Cerebrospinal ceramides and cognition as a function of striatal asymmetry in early stage of Parkinson's disease

Background Parkinson's disease (PD) is characterized by heterogeneous clinical phenotypes that may be influenced by the asymmetry of striatal denervation. The alpha-Synuclein Origin site and Connectome (SOC) model proposes that different disease onset patterns-"body first" versus "brain first"-affect symptom development and cognitive decline. Objective This study aims to explore the relationship between striatal denervation asymmetry, ceramide metabolism, and cognitive performance in early-stage PD. Methods We analyzed data from 329 patients with PD at baseline, categorized by the type of putamen denervation asymmetry predominance at baseline, along with data from 167 healthy controls. We performed generalized linear mixed models introducing ceramides levels and cognitive performance as discriminating factors. Spearman correlations were used to highlight the relationship between cognition and ceramides. Results Our findings revealed that patients with asymmetric striatal denervation exhibited higher concentrations of C18:0 ceramides compared to both symmetric patients and healthy controls. Moreover, patients with symmetric denervation demonstrated greater cognitive impairment than those with right or left asymmetry. Conclusions The study highlights the importance of striatal denervation asymmetry in influencing ceramide metabolism and cognitive function in early-stage PD. These findings suggest that specific ceramide profiles may serve as metabolic markers to distinguish clinical phenotypes, providing insights into disease progression.