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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.
Glossary
- BMI=
- body mass index;
- CI=
- confidence interval;
- GBA-PD=
- Parkinson disease with a GBA mutation;
- GD=
- Gaucher disease;
- HBS=
- Harvard Biomarkers Study;
- HBS-1=
- Harvard Biomarkers Study cohort 1;
- HBS-2=
- Harvard Biomarkers Study cohort 2;
- IQR=
- interquartile range;
- LEDD=
- levodopa equivalent daily dose;
- MMSE=
- Mini-Mental State Examination;
- PD=
- Parkinson disease;
- PDBP=
- Parkinson's Disease Biomarkers Program;
- PDD=
- Parkinson disease with dementia;
- xQTL=
- enzyme quantitative trait locus;
- UPDRS=
- Unified Parkinson’s Disease Rating Scale
Footnotes
↵* These authors contributed equally to this work as co–last authors.
Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
- Received October 10, 2019.
- Accepted in final form January 26, 2020.
- © 2020 American Academy of Neurology
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