Increased gray matter volume of the basal ganglia – a morphometric fingerprint of presymptomatic compensation in genetically determined parkinsonism

Objectives: There is little knowledge about in vivo changes in the human brain that precede the onset of parkinsonism. The present study used voxel-based morphometry (VBM) to investigate brain tissue changes in asymptomatic carriers of heterozygous mutations in Parkin- and PINK1-genes, and 18F-DOPA PET to establish a possible correlation between the metabolic and morphometric status of asymptomatic Parkin and PINK1 mutation-carriers. Methods: We compared structural magnetic resonance (MR) images of asymptomatic heterozygous carriers of Parkin (n=13) and PINK1 mutations (n=10) with 23 age- and sex- matched healthy controls. MR images were preprocessed and analyzed with SPM2 (Wellcome Department of Cognitive Neurology, London, UK) and VBM, a fully automated technique for computerized analysis of differences in local gray matter volume. Categorical comparisons between the gray matter images of asymptomatic mutation carriers and the matched healthy controls were calculated using an exploratory threshold of p<0.01. Small volume correction was performed using a basal ganglia mask from the WFU-pickatlas (Wake Forest University, USA). Available 18F-DOPA-PET data of eight of the 13 Parkin mutation carrriers were employed to perform an individual correlation between the VBM and PET results on the voxel-by-voxel level. In each individual, a region of interest (ROI) was defined in the posterior putamen using the MRICRO software to obtain individual Ki values in this region. These subject specific Ki values were then used as a regressor to identify brain areas in which gray matter density was correlated with 18F-DOPA uptake. Results: The VBM data of the asymptomatic heterozygous Parkin and PINK1 mutations in comparison to sex- and age-matched normal non-carriers revealed an increase in gray matter volume in the basal ganglia, in particular in the putamen, discretely accentuated on the left side in Parkin (left: x=–22, y=–5, z=4, Z=2.86, pFDR=0.021, small volume correction [SVC]; right: x=29, y=–8, z=8, Z=2.68, pFDR=0.032, SVC) and more pronounced on the right side in PINK1 mutation carriers (right: x=28, y=0, z=–5, Z=3.03, pFDR=0.023, SVC; left: x=–32, y=–1, z=–6, Z=2.70, pFDR=0.046, SVC). In the conjunction analysis an increase in volume of the posterior putamen between the VBM data of Parkin and PINK1 mutation carriers could also be observed (right putamen: x=25, y=–1, z=7, Z=2.20; left putamen: x=–29, y=–6, z=–2, Z=2.16) (figure 1). The voxel-by-voxel correlation between the morphometric data and the individual striatal 18F-fluorodopa influx constant (Ki) in eight subjects revealed a significant negative correlation in the left posterior putamen (x=–17, y=1, z=4, Z=3.61, pFDR=0.026, SVC) and a less significant one in the right putamen (x=23, y=–4, z=–2, Z=3.15, pFDR=0.026, SVC) (figure 2).

Fig. 1

Fig. 2

Conclusion: Our data suggest that presynaptic dopaminergic dysfunction in the putamen in asymptomatic carriers of heterozygous Parkin and PINK mutations may lead to a chronic increase in neuronal activity within the basal ganglia and an increase in gray matter volume of the hyperactive structures. This increase in volume might represent a long-term consequence of adaptive plasticity in the basal ganglia, which allows for a compensation for the preclinical dopaminergic deficit, and may represent an active mechanism compensating for preclinical minor motor deficits in Parkinson's disease.