Mean images of relative cerebral glucose metabolism in healthy and parkinsonian macaques acquired using a high-resolution positron emission tomography (PET) instrument (see text). The regional distribution of radiotracer uptake was highly symmetrical in scans from normal (top) and parkinsonian (middle) macaques. (Each image was obtained by averaging the [¹⁸F]fluorodeoxyglucose (FDG) PET scans from each group following spatial registration to a standard brain template (Black et al, 2001). The PET images were compared with magnetic resonance imaging scans (bottom) registered to the same anatomical space.)

Overlays illustrating regional homologies between the abnormal metabolic covariance patterns identified in monkeys with experimental parkinsonism and human patients with Parkinson's disease (PD). (A) Voxel-based whole-brain spatial covariance analysis of high-resolution [¹⁸F]fluorodeoxyglucose (FDG) positron emission tomography (PET) images from a combined group of parkinsonian and healthy macaques (Cohort A). This analysis revealed a significant metabolic pattern (PC1, 48% variance accounted for) that accurately discriminated the two groups of animals (P<0.00001; Supplementary Figure 1A). (B) The topography of this pattern (PRP5) resembled that of the human PD-related covariance pattern (PDRP) described consistently in multiple PD patient cohorts (Eidelberg, 2009). Both topographies were characterized by homologous regional components of the motor cortico-striato-pallido-thalamo-cortical loop and related pathways. (Both spatial covariance patterns were displayed on standard magnetic resonance imaging brain templates. Voxels with positive loadings (metabolic increases) are color coded from red to yellow; those with negative loadings (relative metabolic reductions) are color coded from blue to green). PC, principal component; PRP, parkinsonism-related pattern.

Schematic illustrating the relationships between each of the five parkinsonism-related covariance patterns (PRPs) and the scans from the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned and control animals (Cohorts A and B) used for pattern characterization (see text). The number of scans or hemispheres used for the derivation of each PRP (parkinsonism-related pattern) topography is marked on the flow chart from Cohorts A and B. PRP5 resulted from a whole-brain analysis of data from the animals in Cohort A. (Of note, the seven untreated hemispheres from the MPTP animals with contralateral transplants were included in Cohort B. Five of the parkinsonian monkeys in Cohort A were scanned before MPTP lesioning. These baseline images were used as control scans in Cohort B.)

Abnormal metabolic covariance patterns associated with experimental parkinsonism. (A) Voxel-based spatial covariance analysis of high-resolution [¹⁸F]fluorodeoxyglucose (FDG) positron emission tomography (PET) images from five parkinsonian and six healthy macaques (Cohort A). Hemispheric analysis revealed a spatial covariance pattern (PRP1) characterized by increased metabolic activity (red–yellow) in the putamen and globus pallidus (GP), thalamus, pons, medial frontal/cingulate areas, and sensorimotor cortex, as well as relative reductions (blue–green) in the posterior parietal-occipital cortex. (B) Reliability of PRP1 at each voxel according to a bootstrapping estimation procedure (Habeck and Stern, 2010). This map of inverse coefficient of variation (ICV) was thresholded at ICV=3.09 (P=0.001). (C) Abnormal metabolic covariance pattern (PRP2) from the hemispheres of the five monkeys scanned before and after chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration. (D) Candidate whole-brain PRP topography (PRP5) identified over the entire image volume of FDG PET scans from the MPTP-lesioned and normal monkeys included in Cohort A. There was a high degree of topographic similarity between patterns identified using either the hemispheric or the whole-brain spatial covariance approach. (E) Network activity of the hemispheric PRP (PRP1) in individual hemispheres discriminated MPTP animals and normal controls in the derivation sample (P<0.00001). In the validation sample, network activity computed prospectively also separated (P<0.00001) MPTP and control animals. Pattern expression in the MPTP-lesioned animals in the validation sample was lower than those used for pattern derivation (P=0.002), consistent with the difference in motor severity ratings for the two groups (see text). Compared with preMPTP baseline, network activity increased significantly (P<0.0001) in the five parkinsonian animals in the derivation sample who subsequently underwent MPTP lesioning. (Maps of PRP voxel weights and ICV values were displayed on a standard magnetic resonance imaging brain template. Error bars in the graph refer to the standard error of the mean.) PRP, parkinsonism-related pattern.