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Morphometric fingerprint of asymptomatic Parkin and PINK1 mutation carriers in the basal ganglia

From the Department of Neurology (F.B., K.R., J.H., K.H., C.K.), University Hospital Schleswig-Holstein, Luebeck; Department of Neurology (H.R.S.), University Hospital Schleswig-Holstein, Kiel; Department of Psychiatry (C.G.), University of Jena; Department of Neurology (R.H., A.T.), University of Cologne; Departments of Neurology (T.v.E.) and Systems Neuroscience (C.B.), University Medical Center Hamburg Eppendorf, Hamburg, Germany; Department of Neurology (P.P.P.), Central Hospital and Institute of Genetic Medicine, Eurac-Research, Bolzano-Bozen, Italy; and NeuroImage Nord (F.B., K.R., T.v.E., C.B., H.R.S.), Hamburg-Lübeck-Kiel, Hamburg, Germany.

Address correspondence and reprint requests to Dr. Ferdinand Binkofski, Department of Neurology, University Hospital Schleswig-Holstein, Campus Luebeck, Ratzeburger Allee 160, 23538 Luebeck, Germany ferdinand.binkofski{at}neuro.uni-luebeck.de

Background: Mutations in the Parkin and PINK1 genes can cause parkinsonism. Since asymptomatic carriers of a single mutant allele of the Parkin or PINK1 gene display a presynaptic dopaminergic dysfunction in the striatum, they provide a unique in vivo model to study structural and functional reorganization in response to latent nigrostriatal dysfunction. We hypothesized that subclinical nigrostriatal neurodegeneration caused by these mutations would induce morphologic changes in the dysfunctional striatal gray matter.

Methods: In asymptomatic carriers of a heterozygous Parkin (n = 13) or PINK1 (n = 10) mutation and 23 age-and sex-matched individuals without a mutation, we applied observer independent region-of-interest and voxel-based morphometry to high-resolution structural MRIs.

Results: Relative to controls without a mutation, Parkin and PINK1 mutation carriers displayed a bilateral increase in gray matter volume in the putamen and the internal globus pallidus. In 8 of the 13 Parkin mutation carriers, the presynaptic dopaminergic function was studied with ¹⁸F-DOPA PET. The metabolic-morphometric regression analysis revealed that the linear decrease in individual presynaptic striatal ¹⁸F-DOPA uptake was linked to a reciprocal decrease in the striatal gray matter volume in the putamen bilaterally and in the left caudate nucleus.

Conclusions: The alternative causes of the increased striatal gray matter volume may be either due to excessive levels of neuronal activity caused by chronic dopaminergic dysfunction or due to long-term adaptation to chronic nigrostriatal dysfunction actively compensating for the dopaminergic denervation. In any case, the results indicate that a genetically driven regional dysfunction may be imprinted in the structure of the dysfunctional brain region, for example in the striatum.

*Both authors contributed equally to this work.

This study was sponsored by the Deutsche Forschungsgemeinschaft (Kl-1134-2-2 and Kl-1134-3-1), the PD Foundation, the South Tyrolean Parkinson Association, and the EU-grant GENEPARK (EU-LSHB-CT-2006-037544). F.B., H.R.S., and C.B. were funded by the Bundesministerium für Bildung und Forschung (BMBF) (Neuroimagingzentrum NeuroImage-Nord, grant no. GF GO 01GO0205/-206/-207) and F.B. by (01GW0571). F.B., H.R.S., and C.B. were supported by separate project grants from the Volkswagen Foundation and K.R. and C.K. by intramural grants from the Medical Faculty, University of Luebeck. C.K. is a recipient of a Lichtenberg Career Development Award from the Volkswagen Foundation.

Disclosure: The authors report no conflicts of interest.

Received November 10, 2006. Accepted in final form March 27, 2007.

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