IC‐P‐073: ABNORMAL METABOLIC NETWORK ACTIVITY IN PARKINSON'S DISEASE WITH GBA VARIANTS

Background: Glucocerebrosidase (GBA) mutations represent the most frequent genetic risk factors in Parkinson’s disease (PD). PD patients with the mutation (PD GBA(+)) tend to experience earlier symptom onset and more rapid disease progression than their GBA(-) counterparts. Here, we investigate the influence of the GBA variants on the metabolic network expression using [18F]-fluorodeoxyglucose (FDG) PET. Methods: Of 115 PD subjects 11 subjects (9.6%) had pathogenic GBA variants (i.e., known mutations and the E326K polymorphism), classified as PD GBA (+): 7 subjects had pathogenic mutations on one allele; 2 subjects had the E326K polymorphism on one allele; and 2 subjects had Gaucher’s disease with either homozygous or compound heterozygous pathogenic mutations. We used spatial covariance mapping, an application of principal components analysis to detect and quantify disease-related functional brain networks in resting state imaging data among a group of PD patients with and without GBA variants GBA(-), matched for age, gender, symptom duration, and motor disability (off state UPDRS motor ratings), and a normal control group (ageand gender-matched healthy volunteers without GBAvariants). The expression values of the PD-related covariance pattern (PDRP) and PD-cognition related pattern (PDCP) were computed in the [18F]-FDG PET scans from these subjects. Results: PDRP expression was abnormally elevated (Fig. 1A) in both PD GBA(+) and GBA(-) subjects relative to healthy control values (GBA(+): p<0.0001; GBA(-): p<0.001). Abnormal PDCP elevations (Fig. 1B) were likewise evident in both groups of PD patients (GBA(+): p<0.001; GBA(-): p<0.05). Expression values for both the PDRP and PDCP were significantly higher in the PD GBA(+) subjects than in their PD GBA(-) counterparts (p<0.002 and p<0.03). The 2 PD subjects with Gaucher’s disease exhibited the greatest PDRP elevations of the entire PD GBA(+) group, but network elevations in the GBA(+) group remained significant relative to the GBA(-) PD subjects even after the Gaucher’s disease cases were excluded from the analysis (PDRP: p<0.005; PDCP: p<0.03). Conclusions: These findings show that GBA(+) PD patients have greater PDRP and PDCP expression levels than their durationand severity-matched GBA(-) PD counterparts. Network measures could be used as objective, reproducible biomarkers as outcome measures in clinical trials targeting disease-modifying therapies.