Longitudinal dynamics of mutant huntingtin and neurofilament light in Huntington’s disease: the prospective HD-CSF study

Rodrigues, Filipe B; Byrne, Lauren M.; Tortelli, Rosanna; Johnson, Eileanoir B.; Wijeratne, P. A.; Arridge, Marzena; Vita, Enrico De; Ghazaleh, Naghmeh; Houghton, Richard; Furby, Hannah; Alexander, Daniel C.; Tabrizi, Sarah J.; Schobel, Scott; Scahill, Rachael I.; Heslegrave, Amanda; Zetterberg, Henrik; Wild, Edward J.

doi:10.1101/2020.03.31.20045260

Cited by 7 publications

(9 citation statements)

References 47 publications

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“…Disease groups were well-matched for gender and differed as expected in clinical, cognitive and imaging measures. Age differed significantly between groups due to the control group (50·68 years ± 11·0) being matched to all gene expansion carriers, and manifest HD (56·02 years ± 9·36) being more advanced in their disease course than preHD (42·38 years ± 11·04), as previously reported(32, 38).…”

Section: Resultssupporting

confidence: 58%

“…Quantifying KP metabolites in HD CSF remains desirable, both to study pathobiology in human patients, and as a potential source of biomarkers to quantify pathway dysfunction and the biochemical impact of therapeutic interventions targeting its components. Therefore, we sought to combine modern analytical methods, with CSF and matched blood plasma, collected and processed under strictly standardised conditions, from a large (n = 80) prospective cohort of gene expansion carriers and matched controls (32, 38). Using high-performance liquid-chromatography (HPLC) with tandem mass spectroscopy (MS/MS) quantification methods, we measured levels of six KP metabolites (Figure 1 Overview of the kynurenine pathway.…”

Section: Introductionmentioning

confidence: 99%

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

Rodrigues

Byrne

Lowe

et al. 2020

Preprint

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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.

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Section: Resultssupporting

confidence: 58%

Section: Introductionmentioning

confidence: 99%

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

Rodrigues

Byrne

Lowe

et al. 2020

Preprint

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“…HD-CSF was a prospective single-site study with standardized longitudinal collection of CSF, blood, and phenotypic data [online protocol: digital object identifier (DOI): 10.5522/04/11828448.v1) (14,28). Eighty participants were recruited.…”

Section: Methodsmentioning

confidence: 99%

Mutant huntingtin and neurofilament light have distinct longitudinal dynamics in Huntington’s disease

et al. 2020

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The longitudinal dynamics of the most promising biofluid biomarker candidates for Huntington’s disease (HD)—mutant huntingtin (mHTT) and neurofilament light (NfL)—are incompletely defined. Characterizing changes in these candidates during disease progression could increase our understanding of disease pathophysiology and help the identification of effective therapies. In an 80-participant cohort over 24 months, mHTT in cerebrospinal fluid (CSF), as well as NfL in CSF and blood, had distinct longitudinal trajectories in HD mutation carriers compared with controls. Baseline analyte values predicted clinical disease status, subsequent clinical progression, and brain atrophy, better than did the rate of change in analytes. Overall, NfL was a stronger monitoring and prognostic biomarker for HD than mHTT. Nonetheless, mHTT has prognostic value and might be a valuable pharmacodynamic marker for huntingtin-lowering trials.

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“…Following the levels of the mutant polyglutamine protein would be analogous to following the levels of other proteins in the more common neurodegenerative proteinopathies: A β 42 and tau (including phosphorylated tau) in AD, alpha synuclein in PD, and huntingtin protein in HD. 119 , 120 , 121 , 122 …”

Section: Efforts Toward Clinical Trial Readinessmentioning

confidence: 99%

Spinocerebellar ataxia clinical trials: opportunities and challenges

Brooker

Edamakanti

Akasha

et al. 2021

Ann Clin Transl Neurol

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The spinocerebellar ataxias (SCAs) are a group of dominantly inherited diseases that share the defining feature of progressive cerebellar ataxia. The disease process, however, is not confined to the cerebellum; other areas of the brain, in particular, the brainstem, are also affected, resulting in a high burden of morbidity and mortality. Currently, there are no disease-modifying treatments for the SCAs, but preclinical research has led to the development of therapeutic agents ripe for testing in patients. Unfortunately, due to the rarity of these diseases and their slow and variable progression, there are substantial hurdles to overcome in conducting clinical trials. While the epidemiological features of the SCAs are immutable, the feasibility of conducting clinical trials is being addressed through a combination of strategies. These include improvements in clinical outcome measures, the identification of imaging and fluid biomarkers, and innovations in clinical trial design. In this review, we highlight current challenges in initiating clinical trials for the SCAs and also discuss pathways for researchers and clinicians to mitigate these challenges and harness opportunities for clinical trial development.

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Longitudinal dynamics of mutant huntingtin and neurofilament light in Huntington’s disease: the prospective HD-CSF study

Cited by 7 publications

References 47 publications

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

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

Mutant huntingtin and neurofilament light have distinct longitudinal dynamics in Huntington’s disease

Spinocerebellar ataxia clinical trials: opportunities and challenges

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