Background and Objectives
There is clinical and phenotypic heterogeneity in LRRK2-G2019S PD, including loss of smell. Olfactory scores have defined subgroups of LRRK2 PD at baseline. We now extend this work longitudinally to better determine features associated with olfactory classes, and to gain further insight into this heterogeneity.
Methods
Evaluation of 162 LRRK2 PD and 198 IPD from the LRRK2 Ashkenazi Jewish Consortium with follow-up for 92 LRRK2 PD and 74 IPD. Olfaction (UPSIT), motor function (UPDRS), and cognition (Montreal Cognitive Assessment/MoCA), as well as sleep, non-motor, and mood were measured. Gaussian mixture models were applied on UPSIT percentile score to determine subgroups based on olfactory performance. Linear mixed effects models, using PD duration as the time scale, assessed the relationship between UPSIT subgroup membership and motor/cognitive change.
Results
Baseline olfaction was better in LRRK2 PD compared to IPD (mean UPSIT ± SD: 24.2 ± 8.8 vs 18.9 ± 7.6), with a higher mean percentile scores (difference:15.3 ± 11.6) (p<0.001), and less frequent hyposmia (55.6% vs. 85.4%; p<0.001). Analysis suggested three classes among LRRK2 PD. Age at onset in LRRK2 PD was earlier in the worst olfaction group (group 1) compared with groups 2 and 3 (54.5 ± 11.1 vs. 61.7 ± 9.3) (p=0.012), and separately in the hyposmic group overall (55.0 ± 11.3 vs. 61.7 ± 9.1) (p<0.001). Longitudinal motor deterioration in LRRK2 PD was also significantly faster in the worst UPSIT group than the best UPSIT group (group 3 vs. group 1: B=0.31, SE=0.35 vs. B=0.96, SE=0.28) (rate difference=-0.65, SE=0.29) (p=0.03). However, olfactory group membership was not significantly associated with cognitive decline.
Discussion
In this large LRRK2 cohort with longitudinal analysis, we extend prior work demonstrating subgroups defined by olfaction in LRRK2-G2019S-PD, and show that the worst olfaction group has earlier age at PD onset, and more rapid motor decline. This supports a subgroup of LRRK2 PD that might show more rapid change in a clinical trial of LRRK2 related agents, and highlights the need to integrate careful phenotyping into allocation schema in clinical trials of LRRK2 related agents.
Source: https://n.neurology.org/content/early/2022/06/03/WNL.0000000000200737
DOI: https://doi.org/10.1212/WNL.0000000000200737