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.

[1]  C Nahmias,et al.  Cerebral Metabolism of 6–[18F]Fluoro‐l‐3,4‐Dihydroxyphenylalanine in the Primate , 1987, Journal of neurochemistry.

[2]  K L Leenders,et al.  The nigrostriatal dopaminergic system in familial early onset parkinsonism with parkin mutations , 2001, Neurology.

[3]  A. Myers,et al.  Dopamine D2 receptor bands in normal human temporal cortex are absent in Alzheimer's disease , 1998, Brain Research.

[4]  C D Marsden,et al.  Differing patterns of striatal 18F‐dopa uptake in Parkinson's disease, multiple system atrophy, and progressive supranuclear palsy , 1990, Annals of neurology.

[5]  A. Ishikawa,et al.  Clinical analysis of 17 patients in 12 Japanese families with autosomal-recessive type juvenile parkinsonism , 1996, Neurology.

[6]  Y. Yamamura,et al.  Paralysis agitans of early onset with marked diurnal fluctuation of symptoms , 1973, Neurology.

[7]  J. Joyce,et al.  Limbic circuits and monoamine receptors: dissecting the effects of antipsychotics from disease processes. , 1997, Journal of psychiatric research.

[8]  P S Goldman-Rakic,et al.  Dopamine D2 receptors in the cerebral cortex: distribution and pharmacological characterization with [3H]raclopride. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[9]  Nicola Pavese,et al.  Progressive striatal and cortical dopamine receptor dysfunction in Huntington's disease: a PET study. , 2003, Brain : a journal of neurology.

[10]  T. Spinks,et al.  Physical characteristics of the ECAT EXACT3D positron tomograph. , 2000, Physics in medicine and biology.

[11]  Christer Halldin,et al.  Autoradiographic localization of extrastriatal D2‐dopamine receptors in the human brain using [125I]epidepride , 1996, Synapse.

[12]  W D Heiss,et al.  Positron emission tomographic analysis of the nigrostriatal dopaminergic system in familial Parkinsonism associated with mutations in the Parkin gene , 2001, Annals of neurology.

[13]  S. Dollfus,et al.  A comparison of plasma homovanillic acid in the deficit and nondeficit subtypes of schizophrenia , 1994, Biological Psychiatry.

[14]  Bonifati,et al.  Association between early-onset Parkinson's disease and mutations in the parkin gene. , 2000, The New England journal of medicine.

[15]  T Suhara,et al.  Carbon-11-FLB 457: a radioligand for extrastriatal D2 dopamine receptors. , 1995, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[16]  Nicola Pavese,et al.  Endogenous dopamine release after pharmacological challenges in Parkinson's disease , 2003, Annals of neurology.

[17]  Hitoshi Takahashi,et al.  An autopsy case of autosomal‐recessive juvenile parkinsonism with a homozygous exon 4 deletion in the parkin gene , 2000, Movement disorders : official journal of the Movement Disorder Society.

[18]  C. Patlak,et al.  Striatal 18F-DOPA Uptake: Absence of an Aging Effect , 1993, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[19]  M. Hoehn,et al.  Parkinsonism , 1967, Neurology.

[20]  K. Leenders,et al.  Effect of age on D2 dopamine receptors in normal human brain measured by positron emission tomography and 11C-raclopride. , 1993, Archives of neurology.

[21]  Nicola Pavese,et al.  Progression of nigrostriatal dysfunction in a parkin kindred: an [18F]dopa PET and clinical study. , 2002, Brain : a journal of neurology.

[22]  P. Griffiths,et al.  A detailed anatomical analysis of neurotransmitter receptors in the putamen and caudate in Parkinson's disease and Alzheimer's disease , 1994, Neuroscience Letters.

[23]  T. Ishikawa,et al.  Comparative nigrostriatal dopaminergic imaging with iodine-123-beta CIT-FP/SPECT and fluorine-18-FDOPA/PET. , 1996, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[24]  HOMAS,et al.  ASSOCIATION BETWEEN EARLY-ONSET PARKINSON ’ S DISEASE AND MUTATIONS IN THE PARKIN GENE , 2000 .

[25]  S. Fahn.  Unified Parkinson's Disease Rating Scale , 1987 .

[26]  W. Gibb,et al.  The relevance of the Lewy body to the pathogenesis of idiopathic Parkinson's disease. , 1988, Journal of neurology, neurosurgery, and psychiatry.

[27]  Richard S. J. Frackowiak,et al.  Striatal D2 receptor status in patients with Parkinson's disease, striatonigral degeneration, and progressive supranuclear palsy, measured with 11C‐raclopride and positron emission tomography , 1992, Annals of neurology.

[28]  S. Tsuji,et al.  Familial juvenile parkinsonism , 1994, Neurology.

[29]  C. Nahmias,et al.  Dopamine visualized in the basal ganglia of living man , 1983, Nature.

[30]  K. Leenders,et al.  Long‐term changes of striatal dopamine D2 Receptors in patients with Parkinson's disease: A study with positron emission tomography and [11C]Raclopride , 1997, Movement disorders : official journal of the Movement Disorder Society.

[31]  S. Tsuji,et al.  Novel mutations, pseudo‐dominant inheritance, and possible familial affects in patients with autosomal recessive juvenile parkinsonism , 2000, Annals of neurology.

[32]  A Dürr,et al.  [18F]-dopa PET study in patients with juvenile-onset PD and parkin gene mutations , 2000, Neurology.

[33]  Vincent J. Cunningham,et al.  Parametric Imaging of Ligand-Receptor Binding in PET Using a Simplified Reference Region Model , 1997, NeuroImage.

[34]  M. Polymeropoulos,et al.  Deletions in the Parkin gene and genetic heterogeneity in a Greek family with early onset Parkinson’s disease , 1998, Human Genetics.

[35]  N. Shimizu,et al.  Molecular genetic analysis of a novel Parkin gene in Japanese families with autosomal recessive juvenile parkinsonism: Evidence for variable homozygous deletions in the Parkin gene in affected individuals , 1998, Annals of neurology.

[36]  C. Goetz,et al.  Parkin mutations in a patient with hemiparkinsonism–hemiatrophy: A clinical–genetic and PET study , 2002, Neurology.

[37]  Robert M. Kessler,et al.  Identification of extrastriatal dopamine D2 receptors in post mortem human brain with [125I]epidepride , 1993, Brain Research.

[38]  Richard S. J. Frackowiak,et al.  Striatal function in normal aging: Implications for Parkinson's disease , 1990, Annals of neurology.

[39]  G. Sedvall,et al.  Quantitative analysis of D2 dopamine receptor binding in the living human brain by PET. , 1986, Science.

[40]  S. Minoshima,et al.  Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism , 1998, Nature.

[41]  N. Quinn,et al.  Clinical and pathologic abnormalities in a family with parkinsonism and parkin gene mutations , 2001, Neurology.

[42]  B. Bloch,et al.  Aromatic l-amino-acid decarboxylase (DOPA decarboxylase) gene expression in dopaminergic and serotoninergic cells of the rat brainstem , 1991, Neuroscience Letters.

[43]  J. Petter Gustavsson,et al.  D2 dopamine receptors and personality traits , 1997, Nature.

[44]  Karl J. Friston,et al.  Frontal, midbrain and striatal dopaminergic function in early and advanced Parkinson's disease A 3D [(18)F]dopa-PET study. , 1999, Brain : a journal of neurology.

[45]  David J Brooks,et al.  Plasticity of the nigropallidal pathway in Parkinson's disease , 2003, Annals of neurology.

[46]  Paola Piccini,et al.  Clinical and subclinical dopaminergic dysfunction in PARK6‐linked parkinsonism: An 18F‐dopa PET study , 2002, Annals of neurology.

[47]  Y. Agid,et al.  A wide variety of mutations in the parkin gene are responsible for autosomal recessive parkinsonism in Europe. French Parkinson's Disease Genetics Study Group and the European Consortium on Genetic Susceptibility in Parkinson's Disease. , 1999, Human molecular genetics.

[48]  Nobutaka Hattori,et al.  Ubiquitination of a New Form of α-Synuclein by Parkin from Human Brain: Implications for Parkinson's Disease , 2001, Science.

[49]  Karl J. Friston,et al.  Spatial registration and normalization of images , 1995 .

[50]  V Kaasinen,et al.  Extrastriatal dopamine D2 and D3 receptors in early and advanced Parkinson’s disease , 2000, Neurology.

[51]  J. Hietala,et al.  Sex differences in striatal presynaptic dopamine synthesis capacity in healthy subjects , 2002, Biological Psychiatry.

[52]  Nicolas Costes,et al.  Young-onset Parkinson disease with and without parkin gene mutations: a fluorodopa F 18 positron emission tomography study. , 2003, Archives of neurology.

[53]  C. Marsden,et al.  Recent Developments in Parkinson's Disease , 1986 .

[54]  R J Wyatt,et al.  In vivo PET studies of the dopamine D2 receptors in rhesus monkeys with long‐term MPTP‐induced parkinsonism , 2000, Synapse.

[55]  S. Carmichael,et al.  Reduced D2 dopamine and muscarinic cholinergic receptor densities in caudate specimens from fluctuating parkinsonian patients , 1991, Annals of neurology.

[56]  A. Rajput.  Pathologic and biochemical studies of juvenile parkinsonism linked to chromosome 6q. , 1999, Neurology.

[57]  P. Seeman,et al.  L-DOPA reverses the elevated density of D2 dopamine receptors in Parkinson's diseased striatum , 2005, Journal of Neural Transmission.

[58]  K. Någren,et al.  Sex differences in the striatal dopamine D2 receptor binding characteristics in vivo. , 1998, The American journal of psychiatry.

[59]  C S Patlak,et al.  Graphical Evaluation of Blood-to-Brain Transfer Constants from Multiple-Time Uptake Data , 1983, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[60]  C. Patlak,et al.  Nigrostriatal function in humans studied with positron emission tomography , 1989, Annals of neurology.

[61]  A A Schäffer,et al.  Localization of a gene for an autosomal recessive form of juvenile Parkinsonism to chromosome 6q25.2-27. , 1997, American journal of human genetics.