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 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. Neurofilament light chain and total-Tau concentrations were quantified in CSF and plasma using ultrasensitive single-molecule array (Quanterix) assays, and a novel Quanterix assay was developed for breast regression
protein 39 (mouse homologue of YKL-40) and used to quantify breast regression
protein 39 levels in plasma. CSF levels of neurofilament light chain and plasma levels of neurofilament light chain and breast regression
protein 39 increased in wild-type biofluids with age, whereas total-Tau remained constant. Neurofilament light chain and breast regression
protein 39 were elevated in the plasma and CSF from
Huntington's disease mouse models, as compared with 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 breast regression
protein 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. Neurofilament light chain and Tau are considered markers of neuronal damage, and breast regression
protein 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.