Kynurenine pathway metabolites in cerebrospinal fluid and blood as potential biomarkers in Huntington’s disease

Abstract

Background: Converging lines of evidence from cell, yeast and animal models, and post-mortem human brain tissue studies, support the involvement of the kynurenine pathway (KP) in Huntington's disease (HD) pathogenesis. Quantifying KP metabolites in HD biofluids is desirable, both to study pathobiology, and as a potential source of biomarkers to quantify pathway dysfunction and evaluate the biochemical impact of therapeutic interventions targeting its components. Methods: In a prospective single-site controlled cohort study with standardised collection of CSF, blood, phenotypic and imaging data, we used high-performance liquid-chromatography to measure the levels of KP metabolites - tryptophan, kynurenine, kynurenic acid, 3-hydroxykynurenine, anthranilic acid and quinolinic acid - in CSF and plasma of 80 participants (20 healthy controls, 20 premanifest HD, and 40 manifest HD). We investigated short-term stability, intergroup differences, associations with clinical and imaging measures, and derived sample-size calculation for future studies. Findings: Overall, KP metabolites in CSF and plasma were stable over 6 weeks, displayed no significant group differences and were not associated with clinical or imaging measures. Larger sample sizes would be needed to show differences in future studies. Interpretation: We conclude that the studied metabolites are readily and reliably quantifiable in both biofluids in controls and HD gene expansion carriers. However, we found little evidence to support a substantial derangement of the KP in HD, at least to the extent that it is reflected by the levels of the metabolites in patient-derived biofluids. Fund: This study was supported by the Medical Research Council UK and CHDI foundation.

Kynurenic acid in neurodegenerative disorders—unique neuroprotection or double‐edged sword?

“…There were no differences regarding basal KYNA, L‐kynurenine, or tryptophan levels. However, an increase in 3‐HK/KYNA ratio was detected in the group of patients with evident HD compared with HD patients at early stage of disease 140 …”

“…In a prospective single‐site controlled cohort study with standardized collection of CSF, blood, and phenotypic and imaging data, performed among 80 participants (20 healthy controls, 20 pre‐manifest HD, and 40 manifest HD), the KP metabolites in CSF and plasma were stable over 6 weeks of observation 140 . There were no differences regarding basal KYNA, L‐kynurenine, or tryptophan levels.…”