Background: Reduced β-glucocerebrosidase activity was observed in postmortem brains of both GBA1 mutation carrier and noncarrier Parkinson's disease patients, suggesting that lower β-glucocerebrosidase activity is a key feature in the pathogenesis of PD. The objectives of this study were to confirm whether there is reduced β-glucocerebrosidase activity in the CSF of GBA1 mutation carrier and noncarrier PD patients and verify if other lysosomal enzymes show altered activity in the CSF.
Methods: CSF β-glucocerebrosidase, cathepsin D, and β-hexosaminidase activities were measured in 79 PD and 61 healthy controls from the BioFIND cohort. The whole GBA1 gene was sequenced.
Results: Enzyme activities were normalized according to CSF protein content (specific activity). β-glucocerebrosidase specific activity was significantly decreased in PD versus controls (-28%, P < 0.001). GBA1 mutations were found in 10 of 79 PD patients (12.7%) and 3 of 61 controls (4.9%). GBA1 mutation carrier PD patients showed significantly lower β-glucocerebrosidase specific activity versus noncarriers. β-glucocerebrosidase specific activity was also decreased in noncarrier PD patients versus controls (-25%, P < 0.001). Cathepsin D specific activity was lower in PD versus controls (-21%, P < 0.001). β-Hexosaminidase showed a similar trend. β-Glucocerebrosidase specific activity fairly discriminated PD from controls (area under the curve, 0.72; sensitivity, 0.67; specificity, 0.77). A combination of β-glucocerebrosidase, cathepsin D, and β-hexosaminidase improved diagnostic accuracy (area under the curve, 0.77; sensitivity, 0.71; specificity, 0.85). Lower β-glucocerebrosidase and β-hexosaminidase specific activities were associated with worse cognitive performance.
Conclusions: CSF β-glucocerebrosidase activity is reduced in PD patients independent of their GBA1 mutation carrier status. Cathepsin D and β-hexosaminidase were also decreased. The possible link between altered CSF lysosomal enzyme activities and cognitive decline deserves further investigation. © 2017 International Parkinson and Movement Disorder Society.
Keywords: CSF biomarkers; GBA1 gene; Parkinson's disease; lysosomal enzyme activity; β-glucocerebrosidase.
© 2017 International Parkinson and Movement Disorder Society.