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

• Published in: Movement disorders Vol. 40; no. 8; pp. 1584 - 1594
• Main Authors: Chou, Kelvin L., Kanel, Prabesh, Emde Boas, Miriam, Roytman, Stiven, Carli, Giulia, Albin, Roger L., Bohnen, Nicolaas I.
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01.08.2025; Wiley Subscription Services, Inc
• Subjects: Acetylcholine; Aged; Antiparkinson Agents - therapeutic use; Archicortex; Brain - diagnostic imaging; Brain - drug effects; Brain - metabolism; Cholinergic transmission; Dopamine receptors; Female; Fornix; freezing of gait; Gait; Gait Disorders, Neurologic - diagnostic imaging; Gait Disorders, Neurologic - drug therapy; Gait Disorders, Neurologic - etiology; Gait Disorders, Neurologic - metabolism; Hippocampus; Humans; Levodopa; Levodopa - pharmacology; Levodopa - therapeutic use; levodopa responsiveness; Male; Middle Aged; Movement disorders; Navigation behavior; Neostriatum; Neurodegeneration; Neurodegenerative diseases; Neuroimaging; Parkinson Disease - complications; Parkinson Disease - diagnostic imaging; Parkinson Disease - drug therapy; Parkinson Disease - metabolism; Parkinson's disease; Piperidines; Positron emission tomography; positron emission tomography (PET); Putamen; Sensory integration; Tomography; Vesicular Acetylcholine Transport Proteins - metabolism; Vesicular acetylcholine transporter; Parkinson's disease; acetylcholine; freezing of gait; positron emission tomography (PET); levodopa responsiveness
• ISSN: 0885-3185; 1531-8257; 1531-8257
• DOI: 10.1002/mds.30196

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.