Cholinergic contributions to speech-in-noise processing in Parkinson's disease

Speech perception performance in challenging listening environments declines with age and is particularly impaired in Parkinson's disease, leading to communication difficulties and cognitive strain. Although peripheral hearing loss contributes to these deficits, dysfunction of the central cholinergic system may play a key role. Parkinson's disease is characterized by early and widespread cholinergic degeneration. Accordingly, further describing the contribution of cholinergic integrity to functional hearing may offer better insight into the mechanistic link between sensory and cognitive decline and inform targeted therapeutic approaches. Twenty-nine individuals with Parkinson's disease (20 men, nine women; age range 60-76 years) were enrolled in a cross-sectional study conducted at the University of Michigan Functional Neuroimaging, Cognitive and Mobility Laboratory. Participants completed pure-tone audiometry, tympanometry and Quick Speech-in-Noise testing to assess peripheral and functional hearing. Cholinergic system integrity was quantified using [¹⁸F]-fluoroethoxybenzovesamicol [¹⁸F]-FEOBV positron emission tomography imaging, and magnetic resonance imaging was used for anatomical co-registration. Statistical parametric mapping identified regions where cholinergic binding correlated with speech-in-noise performance after adjusting for high-frequency pure-tone average thresholds. Multiple regression and hierarchical model comparisons tested independent and interactive effects of peripheral hearing and cholinergic integrity. High-frequency pure-tone average explained 21.6% of the variance in Quick Speech-in-Noise signal-to-noise ratio loss [β = 0.494 (0.151-0.838), P = 0.006]. After adjustment for hearing thresholds, reduced [¹⁸F]-FEOBV binding in auditory, thalamic, temporoparietal and cerebellar regions was significantly associated with greater signal-to-noise ratio loss (cluster-level family-wise error corrected P < 0.01). Cholinergic integrity accounted for an additional 27.5% of the variance beyond peripheral hearing [F = 15.596, P < 0.001; β = -0.533 (-0.811 to -0.256), P = 0.001]. An interaction between hearing thresholds and cholinergic integrity explained a further 12.7% of the variance (F = 9.671, P = 0.005), showing that higher cholinergic integrity mitigated the detrimental effects of hearing loss on speech-in-noise understanding. Observed effects were found to be independent of age and global cognition in the post hoc confounder regression analysis. Central cholinergic integrity is a major determinant of speech-in-noise performance in Parkinson's disease, acting both independently and interactively with peripheral hearing function. These findings indicate that speech-in-noise deficits may reflect early subcortical and cortical cholinergic dysfunction rather than only peripheral auditory decline. Recognition of this relationship underscores the potential for cholinergic-enhancing or neurostimulation-based therapies to improve communication and cognitive outcomes in neurodegenerative disorders.