Neurodegenerative disorders are increasingly recognised as disorders of intricate immune-metabolic dysregulation. Among the relevant pathways, the kynurenine pathway (KP) has emerged as a critical intersection between neurochemistry and immune modulation. Research in Alzheimer’s disease (AD), for example, has shown that kynurenic acid (KYNA) levels in cerebrospinal fluid (CSF) are significantly higher in AD patients compared with cognitively healthy controls. Similarly, pathological neuroinflammation has also been observed in multiple system atrophy (MSA) during disease progression. Characterised by autonomic failure, cerebellar ataxia, and parkinsonism, MSA highlights the need for understanding metabolic dysregulation in neurodegenerative disorders.
A recent study by Nagao and colleagues (2026) provides novel insights into alterations in KP metabolism in MSA. Using CSF samples from patients and healthy controls, the authors demonstrated a marked imbalance in KYN metabolites, highlighted by elevated quinolinic acid (QA) and reduced KYNA levels, resulting in a significantly increased QA/KYNA ratio in the CSF of MSA patients. Given the neurotoxic properties of QA and the neuroprotective role of KYNA, the increased QA/KYNA ratio reflects a metabolic bias towards neurotoxicity and neuroinflammatory signalling. Notably, the QA/KYNA ratio showed good discriminative performance for MSA (AUC ≈ 0.86), highlighting its potential as a biomarker. Interestingly, classical markers of neuroinflammation and neurodegeneration, including sTREM2, GPNMB, and NfL, were also elevated in MSA patients, but did not correlate with KP metabolites. This dissociation suggests that KP alterations in MSA are less likely to be a direct consequence of canonical inflammatory processes and instead exist in parallel as an independent metabolic axis.
These findings are consistent with the current broader literature implicating KP metabolic alteration across neurodegenerative disorders, which is marked by elevated QA and reduced KYNA. Mechanistically, the observed profile is aligned with a metabolic shift towards KMO-mediated metabolism, favouring downstream neurotoxic QA production. Together, this study highlights the KP as a distinct and potentially targetable metabolic domain in MSA. Future work integrating metabolic, inflammatory, and imaging approaches will be essential to determine whether modulation of this pathway can modify disease trajectory or serve as an early biomarker of neurodegenerative vulnerability.