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

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. Research in Context Section Evidence before this study The kynurenine pathway is a metabolic process needed for the degradation of tryptophan – an essential amino acid. Several by-products of this pathway have been implicated in the pathobiology of Huntington’s disease, a fatal neurodegenerative condition. Studying these metabolites could help better understand the biology of the condition and accelerate treatment development. In 2018, a systematic review concluded that only a small number of studies attempted to investigate the levels of these by-products in human biofluids, with the majority being limited by methodologic frailties and therefore requiring further study. Added value of this study We used a large prospective cohort consisting of Huntington’s disease mutation carriers and healthy controls to study the metabolic by-products of the kynurenine pathway. Matched cerebrospinal fluid and blood were collected using standardized protocol and analysed with high-performance liquid-chromatography. None of the studied metabolites showed associations with disease stage or with well-known clinical and imaging markers of the disease. Implication of all the available evidence Our results show that substantial alterations of the kynurenine pathway are not present in patients with Huntington’s disease compared to healthy controls, at least to the extent that is measurable in cerebrospinal fluid or blood. Whilst our results discourage the use of these metabolites as diagnostic and prognostic biomarkers, they do not reject the notion that regional- and tissue-specific alterations may exist, and that they may possess value as pharmacodynamic biomarkers in clinical trials targeting the kynurenine pathway.