The dopamine precursor levodopa is the most effective medication available for the treatment of Parkinson's disease (PD), but eventually it causes levodopa-induced dyskinesias (LID) in the vast majority of the patients. Experimental studies in a rodent model indicate that following peripheral levodopa administrafion there is a larger and prompter surge in striatal dopamine levels (DA) in animals with LID. Because the passage of levodopa through the blood-brain barrier (BBB) is critically regulated at the level of the endothelium, neurovascular alterations need to be thoroughly invesfigated as a possible contribufing factor in LID. To that end, we will expand upon our recent observation in PD patients, that levodopa has divergent effects on regional cerebral metabolism and blood flow, and that the magnitude of local flowmetabolism dissociation, a quantitative index of treatment-mediated hemodynamic alterations, is much greater in patients with LID than those with uncomplicated treatment responses.
In Specific Aim 1, we will study two groups of patients, those with LID and those with uncomplicated levodopa responses, using [^?F]-FDG PET (for cerebral metabolism), [^^0]-H20 PET (for cerebral blood flow), and [?^Rb]-Rubidium PET (for BBB permeability) to compare levodopa-mediated changes across groups.
In Specific Aim 2, we will determine whether localized vasomotor and/or BBB changes exist in drug-naive PD patients and whether fiow-metabolism dissociation develops following one year of treatment with levodopa, but not dopamine agonist.
In Specific Aim 3, we will use a rat model of LID to determine whether changes in local cerebral blood flow relate to structural alterations of the microvasculature and BBB permeability in the affected regions. Previous studies in this animal model have indeed revealed increased angiogenesis and BBB permeability in the basal ganglia. Given that analogous changes have very recently been noted in the basal ganglia of human PD brains at autopsy, this project provides a unique opportunity for translational investigation directed at a major challenge confronting PD patients and their caretakers.

Public Health Relevance

The development of levodopa-induced dyskinesias (LID) in Parkinson's disease (PD) is poorly understood. Using a translational approach, this project will further the understanding of the pathophysiology of this potentially disabling side effect of therapy, and should open avenues for the development of new treatments of LID. Furthermore, improved understanding ofthe role of angiogenesis and blood-brain barrier in PD is likely also relevant to other neurodegenerative diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Specialized Center (P50)
Project #
5P50NS071675-05
Application #
8741997
Study Section
Special Emphasis Panel (ZNS1-SRB-E)
Project Start
Project End
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
5
Fiscal Year
2014
Total Cost
$481,732
Indirect Cost
$162,501
Name
Feinstein Institute for Medical Research
Department
Type
DUNS #
110565913
City
Manhasset
State
NY
Country
United States
Zip Code
11030
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Lerner, Renata P; Bimpisidis, Zisis; Agorastos, Stergiani et al. (2016) Dissociation of metabolic and hemodynamic levodopa responses in the 6-hydroxydopamine rat model. Neurobiol Dis 96:31-37
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Jourdain, Vincent A; Tang, Chris C; Holtbernd, Florian et al. (2016) Flow-metabolism dissociation in the pathogenesis of levodopa-induced dyskinesia. JCI Insight 1:e86615
Spetsieris, Phoebe G; Ko, Ji Hyun; Tang, Chris C et al. (2015) Metabolic resting-state brain networks in health and disease. Proc Natl Acad Sci U S A 112:2563-8

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