Neuroinflammation in frontotemporal dementia
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.
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The involvement of microglia in frontotemporal dementia (FTD) and Huntington's disease (HD) is well documented.
“Similarly, the involvement of microglia in frontotemporal dementia (FTD) and Huntington’s disease (HD) is also well documented.90–92”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [91]
The combination of NPTX2, NfL, and GFAP reflects the complexity of pathological mechanisms involved in neurodegenerative disorders and FTD in particular.
“The combination of NPTX2 (representing synaptic plasticity [35]), NfL (marker for overall neurodegeneration [60, 61]), and GFAP (depicting astrogliosis [62]) reflects the complexity of pathological mechanisms involved in neurodegenerative disorders and FTD in particular [63–66]”
In C9orf72 and GRN cases, dipeptide repeats or progranulin haploinsufficiency might set off neuroinflammation prior to the formation of large TDP-43 aggregates.
“while in C9orf72 and GRN cases, neuroinflammation could be triggered by dipeptide repeats or progranulin haploinsufficiency in advance of the large TDP-43 aggregates[14,17].”
From In vivo PET imaging of neuroinflammation in familial frontotemporal dementia (2021) · cites this paper as [14]
Neuroinflammatory cascades in neurodegenerative diseases are complex and not limited to activated microglia.
“However, neuroinflammatory cascade in neurodegenerative diseases is a complex process not confined to activated microglia[14,19].”
From In vivo PET imaging of neuroinflammation in familial frontotemporal dementia (2021) · cites this paper as [14]
The findings align with previous evidence supporting the importance of neuroinflammation in FTD.
“Our findings align with previous evidence that support the importance of neuroinflammation in FTD[14].”
From In vivo PET imaging of neuroinflammation in familial frontotemporal dementia (2021) · cites this paper as [14]
In MAPT mutations, mutant tau misfolding might initiate neuroinflammation, which could then promote tau hyperphosphorylation and aggregation.
“In patients with MAPT mutations, neuroinflammation may be triggered by the misfolding of mutant tau and contribute to its hyperphosphorylation and aggregation[4,14,16], while in C9orf72 and GRN cases, neuroinflammation could be triggered by dipeptide repeats or progranulin haploinsufficiency in advance of the large TDP-43 aggregates[14,17].”
From In vivo PET imaging of neuroinflammation in familial frontotemporal dementia (2021) · cites this paper as [14]
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References 236 · Cited by 280
- Authors
- Bright, F., Werry, E. L., Dobson-Stone, C., Piguet, O., Ittner, L. M., Halliday, G. M., Hodges, J. R., Kiernan, M. C., Loy, C. T., Kassiou, M., & Kril, J. J.
- Affiliations
- The University of Sydney (AU)
- Macquarie University (AU)
- Corresponding author
- Kril, Jillian J.
- ORCID
- Venue
- Nature Reviews Neurology
- Published
- 2019-07-19
- Volume
- 15
- Issue
- 9
- Pages
- 540-555
- ISSN
- 1759-4758 (ISSN-L)
- 1759-4766
- OpenAlex
- W2963582013
- Cited by
- 280
- References
- 236
- Citations by year
- 2026: 28 · 2025: 46 · 2024: 45 · 2023: 45 · 2022: 46 · 2021: 37 · 2020: 31 · 2019: 2
- FWCI
- 3.01
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Nature Reviews Neurology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- frontotemporal dementia, neuroinflammation, microglial activation, astrocyte activation, autoimmunity, fluid biomarkers, neurodegeneration, disease-modifying therapy, diagnostic tools
- MeSH terms
- Animals, Brain, Encephalitis, Humans, Microglia, Frontotemporal Dementia
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