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Motor Learning May Explain Long-Duration Response to Levodopa
- May 03 2012
People with Parkinson’s disease (PD) who are treated with levodopa often experience improvements in motor function that persist even after they stop taking the medication. New research funded by the Parkinson’s Disease Foundation (PDF) and published in Neurology, suggests that motor learning underlies this continued improvement, called long-duration response (LDR) to levodopa therapy.
Prior research performed by Un Jung Kang, M.D., and colleagues at the University of Chicago showed that mice with a condition resembling Parkinson’s were able to learn new motor skills when treated with dopamine, and that these skills persisted for several days after the researchers stopped dopamine therapy. In contrast, mice that were trained in motor tasks but not given dopamine therapy could not learn the new skills. The researchers hypothesized that dopamine may stimulate motor learning in the mice with Parkinson’s, and that the mice were retaining their new skills for a period of time after the therapy stopped.
To see whether a similar mechanism operates in humans, Dr. Kang and Peggy Auinger, M.S., analyzed data from a clinical trial of levodopa therapy, called the Earlier versus Later Levodopa Therapy in Parkinson’s Disease (ELLDOPA) study. In this study, participants with early PD performed a motor test known as two-point finger tapping, in which they touched two mechanical counters with fingers of their left and right hands as many times as possible in one minute. The researchers examined whether each person was left- or right-handed, reasoning that his or her dominant hand might respond more favorably to dopamine treatment because of its wider use in daily activities — similar to the motor training of mice.
At the beginning of the study, none of the people with Parkinson’s had taken levodopa. After an initial finger-tapping test, the participants either began levodopa therapy or received a placebo (an inactive substance, such as a sugar pill). The study participants repeated the test several times over a period of 42 weeks. For the final two weeks, all were taken off levodopa therapy, allowing researchers to examine the long-duration response.
- Over the course of the study, people who received levodopa therapy improved their finger-tapping scores. Their dominant hands showed greater improvement than the non-dominant hands.
- People who received the placebo did not see improvements in their finger tapping scores during the 42-week experiment. Also, the placebo group members showed no difference in finger tapping improvement between the dominant and non-dominant hands.
- The levodopa-treated group retained their improved finger-tapping scores for two weeks after being taken off levodopa therapy.
What Does It Mean?
The ELLDOPA study (funded by the PDF through the Advancing Therapies Grant to the Parkinson Study Group) was a pivotal study in PD. The original hypothesis of the researchers was that that levodopa treatment may be toxic, and that people who were treated with levodopa for a year would perform worse than those treated with placebo. However, not only did the levodopa treated participants perform better than those who were treated with placebo, they also performed better after two weeks of no treatment, suggesting that levodopa has some long lasting effects, the long duration response (LDR). Here, the researchers hypothesized that this LDR effect interacts with “training.” They show that this effect is more prominent in the dominant hand which is more often used than in the non-dominant hand.
The authors propose that the motor improvements observed in people treated with levodopa may explain many of the symptomatic benefits observed in clinical trials. This motor learning in the presence of dopamine may therefore be a form of disease modification, i.e., the body is able to adapt to PD in the presence of levodopa.
Further studies are needed to more directly address the roles of activity and motor learning in the dopamine LDR. If confirmed by additional research studies, these findings suggest that one positive effect of early dopaminergic treatment in people with Parkinson’s, may be an improvement of the body’s ability to adapt to Parkinson’s disease.
This study was funded by an Advancing Parkinson's Therapies grant to the Parkinson Study Group.
Reference: Jung Kang, U., Auinger, P., On behalf of the Parkinson Study Group ELLDOPA Investigators, & Mendis, T. (2012). Activity enhances dopaminergic long-duration response in Parkinson disease. Neurology, 78(15), 1146–1149. doi:10.1212/WNL.0b013e31824f8056
Source Date: May 03 2012