NfL and pNfH are increased in Friedreich\u2019s ataxia

Stefanie Nicole Hayer,Jens Kuhle,Carlo Wilke,Ludger Schöls,Peter Martus,Inga Liepelt,Christian Barro

doi:10.1007/s00415-020-09722-6

Abstract

ObjectiveTo assess neurofilaments as neurodegenerative biomarkers in serum of patients with Friedreich’s ataxia.MethodsSingle 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.ResultsMedian 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).ConclusionSerum 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.

Highlights

Friedreich’s ataxia is the most frequent type of autosomal recessive ataxia in the western world with a prevalence of about 1:36,000 [1]
An integral component of the axonal cytoskeleton is neurofilament light chain (NfL) and phosphorylated neurofilament heavy chain. These markers were recently shown to be increased in the cerebrospinal fluid of several progressive neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Creutzfeldt–Jakob disease (CJD), and adult-onset leukoencephalopathy with axonal spheroids (ALSP) [4,5,6,7,8,9]
The difference we found in the amount of detected NfL between Friedreichs’s ataxia patients and controls compares well with other slowly progressing neurodegenerative diseases such as hereditary spastic paraplegia, Alzheimer’s disease, and spinocerebellar ataxia [17,18,19]

Summary

Introduction

Friedreich’s ataxia is the most frequent type of autosomal recessive ataxia in the western world with a prevalence of about 1:36,000 [1]. The progressive nature of Friedreich’s ataxia leads to continuous destruction of neurons with a focus on long fibre tracts in the spinal cord, causing progressive degeneration of dorsal root ganglia, posterior columns, sensory nerves, and corticospinal tracts [3] During this process, axonal cytoskeletal proteins are likely to be liberated into cerebral spinal fluid (CSF) and even into blood, in consequence of neuro-axonal injury. An integral component of the axonal cytoskeleton is neurofilament light chain (NfL) and phosphorylated neurofilament heavy chain (pNfH) These markers were recently shown to be increased in the cerebrospinal fluid of several progressive neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Creutzfeldt–Jakob disease (CJD), and adult-onset leukoencephalopathy with axonal spheroids (ALSP) [4,5,6,7,8,9]. Ultrasensitive assays allow assessments of NfL and pNfH in serum [10, 11]

Methods

Results

Conclusion