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 2

Dissociation of vasomotor and metabolic drug responses in an independent Parkinson’s disease sample.

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Dissociation of vasomotor and metabolic drug responses in an independent...
(A) We analyzed cerebral blood flow (CBF) and cerebral metabolic rate (CMR) scans acquired ON and OFF levodopa infusion from 14 Parkinson’s disease subjects with levodopa-induced dyskinesia (LID) and found significant dissociation of vasomotor and metabolic response to levodopa in regions near those identified in the non-LID-based (NLID-based) analysis (Figure 1A). Regional dissociation effects identified in the LID-based analysis were generally greater in magnitude and more bilateralized than those seen in their NLID counterparts. Clusters were displayed using a red–yellow scale thresholded at T = 4.50 (P < 0.05, family-wise error-corrected, with cluster extent >100 voxels), superimposed on a single-subject MRI template. (B) Dissociation index (DI) values were highly correlated (r = 0.88–0.99, P < 0.0001, regression analysis) for each of the significant dissociation regions identified in the independent LID- and NLID-based analyses. For each of the significant regions identified in the 2 analyses, volumes of interest (VOI) coordinates representing the peak voxel of the corresponding NLID- and LID-based clusters are provided on the x- and y-axis labels, respectively. For each region, individual DI values computed in the NLID- and LID-based VOIs are separately displayed for the 14 LID (dark gray), 14 NLID (light gray), and the 8 test-retest (TRT) (open circles) subjects.