Morphometric and metabolic evidence for preclinical compensation in Parkin-associated parkinsonism

There is little knowledge about in vivo changes in the human brain that precede the onset of parkinsonism. In this study we sought to investigate potential preclinical changes in brain tissue in asymptomatic carriers of Parkin mutations using voxel-based morphometry and to compare those changes with the sites of chronic metabolic dysfunction identified previously in same patients group using 18-fluorodopa (FDOPA) PET.

In 13 asymptomatic right-handed carriers of heterozygous mutations in the Parkin gene and 13 age-matched right-handed healthy structural MR scanning using a T1-weighted FLASH 3D MR sequence (TE=5 ms; TR=15 ms; flip angle=30°; isotropic voxel size 1×1 x 1mm3) was performed. Using a general linear model, voxel-by-voxel t-tests were computed to detect differences in gray matter volume between groups. At a voxel level, the results were thresholded using p<0.001 (uncorrected). In addition, we applied an extent threshold corresponding to p<0.01 (uncorrected). We found an increase in gray matter volume in the left globus pallidus internus (GPI) extending into the medial and caudal portion of the left putamen and the left nucleus subthalamicus. By lowering the extent threshold, an increase in gray matter volume was also observed in the right basal ganglia. In nine of these patients region of interest analysis of the parametric FDOPA-PET data revealed a small, but significant decrease of the presynaptic dopamine metabolism in the bilateral posterior putamen. In order to compare the metabolic and structural data both PET and MRI data sets have been corregistered and the volume of the hypertrophic tissue was compared voxel-by-voxel with the volume of the hypometabolic volume. Both overlapped to 80%.

The combined analysis revealed that the hypertrophy of the basal ganglia output structures in asymptomatic carriers of Parkin mutations, as revealed by voxel-based morphometry, is related to the chronic dopaminergic deficit, as revealed by FDOPA-PET, and may represent an active mechanism compensating for preclinical minor motor deficits.