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  • Review Article
  • Published:

Imaging and fluid biomarkers in frontotemporal dementia

Key Points

  • Most of the validated biomarkers in frontotemporal dementia (FTD) are used to differentiate patients with FTD from patients with Alzheimer disease or from control individuals

  • Currently validated biomarkers in FTD include grey matter atrophy, alterations in brain metabolism as detected by 18F-fluorodeoxyglucose-PET and cerebrospinal fluid levels of amyloid-β1–42, phospho-tau181 and total-tau.

  • New imaging biomarkers, detected via techniques such as arterial spin labelling and diffusion tensor imaging, are sensitive to the subtle changes that precede grey matter atrophy in FTD, potentially enabling use in diagnosis and disease monitoring

  • Promising fluid biomarkers include neurofilament light chain (for staging, monitoring and prognosis in all FTD subtypes) and dipeptide-repeat proteins and progranulin (for target engagement in gene-specific forms of FTD)

  • Reliable biomarkers that differentiate between tau pathology and TDP-43 pathology are still needed, to facilitate trials of disease-modifying treatments

  • Future research should focus on the multimodal combination of fluid and imaging biomarkers, as well as the harmonization of biomarker collection and analysis protocols

Abstract

Frontotemporal dementia (FTD), the second most common type of presenile dementia, is a heterogeneous neurodegenerative disease characterized by progressive behavioural and/or language problems, and includes a range of clinical, genetic and pathological subtypes. The diagnostic process is hampered by this heterogeneity, and correct diagnosis is becoming increasingly important to enable future clinical trials of disease-modifying treatments. Reliable biomarkers will enable us to better discriminate between FTD and other forms of dementia and to predict disease progression in the clinical setting. Given that different underlying pathologies probably require specific pharmacological interventions, robust biomarkers are essential for the selection of patients with specific FTD subtypes. This Review emphasizes the increasing availability and potential applications of structural and functional imaging biomarkers, and cerebrospinal fluid and blood fluid biomarkers in sporadic and genetic FTD. The relevance of new MRI modalities — such as voxel-based morphometry, diffusion tensor imaging and arterial spin labelling — in the early stages of FTD is discussed, together with the ability of these modalities to classify FTD subtypes. We highlight promising new fluid biomarkers for staging and monitoring of FTD, and underline the importance of large, multicentre studies of individuals with presymptomatic FTD. Harmonization in the collection and analysis of data across different centres is crucial for the implementation of new biomarkers in clinical practice, and will become a great challenge in the next few years.

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Figure 1: Clinical, pathological and genetic spectrum of FTD.
Figure 2: Grey matter atrophy in FTD.
Figure 3: Imaging abnormalities in the presymptomatic stage of genetic FTD.
Figure 4: Cerebrospinal fluid levels of neurofilament light chain.
Figure 5: Gene-specific fluid biomarkers.

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Acknowledgements

We would like to thank S. A. Rombouts, M. W. Vernooij, and R. M. Steketee for their constructive comments on subsections of this Review. We thank C. Scherling and A. L. Boxer for the raw NfL data used to assemble Figure. 4, and T. F. Gendron and L. Petrucelli for the consent to use the poly(GP) figures. L.H.M., L.D.K. and J.C.v.S. received funding from a Memorable grant from Deltaplan Dementie (The Netherlands Organisation for Health Research and Development, and the Netherlands Alzheimer Foundation, grant number 70-73305-98-105), and the European Joint Programme — Neurodegenerative Disease Research (JPND, PreFrontALS). L.H.M. is supported by Alzheimer Nederland (grant number WE.09-2014-04). J.C.v.S. is supported by the Dioraphte Foundation. L.D.K. is supported by The Bluefield Project. J.D.R. is supported by an Medical Research Council Clinician Scientist Fellowship (MR/M008525/1) and has received funding from the National Institute for Health Research Rare Disease Translational Research Collaboration.

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Glossary

Primary progressive aphasia

A progressive clinical syndrome with predominant language impairment.

Progressive supranuclear palsy

A progressive atypical parkinsonism characterized by vertical supranuclear gaze palsy and postural instability with falls, often accompanied by behavioural changes.

Corticobasal syndrome

A progressive atypical parkinsonism characterized by asymmetrical cortical features (such as myoclonus, apraxia and cortical sensory deficits) and extrapyramidal features (such as rigidity and dystonia).

Frontotemporal lobar degeneration

The pathological term for a group of neurodegenerative disorders affecting the frontal and/or temporal lobes accompanied by protein inclusions (such as tau, TDP-43 or FUS).

Diffusion tensor imaging

An MRI technique that analyses microstructural white matter integrity by measuring diffusivity in different directions: axial diffusivity correlates with axonal injury, radial diffusivity with myelin breakdown, and fractional anisotropy is a composite measure that represents general white matter integrity.

Resting-state functional MRI

An MRI technique that measures functional connectivity between brain regions.

Single molecule array technology

A digital form of enzyme-linked immunosorbent assay that runs highly sensitive immunoassays to measure molecules (for example proteins) in biofluids.

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Meeter, L., Kaat, L., Rohrer, J. et al. Imaging and fluid biomarkers in frontotemporal dementia. Nat Rev Neurol 13, 406–419 (2017). https://doi.org/10.1038/nrneurol.2017.75

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