An autoradiographic evaluation of AV-1451 Tau PET in dementia
Open accessAbstract
BACKGROUND: It is essential to determine the specificity of AV-1451 PET for tau in brain imaging by using pathological comparisons. We performed autoradiography in autopsy-confirmed Alzheimer disease and other neurodegenerative disorders to evaluate the specificity of AV-1451 binding for tau aggregates. METHODS: Tissue samples were selected that had a variety of dementia-related neuropathologies including Alzheimer disease, primary age-related tauopathy, tangle predominant dementia, non-Alzheimer disease tauopathies, frontotemporal dementia, parkinsonism, Lewy body disease and multiple system atrophy (n = 38). Brain tissue sections were stained for tau, TAR DNA-binding protein-43, and α-synuclein and compared to AV-1451 autoradiography on adjacent sections. RESULTS: AV-1451 preferentially localized to neurofibrillary tangles, with less binding to areas enriched in neuritic pathology and less mature tau. The strength of AV-1451 binding with respect to tau isoforms in various neurodegenerative disorders was: 3R + 4R tau (e.g., AD) > 3R tau (e.g., Pick disease) or 4R tau. Only minimal binding of AV-1451 to TAR DNA-binding protein-43 positive regions was detected. No binding of AV-1451 to α-synuclein was detected. "Off-target" binding was seen in vessels, iron-associated regions, substantia nigra, calcifications in the choroid plexus, and leptomeningeal melanin. CONCLUSIONS: Reduced AV-1451 binding in neuritic pathology compared to neurofibrillary tangles suggests that the maturity of tau pathology may affect AV-1451 binding and suggests complexity in AV-1451 binding. Poor association of AV-1451 with tauopathies that have preferential accumulation of either 4R tau or 3R tau suggests limited clinical utility in detecting these pathologies. In contrast, for disorders associated with 3R + 4R tau, such as Alzheimer disease, AV-1451 binds tau avidly but does not completely reflect the early stage tau progression suggested by Braak neurofibrillary tangle staging. AV-1451 binding to TAR DNA-binding protein-43 or TAR DNA-binding protein-43 positive regions can be weakly positive. Clinical use of AV-1451 will require a familiarity with distinct types of "off-target" binding.
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Flortaucipir binds weakly or not at all to sole 4R or sole 3R tau deposits in primary tauopathies.
“Flortaucipir binds weakly or not at all to sole 4R or sole 3R tau deposits in primary tauopathies [126–128].”
From NIA‐AA Research Framework: Toward a biological definition of Alzheimer's disease (2018) · cites this paper as [127]
Previous post-mortem work has demonstrated some binding of 18F-AV-1451 to FTLD pathologies, albeit at a lower magnitude than that seen with Alzheimer's pathology.
“Supporting our use of 18F-AV-1451 as a marker of non-amyloid-β protein aggregation, previous post-mortem work has demonstrated some binding to FTLD pathologies, albeit at a lower magnitude than that seen with Alzheimer’s pathology (Marquié et al., 2015; Lowe et al., 2016; Mcmillan et al., 2016; Sander et al., 2016).”
From Neuroinflammation and protein aggregation co-localize across the frontotemporal dementia spectrum (2020) · cites this paper as Lowe et al., 2016
The molecular target in FTD associated with TDP43 is as yet undetermined, but is unlikely to be TDP43 itself.
“The molecular target in FTD associated with TDP43 is also as yet undetermined, but is unlikely to be TDP43 itself (Marquié et al., 2015; Lowe et al., 2016; Sander et al., 2016).”
From Neuroinflammation and protein aggregation co-localize across the frontotemporal dementia spectrum (2020) · cites this paper as Lowe et al., 2016
[18F]AV-1451 shows strong in vivo and post-mortem binding to tau pathology in Alzheimer's disease, but has variable affinity in healthy aging and non-AD tauopathies.
“Although [18F]AV-1451 shows strong in vivo and post-mortem binding to tau pathology in AD, it displays variable affinity in healthy aging and non-AD tauopathies28–30.”
From Neuroinflammation and Tau Colocalize in vivo in Progressive Supranuclear Palsy (2020) · cites this paper as [28]
[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 [28]
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- [38]Xia CF Arteaga J Chen G Gangadharmath U Gomez LF Kasi D Lam C Liang Q Liu C Mocharla VP [(18)F]T807, a novel tau positron emission tomography imaging agent for Alzheimer’s disease Alzheimers Dement 2013 9 666 676 10.1016/j.jalz.2012.11.008 23411393 · DOI · Paper page
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Jack, C. R., Wiste, H. J., Botha, H., Weigand, S. D., Therneau, T. M., Knopman, D. S., Graff-Radford, J., Jones, D. T., Ferman, T. J., Boeve, B. F., et al. (2019) · Brain · doi:10.1093/brain/awz268 · Cited by 200 · see citing works
Self-citationTau-positron emission tomography correlates with neuropathology findings.
Lowe, V. J., Lundt, E. S., Albertson, S. M., Min, H., Fang, P., Przybelski, S. A., Senjem, M. L., Schwarz, C. G., Kantarci, K., Boeve, B., et al. (2020) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2019.09.079 · Cited by 203 · see citing works
Self-citationMicroglial activation and tau burden predict cognitive decline in Alzheimer’s disease
Malpetti, M., Kievit, R. A., Passamonti, L., Jones, P. S., Tsvetanov, K. A., Rittman, T., Mak, E., Nicastro, N., Bevan-Jones, W. R., Su, L., et al. (2020) · Brain · doi:10.1093/brain/awaa088 · Cited by 194 · see citing works
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Self-citationSchonhaut, D. R., McMillan, C. T., Spina, S., Dickerson, B. C., Siderowf, A., Devous, M. D., Tsai, R., Winer, J., Russell, D. S., Litvan, I., et al. (2017) · Annals of Neurology · doi:10.1002/ana.25060 · Cited by 175 · see citing works
18F-flortaucipir (AV-1451) tau PET in frontotemporal dementia syndromes
Tsai, R. M., Bejanin, A., Lesman-Segev, O., LaJoie, R., Visani, A., Bourakova, V., O’Neil, J. P., Janabi, M., Baker, S., Lee, S. E., et al. (2019) · Alzheimer's Research & Therapy · doi:10.1186/s13195-019-0470-7 · Cited by 164 · see citing works
Local and distant relationships between amyloid, tau and neurodegeneration in Alzheimer's Disease
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[<sup>18</sup>F]AV‐1451 tau positron emission tomography in progressive supranuclear palsy
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Self-citationBiomarker-Based Prediction of Longitudinal Tau Positron Emission Tomography in Alzheimer Disease
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Self-citationLessons learned about [F-18]-AV-1451 off-target binding from an autopsy-confirmed Parkinson’s case.
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Artificial intelligence for diagnostic and prognostic neuroimaging in dementia: a systematic review
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Neuroinflammation and protein aggregation co-localize across the frontotemporal dementia spectrum
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Smith, R., Schain, M., Nilsson, C., Strandberg, O., Olsson, T., Hägerström, D., Jögi, J., Borroni, E., Schöll, M., Honer, M., et al. (2017) · Movement Disorders · doi:10.1002/mds.26813 · Cited by 118 · see citing works
Cross-sectional associations of tau-PET signal with cognition in cognitively unimpaired adults
Lowe, V. J., Bruinsma, T. J., Wiste, H. J., Min, H.-K., Weigand, S. D., Fang, P., Senjem, M. L., Therneau, T. M., Boeve, B. F., Josephs, K. A., et al. (2019) · Neurology · doi:10.1212/wnl.0000000000007728 · Cited by 107 · see citing works
Self-citationIn vivo retention of <sup>18</sup> F-AV-1451 in corticobasal syndrome
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PET Neuroimaging of Alzheimer's Disease: Radiotracers and Their Utility in Clinical Research
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Correlation of In Vivo [<sup>18</sup>F]Flortaucipir With Postmortem Alzheimer Disease Tau Pathology
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Flortaucipir tau PET imaging in semantic variant primary progressive aphasia
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Head-to-head comparison of tau positron emission tomography tracers [18F]flortaucipir and [18F]RO948
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Neuroinflammation and Tau Colocalize in vivo in Progressive Supranuclear Palsy
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Neuroinflammation predicts disease progression in progressive supranuclear palsy
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Self-citationTau neuropathology correlates with FDG-PET, but not AV-1451-PET, in progressive supranuclear palsy.
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Self-citationBiomarkers for diseases with TDP-43 pathology
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FTD spectrum: Neuroimaging across the FTD spectrum
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MAO-B Inhibitors Do Not Block In Vivo Flortaucipir([18F]-AV-1451) Binding
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Speech patterns during memory recall relates to early tau burden across adulthood
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SWI and phase imaging reveal intracranial calcifications in the P301L mouse model of human tauopathy
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- Authors
- Lowe, V. J., Curran, G., Fang, P., Liesinger, A. M., Josephs, K. A., Parisi, J. E., Kantarci, K., Boeve, B. F., Pandey, M. K., Bruinsma, T., Knopman, D. S., Jones, D. T., Petrucelli, L., Cook, C. N., Graff-Radford, N. R., Dickson, D. W., Petersen, R. C., Jack, C. R., & Murray, M. E.
- Affiliations
- Mayo Clinic (US)
- Corresponding author
- Lowe, Val J.
- ORCID
- Venue
- Acta Neuropathologica Communications
- Published
- 2016-06-13
- Volume
- 4
- Issue
- 1
- Pages
- 58-58
- ISSN
- 2051-5960 (ISSN-L)
- PMC
- PMC4906968
- OpenAlex
- W2426305809
- Cited by
- 474
- References
- 55
- Citations by year
- 2026: 20 · 2025: 28 · 2024: 34 · 2023: 39 · 2022: 44 · 2021: 51 · 2020: 66 · 2019: 52 · 2018: 57 · 2017: 67 · 2016: 15
- FWCI
- 51.27
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Acta Neuropathologica Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (P50-AG016574, P50-NS072187)
- National Institute on Aging (R01 NS89757, R01 DC10367)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Medical Imaging Techniques and Applications
- Keywords
- tau PET, neurofibrillary tangles, Alzheimer's disease, tauopathy, tau isoforms, off-target binding, alpha-synuclein, dementia, Braak staging, Pick's disease, Lewy body disease, multiple system atrophy, frontotemporal dementia, autoradiography
- MeSH terms
- Aged, Aged, 80 and over, Autoradiography, Brain, Carbolines, Dementia, DNA-Binding Proteins, Female, Humans, Male, Middle Aged, tau Proteins, Radiopharmaceuticals, Neurodegenerative Diseases, Protein Isoforms, Positron-Emission Tomography
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