PROJECT SUIVIMARY (See instructions): 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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Specialized Center (P50)
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Special Emphasis Panel (ZNS1-SRB-E)
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Feinstein Institute for Medical Research
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Ko, Ji Hyun; Lerner, Renata P; Eidelberg, David (2015) Effects of levodopa on regional cerebral metabolism and blood flow. Mov Disord 30:54-63
Peng, Shichun; Ma, Yilong; Spetsieris, Phoebe G et al. (2014) Characterization of disease-related covariance topographies with SSMPCA toolbox: effects of spatial normalization and PET scanners. Hum Brain Mapp 35:1801-14
Peng, Shichun; Eidelberg, David; Ma, Yilong (2014) Brain network markers of abnormal cerebral glucose metabolism and blood flow in Parkinson's disease. Neurosci Bull 30:823-37
Ko, Ji Hyun; Feigin, Andrew; Mattis, Paul J et al. (2014) Network modulation following sham surgery in Parkinson's disease. J Clin Invest 124:3656-66
Holtbernd, Florian; Gagnon, Jean-Fran├žois; Postuma, Ron B et al. (2014) Abnormal metabolic network activity in REM sleep behavior disorder. Neurology 82:620-7
Tomer, Rachel; Slagter, Heleen A; Christian, Bradley T et al. (2014) Love to win or hate to Lose? Asymmetry of dopamine D2 receptor binding predicts sensitivity to reward versus punishment. J Cogn Neurosci 26:1039-48
Ko, Ji Hyun; Spetsieris, Phoebe; Ma, Yilong et al. (2014) Quantifying significance of topographical similarities of disease-related brain metabolic patterns. PLoS One 9:e88119
Holtbernd, Florian; Eidelberg, David (2014) The utility of neuroimaging in the differential diagnosis of parkinsonian syndromes. Semin Neurol 34:202-9
Papay, Kimberly; Xie, Sharon X; Stern, Matthew et al. (2014) Naltrexone for impulse control disorders in Parkinson disease: a placebo-controlled study. Neurology 83:826-33
Spetsieris, Phoebe; Ma, Yilong; Peng, Shichun et al. (2013) Identification of disease-related spatial covariance patterns using neuroimaging data. J Vis Exp :

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