Decoding the metabolic landscape of Parkinson’s disease: dansylated urinary amines and phenols submetabolomes for signature profiling and biomarker discovery

Parkinson’s disease (PD) lacks reliable non-invasive early diagnostic biomarkers with strong discriminative capacity, representing a major unmet clinical demand. We developed a dansylation workflow coupled to trapped ion mobility spectrometry–quadrupole time-of-flight mass spectrometry (TIMS-Q-TOF-MS) for targeted profiling of the urinary amine–phenol submetabolome. Urine samples from 21 patients with PD, 21 patients with Alzheimer’s disease (AD), and 21 healthy controls (HCs) were analyzed, yielding annotations for 196 metabolites: 143 amine-containing species, 49 phenolic metabolites, and 4 dual-function metabolites carrying both amine and phenolic moieties. Partial least squares discriminant analysis (PLS-DA) confirmed the stability of our analytical pipeline. Screening with thresholds VIP > 1.2 and p  < 0.05 identified 47 differentially abundant metabolites linked to PD, enriched in cysteine/methionine metabolism, phenylalanine–tyrosine–tryptophan biosynthesis, pyrimidine metabolism, and tryptophan metabolism. PD was characterized by elevated dopamine 3-O-sulfate—indicative of accelerated peripheral dopamine inactivation—and reduced tryptophan and its hydroxylated derivatives. Receiver operating characteristic (ROC) analysis validated a three-metabolite signature (4-amino-1-piperidinecarboxylic acid, dopamine 3-O-sulfate, methylacetylenic putrescine) with an AUC of 0.923 (95% CI: 0.828–0.986) to discriminate PD from HCs. This panel captures PD-specific neurotransmitter metabolic dysregulation and achieves robust patient stratification. This study’s advantages lie in targeted quantification of pathophysiologically relevant amine–phenol metabolites, convenient non-invasive urinary sampling, and enhanced detection sensitivity via 4D metabolomics. Collectively, our results establish a novel urine-based diagnostic strategy for PD and delineate divergent metabolic signatures that differentiate PD from AD and other prevalent neurodegenerative disorders.