Evolution of prodromal clinical markers of Parkinson disease in a GBA mutation-positive cohort

Abstract

Importance: Numerically, the most important genetic risk factor for the development of Parkinson disease (PD) is the presence of a glucocerebrosidase gene (GBA) mutation.

Objective: To evaluate longitudinally and clinically a GBA mutation-positive cohort and the evolution of the prodromal features of PD.

Design, setting, and participants: Participants in a study of the etiology and prodrome of PD were reevaluated in this clinic-based 2-year follow-up report. Patients with type 1 Gaucher disease (GD) and heterozygous GBA mutation carriers were recruited in 2010 from the Lysosomal Storage Disorder Unit at the Royal Free Hospital, London, England. Thirty patients who previously received a diagnosis of type 1 GD, 28 heterozygous GBA mutation carriers, and 26 genetically unrelated controls were included. Exclusion criteria included a diagnosis of PD or dementia for both the patients with GD and the GBA mutation carriers and any existing neurological disease for the controls.

Main outcomes and measures: Assessment was performed for clinical markers using standardized scales for hyposmia, rapid eye movement sleep behavior disorder, depression, autonomic dysfunction, cognitive function, and parkinsonian motor signs (using the Unified Parkinson's Disease Rating Scale motor subscale [UPDRS part III]).

Results: Over 2 years, depression scores were significantly worse for heterozygous carriers (mean baseline, 0.65; mean follow-up, 2.88; P = .01), rapid eye movement sleep behavior disorder scores were significantly worse for patients with GD (mean baseline, 0.93; mean follow-up, 2.93; P < .001) and heterozygotes (mean baseline, 0.10; mean follow-up, 2.30; P < .001), and UPDRS part III scores were significantly worse for patients with GD (mean baseline, 4.29; mean follow-up, 7.82; P < .001) and heterozygotes (mean baseline, 1.97; mean follow-up, 4.50; P < .001). For controls, there was a small but significant deterioration in the UPDRS part II (activities of daily living) score (mean baseline, 0.00; mean follow-up, 0.58; P = .006). At 2 years, olfactory and cognitive assessment scores were lower in patients with GD and heterozygotes compared with controls, but they did not differ significantly from baseline. When the results from the patients with GD and the heterozygotes were combined, a significant deterioration from baseline was observed, as reflected in the Rapid Eye Movement Sleep Behaviour Disorder Questionnaire (mean baseline, 0.51; mean follow-up, 2.63; P < .001), Beck Depression Inventory (mean baseline, 1.72; mean follow-up, 4.44; P = .002), and UPDRS part II (mean baseline, 0.88; mean follow-up, 2.01; P < .001) and part III scores (mean baseline, 3.09; mean follow-up, 6.10; P < .001) (all P < .01), and at 2 years, significant differences in University of Pennsylvania Smell Identification Test, Unified Multiple System Atrophy Rating Scale, Mini-Mental State Examination, Montreal Cognitive Assessment, and UPDRS part II and part III scores were observed between patients with GD/heterozygotes and controls (all P < .05).

Conclusions and relevance: This study indicates that, as a group, GBA mutation-positive individuals show a deterioration in clinical markers consistent with the prodrome of PD. Within this group of individual, 10% appear to be evolving at a more rapid rate.

Figure 1

Clinical markers show progression in GBA mutation positive individuals in a two-year follow-up study. Figures demonstrate mean baseline and follow-up scores for olfaction (A), mean baseline and follow-up scores for autonomic dysfunction (B), mean baseline and follow-up MoCA scores (C) and mean baseline and follow-up MMSE scores (D) for Type 1 GD patients and heterozygous GBA positive carriers compared to controls. Means are plotted together with the SEM.

Figure 2

Clinical markers show progression in GBA mutation positive individuals in a 2-year follow-up study. Figures demonstrate a statistically significant increase in depressive symptoms for carriers at the follow-up evaluation (F), a statistically significant increase in mean follow-up RBDQ scores (E) and UPDRS III scores (H) in Type 1 GD patients and heterozygous GBA mutation positive carriers compared to controls, and a statistically significant increase in mean follow-up UPDRS II scores in Type 1 GD patients, heterozygous GBA mutation positive carriers, and controls (G). Means are plotted together with the SEM.