Background: The treatment of Parkinson’s Disease (PD) with levodopa results in a meaningful and sustained reduction of symptoms, especially motor symptoms. Although the plasma half-life of levodopa is short, it elicits a lasting effect, termed the long-duration levodopa response (LDR). A decrease in LDR over the course of PD has been implicated in the occurrence of fluctuations and dyskinesias, but evidence on this is limited. To overcome this, we analyzed publicly available data from the Parkinson’s Disease Progression Marker Initiative (PPMI).
Methods: 149 therapy-naïve PD patients from the PPMI cohort were included. LDR, SDR and TR could be calculated for 109 of these patients from Unified Parkinson’s Disease Rating Scale Part III (UPDRS III) assessments before and after levodopa initiation (Figure 1). For further analyses, UPDRS III OFF without levodopa was modeled using a linear model based on the progression of UPDRS III OFF scores in therapy-naïve patients in the PPMI cohort. We then conducted correlations of LDR magnitude to fluctuations and dyskinesias as measured by UPDRS part IV scores.
Results: In the PPMI cohort, the LDR accounts for a substantial amount of the levodopa in PD patients with up to 10 years of PD (0-2 years: 57%, 2-4 years: 53%, 4-6 years: 53%, 6-8 years 60%, 8-10 years 57%, Figure 2). There was no significant change of the magnitude of LDR between time spans (ANOVA, p=0.38). The magnitude of LDR only significantly correlated with UPDRS IV scores in patients 2-4 years after levodopa initiation (Pearson’s r=-0.41, p=0.01, all other correlations p>0.09).
Conclusions: The LDR accounts for at least 50% of the total response to levodopa treatment in the first 10 years of PD in the PPMI cohort. Our findings challenge the notion that a decrease in LDR magnitude drives the occurrence of motor fluctuations in PD.