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Diagnostic and prognostic value of serum NfL and p-Tau181 in frontotemporal lobar degeneration
  1. Alberto Benussi1,
  2. Thomas K Karikari2,
  3. Nicholas Ashton2,3,4,5,
  4. Stefano Gazzina6,
  5. Enrico Premi7,
  6. Luisa Benussi8,
  7. Roberta Ghidoni8,
  8. Juan Lantero Rodriguez2,
  9. Andreja Emeršič2,9,
  10. Joel Simrén10,
  11. Giuliano Binetti11,
  12. Silvia Fostinelli8,
  13. Marcello Giunta1,
  14. Roberto Gasparotti12,
  15. Henrik Zetterberg2,10,13,14,
  16. Kaj Blennow2,10,
  17. Barbara Borroni1
  1. 1Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
  2. 2Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden
  3. 3Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Mölndal, Sweden
  4. 4Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom
  5. 5NIHR Biomedical Research Centre for Mental Health & Biomedical Research Unit for Dementia, South London and Maudsley NHS Foundation Trust, London, United Kingdom
  6. 6Neurophysiology Unit, ASST Spedali Civili di Brescia, Brescia, Italy
  7. 7Vascular Neurology Unit, ASST Spedali Civili di Brescia, Brescia, Italy
  8. 8Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy
  9. 9Department of Neurology, University Medical Centre, Ljubljana, Slovenia
  10. 10Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
  11. 11MAC Memory Clinic and Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy
  12. 12Neuroradiology Unit, University of Brescia, Brescia, Italy
  13. 13UK Dementia Research Institute, University College London, London, United Kingdom
  14. 14Department of Neurodegenerative Disease, Institute of Neurology, University College London, London, United Kingdom
  1. Correspondence to Professor Barbara Borroni, Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy; bborroni{at}inwind.it

Abstract

Objective To assess the diagnostic and prognostic value of serum neurofilament light (NfL) and serum phospho-Tau181 (p-Tau181) in a large cohort of patients with frontotemporal lobar degeneration (FTLD).

Methods In this retrospective study, performed on 417 participants, we analysed serum NfL and p-Tau181 concentrations with an ultrasensitive single molecule array (Simoa) approach. We assessed the diagnostic values of serum biomarkers in the differential diagnosis between FTLD, Alzheimer’s disease (AD) and healthy ageing; their role as markers of disease severity assessing the correlation with clinical variables, cross-sectional brain imaging and neurophysiological data; their role as prognostic markers, considering their ability to predict survival probability in FTLD.

Results We observed significantly higher levels of serum NfL in patients with FTLD syndromes, compared with healthy controls, and lower levels of p-Tau181 compared with patients with AD. Serum NfL concentrations showed a high accuracy in discriminating between FTLD and healthy controls (area under the curve (AUC): 0.86, p<0.001), while serum p-Tau181 showed high accuracy in differentiating FTLD from patients with AD (AUC: 0.93, p<0.001). In FTLD, serum NfL levels correlated with measures of cognitive function, disease severity and behavioural disturbances and were associated with frontotemporal atrophy and indirect measures of GABAergic deficit. Moreover, serum NfL concentrations were identified as the best predictors of survival probability.

Conclusions The assessment of serum NfL and p-Tau181 may provide a comprehensive view of FTLD, aiding in the differential diagnosis, in staging disease severity and in defining survival probability.

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Footnotes

  • Twitter @bobgas@giumbomix

  • Contributors Conception and design of the study: AB and BB. Acquisition and analysis of data: AB, TKK, NA, SG, EP, LB, RG, JLR, AE, JM, GB, SF, MG, RG, HZ, KB and BB. Drafting the manuscript and figures: AB, MG, SG, EP and BB. Revising the manuscript for intellectual content: AB, TKK, NA, SG, EP, LB, RG, JLR, AE, JS, GB, SF, MG, RG, HZ, KB and BB.

  • Funding This study was partially funded by the Italian Ministry of Health (Ricerca Corrente). HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018-02532), the European Research Council (#681712), Swedish State Support for Clinical Research (#ALFGBG-720931), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809-2016862) and the UK Dementia Research Institute at UCL. KB is supported by the Swedish Research Council (#2017-00915), the Alzheimer Drug Discovery Foundation (ADDF), USA (#RDAPB-201809-2016615), the Swedish Alzheimer Foundation (#AF-742881), Hjärnfonden, Sweden (#FO2017-0243), the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (#ALFGBG-715986) and European Union Joint Program for Neurodegenerative Disorders (JPND2019-466-236).

  • Competing interests HZ has served at scientific advisory boards for Denali, Roche Diagnostics, Wave, Samumed and CogRx, has given lectures in symposia sponsored by Fujirebio, Alzecure and Biogen and is a co-founder of Brain Biomarker Solutions in Gothenburg AB, a GU Ventures-based platform company at the University of Gothenburg, all unrelated to the work presented in this paper. KB has served as a consultant or at advisory boards for Abcam, Axon, Biogen, Lilly, MagQu, Novartis and Roche Diagnostics, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB, a GU Venture-based platform company at the University of Gothenburg, all unrelated to the work presented in this paper.

  • Patient consent for publication Not required.

  • Ethics approval Full written informed consent was obtained from all subjects according to the Declaration of Helsinki. The Brescia Ethics Committee approved the study protocol (NP 1965).

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Data are available on reasonable request. All study data, including raw and analysed data, and materials will be available from the corresponding author, BB, on reasonable request.

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