Low brain cholinergic activity links to freezing of gait in Parkinson's patients on medication

Gait problems, especially freezing of gait (FoG), become more common as Parkinson's disease advances and raise the risk of falls. FoG that persists despite dopamine medication is particularly troublesome because it suggests non-dopamine systems are involved. The underlying biology remains incompletely understood.

This study asked whether the brain's cholinergic system contributes. Fourteen people with Parkinson's disease and FoG in the medication ON state underwent two PET scans on separate days: 18F-FEOBV, which marks cholinergic nerve terminals, and 18F-FDG, which reflects glucose metabolism. Using principal component analysis, the team derived spatial covariance networks and correlated individual expression of these patterns with ON-state FoG, a lower body and gait subscore of the MDS-UPDRS part III, and accelerometer-based gait measures collected at home.

A cholinergic pattern correlated with ON-FoG (R² = 0.47, P = 0.045) and with other lower body and gait signs (R² = 0.79, P = 0.0077). Lower cholinergic activity in the thalamus, hippocampus, striatum, anterior cingulate and brainstem areas consistent with the mesencephalic locomotor region accompanied worse freezing and gait. This pattern was unrelated to disease duration or standard motor scores, and there was no correlation with OFF-state FoG. The metabolic pattern did not correlate with FoG, though a subset of gait symptoms showed an association.

The results support a role for cholinergic dysfunction in dopamine-resistant freezing and may help guide future therapies targeting cholinergic pathways.

Caveats are substantial: the sample was very small, there was no control group in the analysis, correlations do not prove causation, and findings need replication in larger cohorts.