Longitudinal evolution of compensatory changes in striatal dopamine processing in Parkinson's disease

Ramachandiran Nandhagopal, Lisa Kuramoto, Michael Schulzer, Edwin Mak, Jacqueline Cragg, Jess McKenzie, Siobhan McCormick, Thomas J. Ruth, Vesna Sossi, Raul De La Fuente-Fernandez, A. Jon Stoessl*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

103 Citations (Scopus)

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) [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.

Original languageEnglish
Pages (from-to)3290-3298
Number of pages9
JournalBrain
Volume134
Issue number11
DOIs
Publication statusPublished - Nov 2011

Keywords

  • PET
  • Parkinson's disease
  • compensatory changes
  • motor dysfunction
  • striatal dopamine processing

ASJC Scopus subject areas

  • Clinical Neurology

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