NfL and pNfH are increased in Friedreich's ataxia

Abstract

Objective: To assess neurofilaments as neurodegenerative biomarkers in serum of patients with Friedreich's ataxia.

Methods: Single molecule array measurements of neurofilament light (NfL) and heavy chain (pNfH) in 99 patients with genetically confirmed Friedreich's ataxia. Correlation of NfL/pNfH serum levels with disease severity, disease duration, age, age at onset, and GAA repeat length.

Results: Median serum levels of NfL were 21.2 pg/ml (range 3.6-49.3) in controls and 26.1 pg/ml (0-78.1) in Friedreich's ataxia (p = 0.002). pNfH levels were 23.5 pg/ml (13.3-43.3) in controls and 92 pg/ml (3.1-303) in Friedreich's ataxia (p = 0.0004). NfL levels were significantly increased in younger patients (age 16-31 years, p < 0.001) and patients aged 32-47 years (p = 0.008), but not in patients of age 48 years and older (p = 0.41). In a longitudinal assessment, there was no difference in NfL levels in 14 patients with repeated sampling 2 years after baseline measurement. Levels of NfL correlated inversely with GAA1 repeat length (r = - 0.24, p = 0.02) but not with disease severity (r = - 0.13, p = 0.22), disease duration (r = - 0.06, p = 0.53), or age at onset (r = 0.05, p = 0.62).

Conclusion: Serum levels of NfL and pNfH are elevated in Friedreich's ataxia, but differences to healthy controls decrease with increasing age. Long-term longitudinal data are required to explore whether this reflects a selection bias from early death of more severely affected individuals or a slowing down of the neurodegenerative process with age. In a pilot study over 2 years of follow-up-a period relevant for biomarkers indicating treatment effects-we found NfL levels to be stable.

Keywords: Biomarker; Friedreich’s ataxia; Neurofilament heavy chain; Neurofilament light chain; NfL; pNfH.

Fig. 1

NfL and pNfH are increased in Friedreich’s ataxia. a Serum NfL of 30 healthy controls and 99 genetically confirmed Friedreich’s ataxia patients. b Serum pNfH in 9 healthy controls and 20 patients with Friedreich’s ataxia. **p = 0.0019, ***p = 0.0004. Data represent median and 95% confidence interval. NfL neurofilament light chain, pNfH phosphorylated neurofilament heavy chain

Fig. 2

NfL levels in healthy controls (white dots) and Friedreich’s ataxia (black dots) relative to age. Serum NfL allows an excellent classification in healthy or affected for younger individuals (16–31 years), a moderately good classification for middle aged individuals (32–47 years), and no classification better than chance for older individuals (48–68 years). a Observed NfL values with LOWESS fit (dashed line for controls and continuous line for patients). b Calculated NfL values with quadratic fit. NfL neurofilament light chain

Fig. 3

NfL and pNfH do not correlate with disease severity, age at onset or disease duration in Friedreich’s ataxia. a Serum NfL levels versus disease severity in Friedreich’s ataxia, quantified by SARA. b Correlation of serum NfL levels with age at symptom onset. c Serum NfL versus disease duration, defined by the interval between first reported symptoms and blood sampling. d Correlation of serum NfL levels with the repeat length of the shorter allele and e with the longer allele. f Quantification of serum pNfH levels versus disease severity in patients with Friedreich’s ataxia that were a priori categorized as moderately (SARA 10–20) or severely (SARA 30–40) affected. g Correlation of pNfH with age at onset, and h with disease duration. Data in f represent median and 95% confidence interval. A linear regression line is only depicted in graphs presenting a statistically significant correlation. NfL neurofilament light chain, pNfH phosphorylated neurofilament heavy chain, SARA scale for the assessment and rating of ataxia, ns not significant

Fig. 4

Longitudinal NfL levels in Friedreich’s ataxia. a NfL levels and level dynamics of individual patients over a period of 2 years. b Comparison of NfL level dynamics and SARA dynamics in individual patients over a period of 2 years. Data in a represent median and 95% confidence interval. BL baseline, 2FU 2-year follow-up, NfL neurofilament light chain, SARA scale for the assessment and rating of ataxia, ns not significant