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Eur J Nucl Med Mol Imaging DOI 10.1007/s00259-009-1267-x

GUIDELINES

EANM procedure guidelines for brain neurotransmission SPECT using 123I-labelled transporter ligands, version 2

Jacques Darcourt & Jan Booij & Klaus Tatsch & Andrea Varrone & Thierry Vander Borght & Özlem L. Kapucu & Kjell Någren & Flavio Nobili & Zuzana Walker & Koen Van Laere

# EANM 2009

Abstract These guidelines summarize the current views of standard of DAT SPECT imaging, which will increase the the European Association of Neuroimaging diagnostic impact of this technique in neurological practice. Committee (ENC). The aim of the guidelines is to assist The present document is an update of the 2002 guidelines [1] nuclear medicine practitioners when making recommenda- and has been guided by the views of various national tions, performing, interpreting, and reporting the results of societies: the Task Group Neuro-Nuclear-Medicine of the clinical (DAT) single photon emission German Society of Nuclear Medicine [2], a consensus computed tomography (SPECT) studies using 123I-labelled statement of the imaging centres included in the “Kompe- radiopharmaceuticals. The aim is to achieve a high-quality tenznetz-Parkinson” sponsored by the German Federal

J. Darcourt K. Någren Nuclear Medicine, Centre Antoine Lacassagne and University Department of Clinical Physiology and Nuclear Medicine, Hospital, Université de Nice Sophia Antipolis, Rigshospitalet, University of Copenhagen University Hospital, Nice, Copenhagen,

J. Booij Department of Nuclear Medicine, F. Nobili Academic Medical Center AMC, Clinical Neurophysiology Unit, Amsterdam, The Netherlands San Martino Hospital, University of Genova, K. Tatsch Genova, Italy Department of Nuclear Medicine, Municipal Hospital of Karlsruhe Inc, Z. Walker Karlsruhe, Germany Psychiatry, Department of Mental Health Sciences, University College London, A. Varrone London, UK Department of Clinical Neuroscience Psychiatry Section, Karolinska Institute, Stockholm, Sweden K. Van Laere Division of Nuclear Medicine, T. Vander Borght University Hospital Leuven, Nuclear Medicine Division, Université Catholique de Louvain Leuven, Belgium Medical Center, Mont-Godinne Medical Center, Louvain-la-Neuve, Belgium J. Darcourt (*) Ö. L. Kapucu Faculté de Médecine, Université de Nice, Department of Nuclear Medicine, Faculty of Medicine, 28 avenue de Valombrose, Gazi University, 06107 Nice cedex 02, France Ankara, Turkey e-mail: [email protected] Eur J Nucl Med Mol Imaging

Ministry of Education, and the Task Group of Neuro- Indications Nuclear-Medicine of the French Society of Nuclear Medicine [3]. The guidelines reflect the individual A. Legal registration experience of experts in European countries. The guide- lines are intended to present information specifically For [123I]FP-CIT [7]: adapted to European practice. The information provided A.1. [123I]FP-CIT imaging is indicated for detecting loss should be taken in the context of local conditions and of functional neuron terminals in the regulations. of patients with clinically uncertain parkin- sonian syndromes. It helps differentiate essential Keywords Brain . DAT. SPECT. Parkinson tremor from parkinsonian syndromes related to Parkinson’s disease (PD), multiple system atrophy and progressive supranuclear palsy. On its own, Background and definitions [123I]FP-CIT imaging is unable to discriminate between PD, multiple system atrophy and supra- From animal studies, clinical investigations and post- nuclear palsy [8–11]. mortem evaluations it is well known that the dopaminer- A.2. [123I]FP-CIT imaging is indicated for the differenti- gic neurotransmitter system plays a major role in ation of dementia with Lewy bodies from other movement disorders and particularly in parkinsonism as dementias [12–14]. well as in dementia with Lewy bodies. The nigrostriatal dopaminergic pathway is best analysed at the striatal level where the nigrostriatal neurons end and connect to B. Other potential indications the postsynaptic nerve terminals using dopamine as neurotransmitter which binds to the postsynaptic (D1 B.1. Establishment of early diagnosis of neurodegenera- and) D2 receptors. Both pre- and postsynaptic levels can tive parkinsonism. DAT SPECT imaging is suitable be targeted by PET or SPECT tracers. Imaging of D2 for assessing the presynaptic deficit in early PD [15, receptors is addressed in another guideline; here we deal 16]. with the evaluation of the presynaptic dopaminergic B.2. Assessment of disease severity. DAT binding is system. related to the clinical stage and severity of PD [17, Presynaptic events can be summarized as follows. 18]. Dopamine is stored in vesicles before being released into B.3. Differentiating patients with presynaptic parkinsonism the synaptic cleft. VMAT-2 transports cytosolic and from those with other forms of parkinsonism, e.g. newly synthesized dopamine into vesicles. The DAT, between PD and neuroleptic-induced parkinsonism. which is located in the membrane of the presynaptic nigrostriatal nerve terminals, is responsible for the C. Contraindications of dopamine from the synaptic cleft. L-DOPA is taken up by the presynaptic neurons via an amino acid C.1. . transporter, decarboxylated to dopamine by an L-aromatic C.2. Breast feeding: mothers should interrupt breast acid decarboxylase. feeding for 24 h if SPECT is indicated. Various PET tracers have been used to study these C.3. Inability to cooperate with the procedure. presynaptic targets such as 18F-DOPA for the aromatic acid decarboxylase, 11C-DTBZ for VMAT-2 and 11C- PE2I for the DAT. Various analogues labelled with 123I suitable for SPECT have shown to bind with Procedure high affinity to DAT [4–6]. Currently β-CIT (DOPAS- CAN) and FP-CIT (DaTSCAN) are commercially avail- A. Patient preparation able in Europe via MAP Medical Technologies Oy () and GE Healthcare (), respec- A.1. Prearrival tively, and are widely used in the clinical evaluation of patients. Prior to the investigation patients should avoid taking any These guidelines deal with the indications, assessment, or of abuse which could significantly processing, interpretation and reporting of DAT SPECT influence the visual and quantitative analysis of DAT investigations using the commercially available radiophar- binding ligands [19] (Table 1) (except if the specific aim maceuticals [123I]β-CIT and [123I]FP-CIT. of the study is to assess the effect of such on Eur J Nucl Med Mol Imaging

Table 1 Medication and drugs of abuse which may significantly class Drug name Comments influence the visual and quanti- 123 tative analysis of [123I]FP-CIT Cocaine May decrease striatal [ I]FP-CIT binding SPECT studies (reproduced from d-, May decrease striatal [123I]FP-CIT binding reference [19], with permission , from Springer) CNS or May decrease striatal [123I]FP-CIT binding; influences are likely when used as tablets May decrease striatal [123I]FP-CIT binding , , May decrease striatal [123I]FP-CIT binding Adrenergic or May increase striatal [123I]FP-CIT binding; influences are likely when infused at high doses Benztropine may decrease striatal binding ratios; other drugs may increase these ratios which will likely not affect visual assessments May decrease striatal [123I]FP-CIT binding Anesthetics , PCP, May decrease striatal [123I]FP-CIT binding; of interest particularly for animal SPECT studies, although ketamine and PCP are sometimes used illicitly

DAT binding). A withdrawal period of at least five times – Information about (recent) morphological imaging the drug’s biological half-life is suggested. It should be studies (CT, MRI). noted that smoking may interfere with DAT availability – Current medication, and when last taken. [20]; however, such an effect would be too small to lead to misinterpretation of an individual scan. Antiparkinsonian C. Precautions medications (e.g. L-DOPA, dopamine agonists, NMDA blockers, MAO-B inhibitors and COMT inhibitors Continuous supervision of the patients during the whole taken in standard dosages) do not markedly affect DAT scanning procedure is necessary. binding and therefore do not need to be withdrawn prior to DAT SPECT [21]. However, caution is advised in intra- D. Radiopharmaceutical individual follow-up studies, since the possibility that L- DOPA downregulates DAT expression cannot be excluded D.1. Radiopharmaceuticals [22]. – [123I]β-CIT: [123I]2β-carboxymethoxy-3β-(4-iodo- A.2. Preinjection phenyl). – [123I]FP-CIT: [123I]N-ω-fluoropropyl-2β-carbome- A.2.1. Check and ensure that the patient is able to thoxy-3β-(4-iodophenyl)nortropane. cooperate during the investigation. A.2.2. Block the gland by an adequate regimen (e.g. at least 200 mg of sodium perchlorate D.2. Preparation of the radiopharmaceutical given at least 5 min prior to injection) to prevent free radioactive iodine accumulating in Radiopharmaceuticals will be delivered ready to use. the thyroid. D.3. Quality control check

B. Information pertinent to performing DAT SPECT studies Check for radiochemical purity and other parameters of quality given in the package inserts and follow the – Patient’s history with particular focus on neurological instructions of the manufacturer. and psychiatric disorders, and current neurological and psychiatric status. D.4. Injection – Patients ability to lie still for approximately 40 to 60 min. If sedation is necessary, it should be Inject the radiopharmaceutical intravenously as a slow given at the earliest 1 h prior to the SPECT bolus over approximately 20 s followed by saline to flush acquisition. the intravenous line. Eur J Nucl Med Mol Imaging

D.5. Time interval for injection – The patient should be informed about the total acquisition time and positioned for maximum comfort. Inject the radiopharmaceuticals within the time frame given Since postprocessing routines allow correction for by the manufacturer (generally on the day of delivery). some obliquities of head orientation, the patient’s comfort (which reduces the likelihood of motion D.6. Activity during acquisition) is more important than perfect alignment of the head. The patient should be told of the – Adults: 150–250 MBq (typically 185 MBq) of either importance of avoiding (voluntary) movements of the radiopharmaceutical. head and should be asked for her/his active coopera- – Children: currently no established clinical indications; tion. If a patient is uncooperative, sedation can be used. if indicated, activity according to the recommendations The patient’s head should be only lightly restrained. It of the EANM Paediatric Task Group. is not recommended to fix the head firmly in place. E.2.2. Imaging device D.7. Radiation dosimetry – Multiple detector (triple or dual head) or other dedicated SPECT cameras for brain imaging The doses of the radiopharmaceuticals in adults and should be used for data acquisition [23]. children are shown in Table 2. – Single detector units cannot generally be recom- mended. They may only be used if the scan time is E. Data acquisition prolonged appropriately (>3 million total counts), an activity in the upper permissible range is E.1. Time from injection to start of data acquisition applied, and meticulous care is taken to produce high-quality images. – [123I]β-CIT: 18 to 24 h after injection. – LEHR or LEUHR parallel-hole collimators are the – [123I]FP-CIT: 3 to 6 h after injection. most frequently available collimator sets for brain It is recommended that a fixed time delay is used imaging. However, fan-beam collimators are preferred between injection and the beginning of data acquisition to over parallel-hole collimators due to the advantageous ensure that data are comparable between subjects and trade-off between resolution and count rate capability. intraindividual follow-up studies. All-purpose collimators are not suitable. The use of medium energy collimators could be advantageous E.2. Set-up for data acquisition regarding septal penetration; however, usually they are hampered by a lower spatial resolution [24]. If E.2.1. Positioning of the patient available, collimator sets specifically adapted to the characteristics of 123I may be used. – The patient should be encouraged to void prior to – Acquisition parameters: the start of acquisition to ensure maximum comfort during the study. The patient should be advised to – Rotational radius: smallest possible with appro- void after the scan session to minimize radiation priate patient safeguards. exposure. – Matrix: 128×128.

Table 2 Radiation dosimetry (adapted from [31–33])

Organ receiving the largest radiation dose Effective dose equivalent (mSv/MBq)

Organ Dose equivalent (mGy/MBq)

Adults [123I]β-CIT Lung, 0.10 0.031–0.035 Basal ganglia 0.27 [123I]FP-CIT Urinary bladder wall 0.054 0.024 Lung, large intestine 0.042 Children [123I]β-CIT No data available [123I]FP-CIT No data available Eur J Nucl Med Mol Imaging

– Angular sampling: 3° is recommended (360° prefiltering of the projection data or by applying a rotation). three-dimensional postfilter to the reconstructed data. – Zoom: acquisition pixel size should be one-third – Low-pass (e.g. Butterworth) filters should generally be to one-half of the expected resolution; therefore used. Resolution recovery or spatially varying filters it may be necessary to use a hardware zoom to should be used with caution, as they may produce achieve an appropriate pixel size. artefacts. Therefore the latter cannot be recommended – Acquisition mode: step and shoot mode is used for general use. predominantly. Continuous mode acquisition may provide shorter total scan times and reduce G.4. Corrections mechanical wear to the system. – Total detected events: Values from semiquantitative analysis are strongly depen- >3 million (FP-CIT); dent on the corrections performed (attenuation, scatter and >1 million (β-CIT). partial volume effect) [26]. Attenuation correction is When scatter correction is applied, lower recommended using either: numbers may be acceptable. – A calculated homogeneous correction matrix according – Total scan time: depending on the imaging to Chang (linear correction coefficient for 123I: µ=0.10– device used, typical scan time for a triple head − 0.12 cm 1). Shape contouring should be used if camera is around 30 min (e.g. 120 projections; available. Contours should include scalp and not just 40 projections per head; 45 s/projection) grey matter. Contours should be defined for each – Segmentation of data acquisition into multiple individual transaxial slice. Correct shape and position sequential acquisitions may permit exclusion of of the contours should be reviewed prior to calculation data with artefacts, e.g. remove segments of of the corrected slices. projection data with patient motion. – The measured attenuation map, e.g. from a simulta- neously or sequentially acquired transmission scan or F. Interventions from a CT scan.

Usually no intervention is performed. G.5. Reformatting

G. Image processing – Transaxial slices should be reformatted into at least three orthogonal planes. Generate transverse sections parallel G.1. Review of projection data to a given anatomic orientation (e.g. AC-PC line) ensuring a high degree of standardization in plane Unprocessed projection data should be reviewed in cine- orientation. Create coronal and sagittal sections orthogo- matic display prior to reconstruction to assess the presence nal to the transverse sections. and degree of motion, target-to-background ratios and other potential artefacts. Inspection of projection data in sinogram G.6. Semiquantitative evaluation form may also be useful. – Region of interest (ROI) techniques should be used to G.2. Reconstruction assess specific DAT binding in the striatum and striatal subregions (caudate nucleus, putamen). Reference – Methods: regions with absent (or low) DAT density (e.g. occipital – Filtered back-projection cortex, cerebellum) are used to assess nonspecific – Iterative reconstruction [25] binding. – It is helpful if ROI size (should be at least twice – Ensure that the entire brain volume is reconstructed. FWHM) and shape are standardized (e.g. use of – Reconstruct data at the highest pixel resolution, i.e. one templates) [27]. If available, ROI definition may be pixel slice thickness. based on individual morphology as obtained by image fusion with MRI, which is particularly impor- G.3. Filtering tant when low specific binding is expected (e.g. in case of a severe loss or blockade of the DAT). – Data should be filtered in all three dimension (x,y,z). Standardized ROIs can be obtained using atlas This can be achieved either by two-dimensional templates [28–30]. Eur J Nucl Med Mol Imaging

– Specific binding [(mean counts of the striatal H.2. Quantification ROI − mean counts of background ROI)/(mean counts of the background ROI)] values obtained from a patient – In addition to visual interpretation, semiquantitative are compared with those in normal (preferably age- analysis is recommended to objectively assess striatal matched) controls obtained with the same technique. DAT binding. The use of control values from a central database may – Usually transverse/oblique slices are selected for ROI reduce the need for each centre to establish its own definition. For semiquantitative evaluation, either only control groups, but only if currently performed phan- the slices with the highest striatal binding are chosen or tom studies turn out to allow comparative calculations the entire striatal volume is taken into account. for the different imaging set-ups used. – Quantification can be performed with standardized or – If intraindividual comparison is performed (i.e. baseline anatomically adjusted ROIs (using templates or MRI vs. follow-up for control or assessment of overlay techniques). disease progression) standardized evaluation using – Interpretation of quantitative results must take into approaches based on, for example, stereotactic normal- account the performed corrections (see above) and is ization are most useful. They allow a more reliable based on comparison of specific DAT binding values verification of even subtle changes. obtained by ROI techniques with those of age-matched normal controls. In general DAT binding is assessed for the entire striatum, the head of the caudate, and the H. Interpretation criteria putamen. Determination of putamen to caudate ratios may also be helpful. H.1. Visual interpretation

– Visual assessment allows the normality of DAT binding I. Reporting to be evaluated, and, if it is abnormal, to evaluate the magnitude of compromised DAT binding. In particular I.1.General visual assessment provides information regarding right to left asymmetry and about the structures (i.e. striatal Reports should include all pertinent information, including subregions) most affected. the name of the patient and other identifiers, such as date of – Images should be read on the computer screen rather birth, name of the referring physician(s), type and date of than from hard copy, because this allows variation in examination, patient history including the reason for colour table and adjustments of background subtraction requesting the study. or contrast. I.2. Body of the report – Data evaluation should take into account age and relevant morphological information (CT, MRI). Specif- I.2.1. Procedures and materials: ic attention should be paid to known structural lesions in the basal ganglia and to the structures selected as – Include a brief description of the imaging proce- reference region for semiquantitative evaluation. dure: radiopharmaceutical including administered – Pitfalls/sources of error: activity, scan acquisition delay and assessment of – Age dependency. The known reduction of DAT scan quality (if compromised give the reason, e.g. motion artefacts, etc.). binding with age has to be appreciated to avoid – If sedation is performed, briefly describe the overinterpretation. – Level of contrast and background subtraction. procedure including type and time of medication given in relation to the radiotracer injection. Inappropriate thresholding may result in arte- facts. Thresholding, if used, must be based I.2.2. Findings: Describe if the SPECT pattern is normal upon knowledge of a normal database for or not. If it is not normal, describe the location and specific radiopharmaceuticals and set-up. intensity of abnormal DAT binding. State what – Technical artefacts. The images should be critically criteria were used for interpretation (visual assess- examined during interpretation for the presence of ment, quantitative or semiquantitative measures, head motion, or attenuation artefacts or other comparison with normal database, etc.). technical artefacts due to problems I.2.3. Limitations: Where appropriate, identify factors that (centre of rotation, lack of homogeneity). could have limited the sensitivity and specificity of – Medication. Possible interaction of concomitant med- the result of the examination (i.e. movement, ication has to be taken into account. concomitant medication). Eur J Nucl Med Mol Imaging

I.2.4. Clinical issues: The report should address or answer A. Pupi and M. Seppänen, as well as the EANM Dosimetry and any pertinent clinical issues raised in the request for Physics Committee. the imaging examination. Disclaimer These guidelines summarize the views of the Neuro- I.2.5. Comparative data: Comparisons with previous imaging Committee of the EANM and reflects recommendation for examinations and reports, if available, should be which the EANM cannot be held responsible. The recommendations part of the report. In particular, information about should be taken in the context of good practice of nuclear medicine and do not substitute for national and international legal or regulatory the postsynaptic D2 receptor status or FDG pattern provisions. (and structural lesions) may be helpful in specific The guidelines have been brought to the attention of the National situations. Societies of Nuclear Medicine.

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