Flow-metabolism dissociation in the pathogenesis of levodopa-induced dyskinesia
Vincent A. Jourdain, … , Vijay Dhawan, David Eidelberg
Vincent A. Jourdain, … , Vijay Dhawan, David Eidelberg
Published September 22, 2016
Citation Information: JCI Insight. 2016;1(15):e86615. https://doi.org/10.1172/jci.insight.86615.
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Clinical Medicine 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 6

Clinical and network correlates of the putamen vasomotor response to levodopa.

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Clinical and network correlates of the putamen vasomotor response to lev...
Multiple regression analysis was performed to evaluate the relationship between vasomotor levodopa response (ΔCBFON-OFF) measured in the putamen dissociation region and independent descriptors of disease progression and chronic levodopa exposure (see Methods). In addition to disease duration and weight-corrected levodopa daily dose [LDD(w)], the model included off-state expression of the PD-related metabolic covariance pattern (PDRP), a metabolic network descriptor of disease progression measured over the entire brain (see text). (A) There was a striking spatial overlap (yellow) between PDRP regions with relatively increased metabolic activity (green) and areas with significant levodopa-mediated dissociation effects in the putamen (black contours). Positive voxel weights on the PDRP topography were thresholded at T = 3.12, P < 0.001, uncorrected, for the putamen. The display was overlaid on a standard MRI template. (B–D) Partial correlation leverage plots of the combined levodopa-induced dyskinesia (LID) (dark gray) and non-LID (NLID) (light gray) sample (n = 11 each) illustrate the unique effect of each predictor on the putamen vasomotor response to levodopa. (B) In accord with the observed spatial overlap, off-state PDRP expression exhibited a significant independent relationship with the putamen vasomotor response. (C) There was a significant relationship between the local dopaminergic vasomotor response and disease duration. (D) Levodopa dose [LDD(w)] was not a significant predictor of putamen ΔCBF.