Tau positron emission tomography (PET) imaging is a recently developed non-invasive tool that can detect the density and extension of tau neurofibrillary tangles. Tau PET tracers have been validated to harmonize and accelerate their development and implementation in clinical practice. Whereas standard protocols including injected dose, uptake time, and duration have been determined for tau PET tracers, reconstruction parameters have not been standardized. The present study conducted phantom experiments based on tau pathology to standardize quantitative tau PET imaging parameters and optimize reconstruction conditions of PET scanners at four Japanese sites according to the results of phantom experiments.
The activity of 4.0 and 2.0 kBq/mL for Hoffman 3D brain and cylindrical phantoms, respectively, was estimated from published studies of brain activity using [18F]flortaucipir, [18F]THK5351, and [18F]MK6240. We developed an original tau-specific volume of interest template for the brain based on pathophysiological tau distribution in the brain defined as Braak stages. We acquired brain and cylindrical phantom images using four PET scanners. Iteration numbers were determined as contrast and recover coefficients (RCs) in gray (GM) and white (WM) matter, and the magnitude of the Gaussian filter was determined from image noise.
Contrast and RC converged at ≥ 4 iterations, the error rates of RC for GM and WM were < 15% and 1%, respectively, and noise was < 10% in Gaussian filters of 2–4 mm in images acquired using the four scanners. Optimizing the reconstruction conditions for phantom tau PET images acquired by each scanner improved contrast and image noise.
The phantom activity was comprehensive for first- and second-generation tau PET tracers. The mid-range activity that we determined could be applied to later tau PET tracers. We propose an analytical tau-specific VOI template based on tau pathophysiological changes in patients with AD to standardize tau PET imaging. Phantom images reconstructed under the optimized conditions for tau PET imaging achieved excellent image quality and quantitative accuracy.
This is a preview of subscription content,to check access.
Access this article
The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.
Payoux P, Delrieu J, Gallini A, Adel D, Salabert AS, Hitzel A, et al. Cognitive and functional patterns of nondemented subjects with equivocal visual amyloid PET findings. Eur J Nucl Med Mol Imaging. 2015;42(9):1459–68.
As A. 2020 Alzheimer’s disease facts and figures. Alzheimers Dement. 2020;16(3):391–460.
Jack CR Jr, Bennett DA, Blennow K, Carrillo MC, Dunn B, Haeberlein SB, et al. NIA-AA research framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement. 2018;14(4):535–62.
Braak H, Alafuzoff I, Arzberger T, Kretzschmar H, Del Tredici K. Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry. Acta Neuropathol. 2006;112(4):389–404.
Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991;82(4):239–59.
Cho H, Choi JY, Hwang MS, Kim YJ, Lee HM, Lee HS, et al. In vivo cortical spreading pattern of tau and amyloid in the Alzheimer disease spectrum. Ann Neurol. 2016;80(2):247–58.
Johnson KA, Schultz A, Betensky RA, Becker JA, Sepulcre J, Rentz D, et al. Tau positron emission tomographic imaging in aging and early Alzheimer disease. Ann Neurol. 2016;79(1):110–9.
Lowe VJ, Wiste HJ, Senjem ML, Weigand SD, Therneau TM, Boeve BF, et al. Widespread brain tau and its association with ageing, Braak stage and Alzheimer’s dementia. Brain. 2018;141(1):271–87.
Scholl M, Lockhart SN, Schonhaut DR, O’Neil JP, Janabi M, Ossenkoppele R, et al. PET imaging of Tau deposition in the aging human brain. Neuron. 2016;89(5):971–82.
Schwarz AJ, Yu P, Miller BB, Shcherbinin S, Dickson J, Navitsky M, et al. Regional profiles of the candidate tau PET ligand 18F-AV-1451 recapitulate key features of Braak histopathological stages. Brain. 2016;139(Pt 5):1539–50.
Villemagne VL, Dore V, Burnham SC, Masters CL, Rowe CC. Imaging tau and amyloid-beta proteinopathies in Alzheimer disease and other conditions. Nat Rev Neurol. 2018;14(4):225–36.
Declercq L, Rombouts F, Koole M, Fierens K, Marien J, Langlois X, et al. Preclinical evaluation of 18F-JNJ64349311, a novel PET tracer for tau imaging. J Nucl Med. 2017;58(6):975–81.
Harada R, Okamura N, Furumoto S, Furukawa K, Ishiki A, Tomita N, et al. 18F-THK5351: A novel PET radiotracer for imaging neurofibrillary pathology in Alzheimer disease. J Nucl Med. 2016;57(2):208–14.
Lu J, Bao W, Li M, Li L, Zhang Z, Alberts I, et al. Associations of [18F]-APN-1607 tau PET binding in the brain of Alzheimer’s disease patients with cognition and glucose metabolism. Front Neurosci. 2020;14:604.
Mueller A, Bullich S, Barret O, Madonia J, Berndt M, Papin C, et al. Tau PET imaging with 18F-PI-2620 in patients with Alzheimer disease and healthy controls: a first-in-humans study. J Nucl Med. 2020;61(6):911–9.
Sanabria Bohorquez S, Marik J, Ogasawara A, Tinianow JN, Gill HS, Barret O, et al. [18F]GTP1 (Genentech Tau Probe 1), a radioligand for detecting neurofibrillary tangle tau pathology in Alzheimer’s disease. Eur J Nucl Med Mol Imaging. 2019;46(10):2077–89.
Shcherbinin S, Schwarz AJ, Joshi A, Navitsky M, Flitter M, Shankle WR, et al. Kinetics of the tau PET tracer 18F-AV-1451 (T807) in subjects with normal cognitive function, mild cognitive impairment, and Alzheimer disease. J Nucl Med. 2016;57(10):1535–42.
Wong DF, Comley R, Kuwabara H, Rosenberg PB, Resnick SM, Ostrowitzki S, et al. First in-human PET study of 3 novel tau radiopharmaceuticals: [11C]RO6924963, [11C]RO6931643, and [18F]RO6958948. J Nucl Med. 2018. https://doi.org/10.2967/jnumed.118.209916.
Wood H. Alzheimer disease: [11C]PBB3–a new PET ligand that identifies tau pathology in the brains of patients with AD. Nat Rev Neurol. 2013;9(11):599.
Leuzy A, Chiotis K, Lemoine L, Gillberg PG, Almkvist O, Rodriguez-Vieitez E, et al. Tau PET imaging in neurodegenerative tauopathies-still a challenge. Mol Psychiatry. 2019;24(8):1112–34.
Lowe VJ, Curran G, Fang P, Liesinger AM, Josephs KA, Parisi JE, et al. An autoradiographic evaluation of AV-1451 Tau PET in dementia. Acta Neuropathol Commun. 2016;4(1):58.
Marquie M, Normandin MD, Vanderburg CR, Costantino IM, Bien EA, Rycyna LG, et al. Validating novel tau positron emission tomography tracer [F-18]-AV-1451 (T807) on postmortem brain tissue. Ann Neurol. 2015;78(5):787–800.
Ng KP, Pascoal TA, Mathotaarachchi S, Therriault J, Kang MS, Shin M, et al. Monoamine oxidase B inhibitor, selegiline, reduces 18F-THK5351 uptake in the human brain. Alzheimers Res Ther. 2017;9(1):25.
Kimura Y, Endo H, Ichise M, Shimada H, Seki C, Ikoma Y, et al. A new method to quantify tau pathologies with 11C-PBB3 PET using reference tissue voxels extracted from brain cortical gray matter. EJNMMI Res. 2016;6(1):24.
Young PNE, Estarellas M, Coomans E, Srikrishna M, Beaumont H, Maass A, et al. Imaging biomarkers in neurodegeneration: current and future practices. Alzheimers Res Ther. 2020;12(1):49.
Ikari Y, Akamatsu G, Nishio T, Ishii K, Ito K, Iwatsubo T, et al. Phantom criteria for qualification of brain FDG and amyloid PET across different cameras. EJNMMI Phys. 2016;3(1):23.
Akamatsu G, Ikari Y, Nishio T, Nishida H, Ohnishi A, Aita K, et al. Optimization of image reconstruction conditions with phantoms for brain FDG and amyloid PET imaging. Ann Nucl Med. 2016;30(1):18–28.
Wagatsuma K, Miwa K, Kamitaka Y, Koike E, Yamao T, Yoshii T, et al. Determination of optimal regularization factor in Bayesian penalized likelihood reconstruction of brain PET images using [18F]FDG and [11C]PiB. Med Phys. 2022;49(5):2995–3005.
Mattay VS, Fotenos AF, Ganley CJ, Marzella L. Brain tau imaging: food and drug administration approval of 18F-Flortaucipir injection. J Nucl Med. 2020;61(10):1411–2.
Tian M, Civelek AC, Carrio I, Watanabe Y, Kang KW, Murakami K, et al. International consensus on the use of tau PET imaging agent 18F-flortaucipir in Alzheimer’s disease. Eur J Nucl Med Mol Imaging. 2022;49(3):895–904.
Weber CJ, Carrillo MC, Jagust W, Jack CR Jr, Shaw LM, Trojanowski JQ, et al. The worldwide Alzheimer’s disease neuroimaging initiative: ADNI-3 updates and global perspectives. Alzheimers Dement (N Y). 2021;7(1): e12226.
Bischof GN, Dodich A, Boccardi M, van Eimeren T, Festari C, Barthel H, et al. Clinical validity of second-generation tau PET tracers as biomarkers for Alzheimer’s disease in the context of a structured 5-phase development framework. Eur J Nucl Med Mol Imaging. 2021;48(7):2110–20.
Chiotis K, Dodich A, Boccardi M, Festari C, Drzezga A, Hansson O, et al. Clinical validity of increased cortical binding of tau ligands of the THK family and PBB3 on PET as biomarkers for Alzheimer’s disease in the context of a structured 5-phase development framework. Eur J Nucl Med Mol Imaging. 2021;48(7):2086–96.
Wolters EE, Dodich A, Boccardi M, Corre J, Drzezga A, Hansson O, et al. Clinical validity of increased cortical uptake of [18F]flortaucipir on PET as a biomarker for Alzheimer’s disease in the context of a structured 5-phase biomarker development framework. Eur J Nucl Med Mol Imaging. 2021;48(7):2097–109.
Hsiao IT, Lin KJ, Huang KL, Huang CC, Chen HS, Wey SP, et al. Biodistribution and Radiation dosimetry for the tau tracer 18F-THK-5351 in healthy human subjects. J Nucl Med. 2017;58(9):1498–503.
Koole M, Lohith TG, Valentine JL, Bennacef I, Declercq R, Reynders T, et al. Preclinical safety evaluation and human dosimetry of [18F]MK-6240, a novel PET tracer for imaging neurofibrillary tangles. Mol Imaging Biol. 2020;22(1):173–80.
Golla SSV, Timmers T, Ossenkoppele R, Groot C, Verfaillie S, Scheltens P, et al. Quantification of tau load using [18F]AV1451 PET. Mol Imaging Biol. 2017;19(6):963–71.
Chen J, Li Y, Pirraglia E, Okamura N, Rusinek H, de Leon MJ, et al. Quantitative evaluation of tau PET tracers 18F-THK5351 and 18F-AV-1451 in Alzheimer’s disease with standardized uptake value peak-alignment (SUVP) normalization. Eur J Nucl Med Mol Imaging. 2018;45(9):1596–604.
He M, Baker SL, Shah VD, Lockhart SN, Jagust WJ. Scan-time corrections for 80–100-min standardizetd uptake volume ratios to measure the 18F-AV-1451 tracer for tau imaging. IEEE Trans Med Imaging. 2019;38(3):697–709.
Lockhart SN, Baker SL, Okamura N, Furukawa K, Ishiki A, Furumoto S, et al. Dynamic PET measures of tau accumulation in cognitively normal older adults and Alzheimer’s disease patients measured using [18F] THK-5351. PLoS ONE. 2016;11(6): e0158460.
Lohith TG, Bennacef I, Vandenberghe R, Vandenbulcke M, Salinas CA, Declercq R, et al. Brain imaging of Alzheimer dementia patients and elderly controls with 18F-MK-6240, a PET tracer targeting neurofibrillary tangles. J Nucl Med. 2019;60(1):107–14.
Ossenkoppele R, Rabinovici GD, Smith R, Cho H, Scholl M, Strandberg O, et al. Discriminative accuracy of [18F]flortaucipir positron emission tomography for Alzheimer disease vs other neurodegenerative disorders. JAMA. 2018;320(11):1151–62.
Ossenkoppele R, Smith R, Mattsson-Carlgren N, Groot C, Leuzy A, Strandberg O, et al. Accuracy of tau positron emission tomography as a prognostic marker in preclinical and prodromal Alzheimer disease: a head-to-head comparison against amyloid positron emission tomography and magnetic resonance imaging. JAMA Neurol. 2021;78(8):961–71.
Pascoal TA, Shin M, Kang MS, Chamoun M, Chartrand D, Mathotaarachchi S, et al. In vivo quantification of neurofibrillary tangles with [18F]MK-6240. Alzheimers Res Ther. 2018;10(1):74.
Pascoal TA, Therriault J, Benedet AL, Savard M, Lussier FZ, Chamoun M, et al. 18F-MK-6240 PET for early and late detection of neurofibrillary tangles. Brain. 2020;143(9):2818–30.
Brambilla M, Secco C, Dominietto M, Matheoud R, Sacchetti G, Inglese E. Performance characteristics obtained for a new 3-dimensional lutetium oxyorthosilicate-based whole-body PET/CT scanner with the national electrical manufacturers association NU 2–2001 standard. J Nucl Med. 2005;46(12):2083–91.
Rausch I, Cal-Gonzalez J, Dapra D, Gallowitsch HJ, Lind P, Beyer T, et al. Performance evaluation of the biograph mCT Flow PET/CT system according to the NEMA NU2-2012 standard. EJNMMI Phys. 2015;2(1):26.
van Sluis J, de Jong J, Schaar J, Noordzij W, van Snick P, Dierckx R, et al. Performance characteristics of the digital biograph vision PET/CT system. J Nucl Med. 2019;60(7):1031–6.
Wagatsuma K, Miwa K, Sakata M, Oda K, Ono H, Kameyama M, et al. Comparison between new-generation SiPM-based and conventional PMT-based TOF-PET/CT. Phys Med. 2017;42:203–10.
Fleisher AS, Pontecorvo MJ, Devous MD Sr, Lu M, Arora AK, Truocchio SP, et al. Positron emission tomography imaging with [18F]flortaucipir and postmortem assessment of Alzheimer disease neuropathologic changes. JAMA Neurol. 2020;77(7):829–39.
Lowe VJ, Lundt ES, Albertson SM, Min HK, Fang P, Przybelski SA, et al. Tau-positron emission tomography correlates with neuropathology findings. Alzheimers Dement. 2020;16(3):561–71.
Leuzy A, Smith R, Cullen NC, Strandberg O, Vogel JW, Binette AP, et al. Biomarker-based prediction of longitudinal tau positron emission tomography in alzheimer disease. JAMA Neurol. 2022;79(2):149–58.
Pascoal TA, Benedet AL, Tudorascu DL, Therriault J, Mathotaarachchi S, Savard M, et al. Longitudinal 18F-MK-6240 tau tangles accumulation follows Braak stages. Brain. 2021;144(11):3517–28.
Leuzy A, Pascoal TA, Strandberg O, Insel P, Smith R, Mattsson-Carlgren N, et al. A multicenter comparison of [18F]flortaucipir, [18F]RO948, and [18F]MK6240 tau PET tracers to detect a common target ROI for differential diagnosis. Eur J Nucl Med Mol Imaging. 2021;48(7):2295–305.
Teng E, Manser PT, Sanabria Bohorquez S, Wildsmith KR, Pickthorn K, Baker SL, et al. Baseline [18F]GTP1 tau PET imaging is associated with subsequent cognitive decline in Alzheimer’s disease. Alzheimers Res Ther. 2021;13(1):196.
Jack CR Jr, Wiste HJ, Weigand SD, Therneau TM, Lowe VJ, Knopman DS, et al. Defining imaging biomarker cut points for brain aging and Alzheimer’s disease. Alzheimers Dement. 2017;13(3):205–16.
Bun S, Moriguchi S, Tezuka T, Sato Y, Takahata K, Seki M, et al. Findings of 18F-PI-2620 tau PET imaging in patients with Alzheimer’s disease and healthy controls in relation to the plasma P-tau181 levels in a Japanese sample. Neuropsychopharmacol Rep. 2022;42(4):437–48.
Ossenkoppele R, Leuzy A, Cho H, Sudre CH, Strandberg O, Smith R, et al. The impact of demographic, clinical, genetic, and imaging variables on tau PET status. Eur J Nucl Med Mol Imaging. 2021;48(7):2245–58.
Dore V, Bohorquez SS, Leuzy A, Shimada H, Bullich S, Bourgeat P, et al. Towards a universal cortical tau sampling mask. Alzheimer’s Dement. 2021. https://doi.org/10.1002/alz.055816.
Dore V, Bullich S, Bohorquez SS, Leuzy A, Shimada H, Rowe C, et al. CenTauRz: A standardized quantification of tau PET scans. Alzheimer’s Dement. 2022. https://doi.org/10.1002/alz.061177.
Verwer EE, Golla SSV, Kaalep A, Lubberink M, van Velden FHP, Bettinardi V, et al. Harmonisation of PET/CT contrast recovery performance for brain studies. Eur J Nucl Med Mol Imaging. 2021;48(9):2856–70.
Hoffman EJCP, Guerrero TM, et al. Assessment of accuracy of PET utilizing a 3-D phantom to simulate the activity distribution of [18F]fluorodeoxyglucose uptake in the human brain. J Cereb Blood Flow Metab. 1991;11:A17-25.
This study was supported in part by JSPS KAKENHI Grant Number (KW, JP20K16747), the Japanese Government, and an Academic Research Grant from the Japanese Society of Radiological Technology.
Conflict of interest
The authors have no potential conflicts of interest to declare.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Below is the link to the electronic supplementary material.
About this article
Cite this article
Wagatsuma, K., Miwa, K., Akamatsu, G. et al. Toward standardization of tau PET imaging corresponding to various tau PET tracers: a multicenter phantom study. Ann Nucl Med 37, 494–503 (2023). https://doi.org/10.1007/s12149-023-01847-8