Journal of Neurology

, Volume 265, Issue 11, pp 2633–2645 | Cite as

Significance of CSF NfL and tau in ALS

  • Stefanie SchreiberEmail author
  • Nicola Spotorno
  • Frank Schreiber
  • Julio Acosta-Cabronero
  • Jörn Kaufmann
  • Judith Machts
  • Grazyna Debska-Vielhaber
  • Cornelia Garz
  • Daniel Bittner
  • Nathalie Hensiek
  • Reinhard Dengler
  • Susanne Petri
  • Peter J. Nestor
  • Stefan Vielhaber
Original Communication


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.


Amyotrophic lateral sclerosis MRI Cerebrospinal fluid Diffusion tensor imaging Neurofilament light chain Ttau Tau phosphorylated at threonine 181 (ptau) Ptau/ttau ratio 



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

Author 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.

Compliance with ethical standards

Conflicts of interest

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

Supplementary material

415_2018_9043_MOESM1_ESM.docx (176 kb)
Supplementary material 1 (DOCX 176 KB)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Stefanie Schreiber
    • 1
    • 2
    Email author
  • Nicola Spotorno
    • 2
  • Frank Schreiber
    • 1
    • 2
    • 3
  • Julio Acosta-Cabronero
    • 2
    • 4
  • Jörn Kaufmann
    • 1
  • Judith Machts
    • 1
    • 2
  • Grazyna Debska-Vielhaber
    • 1
  • Cornelia Garz
    • 1
    • 2
  • Daniel Bittner
    • 1
    • 2
  • Nathalie Hensiek
    • 1
  • Reinhard Dengler
    • 5
  • Susanne Petri
    • 5
  • Peter J. Nestor
    • 2
    • 6
  • Stefan Vielhaber
    • 1
    • 2
  1. 1.Department of NeurologyOtto-von-Guericke UniversityMagdeburgGermany
  2. 2.German Center for Neurodegenerative Diseases (DZNE) Within the Helmholtz AssociationMagdeburgGermany
  3. 3.Institute of Control EngineeringTechnische Universität BraunschweigBrunswickGermany
  4. 4.Wellcome Centre for Human Neuroimaging, UCL Institute of NeurologyUniversity College LondonLondonUK
  5. 5.Department of NeurologyHannover Medical SchoolHannoverGermany
  6. 6.Queensland Brain InstituteUniversity of QueenslandBrisbaneAustralia

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