Understanding the Pattern of Cognitive Decline in GBA1 ‐Related Parkinson's Disease: An Exploratory Longitudinal Multi‐Cohort Study

Abstract Objective People with Parkinson’s disease (PD) who carry a pathogenic GBA1 variant (PD GBA1 ) are at higher risk of cognitive impairment than those without the variant (PD GBA1_wildtype ). To date, little is known about the pattern and evolution of cognitive decline in PD GBA1 . This multi-center study characterized the cognitive profile of PD GBA , focusing on the longitudinal trajectories and the group-specific onset times among cognitive functions, as well as their clinical relevance. Methods In this longitudinal multicohort-study (PPMI, ABC-PD, Luxembourg Parkinson’s Study), comprehensive neuropsychological assessments were standardized across 548 healthy controls (follow-up-years=2.84±4.33), 906 PD GBA1_wildtype (follow-up-years=4.29±4.16), and 210 PD GBA1 (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 ≤-1.5, MoCA<26), and an expanding-time-window approach identified the course of cognitive impairment. Additionally, correlations between cognitive functions were calculated. Results At baseline, PD GBA1 showed lower performance in attention (processing speed) and memory (verbal learning) than PD GBA1_wildtype , but more widespread probability of performance impairment. Over time, attention, visuoperception, memory, and semantic fluency performance declined more rapidly in PD GBA1 compared to PD GBA1_wildtype . Impairment in processing speed occurred earlier in the disease process of PD GBA1 . Risks for clinically relevant cognitive impairment in PD GBA1 during the disease course were generally increased. Moderate-to-strong correlations between cognitive functions were observed within and across cognitive domains in PD GBA1 and PD GBA1_wildtype , particularly in attentional-executive functions. Interpretation PD GBA1 exhibits accelerated domain-generalized cognitive decline compared to PD GBA1_wildtype , with susceptibility of semantic fluency, attention, and memory. Summary for Social Media If you and/or a co-author has a X handle that you would like to be tagged, please enter it here. (format: @AUTHORSHANDLE) . None What is the current knowledge on the topic? (one to two sentences) Pathogenic coding variants in the Glucocerebrosidase (GBA1) gene in Parkinson’s Disease (PD-GBA1) are linked to more severe cognitive impairment. However, the domain-specific trajectories of cognitive decline are currently unknown. What 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. What 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. How 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.