Objective: To analyse glucocerebrosidase (GCase1) activity in GBA1-PD patient-derived fibroblasts and blood and to compare it with sporadic PD (sPD) and controls at baseline and longitudinally

Background: Heterozygous GBA1 variants are the most frequent genetic risk factor for Parkinson’s disease (PD) and are associated with earlier onset, faster progression, and greater cognitive impairment. Although GBA1-PD commonly shows reduced lysosomal GCase1 activity, the association with cognitive decline and variant severity remains unclear.[1]

Method: This cross-sectional and longitudinal observational study included 25 GBA1-PD, 25 sPD, and 13 controls. GCase1 activity was measured in fibroblasts by fluorometric assays and in dried blood spots by UPLC–MS/MS.[2] Motor, functional, and cognitive assessments, including PDCRS, were conducted at baseline and 1 year follow-up. Associations between enzymatic activity, clinical status, and progression were assessed using multivariate models adjusted for demographic, disease-related, and experimental variables (assay plate, processing day).

Results: GCase1 activity was markedly reduced in GBA1-PD compared with sPD and controls, following a severity-dependent gradient, with the lowest activity in severe-variants carriers. sPD showed preserved or slightly increased GCase1 activity. Baseline fibroblast GCase1 independently predicted cognitive performance (PDCRS) in GBA1-PD. Lower baseline activity strongly correlated with 1-year decline in posterior cortical PDCRS domains, but only in severe variant carriers (ρ = 0.89; p < 0.001). No association with motor progression was observed.

Conclusion: Reduced GCase1 is a biochemical feature of GBA1-PD and is linked to mutation severity and cognitive decline. Controlling experimental variability enabled robust clinical–biochemical associations. Functional GCase1 assessment may improve risk stratification beyond genotype and identify patients at risk of cognitive decline.

References: [1] Huh YE, Chiang MSR, Locascio JJ, Liao Z, Liu G, Choudhury K, et al. β-Glucocerebrosidase activity in GBA-linked Parkinson disease. Neurology. 2020;95(6):E685-E96. https://doi.org/:10.1212/WNL.0000000000009989.
[2] García‐Sanz P, Orgaz L, Bueno‐Gil G, Espadas I, Rodríguez‐Traver E, Kulisevsky J, et al. N370S‐GBA1 mutation causes lysosomal cholesterol accumulation in Parkinson’s disease. Movement Disorders. 2017;32(10):1409-22. https://doi.org/:10.1002/mds.27119.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/reduced-glucocerebrosidase-activity-is-associated-with-cognitive-decline-in-severe-gba1-associated-parkinsons-disease/