Physiology of Dopa-Induced Dyskinesias: A Case Study with Pharmacologic Activation PET

Early treatment of Parkinson's Disease (PD) with levodopa, a dopamine precursor, generally produces satisfactory results. However, with disease progression and prolonged treatment, dose-related involuntary movements (dyskinesias) often develop and can be a significant treatment-limiting side effect, often worse than the original PD symptoms. The pathophysiologic reason for dopa-induced dyskinesias is still not clear, but one hypothesis that we are investigating states that dyskinesias are caused by dopamine D1 receptors that develop an abnormal sensitivity to levodopa.

To gather preliminary data to test this hypothesis, we reviewed neuroimaging studies done over the course of several years in a single baboon. Injected with MPTP in one hemisphere of the brain, this baboon developed PD-like symptoms in one half of the body (hemiparkinsonism), allowing for both an experimental and control side of the brain in the same animal during the same study. As expected, the baboon developed dyskinesias after chronic treatment with levodopa. In these studies, regional cerebral blood flow (rCBF) was measured with positron emission tomography (PET) before and after acute administration of a dopamine D1 agonist (SKF82958 0.1 mg/kg iv). We hypothesized that the development of dyskinesias would be accompanied by a change in the rCBF response on the symptomatic side in globus pallidus and the ventrolateral (VL) nucleus of thalamus, locations of interest because they have previously been implicated as possibly playing a role in dopa-induced dyskinesias.

These regions were traced by hand on a structural magnetic resonance image (MRI) of the baboon's brain, with reference to a published atlas. The PET blood flow images were aligned to the MRI using an automated method, and data was extracted from the aligned PET images using the regions defined for globus pallidus and VL nucleus of thalamus.

The rCBF response of the VL nucleus of thalamus (VL) and globus pallidus (GP) to the D1 agonist compared to the whole brain is shown in the table below:

	VL Control Side	VL Lesioned Side	GP Control Side	GP Lesioned Side
Baseline	-5.6%	-13.6%	-8.6%	3.1%
Post-MPTP	-8.7%	-0.2%	-2.9%	1.0%
Post-treatment	-2.8%	-11.2%	-4.4%	-1.9%
Post-dyskinesias	-0.8%	-5.3%	6.9%	-5.4%

This study in a single subject suggests that changes in basal ganglia activity as detected with this PET method may relate to the development of dyskinesias. To confirm these findings would require replication in other subjects.

This research demonstrates the use of methods which will be applied to similar investigations with this subject using D2- or D3-preferring dopamine agonists. Also, a similar strategy is being used to extract regional PET data from human volunteers who have also had an MRI of the brain. This research is taking the next few steps necessary to discover the reasons behind dopa-induced dyskinesias. With this information, we hope to find out how to prevent this devastating side effect from occurring. This could help Parkinson's patients lead more normal lives, and the process will help us to learn more about how the human brain functions.