Cortical α4β2-nicotinic acetylcholine receptors and cognitive decline in Parkinson's disease.

Abstract

Background: Autopsy and in vivo molecular imaging studies suggest altered binding of the α4β2-nicotinic cholinergic receptor (α4β2-nAChR) with cognitive dysfunction in Parkinson's disease (PD).

Objective: To determine the relationship between cortical and hippocampal binding of the α4β2-nAChR with [¹⁸F]XTRA PET, a high-affinity radiotracer that enables quantification of α4β2-nAChR in these regions, and cognitive function in individuals with PD.

Methods: Individuals with PD (N = 32) and age-similar, controls without PD or dementia (N = 10) completed a cognitive assessment and one 90-min, [¹⁸F]XTRA PET scan. Metabolite-corrected arterial input function radioactivity time-activity curves were generated to obtain total distribution volume (V_T) across 12 regions of interest (ROIs). [¹⁸F]XTRA binding was compared 1) between controls and people with PD and 2) between controls, persons with PD with normal cognition (PD-NC), and persons with PD with MCI (PD-MCI).

Results: [¹⁸F]XTRA binding was higher in the occipital cortex of the combined group of PD participants compared to age-similar controls. No regions showed lower binding in PD. V_T with, but not without, partial volume correction was different between controls, PD-NC, and PD-MCI groups, and this was driven by higher binding in PD-MCI compared to controls. Regression of regional V_T on cognitive domain T-scores, adjusting for age, showed that worse performance in visual-spatial memory tasks was associated with higher V_T in the precuneus and the entire parietal cortex.

Conclusions: Higher α4β2-nAChR binding in posterior cortical regions is found in PD and associated with worse visual perception and memory, possibly due to lower receptor occupancy by endogenous acetylcholine.