Glucocerebrosidase activity in Parkinson disease with and without GBA mutations (S7.003)

Importance: Glucocerebrosidase (GBA) mutations are associated with Parkinson’s disease (PD). Whether glucocerebrosidase enzymatic (GCase) activity in dried blood spots is lower in GBA carriers, and in PD cases compared to controls, is unknown.Objective: To measure glucocerebrosidase enzymatic (GCase) activity in dried blood spots in PD patients with and without GBA mutations and controls.Methods: PD patients (n=517) and controls (n=252) were recruited from Columbia University, and fully sequenced for GBA mutations. GCase activity in dried blood spot was measured by mass spectrometry-based assay. GCase activity was compared among carriers of two GBA mutations/variants (homozygotes and compound heterozygotes), GBA heterozygotes, and non-carriers. The association between GCase activity and PD status was measured in adjusted regression models excluding GBA and LRRK2 G2019S mutation carriers. In non-GBA non-LRKK2 PD patients, the association between GCase activity and disease characteristics was examined.Results: PD patients had slightly lower mean GCase activity than controls (11.14µmol/l/h versus 11.85µmol/l/h, p=0.011). GBA Homozygotes/Compound heterozygotes had lower GCase activity than GBA heterozygotes (0.85µmol/l/h versus 7.88µmol/l/h, pu003c0.001), and GBA heterozygotes had lower GCase activity than GBA and LRRK2 non-carriers (7.88µmol/l/h versus 11.93µmol/l/h, pu003c0.001). PD patients had lower GCase activity than controls even after exclusion of all GBA and LRRK2 carriers (11.53µmol/l/h, versus 12.11µmol/l/h, p=0.036) and adjustment for age and gender (p=0.012). However, LRRK2 G2019S carriers (n=36) had higher enzymatic activity than non-carriers (13.7µmol/l/h versus 11.93µmol/l/h, p=0.002). Among PD non-GBA non-LRRK2 carriers, higher GCase activity was associated with longer disease duration (p=0.002) in adjusted models, possibly indicating a milder disease course.Interpretation: Lower GCase activity is strongly associated GBA mutations and modestly with PD after excluding all carriers. High GCase activity in LRRK2 G2019S carriers may reflect a distinct pathogenic mechanism.Funding: Parkinson’s Disease Foundation, NIH (K02NS080915, NS036630 and UL1 TR000040) Disclosure: The NIH K02 NS080915. Parkinson9s Disease Foudnation: research support. Smart Foundation: research support and the Michael J Fox foundation: research support through the L Dr. Levy has nothing to disclose. Dr. Waters has received personal compensation for activities with UCB Pharma and Teva Neuroscience as a speaker. Dr. Fahn has received personal compensation for activities with Merz Pharmaceuticals. Dr. Ford has received personal compensation for activities with Johns Hopkins Medicine CME. Dr. Kuo has nothing to disclose. Dr. Mazzoni has nothing to disclose. Dr. Marder has received personal compensation in an editorial capacity for Current Neuroscience. Dr. Pauciulo has nothing to disclose. Dr. Nichols has nothing to disclose. Dr. Gan-Or has nothing to disclose. Dr. Rouleau has nothing to disclose. Dr. Chung has nothing to disclose. Dr. Wolf has received personal compensation for activities with Genzyme Corporation as an employee. Dr. Oliva has received personal compensation for activities with Genzyme as an employee. Dr. Keutzer has received personal compensation for activities with Sanofi as an employee. Dr. Zhang has received personal compensation for activities with Genzyme Corporation as an employee.