β-Glucocerebrosidase activity in GBA-linked Parkinson disease: The type of mutation matters

Abstract

Objective: To test the relationship between clinically relevant types of GBA mutations (none, risk variants, mild mutations, severe mutations) and β-glucocerebrosidase activity in patients with Parkinson disease (PD) in cross-sectional and longitudinal case-control studies.

Methods: A total of 481 participants from the Harvard Biomarkers Study (HBS) and the NIH Parkinson's Disease Biomarkers Program (PDBP) were analyzed, including 47 patients with PD carrying GBA variants (GBA-PD), 247 without a GBA variant (idiopathic PD), and 187 healthy controls. Longitudinal analysis comprised 195 participants with 548 longitudinal measurements over a median follow-up period of 2.0 years (interquartile range, 1-2 years).

Results: β-Glucocerebrosidase activity was low in blood of patients with GBA-PD compared to healthy controls and patients with idiopathic PD, respectively, in HBS (p < 0.001) and PDBP (p < 0.05) in multivariate analyses adjusting for age, sex, blood storage time, and batch. Enzyme activity in patients with idiopathic PD was unchanged. Innovative enzymatic quantitative trait locus (xQTL) analysis revealed a negative linear association between residual β-glucocerebrosidase activity and mutation type with p < 0.0001. For each increment in the severity of mutation type, a reduction of mean β-glucocerebrosidase activity by 0.85 μmol/L/h (95% confidence interval, -1.17, -0.54) was predicted. In a first longitudinal analysis, increasing mutation severity types were prospectively associated with steeper declines in β-glucocerebrosidase activity during a median 2 years of follow-up (p = 0.02).

Conclusions: Residual activity of the β-glucocerebrosidase enzyme measured in blood inversely correlates with clinical severity types of GBA mutations in PD. β-Glucocerebrosidase activity is a quantitative endophenotype that can be monitored noninvasively and targeted therapeutically.

Figure 1. Flowchart of study participants and β-glucocerebrosidase activity in blood of patients with Parkinson disease (PD) with a GBA mutation (GBA-PD) compared to healthy controls and patients with idiopathic PD

(A) Flowchart of study participants. (B–D) β-glucocerebrosidase activity in blood of patients with GBA-PD compared to healthy controls and patients with idiopathic PD. Results are shown for (B) the Harvard Biomarkers Study cohort 1 (HBS-1), (C) the National Institute of Neurological Disorders and Stroke Parkinson's Disease Biomarkers Program (PDBP) cohort, and (D) the Harvard Biomarkers Study cohort 2 (HBS-2). Unadjusted β-glucocerebrosidase activity values are shown in box and jitter dot blots; box plots indicate the median (bold line), the 25th and 75th percentiles (box edges), and the most extreme data point no more than 1.5x the interquartile range from the box (whiskers). The p values are shown for the comparison of patients with GBA-PD to healthy controls and patients with idiopathic PD, respectively, from generalized linear mixed model analyses adjusting for age, sex, duration of sample storage, and assay batch (B and C) and in addition to body mass index (D). PDD = Parkinson disease with dementia.

Figure 2. Enzymatic quantitative trait locus analysis reveals a negative linear association between β-glucocerebrosidase activity and mutation type

(A) Unadjusted β-glucocerebrosidase activity of 294 unique patients with Parkinson disease (PD) from HBS-1, PDBP, and HBS-2 cohorts is shown in box and jitter dot blots. For each increment in the severity of mutation type, a reduction of mean β-glucocerebrosidase activity by 0.85 μmol/L/h (95% confidence interval, −1.17, −0.54) was predicted. (B) Unadjusted β-glucocerebrosidase activity of 481 healthy controls as well as patients with PD from the 3 cohorts. p Values in A and B from linear mixed model analyses for the association of ordinal severity type of GBA mutations with β-glucocerebrosidase activity adjusted for covariates. GBA-PD = Parkinson disease with a GBA mutation; HBS-1 = Harvard Biomarkers Study cohort 1; HBS-2 = Harvard Biomarkers Study cohort 2; PDBP = Parkinson's Disease Biomarkers Program.

Figure 3. Model-predicted longitudinal β-glucocerebrosidase activity in participants with different types of GBA mutations

A total of 195 participants with 548 blood samples from Harvard Biomarkers Study cohort 1 (HBS-1) and Parkinson's Disease Biomarkers Program (PDBP) were available for the longitudinal analysis (median follow-up time of 2.0 years; interquartile range, 1–2 years). Model predicted values of β-glucocerebrosidase activity of noncarriers and patients with PD with different types of GBA mutations. Estimated mean β-glucocerebrosidase activity is illustrated for each group (solid lines) adjusted for fixed effects covariates with shaded areas representing standard error. Fixed effects covariates included in the model were time in study (years), GBA mutation type (coded as ordinal variables), interaction of mutation type × time in study, cohort (HBS-1 and PDBP), and sex. For the purpose of the graph, sex and study cohort were arbitrarily set to male and HBS-1, respectively, because of the larger number of male patients. Similar results were seen when sex was set to female (not shown). Estimated values below zero were set to zero. GBA-PD = Parkinson disease with a GBA mutation.