Striatal and cortical pre- and postsynaptic dopaminergic dysfunction in sporadic parkin-linked parkinsonism.
To investigate striatal and cortical pre- and postsynaptic dopaminergic function in parkin-linked parkinsonism, 13 unrelated patients homozygous or compound heterozygous for parkin mutations were studied with [(18)F]dopa and [(11)C]raclopride (RAC) PET. Data were compared with a young-onset Parkinson's disease (YOPD) cohort, matched for age, disease severity and duration, but negative for parkin mutations. Significant changes in [(18)F]dopa uptake and RAC binding potential (BP) were localized in striatum using regions of interest (ROIs) and throughout the entire brain volume with statistical parametric mapping (SPM). As expected, both YOPD and parkin patients showed significant decreases in striatal [(18)F]dopa uptake; however, in parkin patients, additional reductions in caudate and midbrain were localized with SPM. The RAC-BP was significantly decreased in striatal, thalamic and cortical areas (temporal, orbito-frontal and parietal cortex) in parkin compared with YOPD patients. Our [(18)F]dopa PET findings suggest that, compared with YOPD, parkin disease is associated with more severe and widespread presynaptic dopaminergic deficits. The global decreases in D2 binding found in parkin compared with YOPD patients could be a direct consequence of the parkin genetic defect itself or a greater susceptibility to receptor downregulation following long-term dopaminergic agent exposure. Cortical reductions in D2 binding may contribute to the behavioural problems reported in parkin patients.
Scherfler
Christoph
C
MRC Clinical Science Centre and Division of Neuroscience, Faculty of Medicine, Imperial College, Hammersmith Hospital, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK.
Khan
Naheed L
NL
Pavese
Nicola
N
Eunson
Louise
L
Graham
Elizabeth
E
Lees
Andrew J
AJ
Quinn
Niall P
NP
Wood
Nicholas W
NW
Brooks
David J
DJ
Piccini
Paola P
PP
D000328:Adult; D017668:Age of Onset; D000368:Aged; D002540:Cerebral Cortex / Q000000981:diagnostic imaging / Q000378:metabolism*; D003342:Corpus Striatum / Q000000981:diagnostic imaging / Q000378:metabolism*; D004295:Dihydroxyphenylalanine / Q000031:analogs & derivatives*; D004298:Dopamine / Q000502:physiology*; D005260:Female; D005462:Fluorine Radioisotopes; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010300:Parkinson Disease / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism*; D017729:Presynaptic Terminals / Q000502:physiology; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D014055:Tomography, Emission-Computed / Q000379:methods; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
D005462:Fluorine Radioisotopes; D017448:Receptors, Dopamine D2; C043437:fluorodopa F 18; D004295:Dihydroxyphenylalanine; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D004298:Dopamine