The purpose of this cross-sectional study was to investigate the cholinergic denervation of the cerebellum and its contribution to specific domains of gait impairment in Parkinson disease (PD).

A mélange of disabling motor and non-motor manifestations frequently affects people with PD. One particularly disabling component of motor dysfunction is gait impairment that leads to falls, reduces quality of life and ultimately leads to residential care placement. Gait imbalance is a key contributor to morbidity and mortality in PD and does not respond well to traditional dopaminergic therapy. 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 possibly new targets for imaging biomarkers. Our prior studies demonstrated altered cerebellar resting-state functional connectivity relate to gait and cognitive dysfunction in PD.

We conducted PET analysis 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. VAT nondisplaceable binding potential (BP_ND) was calculated using multilinear reference tissue model 2 (MRTM2) utilizing 10-110 minutes of PET scan data with optimized eroded white matter reference region. Comprehensive spatiotemporal gait measures were acquired with a GAITRite walkway for behavioral correlations.

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 including step width, variability in step width and step time in PD participants after controlling for confounding variables.

These results demonstrate regional cholinergic denervation of the cerebellum in PD and its gait correlates. Our data reflects the potential of cerebellar cholinergic measures as a novel imaging biomarker of gait impairment in PD.