Cholinergic substrates of gait and postural impairments in Progressive Supranuclear Palsy

Purpose Progressive Supranuclear Palsy (PSP) is an atypical parkinsonian syndrome characterized by significant postural instability and gait difficulties (PIGD). While brain cholinergic deficits are documented in PSP, their role in the pathophysiology of PIGD is an area of active research. This cross-sectional study aimed to elucidate relationships between regional cholinergic denervation, assessed by [ ¹⁸ F]FEOBV PET, and PIGD severity in PSP patients. Methods Nineteen subjects characterized clinically as PSP (twelve males, seven females; mean age of 69.47 ± 6.46 years [range 55–79]). Based on the Movement Disorders Society-PSP diagnostic criteria, sixteen patients had probable PSP (eleven males; five females) and three had suggestive PSP (one male; two females). Clinical assessments showed significant motor impairments, a mean MDS-UPDRS Part III “off state” score of 42.36 ± 13.52 and a mean modified Hoehn and Yahr stage of 3.36 ± 1.22. Results Statistical parametric mapping (SPM) based voxel-wise analysis of [ ¹⁸ F]FEOBV PET data revealed a significant inverse correlation between lower regional [ ¹⁸ F]FEOBV binding and more severe PIGD motor rating scores. This association was observed across brain regions, including orbitofrontal cortices, gyrus rectus, septal nuclei, medial temporal lobe, insula, metathalamus, dorsomedial thalamus, pericentral cortices, caudate nuclei, anterior greater than mid and posterior and retrosplenial cingulate cortices, frontal lobe, and cerebellum. Conclusions These findings highlight the potential roles of cholinergic systems degenerations in mediating PIGD in PSP. This suggests that cholinergic systems degeneration plays a substantial role in the pathophysiology of PIGD in PSP, offering a potential avenue for targeted therapeutic interventions to improve mobility and quality of life for these patients.