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

objectiveClinical heterogeneity exists in the optimal timing and dosage of symptomatic treatments for Parkinson's disease (PD). This study aimed to cluster PD patients on the basis of longitudinal trajectories of levodopa equivalent daily dose (LEDD) and evaluate the clinical features and progression associated with these clusters.

methodsFrom the Parkinson's Progression Markers Initiative database, we enrolled 301 PD patients who were followed up for at least 3 years after the initiation of antiparkinsonian medications. On the basis of the longitudinal trajectories of the LEDD increment, the participants were classified into three clusters: slow-increment, initial-increment, and rapid-increment. The outcomes were initial and longitudinal changes in motor phenotype, on-time motor symptoms, and the efficacy of antiparkinsonian medications.

resultsThe initial-increment cluster exhibited the greatest symptomatic improvements following the 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, whereas the efficacy of antiparkinsonian medications declined over time. The risk of disability related to walking and balance milestones and motor complications was twice as high in the initial-increment and rapid-increment clusters than in the slow-increment cluster.

conclusionHeterogeneity is noted in the increase in the use of antiparkinsonian medications, which is driven by changes in motor phenotype, medication efficacy, and the occurrence of PD-relevant milestones. Subtyping patients on the basis of LEDD trajectories may provide insight into clinical heterogeneity for future research on individualized treatment strategies for patients with PD.