Modelling cholinergic and dopaminergic function over time in Parkinson's disease with and without GBA1 variants

Sofie Slingerland; Eline K R de Meyer; Harm J van der Horn; Giulia Carli; Anne C Slomp; Emile d'Angremont; Jeffrey M Boertien; Ingeborg Goethals; Sanne K Meles; Sygrid van der Zee; Teus van Laar

doi:10.1038/s41531-025-01160-3

Modelling cholinergic and dopaminergic function over time in Parkinson's disease with and without GBA1 variants

Sofie Slingerland^*
, Eline K R de Meyer
, Harm J van der Horn
, Giulia Carli
, Anne C Slomp
, Emile d'Angremont
, Jeffrey M Boertien
, Ingeborg Goethals
, Sanne K Meles
, Sygrid van der Zee
, Teus van Laar

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

Parkinson's Disease (PD) patients carrying GBA1-variants (GBA-PD) often show a faster cognitive decline, suggesting accelerated cholinergic degeneration. This study investigated changes over time in whole-brain cholinergic innervation within the context of dopaminergic changes and clinical outcomes in GBA-PD versus non-GBA-PD. 171 PD participants (44 GBA-PD, 127 non-GBA-PD) underwent clinical and neuropsychological assessments, brain MRI, 18F-fluoroethoxy-benzovesamicol ( 18F-FEOBV) PET (cholinergic) and 3,4-dihydroxy-6- 18F-fluoro-I-phenylalanine ( 18F-FDOPA) PET (dopaminergic) imaging. GBA-PD participants showed worse executive functioning than non-GBA-PD. Voxel-wise linear mixed-effects models showed that GBA-PD exhibited lower 18F-FEOBV binding in the right precentral and middle frontal gyrus, independent of age and sex, despite similar cholinergic decline over time. No GBA1-related differences were found in dopaminergic signal or its progression. Age and time since diagnosis were associated with progressive cholinergic and dopaminergic denervation in all patients. This first dual-tracer longitudinal PET study highlights early cholinergic involvement in GBA-PD and supports further evaluation of 18F-FEOBV PET as biomarker.

Original language	English
Article number	316
Number of pages	10
Journal	NPJ Parkinson's disease
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41531-025-01160-3
Publication status	Published - 12-Nov-2025

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Slingerland, S., de Meyer, E. K. R., van der Horn, H. J., Carli, G., Slomp, A. C., d'Angremont, E., Boertien, J. M., Goethals, I., Meles, S. K., van der Zee, S., & van Laar, T. (2025). Modelling cholinergic and dopaminergic function over time in Parkinson's disease with and without GBA1 variants. NPJ Parkinson's disease, 11(1), Article 316. https://doi.org/10.1038/s41531-025-01160-3

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abstract = "Parkinson's Disease (PD) patients carrying GBA1-variants (GBA-PD) often show a faster cognitive decline, suggesting accelerated cholinergic degeneration. This study investigated changes over time in whole-brain cholinergic innervation within the context of dopaminergic changes and clinical outcomes in GBA-PD versus non-GBA-PD. 171 PD participants (44 GBA-PD, 127 non-GBA-PD) underwent clinical and neuropsychological assessments, brain MRI, 18F-fluoroethoxy-benzovesamicol ( 18F-FEOBV) PET (cholinergic) and 3,4-dihydroxy-6- 18F-fluoro-I-phenylalanine ( 18F-FDOPA) PET (dopaminergic) imaging. GBA-PD participants showed worse executive functioning than non-GBA-PD. Voxel-wise linear mixed-effects models showed that GBA-PD exhibited lower 18F-FEOBV binding in the right precentral and middle frontal gyrus, independent of age and sex, despite similar cholinergic decline over time. No GBA1-related differences were found in dopaminergic signal or its progression. Age and time since diagnosis were associated with progressive cholinergic and dopaminergic denervation in all patients. This first dual-tracer longitudinal PET study highlights early cholinergic involvement in GBA-PD and supports further evaluation of 18F-FEOBV PET as biomarker. ",

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AU - Slingerland, Sofie

AU - de Meyer, Eline K R

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AU - Slomp, Anne C

AU - d'Angremont, Emile

AU - Boertien, Jeffrey M

AU - Goethals, Ingeborg

AU - Meles, Sanne K

AU - van der Zee, Sygrid

AU - van Laar, Teus

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N2 - Parkinson's Disease (PD) patients carrying GBA1-variants (GBA-PD) often show a faster cognitive decline, suggesting accelerated cholinergic degeneration. This study investigated changes over time in whole-brain cholinergic innervation within the context of dopaminergic changes and clinical outcomes in GBA-PD versus non-GBA-PD. 171 PD participants (44 GBA-PD, 127 non-GBA-PD) underwent clinical and neuropsychological assessments, brain MRI, 18F-fluoroethoxy-benzovesamicol ( 18F-FEOBV) PET (cholinergic) and 3,4-dihydroxy-6- 18F-fluoro-I-phenylalanine ( 18F-FDOPA) PET (dopaminergic) imaging. GBA-PD participants showed worse executive functioning than non-GBA-PD. Voxel-wise linear mixed-effects models showed that GBA-PD exhibited lower 18F-FEOBV binding in the right precentral and middle frontal gyrus, independent of age and sex, despite similar cholinergic decline over time. No GBA1-related differences were found in dopaminergic signal or its progression. Age and time since diagnosis were associated with progressive cholinergic and dopaminergic denervation in all patients. This first dual-tracer longitudinal PET study highlights early cholinergic involvement in GBA-PD and supports further evaluation of 18F-FEOBV PET as biomarker.

AB - Parkinson's Disease (PD) patients carrying GBA1-variants (GBA-PD) often show a faster cognitive decline, suggesting accelerated cholinergic degeneration. This study investigated changes over time in whole-brain cholinergic innervation within the context of dopaminergic changes and clinical outcomes in GBA-PD versus non-GBA-PD. 171 PD participants (44 GBA-PD, 127 non-GBA-PD) underwent clinical and neuropsychological assessments, brain MRI, 18F-fluoroethoxy-benzovesamicol ( 18F-FEOBV) PET (cholinergic) and 3,4-dihydroxy-6- 18F-fluoro-I-phenylalanine ( 18F-FDOPA) PET (dopaminergic) imaging. GBA-PD participants showed worse executive functioning than non-GBA-PD. Voxel-wise linear mixed-effects models showed that GBA-PD exhibited lower 18F-FEOBV binding in the right precentral and middle frontal gyrus, independent of age and sex, despite similar cholinergic decline over time. No GBA1-related differences were found in dopaminergic signal or its progression. Age and time since diagnosis were associated with progressive cholinergic and dopaminergic denervation in all patients. This first dual-tracer longitudinal PET study highlights early cholinergic involvement in GBA-PD and supports further evaluation of 18F-FEOBV PET as biomarker.

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DO - 10.1038/s41531-025-01160-3

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Modelling cholinergic and dopaminergic function over time in Parkinson's disease with and without GBA1 variants

Abstract

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