Objective: To identify regions of decreased cholinergic signaling in Parkinson’s disease (PD) participants relative to cognitively normal controls as measured by positron emission tomography imaging of the cholinergic-targeting radioligand, [¹⁸F] vesicular acetylcholine transporter (VAT).

Background: Cholinergic signaling plays an integral part in the regulation of brain state and behavior. Arising from striatal interneurons and basal forebrain and brainstem nuclei, acetylcholine (ACh) alters neuronal firing properties, modulates blood flow, governs thalamocortical gating, and plays a role in behaviors from attention to visuospatial navigation and memory formation. In post-mortem studies, ACh declines in PD in the basal forebrain and brainstem. Despite this, the precise regional pattern of change in cholinergic neurons and their relation to motor and cognitive decline within PD is poorly understood. Here we hypothesized that participants with clinically defined PD would demonstrate decreases in the regional uptake of VAT.

Method: 66 participants enrolled in our study (38 PD, 28 controls) underwent 2 hr [¹⁸F] VAT scans to map the distribution of ACh signaling within the brain. VAT images were aligned to anatomical images for each subject and spatially normalized using PMOD software. Standardized uptake value ratio (SUVR) images were generated, with SUV images averaged over 90-120 minutes, the pons, cerebellar hemispheres, or centrum semiovale used as the reference region to compare reliability. Groups were well matched in age (Control = 68.6±11.3 years of age; PD = 68.9 ± 7.3 years of age), with a female/male distribution (Control = 22/6; PD = 20/18). Statistically significant group differences were calculated using regional ttest values with a familywise (FWE) error rate multiple-comparisons correction of <10%.

Results: With the cerebellar reference region, the thalamus and postcentral gyrus displayed modestly reduced uptake in PD (p<0.05, FWE-corrected). Other reference regions only trended toward significant decreases in these areas (p < 0.05 uncorrected; p > 0.05 FWE-corrected).

Conclusion: Decreases in the thalamus and postcentral gyrus suggest a potentially meaningful result with broad dysregulation of thalamocortical sensory gating and degeneration in multiple sites as the primary cholinergic afferents for these areas arise from distinct nuclei. How individual differences in cholinergic signaling relate to symptomatic phenotype remains unknown.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/decreased-regional-cholinergic-signaling-in-parkinsons-disease/