European Nuclear Medicine Guide
Various PET tracers targeting tau pathology exist, and they are broadly divided in two categories, namely first-generation tau tracers, i.e. the first pharmaceuticals investigated for this purpose ([18F]-THK5317, [18F]-THK5351, [18F]-AV-1451 (Flortaucipir), and [11C]-PBB3) and second-generation tau tracers, developed after the others to overcome some limitations, namely binding to non-tau targets (“off-target” binding) ( these include [18F]-MK-6240, [18F]-PI-2620, [18F]-RO-948, [18F]-JNJ311/069, [18F]-GTP1, and [18F]-PM-PBB3).
Larger clinical series and thus more advanced knowledge about clinical performance are available for first-generation tracers, and the only PET tracer currently approved by the EMA for imaging of tau neurofibrillary tangles is:[18F]-Flortaucipir (Tauvid™).
Tau PET tracers target tau protein aggregates in the brain, which are a hallmark of various neurodegenerative diseases. However, these aggregates differ across disorders in terms of morphology—such as neurofibrillary tangles in Alzheimer’s disease (AD) versus astrocytic plaques, Pick bodies, or globose tangles in other tauopathies—and ultrastructural conformation, with paired helical filaments in AD compared to predominantly straight or twisted filaments in other tauopathies.
The majority of first- and second-generation tracers, including [18F]-Flortaucipir, exhibit a stronger affinity for "AD-like" tau aggregates than for those found in other neurodegenerative tauopathies.
In principle, tau PET imaging is a non-invasive tool that enables the detection of in vivo tau deposition patterns, facilitates the differential diagnosis of neurodegenerative diseases—including various tauopathies—and helps predict disease progression. Additionally, tau PET has the potential to assess the therapeutic efficacy of anti-tau treatments and contribute to the development of new drugs, paving the way for preventive interventions. Despite its value as a research tool in tauopathies, there is currently no consensus or established guidelines regarding the clinical indications and contra-indications for tau PET imaging.
Recently, a workgroup convened by the Alzheimer’s Association and the Society for Nuclear Medicine and Molecular Imaging (SNMMI) published recommendations defining the appropriate use criteria (AUC) for amyloid and tau PET [56].
Following this recommendation, the use of tau PET is considered appropriate in patients with any of the following conditions:
Patients presenting with MCI or dementia who are younger than 65 years and in whom AD pathology is suspected;
Patients presenting with MCI or dementia syndrome that could be consistent with AD pathology but has atypical features (e.g., non-amnestic clinical presentation, rapid or slow progression, etiologically mixed presentation);
To inform the prognosis of patients presenting with MCI due to clinically suspected AD pathology;
To inform the prognosis of patients presenting with dementia due to clinically suspected AD pathology;
To determine eligibility for treatment with an approved amyloid-targeting therapy.
According to the SNMMI/AA AUCs, the use of tau PET is considered rarely appropriate for:
Patients who are CU who are not considered to be at increased risk for AD based on age, known APOE4 genotype, or multigenerational family history;
Determination of dementia severity;
Patients who are CU but considered to be at increased risk for AD based on age, known APOE4 genotype, or multigenerational family history;
Patients with SCD (CU based on objective testing) who are not considered to be at increased risk for AD based on age, known APOE4 genotype, or multigenerational family history;
Patients with SCD (CU based on objective testing) who are considered to be at increased risk for AD based on age, known APOE4 genotype, or multigenerational family history;
Non-medical usage (e.g., legal, insurance coverage, or employment screening);
In lieu of genotyping for suspected autosomal dominant mutation carriers.
Tau PET imaging is contra-indicated in case of pregnancy.
Breastfeeding should be interrupted for 12 hours following the examination.
Clinical trials have been performed administering a baseline dose of 370 MBq of [18F]-Flortaucipir in a total volume of 1–2 mL as a single slow intravenous bolus.
Studies with reduced doses have been performed, with doses as low as 180 MBq of [18F]-Flortaucipir [57–59]. No specific recommendations are provided for paediatric nuclear medicine.
As estimated by dosimetry studies for [18F]-Flortaucipir in clinical trials, the radiation exposure from a tau PET scan (about 4–9 mSv; 0.10-0.20mSv/MBq ) is within the range of other commonly performed imaging studies [60].
Caveat
“Effective Dose” is a protection quantity that provides a dose value related to the probability of health detriment to an adult reference person due to stochastic effects from exposure to low doses of ionizing radiation. It should not be used to quantify the radiation risk for a single individual associated with a particular nuclear medicine examination. It is used to characterize a certain examination in comparison to alternatives, but it should be emphasized that if the actual risk to a certain patient population is to be assessed, it is mandatory to apply risk factors (per mSv) that are appropriate for the gender, the age distribution and the disease state of that population."
Prior to the procedure, a detailed medical history should be collected, and the examination’s purpose and process should be clearly explained to help ease patient anxiety and improve cooperation. Since food intake does not affect [18F]-Flortaucipir imaging, fasting is not required. Likewise, there is no need to discontinue antidementia medications, as they do not interfere with the scan.
When necessary, patients should be accompanied by a caregiver, particularly those with severe cognitive impairment. To minimize radiation exposure, patients should empty their bladder before the scan. Any potential risks should be discussed, and informed consent should be obtained when applicable.
Standard safety measures should be implemented to prevent injection-related infections, radiotracer infiltration, or spillage. [18F]-Flortaucipir dose must be accurately measured using a calibrated dose calibrator before administration.
Patients should also be informed of possible mild side effects, such as headaches, injection site discomfort, or gastrointestinal issues [61]. Caregivers and family members should report any adverse reactions to the physician.
A supine position with suitable head support is preferred to reduce the potential head movement. Extreme neck extension or flexion should be avoided. The entire brain, especially the entire cerebellum, should be included in the view.
A 20- to 30-min brain PET scan is usually performed after 75–80 min of [18F]-Flortaucipir injection. The brain PET images (4–6 frames of 5 minutes duration) are acquired in three-dimensional (3D) mode with appropriate data corrections after the tracer injection.
PET images are reconstructed in an image matrix size of at least 256 × 256 with attenuation correction. The typical pixel size is 2–4 mm with a slice thickness of 2–4 mm. It is recommended that the acquired images be reconstructed using 3D ordered subset expectation maximization (OSEM).
Tau PET detects the presence of tauopathy in a diagnostic setting and additionally provides information about the spatial patterns of tau deposition [62]. The strong association between spatial patterns of tau, neurodegeneration, and cognitive impairment further supports its diagnostic usefulness in AD. Tau PET can strongly predict cognitive changes in the preclinical and prodromal stages of AD, outperforming Aβ-PET, FDG-PET, and structural MRI in direct comparisons [63–65], which highlights the potential of tau PET as a prognostic tool.
Regarding differential diagnosis, the primary utility of tau PET is for distinguishing AD dementia from other neurodegenerative diseases, and all the most established tau PET tracers (i.e.,[18F]-flortaucipir, [18F]-MK6240, and [18F]-RO948) have demonstrated a sensitivity and specificity above 90% for that purpose [62]. According to the conditions of approval of [18F]-Flortaucipir by the U.S. Food and Drug Administration, the current diagnostic utility of tau PET is mainly to differentiate AD dementia from other neurodegenerative diseases [66].
The interpretation of [18F]-Flortaucipir PET scans relies on visual assessment, aiming to detect neocortical regions where tracer uptake surpasses background levels, defined as up to 1.65 times the cerebellar average (inferior cerebellar cortex is used as negative control, since it is generally free of tau protein deposition).
For optimal visualization, a colour scale with a sharp contrast between two distinct colours should be used, ensuring the transition occurs at the 1.65-fold threshold. The evaluation focuses on specific brain regions (lateral anterior temporal, lateral posterior temporal, occipital, parietal, precuneus, and frontal lobes), with each classified as positive or negative based on whether or not flortaucipir uptake exceeds the cerebellar signal by 65% [67].
A scan is interpreted as showing a “negative AD tau pattern” if there is no neocortical tracer uptake, or if uptake is limited to the medial temporal, anterolateral temporal, or frontal cortex (Fig.1). A “positive AD pattern” is defined as showing the extension of tracer retention into the posterolateral temporal or occipital cortex (moderate AD tau pattern), with further extension into the parietal cortex, posterior cingulate/precuneus cortex and frontal cortex seen in more advanced disease (advanced AD tau pattern), as shown in Fig.2 [67].
Major pitfalls might relate to head movement or brain atrophy, both potentially simulating tau positivity.
Off-target binding may be seen in the choroid plexus, striatum, brainstem nuclei and skull (Fig.3). Small foci of non-contiguous tracer uptake may lead to false-positive interpretation. Scans that have isolated or non-contiguous small foci in any region should be interpreted with caution, and scan interpretation should be based on uptake of tracer in the neocortical grey matter regions only.
Other visual strategies have been investigated, including staging approaches, showing overall good diagnostic performances consistent with the standard visual approach described here and a potential added sensitivity for earlier pathology [68].
SUVRs are widely used in clinical practice. The most-used reference region for intensity normalization of tau PET scans is the cerebellar grey matter. However, the inferior cerebellar cortex or crus have also been used to minimize spill-in effect from nearby regions. There is no consensus about the use of partial volume correction approaches to correct for the off-target binding that happens with some radiotracers. It is recommended to report results both with and without partial volume corrections. Tau PET quantification is mostly performed using regions included in the Braak model. Nevertheless, studies have shown that tau distribution is not strictly limited to this model and should be assessed throughout the brain using either a region- or voxel-based approach.
Ongoing efforts aim to establish standardized quantitative tau PET scales across different radiotracers and analytical methods, like the CL scale used for amyloid PET standardization [69,70].
Voxel-wise analysis after spatial and count rate normalization facilitates whole-brain comparisons, either between an individual and a group or between two groups. This method can identify subtle abnormalities without being limited by predefined ROIs [60].
Fig 1. PET/CT with [18F]-Flortaucipir. Sequential axial slices without a significant accumulation of tau neurofibrillary tangles.
Fig.2 PET/CT with [18F]-Flortaucipir. Sequential axial slices indicate a significant accumulation of tau neurofibrillary tangles in parieto-temporal and frontal regions, classified as advanced AD tau pattern.
Fig 3. PET/CT with [18F]-Flortaucipir. Sequential axial slices without a significant accumulation of tau neurofibrillary tangles but with notable off-target binding, which may be observed in the choroid plexus, brainstem nuclei, and skull (red arrows).