Translatable plasma and CSF biomarkers for use in mouse models of Huntington’s disease

Abstract

Huntington’s disease is an inherited neurodegenerative disorder for which a wide range of disease-modifying therapies are in development and the availability of biomarkers to monitor treatment response is essential for the success of clinical trials. Baseline levels of NEFL (neurofilament light chain) in CSF and plasma have been shown to be effective in predicting clinical disease status, subsequent clinical progression and brain atrophy. The identification of further sensitive prognostic fluid biomarkers is an active research area and total-Tau and YKL-40 levels have been shown to be increased in CSF from Huntington’s disease mutation carriers. The use of readouts with clinical utility in the preclinical assessment of potential therapeutics, should aid in the translation of new treatments. Here, we set out to determine how the concentrations of these three proteins change in plasma and CSF with disease progression in representative, well-established mouse models of Huntington’s disease. Plasma and CSF were collected throughout disease progression from R6/2 transgenic mice with CAG repeats of 200 or 90 codons (R6/2:Q200 and R6/2:Q90), zQ175 knock-in mice and YAC128 transgenic mice, along with their respective wild-type littermates. NEFL and total-Tau concentrations were quantified in CSF and plasma using ultrasensitive single-molecule array (SIMOA, Quanterix) assays and a novel Quanterix assay was developed for BRP-39 (breast regression protein 39, mouse homologue of YKL-40) and used to quantify BRP-39 levels in plasma. CSF levels of NEFL and plasma levels of NEFL and BRP-39 increased in wild-type biofluids with age, whereas total-Tau remained constant. NEFL and BRP-39 were elevated in the plasma and CSF from Huntington’s disease mouse models, as compared to wild-type littermates, at presymptomatic stages, whereas total-Tau was only increased at the latest disease stages analysed. Levels of biomarkers that had been measured in the same CSF or plasma samples taken at the latest stages of disease were correlated. The demonstration that BRP-39 constitutes a robust plasma biomarker in Huntington’s disease mouse models, supports the further investigation of YKL-40 as a CSF biomarker for Huntington’s disease mutation carriers. NEFL and Tau are considered markers of neuronal damage and BRP-39 is a marker of inflammation; the similarities and differences in the levels of these proteins between mouse models may provide future insights into their underlying pathology. These data will facilitate the use of fluid biomarkers in the preclinical assessment of therapeutic agents for Huntington’s disease, providing readouts with direct relevance to clinical trials.