Longitudinal measurements of glucocerebrosidase activity in Parkinson’s patients

Roy N. Alcalay*, Pavlina Wolf, Ming Sum Ruby Chiang, Karolina Helesicova, Xiaokui Kate Zhang, Kalpana Merchant, Samantha J. Hutten, Clemens Scherzer, Chelsea Caspell-Garcia, Cornelis Blauwendraat, Tatiana Foroud, Kelly Nudelman, Ziv Gan-Or, Tanya Simuni, Lana M. Chahine, Oren Levy, Dandi Zheng, Gen Li, Sergio Pablo Sardi, PPMI Investigators

*Corresponding author for this work

    Research output: Contribution to journalArticlepeer-review

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    Objective: Reduction in glucocerebrosidase (GCase; encoded by GBA) enzymatic activity has been linked to Parkinson’s disease (PD). Here, we correlated GCase activity and PD phenotype in the Parkinson’s Progression Markers Initiative (PPMI) cohort. Methods: We measured GCase activity in dried blood spots from 1559 samples of participants in the inception PPMI cohort, collected in four annual visits (from baseline visit to Year-3). Participants (PD, n = 392; controls, n = 175) were fully sequenced for GBA variants by means of genome-wide genotyping arrays, whole-exome sequencing, whole-genome sequencing, Sanger sequencing, and RNA-sequencing. Results: Fifty-two PD participants (13.4%) and 13 (7.4%) controls carried a GBA variant. GBA status was strongly associated with GCase activity. Among noncarriers, GCase activity was similar between PD and controls. Among GBA p.E326K carriers (PD, n = 20; controls, n = 5), activity was significantly lower in PD carriers than control carriers (9.53 µmol/L/h vs. 11.68 µmol/L/h, P = 0.035). Glucocerebrosidase activity was moderately (r = 0.45) associated with white blood cell (WBC) count. Next, we divided the noncarriers with PD to tertiles based on WBC count-corrected enzymatic activity. Members of the lower tertile had higher MDS-Unified Parkinson’s Disease Rating Scale motor score in the “off” medication examination at year-III exam. Longitudinal analyses demonstrated slight reduction of activity in samples collected earlier on in the study, likely because of longer storage time. Interpretation: GCase activity is associated with GBA genotype, WBC count, and among p.E326K variant carriers, with PD status. Reduced activity may also be associated with worse phenotype but longer follow up is required to confirm this observation.

    Original languageEnglish
    Pages (from-to)1816-1830
    Number of pages15
    JournalAnnals of Clinical and Translational Neurology
    Issue number10
    Early online date5 Sep 2020
    Publication statusPublished - Oct 2020

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    Copyright the Author(s) 2020. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.


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