Introduction
The prevalence of dementia worldwide has been estimated at 24 million and is expected to double every 20 years or more until 2040 [
1]. Alzheimer’s disease (AD) is the most common cause of dementia, accounting for 60–80% of dementia cases [
2‐
4], and affects approximately 6% of the population over the age of 65 [
5]. According to the National Institute on Aging and Alzheimer’s Association (NIA-AA), AD has been defined for research purposes by its underlying pathological processes that may be documented by postmortem or in vivo biomarker examination, shifting the definition of AD in living people from a syndromal to a biological construct [
6]. The NIA-AA adopted the proposition of “A/T/N system” in which three categories of AD biomarker (imaging and biofluids) are summarized based on the nature of the pathologies mechanisms: A (biomarkers of β-amyloid, Aβ)/T (biomarkers of fibrillar tau)/N (biomarkers of neurodegeneration or neuronal injury) [
7]. The NIA-AA agreed that only biomarkers that are specific to characteristic AD proteinopathy (i.e., Aβ and tau) should be considered potential biomarker definitions of the disease.
The biomarkers of Aβ are the first found to become abnormal in AD [
8]. According to the Aβ cascade hypothesis, abnormal production and accumulation of Aβ in the brain are the primary influences driving AD pathogenesis [
9]. The in vivo measurement of cerebral amyloidosis as obtained using
11C-PiB [
10] or one of the approved
18F-labelled amyloid tracers and positron emission tomography (PET) is associated with cross-sectional regionally specific brain atrophy and longitudinal cognitive decline. PET imaging of amyloid as target has also been extensively 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 drugs further motivated a focus shift to investigate the role of tau pathology in the AD pathogenesis, also as target for novel drug developments [
12]. Human and animal model data suggest a causal upstream role for Aβ in the pathogenesis of AD, but Aβ alone is insufficient to cause cognitive deterioration directly [
13]. Postmortem studies 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 [
14]. However, the role of tau in the pathophysiology of AD and other tauopathies remains unclear. Consequently, the precise targeting of tau deposition in vivo in the brain would be very valuable.
The key tools of “transpathology,” for example, the use of PET, can noninvasively detect the molecular markers in vivo and allow for an earlier disease diagnosis and evaluation than structural imaging methods [
15]. In recent years, with the development of PET technology and the advent of new tracers, the pathophysiological changes of many major neurodegenerative diseases, including AD, have been explored with the help of PET molecular imaging [
16]. There are several tracers for PET that have been developed and used for clinical assessment in patients with various tauopathies as “first-generation” tracers, such as
18F-THK5317 [
17],
18F-THK5351 [
18],
18F-AV-1451 [
19], and
11C-PBB3 [
20]. Limitations of these tracers with regard to off-target binding and diagnostic range provided the motivation to develop a new generation of tau tracers, including
18F-MK-6240,
18F-PI-2620,
18F-RO-948,
18F-JNJ311/069,
18F-GTP1, and
18F-PM-PBB3 [
21‐
24].
In principle, tau PET imaging enables noninvasive detection of in vivo tau deposition patterns, facilitates differential diagnosis between neurodegenerative diseases including different tauopathies, and predicts disease progression. Furthermore, tau PET imaging could potentially be applied to achieve the therapeutic effect evaluation of anti-tau treatment and develop a novel drug, thereby allowing preventive interventions. In May 2020, US Food and Drug Administration (FDA) approved the first tau PET tracer 18F-flortaucipir, representing a great achievement to improve AD diagnosis.
The current consensus summarizes the use of 18F-flortaucipir PET in the clinical setting, including the clinical indications, qualifications and responsibilities of personnel, imaging procedure/specifications, documentation/reporting of the result, imaging equipment specifications, quality control and improvement, imaging safety and infection control, and the patient education concerns and the radiation safety in imaging.
Definitions
Tau
Tau protein is a multifunctional protein mainly locating in axons of central nervous system, playing a crucial role in stabilizing microtubules [
25]. There are six tau isoforms existing in human brain, classified as either 3 (3R) or 4 (4R) repeated binding domains, generated by alternative mRNA splicing of the microtubule-associated protein tau gene (MAPT) [
26]. Several neurodegenerative diseases are characterized by tau aggregates; however, the tau aggregates vary in those disease either for morphology (e.g., neurofibrillary tangles for AD vs. astrocytic plaques, Pick bodies, or globose tangles in other neurodegenerative tauopathies) or ultrastructural conformations (e.g., paired helical filaments in AD vs. mainly straight or twisted filaments in other neurodegenerative tauopathies) [
27].
AD
AD is an age-dependent neurodegenerative disease that is characterized as a slow start and progressive decline in memory, problem-solving, language, and other cognitive abilities, which is the main cause of dementia. The causes of AD are still unclear, while Aβ deposition and abundant tau phosphorylation are the main hallmarks of AD pathology.
Mild cognitive impairment (MCI)
MCI is defined as a potential intermediate state between normal aging and dementia, with a reduction of cognitive 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 in 1982 by Barry et al. [
29]. Individuals at GDS stage III have slight cognitive deficits and may have some impairment in complex executive function. About 3–19% of individuals will develop MCI in natural aging, and the risk of progressing to dementia is 11–33% in 2 years [
30].
Neurodegenerative tauopathies
Neurodegenerative tauopathies are a group of dementia and movement disorders that are characterized as abundant accumulations of filaments assembled by microtubule-associated protein tau (MAPT), which includes AD, frontotemporal lobar degeneration (FTLD), corticobasal syndrome (CBS), and progressive supranuclear palsy (PSP). Though the symptoms of these diseases are different, brain abnormalities and cognitive impairment are associated with the growing accumulation of filaments or tangles.
Tau imaging
Tau PET imaging could allow obtaining tau pathology information non-invasively in vivo. As such, it should be capable of providing the “T” biomarker information to support establishing a biological diagnosis of AD and other tauopathies, potentially already at earlier disease stages, like in MCI. Notably, 18F-flortaucipir presents higher affinity to “AD-like” tau aggregates than that in other neurodegenerative tauopathies, while it should be noticed that the sensitivity of 18F-flortaucipir might not be enough to diagnose early stage of AD, such as Braak stage 0.
Clinical indications
To our knowledge, there is no consensus or recommendation on indications/contraindications for the clinical application of tau PET imaging. Despite tau PET remains as a powerful research tool in tauopathies, we suggest to consider the use of 18F-flortaucipir PET imaging in the following clinical scenarios: the cause of cognitive impairment remains uncertain after a comprehensive clinical evaluation by an expert; the disease history and routine examination cannot confirm the definitive diagnosis of AD (as it would be possible, e.g., in familial AD); there is a need to differentiate AD from other neurodegenerative tauopathies; there is a need to determine the severity of tau deposition in AD.
The
18F-flortaucipir PET is not recommended to be clinically used to evaluate tauopathies other than AD (e.g., in other neurodegenerative tauopathies) [
31], and the sensitivity of
18F-flortaucipir PET is limited in detecting early-stage tau pathology [
32]. Additionally, it should be careful to conduct longitudinal assessment by using
18F-flortaucipir PET, as more evidence is required to support the value of
18F-flortaucipir PET imaging in longitudinal assessment.
Documentation/reporting
The report should include the patient demographics, identifiers, and all pertinent basic study information such as the name, age, gender, examination date, clinical diagnosis, net intravenously injected radioactivity of the administered radiotracer, and the i.v. injection site. The pertinent information associated with cognitive/motor impairment-related clinical symptoms should be included, ideally including respective cognition/motor symptom scores. Results of structural brain imaging, CSF biomarker testing in case of suspected AD, and of other potential nuclear brain imaging exams should also be provided. The reason for the test, such as the presence of uncertain clinical diagnoses, and whether there is a need to differentiate with non-AD tau pathologies, or presence of AD comorbidities, should be briefly described. Pertinent past medical history that might alter the anatomy of the brain, such as brain surgery, head trauma, and stroke, should also be briefly described.
Body of the report
Procedures and materials
The type and the net administrated dose and the site of injected radiotracer should be documented and double-checked by the technologist and nurse. Any unwanted events that occurred during radiotracer injection, such as infiltration should be recorded.
Findings
Abnormalities should be described including the areas in which pathological cerebral and cerebellar uptake is observed. Performed quantitative or semi-quantitative assessments should be stated.
Comparative data
Comparisons with previous 18F-flortaucipir PET examinations and interpretations should be incorporated into the current study report. The findings of pertinent related recent imaging such as the brain MR, CT, 18F-FDG PET, amyloid PET, and neuropsychiatric examination findings should also be considered when interpreting 18F-flortaucipir PET images.
Interpretation and conclusions
The impression should state clearly whether the scan demonstrates positive or negative tau deposition. If the scan is inconclusive, this needs to be stated along with possible 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 choroid plexus, brainstem, basal ganglia, and meninges has been reported [
40]. Although
18F-flortaucipir PET imaging depicts tau deposition in the brain, it is crucial to note that a scan positive for tau deposition should be interpreted in association with amyloid PET imaging and clinical information, at present, to diagnose AD. Negative results of
18F-flortaucipir PET imaging accompanied with positive amyloid PET imaging indicate patients who are possibly developed with AD. Positive results of
18F-flortaucipir PET imaging combined with positive amyloid PET imaging indicate the existence of AD in the patients. Also, a positive
18F-flortaucipir PET result does not exclude other coexistent neurodegenerative disorders. On the contrary, negative results of amyloid PET imaging indicate patients who are unlikely to have AD and negative
18F-flortaucipir PET results among MCI patients may indicate that they are unlikely to advance to AD dementia [
41,
42].
Safety, infection control, and patient education concerns
Policies and procedures on safety, infection control, and patient education should be developed and implemented according to regional and national regulations. For tau PET imaging, special attention should be paid to the safety issues of patients with dementia or other neurodegenerative diseases, in whom falls may frequently occur. Obstacles in the imaging department should be minimized, and patients should be carefully aided when walking in and out of the room. If patients would be restrained on the bed or in a head holder during the examination, frequent explanation and reassurance would help reduce the stress and anxiety. The presence of an accompanying familiar person can be helpful during the uptake phase and the installation of the patient in the scanner room provided general radioprotection of this person can be insured. General recommendations can be found in SNMMI Guideline for General Imaging [
46], ACR Position Statement on Quality Control and Improvement, Safety, Infection Control and Patient Education [
47], and SNMMI Procedure Standard/EANM Practice Guideline for Amyloid PET Imaging of the Brain 1.0 [
48].
Radiation safety in imaging
Following the principle of “as low as reasonably achievable (ALARA),” nuclear medicine physicians, technologists, and medical physicists have a responsibility to minimize radiation exposure to patients, staff, family members, and caregivers, as well as society as a whole, without degradation in image quality. As estimated by dosimetry studies for
18F-flortaucipir in clinical trials, the radiation exposure from a tau PET scan (about 4–9 mSv) is within the range of commonly performed other imaging studies. See also SNMMI Guideline for General Imaging, “EANM procedure guidelines for PET brain imaging using [
18F]FDG, version 2”, and SNMMI Procedure Standard/EANM Practice Guideline for Amyloid PET Imaging of the Brain 1.0 [
44,
46,
48].
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