Subtyping of Parkinson's Disease by Longitudinal Trajectories of Levodopa Equivalent Daily Dose.

Abstract

Objective: There is clinical heterogeneity on the optimal timing and dosage of symptomatic treatments in Parkinson's disease (PD). This study aimed to cluster PD patients based on longitudinal trajectories of LEDD and evaluate the clinical features and progression associated with these clusters.

Methods: From the Parkinson's Progression Markers Initiative database, we enrolled 301 PD participants, who were followed up for at least three years after the initiation of anti-parkinsonian medications. Based on the longitudinal trajectories of LEDD increment, participants were classified into three clusters: slow-increment, initial-increment, and rapid-increment. Outcomes were initial and longitudinal changes in motor phenotype, on-time motor symptoms, and the efficacy of anti-parkinsonian medications.

Results: The initial-increment cluster exhibited greatest symptomatic improvements by administration of higher doses of LEDD, although the motor improvement per unit of LEDD was comparable across clusters. Longitudinally, motor phenotypes changed rapidly in the initial-increment cluster. The initial-increment cluster showed continuous worsening of on-time motor symptoms, with limited LEDD efficacy. In contrast, the rapid-increment cluster exhibited stable on-time motor symptoms, while the efficacy of anti-parkinsonian medications declined over time. The risk of disability related to walking and balance milestone and motor complications were twice as high in the initial-increment and rapid-increment clusters compared to the slow-increment cluster.

Conclusions: There is heterogeneity in the increment of anti-parkinsonian medications, driven by changes in motor phenotype, medication efficacy, and the occurrence of PD-relevant milestones. Subtyping patients based on LEDD trajectories may provide insight into clinical heterogeneity for future research on individualized treatment strategies in PD.