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Plasma Markers of Neurodegeneration Are Raised in Friedreich’s Ataxia

Background: Friedreich’s ataxia (FRDA) is the most common autosomal recessive ataxia. Disease-modifying treatments are not available yet; however, several compounds are currently under investigation. As a result, there is a growing need for the identification of robust and easily accessible biomarke...

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Autores principales: Zeitlberger, Anna M., Thomas-Black, Gilbert, Garcia-Moreno, Hector, Foiani, Martha, Heslegrave, Amanda J., Zetterberg, Henrik, Giunti, Paola
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6218876/
https://www.ncbi.nlm.nih.gov/pubmed/30425621
http://dx.doi.org/10.3389/fncel.2018.00366
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author Zeitlberger, Anna M.
Thomas-Black, Gilbert
Garcia-Moreno, Hector
Foiani, Martha
Heslegrave, Amanda J.
Zetterberg, Henrik
Giunti, Paola
author_facet Zeitlberger, Anna M.
Thomas-Black, Gilbert
Garcia-Moreno, Hector
Foiani, Martha
Heslegrave, Amanda J.
Zetterberg, Henrik
Giunti, Paola
author_sort Zeitlberger, Anna M.
collection PubMed
description Background: Friedreich’s ataxia (FRDA) is the most common autosomal recessive ataxia. Disease-modifying treatments are not available yet; however, several compounds are currently under investigation. As a result, there is a growing need for the identification of robust and easily accessible biomarkers for the monitoring of disease activity and therapeutic efficacy. The simultaneous measurement of multiple brain-derived proteins could represent a time- and cost-efficient approach for biomarker investigation in pathologically complex neurodegenerative diseases like FRDA. Objectives: To investigate the role of plasma neurofilament-light chain (NfL), glial fibrillary acidic protein (GFAP), total tau (t-tau) and ubiquitin C-terminal hydrolase L1(UCHL1) as biomarkers in FRDA. Additionally, NfL measurements derived from the novel multiplex assay were compared to those from an established NfL singleplex assay. Methods: In this study, an ultrasensitive Single molecule array (Simoa) 4-plex assay was used for the measurement of plasma NfL, GFAP, t-tau, and UCHL1 in 33 FRDA patients and 13 age-matched controls. Differences in biomarker concentrations between these groups were computed and associations with genetic and disease related parameters investigated. Additionally, the agreement between NfL measurements derived from the 4-Plex and an established Simoa NfL singleplex assay was assessed. Results: Mean plasma NfL, GFAP and UCHL1 levels were significantly higher in FRDA patients than in controls (NfL: p < 0.001; GFAP: p = 0.006, and UCHL1: p = 0.020). Conversely, there was no significant difference in concentrations of t-tau in the patient and control group (p = 0.236). None of the proteins correlated with the GAA repeat length or the employed measures of disease severity. The individual NfL values derived from the two assays showed a strong concordance (r(c) = 0.93). Although the mean difference of 1.29 pg/mL differed significantly from 0 (p = 0.006), regression analysis did not indicate the presence of a proportional bias. Conclusion: This is the first study demonstrating that NfL, GFAP, and UCHL1 levels are raised in FRDA, potentially reflecting ongoing neuronal degeneration and glial activation. Further studies are required to determine their role as marker for disease activity and progression. Furthermore, the novel 4-plex assay appears to be a valid tool to simultaneously measure brain-derived proteins at extremely low concentrations in the peripheral circulation.
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spelling pubmed-62188762018-11-13 Plasma Markers of Neurodegeneration Are Raised in Friedreich’s Ataxia Zeitlberger, Anna M. Thomas-Black, Gilbert Garcia-Moreno, Hector Foiani, Martha Heslegrave, Amanda J. Zetterberg, Henrik Giunti, Paola Front Cell Neurosci Neuroscience Background: Friedreich’s ataxia (FRDA) is the most common autosomal recessive ataxia. Disease-modifying treatments are not available yet; however, several compounds are currently under investigation. As a result, there is a growing need for the identification of robust and easily accessible biomarkers for the monitoring of disease activity and therapeutic efficacy. The simultaneous measurement of multiple brain-derived proteins could represent a time- and cost-efficient approach for biomarker investigation in pathologically complex neurodegenerative diseases like FRDA. Objectives: To investigate the role of plasma neurofilament-light chain (NfL), glial fibrillary acidic protein (GFAP), total tau (t-tau) and ubiquitin C-terminal hydrolase L1(UCHL1) as biomarkers in FRDA. Additionally, NfL measurements derived from the novel multiplex assay were compared to those from an established NfL singleplex assay. Methods: In this study, an ultrasensitive Single molecule array (Simoa) 4-plex assay was used for the measurement of plasma NfL, GFAP, t-tau, and UCHL1 in 33 FRDA patients and 13 age-matched controls. Differences in biomarker concentrations between these groups were computed and associations with genetic and disease related parameters investigated. Additionally, the agreement between NfL measurements derived from the 4-Plex and an established Simoa NfL singleplex assay was assessed. Results: Mean plasma NfL, GFAP and UCHL1 levels were significantly higher in FRDA patients than in controls (NfL: p < 0.001; GFAP: p = 0.006, and UCHL1: p = 0.020). Conversely, there was no significant difference in concentrations of t-tau in the patient and control group (p = 0.236). None of the proteins correlated with the GAA repeat length or the employed measures of disease severity. The individual NfL values derived from the two assays showed a strong concordance (r(c) = 0.93). Although the mean difference of 1.29 pg/mL differed significantly from 0 (p = 0.006), regression analysis did not indicate the presence of a proportional bias. Conclusion: This is the first study demonstrating that NfL, GFAP, and UCHL1 levels are raised in FRDA, potentially reflecting ongoing neuronal degeneration and glial activation. Further studies are required to determine their role as marker for disease activity and progression. Furthermore, the novel 4-plex assay appears to be a valid tool to simultaneously measure brain-derived proteins at extremely low concentrations in the peripheral circulation. Frontiers Media S.A. 2018-10-30 /pmc/articles/PMC6218876/ /pubmed/30425621 http://dx.doi.org/10.3389/fncel.2018.00366 Text en Copyright © 2018 Zeitlberger, Thomas-Black, Garcia-Moreno, Foiani, Heslegrave, Zetterberg and Giunti. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neuroscience
Zeitlberger, Anna M.
Thomas-Black, Gilbert
Garcia-Moreno, Hector
Foiani, Martha
Heslegrave, Amanda J.
Zetterberg, Henrik
Giunti, Paola
Plasma Markers of Neurodegeneration Are Raised in Friedreich’s Ataxia
title Plasma Markers of Neurodegeneration Are Raised in Friedreich’s Ataxia
title_full Plasma Markers of Neurodegeneration Are Raised in Friedreich’s Ataxia
title_fullStr Plasma Markers of Neurodegeneration Are Raised in Friedreich’s Ataxia
title_full_unstemmed Plasma Markers of Neurodegeneration Are Raised in Friedreich’s Ataxia
title_short Plasma Markers of Neurodegeneration Are Raised in Friedreich’s Ataxia
title_sort plasma markers of neurodegeneration are raised in friedreich’s ataxia
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6218876/
https://www.ncbi.nlm.nih.gov/pubmed/30425621
http://dx.doi.org/10.3389/fncel.2018.00366
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