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Longitudinal measurements of glucocerebrosidase activity in Parkinson's patients

Title: Longitudinal measurements of glucocerebrosidase activity in Parkinson's patients
Authors: Alcalay, RN
Wolf, P
Chiang, MSR
Helesicova, K
Zhang, XK
Merchant, K
Hutten, SJ
Scherzer, C
Caspell-Garcia, C
Blauwendraat, C
Foroud, T
Nudelman, K
Gan-Or, Z
Simuni, T
Chahine, LM
Levy, O
Zheng, D
Li, G
Sardi, SP
Item Type: Journal Article
Abstract: 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.
Issue Date: 5-Sep-2020
Date of Acceptance: 30-Jul-2020
URI: http://hdl.handle.net/10044/1/93529
DOI: 10.1002/acn3.51164
ISSN: 2328-9503
Publisher: Wiley Open Access
Start Page: 1816
End Page: 1830
Journal / Book Title: Annals of Clinical and Translational Neurology
Volume: 7
Issue: 10
Copyright Statement: © 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
Sponsor/Funder: Michael J Fox Foundation
Funder's Grant Number: WBCN_P88063
Keywords: Science & Technology
Life Sciences & Biomedicine
Clinical Neurology
Neurosciences
Neurosciences & Neurology
LYSOSOMAL STORAGE DISORDERS
DISEASE
MUTATIONS
PERFORMANCE
DEMENTIA
Adult
Dementia
Disease Progression
Female
Genotype
Glucosylceramidase
Heterozygote
Humans
Male
Mental Status and Dementia Tests
Middle Aged
Mutation
Parkinson Disease
Phenotype
Parkinson’s Progression Markers Initiative
Humans
Parkinson Disease
Dementia
Disease Progression
Glucosylceramidase
Genotype
Heterozygote
Phenotype
Mutation
Adult
Middle Aged
Female
Male
Mental Status and Dementia Tests
Science & Technology
Life Sciences & Biomedicine
Clinical Neurology
Neurosciences
Neurosciences & Neurology
LYSOSOMAL STORAGE DISORDERS
DISEASE
MUTATIONS
PERFORMANCE
DEMENTIA
1103 Clinical Sciences
1109 Neurosciences
Publication Status: Published
Open Access location: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7545591/
Online Publication Date: 2020-09-05
Appears in Collections:Department of Brain Sciences



This item is licensed under a Creative Commons License Creative Commons