Abstract
Background
Phosphorylated neurofilament heavy (pNfH), a neuronal cytoskeleton protein, might provide a promising blood biomarker of neuronal damage in neurodegenerative diseases (NDDs). The best analytical approaches to measure pNfH levels and whether serum levels correlate with cerebrospinal fluid (CSF) levels in NDDs remain to be determined.
Methods
We here compared analytical sensitivity and reliability of three novel analytical approaches (homebrew Simoa, commercial Simoa and ELISA) for quantifying pNfH in both CSF and serum in samples of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and control subjects.
Results
While all three assays showed highly correlated CSF measurements, Simoa assays also yielded high between-assay correlations for serum measurements (ϱ = 0.95). Serum levels also correlated strongly with CSF levels for Simoa-based measurements (both ϱ = 0.62). All three assays allowed distinguishing ALS from controls by increased CSF pNfH levels, and Simoa assays also by increased serum pNfH levels. pNfH levels were also increased in FTD.
Conclusions
pNfH concentrations in CSF and, if measured by Simoa assays, in blood might provide a sensitive and reliable biomarker of neuronal damage, with good between-assay correlations. Serum pNfH levels measured by Simoa assays closely reflect CSF levels, rendering serum pNfH an easily accessible blood biomarker of neuronal damage in NDDs.
Acknowledgments
Biosamples were obtained from the Neuro-Biobank of the University of Tübingen, Germany, which is supported by the University of Tübingen, the Hertie Institute for Clinical Brain Research (HIH) and the German Center for Neurodegenerative Diseases (DZNE). CW was supported by the Wilhelm Vaillant Stiftung. HZ is a Wallenberg Academy Fellow and is supported by grants from the Swedish Research Council and the European Research Council. JK is supported by the Swiss National Research Foundation (320030_160221) and the University of Basel. FP is funded by the MIROCALS project from the European Union’s Horizon 2020 research and innovation programme under grant agreement No. 633413. This study was further supported by the National Institutes of Health (NCATS, NINDS) through collaborative funding for the CReATe consortium (U54NS092091) which is part of the Rare Diseases Clinical Research Network (RDCRN) (pilot grant to RS and MS) and by funding from the HSP Research Foundation (grant to RS). KB holds the Torsten Söderberg professorship in Medicine and is supported by grants from the Swedish Research Council, the Swedish Alzheimer Foundation, and the Swedish Brain Foundation.
Author contributions: CW: design and conceptualisation of the study, acquisition of data, analysis of the data, drafting and revision of the manuscript. FP: acquisition of data, analysis of the data, revision of the manuscript. CB: acquisition of data, analysis of the data, revision of the manuscript. ES: acquisition of data, revision of the manuscript. KB: revision of the manuscript. ZM: acquisition of data, revision of the manuscript. CD: acquisition of data, revision of the manuscript. AJ: provision of antibodies, analysis of the data, revision of the manuscript. HZ: design and conceptualisation of the study, revision of the manuscript. RS: design and conceptualisation of the study, revision of the manuscript. KH: design and conceptualisation of the study, analysis of the data, revision of the manuscript. JK: design and conceptualisation of the study, analysis of the data, revision of the manuscript. MS: design and conceptualisation of the study, analysis of the data, drafting and revision of the manuscript. All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: None declared.
Competing financial interests: JK’s institution (University Hospital Basel) received in the last 3 years and used exclusively for research support: consulting fees from Novartis, Protagen AG; speaker fees from the Swiss MS Society, Biogen, Novartis, Roche, Genzyme; travel expenses from Merck Serono, Novartis; grants from ECTRIMS Research Fellowship Programme, University of Basel, Swiss MS Society, Swiss National Research Foundation, Bayer (Switzerland) AG, Genzyme, Merck, Novartis. MS received speaker’s honoraria and research support from Actelion Pharmaceuticals, unrelated to the current project and manuscript. AJ is an advisor Quanterix Corporation, Lexington, Massachusetts. HZ has served at scientific advisory boards for Eli Lilly, Roche Diagnostics, CogRx, Samumed and Wave, has received travel support from Teva and is a co-founder of Brain Biomarker Solutions in Gothenburg AB, a GU Ventures-based platform company at the University of Gothenburg. KB has served as a consultant or at scientific advisory boards for IBL International, Fujirebio Europe, Roche Diagnostics, BioArctic, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB, a GU Ventures-based platform company at the University of Gothenburg. The other authors declare no competing financial interests.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
Data availability: The datasets analysed in the current study are available from the corresponding author on reasonable request.
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Supplementary Material
The online version of this article offers supplementary material (https://doi.org/10.1515/cclm-2019-0015).
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