Altered CSF Tryptophan-Kynurenine Pathway Metabolism in Multiple System Atrophy: Distinct from Classic Microglial Markers

BackgroundAlterations in tryptophan (TRP)-serotonin metabolism have been implicated in multiple system atrophy (MSA). However, the involvement of the TRP-kynurenine (KYN) pathway, which is associated with neuroinflammatory and neuroprotective processes, is elusive. ObjectivesTo investigate tryptophan metabolism in cerebrospinal fluid (CSF), we examined the relationships between metabolites and their associations with clinical biomarkers reflecting microglial activation and axonal injury in MSA patients. MethodsCSF and clinical data from 51 patients with clinically established MSA and 56 control subjects were analyzed. CSF concentrations of TRP, KYN, 3-hydroxykynurenine (3-HK), quinolinic acid (QA), and kynurenic acid (KA) were quantified. Additionally, 5-hydroxyindoleacetic acid (5-HIAA), glycoprotein nonmetastatic melanoma protein B (GPNMB), soluble triggering receptor expressed on myeloid cells 2 (sTREM2), and neurofilament light chain (NfL) were measured. Group differences and inter-biomarker correlations were assessed, with hierarchical cluster analysis performed on the resulting correlation matrix. Principal component analysis (PCA) was performed to explore the latent relationships among biomarkers. ResultsPatients with MSA showed higher CSF levels of QA, a neuroinflammatory marker (adjusted median difference controlling for age and sex, 2.56CnM; 95% CI, 0.99-3.60) and lower levels of KA, which is considered neuroprotection (-6.46CnM; 95% CI, -9.08 to -3.12), yielding an elevated QA/KA ratio (+0.52; 95% CI, 0.27-0.88). In contrast, CSF levels of TRP, KYN, and 3-HK did not differ significantly between the two groups. TRP was correlated only with KYN (Spearmans {rho} = 0.56, adjusted for age and sex), while KYN was correlated with 3-HK ({rho} = 0.47) and QA ({rho} = 0.64), forming a shared cluster. KA did not show significant correlations with any of the measured kynurenine metabolites. Although GPNMB, sTREM2, and NfL were also increased, these inflammatory and neurodegenerative markers showed no correlation with kynurenic metabolites and formed distinct clusters. PCA indicated that these markers are independent of KYN pathway metabolites. ConclusionsThis study revealed a marked imbalance in KYN metabolism in MSA, which suggests a metabolic shift that may promote excitotoxicity and proinflammatory processes that are distinct from classic neuroinflammatory markers. These findings may highlight future therapeutic strategies targeting the kynurenine pathway.