European Journal of Nuclear Medicine and Molecular Imaging (2022) 49:895–904 https://doi.org/10.1007/s00259-021-05673-w GUIDELINES International consensus on the use of tau PET imaging agent 18 F‑flortaucipir in Alzheimer’s disease Mei Tian1,2,3 · A. Cahid Civelek4 · Ignasi Carrio5 · Yasuyoshi Watanabe6 · Keon Wook Kang7 · Koji Murakami8 · Valentina Garibotto9 · John O. Prior10 · Henryk Barthel11 · Rui Zhou2 · Haifeng Hou2 · Xiaofeng Dou2 · Chentao Jin2 · Chuantao Zuo1,12 · Hong Zhang2,13,14,15 · Molecular Imaging-based Precision Medicine Task Group of A3 (China-Japan-Korea) Foresight Program Received: 26 November 2021 / Accepted: 24 December 2021 / Published online: 3 January 2022 © The Author(s) 2022 Abstract Purpose Positron emission tomography (PET) with the first and only tau targeting radiotracer of 18F-flortaucipir approved by FDA has been increasingly used in depicting tau pathology deposition and distribution in patients with cognitive impair- ment. The goal of this international consensus is to help nuclear medicine practitioners procedurally perform 18F-flortaucipir PET imaging. Method A multidisciplinary task group formed by experts from various countries discussed and approved the consensus for 18 F-flortaucipir PET imaging in Alzheimer’s disease (AD), focusing on clinical scenarios, patient preparation, and admin- istered activities, as well as image acquisition, processing, interpretation, and reporting. Conclusion This international consensus and practice guideline will help to promote the standardized use of 18F-flortaucipir PET in patients with AD. It will become an international standard for this purpose in clinical practice. 18 Keywords F-flortaucipir · Alzheimer’s disease (AD) · Positron emission tomography (PET) · Brain imaging This article is part of the Topical Collection on Neurology 7 * Mei Tian Department of Nuclear Medicine, Seoul National University tianmei@fudan.edu.cn College of Medicine, Seoul 03080, South Korea 8 * A. Cahid Civelek Department of Radiology, Juntendo University Hospital, acivele1@jhmi.edu Tokyo 113‑8431, Japan 9 * Hong Zhang Diagnostic Department, University Hospitals of Geneva hzhang21@zju.edu.cn and NIMTlab, University of Geneva, Geneva, Switzerland 10 1 Department of Nuclear Medicine and Molecular Imaging, PET Center, Huashan Hospital, Fudan University, Lausanne University Hospital, Lausanne, Switzerland Shanghai 200235, China 11 2 Department of Nuclear Medicine, Leipzig University Department of Nuclear Medicine and PET Center, The Medical Center, Leipzig, Germany Second Affiliated Hospital of Zhejiang University School 12 of Medicine, 88 Jiefang Road, Hangzhou 310009, Zhejiang, National Center for Neurological Disorders & National China Clinical Research Center for Aging and Medicine, Huashan 3 Hospital, Fudan University, Shanghai 200040, China Human Phenome Institute, Fudan University, 13 Shanghai 201203, China Key Laboratory of Medical Molecular Imaging of Zhejiang 4 Province, Hangzhou 310009, China Department of Radiology and Radiological Science, Johns 14 Hopkins Medicine, Baltimore, MD 21287, USA The College of Biomedical Engineering and Instrument 5 Science of Zhejiang University, Hangzhou 310007, China Department of Nuclear Medicine, Hospital Sant Pau, 15 Autonomous University of Barcelona, 08025 Barcelona, Key Laboratory for Biomedical Engineering of Ministry Spain of Education, Zhejiang University, Hangzhou 310007, China 6 Laboratory for Pathophysiological and Health Science, RIKEN Center for Biosystems Dynamics Research, Kobe, Hyogo 650‑0047, Japan 13 Vol.:(0123456789) 896 European Journal of Nuclear Medicine and Molecular Imaging (2022) 49:895–904 Introduction evaluation than structural imaging methods [15]. In recent years, with the development of PET technology and the The prevalence of dementia worldwide has been estimated advent of new tracers, the pathophysiological changes of at 24 million and is expected to double every 20 years many major neurodegenerative diseases, including AD, or more until 2040 [1]. Alzheimer’s disease (AD) is the have been explored with the help of PET molecular imag- most common cause of dementia, accounting for 60–80% ing [16]. There are several tracers for PET that have been of dementia cases [2–4], and affects approximately 6% of developed and used for clinical assessment in patients the population over the age of 65 [5]. According to the with various tauopathies as “first-generation” tracers, such National Institute on Aging and Alzheimer’s Association as 18F-THK5317 [17], 18F-THK5351 [18], 18F-AV-1451 (NIA-AA), AD has been defined for research purposes by [19], and 11C-PBB3 [20]. Limitations of these tracers with its underlying pathological processes that may be docu- regard to off-target binding and diagnostic range provided mented by postmortem or in vivo biomarker examination, the motivation to develop a new generation of tau tracers, shifting the definition of AD in living people from a syn- including 18F-MK-6240, 18F-PI-2620, 18F-RO-948, 18F- dromal to a biological construct [6]. The NIA-AA adopted JNJ311/069, 18F-GTP1, and 18F-PM-PBB3 [21–24]. the proposition of “A/T/N system” in which three catego- In principle, tau PET imaging enables noninvasive detec- ries of AD biomarker (imaging and biofluids) are summa- tion of in vivo tau deposition patterns, facilitates differen- rized based on the nature of the pathologies mechanisms: tial diagnosis between neurodegenerative diseases includ- A (biomarkers of β-amyloid, Aβ)/T (biomarkers of fibril- ing different tauopathies, and predicts disease progression. lar tau)/N (biomarkers of neurodegeneration or neuronal Furthermore, tau PET imaging could potentially be applied injury) [7]. The NIA-AA agreed that only biomarkers that to achieve the therapeutic effect evaluation of anti-tau treat- are specific to characteristic AD proteinopathy (i.e., Aβ ment and develop a novel drug, thereby allowing preventive and tau) should be considered potential biomarker defini- interventions. In May 2020, US Food and Drug Adminis- tions of the disease. tration (FDA) approved the first tau PET tracer 18F-flor- The biomarkers of Aβ are the first found to become taucipir, representing a great achievement to improve AD abnormal in AD [8]. According to the Aβ cascade hypoth- diagnosis. esis, abnormal production and accumulation of Aβ in the The current consensus summarizes the use of 18F-flor- brain are the primary influences driving AD pathogen- taucipir PET in the clinical setting, including the clinical esis [9]. The in vivo measurement of cerebral amyloidosis indications, qualifications and responsibilities of personnel, as obtained using 11C-PiB [10] or one of the approved imaging procedure/specifications, documentation/reporting 18 F-labelled amyloid tracers and positron emission tomog- of the result, imaging equipment specifications, quality con- raphy (PET) is associated with cross-sectional regionally trol and improvement, imaging safety and infection control, specific brain atrophy and longitudinal cognitive decline. and the patient education concerns and the radiation safety PET imaging of amyloid as target has also been exten- in imaging. sively used in clinical trials testing anti-amyloid drugs [11]. The research advances in AD pathogenesis and the repeated failures of clinical trials for the anti-amyloid Goals drugs further motivated a focus shift to investigate the role of tau pathology in the AD pathogenesis, also as tar- The goal of this consensus is to provide a reference for get for novel drug developments [12]. Human and animal nuclear medicine practitioners in procedurally preparing model data suggest a causal upstream role for Aβ in the and performing 18F-flortaucipir PET imaging and properly pathogenesis of AD, but Aβ alone is insufficient to cause interpreting and reporting the results of 18F-flortaucipir PET cognitive deterioration directly [13]. Postmortem studies images (Fig. 1). also found that tau, but not Aβ, correlates to the severity of dementia and neurodegeneration, suggesting a more direct impact of tau aggregation on neurodegeneration than Aβ Definitions [14]. However, the role of tau in the pathophysiology of AD and other tauopathies remains unclear. Consequently, Tau the precise targeting of tau deposition in vivo in the brain would be very valuable. Tau protein is a multifunctional protein mainly locating in The key tools of “transpathology,” for example, the axons of central nervous system, playing a crucial role in use of PET, can noninvasively detect the molecular mark- stabilizing microtubules [25]. There are six tau isoforms ers in vivo and allow for an earlier disease diagnosis and existing in human brain, classified as either 3 (3R) or 4 13 European Journal of Nuclear Medicine and Molecular Imaging (2022) 49:895–904 897 Fig. 1  Flowchart for the recommended procedures in conducting 18F-flortaucipir PET scanning and reporting (4R) repeated binding domains, generated by alternative abilities, which is the main cause of dementia. The causes mRNA splicing of the microtubule-associated protein tau of AD are still unclear, while Aβ deposition and abun- gene (MAPT) [26]. Several neurodegenerative diseases are dant tau phosphorylation are the main hallmarks of AD characterized by tau aggregates; however, the tau aggre- pathology. gates vary in those disease either for morphology (e.g., neurofibrillary tangles for AD vs. astrocytic plaques, Pick Mild cognitive impairment (MCI) bodies, or globose tangles in other neurodegenerative tauopathies) or ultrastructural conformations (e.g., paired MCI is defined as a potential intermediate state between helical filaments in AD vs. mainly straight or twisted fila- normal aging and dementia, with a reduction of cognitive ments in other neurodegenerative tauopathies) [27]. performances but with preserved autonomy [28]. MCI was first proposed as stage III (mild cognitive aging) of global deterioration scale (GDS) for primary degenerative dementia AD in 1982 by Barry et al. [29]. Individuals at GDS stage III have slight cognitive deficits and may have some impairment AD is an age-dependent neurodegenerative disease that in complex executive function. About 3–19% of individuals is characterized as a slow start and progressive decline in will develop MCI in natural aging, and the risk of progress- memory, problem-solving, language, and other cognitive ing to dementia is 11–33% in 2 years [30]. 13 898 European Journal of Nuclear Medicine and Molecular Imaging (2022) 49:895–904 Neurodegenerative tauopathies Qualifications and responsibilities of personnel Neurodegenerative tauopathies are a group of dementia and movement disorders that are characterized as abun- Physician dant accumulations of filaments assembled by microtu- bule-associated protein tau (MAPT), which includes AD, Neurology experts should prescribe the tau PET examination frontotemporal lobar degeneration (FTLD), corticobasal only when appropriately indicated. An adequately trained syndrome (CBS), and progressive supranuclear palsy nuclear medicine physician is responsible for the report and (PSP). Though the symptoms of these diseases are dif- supervision of the quality of tau PET imaging. With the ferent, brain abnormalities and cognitive impairment are authorization of local, state, and national regulations, this associated with the growing accumulation of filaments procedure could also be performed and supervised by a cer- or tangles. tified neurologist with required additional radiation safety and nuclear medicine training. Tau imaging Technologist Tau PET imaging could allow obtaining tau pathology information non-invasively in vivo. As such, it should Tau PET imaging procedure should be performed in a cer- be capable of providing the “T” biomarker information tified imaging facility and operated by a qualified nuclear to support establishing a biological diagnosis of AD and medicine technologist who has appropriate training and other tauopathies, potentially already at earlier disease certification. The operation should be performed under the stages, like in MCI. Notably, 18F-flortaucipir presents supervision of a physician as mentioned, in compliance with higher affinity to “AD-like” tau aggregates than that in existing standard operating policies and procedures at the other neurodegenerative tauopathies, while it should be imaging facility. Please also see references [33, 34] for gen- noticed that the sensitivity of 18F-flortaucipir might not eral requirements of nuclear medicine technologists. be enough to diagnose early stage of AD, such as Braak stage 0. Medical physicist/technologist A qualified medical physicist expert should ensure the safe Clinical indications use of radiotracers, monitor radiation dose, and develop image acquisition and reconstruction algorithms, as well as To our knowledge, there is no consensus or recommen- to better protect the patient and staff alike. Further details dation on indications/contraindications for the clinical can be found in the American College of Radiology, ACR- application of tau PET imaging. Despite tau PET remains AAPM technical standard for medical physics performance as a powerful research tool in tauopathies, we suggest to monitoring of PET/CT imaging equipment, and the Euro- consider the use of 18F-flortaucipir PET imaging in the pean guidelines on medical physics expert could provide following clinical scenarios: the cause of cognitive impair- more details [35, 36]. ment remains uncertain after a comprehensive clinical evaluation by an expert; the disease history and routine examination cannot confirm the definitive diagnosis of Procedure/specifications of the examination AD (as it would be possible, e.g., in familial AD); there is a need to differentiate AD from other neurodegenerative Patient preparation tauopathies; there is a need to determine the severity of tau deposition in AD. Pre‑arrival The 18F-flortaucipir PET is not recommended to be clinically used to evaluate tauopathies other than AD Before the start of the procedure, medical history and per- (e.g., in other neurodegenerative tauopathies) [31], and tinent information on the patient should be obtained. It is the sensitivity of 18F-flortaucipir PET is limited in detect- recommended to carefully explain the purpose of the exami- ing early-stage tau pathology [32]. Additionally, it should nation and the details of the procedure to the patients, which be careful to conduct longitudinal assessment by using would reduce their anxiety and results in a better cooperation 18 F-flortaucipir PET, as more evidence is required to sup- during the procedure. Patients do not need to fast as food port the value of 18F-flortaucipir PET imaging in longi- intake does not interfere with 18F-flortaucipir PET imaging. tudinal assessment. There is no evidence that antidementia drug has an effect on 13 European Journal of Nuclear Medicine and Molecular Imaging (2022) 49:895–904 899 18 F-flortaucipir. Therefore, it is not recommended to with- Image acquisition protocol draw the drug before 18F-flortaucipir PET imaging. When applicable, patients are recommended to arrive at the hos- Positioning pital with an accompanying person. A supine position with suitable head support is preferred to Pre‑injection reduce the potential head movement. Extreme neck exten- sion or flexion should be avoided. The entire brain, espe- All the possible risks should be discussed with the patients, cially the entire cerebellum, should be included in the view. and signature of an informed consent should be performed when applicable. Patients with severe cognitive impairment Static emission scan should be accompanied by a caregiver. Patients need to empty their urinary bladder before scanning to maximally The 20-min brain PET scan is performed after 80–100 min reduce the radiation. of 18F-flortaucipir injection. As this tracer does not ready in apparent steady state, the adherence of this image acquisi- tion time window is of critical importance for inter- and Precautions intra-individual comparison of the PET imaging results. The brain PET images (4 frames: 4 × 5 min) are acquired General precautions should be conducted to avoid injection- in three-dimensional (3D) mode with appropriate data cor- related infection, radiotracer infiltration, and radiotracer rections after the tracer injection. The acquisition protocol spillage. The baseline activity of the 18F-flortaucipir should may vary in different institutions based on their imaging be determined by using an appropriately calibrated dose cali- protocols and on types of equipment and radiotracer used. brator before the administration of the radioactive ‘dose’. Dynamic acquisitions with subsequent reconstructions with Specific precautions should be considered for 18F-flor- different time frames can be considered when appropriate. taucipir PET imaging. It is reported that the administration of 18F-flortaucipir might occasionally lead to adverse events, Image reconstruction such as headache, injection site pain, and gastrointestinal disorders [37]. Therefore, the patients and family members PET images are reconstructed at least in a 256 × 256 image or caregivers should be instructed to inform the physician matrix size with attenuation correction. The typical pixel when such symptoms occurred. size is 2–4 mm with a slice thickness of 2–4 mm. The acquired images are recommended to be reconstructed by using 3D ordered subset expectation maximization (OSEM). Sedation Interpretation of the tau brain PET images Sedation may be exceptionally required for patients who cannot cooperate with the examination. The method might Image quality needs to be evaluated before interpreting the be adjusted for individual patients and modified by the phy- study to ensure the quality of 18F-flortaucipir PET images, sician. Sedation should be conducted just before the 18F-flo- such as the presence of the patient’s head motion. Any noted rtaucipir PET examination so that all the procedures will limitations that might compromise the image interpretation proceed without delay. should be indicated in the report. Visual interpretation of 18F‑flortaucipir PET brain images Radiopharmaceuticals and administered activities PET images are displayed in axial, coronal, and sagittal Among the tau targeting radiotracers investigated, 18F-flo- views and 3D-MIP images. Color scales are often used rtaucipir is the first and only PET tracer approved by FDA and might be selected according to availability and the for clinical practice; we provide additional details of 18F-flo- reader’s preference. It is recommended to adjust the color rtaucipir PET imaging here. The production processes of bar until the display of bilateral striatum with appropriate 18 F-flortaucipir should comply with national and local regu- background. The intensity scales, contrast, and background lations. The manufacturer performs the radiopharmaceuti- subtraction should be adjusted in order to obtain a prede- cal quality control before its release to the imaging cent- fined ratio with the cerebellar cortex used as reference [38]. ers. Baseline activity of 370 MBq 18F-flortaucipir in a total The coregistration of 18F-flortaucipir PET with anatomical volume of 1–2 mL is recommended to inject as a single images such as computer tomography (CT) or magnetic res- intravenous slow bolus. onance imaging (MRI) is recommended for the definition 13 900 European Journal of Nuclear Medicine and Molecular Imaging (2022) 49:895–904 and the localization of 18F-flortaucipir in comparison with regions in case of suspected AD or of other brain regions visual assessment of PET images only. depending on the suspected tauopathy allow to obtain target It is recommend to evaluate tau PET images from the bot- region standardized uptake values (SUVs), which will result tom to the top in the perspective of transaxial plane. Cerebel- in SUV ratios (SUVRs) when compared with the reference lar cortex could be used as negative control, since cerebel- region SUVs. lum is generally free of tau protein deposition. It is worth noting that 18F-flortaucipir retention could be observed in Voxel‑wise analysis The voxel-wise analysis allows com- superior portion of the cerebellar gray matter [39]. There- parison of the difference between one subject and groups, fore, we recommend to use inferior cerebellar gray matter as or two groups directly in the whole brain after spatial and negative control. Tau brain imaging using 18F-flortaucipir in count rate normalization. The voxel-based analysis could cognitively normal (CN) young individuals shows few focal detect subtle tiny abnormalities without the inherent restric- radiotracer retention. In elderly individuals with normal cog- tion of predefined ROIs. nition, it shows no focal cortical retention but an age-related increased radiotracer retention in midbrain, caudate, puta- men, pallidum, and thalamus as well as off-target binding Documentation/reporting in brainstem, striatum, and retina. Patients with AD have significant tau radiotracer retention in the advanced Braak General information stage brain regions, like the inferior lateral temporal, poste- rior cingulate, and lateral parietal regions (Fig. 2). The report should include the patient demographics, identi- fiers, and all pertinent basic study information such as the Quantitative analysis name, age, gender, examination date, clinical diagnosis, net intravenously injected radioactivity of the administered radi- SUVRs (standardized uptake value ratios) SUVRs are widely otracer, and the i.v. injection site. The pertinent information used in clinical practice. Since the cerebellum region has associated with cognitive/motor impairment-related clinical less specific binding to tau protein, it can be used as the ref- symptoms should be included, ideally including respective erence region. Volumes of interest (VOIs) of the Braak stage cognition/motor symptom scores. Results of structural brain Fig. 2  Representative 18F-flortaucipir PET images from a healthy elderly individual and patient with AD. The patient with AD showed marked radiotracer retention in bilateral temporal, temporoparietal, and posterior cingulate cortical regions 13 European Journal of Nuclear Medicine and Molecular Imaging (2022) 49:895–904 901 imaging, CSF biomarker testing in case of suspected AD, PET imaging indicate patients who are possibly developed and of other potential nuclear brain imaging exams should with AD. Positive results of 18F-flortaucipir PET imaging also be provided. The reason for the test, such as the pres- combined with positive amyloid PET imaging indicate the ence of uncertain clinical diagnoses, and whether there is a existence of AD in the patients. Also, a positive 18F-flor- need to differentiate with non-AD tau pathologies, or pres- taucipir PET result does not exclude other coexistent neuro- ence of AD comorbidities, should be briefly described. Per- degenerative disorders. On the contrary, negative results of tinent past medical history that might alter the anatomy of amyloid PET imaging indicate patients who are unlikely to the brain, such as brain surgery, head trauma, and stroke, have AD and negative 18F-flortaucipir PET results among should also be briefly described. MCI patients may indicate that they are unlikely to advance to AD dementia [41, 42]. Body of the report Procedures and materials Equipment specifications The type and the net administrated dose and the site of Tau PET examinations can be performed on different PET injected radiotracer should be documented and double- systems from various manufacturers. Adequate knowledge checked by the technologist and nurse. Any unwanted events of the technique and equipment used would help improv- that occurred during radiotracer injection, such as infiltration ing image quality and reducing imaging artifacts. To ensure should be recorded. optimal imaging performance, all scanners should undergo standard periodic quality control tests according to the man- Findings ufacturer’s specifications. More detailed recommendations can be found on the Society of Nuclear Medicine Procedure Abnormalities should be described including the areas Guideline for FDG PET Brain Imaging (Version 1.0), and in which pathological cerebral and cerebellar uptake is EANM procedure guidelines for PET brain imaging using 18 observed. Performed quantitative or semi-quantitative F-FDG (version 2.0) [43, 44]. assessments should be stated. Comparative data Quality control and improvement Comparisons with previous 18F-flortaucipir PET examina- tions and interpretations should be incorporated into the cur- Standard quality controls (QC) for each system have to be rent study report. The findings of pertinent related recent maintained according to manufacturer recommendations and imaging such as the brain MR, CT, 18F-FDG PET, amyloid national regulations. Preferably a qualified medical physicist PET, and neuropsychiatric examination findings should supervises the establishment of the QC program, and an on- also be considered when interpreting 18F-flortaucipir PET site technologist should be identified to conduct the defined images. routine QC procedures. See also Society of Nuclear Medi- cine Procedure Guideline for FDG PET Brain Imaging (Ver- Interpretation and conclusions sion 1.0), and EANM procedure guidelines for PET brain imaging using 18F-FDG (version 2.0) for details of PET The impression should state clearly whether the scan dem- QC [43, 44], and the ACR–ASNR–SPR practice parameter onstrates positive or negative tau deposition. If the scan for the performance of computed tomography (CT) of the is inconclusive, this needs to be stated along with possi- extracranial head and neck for details of CT QC [45]. ble reasons, such as low counting rate, head motion during imaging, unexpected focal lesion, cortical atrophy, or other difficulties. Notably, off-target binding of 18F-flortaucipir in the cho- Safety, infection control, and patient roid plexus, brainstem, basal ganglia, and meninges has education concerns been reported [40]. Although 18F-flortaucipir PET imaging depicts tau deposition in the brain, it is crucial to note that Policies and procedures on safety, infection control, and a scan positive for tau deposition should be interpreted in patient education should be developed and implemented association with amyloid PET imaging and clinical informa- according to regional and national regulations. For tau tion, at present, to diagnose AD. Negative results of 18F-flo- PET imaging, special attention should be paid to the safety rtaucipir PET imaging accompanied with positive amyloid issues of patients with dementia or other neurodegenerative 13 902 European Journal of Nuclear Medicine and Molecular Imaging (2022) 49:895–904 diseases, in whom falls may frequently occur. Obstacles in Open Access This article is licensed under a Creative Commons Attri- the imaging department should be minimized, and patients bution 4.0 International License, which permits use, sharing, adapta- tion, distribution and reproduction in any medium or format, as long should be carefully aided when walking in and out of the as you give appropriate credit to the original author(s) and the source, room. If patients would be restrained on the bed or in a provide a link to the Creative Commons licence, and indicate if changes head holder during the examination, frequent explanation were made. The images or other third party material in this article are and reassurance would help reduce the stress and anxiety. included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in The presence of an accompanying familiar person can be the article's Creative Commons licence and your intended use is not helpful during the uptake phase and the installation of the permitted by statutory regulation or exceeds the permitted use, you will patient in the scanner room provided general radioprotection need to obtain permission directly from the copyright holder. To view a of this person can be insured. 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