DOI: 10.1101/19011882Nov 27, 2019Paper

Neurofilaments as blood biomarkers at the preataxic and ataxic stage of spinocerebellar ataxia type 3: a cross-species analysis in humans and mice

MedRxiv : the Preprint Server for Health Sciences
Carlo WilkeL. Schoels

Abstract

Spinocerebellar ataxia type 3 (SCA3) is a devastating multisystemic neurodegenerative disease for which targeted molecular therapies are coming into reach (e.g. antisense oligonucleotides). To pave the way for upcoming translational trials, easily accessible biomarkers in SCA3 are needed, particularly for subjects at the preataxic stage and cross-validated also in animal models. We hypothesised that serum neurofilaments might serve as blood biomarkers of disease progression in both human SCA3 and mouse models, expecting increased concentrations already at the preataxic stage. Serum neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH) levels were determined by ultra-sensitive single molecule array (Simoa) in cross-sectional samples of ataxic and preataxic SCA3 subjects and controls in two independent cohorts (ESMI cohort = cohort #1: n=160, EuroSCA/RiSCA cohort = cohort #2: n=89). Serum NfL and pNfH were also assessed in a 304Q SCA3 knock-in mouse model across presymptomatic and symptomatic disease stages (n=147). Ataxic SCA3 subjects showed increased serum NfL (p<0.001) and pNfH (p<0.001) levels in cohort #1, with NfL levels already increased in preataxic subjects (p<0.001). All these results were replicated ...Continue Reading

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