Objective: To determine how cholinergic signaling changes within Parkinson Disease (PD) and how these differences relate to the progression of cognitive and behavioral symptoms.

Background: Cholinergic projections in the brain play an essential role in the regulation of diverse motor and cognitive behaviors. Yet, the specific nature of how these projections change in PD remains poorly understood.  In recent work we demonstrated the utility of the [18F]VAT radiotracer to map cholinergic projections using white matter as a reference region¹. Here we employ this to identify the regional distribution of cholinergic dysfunction in PD.

Method: 68 PD (40 female, 28 male, 70.8±10.6 years old) and 41 control (30 female, 11 male, 68.3±7.0 years old) underwent an [18F]VAT positron emission tomography scan. Images were reconstructed and time-activity curves were extracted using FreeSurfer5.3-based volumes of interest. Partial volume effects were corrected for using the geometric transfer matrix method. With white matter as the reference region, k₂’ was estimated for each participant with cortical gray matter as the target tissue using multilinear reference tissue model (MRTM1).  k₂’ (k₂’ = 0.017±0.003min^-1) was fixed for each participant and non-displaceable binding was estimated using MRTM2². Multiple comparisons were corrected for using the Benjamini-Hochberg method with a false discovery rate of 0.05.

Results: PD participants exhibit widespread, statistically significant differences in [18F]VAT uptake in numerous cortical and subcortical structures, including, 11% lower uptake in the thalamus, 19% in superior parietal cortex, 20% in the postcentral gyrus, and 22% in superior temporal cortex.

Conclusion: These findings suggest that a robust decrease in cholinergic signaling occurs within PD, opening the possibility for further study with cholinergic impacts on motor and cognitive symptoms using [18F]VAT.

References: 1. O’Donnell J, Soda AK, Jiang H, et al. PET Quantification of [18F]VAT in Human Brain and its Test-Retest Reproducibility and Age Dependence. J Nucl Med. 2024. Accepted. 2. Ichise M, Liow JS, Lu JQ, et al. Linearized reference tissue parametric imaging methods: application to [11C] DASB positron emission tomography studies of the serotonin transporter in human brain. J Cereb Blood Flow Metab 2003; Vol 23: Issue 9:1096-112.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/mapping-cholinergic-signaling-in-parkinson-disease-using-18fvat/