Objective: To elucidate cerebrospinal fluid (CSF) tryptophan metabolism in multiple system atrophy (MSA), focusing on alterations in the kynurenine pathway and its pathological implications.
Background: Serotonergic neuronal loss has been reported in MSA. Our previous study demonstrated that CSF5-hydroxyindoleacetic acid (5-HIAA) levels, the major metabolite of serotonin, were significantly lower in patients with MSA than in controls. Moreover, CSF 5-HIAA levels were inversely correlated with the Unified MSA Rating Scale (UMSARS) total score, including the swallowing subscore of UMSARS Part 1, suggesting a potential role of serotonin in motor dysfunction in MSA patients. However, changes in the kynurenine pathway, a branch of tryptophan metabolic pathway, remain unexplored.
Method: We enrolled 46 patients with clinically established MSA (MSA-C: 23, MSA-P: 23, 22 males, 24 females; age at onset: 62.1±8.9 years; disease duration: 32.2±24.7 months) and 51 control subjects (40 males, 11 females; mean age: 63.6±1.3 years). We measured CSF levels of tryptophan, 5-HIAA, kynurenine, 3-hydroxykynurenine, quinolinic acid (QA), and kynurenic acid (KA). Glycoprotein non- melanoma protein B (GPNMB), soluble triggering receptor expressed on myeloid cells 2 (sTREM2), neurofilament light chain (NfL), and clinical scores were also analyzed. Principal component analysis (PCA) assessed the relationships among these parameters.
Results: Compared to controls, MSA patients exhibited significantly lower levels of 5-HIAA (P=0.0016) and KA (P<0.0001), a neuroprotective factor, alongside higher QA levels (P=0.001), a neurotoxic metabolite. The QA/KA ratio, an indicator of neuroinflammation, was significantly elevated in MSA (P<0.0001) and negatively correlated with GPNMB (P=0.0311). PCA identified PC1 as representing kynurenine pathway abnormalities, whereas PC2 reflected microglial activation (sTREM2) and axonal damage (NfL).
Conclusion: Our findings suggest that MSA is characterized by extensive alterations in tryptophan metabolism, particularly a shift in the kynurenine pathway independent of sTREM2 that promotes neuroinflammation. These results indicate that targeting this pathway may offer a novel therapeutic strategy for MSA.
To cite this abstract in AMA style:
R. Nagao, K. Kawabata, Y. Mizutani, H. Watanabe. Altered Tryptophan Metabolism and the Role of the Kynurenine Pathway in Multiple System Atrophy [abstract]. Mov Disord. 2025; 40 (suppl 1). https://www.mdsabstracts.org/abstract/altered-tryptophan-metabolism-and-the-role-of-the-kynurenine-pathway-in-multiple-system-atrophy/. Accessed October 5, 2025.« Back to 2025 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/altered-tryptophan-metabolism-and-the-role-of-the-kynurenine-pathway-in-multiple-system-atrophy/