Evolution and clustering of prodromal parkinsonian features in GBA1 carriers

Abstract

Background: Five to 25% of patients with PD carry glucocerebrosidase gene mutations, and 10% to 30% of glucocerebrosidase carriers will develop PD by age 80. Stratification of PD risk in glucocerebrosidase carriers provides an opportunity to target disease-modifying therapies.

Objective: Cross-sectional and longitudinal survey of prodromal PD signs among glucocerebrosidase carriers.

Design: Prospective assessment of 82 glucocerebrosidase mutation carriers and 35 controls over 4 to 5 years for prodromal clinical PD features.

Results: At all time points, olfactory (measured using University of Pennsylvania Smell Identification Test) and cognitive (Montreal Cognitive Assessment) function and the International Parkinson and Movement Disorder Society UPDRS parts II and III scores were significantly worse amongst glucocerebrosidase mutation carriers. Progression to microsmia (odds ratio: 8.5; 95% confidence interval: 2.6-28.2; P < 0.05) and mild cognitive impairment (odds ratio: 4.2; 95% confidence interval: 1.1-16.6; P < 0.05) were more rapid compared to controls. Those with worse olfaction also had worse cognition (OR, 1.5; 95% CI: 0.0-2.8; P < 0.05) and depression (OR, 1.3; 95% CI: 0.6-2.8; P < 0.05). No participants reached the MDS prodromal PD diagnostic criteria before PD diagnosis. One participant developed PD. He did not fulfill the International Parkinson and Movement Disorder Society prodromal PD criteria before diagnosis.

Conclusion: Assessment of individual and clustered PD prodromal features may serve as a useful tool to identify high-risk subjects for conversion to PD. As a result of the low conversion rate in our glucocerebrosidase mutation carriers to date, prospective validation is needed in larger cohorts to establish the profile of these features in PD convertors. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Keywords: Gaucher; Parkinson's; cognition; depression; glucocerebrosidase; olfaction; prodromal.

Figure 1

Trimmed means of (A) University of Pennsylvania smell identification test (UPSIT), (B) Montreal cognitive assessment (MOCA), and Movement disorders society unified Parkinson disease ratings scale (MDS UPDRS) part II (C) and III (D) scores of combined cohort of GBA carriers (dashed line) and controls (solid line) with exact confidence intervals. At baseline there were 117 participants (35 controls, 39 heterozygous and 43 bi‐allelic), 103 at time‐point 1 (28 controls, 33 heterozygous and 42 bi‐allelic) and 85 at time‐point 2 (19 controls, 26 heterozygous and 40 bi‐allelic).

Figure 2

Shows that overlap of participants with the worst/fastest deteriorating BDI, MOCA and UPSIT scores based on our risk stratification system which used as threshold for each test the (approximately) worst 10% of the cohort score for that variable (UPSIT = 3/8: 86th centile and above, MOCA = 3/8: 91th centile and above, BDI =4/8: 86th centile and above) compared with the control group (UPSIT 2/8: 89th centile, MOCA 3/8: 89th centile, BDI: 2/8 87th centile). Subset analysis showed that this clustering effect was present within the bi‐allelic but not the heterozygous group. At baseline there were 117 participants (35 controls, 39 heterozygous and 43 bi‐allelic), 103 at time‐point 1 (28 controls, 33 heterozygous and 42 biallelic) and 85 at time‐point 2 (19 controls, 26 heterozygous and 40 bi‐allelic).