Dopamine Buffering Capacity Measured by phMRI as a Novel Biomarker of Disease Progression in Parkinson's Disease

Study Rationale:
This project will test a new idea for measuring the severity of Parkinson's disease (PD). The brain acts as if it can store each dose of levodopa (L DOPA) for a short period of time and lets it "leak" into the brain when needed. This levodopa reservoir appears to get "leakier" as PD progresses, contributing to a gradually briefer benefit from each dose of the drug. The new idea we aim to test is whether measuring this "leakiness" in different brain regions can accurately measure the severity of PD.

Hypothesis:
We hypothesize that the effect site rate constant (k_e) measured in the midbrain and putamen will correlate with clinical estimates of disease severity. We also hypothesize that the measured rate constant (k_e's) will be stable several weeks after treatment with levodopa.

Study Design:
We will give an intravenous (IV) infusion of levodopa to 20 participants with PD, covering a wide range of PD severity. Before, during and after the dose, we will repeatedly measure the activity in different brain regions using a method called arterial spin labeling (ASL) magnetic resonance imaging (MRI). We will also check levodopa blood levels during the scan. From these data, we will calculate k_e in the midbrain and in the left and right posterior putamen. Finally, we test whether these k_e values can predict PD severity, measured previously using standard clinical rating scales and speed measurements. To test our second hypothesis, 10 participants with PD who are not yet taking medicine for PD will undergo the same procedures twice, before and after about six weeks of treatment with carbidopa and levodopa.

Impact on Diagnosis/Treatment of Parkinson's Disease:
To test whether a new treatment can slow the course of PD, we need a valid and objective measurement of disease severity, preferably one that can be repeated easily over time. If our new approach works, it will do just that.

Next Steps for Development:
These initial studies will provide a good idea as to whether this new method works but they rely on comparisons between people with different severity of PD. The next step will be to re-test these participants over time, perhaps at 2-3 and at 5-10 years after the initial test, to confirm that individual changes in clinical disease severity are reflected by changes in each person's k_e's.