title: Morphometric fingerprint of asymptomatic Parkin and PINK1 mutation carriers in the basal ganglia.
abstract: 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 (18)F-DOPA PET. The metabolic-morphometric regression analysis revealed that the linear decrease in individual presynaptic striatal (18)F-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.
authors.affiliation: Department of Neurology, University Hospital Schleswig-Holstein, Campus Luebeck, Luebeck, Germany. ferdinand.binkofski@neuro.uni-luebeck.de
authors.forename: F
authors.initials: F
authors.lastname: Binkofski
authors.forename: K
authors.initials: K
authors.lastname: Reetz
authors.forename: C
authors.initials: C
authors.lastname: Gaser
authors.forename: R
authors.initials: R
authors.lastname: Hilker
authors.forename: J
authors.initials: J
authors.lastname: Hagenah
authors.forename: K
authors.initials: K
authors.lastname: Hedrich
authors.forename: T
authors.initials: T
authors.lastname: van Eimeren
authors.forename: A
authors.initials: A
authors.lastname: Thiel
authors.forename: C
authors.initials: C
authors.lastname: Büchel
authors.forename: P P
authors.initials: PP
authors.lastname: Pramstaller
authors.forename: H R
authors.initials: HR
authors.lastname: Siebner
authors.forename: C
authors.initials: C
authors.lastname: Klein
mesh_terms: D000328:Adult; D001480:Basal Ganglia Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D003342:Corpus Striatum / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology*; D004252:DNA Mutational Analysis; D004295:Dihydroxyphenylalanine / Q000031:analogs & derivatives; D004298:Dopamine / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D005838:Genotype; D005917:Globus Pallidus / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006579:Heterozygote; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D049268:Positron-Emission Tomography; D011494:Protein Kinases / Q000235:genetics*; D011699:Putamen / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*; D000099202:PTEN-Induced Putative Kinase
chemical_list: D004295:Dihydroxyphenylalanine; D004298:Dopamine; D011494:Protein Kinases; D044767:Ubiquitin-Protein Ligases; D000099202:PTEN-Induced Putative Kinase; C043437:fluorodopa F 18; C111567:parkin protein