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Brain Advance Access originally published online on April 16, 2004
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Brain, Vol. 127, No. 6, 1332-1342, 2004
© 2004 Guarantors of Brain
doi: 10.1093/brain/awh150

Striatal and cortical pre- and postsynaptic dopaminergic dysfunction in sporadic parkin-linked parkinsonism

Christoph Scherfler1, Naheed L. Khan2, Nicola Pavese1, Louise Eunson2, Elizabeth Graham{dagger},2, Andrew J. Lees4, Niall P. Quinn3, Nicholas W. Wood2, David J. Brooks1 and Paola P. Piccini1

1 MRC Clinical Science Centre and Division of Neuroscience, Faculty of Medicine, Imperial College, Hammersmith Hospital, 2 Department of Molecular Pathogenesis, 3 Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, and 4 Reta Lila Weston Institute of Neurological Studies, Royal Free Hospital and University College Medical School, London, UK.

{dagger}Deceased October 2001Correspondence to: Dr Paola Piccini, Cyclotron Building, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK E-mail: paola.piccini{at}csc.mrc.ac.uk

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 [18F]dopa and [11C]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 [18F]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 [18F]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 [18F]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.

Key Words: parkin gene; PET; [18F]dopa; [11C]raclopride; SPM

Abbreviations: AADC= aromatic amino acid decarboxylase; AI = asymmetry index; BA = Brodmann area; BP = binding potential; Ki0 = influx rate constant; IPD = idiopathic Parkinson’s disease; PCR = polymerase chain reaction; RAC = [11C]raclopride, ROI = region of interest; SPM = statistical parametric mapping; UPDRS = Unified Parkinson’s Disease Rating Scale; YOPD = young-onset Parkinson’s disease

Received September 16, 2003. Revised January 20, 2004. Accepted January 26, 2004.


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