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
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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

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Figure 3

Increased resting activity in the sensorimotor cortex in unmedicated levodopa-induced dyskinesia (LID) and non-LID (NLID) subjects.

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Increased resting activity in the sensorimotor cortex in unmedicated lev...
(A) Voxel-wise comparison of baseline (OFF) cerebral blood flow (CBF) scans from the 14 NLID and 14 LID subjects revealed significantly increased bilateral resting activity in the sensorimotor cortex (SMC) in the latter group. Clusters were displayed using a red–yellow scale thresholded at T = 3.47 (P < 0.001, uncorrected, with cluster extent >100 voxels), superimposed on a single-subject MRI template. (B) Box-and-whisker plots of the individual subject SMC data. During levodopa infusion (ON), regional CBF values (left) increased significantly in both NLID and LID subjects, whereas cerebral metabolic rate (CMR) values (right) were not altered by drug. Arrows indicate post hoc Bonferroni tests for group comparisons in the 2-way 2 × 2 repeated-measures ANOVA. Horizontal lines represent Student’s t tests comparing local values measured in the LID and NLID groups. *P < 0.05, Student’s t test compared with normal (NL; n = 14) values. (C) Receiver-operating characteristic curves showing the discrimination of LID from NLID subjects based upon the combination of putamen dissociation index (DI) and resting SMC CBF (blue curve) or CMR (red curve) values measured in the baseline unmedicated condition. Accurate discrimination of individual subjects was achieved by logistic regression models based on these variables (P < 0.002). Each of the 2-variable discriminant models was superior to a 1-variable model (dotted curve) in which symptom duration was the only predictor (P < 0.02).