EANM procedure guidelines for brain PET imaging using [¹⁸F]FDG, version 3

Information relevant for the procedure

History of diseases, especially neurological and psychiatric disorders, and current neurological and psychiatric status including clinical test results. Surgery, radiation, trauma of the brain.

History of diabetes, fasting state

Patients’ ability to lie still for 15 min to 1 h. If sedation is required, it should be performed as late as possible. The intention should be to administer [¹⁸F]FDG at least 15 min before the sedation.

Information about recent structural imaging studies (CT, MRI), fluid or molecular imaging biomarkers (CSF, plasma, amyloid or tau PET imaging), blood biochemistry indicative of metabolic dysfunction or systemic disease (e.g., hepatic, thyroid, renal), as well as about functional brain explorations (EEG, neuropsychometric tests) in specific conditions.

Ongoing necessary therapies are allowed, but current medications (and timing of their last administration) should be recorded. This information (including duration and dosage) is particularly relevant for sedatives, psychotropic pharmaceuticals, antiseizure medication, and corticosteroids. Possible effects of these medications on regional metabolic rate of glucose consumption (rCMRglc) have been suggested [82–84].

The use and dosage of corticosteroids might be particularly relevant for emerging indications of brain [¹⁸F]FDG-PET such as AE and PCNSL. In whole-body [¹⁸F]FDG-PET, possible false-negative results are well-known for inflammatory and autoimmune diseases treated with corticosteroids [85, 86]. For brain [¹⁸F]FDG-PET, and whenever clinically possible, it is also advised to scan patients before starting (or in any case as soon as possible after initiating) steroid treatment in case of AE and PCNSL. Regarding discontinuation of abuse drugs, it should be noted that reports are also available about the effects of early abstinence on regional brain metabolism. For example, a shifts in cortical-subcortical metabolic balance has been reported during early abstinence from chronic methamphetamine abuse [87]. Similarly, it has been shown that acute alcohol administration may decrease brain glucose utilization that may persist through early sobriety in heavy drinkers [88]. Finally, in the case of parkinsonian patients, it should be recorded whether the examination is conducted in a clinically defined “off” state, as levodopa might reduce glucose metabolism regionally [89, 90].

Preinjection

Blood glucose levels should be checked prior to [¹⁸F]FDG administration. When hyperglycemia is present (>160 mg/dl; >8.9 nmol/L), there is an increased competition of elevated plasma glucose with [¹⁸F]FDG on carrier enzyme and, because it is usually associated with high intracellular glucose levels, also on hexokinase enzyme. As a general rule, there is a decrease in [¹⁸F]FDG influx rate constant (K₁) quantitatively paralleling blood glucose concentrations, resulting in deterioration of image quality with increasing glucose concentrations [91, 92]. In the case of hyperglycemia, [¹⁸F]FDG uptake is expected to be reduced in the whole brain (with stochastic noise increased). Decreased contrast between white and gray matter uptake can be found, which might, at least in theory, impact diagnostic accuracy [93, 94]. In recent years, some lines of evidence have suggested that hyperglycemia might more prominently enhance hypometabolism in the posterior parieto-occipital cortex [95, 96]. These regions encompass the typical AD hypometabolic pattern. Therefore, concerns have been raised about the impact of hyperglycemia on the accuracy of PET in patients with suspected AD [97]. Very few studies directly addressed this issue, and, to date, a measurable effect on scan interpretation has not been proven [98]. In any case, an examination should be postponed until a proper euglycemic state is reached. Notably, acute correction of hyperglycemia with insulin usually does not substantially improve brain image quality, probably because the normalization of an increased intracellular glucose level lags behind the normalization of the plasma glucose level [99]. Quantitation of regional cerebral glucose metabolism with [¹⁸F]FDG-PET also requires steady-state situations which are not maintained during falling plasma glucose levels after administration of insulin. Best results for clinical brain [¹⁸F]FDG-PET imaging in diabetics can be obtained in a euglycemic condition during correct therapeutic management [93, 99, 100]. Alternatively, brain perfusion SPECT should be considered, especially using a new generation of solid detectors [101].

Interestingly, it has been suggested that hyperglycemia obtained by intravenous infusion of 10% glucose solution could enhance detectability in patients with brain tumors [102]. Procedural guidelines for PET imaging in glioma should be considered for further details [74].

Before the scanning procedure, patients should void their bladder for maximum comfort during the study and to reduce radiation dose. Advising the patient to drink water and void the bladder again after the scanning session is also recommended to minimize radiation exposure.

When static scans are acquired, patients should be positioned comfortably in a quiet, dimly lit room at least 15 min before [¹⁸F]FDG administration and during the uptake phase of [¹⁸F]FDG (at least 20 min). The cannula for i.v. administration should be in place at least 10 min before [¹⁸F]FDG administration. Patients should be instructed not to speak, read, listen to music/sounds or otherwise be active. Patients should be awake. Closing the eyes could decrease metabolism in the occipital cortex, a cortical region that might be relevant for specific clinical conditions (as in DLB, characterized by hypometabolism of the occipital cortex) [103]. In any case, a consistent procedure is required in each center to maintain comparability between exams (eyes open/closed), also with respect to the normal control database if semiquantitative analyses based on voxels or regions/volumes of interest is performed.

For presurgical evaluation of epilepsy, close monitoring of the patient is required, ideally using continuous EEG recording. Such monitoring should start before injection, as soon as the patient arrives in the department, in order to ensure that [¹⁸F]FDG is not administered in an ictal/postictal stage. Monitoring should be maintained until at least 20 min after the radiopharmaceutical administration. MRI images acquired in combination with PET or prior to it, as well as a well-documented history of seizures before imaging are of critical importance for adequate image interpretation.

Radionuclide

Fluorine-18

Radiopharmaceutical

2-[¹⁸F]fluoro-2-deoxy-D-glucose ([¹⁸F]FDG)

Recommended activity

Adults

The previous guidelines mentioned 125–250 MBq (typically 150 MBq) when scans are performed in 3D mode [5]. However, for high-sensitivity digital systems (TOF < 400 ps) and/or large axial field of view (also called total body) systems, activity might be lowered, probably by a factor of 2 or more, but limited data are at present available to give clear recommendations.

Children

Activity administered in MBq = 14 × multiple (dosage card)

Administered activities to children may also be lower in the case of high sensitivity digital systems, and should never exceed those recommended in the EANM dosage card v.01.02.2014 [104].

Data acquisition

Instrumentation

PET/CT and PET/MR systems with GSO, LSO, or LYSO crystals acquire images in list mode and in 3D. In addition, more recent PET/CT and PET/MR systems show increased sensitivity because of an increased axial field of views, silicon photomultipliers (“digital PET”) and/or use of time-of-flight technology [107–112]. These properties can be beneficial in those cases where the injected radioactivity and/or the acquisition time need to be reduced (e.g., pediatric cases or patients with limited ability to cooperate).

Positioning of the patient

Careful positioning of the patient’s head is critical, especially for cameras with a limited axial field of view. The orbitomeatal line is often used for standardized positioning, and the patient’s head can be fixed in place. To prevent movement artifacts, the patient should be instructed to avoid any movements of the head.

Type of acquisition

Depending on the clinical question and type of equipment, [¹⁸F]FDG-PET imaging may include:

- Static acquisition: A single set of tomographic images is obtained after brain uptake. Alternatively, the static scan can be divided into several frames to perform post-hoc movement correction. The static image should usually start with a fixed time, generally between 30- and 60-min postinjection (p.i.) for diagnostic purposes, and either evaluated by means of visual assessment or semiquantitative and/or voxel-based analysis.

- Dynamic acquisition: Multiple sequential sets of tomographic images are acquired from the time of administration of [¹⁸F]FDG until 60 or 90 min, usually. This acquisition is especially used when absolute quantification of rCMRglc is required generally for research purposes (see paragraph on absolute quantification) but also possibly in clinical settings to correct patient’s movements and perform parametric analysis.

Attenuation correction

This correction is mandatory for [¹⁸F]FDG PET brain imaging and is currently performed using CT- or MR-based attenuation correction.

- CT-based attenuation correction. PET/CT systems use CT scan for attenuation correction. The advantage of CT scan is that X-ray detection is not impacted by emission photons. Consequently, a CT scan can be performed after the radiopharmaceutical injection. A CT scan can be done for diagnostic purposes, using regular tube current, or only for attenuation correction (i.e., a low-dose CT) with low tube current (typically 10–30 mAs). The latter has the advantage to significantly reduce the radiation exposure well below 0.5 mSv for most systems. The choice of either type of CT scans depends on the purpose of imaging and the clinical indication. If anatomical information is already available, a low-dose CT for the purpose of attenuation correction can be considered. When performing PET/CT, it is recommended to check for movement between CT and the PET sessions, to avoid artifacts in the attenuation correction.

- MR-based attenuation correction [113]. For hybrid PET/MR systems, attenuation corrections (AC) need to be derived using either a dedicated MR sequence (MR-AC) or use of CT templates depending on the system’s available methods. In most of the systems, only MR-AC or CT templates are commercially available now, but improved and more advanced methods using special image reconstruction algorithms and artificial intelligence [114–118] are expected to be offered in future software updates. For MR-AC imaging, the body coil or a dedicated brain/head coil may be required. However, the best performing MR-AC methods work accurately for [¹⁸F]FDG brain PET imaging [119].

In all cases, it is strongly recommended to visually control the generated attenuation correction maps for unforeseen artifacts arising from metal or dental implants, missing air cavities, and missing bones — the latter is usually present in all MR-AC [120]. The reader should be aware of the possible qualitative and quantitative consequences of these artifacts and take them into consideration when reading or interpreting the PET images. For example, tracer uptake in cortical brain regions may be underestimated by about 20%, while uptake in the pons or cerebellum may show upward bias in case air cavities are not correctly considered by the MR-AC. The use of CT templates can overcome these limitations but may also be less accurate in case of abnormal bone anatomy, i.e., the templates assume healthy anatomical bone structures (absence of trauma). The latter can be overcome by separately making individual CT scans and inserting these into the PET/MR reconstruction pipeline for attenuation correction purposes. At present, such a procedure is not routinely available and formally approved on PET/MR systems. Pooling PET data collected on PET/CT and PET/MR systems (and on PET/MR systems with distinct methods for AC) should thus be performed with extreme caution as quantitative biases between these systems may be present.

Emission scan acquisition

As already noted, in the case of a static image acquisition procedure, the acquisition should not start earlier than 30 min p.i.. Better contrast between gray and white matter, as well between tumor and normal brain tissue, can be obtained with a longer time interval between [¹⁸F]FDG administration and data acquisition (e.g., 60 min up to several hours for tumors). A standardized acquisition protocol with a fixed time for acquisition start, generally between 30 min and 60 min p.i., is recommended to improve comparability between exams of different patients, follow-up scans, or different centers (e.g., as in multicenter trials). Standard protocols on modern hybrid PET/CT or PET/MR system includes list mode acquisition in 3D mode. The use of list mode acquisition is particularly useful in case of motion, allowing to exclude artifacts due to the patient’s movements. The duration of emission image acquisition should be related to the minimum required number of detected events. Typically, data are acquired over 10–15 min, possibly less if a higher [¹⁸F]FDG dose activity is administrated, for example, during an additional whole-body PET procedure. This whole-body PET/CT scan is particularly recommended in case of suspected paraneoplastic syndromes, lymphoma, or autoimmune/inflammatory/infectious systemic diseases also involving the brain (e.g., neurosarcoidosis). In special circumstances, when moderately agitated patients are examined, acquisition times down to 5 min can be used for diagnostic pattern evaluation [121].

In the case of a dynamic procedure, typically a 60-min 3D dynamic scan is acquired in list mode shortly before (10s) or simultaneously with the administration of [¹⁸F]FDG. During the PET acquisition, it is required to monitor head movement and to correct for any displacements. The use of a dedicated head holder or immobilization device to avoid or limit head movements is recommended. When available, a motion tracking system may be used to detect motion to retrospectively correct for any head displacements. It is beyond these guidelines to recommend motion correction methods as these are not widely available and/or generally accepted, as they are still under development. Yet, the reader should be aware that it is important to avoid and/or correct for patient motion in case of long dynamic PET brain studies. After completion of the dynamic scan, the list mode data can be binned (and reconstructed) into, e.g., 20 to 30 successive time frames to capture kinetics in brain tissue over time. Typically, time frames are short (~5 to 30s) on the first 5 min of the scan if input function is required, progressively increasing to about 300 s time frames at later uptake times.

Image reconstruction

Preferably, images are reconstructed using (ordered subset) iterative reconstruction including the use of TOF information, when available, and with an image matrix size of at least 128 × 128 pixels. Voxel size should be smaller than 2 mm in any direction at the smallest possible slice thickness. The number of iterations and subsets applied should guarantee sufficient convergence of the reconstructed data. It depends on the specific PET system and TOF performance. Resolution modeling is also part as a new feature in reconstruction software on many available PET/CT and PET/MR systems. This resolution modeling may be applied to enhance the detection of small abnormalities, but it is not yet recommended for quantitative evaluation due to pronounced Gibbs artifacts. At the time of writing these guidelines, dedicated brain PET harmonization is being explored and more specific recommendations may be provided soon by EARL [122]. Depending on PET system, a final image resolution of 4–6 mm FWHM (full width at half maximum) typically yields images of adequate resolution and noise. If movement artifacts are observed (especially in children or in patients with dementia or movement disorder), it can be helpful to reconstruct the data in short frames (e.g., 5-min frames) and evaluate only those frames that are not affected by patient motion or spatially align the individual frames prior to further analysis. In the case of severe patient motion, the attenuation correction (spatial mismatch between CT or MR-AC and PET) may no longer be accurate enough and cause image artifacts. It should be noted that non-attenuated series (which should be reconstructed and archived) could be useful in this setting to check for artifacts and for reporting.

Interventions

Usually, interventions are not necessary to answer routine clinical questions; they are mostly used in research. In the localization of eloquent cortical areas before surgery, stimulation paradigms like language or motor tasks can be performed. Currently, such activation imaging is mostly performed with functional MRI (fMRI). If performed with [¹⁸F]FDG-PET to image special clinical states [123–125], these paradigms usually start at the time of injection and have to be maintained for a time period of at least 20 min [126, 127].

Quantification procedures

The quantitative assessment of cerebral [¹⁸F]FDG/glucose metabolism requires, besides a dynamic emission scan, an arterial input function, i.e., the measurement of plasma [¹⁸F]FDG (over time) and glucose concentrations. There is a need for a calibration factor between scanner events in terms of detected events/voxel/s and in vitro (or online) measurements of plasma activity concentrations in counts/mL/s [128].

Glucose metabolism may be derived with either a Patlak plot or a pharmacokinetic model using the dynamic PET series and the arterial input function. The primary outcome parameter, the net influx rate constant Ki, then needs to be multiplied with plasma glucose levels to derive the rCMRglc which also takes into account the lumped constant. It is required to measure blood glucose levels during the scan or directly prior to or after the dynamic PET examination.

Although dynamic image acquisition from the start of injection up to usually 60 min p.i. is considered to be the most accurate procedure, most centers use simplified protocols based on static images in the clinical setting [129–131].

For brain tumor imaging, typically semiquantitative estimates of glucose metabolism like SUV (standardized uptake value) or SUVr (SUV relative to a normal brain region; usually in oncology to the contralateral metabolic uptake) are used. For such quantification, standardized acquisition times are required. The total activity of administered [¹⁸F]FDG and the patient’s height and weight for the estimation of body surface are also required. A calibration factor can also be applied as well as for comparative studies between different PET cameras. A static image is sufficient, acquired between 30 and 60 min p.i., typically. These semiquantitative estimates can be corrected for blood glucose concentration.

Data display for analysis

Color scales typically used for the display of the images are gray scales (specially to detect lesion), or rainbow scales, with a continuous progression of the colors from low to high uptake.

A standardized image display, also in terms of upper/lower color scale thresholding, is advocated to ensure appropriate and best interpretable representation of the reconstructed dataset.

Internal landmarks can be used for reorientation to achieve a standardized image display. Reorientation procedures based on the inter-commissural line are generally used [137]. A proper reorientation of the coronal view is crucial for visual inspection of the scan as the presence of asymmetry between homologs structures in the two hemispheres is one of the cornerstones of visual reading. For a more accurate inspection of the medial temporal lobe, a second reorientation can be made along the hippocampal axis (the so-called Ohnishi reorientation in which a patients’ brain is reoriented 30 degrees upward with respect to the bi-commissural line on sagittal view [138]), for example, for temporal epilepsy or AD.

The display of additional coronal and sagittal images is recommended.

Three-dimensional display of the dataset can be helpful for more accurate topographic orientation in some clinical questions.

Visual interpretation

The images should be critically examined during interpretation for the presence of movement or attenuation artifacts.

It is suitable to have a normal database available, preferably studied on the same type of camera, under the same acquisition circumstances (e.g., eyes open/closed) and using the same type of reconstruction and attenuation correction. Matching spatial resolution is the most important parameter needed for optimal database use. This allows assessment of normal variability of regional [¹⁸F]FDG uptake and improves diagnostic accuracy.

Variation in color scale, background subtraction, or change in contrast can be used to facilitate data interpretation. Data interpretation should take into consideration global changes and regional decreases or increases in [¹⁸F]FDG uptake. Tables 1 and 2 describe the most typical metabolic pattern in neurodegenerative diseases. Increased uptake can be observed in active epileptogenic foci, tumors, inflammation/infection, and physiologically activated brain areas.

Known morphological changes like atrophy should be considered for the full interpretation of the data. It is helpful to fuse [¹⁸F]FDG images with a MRI (or CT) scan of the individual performed within 6 months prior to the PET scan. In PET/CT and PET/MRI systems, fused PET/CT or PET/MRI images can be immediately visualized after image reconstruction without the need for specific software for image registration. Examples where image fusion is required are:

Presence of localized abnormalities with hypometabolism or hypermetabolism that can be related to, e.g., neuroinflammation, structural damage, atrophy, or infarcts.

Accurate evaluation of brain tumors and identification of the metabolically most active part of a brain tumor prior to biopsy.

Matching of cortical hypometabolism with morphological abnormalities on MRI or with the EEG focus for the planning of epilepsy surgery.

Localization of eloquent cortical areas (e.g., Broca’s area) prior to tumor resection.

General

The report should include all pertinent information, including the name of the patient and other identifiers, such as date of birth, name of the referring physician(s), potentially interfering medications or abnormal glycemia, type of examination, date of examination, PET system used, administered activity, and patient history, including reasons for requesting the study.

Body of the report

Procedures and materials: Include in the report a description of image acquisition and processing, i.e., whether the images were acquired using a PET/CT or PET/MR system and procedure performed, such as arterial blood sampling. If CT is acquired for diagnostic purposes, include also a description of the scanning parameters including dosimetry. In the case of PET/MR, report the type of sequences that were acquired during the imaging session (e.g., structural MR, T1-w, T2-w, FLAIR, diffusion-weighted, arterial spin labeling, resting-state fMRI). If sedation is performed, briefly describe the procedure, including the type of medication and time of sedation in relation to the radiotracer injection. In epileptic patients, briefly describe the procedure of EEG recording, when performed.

Findings: Describe whether [¹⁸F]FDG-PET findings are normal or abnormal. If findings are abnormal, describe the location and intensity of abnormal [¹⁸F]FDG uptake. Functional topography can be used as well as anatomical descriptions. State quantitative or semiquantitative measures if performed. If the CT is acquired for diagnostic purposes, it is recommended to also include a description of the findings. In case of PET/MR, a description of the findings evaluated on structural MR images should be included.

Limitations: Where appropriate, identify factors that can limit the sensitivity and specificity of the examination (i.e., movement, small lesion size, systemic disease but also the deviation from standard procedure).

Clinical issues: The report should address or answer any pertinent clinical issues raised in the request for the imaging examination.

Comparative data: Comparisons with previous examinations and reports, if available, have to be part of the report. Furthermore, results of morphological imaging modalities should also be considered for interpretation. Nondiagnostic CT scans only used for attenuation in PET/CT should be used with caution for structural interpretation.

Interpretation and conclusion: If the PET examination presents a generally accepted disease pattern, this should be said in the conclusion and, if possible, using a statement that indicates the most probable diagnosis considering the pattern only in the context of the clinical presentation and hypothesis. Any (subjective) interpretation not based on such criteria has to be explicitly stated and considered as hypothetical. A differential diagnosis should be given when appropriate. When appropriate, follow-up or additional studies should be recommended to clarify or confirm the suspected diagnosis.