Serum NfL in spinocerebellar ataxia type 1 is increased already at the preataxic stage, correlating with proximity to clinical onset

Background and Objectives Neurofilament light (NfL) appears a promising fluid biomarker in repeat-expansion spinocerebellar ataxias (SCAs), with piloting studies in mixed SCA cohorts suggesting that NfL might be increased at the ataxic stage of spinocerebellar ataxia type 1 (SCA1). We here hypothesised that NfL is increased not only at the ataxic stage of SCA1, but also at its – likely most treatment-relevant – preataxic stage. Methods We assessed serum (sNfL) and cerebrospinal fluid (cNfL) levels of NfL in both preataxic and ataxic SCA1, leveraging a multicentric cohort of 40 SCA1 carriers (23 preataxic, 17 ataxic) and >80 controls, and clinical follow-up data including actually observed (rather than only predicted) conversion to the ataxic stage (11 carriers). Results sNfL levels were increased with high age-corrected effect sizes at the preataxic (r=0.62) and ataxic stage (r=0.63), paralleling increases of cNfL levels. In preataxic subjects, sNfL levels increased with proximity to predicted ataxia onset, with significant sNfL elevations already 5 years before onset, and confirmed in preataxic subjects with actually observed ataxia onset. sNfL increases were detected already in preataxic SCA1 subjects without volumetric atrophy of cerebellum or pons, suggesting that sNfL might be more sensitive to early preataxic neurodegeneration than the currently known most change-sensitive regions in volumetric MRI. Using longitudinal sNfL measurements, we estimated sample sizes for clinical trials using the reduction of sNfL as endpoint. Conclusions sNfL levels might thus provide easily accessible peripheral biomarkers in both preataxic and ataxic SCA1, allowing stratification of preataxic subjects regarding proximity-to-onset, early detection of neurodegeneration even before volumetric MRI alterations, and potentially capture of treatment response in clinical trials.