Lack of Evidence for Kynurenine Pathway Dysfunction in Huntington's Disease: CSF and Plasma Analyses from the HDClarity Study.

Background: Evidence from animal studies and post-mortem studies of brains from people with Huntington's disease (PwHD) has suggested that the kynurenine pathway (KP) may be dysregulated in Huntington's disease (HD).

Objective: To determine whether there are differences in KP metabolites in the CSF and plasma of PwHD versus healthy controls enrolled in the HDClarity study.

Methods: CSF and plasma samples from 141 PwHD with mild and moderate manifest disease and 75 healthy controls were analyzed for 3-hydroxykynurenine (3-OH-KYN), quinolinic acid, kynurenine, anthranilic acid, kynurenic acid, and tryptophan concentrations using validated high-performance liquid chromatography with tandem mass spectrometry (LC-MS/MS) methods. The primary and secondary endpoints compared metabolite concentrations between groups, and an exploratory analysis (PwHD only) evaluated the association between the metabolite levels and severity of disease.

Results: No significant differences in CSF or plasma concentrations of any of the six KP metabolites were observed between PwHD and controls, and there were no strong associations between the concentration of any KP metabolite and disease severity. A principal component analysis of the combined CSF and plasma measures showed a substantial positive correlation among all metabolites except for tryptophan in plasma.

Conclusions: We found no evidence to support the hypothesis of dysregulation of KP metabolites in HD based on CSF and plasma metabolite levels. The monitoring of KP metabolites in CSF or plasma is unlikely to serve as a pharmacodynamic biomarker for disease progression or therapeutic intervention in HD.