Fluid biomarkers in frontotemporal dementia: past, present and future
Open accessAbstract
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.
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Increased amounts of CSF tau protein and medial temporal lobe atrophy on MRI are often considered Alzheimer's disease biomarkers, but these findings are not specific for Alzheimer's disease as they are also seen in a proportion of frontotemporal dementia cases.
“Notably, increased amounts of CSF tau protein and medial temporal lobe atrophy on MRI are often considered Alzheimer's disease biomarkers, but these findings are not specific for Alzheimer's disease as these biomarkers are also seen in a proportion of frontotemporal dementia cases.6,7”
From Advances and controversies in frontotemporal dementia: diagnosis, biomarkers, and therapeutic considerations (2022) · cites this paper as [7]
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Experimental — accuracy not yet measuredThere is increasing research in developing fluid biomarkers for frontotemporal dementia, with neurofilament light chain showing promise as a marker of neurodegeneration but without specificity.
“There is increasing research in developing fluid biomarkers for this form of dementia, with NfL showing promise as marker of neurodegeneration 176 , but without specificity.”
From Mental health care for older adults: recent advances and new directions in clinical practice and research (2022) · cites this paper as [176]
In FTD, NPTX2 and NPTXR are decreased in symptomatic genetic mutation carriers compared to non-carriers and pre-symptomatic carriers.
“In FTD, neuronal pentraxin-2 (NPTX2) and neuronal pentraxin receptor (NPTXR) have been found to be decreased in symptomatic genetic mutation carriers compared to non-carriers and pre-symptomatic carriers [43, 44].”
To date, specific fluid diagnostic biomarkers are missing for FTLD.
“To date, specific fluid diagnostic biomarkers are missing (Swift et al. 2021).”
From Neuronal pentraxins as biomarkers of synaptic activity: from physiological functions to pathological changes in neurodegeneration (2022) · cites this paper as Swift et al. 2021
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Frontotemporal dementia: Plasma metabolomic signature using gas chromatography–mass spectrometry
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CSF placental growth factor – a novel candidate biomarker of frontotemporal dementia
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Metabolomic changes associated with frontotemporal lobar degeneration syndromes
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- Authors
- Swift, I. J., Sogorb-Esteve, A., Heller, C., Synofzik, M., Otto, M., Graff, C., Galimberti, D., Todd, E., Heslegrave, A. J., van der Ende, E. L., Van Swieten, J. C., Zetterberg, H., & Rohrer, J. D.
- Affiliations
- UK Dementia Research Institute (GB)
- German Center for Neurodegenerative Diseases (DE)
- Universität Ulm (DE)
- Karolinska University Hospital (SE)
- University of Milan (IT)
- UCL Queen Square Institute of Neurology (GB)
- Corresponding author
- Rohrer, Jonathan Daniel
- ORCID
- Venue
- Journal of Neurology, Neurosurgery & Psychiatry
- Publisher
- BMJ
- Published
- 2020-11-13
- Volume
- 92
- Issue
- 2
- Pages
- 204-215
- ISSN
- 0022-3050 (ISSN-L)
- 1468-330X
- OpenAlex
- W3098615777
- Cited by
- 122
- References
- 157
- Citations by year
- 2026: 9 · 2025: 19 · 2024: 33 · 2023: 20 · 2022: 26 · 2021: 14
- FWCI
- 2.49
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neurology Neurosurgery & Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (acceptedVersion, other-oa)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, other-oa)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
- UCL Discovery (University College London) (submittedVersion)
- DZNE Pub (submittedVersion)
- Funders
- Medical Research Council (MR/M008525/1, MR/M023664/1)
- Research Trainees Coordinating Centre (BRC149/NS/MH)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- frontotemporal dementia, fluid biomarkers, cerebrospinal fluid biomarkers, blood biomarkers, neurofilament light chain, tauopathy, TDP-43 proteinopathy, progranulin, dipeptide repeat proteins, Alzheimer's disease differential diagnosis, neurodegeneration biomarkers, neuroinflammation, lysosomal function, treatment response monitoring, multimodal biomarkers, proteomics, metabolomics, lipidomics
- MeSH terms
- Diagnosis, Differential, Forecasting, Humans, Biomarkers, Frontotemporal Dementia
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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