Searching for novel cerebrospinal fluid biomarkers of tau pathology in frontotemporal dementia: an elusive quest

• Type of Material: Article
• Authors: Martha S. Foiani, UCL Institute of Neurology; Claudia Cicognola, University of Gothenburg; Natalia Ermann, Universität Erlangen‐Nuremberg; Ione O C Woollacott, UCL Institute of Neurology; Carolin Heller, UCL Institute of Neurology; Amanda J. Heslegrave, UCL Institute of Neurology; Ashvini Keshavan, UCL Institute of Neurology; Ross W. Paterson, UCL Institute of Neurology; Keqiang Ye, Emory University; Johannes Kornhuber, Universität Erlangen‐Nuremberg; Nick C. Fox, UCL Institute of Neurology; Jonathan M. Schott, UCL Institute of Neurology; Jason D. Warren, UCL Institute of Neurology; Piotr Lewczuk, Universität Erlangen‐Nuremberg; Henrik Zetterberg, UCL Institute of Neurology; Kaj Blennow, University of Gothenburg; Kina Hoglund, University of Gothenburg; Jonathan D. Rohrer, UCL Institute of Neurology
• Language: English
• Date: 2019-07-01
• Publisher: BMJ Publishing Group
• Publication Version: Final Published Version
• Copyright Statement: © Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1136/jnnp-2018-319266
• Title of Journal or Parent Work: Journal of Neurology, Neurosurgery and Psychiatry
• ISSN: 0022-3050
• Volume: 90
• Issue: 7
• Start Page: 740
• End Page: 746
• Grant/Funding Information: AK is the recipient of a PhD Fellowship awarded by the Wolfson Foundation and a grant from the Weston Brain Institute.; 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).; JW has received funding support from the Alzheimer’s Society.; 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.; 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.; 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).; PL received consultation and/or lecture honoraria from IBL International, Fujirebio Europe, AJ Roboscreen and Roche.; RWP is funded by an NIHR Clinical Lectureship.
• Keywords: Psychiatry; Science & Technology; Surgery; Life Sciences & Biomedicine; RATIO; Clinical Neurology; Neurosciences & Neurology
• Research Categories: Health Sciences, Pathology; Biology, Neuroscience

Abstract

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 Aβ 42 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.