Longitudinal cognitive decline characterizes the profile of non-PD-manifest GBA1 mutation carriers

With disease-modifying treatment for Parkinson's disease (PD) associated with variants in the glucocerebrosidase gene (GBA1) under way, the challenge to design clinical trials with non-PD-manifest GBA mutation carriers (GBA1(NMC)) comes within close reach. To delineate trajectories of motor and non-motor markers as well as serum neurofilament light (sNfL) levels and to evaluate clinical endpoints as outcomes for clinical trials in GBA1(NMC), longitudinal data of 56 GBA1(NMC) carriers and 112 age- and sex-matched GBA1 wildtype participants (GBA1(wildtype)) with up to 9 years of follow-up was analyzed using linear mixed-effects models (LMEM) and Kaplan-Meier survival analysis of clinical endpoints for motor and cognitive function. GBA1(NMC) showed worse performance in Pegboard, 20 m fast walking, global cognition as well as in executive and memory function at baseline. Longitudinally, LMEM revealed a higher annual increase of the MDS-UPDRS III bradykinesia subscore in GBA1(NMC) compared to GBA1(wildtype), but comparable trajectories of all other motor and non-motor markers as well as sNfL. Kaplan-Meier survival analysis showed a significantly earlier progression to clinical endpoints of cognitive decline in GBA1(NMC). Incidence of PD was significantly higher in GBA1(NMC). In conclusion, our study extends data on GBA1(NMC) indicating early cognitive decline as a potentially characteristic feature. Comprehensive longitudinal assessments of cognitive function are crucial to delineate the evolution of early changes in GBA1(NMC) enabling a more accurate stratification and allow for a more precise definition of trial design and sample size.