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

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 in cohort #2 (all p<0.001). Cross-sectional NfL levels correlated with clinical disease severity (Scale for the Assessment and Rating of Ataxia [SARA]; r=0.43, p<0.001) and with longitudinal disease progression (annual SARA score change, ϱ=0.42, p=0.012). CAG count and age were significant predictors of individual NfL concentrations (each p<0.001). NfL levels in preataxic subjects increased with proximity to individual expected onset of ataxia (p<0.001), with significant elevations already 7.5 years before onset. Serum NfL and pNfH increases in SCA3 subjects were paralleled by similar changes in SCA3 knock-in mice, here also already starting at the presymptomatic stage and close to the onset of ataxin-3 protein increase. Serum concentrations of neurofilaments, particularly NfL, might provide easily accessible biomarkers of disease severity in both ataxic and preataxic SCA3 subjects and mice prior to conversion. Neurofilaments thus entail potential applications as progression, onset/proximity and treatment-response markers in both human and murine SCA3 trials.