Longitudinal Measurements of Glucocerebrosidase activity in Parkinson's patients and controls: the PPMI study

Objective: Reduction in glucocerebrosidase (GCase; encoded byGBA) 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 forGBAvariants 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 aGBAvariant.GBAstatus was strongly associated with GCase activity. Among noncarriers, GCase activity was similar between PD and controls. AmongGBAp.E326K carriers (PD,n = 20; controls,n = 5), activity was significantly lower in PD carriers than control carriers (9.53 mu mol/L/h vs. 11.68 mu mol/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 withGBAgenotype, 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.