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Fluid biomarkers in frontotemporal dementia: past, present and future
  1. Imogen Joanna Swift1,
  2. Aitana Sogorb-Esteve1,2,
  3. Carolin Heller1,
  4. Matthis Synofzik3,4,
  5. Markus Otto5,
  6. Caroline Graff6,7,
  7. Daniela Galimberti8,9,
  8. Emily Todd2,
  9. Amanda J Heslegrave1,
  10. Emma Louise van der Ende10,
  11. John Cornelis Van Swieten10,
  12. Henrik Zetterberg1,11,
  13. Jonathan Daniel Rohrer2
  1. 1UK Dementia Research Institute at University College London, UCL Queen Square Institute of Neurology, London, UK
  2. 2Dementia Research Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK
  3. 3Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, Tübingen, Germany
  4. 4German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
  5. 5Department of Neurology, University of Ulm, Ulm, Germany
  6. 6Division for Neurogeriatrics, Center for Alzheimer Research, Department of NVS, Karolinska Institutet, Stockholm, Sweden
  7. 7Unit for Hereditary Dementias, Theme Aging, Karolinska University Hospital, Solna, Sweden
  8. 8Department of Biomedical, Surgical and Dental Sciences, University of Milan, Centro Dino Ferrari, Milan, Italy
  9. 9Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milan, Italy
  10. 10Department of Neurology, Erasmus Medical Centre, Rotterdam, The Netherlands
  11. 11Department of Psychiatry and Neurochemistry, Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden
  1. Correspondence to Dr Jonathan Daniel Rohrer, Dementia Research Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK; j.rohrer{at}


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.

  • frontotemporal dementia
  • CSF
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  • Contributors IS, AS-E, CH and JDR performed the initial literature search and wrote the initial draft of the manuscript. MS, MO, CG, DG, ET, AJH, ELvdE, JCVS and HZ all critically reviewed the initial draft of the manuscript and contributed additional literature to the review. IS, AS-E, CH, MS, MO, CG, DG, ET, AJH, ELvdE, JCVS, HZ and JDR all contributed to the writing of the final version of the manuscript.

  • 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.

  • Competing interests HZ has served at scientific advisory boards for Denali, Roche Diagnostics, Wave Life Sciences, Samumed, Siemens Healthineers, Pinteon Therapeutics and CogRx; has given lectures in symposia sponsored by Fujirebio, Alzecure and Biogen; and is a cofounder of Brain Biomarker Solutions in Gothenburg AB, which is a part of the GU Ventures Incubator Program. JDR has served on medical advisory boards for Ionis, Wave Life Sciences, Alector and Prevail.

  • Patient consent for publication Not required.

  • Provenance and peer review Commissioned; externally peer reviewed.

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