Cholinergic System Changes in Dopa-Unresponsive Freezing of Gait in Parkinson's Disease

Abstract

Background: Freezing of gait (FoG) is a debilitating mobility disturbance that becomes increasingly resistant to dopaminergic pharmacotherapies with advancing Parkinson's disease (PD). The pathophysiology underlying the response of FoG to dopaminergic treatment is poorly understood. Prior vesicular acetylcholine transporter positron emission tomography (VAChT PET) imaging studies implicate the degeneration of cholinergic pathways, including bilateral striatal and limbic archicortex deficits, as significant contributors to FoG.

Objective: We aim to investigate whether specific cholinergic system changes are associated with FoG responsiveness to levodopa treatment in PD patients.

Methods: Thirty six PD subjects (31M/5F) completed [¹⁸F]-fluoroethoxybenzovesamicol ([¹⁸F]FEOBV) vesicular acetylcholine transporter positron emission tomography (VAChT PET) and underwent videotaped clinical assessments for FoG on and off levodopa.

Results: Sixteen subjects had l-dopa-unresponsive FoG. Whole brain voxel-based analyses of [¹⁸F]FEOBV PET (false discovery rate-corrected at P < 0.05 and adjusted for levodopa-equivalent dose) showed that those with l-dopa-unresponsive FoG had more severe cholinergic terminal deficits in the bilateral insula, hippocampi, fimbria, and lateral geniculate nuclei; left mid-temporal, putamen, and posterior cingulate regions; and the right mid-frontal region and anterior ventral nucleus of the thalamus compared to those with l-dopa-responsive FoG.

Conclusion: FoG unresponsive to levodopa is associated with bilateral cholinergic terminal reductions, mostly in extra-striatal regions involved in multisensory and cognitive integration of gait and postural control as well as spatial navigation. The lack of specific striatal involvement points to the disruption of widespread cerebral network functions underlying l-dopa-unresponsive FoG in PD and may explain the treatment-resistant nature of FoG to levodopa. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Keywords: Parkinson's disease; acetylcholine; freezing of gait; levodopa responsiveness; positron emission tomography (PET).

FIG. 1

Whole brain voxel‐based comparison of [¹⁸F]FEOBV ([¹⁸F]‐fluoroethoxybenzovesamicol) PET (positron emission tomography) between l‐dopa‐responsive and l‐dopa‐unresponsive freezers. More severe cholinergic reductions in the bilateral insula, hippocampi, fimbria, and lateral geniculate nuclei; left mid‐temporal, putamen, and posterior cingulate regions; and the right mid‐frontal region and anterior ventral nucleus of thalamus, in patients with l‐dopa‐unresponsive FoG (freezing of gait) compared to l‐dopa‐responsive FoG, FDR (false discovery rate) corrected at P < 0.05. Partial‐volume correction was applied to the analyzed images. [Color figure can be viewed at wileyonlinelibrary.com]

FIG. 2

Rank‐difference voxel‐wise correlation analysis of flipped [¹⁸F]FEOBV ([¹⁸F]‐fluoroethoxybenzovesamicol) images (hemisphere with more affected nigrostriatal integrity on the right) with ordinal levodopa responsiveness of FoG (freezing of gait), FDR (false discovery rate) corrected at P < 0.05. Partial‐volume correction was applied to the analyzed images. The statistical correlation map was enhanced using threshold free cluster enhancement (TFCE). Lower cholinergic integrity was associated with lower responsiveness of levodopa to FoG. [Color figure can be viewed at wileyonlinelibrary.com]