Flow-metabolism dissociation in the pathogenesis of levodopa-induced dyskinesia
Vincent A. Jourdain, Chris C. Tang, Florian Holtbernd, Christian Dresel, Yoon Young Choi, Yilong Ma, Vijay Dhawan, David Eidelberg
Vincent A. Jourdain, Chris C. Tang, Florian Holtbernd, Christian Dresel, Yoon Young Choi, Yilong Ma, Vijay Dhawan, David Eidelberg
View: Text | PDF
Clinical Research and Public Health Neuroscience

Flow-metabolism dissociation in the pathogenesis of levodopa-induced dyskinesia

Abstract

Levodopa-induced dyskinesia (LID) is the most common, disruptive complication of Parkinson’s disease (PD) pharmacotherapy, yet despite decades of research, the changes in regional brain function underlying LID remain largely unknown. We previously found that the cerebral vasomotor and metabolic responses to levodopa are dissociated in PD subjects. Nonetheless, it is unclear whether levodopa-mediated dissociation is exaggerated in LID or distinguishes LID from non-LID subjects. To explore this possibility, we used dual-tracer positron emission tomography to quantify regional cerebral blood flow and metabolic activity in 28 PD subjects (14 LID, 14 non-LID), scanned before and during intravenous levodopa infusion. Levodopa-mediated dissociation was most prominent in the posterior putamen (P < 0.0001) and greater in LID than in non-LID and test-retest subjects. Strikingly, LID subjects also showed increased sensorimotor cortex (SMC) activity in the baseline, unmedicated state. Imaging data from an independent PD sample (106 subjects) linked these differences to loss of mesocortical dopamine terminals in advanced patients. In aggregate, the data suggest that LID results from an overactive vasomotor response to levodopa in the putamen on a background of disease-related increases in SMC activity. LID may thus be amenable to treatment that modulates the function of these 2 regions.

Authors

Vincent A. Jourdain, Chris C. Tang, Florian Holtbernd, Christian Dresel, Yoon Young Choi, Yilong Ma, Vijay Dhawan, David Eidelberg

×

Figure 4

Colocalization of levodopa-mediated cerebral blood flow (CBF) responses and dopaminergic deafferentation in the putamen and sensorimotor cortex of subjects with advanced Parkinson’s disease (PD).

Options: View larger image (or click on image) Download as PowerPoint
Colocalization of levodopa-mediated cerebral blood flow (CBF) responses ...
(A) Left: [18F]fluorodopa (FDOPA) uptake was significantly reduced in the putamen (top) in both the 59 mild (light gray) and 47 advanced (dark gray) PD subjects, and in the sensorimotor cortex (SMC) (bottom) in the advanced patients, compared with 10 healthy control (NL) subjects. Right: In advanced PD subjects, cerebral metabolic rate (CMR) values were significantly higher than normal in the putamen (P < 0.001; Student’s t test) but only marginally increased in the SMC (P = 0.08), compared with 19 NL subjects. Arrows indicate Student’s t tests between the 2 PD groups. P < 0.10, ***P < 0.001, Student’s t test compared to NL values. Note the outlier with extremely low FDOPA uptake in the SMC (left, bottom); excluding this subject did not alter the significance of the group comparisons. (B) Regions with significant reduction in dopaminergic input (identified in a voxel-wise analysis of FDOPA PET scans from 47 advanced PD subjects) are denoted in red. Similarly, regions with significant CMR elevation (identified by voxel-wise analysis of [18F]fluorodeoxyglucose PET scans acquired in the same individuals) are denoted in green (see text). Areas of overlap (yellow) exhibit both dopaminergic deafferentation and increased local metabolic activity. In the current study, areas of dissociation (black contours) in the putamen (top) and areas of increased baseline CBF in the SMC (bottom) colocalized almost exclusively with areas of overlap (yellow) (insets). Maps of reduced FDOPA uptake were thresholded at T = 6.0, P < 0.001, uncorrected, for the putamen (top) and at T = 1.67, P < 0.05, uncorrected, for the SMC (bottom). Maps of increased CMR were thresholded at T = 1.67, P < 0.05, uncorrected, for both regions. Displays were superimposed on a standard MRI template.