Article Figures & Data
Figures
- FIGURE 1.
Clinical improvement in individual macaques after cell-based therapy. hRPE-implanted animals showed motor recovery from 6 mo to 4 y after unilateral implantation but continued to express mild to moderate bradykinesia and hypokinesia. Maximal benefit was achieved within 1 y and remained stable afterward. Sham-implanted animals showed no clinical responses. Animal 6 was transplanted sequentially with GM and hRPE-GM in 2 different hemispheres. Animals 1–4 received fetal cells used in the successful phase I trial (15), and animals 5–6a received neonatal cells used in the failed phase II trial (22). ■ = hRPE-GM; ▲ = GM.
- FIGURE 2.
Mean images of relative glucose metabolism in healthy and parkinsonian macaques acquired using Siemens HRRT scanner. This high-resolution PET scanner provides superior image quality for revealing distinct regional differences in cortical and subcortical metabolism among normal, MPTP, and hRPE- and sham-implanted hemispheres. Each image represents brain 18F-FDG scans averaged over hemispheres in individual animal group spatially normalized to macaque PET brain template (23).
- FIGURE 3.
Modulation of abnormal metabolic brain networks in MPTP-induced experimental parkinsonism by hRPE cell transplantation therapy. (A) PRPs identified on a hemispheric (PRPs 1 and 2) and whole-brain (PRP 5) basis using 18F-FDG PET images in parkinsonian and age-matched healthy macaques (10). All PRPs shared analogous topographies with increased (red to yellow) and decreased (blue to green) metabolic activity in subcortical and cortical regions. (B) Network activity in individual hemispheres or brains was elevated (P < 0.00005) in the 7 untreated MPTP hemispheres compared with the 8 normal controls but declined consistently (P < 0.05) in the 6 contralateral MPTP hemispheres after hRPE cell implantation. The patterns are overlaid on macaque MRI brain template (23).
- FIGURE 4.
Modulation of abnormal regional metabolism in MPTP-induced experimental parkinsonism by hRPE cell transplantation therapy. (A) Metabolism in the 7 untreated MPTP hemispheres increased (red to yellow) in a set of subcortical and cortical motor regions relative to the 8 normal controls. (B) Metabolism in the 6 hRPE-implanted hemispheres decreased (blue to green) in the same set of subcortical and cortical motor regions compared with the 6 untreated MPTP hemispheres. SPM t maps of unpaired and paired comparisons are displayed at lower threshold (P = 0.025) for better visualization on macaque MRI brain template (23).
- FIGURE 5.
Test–retest reproducibility in PRP network activity. (A) Network scores in individual hemispheres or brains were highly reproducible (A: P > 0.29) and correlated (B: R2 > 0.92; P < 0.00005) between 9 test and retest scans in 4 subgroups of 7 macaques. Network scores were computed on hemispheric (PRPs 1–2) and whole-brain (PRP 5) basis, respectively.
Tables
Summary of analysis PRP1 PRP2 PRP3 PRP4 PRP5 Pattern derivation Eigenvalue (%) 42.9 43.3 27.8 27.2 48.2 Control 1 0.00 ± 0.41 0.00 ± 0.45 0.00 ± 0.36 0.00 ± 0.33 0.00 ± 0.41 MPTP 1 7.67 ± 1.37 7.91 ± 1.56 3.11 ± 0.25 2.66 ± 0.25 7.78 ± 1.41 MPTP 1 vs. control 1* 0.0037 0.0031 0.00003 0.00008 0.004 Pattern validation Control 2 0.46 ± 0.36 0.09 ± 0.36 0.22 ± 0.32 0.36 ± 0.28 0.51 ± 0.37 MPTP 2 3.80 ± 0.33 3.88 ± 0.32 3.04 ± 0.22 2.64 ± 0.21 3.64 ± 0.16 MPTP 2 vs. control 2* 0.00001 0.000003 0.00001 0.00003 0.00002 Implant effect Implant 2.85 ± 0.43 3.10 ± 0.48 2.62 ± 0.39 1.92 ± 0.35 3.21 ± 0.21 Implant vs. MPTP 2 (change %) −24.6 ± 5.9 −21.6 ± 5.9 −17.6 ± 7.2 −26.8 ± 11.5 −10.9 ± 2.3 Implant vs. MPTP 2† 0.0025 0.011 0.036 0.033 0.0039 Implant vs. control 2* 0.001 0.0003 0.0005 0.004 0.00008 Test–retest effect Test vs. retest† 0.292 0.342 0.577 0.505 0.351 R2 (Pearson correlation) 0.954 0.952 0.953 0.956 0.926 P 0.000006 0.000007 0.000007 0.000005 0.00003 - TABLE 3
Brain Regions with Significant Metabolic Changes Before and After hRPE Cell Implantation in Parkinsonian Macaques
Metabolic increase* (MPTP > normal) Metabolic decrease† (implant < MPTP) Brain region X Y Z Zmax Size (mm3) X Y Z Zmax Size (mm3) Medial frontal/cingulate 8 6 28 3.3 376 4 6 36 2.9 208 Insula/SMC/putamen 30 16 18 4.9 1304 26 8 18 3.0 744 Frontal/SMA 28 24 18 4.5 26 26 16 3.4 160 Thalamus 6 14 8 2.9 1872 6 14 6 2.8 320 Pons 4 0 −14 3.9 4 0 −14 3.3 184
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