Cholinergic innervation topography in GBA-associated de novo Parkinson's disease patients.

The most common genetic risk factors for Parkinson's disease are GBA1 mutations, encoding the lysosomal enzyme glucocerebrosidase. Patients with GBA1 mutations (GBA-PD) exhibit earlier age of onset and faster disease progression with more severe cognitive impairments, postural instability and gait problems. These GBA-PD features suggest more severe cholinergic system pathologies. PET imaging with the vesicular acetylcholine transporter ligand 18F-F-fluoroethoxybenzovesamicol (18F-FEOBV PET) provides the opportunity to investigate cholinergic changes and their relationship to clinical features in GBA-PD. The study investigated 123 newly diagnosed, treatment-naïve Parkinson's disease subjects-with confirmed presynaptic dopaminergic deficits on PET imaging. Whole-gene GBA1 sequencing of saliva samples was performed to evaluate GBA1 variants. Patients underwent extensive neuropsychological assessment of all cognitive domains, motor evaluation with the Unified Parkinson's Disease Rating Scale, brain MRI, dopaminergic PET to measure striatal-to-occipital ratios of the putamen and 18F-FEOBV PET. We investigated differences in regional cholinergic innervation between GBA-PD carriers and non-GBA1 mutation carriers (non-GBA-PD), using voxel-wise and volume of interest-based approaches. The degree of overlap between t-maps from two-sample t-test models was quantified using the Dice similarity coefficient. Seventeen (13.8%) subjects had a GBA1 mutation. No significant differences were found in clinical features and dopaminergic ratios between GBA-PD and non-GBA-PD at diagnosis. Lower 18F-FEOBV binding was found in both the GBA-PD and non-GBA-PD groups compared to controls. Dice (P < 0.05, cluster size 100) showed good overlap (0.7326) between the GBA-PD and non-GBA-PD maps. GBA-PD patients showed more widespread reduction in 18F-FEOBV binding than non-GBA-PD when compared to controls in occipital, parietal, temporal and frontal cortices (P < 0.05, FDR-corrected). In volume of interest analyses (Bonferroni corrected), the left parahippocampal gyrus was more affected in GBA-PD. De novo GBA-PD show a distinct topography of regional cholinergic terminal ligand binding. Although the Parkinson's disease groups were not distinguishable clinically, in comparison to healthy controls, GBA-PD showed more extensive cholinergic denervation compared to non-GBA-PD. A larger group is needed to validate these findings. Our results suggest that de novo GBA-PD and non-GBA-PD show differential patterns of cholinergic system changes before clinical phenotypic differences between carriers versus non-carrier groups are observable.

Cholinergic deficiency in Parkinson's disease patients with visual hallucinations.

Visual hallucinations (VH) can increase the burden of disease for both patients with Parkinson's disease (PD) and their caregivers. Multiple neurotransmitters have been implicated in the neuropathology of VH, which provide targets for treatment and prevention. In this study, we assessed the association between cholinergic denervation and VH in PD in vivo, using PET imaging of the cholinergic system. A total of 38 PD patients participated in this study. A group of 10 healthy subjects, matched for age, sex and education, was included for comparison. None of the participants used cholinergic drugs. Thirteen patients who had experienced VH in the past month (VH+) were compared to 20 patients who had never experienced VH in their lives (VH-). Cholinergic system integrity was assessed with PET imaging using [18F]fluoroethoxybenzovesamicol ([18F]FEOBV) as the tracer. We assessed the differences in tracer uptake between groups by cluster-based analysis and by analysis of predefined regions of interest (ROIs) consisting of the ventral visual stream, the dorsal attentional network, the ventral attentional network and the lateral geniculate nucleus and mediodorsal nucleus of the thalamus. The PD group (n=38) showed an extensive pattern of decreased tracer uptake throughout the brain, compared to the controls (n=10). Within the PD group, the VH+ group (n=13) showed a cluster of decreased tracer uptake compared to the VH- group (n=20), which covered most of the left ventral visual stream and extended towards superior temporal areas. These results were mirrored in the ROI-based analysis, where the VH+ group showed the strongest deficits in the left inferior temporal gyrus and the left superior temporal gyrus, compared to the VH- group. VH in PD are associated with a marked cholinergic deficiency in the left ventral visual stream and the left superior temporal lobe, in addition to an extensive global cholinergic denervation in the general PD population.