title: Longitudinal evolution of compensatory changes in striatal dopamine processing in Parkinson's disease.
abstract: Parkinson's disease is a relentlessly progressive neurodegenerative disease. Breakdown of compensatory mechanisms influencing putaminal dopamine processing could contribute to the progressive motor symptoms. We studied a cohort of 78 subjects (at baseline) with sporadic Parkinson's disease and 35 healthy controls with multi-tracer positron emission tomography scans to investigate the evolution of adaptive mechanisms influencing striatal dopamine processing in Parkinson's disease progression. Presynaptic dopaminergic integrity was assessed with three radioligands: (i) [(11)C](±)dihydrotetrabenazine, to estimate the density of vesicular monoamine transporter type 2; (ii) [(11)C]d-threo-methylphenidate, to label the dopamine transporter; and (iii) 6-[(18)F]fluoro-L-DOPA, to assess the activity of aromatic amino acid decarboxylase and storage of 6-[(18)F]-fluorodopamine in synaptic vesicles. The subjects with Parkinson's disease and the healthy controls underwent positron emission tomography scans at the initial visit and after 4 and 8 years of follow-up. Non-linear multivariate regression analyses with random effects were utilized to model the longitudinal changes in tracer values in the putamen standardized relative to normal controls. We found evidence for possible upregulation of dopamine synthesis and downregulation of dopamine transporter in the more severely affected putamen in the early stage of Parkinson's disease. The standardized 6-[(18)F]fluoro-L-DOPA and [(11)C]d-threo-methylphenidate values tended to approach [(11)C](±)dihydrotetrabenazine values in the putamen in later stages of disease (i.e. for [(11)C](±)dihydrotetrabenazine values <25% of normal), when the rates of decline in the positron emission tomography measurements were similar for all the markers. Our data suggest that compensatory mechanisms decline as Parkinson's disease progresses. This breakdown of compensatory strategies in the putamen could contribute to the progression of motor symptoms in advanced disease.
authors.affiliation: Pacific Parkinson's Research Centre, University of British Columbia and Vancouver Coastal Health, Vancouver, BC V6T 2B5, Canada.
authors.forename: Ramachandiran
authors.initials: R
authors.lastname: Nandhagopal
authors.forename: Lisa
authors.initials: L
authors.lastname: Kuramoto
authors.forename: Michael
authors.initials: M
authors.lastname: Schulzer
authors.forename: Edwin
authors.initials: E
authors.lastname: Mak
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Cragg
authors.forename: Jess
authors.initials: J
authors.lastname: McKenzie
authors.forename: Siobhan
authors.initials: S
authors.lastname: McCormick
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Ruth
authors.forename: Vesna
authors.initials: V
authors.lastname: Sossi
authors.forename: Raul
authors.initials: R
authors.lastname: de la Fuente-Fernandez
authors.forename: A Jon
authors.initials: AJ
authors.lastname: Stoessl
mesh_terms: D000328:Adult; D000368:Aged; D003342:Corpus Striatum / Q000000981:diagnostic imaging / Q000378:metabolism*; D018450:Disease Progression; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease / Q000000981:diagnostic imaging / Q000378:metabolism*; D011877:Radionuclide Imaging
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D004298:Dopamine