A multicenter longitudinal study of cholinergic subgroups in Parkinson disease

Introduction

Parkinson disease (PD) is a heterogeneous neurodegenerative syndrome with the defining feature of relatively early degeneration of nigrostriatal dopaminergic projections¹. PD pathophysiology is multifactorial, reflecting dysfunction and degeneration of multiple central and peripheral nervous systems components². Current subtyping approaches are mainly based on clinical features that inadequately reflect disease heterogeneity and natural history³. There is a need for objective, biologically informed subtyping that meaningfully reflects clinical heterogeneity, varying natural history, and informs development of more specific therapies⁴. Recent subtyping proposals focus on biomarkers correlating with a-synuclein deposition⁵. These proposals are controversial as not all forms of PD exhibit a-synuclein deposition and this categorization may not reflect clinical and natural history heterogeneity^6,7. Alternative, potentially complementary, biologically driven subtyping approaches could be based on relatively differential involvement of nervous system components^{8, 9–10}. More severe cholinergic denervation is implicated in a proposed ‘malignant’ subtype of PD^{11, 12–13}, characterized by more severe dopaminergic medication-refractory postural instability and gait difficulties and cognitive decline/dementia^11,14. Therefore, cholinergic system changes may uniquely predict clinically relevant disease milestones in PD.

[¹⁸F]fluoroethoxybenzovesamicol ([¹⁸F]FEOBV) is a selective positron emission tomography (PET) ligand for the vesicular acetylcholine transporter (VAChT), uniquely expressed by cholinergic terminals^{15, 16–17}. [¹⁸F]FEOBV PET has excellent anatomic resolution and regional [¹⁸F]FEOBV binding likely reflects both cholinergic terminal integrity and cholinergic neuron activity^18,19. The gene encoding VAChT, SLC18A3, is embedded in the first intron of the gene encoding choline O-acetyltransferase (ChAT; CHAT), the biosynthetic enzyme for acetylcholine (ACh)²⁰. VAChT and ChAT expressions are subject to coordinated regulation²¹. Regional decreases in [¹⁸F]FEOBV binding are most parsimoniously interpreted as cholinergic terminal degeneration, though down-regulation of VAChT expression is plausible. Regional [¹⁸F]FEOBV binding above normal levels likely reflects a joint increase in VAChT and ChAT expression, possibly related to increased cholinergic neurotransmission.

Prior studies showed initial cholinergic denervation in posterior (parieto-occipital) cortices but potential up-regulation of cholinergic neurotransmission in other regions, especially in prodromal or earlier stage disease^10,14,22. We previously reported bidirectional changes with evidence of posterior cortical cholinergic terminal losses but higher than normal...