FDOPA uptake in striatal regions thresholded at 30%.

FIGURE 3

Voxelwise comparisons of 18F-FDOPA uptake within striatum at baseline (pre) and at 1 (post 1 y), 2 (post 2 y), and 4 (post 4 y) years after transplantation. (A) Transplantation resulted in significantly increased 18F-FDOPA uptake in bilateral posterior putamen and concurrent declines in nongrafted caudate and ventrorostral putamen (P < 0.001; RMANOVA). SPM was displayed on standard MRI brain template. Color stripe represents T values thresholded at P < 0.001 for increasing regions (color-coded red) and P < 0.01 for decreasing regions (color-coded blue). (B) Post hoc plot revealed sustained increases of 18F-FDOPA uptake in posterior putamen (coordinates, −28 −6 0 mm) at each postoperative time point relative to baseline. (C) Post hoc plot demonstrated progressive decreases of postoperative 18F-FDOPA uptake in ventrorostral putamen (coordinates, 12 18 −8 mm) relative to baseline. Data from spheric VOI (4-mm radius) centered at peak voxel.

FIGURE 4

Voxelwise correlation of 18F-FDOPA uptake within striatum at baseline with posttransplantation improvement in UPDRS motor ratings 1 y after surgery. (A) Baseline 18F-FDOPA uptake in ventrorostral putamen correlated with clinical benefit in transplant recipients. SPM was displayed on standard MRI brain template. Color stripe represents T values thresholded at P < 0.05. (B) Post hoc analysis disclosed positive correlation (r = 0.59; P < 0.01) between baseline 18F-FDOPA uptake in this region (coordinates, 14 18 −4 mm) and percentage change in off-state motor ratings in subjects with clinical improvement after transplantation. Data from spheric VOI (4-mm radius) centered at peak voxel.