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

Research output: Contribution to journalArticlepeer-review

Filipe B. Rodrigues, Lauren M. Byrne, Alexander J. Lowe, Rosanna Tortelli, Mariette Heins, Gunnar Flik, Eileanoir B. Johnson, Enrico De Vita, Rachael I. Scahill, Flaviano Giorgini, Edward J. Wild

Original languageEnglish
Pages (from-to)539-553
Number of pages15
JournalJournal of Neurochemistry
Volume158
Issue number2
Early online date5 May 2021
DOIs
Accepted/In press2021
E-pub ahead of print5 May 2021
PublishedJul 2021

Bibliographical note

Funding Information: We would like to thank all the participants from the HD community who donated samples and gave their time to take part in this study. This study was supported by the Medical Research Council UK (MR/N00373X/1 to FG and MR/M008592/1 to EJW) and CHDI foundation. A preprint of this article has been published on medRxiv ( www.medrxiv.org/content/10.1101/2020.08.06.20169524v1 ). Funding Information: FBR, LMB, AJL, RT, EBJ, RIS, EJW are University College London employees. MA is a University College London Hospitals NHS Foundation Thrust employee. EDV is a King's College London employee. MH and GF are full‐time employees of Charles River Laboratories. FG is an employee of the University of Leicester. FG has the following patent pending ‘KYNURENINE 3‐MONOOXYGENASE (KMO) INHIBITORS, AND USES AND COMPOSITIONS THEREOF’. FBR has provided consultancy services to GLG and F. Hoffmann‐La Roche Ltd. LMR has provided consultancy services to GLG, F. Hoffmann‐La Roche Ltd, Genentech and Annexon. RIS has undertaken consultancy services for Ixico Ltd. EJW reports grants from Medical Research Council (MRC), CHDI Foundation, and F. Hoffmann‐La Roche Ltd during the conduct of the study; personal fees from Hoffman La Roche Ltd, Triplet Therapeutics, PTC Therapeutics, Shire Therapeutics, Wave Life Sciences, Mitoconix, Takeda, Loqus23. All honoraria for these consultancies were paid through the offices of UCL Consultants Ltd., a wholly owned subsidiary of University College London. University College London Hospitals NHS Foundation Trust has received funds as compensation for conducting clinical trials for Ionis Pharmaceuticals, Pfizer and Teva Pharmaceuticals. Publisher Copyright: © 2021 The Authors. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

King's Authors

Abstract

Converging lines of evidence from several 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. In a prospective single-site controlled cohort study with standardised collection of cerebrospinal fluid (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. 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. 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. (Figure presented.).

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