Abstract: OBJECTIVES: Parkinson's disease (PD) may be associated with increased energy metabolism in overactive regions of the basal ganglia. Therefore, we hypothesized that treatment with the N-methyl-d-aspartate receptor (NMDAR) antagonist memantine would decrease regional cerebral blood flow (rCBF) and oxygen metabolism in the basal ganglia of patients with early-stage PD. METHODS: Quantitative positron emission tomography (PET) recordings were obtained with 15O]water and 15O]oxygen in 10 patients, scanned first in a baseline condition, and again 6 weeks after treatment with a daily dose of 20 mg memantine. Dynamic PET data were analyzed using volume of interest and voxel-based approaches. RESULTS: The treatment evoked rCBF decreases in basal ganglia, and in several frontal cortical areas. The regional cerebral metabolic rate of oxygen (rCMRO2) did not decrease in any of the a priori defined regions, and consequently the oxygen extraction fraction was increased in these regions. Two peaks of significantly decreased rCMRO2 were detected near the frontal poles in both hemispheres, using a posteriori voxel-based analysis. CONCLUSIONS: Although we did not find the predicted decrease in basal ganglia oxygen consumption, our data suggest that treatment with memantine actively modulates neuronal activity and/or hemodynamic response in basal ganglia of PD patients. This finding may be relevant to the putative neuroprotective properties of NMDAR antagonists.
Abstract: INTRODUCTION: In positron emission tomography (PET) studies of cerebral blood flow (CBF) and metabolism, the large interindividual variation commonly is minimized by normalization to the global mean prior to statistical analysis. This approach requires that no between-group or between-state differences exist in the normalization region. Given the variability typical of global CBF and the practical limit on sample size, small group differences in global mean easily elude detection, but still bias the comparison, with profound consequences for the physiological interpretation of the results. MATERIALS AND METHODS: Quantitative [15O]H2O PET recordings of CBF were obtained in 45 healthy subjects (21-81 years) and 14 patients with hepatic encephalopathy (HE). With volume-of-interest (VOI) and voxel-based statistics, we conducted regression analyses of CBF as function of age in the healthy group, and compared the HE group to a subset of the controls. We compared absolute CBF values, and CBF normalized to the gray matter (GM) and white matter (WM) means. In additional simulation experiments, we manipulated the cortical values of 12 healthy subjects and compared these to unaltered control data. RESULTS: In healthy aging, CBF was shown to be unchanged in WM and central regions. In contrast, with normalization to the GM mean, CBF displayed positive correlation with age in the central regions. Very similar artifactual increases were seen in the HE comparison and also in the simulation experiment. CONCLUSION: Ratio normalization to the global mean readily elevates CBF in unchanged regions when a systematic between-group difference exists in gCBF, also when this difference is below the detection threshold. We suggest that the routine normalization to the global mean in earlier studies resulted in spurious interpretations of perturbed CBF. Normalization to central WM yields less biased results in aging and HE and could potentially serve as a normalization reference region in other disorders as well.
Abstract: Conventional indices of the utilization of FDOPA in living human brain have not consistently revealed important declines in dopamine function with normal aging. However, most methods of kinetic analysis have assumed irreversible trapping of decarboxylated FDOPA metabolites in brain, an assumption that is violated even in PET recordings of short duration. Therefore, we have developed methods for the calculation of steady-state storage of FDOPA together with its decarboxylated metabolites (V(d), mlg(-1)), based upon improved kinetic analysis of 120-min emission recordings. In a group of 28 normal male subjects, of age ranging from 23 to 73 years, the magnitude of V(d) in the striatum and in extrastriatal regions declined by approximately 10% with each decade. The utilization of FDOPA was also calculated by several conventional methods assuming irreversible trapping, i.e. the net blood brain clearance (K(in)(app), mlg(-1)min(-1)), the DOPA decarboxylase activity relative to a reference tissue input (k(3)(S), min(-1)), and relative to the arterial input (k(3)(D), min(-1)). None of these methods revealed an age-related decline in FDOPA utilization in the extended striatum, although the magnitude of K(in)(app) did decline in cerebral cortex. Thus, the capacity to synthesize [(18)F]fluorodopamine remained largely intact in striatum of the elderly subjects, but in the presence of a substantially increased rate of washout (k(loss)), which was evident in all brain regions examined. Consequently, the magnitude of V(d) declined with healthy aging, possibly reflecting impaired vesicular storage capacity, resulting in enhanced exposure of cytosolic [(18)F]fluorodopamine to monoamine oxidase.
