Humoral response to neurofilaments and dipeptide repeats in ALS progression.

Fabiola Puentes,Pietro Fratta,Ching‐Hua Lu,Joanne Wuu,Michael Benatar,Vittoria Lombardi,Adrian Isaacs,Ozlem Yildiz,Yoana Bobeva,Andrea Malaspina

doi:10.1002/acn3.51428

Abstract

ObjectiveTo appraise the utility as biomarkers of blood antibodies and immune complexes to neurofilaments and dipeptide repeat proteins, the products of translation of the most common genetic mutation in amyotrophic lateral sclerosis (ALS).MethodsAntibodies and immune complexes against neurofilament light, medium, heavy chains as well as poly‐(GP)‐(GR) dipeptide repeats were measured in blood samples from the ALS Biomarkers (n = 107) and the phenotype–genotype biomarker (n = 129) studies and in 140 healthy controls. Target analyte levels were studied longitudinally in 37 ALS cases. Participants were stratified according to the rate of disease progression estimated before and after baseline and C9orf72 genetic status. Survival and longitudinal analyses were undertaken with reference to matched neurofilament protein expression.ResultsCompared to healthy controls, total neurofilament proteins and antibodies, neurofilament light immune complexes (p < 0.0001), and neurofilament heavy antibodies (p = 0.0061) were significantly elevated in ALS, patients with faster progressing disease (p < 0.0001) and in ALS cases with a C9orf72 mutation (p < 0.0003). Blood neurofilament light protein discriminated better ALS from healthy controls (AUC: 0.92; p < 0.0001) and faster from slower progressing ALS (AUC: 0.86; p < 0.0001) compared to heavy‐chain antibodies and light‐chain immune complexes (AUC: 0.79; p < 0.0001 and AUC: 0.74; p < 0.0001). Lower neurofilament heavy antibodies were associated with longer survival (Log‐rank Chi‐square: 7.39; p = 0.0065). Increasing levels of antibodies and immune complexes between time points were observed in faster progressing ALS.ConclusionsWe report a distinctive humoral response characterized by raising antibodies against neurofilaments and dipeptide repeats in faster progressing and C9orf72 genetic mutation carriers ALS patients. We confirm the significance of plasma neurofilament proteins in the clinical stratification of ALS.

Highlights

The lack of individualized biomarkers that can be used to define the future course of the disease and measure treatment response is holding back therapeutic development in amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder.[1]
Plasma concentrations of neurofilament proteins (Nf-L and Nf-H) and Nf Abs (Nf-L, Nf-M, and Nf-H Abs) were elevated among ALS patients compared to healthy controls (HC)-1 (Fig. 1A and B; p < 0.0001)
Consistent with previous reports, plasma concentrations of Nf isoforms light (Nf-L) and Nf-H proteins were increased among ALS patients compared to HC-1 (p < 0.0001; Fig. 2A and B) and significantly elevated in ALS-F and ALS-S compared to HC-1 (p < 0.0001 and p = 0.0014; Fig. 2A).[8,25]

Summary

Introduction

The lack of individualized biomarkers that can be used to define the future course of the disease and measure treatment response is holding back therapeutic development in amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder.[1] Axonal proteins like neurofilaments (Nf) have recently emerged as biomarkers with potential prognostic and pharmacodynamic utility in ALS.[1,2,3,4,5,6,7,8,9] After an initial increase in the prodromal and early stages of ALS, Nf concentrations remain largely stable, against the observed remarkable variability in the Their concentration in blood may be informative as pharmacodynamic biomarker in clinical trials where faster progressing ALS and individuals with the C9orf[72] genetic mutation (C9+ve ALS) have been recently singled out for their response to high-caloric diet and gene-modifying treatments.[15]

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Conclusion