Integrated peripheral metabolic and inflammatory biomarker signatures are associated with clinical deterioration in Creutzfeldt–Jakob disease

INTRODUCTION: Systemic metabolic and inflammatory disturbances are implicated in neurodegenerative diseases, but comprehensive metabolomic profiling in Creutzfeldt-Jakob disease (CJD) remains limited, and the potential interplay between peripheral metabolism and inflammatory or tissue-remodeling processes is poorly understood. OBJECTIVES: This study aimed to characterize the plasma metabolome and inflammatory/proteolytic profile in CJD, and to evaluate their individual and combined associations with cerebral glucose metabolism and clinical severity. METHODS: F-FDG PET/MRI, and clinical assessments. Orthogonal projections to latent structures-discriminant analysis (OPLS-DA) identified differentially abundant metabolites (variable importance in projection >1, p < 0.05). Linear and interaction models, adjusted for age and sex, evaluated associations with cerebral hypometabolism and clinical outcomes. RESULTS: We enrolled 40 CJD patients (mean age 60.8 years, 42.5 % female) and 40 HCs. OPLS-DA revealed clear separation between groups, and 42 differentially abundant metabolites were identified from the initial 163 metabolites that differed between groups. Enrichment analysis revealed dysregulation in metabolic pathways related to amino acid biosynthesis, alanine, aspartate and glutamate metabolism, ABC transporters, glycerophospholipid metabolism, and others. Levels of IL-4, IL-18, IL-22, IFN-γ, IL-1β, IL-6, MMP-1, and MMP-8 were significantly elevated in CJD patients. Multiple metabolites and these peripheral factors correlated with hypometabolism in vulnerable brain regions and with cognitive and functional decline. Interaction analyses further showed that specific metabolite-mediator combinations (e.g., Glycerophosphocholine, Glyceric acid, Asparagine, Dimethylglycine, 3-Phosphoglycerate with IL-1β, IL-4, IL-6, IL-22, MMP-8) were significantly associated with regional hypometabolism and clinical deterioration. CONCLUSION: CJD involves coupled peripheral metabolic and inflammatory/proteolytic disturbances that may be associated with more severe brain degeneration and clinical decline, suggesting a possible multifaceted systemic component accompanying disease pathology.