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Significance of CSF NfL and tau in ALS

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Abstract

Cerebrospinal fluid (CSF) neurofilament light chain (NfL) has emerged as putative diagnostic biomarker in amyotrophic lateral sclerosis (ALS), but it remains a matter of debate, whether CSF total tau (ttau), tau phosphorylated at threonine 181 (ptau) and the ptau/ttau ratio could serve as diagnostic biomarker in ALS as well. Moreover, the relationship between CSF NfL and tau measures to further axonal and (neuro)degeneration markers still needs to be elucidated. Our analysis included 89 ALS patients [median (range) age 63 (33–83) years, 61% male, disease duration 10 (0.2–190) months] and 33 age- and sex-matched disease controls [60 (32–76), 49%]. NfL was higher and the ptau/ttau ratio was lower in ALS compared to controls [8343 (1795–35,945) pg/ml vs. 1193 (612–2616), H(1) = 70.8, p < 0.001; mean (SD) 0.17 (0.04) vs. 0.2 (0.03), F(1) = 14.3, p < 0.001], as well as in upper motor neuron dominant (UMND, n = 10) compared to classic (n = 46) or lower motor neuron dominant ALS [n = 31; for NfL: 16,076 (7447–35,945) vs. 8205 (2651–35,138) vs. 8057 (1795–34,951)], Z ≥ 2.5, p ≤ 0.01; for the ptau/ttau ratio: [0.13 (0.04) vs. 0.17 (0.04) vs. 0.18 (0.03), p ≤ 0.02]. In ALS, NfL and the ptau/ttau ratio were related to corticospinal tract (CST) fractional anisotropy (FA) and radial diffusivity (ROI-based approach and whole-brain voxelwise analysis). Factor analysis of mixed data revealed a co-variance pattern between NfL (factor load − 0.6), the ptau/ttau ratio (0.7), CST FA (0.8) and UMND ALS phenotype (− 2.8). NfL did not relate to any further neuroaxonal injury marker (brain volumes, precentral gyrus thickness, peripheral motor amplitudes, sonographic cross-sectional nerve area), but a lower ptau/ttau ratio was associated with whole-brain gray matter atrophy and widespread white matter integrity loss. Higher NfL baseline levels were associated with greater UMN disease burden, more rapid disease progression, a twofold to threefold greater hazard of death and shorter survival times. The findings that higher CSF NfL levels and a reduced ptau/ttau ratio are more associated with clinical UMN involvement and with reduced CST FA offer strong converging evidence that both are markers of central motor degeneration. Furthermore, NfL is a marker of poor prognosis, while a low ptau/ttau ratio indicates extramotor pathology in ALS.

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Acknowledgements

We thank Christa Sobetzko, Department of Neurology, Otto-von-Guericke University, Magdeburg, Germany, for data collection.

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Authors and Affiliations

  1. Department of Neurology, Otto-von-Guericke University, Leipziger Straße 44, 39120, Magdeburg, Germany

    Stefanie Schreiber, Frank Schreiber, Jörn Kaufmann, Judith Machts, Grazyna Debska-Vielhaber, Cornelia Garz, Daniel Bittner, Nathalie Hensiek & Stefan Vielhaber

  2. German Center for Neurodegenerative Diseases (DZNE) Within the Helmholtz Association, Leipziger Straße 44, 39120, Magdeburg, Germany

    Stefanie Schreiber, Nicola Spotorno, Frank Schreiber, Julio Acosta-Cabronero, Judith Machts, Cornelia Garz, Daniel Bittner, Peter J. Nestor & Stefan Vielhaber

  3. Institute of Control Engineering, Technische Universität Braunschweig, Hans-Sommer-Straße 66, 38106, Brunswick, Germany

    Frank Schreiber

  4. Wellcome Centre for Human Neuroimaging, UCL Institute of Neurology, University College London, London, UK

    Julio Acosta-Cabronero

  5. Department of Neurology, Hannover Medical School, Carl-Neuberg-Straße 1, 30625, Hannover, Germany

    Reinhard Dengler & Susanne Petri

  6. Queensland Brain Institute, University of Queensland, Brisbane, 4072, Australia

    Peter J. Nestor

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Contributions

SS: data analysis, data interpretation, study concept and design, and drafting the manuscript. NS, FS: data analysis, data interpretation, study concept and design, and critical revision of the manuscript for important intellectual content. JAC, JK, JM, GDV, CG, DB, NH, RD, SP: acquisition of data and critical revision of the manuscript for important intellectual content. PJN: critical revision of the manuscript for important intellectual content. SV: acquisition of data, data interpretation, study concept and design, drafting the manuscript, critical revision of the manuscript for important intellectual content, and study supervision. SS had full access to all of the data of the study, and takes responsibility for the integrity of the data and the accuracy of the data analysis. Statistical analysis conducted by SS, MD, NS, PhD, and FS, Otto-von-Guericke University and DZNE Magdeburg.

Funding

This work was supported by a grant to SS from the Otto-von-Guericke University Magdeburg (Grant for young scientists 2016) and by a grant to SS and SV from the Foundation of Medical Research, Frankfurt/Main, Germany.

Corresponding author

Correspondence to Stefanie Schreiber.

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On behalf of all authors, the Stefanie Schreiber states that there is no conflict of interest.

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Schreiber, S., Spotorno, N., Schreiber, F. et al. Significance of CSF NfL and tau in ALS. J Neurol 265, 2633–2645 (2018). https://doi.org/10.1007/s00415-018-9043-0

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  • DOI: https://doi.org/10.1007/s00415-018-9043-0

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