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

Area of Science:

• Neuroscience
• Neurology
• Radiology

Background:

• Parkinson's Disease (PD) patients with GBA1-variants (GBA-PD) often experience accelerated cognitive decline.
• This suggests potential degeneration of cholinergic pathways in GBA-PD.

Purpose of the Study:

• To investigate longitudinal changes in whole-brain cholinergic and dopaminergic innervation in GBA-PD versus non-GBA-PD.
• To correlate these neurochemical changes with clinical outcomes and cognitive function.

Main Methods:

• 171 PD participants (44 GBA-PD, 127 non-GBA-PD) underwent clinical/neuropsychological assessments, MRI, and dual-tracer PET imaging.
• ¹⁸F-fluoroethoxy-benzovesamicol (¹⁸F-FEOBV) PET measured cholinergic function; 3,4-dihydroxy-6-¹⁸F-fluoro-I-phenylalanine (¹⁸F-FDOPA) PET measured dopaminergic function.
• Voxel-wise linear mixed-effects models analyzed longitudinal changes.

Main Results:

• GBA-PD patients exhibited worse executive functioning compared to non-GBA-PD.
• GBA-PD showed reduced ¹⁸F-FEOBV binding in specific frontal regions, independent of age/sex, despite similar overall cholinergic decline rates.
• No significant GBA1-related differences were observed in dopaminergic signal or its progression.

Conclusions:

• This study reveals early cholinergic system involvement in GBA-PD, preceding significant dopaminergic changes.
• ¹⁸F-FEOBV PET shows promise as a biomarker for tracking neurodegeneration in GBA-PD.
• Age and disease duration are key factors in progressive cholinergic and dopaminergic denervation across all PD patients.