Striatal Acetylcholine-Dopamine Imbalance in Parkinson Disease: InVivo Neuroimaging Study with Dual-Tracer PET and Dopaminergic PET-Informed Correlational Tractography.

Abstract

Previous studies of animal models of Parkinson disease (PD) suggest an imbalance between striatal acetylcholine and dopamine, although other studies have questioned this. To our knowledge, there are no previous invivo neuroimaging studies examining striatal acetylcholine-dopamine imbalance in PD patients. Using cholinergic and dopaminergic PET (18F-fluoroethoxybenzovesamicol [18F-FEOBV] and 11C-dihydrotetrabenazine [11C-DTBZ], respectively) and correlational tractography, our aim was to investigate the acetylcholine-dopamine interaction at 2 levels of dopaminergic loss in PD subjects: integrity loss of the nigrostriatal dopaminergic white matter tract and loss at the presynaptic-terminal level. Methods: The study involved 45 subjects with mild to moderate PD (36 men, 9 women; mean age, 66.3 ± 6.3 y, disease duration, 5.8 ± 3.6 y; Hoehn and Yahr stage, 2.2 ± 0.6) and 15 control subjects (9 men, 6 women; mean age, 69.1 ± 8.6 y). PET imaging was performed using standard protocols. We first estimated the integrity of the dopaminergic nigrostriatal white matter tracts in PD subjects by incorporating molecular information from striatal 11C-DTBZ PET into the fiber tracking process using correlational tractography (based on quantitative anisotropy [QA], a measure of tract integrity). Subsequently, we used voxel-based correlation to test the association of the mean QA of the nigrostriatal tract of each cerebral hemisphere with the striatal 18F-FEOBV distribution volume ratio (DVR) in PD subjects. The same analysis was performed for 11C-DTBZ DVR in 12 striatal subregions (presynaptic-terminal level). Results: Unlike 11C-DTBZ DVR in striatal subregions, the mean QA of the nigrostriatal tract of the most affected hemisphere showed a negative correlation with a striatal cluster of 18F-FEOBV DVR in PD subjects (corrected P = 0.039). We also found that the mean 18F-FEOBV DVR within this cluster was higher in the PD group than in the control group (P = 0.01). Cross-validation analyses confirmed these findings. We also found an increase in bradykinesia ratings associated with increased acetylcholine-dopamine imbalance in the most affected hemisphere (r = 0.41, P = 0.006). Conclusion: Our results provide evidence for the existence of striatal acetylcholine-dopamine imbalance in early PD and may provide an avenue for testing invivo effects of therapeutic strategies aimed at restoring striatal acetylcholine-dopamine balance in PD.