Cholinergic Denervation Patterns in Parkinson's Disease Associated With Cognitive Impairment Across Domains

Abstract

Cognitive impairment is considered to be one of the key features of Parkinson's disease (PD), ultimately resulting in PD-related dementia in approximately 80% of patients over the course of the disease. Several distinct cognitive syndromes of PD have been suggested, driven by different neurotransmitter deficiencies and thus requiring different treatment regimes. In this study, we aimed to identify characteristic brain covariance patterns that reveal how cholinergic denervation is related to PD and to cognitive impairment, focusing on four domains, including attention, executive functioning, memory, and visuospatial cognition. We applied scaled sub-profile model principal component analysis to reveal cholinergic-specific disease-related and cognition-related covariance patterns using [¹⁸F]fluoroethoxybenzovesamicol PET imaging. Stepwise logistic regression was applied to predict disease state (PD vs. healthy control). Linear regression models were applied to predict cognitive functioning within the PD group, for each cognitive domain separately. We assessed the performance of the identified patterns with leave-one-out cross validation and performed bootstrapping to assess pattern stability. We included 34 PD patients with various levels of cognitive dysfunction and 10 healthy controls, with similar age, sex, and educational level. The disease-related cholinergic pattern was strongly discriminative (AUC 0.91), and was most prominent in posterior brain regions, with lower tracer uptake in patients compared to controls. We found largely overlapping cholinergic-specific patterns across cognitive domains, with positive correlations between tracer uptake in the opercular cortex, left dorsolateral prefrontal cortex and posterior cingulate gyrus, among other regions, and attention, executive, and visuospatial functioning. Cross validation showed significant correlations between predicted and measured cognition scores, with the exception of memory. We identified a robust structural covariance pattern for the assessment of cholinergic dysfunction related to PD, as well as overlapping cholinergic patterns related to attentional, executive- and visuospatial impairment in PD patients.