Experimental evaluation of absolute quantification in 99m Tc-TRODAT-1 SPECT/CT brain dopamine transporter (DAT) studies.

OBJECTIVE: To evaluate the quantitative accuracy of clinical brain dopamine transporters (DAT) investigations utilizing 99m Tc-TRODAT-1 single-photon emission computed tomography (SPECT)/computed tomography (CT) in experimental and clinical settings. MATERIALS AND METHODS: The study used an experimental phantom evaluation and a clinical dataset. Three-dimensional-ordered subsets expectation-maximization reconstructed the original and resampled datasets using attenuation correction, scatter correction, and resolution recovery. The reconstructed data were analyzed and reported as percentage difference, standardized uptake value reference (SUVr), and a coefficient of variation (CoV). The Taguchi method tested the impact of the three different parameters on signal-to-noise ratio (SNR) and SUVr, including number iteration, Poisson resampling, and phantom setup, with and without the plaster of Paris (POP). Six 99m Tc-TRODAT-1 SPECT/CT scans were acquired in healthy subjects for verification purposes. RESULTS: The percentage activity difference between the phantom with and without POP is 20% and 5%, respectively. The SUVr reveals a 10% underestimate for both with and without POP. When it comes to the influence of Poisson resampling, the SUVr value for 75% Poisson resampling indicates 10% underestimation on both sides of the caudate and putamen area, with and without POP. When 25% of Poisson resampling is applied, the SUVr value is overestimated (±35%). In the Taguchi analysis, iteration numbers were the most dominant factor with the F-value of 9.41 and the contribution rate of 52.66% (p < 0.05) for SNR. In comparison, F-value of 9.1 for Poisson resampled with contribution rate of 58.91% (p < 0.05) for SUVr. Reducing counts by 25% from the original dataset resulted in a minimal bias in SUVr, compared to 50% and 75%. CONCLUSION: The optimal absolute SPECT/CT quantification of brain DAT studies using 99m Tc-TRODAT-1 appears achievable with at least 4i10s and SUVr as the surrogate parameter. In clinical investigations, it is possible to reduce the recommended administered dose by up to 25% while maintaining accurate measurement.

Spatially constrained kinetic modeling with dual reference tissues improves 18F-flortaucipir PET in studies of Alzheimer disease.

PURPOSE: Recent studies have shown that standard compartmental models using plasma input or the cerebellum reference tissue input are generally not reliable for quantifying tau burden in dynamic 18F-flortaucipir PET studies of Alzheimer disease. So far, the optimal reference region for estimating 18F-flortaucipir delivery and specific tau binding has yet to be determined. The objective of the study is to improve 18F-flortaucipir brain tau PET quantification using a spatially constrained kinetic model with dual reference tissues. METHODS: Participants were classified as either cognitively normal (CN) or cognitively impaired (CI) based on clinical assessment. T1-weighted structural MRI and 105-min dynamic 18F-flortaucipir PET scans were acquired for each participant. Using both a simplified reference tissue model (SRTM2) and Logan plot with either cerebellum gray matter or centrum semiovale (CS) white matter as the reference tissue, we estimated distribution volume ratios (DVRs) and the relative transport rate constant R1 for region of interest-based (ROI) and voxelwise-based analyses. Conventional linear regression (LR) and LR with spatially constrained (LRSC) parametric imaging algorithms were then evaluated. Noise-induced bias in the parametric images was compared to estimates from ROI time activity curve-based kinetic modeling. We finally evaluated standardized uptake value ratios at early phase (SUVREP, 0.7-2.9 min) and late phase (SUVRLP, 80-105 min) to approximate R1 and DVR, respectively. RESULTS: The percent coefficients of variation of R1 and DVR estimates from SRTM2 with spatially constrained modeling were comparable to those from the Logan plot and SUVRs. The SRTM2 using CS reference tissue with LRSC reduced noise-induced underestimation in the LR generated DVR images to negligible levels (< 1%). Inconsistent overestimation of DVR in the SUVRLP only occurred using the cerebellum reference tissue-based measurements. The CS reference tissue-based DVR and SUVRLP, and cerebellum-based SUVREP and R1 provided higher Cohen's effect size d to detect increased tau deposition and reduced relative tracer transport rate in CI individuals. CONCLUSION: Using a spatially constrained kinetic model with dual reference tissues significantly improved quantification of relative perfusion and tau binding. Cerebellum and CS are the suggested reference tissues to estimate R1 and DVR, respectively, for dynamic 18F-flortaucipir PET studies. Cerebellum-based SUVREP and CS-based SUVRLP may be used to simplify 18F-flortaucipir PET study.

A Pilot Study of the Striatal Dopamine Transporter Levels in Kratom-Dependent and Normal Subjects Using 99mTc-TRODAT-1 Single Photon Emission Computed Tomography-Computed Tomography (SPECT-CT).

OBJECTIVE: The study aims to elucidate the effects of kratom addiction on dopamine transporter (DAT) using [2-[[2-[[[3-(4-chlorophenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-yl]methyl](2-mercaptoethyl)amino]ethyl]amino]ethanethiolato(3-)-N2,N20,S2,S20]oxo-[1R-(exo-exo)]-[99mTc] technetium (99mTc-TRODAT-1) brain single photon emission computed tomography-computed tomography (SPECT-CT) in kratom-dependent and healthy subjects. MATERIALS AND METHODS: We recruited 12 kratom-dependent subjects and 13 healthy men to participate in this study. Addiction, craving, depression, and cognitive scores were assessed. All subjects received a single bolus injection of 99mTc-TRODAT-1 with 914.1 MBq ± 65.5 of activity (mean ± SD). The brain SPECT-CT images were reconstructed using 3D ordered subset expectation maximization (3D-OSEM) along with attenuation correction (AC), scatter correction (SC), and resolution recovery (RR) with an iteration number of four and a subset of 10. The Cohen's Kappa interrater-reliability between two raters, the standardized uptake value of body weight (SUVBW), and the asymmetrical index percentage (AI%) were evaluated. RESULTS: Kappa statistics showed a fine agreement of abnormal 99mTc-TRODAT-1 uptake in the striatum region for the kratom-dependent group with the κ value of 0.69 (p = 0.0001), and the percentage of agreement for rater 1 and rater 2 was 56% and 64%, respectively. There was a reduction in average SUV in kratom-dependent subjects compared to healthy control subjects in the left caudate and left striatum (0.938 vs. 1.251, p = 0.014, and 1.055 vs. 1.29, p = 0.036, respectively). There was a significant difference in the AI% of the caudate region between the kratom-dependent group and the normal group (33% vs. 14%, p = 0.019). CONCLUSION: Our findings signify that kratom addiction, may cause a change in DAT level and the results can be confirmed using 99mTc-TRODAT-1 SPECT-CT.

Re-irradiation Using Stereotactic Radiotherapy: A Bibliometric Analysis of Research Trends.

The objective of this research is to conduct a comprehensive bibliometric analysis using the Web of Science Core Collection (WoSCC) to examine the current research topics and trends pertaining to stereotactic-based re-irradiation. A bibliometric search was conducted for re-irradiation-related literature published in English from the WoSCC database from 1991 to 2022, using VOSviewer to visualize the results. The extracted information comprises the publication year, overall citation count, average citation rate, keywords, and research domains. We conducted a literature review to identify trends in research on re-irradiation. A total of 19,891 citations were found in 924 qualifying papers that came from 48 different nations. The number of publications and citations has grown steadily since 2008 with the highest number of publications in the year 2018. Similarly, a substantial increase in the number of citations has increased since 2004 and the citation growth rate has been positive between 2004 and 2019 with a peak in 2013. The top authorship patterns were six authors (111 publications and 2498 citations), whereas the highest number of citations per publication was attained with an authorship pattern of 17 authors (C/P = 41.1). The collaboration patterns analysis showed that the largest proportion of publications emanated from the United States with 363 publications (30.9%), followed by Germany with 102 publications (8.7%), and France with 92 publications (7.8%). The majority of the analyzed studies were focused on the brain (30%), head and neck (13%), lung (12%), and spine (10%) and there have been emerging studies on the use of re-irradiation for lung, prostate, pelvic and liver utilizing stereotactic radiotherapy. The main areas of interest have changed over time and are now based on a multidisciplinary approach that integrates advanced imaging techniques, stereotactic treatment delivery, the toxicity of organs at risk, quality of life, and treatment outcomes.

Effectiveness of Robotic Stereotactic Radiotherapy in Patients Undergoing Re-irradiation: A Review.

Stereotactic ablative radiotherapy (SABR) is a possible treatment option for patients who develop recurrence within or at the edge of a previously irradiated volume. Robotic stereotactic radiotherapy is the result of technological advances in robotic precision, real-time imaging, non-invasive, highly customizable treatment plan, and delivery with sub-millimeter accuracy. This article reviews the radiobiologic, technical, and clinical aspects of robotic-based SABR re-irradiation for various anatomical sites. An extensive literature search was performed to identify articles on the utilization of robotic stereotactic radiotherapy for patients undergoing re-irradiation. The reported prescription dose and fractionation data along with outcomes such as overall survival, local control rates, and toxicities were qualitatively reviewed. The findings consistently indicate that re-irradiation using robotic SABR provides encouraging survival rates with minimal toxicity in the clinical setting of various anatomical sites delivered using locally non-invasive means where other treatment options are scarce.

Phase 1 Evaluation of 11C-CS1P1 to Assess Safety and Dosimetry in Human Participants.

This study evaluated the safety, dosimetry, and characteristics of 3-((2-fluoro-4-(5-(2'-methyl-2-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-1,2,4-oxadiazol-3-yl)benzyl)(methyl-11C)amino)propanoic acid (11C-CS1P1), a radiotracer targeting sphingosine-1-phosphate receptor (S1PR) 1 (S1PR1). S1PR1 is of clinical interest because of its role in multiple sclerosis (and other conditions), with an expanding class of S1PR modulators approved for relapsing multiple sclerosis. 11C-CS1P1 binds S1PR1 with high specificity and has shown promise in animal models of inflammatory diseases. Methods: 11C-CS1P1 was injected into 5 male and 6 female healthy participants. Ten participants were imaged with PET using a multipass whole-body continuous-bed-motion acquisition, and one had dedicated head and neck PET and MRI. Participants were continuously monitored for safety events. Organ time-activity curve data were collected, integrated, and normalized to the injected activity. Organ radiation doses and effective dose were computed using the adult male and female models in OLINDA, version 2.2. SUV images were evaluated for qualitative biodistribution. Results: No adverse events were observed after the dose, including no bradycardia. The liver was the critical organ from dosimetry analysis (mean ± SD: female, 23.12 ± 5.19 µSv/MBq; male, 21.06 ± 1.63 µSv/MBq). The whole-body effective dose (as defined by International Commission on Radiological Protection publication 103) was 4.18 ± 0.30 µSv/MBq in women and 3.54 ± 0.14 µSv/MBq in men. Using a maximum delivered dose of 740 MBq (20 mCi), the effective dose for women would be 3.1 mSv (0.31 rem), with a liver dose of 17.1 mSv (1.7 rem); the effective dose for men would be 2.6 mSv (0.26 rem), with a liver dose of 15.6 mSv (1.56 rem). Brain uptake was seen predominantly in gray matter and correlated with regional S1PR1 RNA expression (r = 0.84). Conclusion: These results support the safety of 11C-CS1P1 for evaluation of inflammation in human clinical populations. Dosimetry permits repeated measures in the same participants. Brain uptake correlates well with known target topography.

Accuracy Assessment of SUV Measurements in SPECT/CT: A Phantom Study.

Advances in iterative image reconstruction enable absolute quantification of SPECT/CT studies by incorporating compensations for collimator-detector response, attenuation, and scatter. This study aimed to assess the quantitative accuracy of SPECT/CT based on different levels of 99mTc activity (low/high) using different SUV metrics (SUVmean, SUVmax, SUV0.6 max, and SUV0.75 max [the average values that include pixels greater than 60% and 75% of the SUVmax in the volume of interest, respectively]). Methods: A Jaszczak phantom equipped with 6 fillable spheres was set up with low and high activity ratios of 1:4 and 1:10 (background-to-sphere) on background activities of 10 and 60 kBq/mL, respectively. The fixed-size volume of interest based on the diameter of each sphere was drawn on SPECT images using various metrics for SUV quantification purposes. Results: The convergence of activity concentration was dependent on the number of iterations and application of postfiltering. For the background-to-sphere ratio of 1:10 with a low background activity concentration, the SUVmean metric showed an underestimation of about 38% from the actual SUV, and SUVmax exhibited an overestimation of about 24% for the largest sphere diameter. Meanwhile, bias reductions of as much as -6% and -7% for SUV0.6 max and SUV0.75 max, respectively, were observed. SUVmax gave a more accurate reading than the others, although points that exceeded the actual value were detected. At 1:4 and 1:10 background activity of 10 kBq/mL, a low activity concentration attained a value close to the actual ratio. Use of 2 iterations and 10 subsets without postfiltering gave the most accurate values for reconstruction and the best image overall. Conclusion: SUVmax is the best metric in a high- or low-contrast-ratio phantom with at least 2 iterations, 10 subsets, and no postfiltering.

InVitro and In Vivo Investigation of S1PR1 Expression in the Central Nervous System Using [3H]CS1P1 and [11C]CS1P1.

Sphingosine-1-phosphate receptor 1 (S1PR1) is ubiquitously expressed among all tissues and plays key roles in many physiological and cellular processes. In the central nervous system (CNS), S1PR1 is expressed in different types of cells including neurons, astrocytes, and oligodendrocyte precursor cells. S1PR1 has been recognized as a novel therapeutic target in multiple sclerosis and other diseases. We previously reported a promising S1PR1-specific radioligand, [11C]CS1P1 (previously named [11C]TZ3321), which is under clinical investigation for human use. In the current study, we performed a detailed characterization of [3H]CS1P1 for its binding specificity to S1PR1 in CNS using autoradiography and immunohistochemistry in human and rat CNS tissues. Our data indicate that [3H]CS1P1 binds to S1PR1 in human frontal cortex tissue with a Kd of 3.98 nM and a Bmax of 172.5 nM. The distribution of [3H]CS1P1 in human and rat CNS tissues is consistent with the distribution of S1PR1 detected by immunohistochemistry studies. Our microPET studies of [11C]CS1P1 in a nonhuman primate (NHP) show a standardized uptake value of 2.4 in the NHP brain, with test-retest variability of 0.23% among six different NHPs. Radiometabolite analysis in the plasma samples of NHP and rat, as well as in rat brain samples, showed that [11C]CS1P1 was stable in vivo. Kinetic modeling studies using a two-compartment tissue model showed that the positron emission tomography (PET) data fit the model well. Overall, our study provides a detailed characterization of [3H]CS1P1 binding to S1PR1 in the CNS. Combined with our microPET studies in the NHP brain, our data suggest that [11C]CS1P1 is a promising radioligand for PET imaging of S1PR1 in the CNS.

Impact of Resolution Recovery in Quantitative 99mTc SPECT/CT Cardiac Phantom Studies.

BACKGROUND: The aim of this study was to validate the quantitative accuracy of single photon emission computed tomography with computed tomography (SPECT/CT) images in cardiac phantom studies. The study was performed by assessing the effect of resolution recovery (RR) when using half-time of imaging acquisition in cardiac phantom. METHODS: The SPECT/CT images of the anthropomorphic phantom with a cardiac insert, liver, lung, and spine were acquired using the GE Discovery (NM/CT 670) SPECT/CT system. Different concentration activity ratios for different organ (10:10:1:0, cardiac:liver:background:lung) regions were acquired by using full- and half-time protocols for 643 and 1283 voxel sizes that were reconstructed using filtered back projection (FBP) method and 3D ordered subset expectation maximization (3D-OSEM). Attenuation correction and scatter correction were applied to both reconstructions, whereas the RR only can be applied for 3D-OSEM. The data were analyzed and reported in terms of absolute recovery coefficient percentage between the cardiac insert and background activity concentration. Another parameter used to assess the quantitative accuracy for defect region was the relative error percentage. RESULTS: The result of recovery coefficient percentage shows that the 3D-OSEM reconstruction with the RR gives the highest percentage estimation accuracy of 70% of activity recovery in the cardiac phantom wall compared with FBP (10.6%). The relative error percentage for reconstructed SPECT/CT images using 3D-OSEM reconstruction with RR shows the least error compared with FBP (21% vs. 45.1%) both in the full-and half-time acquisition of images with a larger number of matrix size used. CONCLUSIONS: 3D-OSEM reconstruction with the RR is beneficial in giving better quantitative evaluation with a good resolution myocardial perfusion image. To accomplish this, a larger matrix size is required for 3D-OSEM reconstruction with the RR and it demonstrated an improvement in image resolution and increased quantitative accuracy of the final reconstructed SPECT/CT images.

Impact of PET/CT system, reconstruction protocol, data analysis method, and repositioning on PET/CT precision: An experimental evaluation using an oncology and brain phantom.

PURPOSE: In longitudinal oncological and brain PET/CT studies, it is important to understand the repeatability of quantitative PET metrics in order to assess change in tracer uptake. The present studies were performed in order to assess precision as function of PET/CT system, reconstruction protocol, analysis method, scan duration (or image noise), and repositioning in the field of view. METHODS: Multiple (repeated) scans have been performed using a NEMA image quality (IQ) phantom and a 3D Hoffman brain phantom filled with 18 F solutions on two systems. Studies were performed with and without randomly (< 2 cm) repositioning the phantom and all scans (12 replicates for IQ phantom and 10 replicates for Hoffman brain phantom) were performed at equal count statistics. For the NEMA IQ phantom, we studied the recovery coefficients (RC) of the maximum (SUVmax ), peak (SUVpeak ), and mean (SUVmean ) uptake in each sphere as a function of experimental conditions (noise level, reconstruction settings, and phantom repositioning). For the 3D Hoffman phantom, the mean activity concentration was determined within several volumes of interest and activity recovery and its precision was studied as function of experimental conditions. RESULTS: The impact of phantom repositioning on RC precision was mainly seen on the Philips Ingenuity PET/CT, especially in the case of smaller spheres (< 17 mm diameter, P < 0.05). This effect was much smaller for the Siemens Biograph system. When exploring SUVmax , SUVpeak , or SUVmean of the spheres in the NEMA IQ phantom, it was observed that precision depended on phantom repositioning, reconstruction algorithm, and scan duration, with SUVmax being most and SUVpeak least sensitive to phantom repositioning. For the brain phantom, regional averaged SUVs were only minimally affected by phantom repositioning (< 2 cm). CONCLUSION: The precision of quantitative PET metrics depends on the combination of reconstruction protocol, data analysis methods and scan duration (scan statistics). Moreover, precision was also affected by phantom repositioning but its impact depended on the data analysis method in combination with the reconstructed voxel size (tissue fraction effect). This study suggests that for oncological PET studies the use of SUVpeak may be preferred over SUVmax because SUVpeak is less sensitive to patient repositioning/tumor sampling.

Parametric Methods for Dynamic 11C-Phenytoin PET Studies.

In this study, the performance of various methods for generating quantitative parametric images of dynamic 11C-phenytoin PET studies was evaluated. Methods: Double-baseline 60-min dynamic 11C-phenytoin PET studies, including online arterial sampling, were acquired for 6 healthy subjects. Parametric images were generated using Logan plot analysis, a basis function method, and spectral analysis. Parametric distribution volume (VT) and influx rate (K1) were compared with those obtained from nonlinear regression analysis of time-activity curves. In addition, global and regional test-retest (TRT) variability was determined for parametric K1 and VT values. Results: Biases in VT observed with all parametric methods were less than 5%. For K1, spectral analysis showed a negative bias of 16%. The mean TRT variabilities of VT and K1 were less than 10% for all methods. Shortening the scan duration to 45 min provided similar VT and K1 with comparable TRT performance compared with 60-min data. Conclusion: Among the various parametric methods tested, the basis function method provided parametric VT and K1 values with the least bias compared with nonlinear regression data and showed TRT variabilities lower than 5%, also for smaller volume-of-interest sizes (i.e., higher noise levels) and shorter scan duration.

Impact of New Scatter Correction Strategies on High-Resolution Research Tomograph Brain PET Studies.

PURPOSE: The aim of this study is to evaluate the impact of different scatter correction strategies on quantification of high-resolution research tomograph (HRRT) data for three tracers covering a wide range in kinetic profiles. PROCEDURES: Healthy subjects received dynamic HRRT scans using either (R)-[(11)C]verapamil (n = 5), [(11)C]raclopride (n = 5) or [(11)C]flumazenil (n = 5). To reduce the effects of patient motion on scatter scaling factors, a margin in the attenuation correction factor (ACF) sinogram was applied prior to 2D or 3D single scatter simulation (SSS). RESULTS: Some (R)-[(11)C]verapamil studies showed prominent artefacts that disappeared with an ACF-margin of 10 mm or more. Use of 3D SSS for (R)-[(11)C]verapamil showed a statistically significant increase in volume of distribution compared with 2D SSS (p < 0.05), but not for [(11)C]raclopride and [(11)C]flumazenil studies (p > 0.05). CONCLUSIONS: When there is a patient motion-induced mismatch between transmission and emission scans, applying an ACF-margin resulted in more reliable scatter scaling factors but did not change (and/or deteriorate) quantification.

Quantification of Dynamic 11C-Phenytoin PET Studies.

UNLABELLED: The overexpression of P-glycoprotein (Pgp) is thought to be an important mechanism of pharmacoresistance in epilepsy. Recently, (11)C-phenytoin has been evaluated preclinically as a tracer for Pgp. The aim of the present study was to assess the optimal plasma kinetic model for quantification of (11)C-phenytoin studies in humans. METHODS: Dynamic (11)C-phenytoin PET scans of 6 healthy volunteers with arterial sampling were acquired twice on the same day and analyzed using single- and 2-tissue-compartment models with and without a blood volume parameter. Global and regional test-retest (TRT) variability was determined for both plasma to tissue rate constant (K1) and volume of distribution (VT). RESULTS: According to the Akaike information criterion, the reversible single-tissue-compartment model with blood volume parameter was the preferred plasma input model. Mean TRT variability ranged from 1.5% to 16.9% for K1 and from 0.5% to 5.8% for VT. Larger volumes of interest showed better repeatabilities than smaller regions. A 45-min scan provided essentially the same K1 and VT values as a 60-min scan. CONCLUSION: A reversible single-tissue-compartment model with blood volume seems to be a good candidate model for quantification of dynamic (11)C-phenytoin studies. Scan duration may be reduced to 45 min without notable loss of accuracy and precision of both K1 and VT, although this still needs to be confirmed under pathologic conditions.

Comparison of HRRT and HR+ scanners for quantitative (R)-[11C]verapamil, [11C]raclopride and [11C]flumazenil brain studies.

PURPOSE: This study was conducted to directly compare the high-resolution research tomograph (HRRT) (high-resolution brain) and HR+ (standard whole-body) positron emission tomography (PET) only scanners for quantitative brain studies using three tracers with vastly different tracer distributions. PROCEDURES: Healthy volunteers underwent successive scans on HR+ and HRRT scanners (in random order) using either (R)-[(11)C]verapamil (n = 6), [(11)C]raclopride (n = 7) or [(11)C]flumazenil (n = 7). For all tracers, metabolite-corrected plasma-input functions were generated. RESULTS: After resolution matching, HRRT-derived kinetic parameter values correlated well with those of HR+ for all tracers (intraclass correlation coefficients ≥0.78), having a good absolute interscanner test-retest variability (≤15 %). However, systematic differences can be seen for HRRT-derived kinetic parameter values (range -13 to +15 %). CONCLUSION: Quantification of kinetic parameters based on plasma-input models leads to comparable results when spatial resolution between HRRT and HR+ data is matched. When using reference-tissue models, differences remain that are likely caused by differences in attenuation and scatter corrections and/or image reconstruction.