Neurology | March 9, 2022

Wilke C, Mengel D, Schöls L, Hengel H, Rakowicz M, Klockgether T, Durr A, Filla A, Melegh B, Schüle R, Reetz K, Jacobi H and Synofzik M

Neurology. 2022

https://doi.org/10.1212/WNL.0000000000200257

Abstract

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 recruited at six European university centres, and clinical follow-up data including actually observed (rather than only predicted) conversion to the ataxic stage. Levels of sNfL and cNfL were assessed by Single molecule array (Simoa) and ELISA technique, respectively.

Results

40 SCA1 subjects (23 preataxic, 17 ataxic) and 89 controls were enrolled, including 11 preataxic subjects converting to the ataxic stage. sNfL levels were increased at the preataxic (15.5 pg/ml (10.5-21.1), median and interquartile range) and ataxic stage (31.6 pg/ml (26.2-37.7) compared to controls (6.0 pg/ml (4.7-8.6)), yielding high age-corrected effect sizes (preataxic: r=0.62, ataxic: r=0.63). sNfL increases were paralleled by increases of cNfL both at the preataxic and ataxic stage. 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.

Discussion

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.