Parkinson's Disease: Glucocerebrosidase 1 Mutation Severity Is Associated with CSF Alpha-Synuclein Profiles

Background Mutations in the gene glucocerebrosidase (GBA1) are specifically associated with alpha-synucleinopathies, namely, Parkinson's disease (PD) and dementia with Lewy bodies. As disease-modifying treatment options such as alpha-synuclein lowering compounds are under way, patient stratification according to alpha-synuclein-specific enrichment strategies, possibly reflected by cerebrospinal fluid (CSF) profiles, is a much needed prerequisite. Objective Are GBA1 mutations associated with a CSF alpha-synuclein profile in PD? Methods Screening of the GBA1 gene and analysis of CSF levels of total alpha-synuclein were performed in 80 PDGBA, 80 PDGBA_(wildtype) and 39 healthy controls cross-sectionally. Subgroup analyses based on mutation severity was done for PDGBA. Results Patients carrying severe GBA1 mutations showed (1) an earlier age at onset, (2) more pronounced cognitive decline and higher prevalence of rapid eye movement sleep behavior disorder, and (3) reduced CSF levels of total alpha-synuclein. Conclusion The effects of GBA1 mutations on CSF alpha-synuclein profiles and phenotypical characteristics seem dependent on GBA1 mutation severity. (c) 2019 International Parkinson and Movement Disorder Society