Progression in the LRRK2-Asssociated Parkinson Disease Population

Abstract

Importance: Few prospective longitudinal studies have evaluated the progression of Parkinson disease (PD) in patients with the leucine-rich repeat kinase 2 (LRRK2 [OMIM 609007]) mutation. Knowledge about such progression will aid clinical trials.

Objective: To determine whether the longitudinal course of PD in patients with the LRRK2 mutation differs from the longitudinal course of PD in patients without the mutation.

Design, setting, and participants: A prospective comprehensive assessment of a large cohort of patients from 3 sites with LRRK2 PD or with nonmutation PD was conducted from July 21, 2009, to September 30, 2016. All patients of Ashkenazi Jewish ancestry with PD were approached at each site; approximately 80% agreed to an initial visit. A total of 545 patients of Ashkenazi Jewish descent with PD who had 1 to 4 study visits were evaluated. A total of 144 patients (26.4%) had the LRRK2 G2019S mutation. Patients with GBA (OMIM 606463) mutations were excluded from the analysis.

Main outcomes and measures: Linear mixed-effects models for longitudinal motor scores were used to examine the association of LRRK2 mutation status with the rate of change in Unified Parkinson's Disease Rating Scale III scores using disease duration as the time scale, adjusting for sex, site, age, disease duration, cognitive score, and levodopa-equivalent dose at baseline. Mixed-effects models were used to assess change in cognition, as measured by Montreal Cognitive Assessment scores.

Results: Among the 545 participants, 233 were women, 312 were men, and the mean (SD) age was 68.2 (9.1) years for participants with the LRRK2 mutation and 67.8 (10.7) years for those without it. Seventy-two of 144 participants with the LRRK2 mutation and 161 of 401 participants with no mutation were women. The estimate (SE) of the rate of change in the Unified Parkinson's Disease Rating Scale III motor score per year among those with the LRRK2 mutation (0.689 [0.192] points per year) was less than among those without the mutation (1.056 [0.187] points per year; difference, -0.367 [0.149] points per year; P = .02). The estimate (SE) of the difference in the rate of change of the Montreal Cognitive Assessment score between those with the LRRK2 mutation (-0.096 [0.090] points per year) and those without the mutation (-0.192 [0.102] points per year) did not reach statistical significance (difference, 0.097 [0.055] points per year; P = .08).

Conclusions and relevance: Prospective longitudinal follow-up of patients with PD with or without the LRRK2 G2019S mutation supports data from a cross-sectional study and demonstrates a slower decline in motor Unified Parkinson's Disease Rating Scale scores among those with LRRK2 G2019S-associated PD.

Figure 1.. Longitudinal Trajectories of Mean Unified Parkinson’s Disease Rating Scale III (UPDRS III) Scores for Patients With Parkinson Disease (PD) Who Carry the Leucine-Rich Repeat Kinase 2 (LRRK2) Mutation Compared With Patients With Idiopathic PD (IPD)

Longitudinal trajectories of mean UPDRS III scores show slower progression for patients with PD who carry the LRRK2 mutation than for patients with IPD. This included individuals sampled at different time points in the course of the disease. Individuals were followed up between 0 and 6 follow-up visits. Thus, no individual was followed up for the full duration described on the x-axis. The graphs demonstrate the mean UDPRS III score change in the IPD and LRRK2 PD groups with covariates fixed at the following values: baseline age = 67 years, baseline disease duration = 0 years, Montreal Cognitive Assessment score = 25, levodopa-equivalent dose = 457 mg levodopa, sex = female, and site = Tel Aviv. Trajectories are adjusted for the covariates described in Table 2. Spaghetti plots demonstrating the change for individual participants are shown in eFigure 5 in the Supplement.

Figure 2.. Longitudinal Trajectories of Montreal Cognitive Assessment (MoCA) Scores in Patients With Parkinson Disease (PD) Who Carry the Leucine-Rich Repeat Kinase (LRRK2) Mutation Compared With Patients With Idiopathic PD (IPD)

Longitudinal trajectories of MoCA scores show slower progression for patients with PD who carry the LRRK2 mutation than for patients with IPD. This included individuals sampled at different time points in the course of the disease. Individuals were followed up between 0 and 6 follow-up visits. Thus, no individual was followed for the full duration described on the x-axis. Spaghetti plots demonstrating the change for individual participants are shown in eFigure 5 in the Supplement.