Early GCase activity is a predictor of long-term cognitive decline in Parkinson’s disease

• Published in: Translational neurodegeneration Vol. 12; no. 1; pp. 1 - 41
• Main Authors: Oftedal, Linn, Lange, Johannes, Pedersen, Kenn Freddy, Erga, Aleksander Hagen, Dalen, Ingvild, Tysnes, Ole-Bjørn, Alves, Guido, Maple-Grødem, Jodi
• Format: Journal Article
• Language: English
• Published: London BioMed Central 28.08.2023; BMC
• Subjects: Alzheimer's disease; Clinical trials; Cognitive ability; Confidence intervals; Dementia; Executive function; Letter; Memory; Mutation; Neuropsychology; Parkinson's disease; Pathology; Verbal learning
• ISSN: 2047-9158; 2047-9158
• DOI: 10.1186/s40035-023-00373-x

[...]both the medium (β =  − 1.58 transformed points; 95% confidence interval [CI] − 2.91 to − 0.25, P = 0.022) and the low GCase activity groups (β =  − 2.26 transformed points; 95%CI − 3.59 to − 0.94, P = 0.001) were predicted to experience a faster annual decline in MMSE score, compared to the high activity group. Specifically, we found that the size of the effect and significance of the association of GCase activity status with the decline in cognitive function remained comparable apart from the scores for executive function, for which there was no significant difference in the annual decline between the high and the low activity groups (P = 0.086). By contrast, cognitive decline is a gradual process that starts early in a substantial subset of patients and is frequently included as an outcome in PD clinical trials. [...]we performed a power calculation to estimate the predicted benefit (concerning trial size) of limiting enrolment to a clinical trial to patients in the lowest tertile of GCase activity, compared to a design in which all newly diagnosed patients are eligible for trial inclusion (an “all-comer” design) (Additional file 2: [...]we found that low CSF GCase activity at the time of initial diagnosis is linked to a faster annual decline in clinical scales measuring global cognition and specific cognitive domains over the first 10 years of PD. The link between GCase dysfunction and disease progression provides insight into the pathogenesis of the disease and novel perspectives for GCase-targeted therapies to prevent neurodegeneration, and could provide a valuable biomarker to identify patients at risk of more severe disease.