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  • Review Article
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Neuroinflammation in frontotemporal dementia

Nature Reviews Neurology volume 15, pages 540–555 (2019)Cite this article

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Abstract

Frontotemporal dementia (FTD) refers to a group of progressive neurodegenerative disorders with different pathological signatures, genetic variability and complex disease mechanisms, for which no effective treatments exist. Despite advances in understanding the underlying pathology of FTD, sensitive and specific fluid biomarkers for this disease are lacking. As in other types of dementia, mounting evidence suggests that neuroinflammation is involved in the progression of FTD, including cortical inflammation, microglial activation, astrogliosis and differential expression of inflammation-related proteins in the periphery. Furthermore, an overlap between FTD and autoimmune disease has been identified. The most substantial evidence, however, comes from genetic studies, and several FTD-related genes are also implicated in neuroinflammation. This Review discusses specific evidence of neuroinflammatory mechanisms in FTD and describes how advances in our understanding of these mechanisms, in FTD as well as in other neurodegenerative diseases, might facilitate the development and implementation of diagnostic tools and disease-modifying treatments for FTD.

Key points

  • Neuroinflammation is a major contributor to the pathogenic process in frontotemporal dementia (FTD).

  • Exploration of neuroinflammatory pathways, immune-mediated mechanisms and the use of immunomodulation as a disease-modification strategy are promising research directions in this setting.

  • Growing understanding of the complexity of microglial subpopulations provides an opportunity to explore the phenotypic landscape of microglia-driven neuroinflammation in FTD.

  • Replication and validation of previous studies in human FTD using appropriate controls, independent cohorts and quantitative methods is pivotal for the identification of new treatment targets and drug and biomarker candidates.

  • More knowledge is required on the context (cell type, timing of assessment and disease stage) of FTD-related gene effects on neuroinflammation.

  • A combination of clinical biomarker discovery and studies of patients with FTD carrying mutations that target a specific protein or underlying pathology will be essential in future investigations.

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Fig. 1: Neuroinflammation and immune-mediated mechanisms in FTD.

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Acknowledgements

The authors’ research is supported by the National Health and Medical Research Council of Australia (NHMRC) grant numbers 1132524, 1095127, 1140708 and 1081916 to G.M.H., J.J.K., O.P., M.C.K., J.R.H., L.M.I. and M.K. and by the University of Sydney. C.D.-S. is an NHMRC Boosting Dementia Research Leadership Fellow (NHMRC grant number 1138223); G.M.H. is an NHMRC Senior Principal Research Fellow (NHMRC grant number 1079679); L.M.I. is an NHMRC Principal Research Fellow (NHMRC grant number 1136241); O.P. is an NHMRC Senior Research Fellow (NHMRC grant number APP1103258); C.T.L. is an NHMRC Dementia Fellow (NHMRC grant number 1107657). The authors thank H. Cartwright from the Brain and Mind Centre, University of Sydney, Australia, for her assistance with figure design and creation.

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Authors and Affiliations

  1. School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia

    Fiona Bright & Jillian J. Kril

  2. School of Chemistry, Faculty of Science, University of Sydney, Sydney, NSW, Australia

    Eryn L. Werry & Michael Kassiou

  3. Brain and Mind Centre, University of Sydney, Sydney, NSW, Australia

    Carol Dobson-Stone, Olivier Piguet, Glenda M. Halliday, John R. Hodges & Matthew C. Kiernan

  4. Central Clinical School, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia

    Carol Dobson-Stone, Glenda M. Halliday, John R. Hodges & Matthew C. Kiernan

  5. School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia

    Carol Dobson-Stone

  6. School of Psychology, Faculty of Science, University of Sydney, Sydney, NSW, Australia

    Olivier Piguet

  7. Centre of Excellence in Cognition and its Disorders, Australian Research Council, Sydney, NSW, Australia

    Olivier Piguet & John R. Hodges

  8. Dementia Research Centre, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW, Australia

    Lars M. Ittner

  9. Institute of Clinical Neurosciences, Royal Prince Alfred Hospital, Sydney, NSW, Australia

    Matthew C. Kiernan

  10. Sydney School of Public Health, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia

    Clement T. Loy

Authors
  1. Fiona Bright
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  2. Eryn L. Werry
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  3. Carol Dobson-Stone
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  4. Olivier Piguet
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  5. Lars M. Ittner
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  6. Glenda M. Halliday
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  7. John R. Hodges
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  8. Matthew C. Kiernan
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  9. Clement T. Loy
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  10. Michael Kassiou
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  11. Jillian J. Kril
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Contributions

J.J.K., F.B., E.L.W., C.D.-S. and C.T.L. researched data for the manuscript. F.B., E.L.W. and C.D.-S. wrote the first draft. J.J.K., F.B., E.L.W., C.D.-S. and M.K. contributed substantially to discussions of the article content. J.J.K., O.P., L.M.I., G.M.H., J.R.H., M.C.K., C.T.L. and M.K. contributed to review and/or editing of the manuscript before submission.

Corresponding author

Correspondence to Jillian J. Kril.

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Competing interests

J.R.H. declares that he is an editorial board member of the journals Cognitive Neuropsychiatry, Aphasiology, Cognitive Neuropsychology, Nature Reviews Neurology, Journal of Alzheimer’s Disease, Acta Neuropsychologica, ALS-FTD Journal, Neurology and Clinical Neuroscience, Dementia Neurospsychologia; and has received research support from the National Health and Medical Research Council of Australia (NHMRC), the Australian Research Council and institutional support from the University of Sydney. M.C.K. declares that he serves as Editor-in-Chief of the Journal of Neurology, Neurosurgery and Psychiatry. The other authors declare no competing interests.

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Peer review information

Nature Reviews Neurology thanks M. Heneka, D. Galimberti, and other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Bright, F., Werry, E.L., Dobson-Stone, C. et al. Neuroinflammation in frontotemporal dementia. Nat Rev Neurol 15, 540–555 (2019). https://doi.org/10.1038/s41582-019-0231-z

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