Short- and Long-Duration Response to Levodopa Critical to Improving Motor Performance in Parkinson Disease

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In a recent analysis, acute levodopa induced a robust short-duration response (SDR) and long-duration response (LDR), with further improvement in the combined SDR plus LDR state in patients with Parkinson disease.

Taraz G. Lee PhD, assistant professor of psychology at University of Michigan

Taraz G. Lee PhD

Newly published in Movement Disorders, findings from a recent observational study (NCT04821830) on impaired movement vigor, or bradykinesia, showed that acute levodopa (l-dopa) induced a robust short-duration response (SDR) and long-duration response (LDR) among patients with Parkinson disease (PD), with further improvement in the combined SDR+LDR state.1 Although consistent with prior results in chronically treated patients with PD, these results suggest that bradykinesia, a cardinal feature of PD, is not solely secondary to deficient modulation of motivational processes.2

Among 11 de novo participants with PD, the initial dose of l-dopa (SDR session) produced a mean Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS III) score improvement of 22.5% relative to pre-treatment baseline and finger tapping rates improved by 16.6%. Following LDR induction, participants demonstrated further improvement 40.75% in UPDRS-III scores and 25.25% in finger tapping rates. The combined treatment state (SDR + LDR) yielded further improvement (UPDRS-III, 52.98% decrease; finger tapping, 31.98% increase).

Clinical Takeaways

  • This study challenges the simplistic view of bradykinesia in PD, revealing its multifaceted nature with distinct short and long-duration responses to acute levodopa.
  • The introduced task offers a promising alternative for assessing motor performance, providing richer datasets aligned with traditional measures in PD.
  • These findings underscore the interplay of short and long-duration responses with levodopa, emphasizing the need to consider both aspects for motor dysfunction in PD.

"Our work is unique in that we examined patients with PD as they began dopamine replacement therapy (DRT). This allowed us to characterize the effects of the SDR of DRT (i.e., an acute dose), the LDR of DRT (the effect of sustained treatment in the absence of an acute dose on a given day), and their combined effect on motor performance. Almost all prior work looking at the effect of dopamine agonists on patients with PD has examined people with chronic treatment on- and off-drug after either taking or abstaining from a single dose," senior author Taraz G. Lee PhD, assistant professor of psychology at University of Michigan, told NeurologyLive®. "Here, we are able to show the independent effects of the SDR and the LDR. The main (and somewhat surprising finding) from our research is that while overall motor performance improves quite a bit with both the SDR and LDR individually, reinstating the link between motivation and movement vigor (speed/force of movement) requires the combined action of the SDR and the LDR. No current theories of dopaminergic function predict that both would be required."

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Investigators studied de novo participants with PD (men, n = 6; women, n = 5; mean age, 67) before treatment, after an acute levodopa dose, and in both the practical "off" (LDR) and "on" (LDR + SDR) states after chronic stable treatment to disambiguate the 2 types of responses. At each visit, the participants were characterized with a standard battery including the MDS-UPDRS and an incentivized joystick task to evaluate motor performance in response to varying rewards.

All told, participants' movement times improved substantially relative to baseline following SDR induction (probability of direction [pd] = 100%), with little evidence of improvement in movement error (pd = 64.98%). Notably, the movement times were similar between SDR sessions and LDR sessions (pd = 65.93%) as participants showed a marked improvement in movement error between these sessions (pd = 99.03%). Additionally, the LDR + SDR sessions showed improvements in both movement time and accuracy relative to previous sessions (all pd > 98.43%).

The joystick outcome measures were highly correlated with both UPDRS-III scores and finger tapping rates. Investigators reported that UPDRS-III scores strongly predicted movement time, linearity, and efficiency (time: median = 0.012 seconds [HDI, 0.006-0.017], pd = 100%; Spearman's ρ = 0.298, P = .059; linearity: median = 0.122 [HDI, 0.018-0.226], pd = 98.94%; ρ = 0.462, P = .002; efficiency: median = 0.013 [HDI, 0.004-0.023], pd = 100%; ρ = 0.418, P = 0.006). Similarly, authors also noted that the finger tapping rates strongly predicted movement times (median = −0.005 s [HDI, −0.007 to −0.004], pd = 100%; ρ = −0.733, P = 5e−08).

“The major implication of these results are that we still don't yet fully understand how dopaminergic function relates to motivation and motor control and more theoretical and experimental work is needed. For patients, I think our work should reinforce the notion that it's not just the acute dose of dopaminergic drugs that has benefits, but rather the sustained use over longer periods of time (weeks/months) that has very large beneficial effects,” Lee told.

Participants displayed no modulation of movement time, error, or efficiency related to rewards at baseline and during the SDR sessions. Authors noted that a discrepancy in movement error emerged in the SDR session between $20 and both $10 and $5 rewards, contrary to expected scaling of movement linearity with reward. Notably, participants showed lower precision when anticipating a $20 reward compared with both $10 and $5. In the LDR session, no modulation of motor performance by reward was observed (all pd < 86%). However, a reward effect surfaced in the final SDR + LDR session, which provided strong evidence that participants were faster and more precise in their movements on high reward ($20) trials than on low reward ($5) trials (all pd > 95%).

Limitations of the study include the small sample size, because of challenges with recruitment of a large sample of de novo participants with PD. Authors note that it is unclear whether these new results will extend to alternative tasks with different motor requirements for successful performance. Additionally, the current study only examined 2 aspects of bradykinesia, slowing of movement and movement linearity, but it also encompasses progressive decrements in movement speed and amplitude with repetition.3

"We are interested in following up to examine how the LDR might contribute to improving other symptoms of PD, such as different facets of bradykinesia. We would encourage other researchers to consider that the LDR has very large effects and to acknowledge that we still have a relatively poor understanding of how DRT produces such amazing benefits,” Lee added.

REFERENCES
1. Brissenden JA, Scerbak T, Albin RL, Lee TG. Motivational Vigor in Parkinson's Disease Requires the Short and Long Duration Response to Levodopa. Mov Disord. Published online December 7, 2023. doi:10.1002/mds.29659
2. Mazzoni P, Hristova A, Krakauer JW. Why don't we move faster? Parkinson's disease, movement vigor, and implicit motivation. J Neurosci. 2007;27(27):7105-7116. doi:10.1523/JNEUROSCI.0264-07.2007
3. Postuma RB, Berg D, Stern M, et al. MDS clinical diagnostic criteria for Parkinson's disease. Mov Disord. 2015;30(12):1591-1601. doi:10.1002/mds.26424
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