Plasma ceramide ratios define metabolic–inflammatory associations with cognitive impairment in Parkinson’s disease

Cognitive impairment in Parkinson's disease (PD) remains difficult to stratify using accessible fluid biomarkers, and the metabolic-inflammatory relationships associated with cognitive decline remain incompletely quantified. Here, we examined the relationships among plasma ceramides, inflammatory cytokines, neurodegeneration biomarkers, and cognitive function in PD patients with varying degrees of cognitive impairment, patients with multiple system atrophy (MSA), and healthy controls. MSA was distinguished from PD by higher Cer 18:0/Cer 24:0 and Cer 24:1/Cer 24:0 ratios, despite overlapping cytokine and neurofilament light chain (NFL) profiles. Within PD, worsening cognitive status was accompanied by graded increases in specific ceramide ratios, inflammatory cytokines, and NFL. Cer 24:1/Cer 24:0 was independently associated with cognitive performance (B = - 2.01, P = 0.003). Structural equation modeling identified two association pathways between ceramide-related measures and cognition: a larger direct association (standardized β = -0.223; 60.8% of the total effect) and a smaller inflammation-related indirect association (standardized β = -0.133; 36.2%), whereas pathways involving NFL were not significant. These findings establish a ceramide-centered quantitative framework integrating metabolic and inflammatory dimensions of cognitive impairment in PD, supporting stratified biomarker development.