[18F]AV-1451 binding in vivo mirrors the expected distribution of TDP-43 pathology in the semantic variant of primary progressive aphasia
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Introduction: Semantic dementia, including the semantic variant of primary progressive aphasia (svPPA), is strongly associated with TAR-DNA binding protein 43 (TDP-43) type C pathology. It provides a useful model in which to test the specificity of in vivo binding of the putative tau ligand [18 F]AV-1451, which is elevated in frontotemporal lobar degeneration tauopathies. Methods and results: Seven patients (five with svPPA and two with ‘right’ semantic dementia) and 12 healthy controls underwent positron emission tomography brain imaging with [18 F]AV-1451. Two independent preprocessing methods were used. For both methods, all patients had clearly elevated binding potential (BP ND(non-displaceable binding potential)) in temporal lobes, lateralising according to their clinical syndrome and evident in raw images. Region of interest analyses confirmed that BP ND was significantly increased in temporal regions, insula and fusiform gyrus, consistent with those areas known to be most affected in semantic dementia. Hierarchical cluster analysis, based on the distribution of [18 F]AV-1451 binding potential, separated semantic dementia from controls with 86% sensitivity and 100% specificity. Conclusions: [18 F]AV-1451 binds in vivo regions that are likely to contain TDP-43 and not significant tau pathology. While this suggests a non-tau target for [18 F]AV-1451, the pathological regions in semantic dementia do not normally contain significant levels of recently proposed ‘off target’ binding sites for [18 F]AV-1451, such as neuronal monoamine oxidase or neuromelanin. Postmortem and longitudinal data will be useful to assess the utility of [18 F]AV-1451 to differentiate and track different types of frontotemporal lobar degeneration.
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Initial tau PET tracers showed good specificity for cortical tau tangles but had evidence of non-specific binding in subcortical structures, suggesting they are not suitable for non-AD tauopathies.
“The initial tau PET tracers showed good specificity for cortical tau tangles however there has been evidence of non-specific binding in subcortical structures suggesting that tau PET with these tracers is not suitable for non-AD tauopathies [179–183].”
From The use of neuroimaging techniques in the early and differential diagnosis of dementia (2023) · cites this paper as [180]
The Discussion reports possible off-target [18F]AV-1451 binding in the basal ganglia and says its lack of selectivity challenges its use for distinguishing pathologies in vivo. It also describes Alzheimer’s-disease binding evidence as compelling, but does not establish good specificity for cortical tau tangles or conclude that these tracers are unsuitable for all non-AD tauopathies; it says binding in those conditions remains controversial. (LLM, conf=0.85)
Experimental — accuracy not yet measured[18F]AV-1451 binds to non-tau proteinopathies and to other targets such as neuromelanin, choroid plexus, and monoamine oxidase.
“The tracer also binds to non-tau proteinopathies (i.e., is positive in TDP43 pathology with C9orf72 mutations and semantic dementia31), and other targets such as neuromelanin29, choroid plexus28 and monoamine oxidase (MAO)32.”
From Neuroinflammation and Tau Colocalize in vivo in Progressive Supranuclear Palsy (2020) · cites this paper as [31]
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]).”
From In vivo PET imaging of neuroinflammation in familial frontotemporal dementia (2021) · cites this paper as [13]
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]).”
From In vivo PET imaging of neuroinflammation in familial frontotemporal dementia (2021) · cites this paper as [13]
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- Authors
- Bevan-Jones, W. R., Cope, T. E., Jones, P. S., Passamonti, L., Hong, Y. T., Fryer, T. D., Arnold, R., Allinson, K. S. J., Coles, J. P., Aigbirhio, F. I., Patterson, K., O’Brien, J. T., & Rowe, J. B.
- Affiliations
- University of Cambridge (GB)
- Addenbrooke's Hospital (GB)
- MRC Cognition and Brain Sciences Unit (GB)
- Corresponding author
- Bevan-Jones, W R
- ORCID
- Venue
- Journal of Neurology, Neurosurgery & Psychiatry
- Publisher
- BMJ
- Published
- 2017-09-14
- Volume
- 89
- Issue
- 10
- Pages
- 1032-1037
- ISSN
- 0022-3050 (ISSN-L)
- 1468-330X
- PMC
- PMC6166613
- OpenAlex
- W2743089093
- Cited by
- 84
- References
- 33
- Citations by year
- 2025: 3 · 2024: 5 · 2023: 4 · 2022: 8 · 2021: 14 · 2020: 13 · 2019: 16 · 2018: 18 · 2017: 3
- FWCI
- 11.22
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- Journal of Neurology Neurosurgery & Psychiatry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- HighWire Press Open Archive (submittedVersion)
- Apollo (cc-by)
- Funders
- Wellcome Trust
- Association of British Neurologists and the Patrick Berthoud Charitable Trust
- National Institute for Health Research
- Cambridge Biomedical Research Centre and Biomedical Research Unit in Dementia
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Keywords
- 18F-AV-1451, TDP-43 pathology, semantic dementia, frontotemporal lobar degeneration, tau PET imaging, off-target binding, non-displaceable binding potential, fusiform gyrus, insula
- MeSH terms
- Aged, Brain, DNA-Binding Proteins, Female, Humans, Male, Middle Aged, Aphasia, Primary Progressive, Positron-Emission Tomography
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