Levels of Neurofilament Light at the Preataxic and Ataxic Stages of Spinocerebellar Ataxia Type 1

Abstract

Background and ObjectivesNeurofilament light (NfL) appears to be 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 SCA type 1 (SCA1). We here hypothesized that NfL is increased not only at the ataxic stage of SCA1, but also at its (likely most treatment-relevant) preataxic stage.MethodsWe assessed serum NfL (sNfL) and CSF NfL (cNfL) levels in both preataxic and ataxic SCA1, leveraging a multicentric cohort recruited at 6 European university centers, 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 and ELISA technique, respectively.ResultsForty individuals with SCA1 (23 preataxic, 17 ataxic) and 89 controls were enrolled, including 11 preataxic individuals converting to the ataxic stage. sNfL levels were increased at the preataxic (median 15.5 pg/mL [interquartile range 10.5–21.1 pg/mL]) and ataxic stage (31.6 pg/mL [26.2–37.7 pg/mL]) compared to controls (6.0 pg/mL [4.7–8.6 pg/mL]), yielding high age-corrected effect sizes (preataxic: r = 0.62, ataxic: r = 0.63). sNfL increases were paralleled by increases of cNfL at both the preataxic and ataxic stage. In preataxic individuals, sNfL levels increased with proximity to predicted ataxia onset, with significant sNfL elevations already 5 years before onset, and confirmed in preataxic individuals with actually observed ataxia onset. sNfL increases were detected already in preataxic individuals with SCA1 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 with the reduction of sNfL as the endpoint.DiscussionsNfL levels might provide easily accessible peripheral biomarkers in both preataxic and ataxic SCA1, allowing stratification of preataxic individuals regarding proximity to onset, early detection of neurodegeneration even before volumetric MRI alterations, and potentially capture of treatment response in clinical trials.Trial Registration InformationClinicalTrials.gov Identifier: NCT01037777.Classification of EvidenceThis study provides Class III evidence that NfL levels are increased in both ataxic and preataxic SCA1 and are associated with ataxia onset.

Baseline Clinical and Blood Biomarkers in Patients With Preataxic and Early-Stage Disease Spinocerebellar Ataxia 1 and 3

“…In addition, among the at-risk participants, 27 did not carry a pathologic expansion in ATXN1 or ATXN3 (0 [0-1]) (Tables 1 and 2). [ [32][33][34][35][36][37][38][39][40][41], p_PA = 0.0001) and the controls (38 [31-47], SCA1: p_CA = 0.0092, SCA3: p_CA = 0.0009) (Tables 1 and 2). As expected, they had significantly more severe cerebellar and functional scores than expansion carriers without ataxia.…”

“…In a recent study on SCA1 NfL levels, there were 23 SCA1 preataxic carriers and they had lower NfL levels than in our study (aged 25 years and 15.5 pg/ml (10.5-21.1) versus 39 years and 18.0 pg/mL [12.3;21.9]). 37 The increase can be explained by older age but not by the clinical stage. Therefore, NfL allows stratification for homogenous groups of mutation carriers without ataxia and the combination with other biomarkers such as enotaxin can be promising.…”

“…Comparisons Between Controls, Expansion Carriers With and Without AtaxiaFor both groups, patients with ataxia were older (SCA1 median: 47 [41-54], SCA3: 49[41][42][43][44][45][46][47][48][49][50][51][52][53][54]) than both the preataxic participants (SCA1: 39[34][35][36][37][38][39][40][41][42][43][44][45][46], p_PA = 0.0619; SCA3: 36…”

Blood neurofilament light chain levels are associated with disease progression in a transgenic SCA3 mouse model

“…These neurodegenerative diseases differ in the implicated gene but share a common mechanism of protein gain of toxic function caused by a polyQ-expansion from a CAG repeat in the disease gene. Of the polyQ diseases, biofluid NfL has been studied in patients with Huntington's Disease (Johnson et al, 2018, Johnson et al, 2021, Byrne et al, 2017 and multiple spinocerebellar ataxias (SCAs), including SCA1 (Wilke et al, 2018, Coarelli et al, 2021, Peng et al, 2022, Wilke et al, 2022a, SCA2 (Peng et al, 2022, Coarelli et al, 2021, SCA3 (Wilke et al, 2020b, Peng et al, 2022, Garcia-Moreno et al, 2022, Coarelli et al, 2021, Prudencio et al, 2020, Li et al, 2019, Wilke et al, 2018, SCA6 (Peng et al, 2022, Wilke et al, 2018, and SCA7 (Peng et al, 2022, Coarelli et al, 2021. SCA3, caused by an expanded CAG repeat in the ATXN3 gene (Kawaguchi et al, 1994), is one of the most common dominantly inherited ataxias worldwide (Gaspar et al, 2001, Schols et al, 2004 and is characterized by cerebellar degeneration and progressive ataxia.…”

“…Elevated levels of NfL in biofluids are considered a strong biomarker for the rate of neuronal turnover, e.g. due to death and degeneration (Benatar et al, 2022, Wilke et al, 2022b, Wilke et al, 2022a, Wilke et al, 2020b) therefore, NfL has been investigated as a biomarker in individuals afflicted with neurodegenerative diseases.…”