Fluid biomarkers in frontotemporal dementia: past, present and future

IJ Swift, A Sogorb-Esteve, C Heller, M Synofzik, M Otto, C Graff, D Galimberti, E Todd, AJ Heslegrave, Emma van der Ende, J.C. van Swieten, H Zetterberg, JD Rohrer

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Abstract

The frontotemporal dementia (FTD) spectrum of neurodegenerative disorders includes a heterogeneous group of conditions. However, following on from a series of important molecular studies in the early 2000s, major advances have now been made in the understanding of the pathological and genetic underpinnings of the disease. In turn, alongside the development of novel methodologies for measuring proteins and other molecules in biological fluids, the last 10 years have seen a huge increase in biomarker studies within FTD. This recent past has focused on attempting to develop markers that will help differentiate FTD from other dementias (particularly Alzheimer's disease (AD)), as well as from non-neurodegenerative conditions such as primary psychiatric disorders. While cerebrospinal fluid, and more recently blood, markers of AD have been successfully developed, specific markers identifying primary tauopathies or TDP-43 proteinopathies are still lacking. More focus at the moment has been on non-specific markers of neurodegeneration, and in particular, multiple studies of neurofilament light chain have highlighted its importance as a diagnostic, prognostic and staging marker of FTD. As clinical trials get under way in specific genetic forms of FTD, measures of progranulin and dipeptide repeat proteins in biofluids have become important potential measures of therapeutic response. However, understanding of whether drugs restore cellular function will also be important, and studies of key pathophysiological processes, including neuroinflammation, lysosomal function and synaptic health, are also now becoming more common. There is much still to learn in the fluid biomarker field in FTD, but the creation of large multinational cohorts is facilitating better powered studies and will pave the way for larger omics studies, including proteomics, metabolomics and lipidomics, as well as investigations of multimodal biomarker combinations across fluids, brain imaging and other domains. Here we provide an overview of the past, present and future of fluid biomarkers within the FTD field.

Original languageEnglish
Pages (from-to)204-215
Number of pages12
JournalJournal of Neurology Neurosurgery and Psychiatry
Volume92
Issue number2
DOIs
Publication statusPublished - 15 Jan 2021

Bibliographical note

Funding Information:
1UK Dementia Research Institute at University College London, UCL Queen Square Institute of Neurology, London, UK 2Dementia Research Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK 3Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, Tübingen, Germany 4German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany 5Department of Neurology, University of Ulm, Ulm, Germany 6Division for Neurogeriatrics, Center for Alzheimer Research, Department of NVS, Karolinska Institutet, Stockholm, Sweden 7Unit for Hereditary Dementias, Theme Aging, Karolinska University Hospital, Solna, Sweden 8Department of Biomedical, Surgical and Dental Sciences, University of Milan, Centro Dino Ferrari, Milan, Italy 9Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milan, Italy 10Department of Neurology, Erasmus Medical Centre, Rotterdam, The Netherlands 11Department of Psychiatry and Neurochemistry, Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden Acknowledgements The Dementia Research Centre is supported by Alzheimer’s Research UK, Alzheimer’s Society, Brain Research UK, and The Wolfson Foundation.

Funding Information:
This work was supported by the NIHR UCL/H Biomedical Research Centre, the Leonard Wolfson Experimental Neurology Centre (LWENC) Clinical Research Facility and the UK Dementia Research Institute, which receives its funding from UK DRI Ltd, funded by the UK Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK. MO has received funding from BMBF (FTLDc, PreFrontALS, Genfi-Prox), EU (Miriade, Fairpark II, Moodmarker), Thierry Latran Foundation and the ALS Association. CG is supported by grants from Schörling Foundation, Swedish FTD Initiative, Swedish Research Council (2015–02926, 2018–02754 and 2019–02248: JPND GENFI-PROX), Swedish Alzheimer’s Foundation, Brain Foundation, Demensfonden, Stiftelsen för Gamla Tjänarinnor, Stohnes Foundation, and grants provided by Region Stockholm (ALF project). DG has received support from the EU Joint Programme, Neurodegenerative Disease Research (JPND) and the Italian Ministry of Health (PreFrontALS, grant 733 051 042). JCVS was supported by the Dioraphte Foundation (grant 09-02-03-00), the Association for Frontemporal Dementias Research Grant 2009, The Netherlands Organisation for Scientific Research (NWO) (grant HCMI 056-13-018), ZonMw Memorabel (Deltaplan Dementie, project number 733 051 042), Alzheimer Nederland and the Bluefield project. 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 (#2 01 809–2016862), and the UK Dementia Research Institute at UCL. Several authors of this publication are members of the European Reference Network for Rare Neurological Diseases (Project ID No 739 510). The JPND GENFI-PROX grant (2019–02248) provides support to JDR (through the MRC), MS and MO (through the DLR/BMBF), CG and JCVS.

Funding Information:
Funding JDR has received funding from an MRC Clinician Scientist Fellowship (MR/ M008525/1), the NIHR Rare Disease Translational Research Collaboration (BRC149/ NS/MH), the MRC UK GENFI grant (MR/M023664/1), and the Bluefield Project.

Publisher Copyright:
© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.

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