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Searching for novel cerebrospinal fluid biomarkers of tau pathology in frontotemporal dementia: an elusive quest
  1. Martha S Foiani1,2,
  2. Claudia Cicognola3,
  3. Natalia Ermann4,
  4. Ione O C Woollacott2,
  5. Carolin Heller1,2,
  6. Amanda J Heslegrave1,2,
  7. Ashvini Keshavan2,
  8. Ross W Paterson2,
  9. Keqiang Ye5,
  10. Johannes Kornhuber4,
  11. Nick C Fox2,
  12. Jonathan M Schott2,
  13. Jason D Warren2,
  14. Piotr Lewczuk4,6,
  15. Henrik Zetterberg1,2,3,7,
  16. Kaj Blennow3,7,
  17. Kina Höglund3,7,
  18. Jonathan D Rohrer2
  1. 1 UK Dementia Research Institute, UCL Institute of Neurology, London, UK
  2. 2 Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK
  3. 3 Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
  4. 4 Department of Psychiatry and Psychotherapy, Universitätsklinikum Erlangen and Friedrich‐Alexander Universität Erlangen‐Nuremberg, Erlangen, Germany
  5. 5 Pathology & Laboratory Medicine, Experimental Pathology, Emory University School of Medicine, Atlanta, Georgia, USA
  6. 6 Department of Neurodegeneration Diagnostics, Medical University of Bialystok, Bialystok, Poland
  7. 7 Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
  1. Correspondence to Dr Jonathan D Rohrer, Department of Neurodegenerative Disease, UCL Institute of Neurology, London WC1N 3BG, UK; j.rohrer{at}


Background Frontotemporal dementia (FTD) is a pathologically heterogeneous neurodegenerative disorder associated usually with tau or TDP-43 pathology, although some phenotypes such as logopenic variant primary progressive aphasia are more commonly associated with Alzheimer’s disease pathology. Currently, there are no biomarkers able to diagnose the underlying pathology during life. In this study, we aimed to investigate the potential of novel tau species within cerebrospinal fluid (CSF) as biomarkers for tau pathology in FTD.

Methods 86 participants were included: 66 with a clinical diagnosis within the FTD spectrum and 20 healthy controls. Immunoassays targeting tau fragments N-123, N-mid-region, N-224 and X-368, as well as a non-phosphorylated form of tau were measured in CSF, along with total-tau (T-tau) and phospho-tau (P-tau(181)). Patients with FTD were grouped based on their Aβ42 level into those likely to have underlying Alzheimer’s disease (AD) pathology (n=21) and those with likely frontotemporal lobar degeneration (FTLD) pathology (n=45). The FTLD group was then subgrouped based on their underlying clinical and genetic diagnoses into those with likely tau (n=7) or TDP-43 (n=18) pathology.

Results Significantly higher concentrations of tau N-mid-region, tau N-224 and non-phosphorylated tau were seen in both the AD group and FTLD group compared with controls. However, none of the novel tau species showed a significant difference between the AD and FTLD groups, nor between the TDP-43 and tau pathology groups. In a subanalysis, normalising for total-tau, none of the novel tau species provided a higher sensitivity and specificity to distinguish between tau and TDP-43 pathology than P-tau(181)/T-tau, which itself only had a sensitivity of 61.1% and specificity of 85.7% with a cut-off of <0.109.

Conclusions Despite investigating multiple novel CSF tau fragments, none show promise as an FTD biomarker and so the quest for in vivo markers of FTLD-tau pathology continues.

  • frontotemporal dementia
  • CSF
  • tau

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  • MSF and CC are joint first authors.

  • KH and JDR are joint senior authors.

  • Contributors JDR and MSF designed the study. JDR, MSF, CC, NE, PL and KH analysed the data. JDR and MSF wrote the initial manuscript. AK, RWP, IOCW, CH, AJH, KY, JK, NCF, JMS, JW, HZ and KB helped with data collection, analysis and review of the manuscript.

  • Funding The Dementia Research Centre is an Alzheimer’s Research UK coordinating centre and is supported by Alzheimer’s Research UK, the Brain Research Trust and the Wolfson Foundation. This work was supported by the National Institute for Health Research (NIHR) UCL/H Biomedical Research Centre, the Leonard Wolfson Experimental Neurology Centre and the UK Dementia Research Institute. This study was also funded by the AFTD Biomarkers Initiative. JDR is an MRC Clinician Scientist (MR/M008525/1) and has received funding from the NIHR Rare Diseases Translational Research Collaboration (BRC149/NS/MH), the Bluefield Project and the Association for Frontotemporal Degeneration. IOCW is funded by an MRC Clinical Research Training Fellowship (MR/M018288/1). RWP is funded by an NIHR Clinical Lectureship. AK is the recipient of a PhD Fellowship awarded by the Wolfson Foundation and a grant from the Weston Brain Institute. JW has received funding support from the Alzheimer’s Society. JMS has received support from the EPSRC (EP/J020990/1), MRC Dementias Platform UK (MR/L023784/1), ARUK (ARUK-Network 2012-6-ICE; ARUK-PG2017-1946; ARUK-PG2017-1946), Brain Research UK (UCC14191), Weston Brain Institute (UB170045) and European Union’s Horizon 2020 research and innovation programme (grant 666992). HZ is a Wallenberg Academy Fellow.

  • Competing interests PL and HZ have received support from the Innovative Medicines Initiative Joint Undertaking under EMIF grant agreement no. 115372, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007–2013) and EFPIA companies’ in-kind contribution. PL received consultation and/or lecture honoraria from IBL International, Fujirebio Europe, AJ Roboscreen and Roche.

  • Patient consent for publication Not required.

  • Ethics approval The use of human samples involved in this study was approved by the Queen Square NRES Committee.

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

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