Objective: The purpose of this cross-sectional study was to investigate the cholinergic denervation of the cerebellum and its contribution to impaired gait and cerebellocortical resting-state functional connectivity (FC) in Parkinson disease (PD).

Background: A mélange of disabling motor and non-motor manifestations frequently affects people with PD. Gait imbalance and falls do not respond adequately to dopaminergics and amplify morbidity and mortality in PD. Most functional neuroimaging studies focus on nigrostriatal dopaminergic pathways and do not adequately explain gait impairments in PD. This suggests involvement of other neurotransmitter systems or brain regions beyond the nigrostriatal pathway and potentially, new targets for imaging biomarkers and therapies. Our prior studies demonstrated altered cerebellar FC with sensorimotor cortex and paracentral lobules relate to gait dysfunction in PD, but the pathophysiologic underpinnings remain unknown.

Method: PET analysis was conducted with radioligand [¹⁸F]VAT targeting vesicular acetylcholine transporter (VAChT) contrasting cerebellar cholinergic activity in 64 people with PD and 41 age-matched healthy control participants. Cross-sectional FC-MRI measures that satisfied stringent quality assurance metrics were available in a subset of PD (n=39) and control (n=28) participants. VAT nondisplaceable binding potential (BP_ND) was calculated using multilinear reference tissue model 2 (MRTM2) with optimized eroded white matter reference region. Comprehensive spatiotemporal gait measures were acquired with a GAITRite walkway for behavioral correlations.

Results: The PD participants had significantly reduced VAChT expression in distinct cerebellar regions including hemispheric motor and cognitive lobules and midline vermis. The reduced cerebellar cholinergic activity (VAT BP_ND) correlated with key gait measures and cross-sectional cerebellar FC with the sensorimotor cortex and paracentral lobules in PD participants after controlling for confounding variables.

Conclusion: These results demonstrate regional cholinergic denervation of the cerebellum in PD and its FC and gait correlates. This multimodal analysis reflects the potential of cerebellar cholinergic measures and FC as novel imaging biomarkers of gait impairment in PD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/cerebellar-cholinergic-denervation-relates-to-impaired-gait-and-cerebellocortical-resting-state-functional-connectivity-in-parkinson-disease/