Humoral response to neurofilaments and dipeptide repeats in ALS progression

Abstract Objective To 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). Methods Antibodies and immune complexes against n...

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Autores principales:	Fabiola Puentes, Vittoria Lombardi, Ching‐Hua Lu, Ozlem Yildiz, Pietro Fratta, Adrian Isaacs, Yoana Bobeva, Joanne Wuu, ALS Biomarker Consortium, CReATe Consortium, Michael Benatar, Andrea Malaspina
Formato:	article
Lenguaje:	EN
Publicado:	Wiley 2021
Materias:	Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 Neurology. Diseases of the nervous system RC346-429
Acceso en línea:	https://doaj.org/article/831d47c10edf428f8b511cafea05761e
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spelling	oai:doaj.org-article:831d47c10edf428f8b511cafea05761e2021-11-19T13:55:31ZHumoral response to neurofilaments and dipeptide repeats in ALS progression2328-950310.1002/acn3.51428https://doaj.org/article/831d47c10edf428f8b511cafea05761e2021-09-01T00:00:00Zhttps://doi.org/10.1002/acn3.51428https://doaj.org/toc/2328-9503Abstract Objective To 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). Methods Antibodies 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. Results Compared 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. Conclusions We 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.Fabiola PuentesVittoria LombardiChing‐Hua LuOzlem YildizPietro FrattaAdrian IsaacsYoana BobevaJoanne WuuALS Biomarker ConsortiumCReATe ConsortiumMichael BenatarAndrea MalaspinaWileyarticleNeurosciences. Biological psychiatry. NeuropsychiatryRC321-571Neurology. Diseases of the nervous systemRC346-429ENAnnals of Clinical and Translational Neurology, Vol 8, Iss 9, Pp 1831-1844 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 Neurology. Diseases of the nervous system RC346-429
spellingShingle	Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 Neurology. Diseases of the nervous system RC346-429 Fabiola Puentes Vittoria Lombardi Ching‐Hua Lu Ozlem Yildiz Pietro Fratta Adrian Isaacs Yoana Bobeva Joanne Wuu ALS Biomarker Consortium CReATe Consortium Michael Benatar Andrea Malaspina Humoral response to neurofilaments and dipeptide repeats in ALS progression
description	Abstract Objective To 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). Methods Antibodies 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. Results Compared 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. Conclusions We 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.
format	article
author	Fabiola Puentes Vittoria Lombardi Ching‐Hua Lu Ozlem Yildiz Pietro Fratta Adrian Isaacs Yoana Bobeva Joanne Wuu ALS Biomarker Consortium CReATe Consortium Michael Benatar Andrea Malaspina
author_facet	Fabiola Puentes Vittoria Lombardi Ching‐Hua Lu Ozlem Yildiz Pietro Fratta Adrian Isaacs Yoana Bobeva Joanne Wuu ALS Biomarker Consortium CReATe Consortium Michael Benatar Andrea Malaspina
author_sort	Fabiola Puentes
title	Humoral response to neurofilaments and dipeptide repeats in ALS progression
title_short	Humoral response to neurofilaments and dipeptide repeats in ALS progression
title_full	Humoral response to neurofilaments and dipeptide repeats in ALS progression
title_fullStr	Humoral response to neurofilaments and dipeptide repeats in ALS progression
title_full_unstemmed	Humoral response to neurofilaments and dipeptide repeats in ALS progression
title_sort	humoral response to neurofilaments and dipeptide repeats in als progression
publisher	Wiley
publishDate	2021
url	https://doaj.org/article/831d47c10edf428f8b511cafea05761e
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Humoral response to neurofilaments and dipeptide repeats in ALS progression

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