Understanding the pattern of cognitive decline in GBA1-related Parkinson's Disease: a longitudinal multi-cohort study

ObjectivePeople with Parkinsons disease (PD) who carry a pathogenic GBA1 variant (PDGBA1) are at higher risk of cognitive impairment than those without the variant (PDGBA1_wildtype). To date, little is known about the pattern and evolution of cognitive decline in PDGBA1. This multi-center study characterized the cognitive profile of PDGBA, focusing on the longitudinal trajectories and the group-specific onset times among cognitive functions, as well as their clinical relevance. MethodsIn this longitudinal multicohort-study (PPMI, ABC-PD, Luxembourg Parkinsons Study), comprehensive neuropsychological assessments were standardized across 548 healthy controls (follow-up-years=2.84{+/-}4.33), 906 PDGBA1_wildtype (follow-up-years=4.29{+/-}4.16), and 210 PDGBA1 (follow-up-years=4.09{+/-}3.35). We evaluated performance across age and disease duration using regression (generalized) linear mixed models within each cognitive domain. Time-to-first-event models, assessing risks of clinically relevant performance impairment (test-score z[&le;]-1.5, MoCA<26), and an expanding-time-window approach identified the course of cognitive impairment. Additionally, correlations between cognitive functions were calculated. ResultsAt baseline, PDGBA1 showed lower performance in attention (processing speed) and memory (verbal learning) than PDGBA1_wildtype, but more widespread probability of performance impairment. Over time, attention, visuoperception, memory, and semantic fluency performance declined more rapidly in PDGBA1 compared to PDGBA1_wildtype. Impairment in processing speed occurred earlier in the disease process of PDGBA1. Risks for clinically relevant cognitive impairment in PDGBA1 during the disease course were generally increased. Moderate-to-strong correlations between cognitive functions were observed within and across cognitive domains in PDGBA1 and PDGBA1_wildtype, particularly in attentional-executive functions. InterpretationPDGBA1 exhibits accelerated domain-generalized cognitive decline compared to PDGBA1_wildtype, with susceptibility of semantic fluency, attention, and memory. Summary for Social MediaO_LIIf you and/or a co-author has a X handle that you would like to be tagged, please enter it here. (format: @AUTHORSHANDLE). None C_LIO_LIWhat is the current knowledge on the topic? (one to two sentences) Pathogenic coding variants in the Glucocerebrosidase (GBA1) gene in Parkinsons Disease (PD-GBA1) are linked to more severe cognitive impairment. However, the domain-specific trajectories of cognitive decline are currently unknown. C_LIO_LIWhat question did this study address? (one to two sentences) This study aimed to analyze the course of longitudinal cognitive profile in PD-GBA1 across disease duration and age in regard to cognitive domains and clinical relevance. C_LIO_LIWhat does this study add to our knowledge? (one to two sentences) PD-GBA1 exhibits accelerated cognitive decline with susceptibility of semantic fluency, attention, and memory. Cognitive decline risk elevated 2-to-3 years post-diagnosis. C_LIO_LIHow might this potentially impact on the practice of neurology? (one to two sentences) The results can help to identify individuals at risk of cognitive decline and to better design clinical trials aiming at disease modification with cognition as endpoint. C_LI