Blood Neurofilament Light Chain in Genetic Ataxia: A Meta‐Analysis

Abstract

A BS TRACT: Background: No comprehensive metaanalysis has ever been performed to assess the value of neurofilament light chain (NfL) as a biomarker in genetic ataxia.Objective: We conducted a meta-analysis to summarize NfL concentration and evaluate its utility as a biomarker in genetic ataxia. Methods: Studies were included if they reported NfL concentration of genetic ataxia. We used log (mean AE SD) NfL to describe mean raw value of NfL. The effect size of NfL between genetic ataxia and healthy controls (HC) was expressed by mean difference. Correlation between NfL and disease severity was calculated. Results: We identified 11 studies of 624 HC and 1006 patients, here referred to as spinocerebellar ataxia (SCA1, 2, 3, 6, and 7), Friedreich ataxia (FRDA), and ataxia telangiectasia (A-T). The concentration of blood NfL (bNfL) elevated with proximity to expected onset, and progressively increased from asymptomatic to preclinical to clinical stage in SCA3. Compared with HC, bNfL levels were significantly higher in SCA1, 2, 3, and 7, FRDA, as well as A-T, and the difference increased with the advancing disease in SCA3. bNfL levels correlated with disease severity in SCA3. There was a significant correlation between bNfL and longitudinal progression in SCA3. Additionally, bNfL increased with age in HC, yet this is probably masked by higher diseaserelated effects on bNfL in genetic ataxia. Conclusions: bNfL can be used as a potential biomarker to predict disease onset, severity, and progression of genetic ataxia. Reference-value setting of bNfL should

The 2022 Lady Estelle Wolfson lectureship on neurofilaments

“…There have been 33 meta‐analyses on the wealth of data on Nf as a biomarker for neurodegeneration over the past 15 years (Agah et al, 2018; Alagaratnam, Widekind, et al, 2021; Angelopoulou et al, 2021; Arneth & Kraus, 2022; Cai & Huang, 2018; Choong et al, 2019; Cong et al, 2021; Forgrave et al, 2019; Gao et al, 2020b; Ge et al, 2018; Hoiland et al, 2022; Hu et al, 2017; Jin et al, 2019; Karantali, Kazis, Chatzikonstantinou, et al, 2021; Karantali, Kazis, McKenna, et al, 2021; Katayama et al, 2020; Koychev et al, 2021; Li et al, 2016; Liu et al, 2022; Liu, Chen, et al, 2020; Martin et al, 2019; Mondello et al, 2021; Peng et al, 2022; Petzold et al, 2007; Rübsamen et al, 2022; Sako et al, 2015; Sferruzza et al, 2021; Wang et al, 2019; Wang et al, 2020a; Wang et al, 2020b; Xu et al, 2016; Zhang et al, 2022; Zhao et al, 2019; Zhou et al, 2021).…”

Plasma PolyQ-ATXN3 Levels Associate With Cerebellar Degeneration and Behavioral Abnormalities in a New AAV-Based SCA3 Mouse Model

“…The degeneration of neurons is believed to lead to an increase in the levels of NFL in patient biofluids, making it a useful biomarker for neurodegenerative diseases ( Gaiottino et al, 2013 ; Zeitlberger et al, 2018 ; Siller et al, 2019 ; Weishaupl et al, 2019 ). In SCA3, we and others have observed that NFL levels in the plasma and CSF can distinguish patients from controls ( Li et al, 2019 ; Peng et al, 2020 ; Prudencio et al, 2020 ; Wilke et al, 2020 ; Peng et al, 2021 ), and some studies have detected a significant correlation between serum NFL levels and disease severity ( Li et al, 2019 ; Peng et al, 2020 ; Wilke et al, 2020 ). Levels are also increased in asymptomatic expanded ATXN3 carriers compared to healthy controls and may further increase as patients near their anticipated age of onset ( Peng et al, 2020 ; Prudencio et al, 2020 ; Wilke et al, 2020 ; Peng et al, 2021 ).…”

“…In SCA3, we and others have observed that NFL levels in the plasma and CSF can distinguish patients from controls ( Li et al, 2019 ; Peng et al, 2020 ; Prudencio et al, 2020 ; Wilke et al, 2020 ; Peng et al, 2021 ), and some studies have detected a significant correlation between serum NFL levels and disease severity ( Li et al, 2019 ; Peng et al, 2020 ; Wilke et al, 2020 ). Levels are also increased in asymptomatic expanded ATXN3 carriers compared to healthy controls and may further increase as patients near their anticipated age of onset ( Peng et al, 2020 ; Prudencio et al, 2020 ; Wilke et al, 2020 ; Peng et al, 2021 ). In our mice, we found that NFL was increased in the CSF of Q84 mice compared to Q28 controls ( Figure 2H ).…”

“…Increases in NFL are therefore considered a marker of neuronal injury and are predicted to be elevated in neurodegenerative diseases. NFL levels are elevated in both the blood and CSF of SCA3 patients and can accurately distinguish patients from controls ( Li et al, 2019 ; Peng et al, 2020 ; Prudencio et al, 2020 ; Wilke et al, 2020 ; Peng et al, 2021 ). Blood NFL levels have also been found to associate with disease severity ( Li et al, 2019 ; Peng et al, 2020 ; Wilke et al, 2020 ) and some studies suggest it could potentially be used as an indicator of disease progression and potential onset in asymptomatic expanded ATXN3 carriers ( Wilke et al, 2020 ; Peng et al, 2021 ).…”

“…NFL levels are elevated in both the blood and CSF of SCA3 patients and can accurately distinguish patients from controls ( Li et al, 2019 ; Peng et al, 2020 ; Prudencio et al, 2020 ; Wilke et al, 2020 ; Peng et al, 2021 ). Blood NFL levels have also been found to associate with disease severity ( Li et al, 2019 ; Peng et al, 2020 ; Wilke et al, 2020 ) and some studies suggest it could potentially be used as an indicator of disease progression and potential onset in asymptomatic expanded ATXN3 carriers ( Wilke et al, 2020 ; Peng et al, 2021 ). PolyQ-ATXN3 can also be detected in the blood and CSF of SCA3 patients using immunoassays, and it is elevated in patients compared to controls ( Prudencio et al, 2020 ; Hubener-Schmid et al, 2021 ).…”