Objective: We aimed to investigate the dynamics of whole-blood energy metabolism in Parkinson’s disease (PD) and evaluate its clinical relevance.

Background: Emerging evidence indicates that PD represents a disorder of systemic energy metabolism rather than solely a dopaminergic condition.

Method: Whole-blood AMP, ADP, ATP, NAD, NADP, and NMN were quantified by LC-MS/MS in 104 patients with PD and 65 controls. Adenylate energy charge (AEC) was subsequently calculated from AMP, ADP, and ATP levels. Integrated statistical analyses were performed, including age- and sex-adjusted group comparisons, correlation and partial correlation analyses, and multivariate modeling using principal component analysis (PCA) and structural equation modeling (SEM). Associations with plasma energy-related metabolites involved in glycolysis, the TCA cycle, and fatty acid metabolism were examined. Longitudinal relationships with changes in clinical scores were also assessed.

Results: ATP, NAD, NADP, and NMN were reduced in PD, indicating depletion of both adenylate and pyridine nucleotide pools, which remained strongly intercorrelated after adjustment. ATP was positively associated with the lactate-to-pyruvate ratio and inversely with citrate and 2-ketoglutarate, suggesting disrupted TCA-linked energy metabolism rather than isolated glycolytic impairment. PCA revealed coordinated variation of nucleotide pools, and SEM showed that energy charge was more closely linked to TCA and ketone-related markers than to glycolytic redox status. Longitudinally, lower baseline ATP predicted worsening of MDS-UPDRS part III, whereas higher baseline NAD and lower NADP/NAD ratio were associated with progression of MDS-UPDRS part I and II. The lactate-to-pyruvate ratio showed no longitudinal association, suggesting that redistribution within the pyridine nucleotide pool rather than glycolytic flux underlies non-motor progression.

Conclusion: PD patients showed a characteristic reduction of major nucleotide pools accompanied by impaired glycolytic redox balance and upstream disruption of the TCA cycle. These alterations were linked to longitudinal motor and non-motor progression. Whole-blood nucleotide profiling may provide a biomarker framework reflecting systemic bioenergetic vulnerability, with distinct associations of ATP availability and pyridine nucleotide balance with motor and non-motor progression in PD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/reduced-whole-blood-energy-metabolism-in-parkinsons-disease/