Nuclear Medicine
CLINICAL DECISION SUPPORT
[123I]Ioflupane selectively binds to the presynaptic dopamine transporters (DaT) in the striatum (caudate and putamen).
[18F]fluorodopa crosses the blood-brain-barrier and is metabolized by the aromatic amino aciddecarboxylase into fluorodopamine and stored in the vesicles of the presynaptic dopaminergic neuronal terminals of the striatum. Human studies have shown that the uptake of fluorodopa in the striatum and cerebellum can be increased approximately two-fold by administration of the amino acid decarboxylase inhibitor carbidopa.
Uptake of [123I]Ioflupane and [18F]fluorodopa is reduced in diseases in which there is a loss of dopaminergic neurons in the Substantia Nigra (SN) and of nigrostriatal Dopaminergic innervation.
The indication for [123I]Ioflupane and [18F]fluorodopa are defined by the European Medicines Agency (EMA) and their corresponding package inserts:
DaTScan™ and DOPACIS™ are indicated for detecting loss of functional dopaminergic neuron terminals in the striatum:
The only absolute contra-indication of these two radiotracers is pregnancy. Breast feeding should be interrupted for 4 days ([123I]Ioflupane) or 12 h ([18F]FDOPA) after injection [40].
[123I]Ioflupane. A pooled analysis of the phase 3 and phase 4 clinical trials including 764 subjects used for the US new drug application to the Food and Drug Administration (FDA) was performed [50]. Overall the sensitivity and specificity for identifying a striatal dopaminergic deficit was 91.9% and 83.6%, respectively. These values were 88.7% and 91.2%, respectively, when considering only the readings by a panel of independent experts. It should be noted that the reference standard is the clinical diagnosis, usually at 12 months. Such reference standard obviously has its own limitations. Interestingly, the agreement between imaging and clinical diagnosis increases with a longer follow up, which tends to indicate an improvement in the clinical reference standard over time and supports the robustness of the early imaging diagnosis. Other studies have shown high interobserver agreement with k values comprised between 0.8 and 1.0 [51]
[18F]fluorodopa. Early -PET studies showed that putamen dopamine storage contralateral to the affected limbs is consistently reduced in early hemi-PD [52–54]. Recent 3-D studies, however, revealed loss of [18F]fluorodopa uptake in both the contralateral and ipsilateral putamen as well as in the contralateral caudate in early hemi-PD patients, with dorsal structures being more severely affected than ventral ones. Whereas patients with essential tremor show normal striatal FD [18F]fluorodopa Ki [54], a significant decrease of [18F]fluorodopa uptake in the putamen was demonstrated in patients with monosymptomatic resting tremor (mRT) despite the absence of rigor and hypokinesia [55]. The characteristic pattern of [18F]fluorodopa uptake reduction usually allows an early and reliable diagnosis in cases with isolated resting, postural and kinetic tremor of the limbs in which the differential diagnosis remains unclear after clinical examination. In general, it should be emphasized that the implementation of [18F]fluorodopa and other functional imaging modalities in the management of PD patients has its significance and eligibility in clinically questionable or ambiguous cases [56]. At time of symptom onset, PD patients show a nearly 30% loss of [18F]fluorodopa uptake in the putamen contralateral to the most affected limbs [57]. [18F]fluorodopa -PET therefore provides a potential mean of detecting subclinical nigral dysfunction in subjects at risk of PD: putamen FD [18F]fluorodopa OPA uptake has been found to be reduced in asymptomatic co-twins of affected PD patients, with a rate of 40% of monozygotic and 8% of dizygotic cases (30,31). Piccini et al. studied [18F]fluorodopa -PET in 32 asymptomatic relatives of seven kindreds with familial PD and found evidence for dopaminergic dysfunction in 25% of these cases [58]. In atypical parkinsonism the number of intact dopaminergic neurons is considerably decreased and [18F]fluorodopa uptake is, therefore, an unreliable discriminator between them and idiopathic PD [56].
The suggested activities to administer for adults are:
The effective dose for per administered activity is 25 µSv/MBq [3]:
The range of the effective doses for the suggested activities is: 1.3-6.3 mSv.
The effective dose for [18F]fluorodopa is 25 µSv/MBq [3]. The organ with the highest absorbed dose is the urinary bladder wall: 300 µGy/MBq
The range in effective dose for [18F]fluorodopa is: 1.3-10 mSv per procedure.
Caveat
“Effective Dose” is a protection quantity that provides a dose value related to the probability of health detriment to an adult reference person due to stochastic effects from exposure to low doses of ionizing radiation. It should not be used to quantify the radiation risk for a single individual associated with a particular nuclear medicine examination. It is used to characterize a certain examination in comparison to alternatives, but it should be emphasized that if the actual risk to a certain patient population is to be assessed, it is mandatory to apply risk factors (per mSv) that are appropriate for the gender, the age distribution and the disease state of that population."
Visual assessment is fairly simple for both radiotracers. A normal finding shows homogenous and symmetrical uptake in the striatum. Abnormal scans include 1) asymmetric uptake with normal or almost normal putamen activity in one hemisphere and a more marked change on the side contralateral to the most affected clinical side; 2) reduced uptake in the putamen on both sides; and 3) uptake virtually absent bilaterally in the striatum. Such dichotomized answer based upon the visual analysis was used in the validation trials of Ioflupane, and is effective in the routine clinical practice. Semiquantitative analysis using DAT binding values obtained by ROI techniques with those of age-matched normal controls can also be of help, although there is no consensus regarding the optimal methodology and its added clinical value. The interpretation of fluorodopa (18F) uptake values in the different parts of the brain requires the comparison to age and sex matched controls. Recent publications refer to data base of normal cases and voxel-based Statistical Parametric Mapping (SPM) and automated region of interest (ROI) analysis (EMA Package leaflet).
The major pitfalls include the age of the patient, as the binding decreases with age in both radiotracers, and drugs that affect the radiotracer uptake.
Ioflupane. Drugs affecting the uptake should be withdrawn for at least 5 times the biological half-life of the drug.
It is also important to prevent the accumulation of free 123I in the thyroid by temporarily blocking the gland. This may be achieved for instance by administering 200 mg of sodium perchlorate at least 5 min before injecting the tracer.
[18F]fluorodopa should be given to patients fasting for a minimum of 4 h without limiting water intake. In order to obtain images of best quality and to reduce the radiation exposure of the bladder, patients should be encouraged to drink sufficient amounts and to empty their bladder prior to and after the PET examination. It is recommended to suspend any antiparkinsonian treatment at least 12 h before the PET examination.
The detailed recommendations regarding procedures for presynaptic Dopaminergic Imaging with SPECT tracers and [18F]fluorodopa are detailed in the joint EANM Practice guideline/SNMMI Procedure Standard for Dopaminergic Imaging in Parkinsonian Syndromes 1.0 [59].