Method to determine the statistical technical variability of SUV metrics.

BACKGROUND: The Standardized Uptake Value (SUV) Max, SUVMean, and SUVPeak are metrics used to quantify positron emission tomography (PET) images. In order to assess the significance of a change in these metrics for diagnostic purposes, it is relevant to know their variation. The sources of variation can be biological or technical. In this study, we present a method to determine the statistical technical variation of SUV in PET images. RESULTS: This method was tested on a NEMA quality phantom with spheres of various diameters with a full-length acquisition time of 150 s per bed position and foreground-to-background activity ratio of F18-2-fluoro-2-deoxy-D-glucose (FDG) of 10:1. Our method divides the 150 s acquisition into subsets with statistically independent frames of shorter reconstruction length. SUVMax, Mean and Peak were calculated for each reconstructed image in a subset. The coefficient of variation of SUV within each subset has been used to estimate the expected coefficient of variation at 150 s reconstruction length. We report the largest coefficient of variation of the SUV metrics for the smallest sphere and the smallest variation for the largest sphere. The expected variation at 150 s reconstruction length does not exceed 6% for the smallest sphere and 2% for the largest sphere. CONCLUSIONS: With the presented method, we aim to determine the statistical technical variation of SUV. The method enables the evaluation of the effect of SUV metric choice (Max, Mean, Peak) and lesion size on the technical variation and, therefore, to evaluate its relevance on the total variation of the SUV value between clinical studies.

Validation of quantitative salivary gland scintigraphy in relation to the American-European concensus criteria for Sjögren's syndrome.

PURPOSE: The aim of this retrospective study was to evaluate the diagnostic value of semiquantitative parameters in salivary gland scintigraphy (SGS) in the diagnostic work-up of primary Sjögren's Syndrome (SS) using the American-European consensus criteria (AECC) as the gold standard. PATIENTS AND METHODS: 99mTc-pertechnetate-SGS was performed in 110 patients with suspected primary SS. Uptake ratios (URs) and excretion fractions (EFs) for all parotid and submandibular salivary glands were calculated. Patients were divided into SS-positive, SS-negative, and SS-equivocal groups on the basis of the AECC criteria. SGS semiquantitative parameters were compared per group and cut-off values were defined. RESULTS: Ninety-six (87%) women and 14 (13%) men with a mean age of 51 years (range: 18-77 years) were included. All patients underwent SGS, labial biopsy, Schirmer's test, and antibody tests (anti-SS-A and anti-SS-B). Twenty-four patients were SS positive, 56 patients were SS negative, and 30 patients were SS-equivocal.UR of the parotid glands did not differ between SS-positive and SS-negative groups [mean (range): 3.4 (1.4-6.9) and 3.9 (2.2-6.5), respectively], whereas UR of the submandibular glands were significantly lower in SS-positive patients [mean (range): 2.7 (1.1-5.6) and 3.5 (2.3-5.3), respectively]. EF in both parotid and submandibular glands was significantly lower in SS-positive patients compared with SS-negative patients: parotid 24% (range: -4 to 53%) and 36% (range: 15-58%), respectively; submandibular 16% (range: -5 to 46%) and 29% (range: 9-49%), respectively.On the basis of a cut-off value of 2.0 for UR and 20% for EF, the sensitivity, specificity, positive predictive value, and negative predictive value were 0.67, 0.86, 86, and 67%, respectively. Of 30 SS-equivocal patients, 15 had a positive SGS, whereas the other 15 were SGS negative. In both, there was no correlation with the AECC criteria IV (histopathology) and VI (antibodies). In these cases, the SGS result was decisive. CONCLUSION: Quantitative SGS is a valuable tool in the diagnostic management of patients with suspected primary SS, especially in those in whom the nonscintigraphic AECC criteria are not conclusive. The straightforward quantitative analysis of SGS used in this study can be implemented in any nuclear medicine department.

A method to measure the absorbed dose of the thyroid during I-131 therapy, using a collar detector system and a SPECT acquisition.

PURPOSE: Due to variations in biological half-life, accurate thyroid dosimetry for I-131 therapy is not trivial in clinical practice. In recent publications, systems are described to measure the uptake of I-131 in the thyroid repeatedly over time. In this work, we present a method to calculate patient specific pharmacokinetics and absorbed dose using such a collar detector system (CoTI) in combination with a SPECT acquisition and a two-compartment model fit. METHODS: For three patients receiving I-131 therapy for benign thyroid conditions, the complete uptake profile is measured over a period of 15 to 25 days after administration. A SPECT measurement is performed to assess the functional volume of the thyroid and the amount of I-131 in the thyroid. The uptake profile measured in counts-per-second is converted to absolute activity in MBq using the absolute quantification of the SPECT. A two-compartment model is used as a fit to the uptake data of the thyroid and to estimate the activity in the blood-pool. The estimated absorbed dose to the thyroid is then calculated from the integral of the activity. The assessed parameters from the method (6- and 24-h uptake, thyroid volume and I-131 uptake concentration) are compared with the values as determined in clinical practice. Furthermore, the convergence of the calculated absorbed dose as a function of measurement series duration is determined to assess the required measurement duration of the uptake profile. RESULTS: The two-compartment model fit shows a good agreement with the measured data points. Resulting dynamic uptake profiles of the three patients differ from each other. The uptake percentages differ from the pretherapy I-123 uptake measurements that are used in usual clinical practice, which shows the potential added value of the proposed method. The duration of the required measurement series appears to be patient dependent and therefore needs to be determined for each patient individually. The proposed method allows for a basic investigation of the individual dynamic uptake profile of I-131 in the thyroid and the calculation of the absorbed dose. CONCLUSIONS: The proposed measurement method is feasible and easily implementable given a system that can measure the uptake of I-131 in the thyroid repeatedly over time. The observed differences in dynamic uptake profiles and the differences in the absorbed thyroid dose as calculated with our method and the parameters of the usual clinical care support the relevance of the proposed method. In future studies, this approach may possibly be used for outcome prediction and therapeutic activity optimization.

Measuring the actual I-131 thyroid uptake curve with a collar detector system: a feasibility study.

Radionuclide therapy using I-131 is commonly used for the treatment of benign thyroid diseases. The therapeutic dose to be administered is calculated based on the type of disease, the volume of the thyroid, and the measured uptake percentage. This methodology assumes a similar biological half-life of iodine, whereas in reality a large variation in biological half-life is observed. More knowledge about the actual biological half-life of iodine for individual patients will improve the quantification of the delivered radiation dose during radioiodine therapy and could aid the evaluation of the success of the therapy. In this feasibility study we used a novel measurement device [Collar Therapy Indicator (CoTI)] to measure the uptake curve of patients undergoing I-131 radioiodine therapy. The CoTI device is a light-weight wearable device that contains two independent gamma radiation detectors that are placed in a collar. By comparing results of thyroid uptake measurements with results obtained with a gamma camera, the precision of the system is demonstrated. Additionally, for three patients the uptake curve is measured during 48 h of admission in the hospital. The presented results demonstrate the feasibility of the new measurement device to measure the uptake curve during radioiodine therapy.

Variations in 123I-metaiodobenzylguanidine (MIBG) late heart mediastinal ratios in chronic heart failure: a need for standardisation and validation.

BACKGROUND: There is lack of validation and standardisation of acquisition parameters for myocardial (123)I-metaiodobenzylguanidine (MIBG). This lack of standardisation hampers large scale implementation of (123)I-MIBG parameters in the evaluation of patients with chronic heart failure (CHF). METHODS: In a retrospective multi-centre study (123)I-MIBG planar scintigrams obtained on 290 CHF patients (82% male; 58% dilated cardiomyopathy; New York Heart Association [NYHA classification] > I) were reanalysed to determine the late heart-to-mediastinum ratio (H/M). RESULTS: There was a large variation in acquisition parameters. Multivariate forward stepwise regression showed that a significant proportion (31%, p < 0.001) of the variation in late H/M could be explained by a model containing patient-related variables and acquisition parameters. Left ventricular ejection fraction (p < 0.001), type of collimation (p < 0.001), acquisition duration (p = 0.001), NYHA class (p = 0.028) and age (p = 0.034) were independent predictors of late H/M. CONCLUSIONS: Acquisitions parameters are independent contributors to the variation of semi-quantitative measurements of cardiac (123)I-MIBG uptake. Improved standardisation of cardiac (123)I-MIBG imaging parameters would contribute to increased clinical applicability for this procedure.

No-carrier-added versus carrier-added123I-metaiodobenzylguanidine for the assessment of cardiac sympathetic nerve activity.

PURPOSE: No-carrier-added (nca) MIBG is primarily associated with specific uptake (i.e. uptake-1 mechanism). We evaluated the hypothesis that nca MIBG will be less influenced by changes in extra-neuronal uptake (i.e. uptake-2 mechanism) compared with carrier-added (ca) MIBG. METHODS: No-carrier-added MIBG was compared with ca MIBG of two different manufacturers (ca MIBG-1 and ca MIBG-2, with a specific activity of 200 Mq/mumol and 40 MBq/mumol MIBG respectively) in rats (n=6 per group): controls, blocking uptake-1 (desipramine) and blocking uptake-2 (phenoxybenzamine hydrochloride). Dedicated pinhole SPECT was performed 2 h after injection of the radiotracer. After SPECT, biodistribution was assessed [% injected dose per gram tissue (%ID)]. RESULTS: No-carrier-added MIBG had the highest absolute cardiac uptake. Although a clear trend was observed, nca MIBG was not statistically significantly different from ca MIBG-1 (0.31+/-0.05 %ID vs 0.25+/-0.01 %ID,p=0.05). Blocking uptake-1 resulted in a significant decrease in absolute cardiac uptake only for nca MIBG (0.22+/-0.03 %ID,p=0.004). Blocking uptake-2 resulted in a significant reduction in ca MIBG-1 cardiac uptake (0.14+/-0.02 %ID,p=0.0001), but not in the cardiac uptake of nca MIBG or MIBG-2. SPECT showed the highest relative cardiac uptake for nca MIBG. Poor contrast between myocardium and surrounding tissue hampered assessment of relative cardiac uptake on SPECT of both ca MIBG-1 and ca MIBG-2. CONCLUSION: No-carrier-added MIBG yields a higher myocardial uptake than ca MIBG and is associated with a higher specific as well as a lower non-neuronal uptake. We therefore conclude that for the scintigraphic assessment of the myocardial sympathetic nervous system, nca MIBG is to be preferred over ca MIBG.

Pinhole SPECT imaging of dopamine transporters correlates with dopamine transporter immunohistochemical analysis in the MPTP mouse model of Parkinson's disease.

The in vivo analysis of dopaminergic degeneration in animal models of Parkinson's disease (PD), using pinhole single photon emission computed tomography (SPECT), ideally should afford a serial study design, enabling the analysis of the degenerative process as well as the potential neuroprotective and/or restorative properties of drugs over time in living animals. Previously, we demonstrated that striatal dopamine transporter (DAT) levels in rats could be analyzed reproducibly, using pinhole SPECT with the DAT probe [(123)I]N-omega-fluoropropyl-2beta-carbomethoxy-3beta-{4-iodophenyl}nortropane (FP-CIT). However, the capacity of this approach to accurately detect a range of striatal DAT levels in the most widely used animal model of PD, i.e., the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mouse, remains to be determined. For this purpose, various levels of DAT were induced by treating c57BL/6J mice for 1, 3, or 5 days with MPTP (25 mg/kg ip), respectively. [(123)I]FP-CIT SPECT scans were performed 5 days after the last MPTP injection. Mice were perfused 6 days after the last MPTP injection, and the SPECT data were compared to ex vivo striatal and nigral DAT levels as measured by immunohistochemistry within the same animals. The analysis of striatal DAT levels using SPECT and DAT immunohistochemistry yielded highly comparable results on the percentage of DAT reduction in each MPTP group. The in vivo data showed a decrease of specific striatal to non-specific binding ratios by 59%, 82%, and 76% in mice treated for 1, 3, and 5 days, respectively. Moreover, a strong, positive correlation was observed between the in vivo and ex vivo parameters. The present study provides the first evidence that [(123)I]FP-CIT pinhole SPECT allows the accurate detection of a range of striatal DAT (i.e., losses of approximately 60-80%) levels in mice. Since such large dopaminergic lesions could be detected, this SPECT method may at least be useful for analyzing neuroprotective treatment with a clear-cut positive (i.e., complete protection) or negative (i.e., not any protection) effect. Whether this method is also useful for analyzing more subtle effects of neuroprotective treatment (partial protection) remains to be established, by studying mice with small dopaminergic lesions.

Validation of [(123)I]beta-CIT SPECT to assess serotonin transporters in vivo in humans: a double-blind, placebo-controlled, crossover study with the selective serotonin reuptake inhibitor citalopram.

Disturbances in the serotonin (5-HT) system are associated with various neuropsychiatric disorders. The 5-HT system can be studied in vivo by measuring 5-HT transporter (SERT) densities using (123)iodine-labeled 2beta-carbomethoxy-3beta(4-iodophenyl)tropane ([(123)I]beta-CIT) and single photon emission computed tomography (SPECT). Validation of this technique is important because [(123)I]beta-CIT does not bind selectively to SERTs. Some studies have validated this technique in vivo in the human brain in SERT-rich areas, but the technique has not been validated yet in SERT-low cortical areas. The aim of this study was to further validate [(123)I]beta-CIT SPECT in assessing SERTs in vivo in humans in both SERT-rich and SERT-low areas. A double-blind, placebo-controlled, crossover design was used with the selective 5-HT reuptake inhibitor (SSRI) citalopram. Six male subjects underwent two [(123)I]beta-CIT SPECT sessions: one after pretreatment with citalopram and one after placebo. Scans were acquired 4 h and 22-27 h p.i., and both region-of-interest and voxel-by-voxel analyses were performed. Citalopram reduced [(123)I]beta-CIT binding ratios in SERT-rich midbrain and (hypo)thalamus. Binding ratios were also lower after citalopram in SERT-low cortical areas, but statistical significance was only reached in several cortical areas using voxel-by-voxel analysis. In addition, citalopram increased binding ratios in the DAT-rich striatum and increased absolute uptake in the cerebellum. The results show that [(123)I]beta-CIT SPECT is a valid technique to study SERT binding in vivo in human brain in SERT-rich areas. Although we provide some evidence that [(123)I]beta-CIT SPECT may be used to measure SERTs in SERT-low cortical areas, these measurements must be interpreted with caution.

Cerebral blood flow changes during script-driven imagery in police officers with posttraumatic stress disorder.

BACKGROUND: Functional brain imaging studies in posttraumatic stress disorder (PTSD) have focused mostly on war or sexual abuse victims, many of whom also had comorbid disorders. The aim of this study was to examine the neuronal circuitry underlying responses to script-driven imagery in traumatized police officers with and without PTSD and with low comorbidity rates. METHODS: In a case-matched control study, 30 traumatized police officers with and without PTSD underwent clinical assessment and (99m)technetium-hexa-methyl-propylene-amine-oxime single photon emission computed tomography scanning with neutral and trauma scripts. Statistical parametric mapping was applied to analyze changes in regional cerebral blood flow. RESULTS: The main findings were significantly less activation in the medial frontal gyrus and more activation in the right cuneus in the PTSD group relative to the trauma-exposed control group in reaction to trauma versus neutral scripts. Within the PTSD group, subjects showed less activation in the superior temporal gyrus, left lentiform nucleus, left middle frontal gyrus, and left inferior frontal gyrus in reaction to trauma scripts. CONCLUSIONS: We confirmed previous findings of dysfunction of the medial frontal gyrus in PTSD in a new population with low comorbidity rates. Other alterations were found in certain brain structures involved in emotional, memory, linguistic, visuospatial, and motor processing.

A realistic 3-D gated cardiac phantom for quality control of gated myocardial perfusion SPET: the Amsterdam gated (AGATE) cardiac phantom.

A realistic 3-D gated cardiac phantom with known left ventricular (LV) volumes and ejection fractions (EFs) was produced to evaluate quantitative measurements obtained from gated myocardial single-photon emission tomography (SPET). The 3-D gated cardiac phantom was designed and constructed to fit into the Data Spectrum anthropomorphic torso phantom. Flexible silicone membranes form the inner and outer walls of the simulated left ventricle. Simulated LV volumes can be varied within the range 45-200 ml. The LV volume curve has a smooth and realistic clinical shape that is produced by a specially shaped cam connected to a piston. A fixed 70-ml stroke volume is applied for EF measurements. An ECG signal is produced at maximum LV filling by a controller unit connected to the pump. This gated cardiac phantom will be referred to as the Amsterdam 3-D gated cardiac phantom, or, in short, the AGATE cardiac phantom. SPET data were acquired with a triple-head SPET system. Data were reconstructed using filtered back-projection following pre-filtering and further processed with the Quantitative Gated SPECT (QGS) software to determine LV volume and EF values. Ungated studies were performed to measure LV volumes ranging from 45 ml to 200 ml. The QGS-determined LV volumes were systematically underestimated. For different LV combinations, the stroke volumes measured were consistent at 60-61 ml for 8-frame studies and 63-65 ml for 16-frame studies. QGS-determined EF values were slightly overestimated between 1.25% EF units for 8-frame studies and 3.25% EF units for 16-frame studies. In conclusion, the AGATE cardiac phantom offers possibilities for quality control, testing and validation of the whole gated cardiac SPET sequence, and testing of different acquisition and processing parameters and software.

Validity of in vivo [123I]beta-CIT SPECT in detecting MDMA-induced neurotoxicity in rats.

This study investigated the ability of a high-resolution pinhole single-photon emission computed tomography (SPECT) system, with [(123)I]beta-CIT as a radiotracer, to detect 3,4-methelenedioxymethamphetamine (MDMA, 'Ecstasy')-induced loss of serotonin transporters (SERTs) in the living rat brain. In vivo striatal and thalamic [(123)I]beta-CIT binding ratios, representing specific binding to dopamine and serotonin transporters, respectively, were determined 7 days before as well as 10 days after treatment of rats with neurotoxic doses of MDMA using SPECT. At the end of the experiment, radioactivity ratios were also determined ex vivo, and compared to control data. Both in vivo and ex vivo, thalamic, but not striatal, uptake ratios were statistical significantly reduced after MDMA treatment. These data show that [(123)I]beta-CIT SPECT may be able to detect MDMA-induced loss of SERTs. Therefore, this may be a promising technique to perform serial studies on MDMA-induced serotonergic neurotoxicity in living small animals.

Imaging of striatal dopamine transporters in rat brain with single pinhole SPECT and co-aligned MRI is highly reproducible.

A recently developed pinhole high-resolution SPECT system was used to measure striatal to non-specific binding ratios in rats (n = 9), after injection of the dopamine transporter ligand (123)I-FP-CIT, and to assess its test/retest reproducibility. For co-alignment purposes, the rat brain was imaged on a 1.5 Tesla clinical MRI scanner using a specially developed surface coil. The SPECT images showed clear striatal uptake. On the MR images, cerebral and extra-cerebral structures could be easily delineated. The mean striatal to non-specific [(123)I]FP-CIT binding ratios of the test/retest studies were 1.7 +/- 0.2 and 1.6 +/- 0.2, respectively. The test/retest variability was approximately 9%. We conclude that the assessment of striatal [(123)I]FP-CIT binding ratios in rats is highly reproducible.

Imaging of dopamine transporters in rats using high-resolution pinhole single-photon emission tomography.

To date, the vast majority of investigations on the dopaminergic system in small animals have been in vitro studies. In comparison with in vitro studies, single-photon emission tomography (SPET) or positron emission tomography (PET) imaging of the dopaminergic system in small animals has the advantage of permitting repeated studies within the same group of animals. Dopamine transporter imaging is a valuable non-invasive tool with which to investigate the integrity of dopaminergic neurons. The purpose of this study was to investigate the feasibility of assessing dopamine transporter density semi-quantitatively in rats using a recently developed high-resolution pinhole SPET system. This system was built exclusively for imaging of small animals. In this unique single-pinhole system, the animal rotates instead of the collimated detector. The system has proven to have a high spatial resolution. We performed SPET imaging with [(123)I]FP-CIT to quantify striatal dopamine transporters in rat brain. In all seven studied control rats, symmetrical striatal binding to dopamine transporters was seen 2 h after injection of the radiotracer, with striatal-to-cerebellar binding ratios of approximately 3.5. In addition, test/retest variability of the striatal-to-cerebellar binding ratios was studied and found to be 14.5%. Finally, in unilaterally 6-hydroxydopamine-lesioned rats, striatal binding was only visible on the non-lesioned side. Quantitative analysis revealed that striatal-to-cerebellar SPET ratios were significantly lower on the lesioned (mean binding ratio 2.2 +/- 0.2) than on the non-lesioned (mean ratio 3.1 +/- 0.4) side. The preliminary results of this study indicate that semi-quantitative assessment of striatal dopamine transporter density using our recently developed high-resolution single-pinhole SPET system is feasible in living rat brain.

Validity of [123I]beta-CIT SPECT in detecting MDMA-induced serotonergic neurotoxicity.

Recent [123I]beta-CIT single-photon emission computed tomography (SPECT) studies revealed decreased serotonin transporters (SERT) density in the brain of humans with a history of MDMA ("Ecstasy") use. However, [123I]beta-CIT SPECT has until now not been validated as a method for detecting such serotonergic lesions. Therefore, the present study was undertaken. Following baseline [123I]beta-CIT SPECT scans, a rhesus monkey was treated with MDMA (5 mg/kg, s.c. twice daily for 4 consecutive days). SPECT studies 4, 10, and 31 days after MDMA treatment revealed decreases in [123I]beta-CIT binding ratios in the SERT-rich brain region studied (hypothalamic/midbrain region), with SERT density reduced by 39% in this brain region 31 days after treatment. Data obtained with SPECT studies correlated well with SERT density determined with autoradiography after sacrifice of the animal (-34%). In addition, ex vivo [123I]beta-CIT binding studies in rats 1 week after treatment with neurotoxic doses of MDMA (20 mg/kg s.c. twice daily for 4 consecutive days) revealed significant reductions in [123I]beta-CIT binding in SERT-rich regions (including the hypothalamus) when compared to saline-treated rats. The combined results of these studies indicate that SPECT imaging of SERT with [123I]beta-CIT can detect changes in SERT density secondary to MDMA-induced neurotoxicity in the hypothalamic/midbrain region, and possibly other brain regions.