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.
BACKGROUND: Reduced β-glucocerebrosidase activity was observed in postmortem brains of both GBA1 mutation carrier and noncarrier Parkinson's diseasepatients, 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 PDpatients 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 PDpatients (12.7%) and 3 of 61 controls (4.9%). GBA1 mutation carrier PDpatients showed significantly lower β-glucocerebrosidase specific activity versus noncarriers. β-glucocerebrosidase specific activity was also decreased in noncarrier PDpatients 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 PDpatients 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.
Authors: Matthew C Deen; Yanping Zhu; Christina Gros; Na Na; Pierre-André Gilormini; David L Shen; Sandeep Bhosale; Nadia Anastasi; RuiQi Wang; Xiaoyang Shan; Eva Harde; Ravi Jagasia; Francis C Lynn; David J Vocadlo Journal: Proc Natl Acad Sci U S A Date: 2022-07-12 Impact factor: 12.779
Authors: R N Alcalay; P Wolf; O A Levy; U J Kang; C Waters; S Fahn; B Ford; S H Kuo; N Vanegas; H Shah; C Liong; S Narayan; M W Pauciulo; W C Nichols; Z Gan-Or; G A Rouleau; W K Chung; P Oliva; J Keutzer; K Marder; X K Zhang Journal: Neurobiol Dis Date: 2018-02-02 Impact factor: 5.996
Authors: Young Eun Huh; Ming Sum Ruby Chiang; Joseph J Locascio; Zhixiang Liao; Ganqiang Liu; Karbi Choudhury; Yuliya I Kuras; Idil Tuncali; Aleksandar Videnovic; Ann L Hunt; Michael A Schwarzschild; Albert Y Hung; Todd M Herrington; Michael T Hayes; Bradley T Hyman; Anne-Marie Wills; Stephen N Gomperts; John H Growdon; Sergio Pablo Sardi; Clemens R Scherzer Journal: Neurology Date: 2020-06-15 Impact factor: 9.910