Preamble
The Society of Nuclear Medicine and Molecular Imaging (SNMMI) is an international scientific and professional organization founded in 1954 to promote the science, technology, and practical application of nuclear medicine. Its 15,000 members are physicians, technologists, and scientists specializing in the research and practice of nuclear medicine. In addition to publishing journals, newsletters, and books, the SNMMI also sponsors international meetings and workshops designed to increase the competencies of nuclear medicine practitioners and to promote new advances in the science of nuclear medicine. The European Association of Nuclear Medicine (EANM) is a professional nonprofit medical association that facilitates communication worldwide between individuals pursuing clinical and research excellence in nuclear medicine. The EANM was founded in 1985.
The SNMMI/EANM periodically define new standards/guidelines for nuclear medicine practice to help advance the science of nuclear medicine and to improve the quality of service to patients. Existing standards/guidelines will be reviewed for modifications or renewal, as appropriate, on their fifth anniversary or sooner, if indicated. As of February 2014, the SNMMI guidelines are referred to as procedure standards. Any previous practice guideline or procedure guideline that describes how to perform a procedure is now considered an SNMMI procedure standard.
Each standard/guideline, representing a policy statement by the SNMMI/EANM, has undergone a thorough consensus process in which it has been subjected to extensive review. The SNMMI/EANM recognizes that the safe and effective use of diagnostic nuclear medicine imaging requires specific training, skills, and techniques, as described in each document.
The EANM and SNMMI have written and approved these standards/guidelines to promote the use of nuclear medicine procedures with high quality. These standards/guidelines are intended to assist practitioners in providing appropriate nuclear medicine care for patients. They are not inflexible rules or requirements of practice and are not intended, nor should they be used, to establish a legal standard of care. For these reasons and those set forth below, the SNMMI/EANM cautions against the use of these standards/guidelines in litigation in which the clinical decisions of a practitioner are called into question.
The ultimate judgment regarding the propriety of any specific procedure or course of action must be made by medical professionals considering the unique circumstances of each case. Thus, there is no implication that an approach differing from the standards/guidelines, standing alone, is below the standard of care. To the contrary, a conscientious practitioner may responsibly adopt a course of action different from that set forth in the standards/guidelines when, in the reasonable judgment of the practitioner, such course of action is indicated by the condition of the patient, limitations of available resources, or advances in knowledge or technology subsequent to publication of the standards/guidelines.
The practice of medicine involves not only the science but also the art of dealing with the prevention, diagnosis, alleviation, and treatment of disease. The variety and complexity of human conditions make it impossible to always reach the most appropriate diagnosis or to predict with certainty a particular response to treatment. Therefore, it should be recognized that adherence to these standards/guidelines will not ensure an accurate diagnosis or a successful outcome. All that should be expected is that the practitioner will follow a reasonable course of action based on current knowledge, available resources, and the needs of the patient to deliver effective and safe medical care. The sole purpose of these standards/guidelines is to assist practitioners in achieving this objective.
The present guideline/standard was developed collaboratively by the EANM and SNMMI. It summarizes the views of the Neuroimaging Committee of the EANM and the Brain Imaging Council of the SNMMI and reflects recommendations for which the EANM and SNMMI cannot be held responsible. The recommendations should be taken into context of good practice of nuclear medicine and do not substitute for national and international legal or regulatory provisions.
Introduction
Parkinsonian syndromes are a group of diseases characterized by signs of parkinsonism, such as bradykinesia, rigidity, tremor, and postural instability. Idiopathic Parkinson’s disease (IPD) is the most common cause of parkinsonism, but several other etiologies result to the presence of parkinsonism. Indeed, parkinsonism can be present in all alpha synucleinopathies, which include Lewy body diseases (LBDs), a subset of disorders associated with the accumulation of Lewy bodies (LB) and neurites, i.e., intracytoplasmic inclusions composed of aggregated alpha-synuclein and other proteins such as ubiquitin [
1]. The most clinically relevant subtypes of LBDs are IPD and dementia with Lewy bodies (DLB) [
1]. Alpha synucleinopathies also include multiple system atrophy (MSA), an atypical parkinsonism characterized by the presence of glial and neural silver staining aggregates of alpha-synuclein [
2]. Finally, the tauopathies corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) are movement disorders belonging to the spectrum of frontotemporal degeneration (and they are also defined as atypical parkinsonisms) [
3,
4]. The differential diagnosis of the neurodegenerative parkinsonian syndromes includes clinical entities such as essential tremor (ET), drug-induced parkinsonism, vascular parkinsonism, and psychogenic parkinsonism. ET is characterized by the presence of tremor during voluntary movement rather than at rest. Resting tremor and cogwheel rigidity or other isolated parkinsonian characteristics can be present in a subgroup of patients with ET, thus making the clinical diagnosis more challenging [
5].
In many patients, the clinical differential diagnosis of parkinsonism is relatively straightforward [
1]. However in numerous conditions, an improvement in diagnostic accuracy is possible using dopaminergic imaging [
6]. This imaging technology may be particularly helpful in patients with incomplete or atypical syndromes, unsatisfying response to therapy, and overlapping symptoms or in patients with early/mildly symptomatic stages of disease.
Currently, nuclear medicine investigations can assess both presynaptic and postsynaptic function of dopaminergic synapses [
6‐
8]. Presynaptic dopaminergic imaging helps clarify the differential diagnosis between neurodegenerative parkinsonian syndromes and non-dopamine deficiency etiologies of parkinsonism [
6‐
8].
Presynaptic dopaminergic function can be summarized as follows. Dopamine is produced via two amino acids. First, L-tyrosine is hydroxylated to form L-dopa, which subsequently is decarboxylated to dopamine by aromatic L-amino-acid decarboxylase (AADC; also known as dopa decarboxylase). Next, dopamine is transported to intracellular vesicles by vesicular monoamine transporter 2 (VMAT2). As a result of neuronal depolarization, these vesicles are emptied into the synaptic cleft where the synaptic dopamine then interacts with postsynaptic dopamine receptors. After dopamine has been emptied into the synaptic cleft, it can be subject to reuptake into the presynaptic neuron by dopamine transporter (a.k.a. dopamine active transporter—DAT).
Postsynaptic dopamine receptors can be divided into D
1-like receptors (D
1, D
5) and D
2-like receptors (D
2, D
3, and D
4) [
9]. Over 90% of D
2 receptors are located postsynaptically and so imaging of D
2 receptors is frequently referred to as imaging of postsynaptic D
2 receptors [
10]. To date, three procedure guidelines/procedure standards have been published by EANM and SNMMI, respectively. Both EANM and SNMMI have published guidelines/standards for dopamine transporter imaging with SPECT (in 2009 and 2011, respectively) An EANM Guideline for D
2 SPECT imaging is also available (2009) [
9,
11‐
13]. Since the publication of these previous documents, new lines of evidence have been made available on semiquantification, harmonization, comparison with normal datasets, and longitudinal analyses of DAT SPECT. Similarly, details on acquisition protocols and simplified quantification methods are now available for dopamine transporter imaging with PET, including recently developed fluorinated tracers. Finally, especially in some nuclear medicine centers equipped with PET and without cyclotron, [
18F]fluorodopa PET is performed for in patients with parkinsonism, although procedural GLs aiming to define standard procedures for [18F]fluorodopa imaging in this setting are still lacking.
Goals.
The aim of this guideline is to assist nuclear medicine physicians in recommending, performing, interpreting, and reporting the results of dopaminergic imaging in parkinsonian patients.
Definitions
1.
SPECT—single photon emission computed tomography (also known as SPET). It allows imaging of the three dimensional distribution of radiopharmaceuticals labeled with gamma-ray emitting radionuclide such as 123I and 99mTc.
2.
SPECT/CT—SPECT imaging combined with CT (computed tomography) in a hybrid scanner.
3.
Positron emission tomography. This imaging modality is specific for imaging positron-emitting radionuclides such as 11C and 18F through coincidence detection of annihilation photon pairs.
4.
PET/CT—PET imaging combined with CT (computed tomography) in a hybrid scanner. PET may also be combined with magnetic resonance imaging (MRI); however, the use of these scanners in patients with movement disorders has not yet been adequately addressed in the literature.
5.
Presynaptic dopaminergic imaging refers to SPECT and PET imaging studies evaluating the integrity of presynaptic nigrostriatal dopaminergic synapses.
6.
Postsynaptic dopaminergic imaging refers to SPECT and PET imaging studies that evaluate the integrity of dopaminergic neurons at the postsynaptic level (frequently referred to as imaging of the postsynaptic D2 receptors).
Clinical indications
Presynaptic dopaminergic imaging is indicated for detecting loss of nigrostriatal dopaminergic neuron terminals of patients with parkinsonian syndromes, especially:
-
To support the differential diagnosis between essential tremor and neurodegenerative parkinsonian syndromes. Note that presynaptic dopaminergic imaging is unable to distinguish IPD and DLB from PSP, CBD, or putaminal variant of MSA [
14‐
17].
-
To help distinguish between DLB and other dementias (in particular, Alzheimer’s disease, AD) [
18‐
20].
-
To support the differential diagnosis between parkinsonism due to presynaptic degenerative dopamine deficiency and other forms of parkinsonism, e.g., between IPD and drug-induced, psychogenic, or vascular parkinsonism [
21‐
23].
-
To detect early presynaptic parkinsonian syndromes [
24,
25].
Postsynaptic dopaminergic imaging can help separate typical from atypical parkinsonian syndromes. The main indication is the differentiation of IPD from other neurodegenerative parkinsonian syndromes where loss of D2 receptors occurs (e.g., MSA, PSP) [
26]. However, the clinical use of SPECT or PET tracers for postsynaptic dopaminergic imaging is currently limited by several factors and has been in many centers replaced by other molecular imaging targets [
27,
28] (see section IX).
Less common indications for postsynaptic dopaminergic imaging in parkinsonian syndromes:
1.
Assessment of the extent of D2 receptor blockade during treatment with dopamine D2 antagonists (neuroleptics).
2.
Wilson’s disease. Loss of striatal D2 receptor function is related to the severity of neurological symptoms in Wilson’s disease and may show the degree of neuronal damage due to cytotoxic copper deposition in the striatum.
Qualification and responsibilities of the personnel
Procedure/specifications of the examination
Request/history
1.
The nuclear medicine imaging facility should check with the radiopharmaceutical provider to ensure availability before scheduling the exam. Advanced notice may be required for tracer delivery.
2.
The requisition should include a brief description of symptoms and the clinical question. Information should be obtained regarding the following:
a.
Past or current recreational drug use, head trauma, stroke, psychiatric illness, epilepsy, or tumor.
b.
Neurologic symptoms: type, duration, and left- or right-sidedness.
c.
Current medications and when last taken.
d.
Patient’s ability to lie still for approximately 30–45 min (for SPECT imaging with [123I]FP-CIT).
e.
Prior brain imaging studies (e.g., CT, MRI, PET, and SPECT).
Radiopharmaceuticals
Presynaptic tracers
-
[123I]β-CIT: 2β-carboxymethoxy-3β-(4-[123I]iodophenyl)tropane
-
[123I]FP-CIT: N-3-fluoropropyl-2β-carbomethoxy-3β-(4-[123I]iodophenyl)nortropane ([123I]-ioflupane)
-
[99mTc]TRODAT-1: [2[[2-[[[3-(4-chlorophenyl)-8-methyl-8-azabicyclo[3,2,1]-oct-2-yl]-methyl](2-mercaptoethyl)amino]ethyl]amino]ethanethiolato(3-)-N2,N2’,S2,S2]oxo-[1R-exo-exo)])- [99mTc]-technetium
-
[18F]fluorodopa: 3,4-dihydroxy-6-[18F]fluoro-L-phenylalanine
-
[11C]PE2I: N-(3-iodopro-2E-enyl)-2β-carbo[11C]methoxy-3β-(4′-methylphenyl)nortropane
-
[18F]FE-PE2I: N-(3-iodoprop-2E-enyl)-2β-carbo[18F]fluoroethoxy-3β-(4-methylphenyl)-nortropane
-
(+)[11C]dihydrotetrabenazine: (+)2-Hydroxy-3-isobutyl-9-[11C]methoxy-10-methoxy-1,2,3,4,6,7,-hexahydro-11bH-bezo[α]-quinolizine; (+)[11C]DTBZ
-
(+)[18F]FP-DTBZ: (+)-α-9-O-(3-[18F]fluoropropyl)DTBZ; [18F]AV-133
Postsynaptic tracers
-
[123I]IBZM: (S)-3-[123I]iodo-N-[(1-ethyl-2-pyrrolidinyl)]methyl-2-hydroxy-6-methoxybenzamide
-
[123I]epidepride: (S)-N-((1-ethyl-2-pyrrolidinyl) methyl)-5-[123I]iodo-2,3-dimethoxybenzamide; [123I]epidepride is the iodine analogue of isoremoxipride (FLB 457)
-
[18F]fallypride: 5-(3-[18F]fluoropropyl)-2,3-dimethoxy-N-[(2S)-1-prop-2-enylpyrrolidin-2-yl]methyl]benzamide; [18F]N-allyl-5-fluorpropylepidepride
-
[18F]desmethoxyfallypride: (S)-N-((1-allyl-2-pyrrolidinyl)methyl)-5-(3-[18F]fluoropropyl)-2-methoxybenzamide; [18F]DMFP
-
[11C]raclopride: (2S)-3,5-Dichloro-N-[(1-ethyl-2-pyrrolidinyl)methyl]- 6-hydroxy-2-[11C]methoxybenzamide
Procedure/specifications of the examination for presynaptic dopaminergic imaging with SPECT using 123I-labeled dopamine transporter ligands and with PET using [18F]fluorodopa
As of 2019, among SPECT tracers, only [
123I]FP-CIT has been approved by both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for testing of dopaminergic neuronal integrity in suspected parkinsonian syndromes. A clinical alternative for DAT SPECT imaging is [
18F]fluorodopa PET. [
18F]fluorodopa is approved by EMA. Until 2019, [
18F]fluorodopa was not approved by US FDA for marketing by manufacturer(s) nor distributing/dispensing by commercial radiopharmacies. In October 2019, a US academic medical center received FDA approval to manufacture [
18F]fluorodopa for clinical use [
29]. This approval may facilitate production and distribution of [
18F]fluorodopa by other centers as well as commercial radiopharmacies for clinical applications. US medical centers can continue to use [
18F]fluorodopa in human subjects under an investigational new drug application (IND), as approved by the FDA for clinical research purposes.
From the pathophysiological point of view, it should be noted that the effect of dopaminergic neurodegeneration as detected with [
18F]fluorodopa PET tends to be smaller than with DAT SPECT [
30]. Indeed, the pathophysiology of DAT and DOPA reduction in the nigrostriatal degeneration follows different timeframes as the two processes are parallel but not synchronous. This is presumably due to the presence, in the presymptomatic and early symptomatic phases, of opposite compensatory mechanisms to the reduction of the number of dopaminergic terminals: on one hand the reduction of DAT, which increases the synaptic availability of dopamine, and on the other hand, the upregulation of DOPA conversion to dopamine by aromatic L-amino-acid decarboxylase (AADC) in the nerve terminal [
31]. A recent, meta-analysis of 142 positron emission tomography and single photon emission computed tomography studies demonstrated that AADC defect is consistently smaller than the dopamine transporter and vesicular monoamine transporter 2 defects, suggesting upregulation of AADC function in IPD [
30,
31]. However, available studies in small number of patients and controls demonstrated that DAT SPECT and [
18F]fluorodopa PET scans are both able to diagnose presynaptic dopaminergic deficits in early phases of PD with excellent sensitivity and specificity [
32].
SPECT using iodine-123-labeled dopamine transporter ligands
Patient preparation and precautions
Injection
Injection of the radiopharmaceutical should be performed (within the time frame given by the manufacturer) as a slow bolus over followed by a saline flush of the intravenous line.
Equipment specifications
1.
Multiple detector (triple or dual head) or other dedicated SPECT cameras for brain imaging should be used for data acquisition [
40,
41]. Single detector units are not recommended as excessively long scan times is needed to acquire the required number of counts. They may be used only if the scan time is prolonged appropriately; injected activity in the upper permissible range is used to produce high-quality images.
2.
Low energy high (or ultrahigh) resolution (LEHR or LEUHR) parallel-hole collimators are the most frequently available collimator sets for brain imaging. All-purpose collimators are not suitable, while fan-beam collimators have a more advantageous trade-off between resolution and count rate capability with respect to parallel-hole collimators. Medium energy collimators have a lower spatial resolution although they have advantages due to septal penetration [
42]. If available, collimator sets specifically adapted to the characteristics of
123I may be used. [
42]
Interpretation/semiquantification
Semiquantification
The output images from image reconstruction are considered the input for image analysis.
1.
In the clinical setting, semiquantitative analysis can be an adjunct to visual interpretation. Some studies have shown the addition of quantitative information results in improved diagnostic performance [
50,
77,
78]. In research settings, semiquantitative methods are considered to provide a more precise assessment of dopamine transporter density, allowing for more reproducible measurements of disease and response to therapy.
2.
The most commonly used semiquantitative outcome measure in both research and clinical settings is the specific binding ratio (SBR) calculated as the striatal target-to-background ratio [
79,
80]. SBR is related to, but not a specific measure of, the density of dopamine transporters; however, it is not a direct measure of DAT density (Bmax), synaptic density, or neuronal number. Many factors that are unrelated to the density of dopamine transporters influence the determination of SBR (Tables
3 reports both biological and technical factors affecting SBR).
3.
It should be noted that interobserver variation and errors can be considerable during the placement of the regions of interest (ROIs) for semiquantification. Variability in the reorientation of the brain can also affect the interpretation.
4.
Semiquantification allow more objective measurements of SBR (with improved inter-reader agreement and reader confidence). The potential correlation between clinical variables and semiquantitative parameters expressing loss of presynaptic dopaminergic neurons is a further added value [
81].
5.
ROI-based techniques can be used to assess specific DAT binding in the striatum and striatal subregions. Transverse slices are generally selected and the slices with the highest striatal uptake or the entire striatal volume can be considered to draw manual ROIs. The use of standardized ROIs is helpful in limiting operator variability to the positioning task. The shape of the template ROIs could be either geometrical or anatomical, the size should be at least twice the FWHM.
-
Reference regions with absent (or low) DAT density are used to assess nonspecific binding. The reference region is ideally the cerebellum as it contains no known dopaminergic neurons. The occipital cortex can be also used particularly when the axial field of view is limited. The methodology used for defining the reference region should be consistent across all patients measured. It is particularly important when comparing measurements at different time points in the same patient
-
If anatomical scans (MRI or CT) are available, volumetric regions encompassing the anatomic extent of the basal ganglia can be used. This is particularly important when low specific binding is expected (e.g., in case of a severe loss or blockade of the DAT), especially in the absence of an automated method.
6.
Once the volumetric ROI (VOI) are placed, SBR values are generally obtained as follows:
Table 3
Factors affecting specific binding ratio (SBR) in [123I]-FP-CIT SPECT imaging
Biological factors |
Dopamine transporter density |
Age and gender |
Pharmacokinetics factors (rate of uptake, metabolism, and elimination of tracers) |
Genetic: allelic variants of DAT |
Drugs competing with the tracer for DAT binding |
Technical factors |
Patient ability to remain motionless in the camera |
Equipment |
Resolution and sensitivity of selected camera |
Collimator |
CT-based vs. uniform attenuation map* |
Performance drifts overtime |
Acquisition |
Dose extravasations (counts in image**) |
Time postinjection |
Head position§ |
Patient movement |
Radius of rotation |
Reconstruction |
Osem vs. FBP |
Filtration |
Attenuation correction |
Scatter and septal penetration correction |
PVE correction |
Choice of SBR algorithm§§ |
Size and placement (spatial registration) of regions of interest (including background region used) |
(Mean Counts of striatal VOI − Mean Counts of background VOI)/(Mean Counts of the background VOI)
Several approaches have been proposed to perform semiquantification of DAT SPECT, and several commercial and freeware software are available.
Some of them include a one- or two-step–based fully automated registration of the patient SPECT scan to a template or to an averaged, spatially normalized brain volume. Predefined VOIs are then automatically placed on the striatal and the background regions [
82‐
88].
VOIs can also be defined for striatal substructures, allowing to quantify the SBR for caudate and putamen, as well as other parameters such as asymmetry between left and right putamen and caudate, putamen-to-caudate ratio (PCR), and caudate-putamen ratio (CPR).
The availability of these parameters can be useful in complex or borderline cases. In particular, PCR is most sensitive in borderline and early stage cases because of a higher degree of independence on camera, reconstruction algorithm, and background region. Some studies have reported a mild reduction of PCR with age, but there are conflicting data in the literature on this topic (possibly due to the number and age range of included subjects and the modalities of VOI drawing) [
87]. Evaluation of asymmetry between left and right sides is also useful in the earliest stages, although mild asymmetry between striata or striatal subregions may occur in normal subjects [
88].
All the numeric parameters are dependent on acquisition and reconstruction parameters and on the corrections applied [
49,
50]. As a result, there are no universal (age-dependent) cutoffs for normal vs. abnormal [
89‐
91]. Accordingly, each site would ideally need to establish its own reference using a healthy control group. If a local normal subject database is not available, calibration of the procedure with the characteristics of normal controls databases is needed (see below).
Differences in SBR also occur as the result of VOI strategy, with two approaches commonly employed. The first incorporates regions for the caudate and putamen on left and right sides, which tries to capture the anatomic bounds of these structures. The second approach utilizes small regions of interest sampling the tracer uptake in the caudate, mid-putamen, and posterior putamen on the right and left sides [
92,
93].
A different approach for determining the SBR is used in the so-called Southampton method [
93], based on the measurement of total counts from each striatum. It uses striatal VOIs of geometrical shape, sufficiently large to capture all counts originating from the striatum including those detected outside its anatomical boundaries, and a background region derived from the whole brain minus the striatal VOIs. The SBR is then calculated as follows:
VolStrVOI/VolStr × (CountsStrVOI/counts per voxelbkg × VolStrVOI − 1)
Individual computed tomography (CT) or MRI-guided methods [
94] and, more recently, machine-learning techniques for pattern recognition as well as parametrization of textural patterns have also been proposed as user-independent methods for DAT SPECT result classification. These methods still remain in the realm of promising research [
95,
96].
Some studies have applied PVE in the process of binding computation of the caudate nucleus, putamen, and background, but the added value of PVE in this settings has not been systematically investigated and is not recommended in routine clinical practice.
As previously mentioned, great caution must be exercised when using SBR data from the literature as differences regarding to the camera system how the images were acquired, processed, and analyzed will result in different values [
50,
87,
97,
98].
Calibrations across cameras have been described using anthropomorphic phantoms to develop relative correction factors for standardization between instruments [
46,
87,
99]. The QIBA of the RSNA is developing a protocol for quantitative standardization of [
123I]-FP-CIT SPECT analysis, which will detail a validated protocol for imaging centers to apply in order to obtain the high reproducibility [
45].
In recent years, two normative database have been provided:
The ENC-DAT (European Normal Control Database of DaTSCAN) database was developed from 2009. The study was promoted by the EANM Neuroimaging Committee, in the framework of a cooperative effort among European Nuclear Medicine centers. This multicenter project aimed to collect a large number of [
123I]FP-CIT SPECT scans of healthy controls, thus providing reference images and values of DAT availability measures across a wide age range of both genders. The final database included SPECT data from 139 healthy controls (74 men, 65 women; age range 20–83 years, mean 53 years) acquired in 13 different centers [
100].
The second database of healthy controls was collected in the framework of the Parkinson’s Progression Marker Initiative (PPMI), which is a multicenter, international, longitudinal study evaluating clinical, biochemical, and imaging measures of PD progression. PPMI aimed (1) to confirm the presence or absence of a DAT deficit for PD and healthy volunteers enrolled in the study, (2) to acquire DAT SPECT data with rigorous standardized acquisition protocols, and (3) to process images through a central core lab reconstruction of raw projection data for subsequent uniform analyses to be made available to the investigator community. PPMI includes 423 progressing Parkinson’s patients and 196 age-matched controls studied over 3 to 4 years with serial [
123I]-FP-CIT SPECT imaging and other clinical, imaging, and fluid biomarkers [
101].
Normative data provided by these two multicenter initiatives demonstrated that normal aging is associated with about 5.5–6% signal loss per decade (0.6%/year). Gender had also an effect on SBR in the caudate and putamen (often not considered in the software available for comparison) [
81,
94,
96]. Dependency of DAT on BMI, handedness, circadian rhythm, or season was not demonstrated [
87,
100,
102].
SPECT/CT: Very few studies tested the use of CT images acquired on the SPECT/CT system to derive either warping parameters for VOI or for regional SBR assessment, and the anatomical information provided by CT did not demonstrate a relevant impact on diagnostic performance [
103].
Serial imaging within the individual patient in order to track disease progression by visual or semiquantitative analysis might be clinically useful only once it has been demonstrated that signal size is able to capture the slow progression of the disease process.
Besides providing a healthy subjects database, the PPMI initiative has provided an assessment of within-subject changes of SPECT imaging in a PD patient cohort followed longitudinally over 3–5 years. The aim is to understand the utility of DAT SPECT as a putative biomarker of PD progression after early motor signs of PD appear [
104]. In fact, if intraindividual comparison is performed (i.e., baseline vs. follow-up for therapy control or assessment of disease progression), more subtle changes might need to be highlighted.
In the PPMI study, regional SBR were measured in ipsilateral and contralateral caudate, anterior putamen, and posterior putamen at baseline and 1, 2, and 4 years during the follow up of IPD patients. During the 4 years, there was a significant longitudinal change in dopamine transporter binding in all striatal regions [
104]. Available analyses seem to suggest that, given the size of signal change in an early PD cohort, [
123I]FP-CIT SPECT might be a suitable biomarker of PD progression. In fact, initial longitudinal data suggest SBR reductions over 1 year are approximately 20 times the rate of signal loss seen in normal aging [
104].
Multicenter trial harmonization
In order to harmonize imaging equipment sites for multicenter research or trials, there are several areas to be considered [
105].
1.
Data acquisition: the acquisition protocol should be harmonized as much as possible. Collimators, energy windows, pixel sizes, and required number of counts are key considerations. During this process, attention should be given to manufacturer specific requirements, e.g., energy windows for scatter correction.
2.
Image reconstruction and filtering: the choice of reconstruction and filtering is very important in harmonization particularly given that semiquantification is strongly dependent on the approach taken and the corrections included. Variability in reconstruction algorithms and functionality across centers may drive the choice of reconstruction to an approach that is comparable and achievable by centers, i.e., typically one with no corrections. Alternatively, to overcome this variability, reconstruction at a central core lab using a generic algorithm could be considered.
3.
Comparability of system performance: the use of an anthropomorphic striatal phantom can help assess comparability of visual and semiquantitative performance across sites/scanners and is, therefore, recommended [
46]. One or more data acquisitions with varying filling ratios is suggested to determine the relationship between scanner semiquantitative performances over a range of SBRs.
Presynaptic dopaminergic imaging with PET using [18F]fluorodopa
Preparation of the radiopharmaceuticals
[18F]fluorodopa as all radiopharmaceuticals must be produced by qualified personnel according to cGMP or using GMP-compliant methods that conform to regulatory requirements. The quality control is carried out by the manufacturer prior to delivery of the final product when the radiopharmaceutical is delivered ready to use.
Patient preparation and precautions
Injection
The recommended injected activity for brain imaging in adults for PET-CT is 185 MBq. If no carbidopa is given ahead of [18F]fluorodopa, higher doses may be necessary. [18F]fluorodopa should be injected as a bolus.
Image reconstruction
1.
Iterative reconstructions are currently the standard. When Ordered-Subsets Expectation Maximization (OSEM) type methods are used, the number of iterations depends on the equipment characteristics, the injected activity, and the acquisition duration as well as on the corrections included in the reconstruction process.
2.
Matrix sizes and zoom factors during reconstruction should consider the small size of the caudate and putamen. When possible, matrix sizes and zoom factors during reconstruction should be large enough in order that reconstructed voxel sizes are within 2.0–3.0 mm in any direction.
3.
Regular corrections are necessary before or during image reconstruction such as attenuation, scatter, random, dead time and decay corrections, and sensitivity normalization. To date, the benefit of time-of-flight correction has been modest, but it can be applied [
117,
118].
4.
Resolution modeling during reconstruction, called point-spread function (PSF) reconstruction, deserves specific consideration. Resolution modeling has been developed to compensate for cross-contamination between adjacent functional regions with distinct activities, referred to as PVE [
119]. In theory, given the size of the striatal structures, it would be beneficial to reconstruct the exact activity distribution using this correction. However, there is a limit to the recovery achievable by PSF correction, even at high iterations due to the loss of high frequency information during data acquisition [
119]. The application of PSF correction modifies the noise structure and it produces a “lumpiness” aspect [
120] (referred to as the Gibbs phenomenon). Therefore, PSF reconstruction artifacts can lead to misinterpretations when used to analyze small subcentimeter structures and is currently not recommended for striatal imaging
5.
Spatial filters applied during or after reconstruction should be selected as not to impair the spatial resolution needed for striatal imaging. However, the choice is highly dependent on the acquisition data (noise) and the entire reconstruction process. Ideally, the final reconstructed spatial resolution should aim at a FWHM < 6 mm.
6.
Head-movement correction can be performed if the acquisition is performed in list mode or multiframe setting (dynamic scans). Data acquired during patient movement can be discarded before reconstruction or corrected post reconstruction with dynamic or list mode acquisitions.
Interpretation/semiquantification
The uptake of [
18F]fluorodopa over the first 90 min into the striatum primarily reflects influx and decarboxylation of the tracer to [
18F]fluorodopamine [
121].
Equipment specifications
7.
State-of-the-art 3D PET/CT or PET/MRI systems should preferably be used. The equipment should allow for the acquisition of data needed for attenuation and scatter correction. Low-dose CT is the preferred option, although PET/MRI can use MRI sequences dedicated to attenuation and scatter correction of PET emission data. Transmission sources are also capable of producing adequate attenuation maps on dedicated brain PET only systems.
8.
The equipment should have an axial field of view > 15 cm to assure sufficient coverage of the entire brain, including the cerebellum and brain stem.
9.
The PET camera should be able to acquire both static and dynamic and frame or list mode PET emission data in 3D mode.
Quality control and interinstitutional PET system performance harmonization
The present guidelines are focused on the use of dopaminergic imaging in parkinsonian syndromes. However, there are both technical and imaging physics related uncertainties that apply to any PET examination regardless of radiotracer or specific application. These aspects have been detailed in previous guidelines [
129]. These recommendations should be considered for the use of brain PET examinations in multicenter studies and/or when data are compared with a reference database or disease patterns. In order to guarantee sufficient image quality, quantitative performance, and image harmonization, the correct performance of the PET system must be regularly checked by several QC experiments that have also already previously listed in EANM and joint EANM/SNMMI guidelines. Cross-calibration of the PET(/CT) system against the locally used dose calibrator to prepare and measure patient-specific radiotracer activities is needed. Cross-calibrations should be performed following EARL recommendations and criteria (
http://earl.eanm.org).
Documentation and reporting for presynaptic dopaminergic imaging with either SPECT using iodine-123-labeled dopamine transporter ligands or with PET using [18F]fluorodopa
Reporting
Patient’s name and other identifier (date of birth, name of the referring physician(s), type and date of examination) and patient’s history including the reason for requesting the study are mandatory parts of the report.
Interpretation and conclusions
New tracers for dopaminergic imaging in Parkinsonian syndromes
PET imaging of DAT using 11C-PE2I and 18F-FE-PE2I
Among several DAT radioligands available for PET imaging, [
11C]-PE2I (N-(3-iodopro-2
E-enyl)-2β-carbo[
11C]methoxy-3β-(4′-methylphenyl)nortropane) was developed in early 2000 in order to image and quantify the DAT not only in the striatum but also in extra-striatal regions, such as the substantia nigra [
130‐
132]. [
11C]PE2I is highly selective for the DAT and displays high target-to-background ratio and good test-retest reliability [
133]. It has been already used in the context of clinical trials and PET studies in patients with PD and in animal models of parkinsonism [
134‐
138].
Despite the suitable properties as a PET radioligand for the DAT, absolute quantification requires long duration of imaging for at least 90 min due to slow wash-out from the brain [
139]. In addition, a radioactive metabolite of [
11C]PE2I has been found to cross the blood-brain barrier and accumulate in the striatum in rodents. Therefore, further efforts have been made in order to develop an analog of [
11C]PE2I with improved imaging properties. [
18F]FE-PE2I (N-(3-iodoprop-2E-enyl)-2β-carbo[
18F]fluoroethoxy-3β-(4-methylphenyl)-nortropane) is a fluoroethyl analog of [
11C]PE2I developed at Karolinska Institute and highly selective for the DAT with improved pharmacokinetic properties compared with [
11C]PE2I: (i) faster washout from the brain and (ii) lower production of a radiometabolite (< 2% of plasma radioactivity) that crosses the blood-brain barrier [
140‐
143].
The quantification can be done using the cerebellum as reference region [
143]. A simplified method for the quantification of the SBR can also be used by acquiring a static image around the peak specific binding between 16.5 and 42 min after injection [
144].
The affinity of [
18F]FE-PE2I for the DAT (K
i = 12 nM) and the high target-to-background ratio permit to quantify the DAT in the striatum and in the substantia nigra [
142‐
145]. Compared with other tropane analogs including ß-CIT and FP-CIT, FE-PE2I is by far more selective for the DAT than for other monoamine transporters [
130].
Initial studies have shown that in early PD, DAT is decreased by approximately 70% in the putamen and 30% in the substantia nigra, indicating a preferential loss of the DAT in the axonal terminals [
145].
The dosimetry of [
18F]FE-PE2I has been estimated in nonhuman primates and human subjects [
146,
147]. The estimated effective dose (ED) is 0.023 mSv/MBq, which is similar to that of other
18F-labeled radioligands for brain imaging [
148].
Further studies with [
18F]FE-PE2I are ongoing to examine the DAT loss across different stages of IPD, the test-retest reliability, clinical most appropriate imaging interval, and the longitudinal assessment in IPD patients. Head-to-head comparative studies with [
123I]FP-CIT are also ongoing to examine the relative performance of [
18F]FE-PE2I in differentiating IPD from controls. The first published comparative study reported that binding potential (
BPND) of [
18F]FE-PE2I was highly correlated with [
123I]FP-CIT data, with intraclass correlation coefficients > 0.9 [
148]. Similar effect sizes were reported for both radioligands, indicating that [
18F]FE-PE2I has similar capability to differentiate patients with parkinsonism from controls as [
123I]FP-CIT [
148].
Further studies (and probably long term follow-up) will be needed to assess if patients with uncertain borderline [18F]FE-PE2I PET that cannot be explained by structural change/lesions can be better separated based on high or low uptake in the substantia nigra.
The primary clinical benefits compared with DAT SPECT include the improved resolution of PET, an improved clinical workflow, patient and caregiver convenience as a thyroid-blocking agent is not required, and shorter injection-to-scan and acquisition times.
Radiopharmaceutical’s characteristics
1.
Administered activity to adults: 100–250 MBq (typically 200 MBq)
2.
PET data acquisition:
Suggested dynamic acquisition for estimation of binding potential (BPND): duration, 60 min
Suggested static acquisitions: for best simplified estimation of specific binding ratios: 25 min from 17 to 42 min.; for routine clinical use: 10 min from 30 to 40 min
Measured or CT attenuation correction
OSEM reconstruction: resolution/PSF modeling not needed for routine clinical use. Final image resolution: 5–8 mm
Binding potential (
BPND) estimated with simplified reference tissue method or Logan graphical analysis using cerebellum as reference region [
143].
SBR calculated with cerebellar gray matter as reference. Target metrics: SBR Caudate, SBR Putamen, SBR Striatum; Putamen/Caudate ratio; Hemisphere asymmetry index = (R − L)/(R + L)
PET imaging of VMAT2
After synthesis, monoaminergic neurotransmitters are concentrated in synaptic vesicles for exocytotic release. The vesicular monoamine transporter type-2 (VMAT2) is expressed by all monoaminergic neurons and serves to transport transmitter from cytoplasm into vesicles [
149]. In the CNS, VMAT2 is expressed exclusively by monoaminergic (dopaminergic, serotonergic, norepinephrinergic, or histaminergic) neurons [
150], albeit it is also expressed in pancreatic beta cells and several monoaminergic neurons of the human enteric nervous system [
151]. Over 95% of striatal VMAT2 binding sites are associated with dopaminergic terminals [
152]. In vivo imaging and quantification of VMAT2 has been reported for a series of radioligands based on the vesicle-depleting drug tetrabenazine. The most widely used ligand for research purposes is (+)-[
11C]dihydrotetrabenazine ([
11C]DTBZ), which binds specifically and reversibly to VMAT2 and is amenable to quantification of striatal, diencephalic, and brainstem neurons and terminals with PET [
153,
154]. As only the (+)-enantiomer binds specifically to VMAT2, use of the racemic tracer reduces specificity with ensuing lower image contrast. Despite the successful application of (+)-[
11C]DTBZ for human studies, clinical utilization will likely require radioligands with longer half-lives. Fortunately, development of fluorine-18-labeled VMAT2 radioligands such as (+)-[
18F]FP-DTBZ ((+)-α-9-O-(3-[
18F]fluoropropyl)DTBZ) provides a
18F-labeled VMAT2 ligand that will be more suitable for routine use in clinical practice [
155]. When compared with (+)-[
11C]DTBZ, it is not only more favorable due to the longer half-life fluorine-18 labelling but also has higher affinity for the VMAT2 receptor (K
i = 0.3 nM vs. 0.1 nM).
Radiopharmaceutical’s characteristics
1.
Administered activity to adults: 300–450 MBq
Radioactivity uptake in the brain is highest at 7.5 ± 0.6% injected dose at 10 min after injection. High absorbed doses were found in pancreas, liver, and upper large intestine wall. The highest-dosed organ, which received 153 ± 24 μGy/MBq, was the pancreas. The effective dose for (+)-[
18F]FP-DTBZ was 28 ± 3 μSv/MBq. These values are comparable with those reported for other fluorine-18 labeled radiopharmaceuticals [
155].
A single 10-min PET scan can be acquired 90 min postinjection in 3D mode. Scanning time of 90–100 min for (+)-[
18F]FP-DTBZ is considered as the optimal time window for summed uptake measurements in terms of correlation of standardized uptake value ratio (SUVRs of striatum to occipital cortex) to distribution volume ratios (obtained with dynamic acquisition) as well as in terms of differential power, stability, and clinical feasibility across and between patients with IPD and control subjects [
156].
4.
Image processing
Measured or CT attenuation correction
PET images can be reconstructed using 3D OSEM algorithm
(+)-[
18F]FP-DTBZ binding in normal control subjects shows symmetric and highest uptake of (+)-[
18F]FP-DTBZ in striatum, followed by nucleus accumbens, hypothalamus, substantia nigra, and raphe nuclei [
157].
6.
Quantification analysis
Striatal VMAT2 density of anterior putamen is higher than posterior putamen, which is higher than that of the caudate nucleus. Lowest uptake is seen in the cortex with essentially no specific binding in the occipital cortex [
157].
Procedure/specifications of the examination for postsynaptic dopaminergic imaging
Historically, the most widely applied radiotracers for imaging D2-like receptors with SPECT has been [
123I]IBZM [
158,
159]. For PET, [
11C]raclopride, [
18F]fallypride and [
18F]Desmethoxyfallypride (DMFP) have been used. These dopamine receptor antagonist derivatives are not selective radiopharmaceuticals for the D2 receptor since they also bind to the D3 receptor [
159]. However, the vast majority of D2-like receptors in the striatum are D2 receptors. EANM GLs aiming to describe standard procedures for brain neurotransmission using dopamine D2 receptor ligands have been published in 2009 [
9]. These guidelines dealt with indications, assessment, processing, interpretation, and reporting of D2 imaging. The procedural recommendations defined in these GLs are still presently valid with the exception of details on equipment specification, which should be updated in agreement of what already described in previous paragraphs of the present GLs. It should be noted that the main added clinical value of D2 imaging in patients with parkinsonian syndromes was the proposed capability of this imaging to support the differential diagnosis within neurodegenerative parkinsonisms by differentiating between diseases with (i.e., atypical parkinsonism such as MSA, CBD, and PSP) and without (i.e., IPD) degeneration at postsynaptic level [
10]. However, D2 SPECT imaging is at the moment not clinically available in several countries, and it has been suggested that FDG PET outperforms D2 SPECT Imaging for the differential diagnosis between PD/DLB and the other atypical parkinsonisms [
27]. Similarly, [
123I]mIBG myocardial scintigraphy can be used to differentiate between IPD and MSA, PSP and CBD [
160]. Accordingly, updated data on the use of these tracers are beyond the aims of the present clinical use-oriented standard procedures, and the procedural published by the EANM NeuroImaging Committee in 2009 should be still considered as the main reference for D2 dopaminergic imaging in parkinsonian syndromes [
9].
Radiation safety
In this section, we present a set of values and advice that are compliant with the legal requirements in the European Basic Safety Standards Directive and with IAEA Safety Guides and the SNMMI Guideline for General Imaging [
161,
162]. However, the way the EU directive is being implemented in the national member states in Europe varies considerably. In addition, regional and local rules, e.g., from local ethical committees, may also apply in a specific setting and supersede this guideline. The general system of radiation protection is based on the three concepts of (1) justification, (2) optimization, and (3) dose limits.
Justification for an examination at the individual level is implicit when following the indications in this guideline. The set of acquisition parameters given in this guide serves to optimize the activity used (and the dose provided) for current standard equipment. Further local optimization may apply when special, more sensitive equipment is available. Dose limits do not apply for medical exposure of patients; protection is managed through the justification and optimization only. For biomedical research performed on patients or volunteers, however, ICRP (ICRP62 and ICRP103), WHO, and EC (EC RP99) have issued guidance balancing the value for society of the expected outcome of the research against (effective) dose. This is the source of information that ethics committees (institutional review boards) will typically consider.
In addition—since medical use of radiation is a “planned exposure”—the concept of dose constraints applies to “comforters and cares,” to relatives, to “other” hospital staff not working directly with ionizing radiation, and to members of the public. The relevant radiation exposure for these groups is highly dependent on local factors and procedures. It therefore falls outside the scope of this guideline and must be handled by the associated medical physics expert.
For the tracers described in this guideline, effective dose and absorbed dose (per MBq) to the highest exposed organs has been compiled from the available literature and is given in Table
4 [
40,
147,
155,
163‐
169]. In most cases, following this guideline will lead to effective doses below 5 mSv per examination.
Table 4
Radiation dosimetry (in adults)
[123I]β-CIT | Lung | 0.10 | 0.031–0.04 | |
Liver | 0.09 |
Basal Ganglia* | 0.27** |
[123I]FP-CIT | Liver | 0.085 | 0.025 | |
Colon | 0.059 |
Gall bladder wall | 0.044 |
Lung | 0.042 |
[99mTc]Trodat-1 | Liver | 0.047 | 0.012 | |
Kidney | 0.035 |
[18F]-FDOPA | Urinary bladder wall | 0.30 | 0.025 | |
Kidney | 0.031 |
[123I]-PE2I | Urinary bladder wall | 0.07 | 0.022 | |
[11C]-PE2I | Urinary bladder wall | 0.018 | 0.0064 | |
Kidney | 0.016 |
Stomach wall | 0.014 |
[18F]FE-PE2I | Urinary bladder wall | 0.119 | 0.023 | |
Liver | 0.046 |
[11C]DTBZ | Stomach wall | 0.016 | 0.0066 | |
Kidney | 0.013 |
[18F]FP-DTBZ ([18F]AV-133) | Pancreas | 0.153 | 0.028 | |
Liver | 0.072 |
Upper large intestine | 0.055 |
If a CT scan is utilized for attenuation correction only, the lowest possible exposure settings should be used, resulting in a contribution to effective dose of less than 0.1 mSv.
In radiation protection, there is a special concern for a fetus (pregnancy) and small children (breastfeeding) due to their higher radiosensitivity. General rules for obtaining information about pregnancy status must be established and followed as locally implemented. Neither pregnancy nor breastfeeding are absolute contraindications for imaging using ionizing radiation, but require careful considerations for the justification. The need to support the diagnosis of parkinsonian syndromes with SPECT or PET examinations rarely apply to pregnant or breastfeeding patients.
However, like for any other diagnostic procedure in a female patient known or suspected to be pregnant, a clinical decision is necessary in which the benefits are weighed against the possible (hypothetical) harm. If the procedure consists of a static scan, it may be possible to reduce the activity (hence the absorbed dose to organs and effective dose) and prolong the acquisition time to maintain image quality; a reduction in image quality is not recommended.
Acknowledgments
We thank the EANM Committees, EANM National Societies, and the SNMMI bodies for their review and contribution. We are also truly grateful to the members of the EANM Radiation Protection Committee for their contribution to the “
Radiation safety” paragraph. Also, we thank Sonja Niederkofler and Michaela Bartaun from the EANM office in Vienna and Julie Kauffman from the SNMMI office in Reston for their great support during the development of this guideline. We acknowledge the contribution of previous guidelines on which the present are based [
9,
11,
12].
Compliance with ethical standards
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Approval
These practice guidelines were approved by the Board of Directors of the EANM and SNMMI.
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