TY - JOUR
T1 - Longitudinal evolution of compensatory changes in striatal dopamine processing in Parkinson's disease
AU - Nandhagopal, Ramachandiran
AU - Kuramoto, Lisa
AU - Schulzer, Michael
AU - Mak, Edwin
AU - Cragg, Jacqueline
AU - McKenzie, Jess
AU - McCormick, Siobhan
AU - Ruth, Thomas J.
AU - Sossi, Vesna
AU - De La Fuente-Fernandez, Raul
AU - Stoessl, A. Jon
PY - 2011/11
Y1 - 2011/11
N2 - 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) [11C](±) dihydrotetrabenazine, to estimate the density of vesicular monoamine transporter type 2; (ii) [11C]d-threo-methylphenidate, to label the dopamine transporter; and (iii) 6-[18F]fluoro-l-DOPA, to assess the activity of aromatic amino acid decarboxylase and storage of 6-[18F]- 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-[18F]fluoro-l-DOPA and [11C]d-threo-methylphenidate values tended to approach [ 11C](±)dihydrotetrabenazine values in the putamen in later stages of disease (i.e. for [11C](±)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.
AB - 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) [11C](±) dihydrotetrabenazine, to estimate the density of vesicular monoamine transporter type 2; (ii) [11C]d-threo-methylphenidate, to label the dopamine transporter; and (iii) 6-[18F]fluoro-l-DOPA, to assess the activity of aromatic amino acid decarboxylase and storage of 6-[18F]- 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-[18F]fluoro-l-DOPA and [11C]d-threo-methylphenidate values tended to approach [ 11C](±)dihydrotetrabenazine values in the putamen in later stages of disease (i.e. for [11C](±)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.
KW - PET
KW - Parkinson's disease
KW - compensatory changes
KW - motor dysfunction
KW - striatal dopamine processing
UR - http://www.scopus.com/inward/record.url?scp=81055144433&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=81055144433&partnerID=8YFLogxK
U2 - 10.1093/brain/awr233
DO - 10.1093/brain/awr233
M3 - Article
C2 - 22075521
AN - SCOPUS:81055144433
SN - 0006-8950
VL - 134
SP - 3290
EP - 3298
JO - Brain
JF - Brain
IS - 11
ER -