Objective: Analyze which cognitive functions are affected in PD_{_GBA+}, and which factors are linked to dropout risk.

Background: People with Parkinson’s disease (PD) who carry heterozygous mutations in the glucocerobrosidase gene (PD_{_GBA+}) are an important group for clinical trials, as they experience earlier and more severe cognitive decline than PD patients without GBA mutations (PD_{_GBA-})[1]. An understanding of cognitive decline and dropout risk is crucial for designing such clinical trials. Cognitive impairment negatively impacts study retention in PD_{_GBA-}[2], and those with more severe deficits may be less inclined to participate in clinical trials.

Method: In this longitudinal multicohort study (PPMI, ABC-PD, NCER-PD), N=1,105 people with PD (PD_{_GBA-} =899, PD_{_GBA+} =206) were longitudinally compared for cognitive progression. Linear mixed effects models were inverse probability weighted to account for dropout, predicting global- and domain specific cognitive decline among study groups as well as mean and distributional composite scores. The relationship between baseline cognition and dropout risk was assessed with logistic regression, based on a cut-off of 8.25 years to define robust dropout and entry time window.

Results: At baseline (PD_{_GBA-} 2.6±3.3,PD_{_GBA+} 2.8±2.8 years of disease duration), PD_{_GBA+} showed worse attentional functioning and lower learning performance than PD_{_GBA-}. The cognitive profile of PD_{_GBA+} was more heterogeneous, indicated by a negatively skewed distribution of attentional-executive test scores. Over the disease course, PD_{_GBA+} declined more rapidly than PD_{_GBA-} in attentional-executive functions, in visual perception, and in verbal memory. Individuals who dropped out performed worse in various functions at baseline than individuals who remained in the study. Within the dropout group, in particular, PD_{_GBA+} declined more in processing speed and verbal memory discrimination, as compared to PD_{_GBA-}. Cognitive baseline performance, including test score distribution, was associated with greater dropout risk in PD_{_GBA+} than in PD_{_GBA-.}

Conclusion: Compared to PD_{_GBA-}, cognitive decline in PD_{_GBA+} is more rapid and widespread. Cognitive deficits in PD_{_GBA+} may initially manifest in attention and verbal memory discrimination but eventually generalize across various domains as the disease progresses. Distributional composites might capture early deficits and could identify PD_{_GBA+} patients at risk for study dropout.

References: [1] Brockmann K, Srulijes K, Pflederer S, Hauser AK, Schulte C, Maetzler W, et al. GBA-associated Parkinson’s disease: Reduced survival and more rapid progression in a prospective longitudinal study. Mov Disord. 2015;30(3):407–11.
[2]Sulzer P, Gräber S, Schaeffer E, van Lummel R, Berg D, Maetzler W, et al. Cognitive impairment and sedentary behavior predict health-related attrition in a prospective longitudinal Parkinson’s disease study. Parkinsonism Relat Disord. 2021 Jan;82:37–43.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/tracking-cognitive-decline-and-understanding-study-dropout-in-pd-gba/