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Effect of Off-Target Binding on 18F-Flortaucipir Variability in Healthy Controls Across the Life Span
Open accessAbstract
Measuring early tau accumulation is important in studying aging and Alzheimer disease and is only as accurate as the signal-to-noise ratio of the tracer. Along with aggregated tau in the form of neurofibrillary tangles, 18F-flortaucipir has been reported to bind to neuromelanin, monoamine oxidase, calcifications, iron, leptomeningeal melanocytes, and microhemorrages. Although 18F-flortaucipir successfully differentiates healthy controls (HCs) from subjects with Alzheimer disease, variability exists in the cortical signal in amyloid-negative HCs. We aimed to explore the relationship between off-target binding signal and variability in the cortical signal in HCs. Methods: Subjects (n = 139) received 11C-Pittsburgh compound B (PIB) and 18F-flortaucipir PET scans and a magnetization-prepared rapid gradient echo MRI scan. PET frames were realigned and coregistered to the MR images, which were segmented using FreeSurfer. In amyloid-negative HCs (n = 90; age range, 21–94 y), 7 nonspecific or off-target binding regions were considered: caudate, pallidum, putamen, thalamus, cerebellar white matter, hemispheric white matter, and choroid plexus. These regions of interest were assigned to 3 similarly behaving groups using principle components analysis, exploratory factor analysis, and Pearson correlations for caudate, putamen, and pallidum (also correlated with age); thalamus and white matter; and choroid plexus. In amyloid-negative HCs with 11C-PIB and 18F-flortaucipir scans, correlations were calculated between white and gray matter before and after partial-volume correction. Results: The correlation between white and gray matter disappeared after partial-volume correction in 11C-PIB (r2 = 0) but persisted for 18F-flortaucipir (r2 = 0.27), demonstrating that the correlation between white and gray matter signal in 18F-flortaucipir is not solely due to partial-volume effects. A linear regression showed that off-target signal from putamen and thalamus together explained 64% of the variability in the cortical signal in amyloid-negative HCs (not seen in amyloid-positive HCs). Variability in amyloid-negative HCs but not amyloid-positive HCs correlated with white matter signal (unrelated to partial-volume effects) and age-related off-target signal (possibly related to iron load). Conclusion: The noise in the 18F-flortaucipir measurement could pose challenges when studying early tau accumulation.
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In the citing paper
“18F-AV-1451 can have other non-tau, non-TDP-43, targets such as neuromelanin (Marquié et al., 2015) and mono-amine oxidase (MAO) (Vermeiren et al., 2018), and such off-target binding is an important caveat in clinical studies using 18F-AV-1451 (Baker et al., 2019).”
From Neuroinflammation and protein aggregation co-localize across the frontotemporal dementia spectrum (2020) · cites this paper as Baker et al., 2019
In the citing paper
“Neuroimaging studies using tau-specific positron emission tomography radiotracers have demonstrated accumulation of flortaucipir (AV1451) in patients with TSC, a tracer with high affinity for phosphorylated tau 181 (ptau-181) linked to AD.”
In the citing paper
“This radioligand is well established to exhibit off-target binding (9, 12, 13).”
In the citing paper
“AV1451 has a high affinity for pTau-181 related to Alzheimer’s disease by PET imaging [6]; however, AV1451 also displays significant off-target binding [1].”
From Tuberous sclerosis complex is a novel, amyloid-independent tauopathy associated with elevated phosphorylated 3R/4R tau aggregation (2022) · cites this paper as [1]
In the citing paper
“Additionally, the FTP PET ligand is not specific for tau pathology and can show elevated binding unrelated to tau in normal individuals and in patients with non–tau-related neueodegeneration.42”
From Association of Cognitive and Behavioral Features Between Adults With Tuberous Sclerosis and Frontotemporal Dementia (2020) · cites this paper as [42]
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Citations
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Early clinical PET imaging results with the novel PHF-tau radioligand [F-18]-T807
Chien, D. T., Bahri, S., Szardenings, A. K., Walsh, J. C., Mu, F., Su, M.-Y., Shankle, W. R., Elizarov, A., & Kolb, H. C. (2013) · Journal of Alzheimer's Disease · doi:10.3233/jad-122059 · Cited by 651 · cited 1×
“18F-flortaucipir (also known as T807 and 18F-AV-1451) is a PET tracer that binds with high affinity to paired helical filament tau in neurofibrillary tangles (2,3).”
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Four distinct trajectories of tau deposition identified in Alzheimer’s disease
Initiative, T. A. D. N., Vogel, J. W., Young, A. L., Oxtoby, N. P., Smith, R., Ossenkoppele, R., Strandberg, O. T., La Joie, R., Aksman, L. M., Grothe, M. J., et al. (2021) · Nature Medicine · doi:10.1038/s41591-021-01309-6 · Cited by 741
Spread of pathological tau proteins through communicating neurons in human Alzheimer’s disease
Vogel, J. W., Iturria‐Medina, Y., Strandberg, O. T., Smith, R. A., Levitis, E., Evans, A. C., Hansson, O., Initiative, A. D. N., Weiner, M. W., Aisen, P., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-15701-2 · Cited by 537
Self-citationAmyloid and tau imaging biomarkers explain cognitive decline from late middle-age
Betthauser, T. J., Koscik, R. L., Jonaitis, E. M., Allison, S. L., Cody, K. A., Erickson, C. M., Rowley, H. A., Stone, C. K., Mueller, K. D., Clark, L. R., et al. (2019) · Brain · doi:10.1093/brain/awz378 · Cited by 176
Soleimani‐Meigooni, D. N., Iaccarino, L., Joie, R. L., Baker, S. L., Bourakova, V., Boxer, A. L., Edwards, L., Eser, R. A., Gorno‐Tempini, M., Jagust, W. J., et al. (2020) · Brain · doi:10.1093/brain/awaa276 · Cited by 186
Self-citationTranslational value of choroid plexus imaging for tracking neuroinflammation in mice and humans
Fleischer, V., Gonzalez-Escamilla, G., Ciolac, D., Albrecht, P., Küry, P., Gruchot, J., Dietrich, M., Hecker, C., Müntefering, T., Bock, S., et al. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2025000118 · Cited by 152
Metadata
- Authors
- Baker, S. L., Harrison, T. M., Maass, A., La Joie, R., & Jagust, W. J.
- Affiliations
- Lawrence Berkeley National Laboratory (US)
- University of California, Berkeley (US)
- German Center for Neurodegenerative Diseases (DE)
- Venue
- Journal of Nuclear Medicine
- Publisher
- Society of Nuclear Medicine
- Published
- 2019-03-15
- Volume
- 60
- Issue
- 10
- Pages
- 1444-1451
- ISSN
- 0161-5505 (ISSN-L)
- 2159-662X
- PMC
- PMC6785795
- OpenAlex
- W2921651552
- Cited by
- 132
- References
- 38
- Citations by year
- 2026: 19 · 2025: 13 · 2024: 18 · 2023: 16 · 2022: 20 · 2021: 19 · 2020: 22 · 2019: 5
- FWCI
- 13.15
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Nuclear Medicine (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- DZNE Pub (submittedVersion)
- Funders
- Biogen
- BioClinica
- National Institutes of Health (AG034570)
- Genentech
- National Institute on Aging (F32AG057107, R01AG034570)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Medical Imaging Techniques and Applications
- Keywords
- 18F-flortaucipir, off-target binding, tau PET, partial volume correction, 11C-Pittsburgh compound B, thalamus, putamen, choroid plexus, aging, Alzheimer's disease, signal-to-noise ratio, neurofibrillary tangles
- MeSH terms
- Adult, Aged, Aged, 80 and over, Aniline Compounds, Brain, Brain Mapping, Carbolines, Female, Humans, Image Processing, Computer-Assisted, Magnetic Resonance Imaging, Male, Middle Aged, Protein Binding, Thiazoles, Reproducibility of Results, Linear Models, Positron-Emission Tomography, Young Adult, Healthy Volunteers
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