In vivo PET imaging of neuroinflammation in familial frontotemporal dementia
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Abstract
Introduction: We report in vivo patterns of neuroinflammation and abnormal protein aggregation in seven cases of familial frontotemporal dementia (FTD) with mutations in MAPT, GRN and C9orf72 genes. Methods: Using positron emission tomography (PET), we explored the association of the distribution of activated microglia, as measured by the radioligand [ 11 C]PK11195, and the regional distribution of tau or TDP-43 pathology, indexed using the radioligand [ 18 F]AV-1451. The familial FTD PET data were compared with healthy controls. Results: Patients with familial FTD across all mutation groups showed increased [ 11 C]PK11195 binding predominantly in frontotemporal regions, with additional regions showing abnormalities in individuals. Patients with MAPT mutations had a consistent distribution of [ 18 F]AV-1451 binding across the brain, with heterogeneous distributions among carriers of GRN and C9orf72 mutations. Discussion: This case series suggests that neuroinflammation is part of the pathophysiology of familial FTD, warranting further consideration of immunomodulatory therapies for disease modification and prevention.
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- Findingown data
The two MAPT mutation carriers showed a consistent brain-wide distribution of [18F]AV-1451 binding.
“Patients with MAPT mutations had a consistent distribution of [18F]AV-1451 binding across the brain, with heterogeneous distributions among carriers of GRN and C9orf72 mutations.”
Quote in the paperNot a substantial claim - Findingown data
The GRN and C9orf72 mutation carriers showed heterogeneous distributions of [18F]AV-1451 binding.
“Patients with MAPT mutations had a consistent distribution of [18F]AV-1451 binding across the brain, with heterogeneous distributions among carriers of GRN and C9orf72 mutations.”
Quote in the paperSubstantial claim - Findingown data
In C9orf72 patients E and F, language impairments were accompanied by increased inflammation in the left inferior frontal gyrus and temporal regions.
“Patients E and F also presented language impairments, and increased inflammation in left inferior frontal gyrus and temporal regions.”
Quote in the paperNot a substantial claim - Findingown data
In the GRN case with non-fluent aphasia (Patient D), focal left inferior frontal inflammation was associated with the phenotype.
“The GRN cases had different phenotypes for which the bvFTD in Patient C accompanied prominent orbitofrontal inflammation, but focal left inferior frontal inflammation in Patient D was associated with non-fluent aphasia.”
Quote in the paperNot a substantial claim - Findingown data
In the GRN case with bvFTD (Patient C), prominent orbitofrontal inflammation accompanied the phenotype.
“The GRN cases had different phenotypes for which the bvFTD in Patient C accompanied prominent orbitofrontal inflammation, but focal left inferior frontal inflammation in Patient D was associated with non-fluent aphasia.”
Quote in the paperNot a substantial claim
- Findingcitation
In C9orf72 carriers, [18F]AV-1451 binding was not intense or extensive relative to the distribution of neuroinflammation.
“In these latter patients, who are expected to have TDP-43 pathology but not significant tauopathy, [18F]AV-1451 binding was not intense or extensive compared to the distribution of neuroinflammation ([18F]AV-1451 binding in the C9orf72 carriers was less marked than in semantic dementia, which typically has another form of TPD-43 pathology[13]).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [13] source
Not checked in the free run.
- Rests on an assumption: [18F]AV-1451 binding is sensitive to tau and TDP-43 pathology.
- Findingown data
Patient A's language impairments were accompanied by increased [11C]PK11195 binding in temporal regions.
“but Patient A’s language impairments accompany increased binding in temporal regions.”
Quote in the paperNot a substantial claim - Interpretationown data
Activated microglia have an important role in shaping the clinical syndromes linked to genetic FTD mutations.
“We suggest that activated microglia play an important role in defining clinical syndromes associated with genetic FTD-related mutations.”
Quote in the paperSubstantial claim- Rests on an assumption: [11C]PK11195 binding is a valid marker of microglial activation and thus neuroinflammation.
- Interpretationown data
Neuroinflammation forms part of the pathophysiology of familial FTD.
“This case series suggests that neuroinflammation is part of the pathophysiology of familial FTD, warranting further consideration of immunomodulatory therapies for disease modification and prevention.”
- Also stated in: § Discussion · boosted
“The study demonstrates in vivo neuroinflammation with the three most common monogenic forms of FTD.”
Quote in the paperSubstantial claim- Rests on an assumption: [11C]PK11195 binding is a valid marker of microglial activation and thus neuroinflammation.
- Also stated in: § Discussion · boosted
- Interpretationown data
In genetic FTD, inflammation in specific regions is a typical characteristic.
“In conclusion, we suggest that regional inflammation is a typical feature of genetic FTD and future disease-modifying treatment strategies may be enhanced by immunomodulation.”
Quote in the paperSubstantial claim- Rests on an assumption: [11C]PK11195 binding is a valid marker of microglial activation and thus neuroinflammation.
- Premisecitation
Earlier autopsy work in FTD found increased microglial activation in tau- and TDP-43-related pathologies.
“Previous post mortem evidence in FTD reported upregulated microglial activation in both tau and TDP-related pathologies [15].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [15] source
Not checked in the free run.
- Premisecitation
Small sample sizes can still inform about the typicality of a feature in a population when the feature is present in most sampled cases.
“However, small sample sizes can be informative about typicality of a feature in a population, when features are identified in the majority of cases sampled[18].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [18] source
Not checked in the free run.
- Study design and conductreasoning
The small case series cannot support correlation analyses linking PET measures to clinical severity within each genetic subgroup.
“The case report approach is limited by its small size, which does not permit correlational analyses between PET imaging and clinical severity by genetic subgroups.”
Quote in the paperNot a substantial claim - Interpretationreasoning
In the C9orf72 cases, orbitofrontal inflammation may be associated with neuropsychiatric symptoms.
“While inflammation in orbitofrontal regions may be associated with the neuropsychiatric symptomatology reported in the three C9orf72 cases, Patients E and F also presented language impairments, and increased inflammation in left inferior frontal gyrus and temporal regions.”
Quote in the paperNot a substantial claim- Rests on an assumption: [11C]PK11195 binding is a valid marker of microglial activation and thus neuroinflammation.
- Interpretationcitation
Compared with semantic dementia, which usually has a different TDP-43 pathology, C9orf72 carriers showed weaker [18F]AV-1451 binding.
“([18F]AV-1451 binding in the C9orf72 carriers was less marked than in semantic dementia, which typically has another form of TPD-43 pathology[13]).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [13] source
Not checked in the free run.
- Rests on an assumption: [18F]AV-1451 binding is sensitive to tau and TDP-43 pathology.
- Interpretationcitation
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].”
Quote in the paperNot a substantial claim0 of 2 sources checked- Rests on an assumption: [11C]PK11195 binding is a valid marker of microglial activation and thus neuroinflammation.
- Study design and conductreasoning
Because controls were on average older than patients, the study may have underestimated the elevated binding seen in symptomatic cases.
“However, the control groups were older than patients on average, and the increased binding levels in symptomatic cases may therefore be underestimated.”
Quote in the paperNot a substantial claim - Interpretationown data
Variation in where neuroinflammation appears could correspond to differences in clinical presentation.
“The distribution of neuroinflammation might reflect clinical heterogeneity.”
Quote in the paperSubstantial claim- Rests on an assumption: [11C]PK11195 binding is a valid marker of microglial activation and thus neuroinflammation.
- Interpretationcitation
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].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [14] source
Not checked in the free run.
- Rests on an assumption: [11C]PK11195 binding is a valid marker of microglial activation and thus neuroinflammation.
- May combine two claims. 4
- Classified as probably not a substantial claim. 2
May combine two claims.
FindingcitationAmong the MAPT carriers, elevated [11C]PK11195 binding occurred in fronto-striatal areas and was linked to behavioural variant FTD.
“For example, in both MAPT patients, [11C]PK11195 binding was elevated in fronto-striatal regions in association with behavioural variant FTD[12], but Patient A’s language impairments accompany increased binding in temporal regions.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [12] source
Not checked in the free run.
May combine two claims.
Findingown dataIn the seven patients with familial FTD due to MAPT, GRN, or C9orf72 mutations, [11C]PK11195 binding was increased mainly in frontotemporal regions, with some individuals showing additional affected regions.
“Familial FTD patients across all mutation groups showed increased [11C]PK11195 binding predominantly in frontotemporal regions, with additional regions showing abnormalities in individuals.”
- Also stated in: § Discussion · plain
“Familial FTD was associated with neuroinflammation in frontotemporal regions, across all genes.”
Quote in the paperSubstantial claim- Also stated in: § Discussion · plain
Classified as probably not a substantial claim.
Study design and conductown dataFor voxel-wise and regional comparisons, the study used two control groups of healthy older adults matched to patients by age and sex.
“For the voxel-wise and regional comparisons between patients and controls, we used two age- and sex-matched groups of healthy elderly adults (Supplementary Table 2), who underwent either [11C]PK11195 PET (N=15) or [18F]AV-1451 PET (N=15).”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationcitationIn 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].”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [4] source
Not checked in the free run.
- cites [14] source
Not checked in the free run.
- cites [16] source
Not checked in the free run.
- Rests on an assumption: [11C]PK11195 binding is a valid marker of microglial activation and thus neuroinflammation.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationNeuroinflammatory 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].”
Quote in the paperNot a substantial claim0 of 2 sources checked
The paper relies on this without support.
[11C]PK11195 binding is a valid marker of microglial activation and thus neuroinflammation.
“In addition, [11C]PK11195 enables the visualisation of increased TSPO expression, which is a marker for microglial activation.”
The paper relies on this without support.
[18F]AV-1451 binding is sensitive to tau and TDP-43 pathology.
“a radioligand sensitive to the presence of tau and TDP-43 pathology.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
PK-PET is increased in entorhinal, temporal, parietal, and cingulate cortex in AD, in frontotemporal regions in FTD, while PSP shows increased PK-PET binding in thalamus, putamen, and pallidum, showing differential distribution of neuroinflammatory processes in different types of dementia.
“PK-PET is increased in the entorhinal, temporal, parietal and cingulate cortex in AD, in the frontotemporal regions in FTD, while PSP shows increased PK-PET binding in the thalamus, putamen and pallidum, showing differential distribution of neuroinflammatory processes in different types of dementia [215–218].”
From The use of neuroimaging techniques in the early and differential diagnosis of dementia (2023) · cites this paper as [217]
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredIn vivo PET and immunohistochemistry studies found increased microglial activation in the frontal and temporal cortices of patients with FTD.
“In vivo PET studies320,321 and immunohistochemistry studies322–324 have found increased microglial activation in the frontal and temporal cortices of patients with FTD.”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [321]
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Hashimoto, K., Jahan, N., Miller, Z., & Huang, E. J. (2022) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2022.102599 · Cited by 12 · see citing works
Cell autonomous microglia defects in a stem cell model of frontotemporal dementia tau
Iyer, A. K., Vermunt, L., Mirfakhar, F. S., Minaya, M., Acquarone, M., Koppisetti, R. K., Renganathan, A., You, S., Danhash, E., Schache, K. J., et al. (2025) · Molecular Psychiatry · doi:10.1038/s41380-025-03073-2 · Cited by 13 · see citing works
Machado, L. S., Vidor, P. R., Perquim, L., Limberger, C., Machado, L., da Rocha, A. S., Soares, C., Rahmouni, N., Brum, W. S., Bellaver, B., et al. (2025) · Molecular Psychiatry · doi:10.1038/s41380-025-03160-4 · Cited by 5 · see citing works
Self-citationMolecular imaging biomarkers in familial frontotemporal lobar degeneration: Progress and prospects
Wang, R., Gao, H., Xie, H., Jia, Z., & Chen, Q. (2022) · Frontiers in Neurology · doi:10.3389/fneur.2022.933217 · Cited by 5 · see citing works
In vivo PET imaging of neuroinflammation in familial frontotemporal dementia
Seelaar, H., & Swieten, J. C. V. (2020) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp-2020-324348 · Cited by 5 · see citing works
Complement dysregulation in human tauopathies
Nimmo, J., Keat, S., Muynck, L. D., & Morgan, B. P. (2025) · Brain Pathology · doi:10.1111/bpa.70017 · Cited by 4 · see citing works
Guardians of memory: The urgency of early dementia screening in an aging society
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Analysis of brain atrophy and local gene expression in genetic frontotemporal dementiaPreprint
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Self-citationCell autonomous microglia defects in a stem cell model of frontotemporal dementiaPreprint
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Self-citationThe future of nuclear medicine in Italy
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Constipation Is Linked to Neuroinflammation in Early Parkinson's Disease
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- Authors
- Malpetti, M., Rittman, T., Jones, P. S., Cope, T. E., Passamonti, L., Bevan-Jones, W. R., Patterson, K., Fryer, T. D., Hong, Y. T., Aigbirhio, F. I., O'Brien, J. T., & Rowe, J. B.
- Affiliations
- University of Cambridge (GB)
- MRC Cognition and Brain Sciences Unit (GB)
- Corresponding author
- Rowe, James Benedict
- ORCID
- Venue
- Journal of Neurology, Neurosurgery & Psychiatry
- Publisher
- BMJ
- Published
- 2020-10-29
- Volume
- 92
- Issue
- 3
- Pages
- 319-322
- ISSN
- 0022-3050 (ISSN-L)
- 1468-330X
- PMC
- PMC7892378
- OpenAlex
- W3095515993
- Cited by
- 43
- References
- 24
- Citations by year
- 2026: 2 · 2025: 11 · 2024: 10 · 2023: 11 · 2022: 5 · 2021: 1 · 2020: 2 · 2019: 1
- FWCI
- 1.84
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Journal of Neurology Neurosurgery & Psychiatry (publishedVersion, cc-by)
- medRxiv (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Apollo (University of Cambridge) (submittedVersion)
- Apollo
- Funders
- Cambridge Centre for Parkinson-Plus (RG95450)
- NIHR Cambridge Biomedical Research Centre (146281)
- Medical Research Council (MR/P01271X/1)
- Wellcome Trust (103838)
- 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
- familial frontotemporal dementia, neuroinflammation, activated microglia, [11C]PK11195, tau pathology, TDP-43 pathology, 18F-AV-1451, MAPT mutations, GRN mutations, C9orf72 mutation, protein aggregation, immunomodulatory therapy
- MeSH terms
- C9orf72 Protein, Progranulins, Aged, Female, Humans, Male, Middle Aged, tau Proteins, Positron-Emission Tomography, Frontotemporal Dementia
About these checks
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.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.
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