Tracer Kinetics Research Articles

Characterising 18F-fluciclovine uptake in breast cancer through the use of dynamic PET/CT imaging

Background18F-fluciclovine is a synthetic amino acid positron emission tomography (PET) radiotracer that is approved for use in prostate cancer. In this clinical study, we characterised the kinetic model best describing the uptake of 18F-fluciclovine in breast cancer and assessed differences in tracer kinetics and static parameters for different breast cancer receptor subtypes and tumour grades.MethodsThirty-nine patients with pathologically proven breast cancer underwent 20-min dynamic PET/computed tomography imaging following the administration of 18F-fluciclovine. Uptake into primary breast tumours was evaluated using one- and two-tissue reversible compartmental kinetic models and static parameters.ResultsA reversible one-tissue compartment model was shown to best describe tracer uptake in breast cancer. No significant differences were seen in kinetic or static parameters for different tumour receptor subtypes or grades. Kinetic and static parameters showed a good correlation.Conclusions18F-fluciclovine has potential in the imaging of primary breast cancer, but kinetic analysis may not have additional value over static measures of tracer uptake.Clinical Trial RegistrationNCT03036943.

Discovery of a highly specific 18F-labeled PET ligand for phosphodiesterase 10A enabled by novel spirocyclic iodonium ylide radiofluorination

As a member of cyclic nucleotide phosphodiesterase (PDE) enzyme family, PDE10A is in charge of the degradation of cyclic adenosine (cAMP) and guanosine monophosphates (cGMP). While PDE10A is primarily expressed in the medium spiny neurons of the striatum, it has been implicated in a variety of neurological disorders. Indeed, inhibition of PDE10A has proven to be of potential use for the treatment of central nervous system (CNS) pathologies caused by dysfunction of the basal ganglia–of which the striatum constitutes the largest component. A PDE10A-targeted positron emission tomography (PET) radioligand would enable a better assessment of the pathophysiologic role of PDE10A, as well as confirm the relationship between target occupancy and administrated dose of a given drug candidate, thus accelerating the development of effective PDE10A inhibitors. In this study, we designed and synthesized a novel 18F-aryl PDE10A PET radioligand, codenamed [18F]P10A-1910 ([18F]9), in high radiochemical yield and molar activity via spirocyclic iodonium ylide-mediated radiofluorination. [18F]9 possessed good in vitro binding affinity (IC50 = 2.1 nmol/L) and selectivity towards PDE10A. Further, [18F]9 exhibited reasonable lipophilicity (logD = 3.50) and brain permeability (Papp > 10 × 10−6 cm/s in MDCK-MDR1 cells). PET imaging studies of [18F]9 revealed high striatal uptake and excellent in vivo specificity with reversible tracer kinetics. Preclinical studies in rodents revealed an improved plasma and brain stability of [18F]9 when compared to the current reference standard for PDE10A-targeted PET, [18F]MNI659. Further, dose–response experiments with a series of escalating doses of PDE10A inhibitor 1 in rhesus monkey brains confirmed the utility of [18F]9 for evaluating target occupancy in vivo in higher species. In conclusion, our results indicated that [18F]9 is a promising PDE10A PET radioligand for clinical translation.

Incorporating cross-voxel exchange into the analysis of dynamic contrast-enhanced imaging data: theory, simulations and experimental results

Predictions of tumour perfusion are key determinants of drug delivery and responsiveness to therapy. Pharmacokinetic models allow for the estimation of perfusion properties of tumour tissues but many assume no dispersion associated with tracer transport away from the capillaries and through the tissue. At the level of a voxel, this translates to assuming no cross-voxel tracer exchange, often leading to the misinterpretation of derived perfusion parameters. Tofts model (TM), a compartmental model widely used in oncology, also makes this assumption. A more realistic description is required to quantify kinetic properties of tracers, such as convection and diffusion. We propose a Cross-Voxel Exchange Model (CVXM) for analysing cross-voxel tracer kinetics. In silico datasets quantifying the roles of convection and diffusion in tracer transport (which TM ignores) were employed to investigate the interpretation of Tofts’ perfusion parameters compared to CVXM. TM returned inaccurate values of and where diffusive and convective mechanisms are pronounced (up to 20% and 300% error respectively). A mathematical equation, developed in this work, predicts and gives the correct physiological interpretation of Tofts’ Finally, transport parameters were derived from dynamic contrast enhanced-magnetic resonance imaging of a TS-415 human cervical carcinoma xenograft by using TM and CVXM. The latter deduced lower values of and compared to TM (lower by up to 63% and 76% respectively). It also allowed the detection of a diffusive flux (mean diffusivity 155 μm2 s−1) in the tumour tissue, as well as an increased convective flow at the periphery (mean velocity 2.3 μm s−1 detected). The results serve as a proof of concept establishing the feasibility of using CVXM for accurately determining transport metrics that characterize the exchange of tracer between voxels. CVXM needs to be investigated further as its parameters can be linked to the tumour microenvironment properties (permeability, pressure…), potentially leading to enhanced personalized treatment planning.

Evaluation of [18F]PI-2620, a second-generation selective tau tracer, for assessing four-repeat tauopathies.

Tau aggregates represent a key pathologic feature of Alzheimer’s disease and other neurodegenerative diseases. Recently, PET probes have been developed for in vivo detection of tau accumulation; however, they are limited because of off-target binding and a reduced ability to detect tau in non-Alzheimer’s disease tauopathies. The novel tau PET tracer, [18F]PI-2620, has a high binding affinity and specificity for aggregated tau; therefore, it was hypothesized to have desirable properties for the visualization of tau accumulation in Alzheimer’s disease and non-Alzheimer’s disease tauopathies. To assess the ability of [18F]PI-2620 to detect regional tau burden in non-Alzheimer’s disease tauopathies compared with Alzheimer’s disease, patients with progressive supranuclear palsy (n = 3), corticobasal syndrome (n = 2), corticobasal degeneration (n = 1) or Alzheimer’s disease (n = 8), and healthy controls (n = 7) were recruited. All participants underwent MRI, amyloid β assessment and [18F]PI-2620 PET (Image acquisition at 60–90 min post-injection). Cortical and subcortical tau accumulations were assessed by calculating standardized uptake value ratios using [18F]PI-2620 PET. For pathologic validation, tau pathology was assessed using tau immunohistochemistry and compared with [18F]PI-2620 retention in an autopsied case of corticobasal degeneration. In Alzheimer’s disease, focal retention of [18F]PI-2620 was evident in the temporal and parietal lobes, precuneus, and cingulate cortex. Standardized uptake value ratio analyses revealed that patients with non-Alzheimer’s disease tauopathies had elevated [18F]PI-2620 uptake only in the globus pallidus, as compared to patients with Alzheimer’s disease, but not healthy controls. A head-to-head comparison of [18F]PI-2620 and [18F]PM-PBB3, another tau PET probe for possibly visualizing the four-repeat tau pathogenesis in non-Alzheimer’s disease, revealed different retention patterns in one subject with progressive supranuclear palsy. Imaging-pathology correlation analysis of the autopsied patient with corticobasal degeneration revealed no significant correlation between [18F]PI-2620 retention in vivo. High [18F]PI-2620 uptake at 60–90 min post-injection in the globus pallidus may be a sign of neurodegeneration in four-repeat tauopathy, but not necessarily practical for diagnosis of non-Alzheimer’s disease tauopathies. Collectively, this tracer is a promising tool to detect Alzheimer’s disease-tau aggregation. However, late acquisition PET images of [18F]PI-2620 may have limited utility for reliable detection of four-repeat tauopathy because of lack of correlation between post-mortem tau pathology and different retention pattern than the non-Alzheimer’s disease-detectable tau radiotracer, [18F]PM-PBB3. A recent study reported that [18F]PI-2620 tracer kinetics curves in four-repeat tauopathies peak earlier (within 30 min) than Alzheimer’s disease; therefore, further studies are needed to determine appropriate PET acquisition times that depend on the respective interest regions and diseases.

Mathematical Models for FDG Kinetics in Cancer: A Review.

Compartmental analysis is the mathematical framework for the modelling of tracer kinetics in dynamical Positron Emission Tomography. This paper provides a review of how compartmental models are constructed and numerically optimized. Specific focus is given on the identifiability and sensitivity issues and on the impact of complex physiological conditions on the mathematical properties of the models.

Impact of 18F-FET PET/MRI on Clinical Management of Brain Tumor Patients.

Multiparametric PET/MRI with the amino-acid analog O-(2-18F-fluoroethyl)-l-tyrosine (18F-FET) enables the simultaneous assessment of molecular, morphologic, and functional brain tumor characteristics. Although it is considered the most accurate noninvasive approach in brain tumors, its relevance for patient management is still under debate. Here, we report the diagnostic performance of 18F-FET PET/MRI and its impact on clinical management in a retrospective patient cohort. Methods: We retrospectively analyzed brain tumor patients who underwent 18F-FET PET/MRI between 2017 and 2018. 18F-FET PET/MRI examinations were indicated clinically because of equivocal standard imaging results or the clinical course. Histologic confirmation or clinical and standard imaging follow-up served as the reference standard. We evaluated 18F-FET PET/MRI accuracy in identifying malignancy in untreated suspected lesions (category, new diagnosis) and true progression during adjuvant treatment (category, detection of progression) in a clinical setting. Using multiple regression, we also estimated the contribution of single modalities to produce an optimal PET/MRI outcome. We assessed the recommended and applied therapies before and after 18F-FET PET/MRI and noted whether the treatment changed on the basis of the 18F-FET PET/MRI outcome. Results: We included 189 patients in the study. 18F-FET PET/MRI allowed the identification of malignancy at new diagnosis with an accuracy of 85% and identified true progression with an accuracy of 93%. Contrast enhancement, 18F-FET PET uptake, and tracer kinetics were the major contributors to an optimal PET/MRI outcome. In the previously equivocal patients, 18F-FET PET/MRI changed the clinical management in 33% of the untreated lesions and 53% of the cases of tumor progression. Conclusion: Our results suggest that 18F-FET PET/MRI helps clarify equivocal conditions and profoundly supports the clinical management of brain tumor patients. The optimal modality setting for 18F-FET PET/MRI and the clinical value of a simultaneous examination need further exploration. At a new diagnosis, multiparametric 18F-FET PET/MRI might help prevent unnecessary invasive procedures by ruling out malignancy; however, adding static 18F-FET PET to an already existing MRI examination seems to be of equal value. At detection of progression, multiparametric 18F-FET PET/MRI may increase therapy effectiveness by distinguishing between tumor progression and therapy-related imaging alterations.

Low activity [11C]raclopride kinetic modeling in the mouse brain using the spatiotemporal kernel method

Depending on the molar activity of the tracer, the maximal allowable injected activity in mouse brain PET studies can be extremely low in order to avoid receptor saturation. Therefore, a high level of noise can be present in the image. We investigate several dynamic PET reconstruction methods in reduced counts, or equivalently in reduced injected activity, data exemplified in [11C]raclopride BP ND and quantification using the simplified reference tissue model (SRTM). We compared independent frame reconstruction (IFR), post-reconstruction HYPR denoising (IFR + HYPR), direct reconstruction using the SRTM model (DIR-SRTM), and the spatial (KERS) and spatiotemporal kernel reconstruction (KERST). Additionally, HYPR denoising of the frames used as features for the calculation of the spatial kernel matrix, was investigated (KERS-HYPR and KERST-HYPR). In vivo data of 11 mice, was used to generate list-mode data for five reduced count levels corresponding to reductions by a factor 4, 8, 12, 16 and 32 (equivalently 2.07, 1.04, 0.691, 0.518, and 0.260 MBq). Correlation of regional BP ND and values (reduced versus full counts reconstructions) was high (r > 0.94) for all methods, with KERS-HYPR and KERST-HYPR reaching the highest correlation (r > 0.96). Among methods with regularization, DIR-SRTM showed the largest variability in BP ND (Bland–Altman SD from 3.0% to 12%), while IFR showed it for (5.1%–14.6%). KERST and KERST-HYPR were the only methods with Bland–Altman bias and SD below 5% for noise level up to a reduction factor of 16. At the voxel level, BP ND and correlation was gradually decreased with increasing noise, with the largest correlation (BP ND r > 0.88, r > 0.62) for KERS-HYPR and KERST-HYPR. The spatial and the spatiotemporal kernel methods performed similarly, while using only temporal regularization with direct reconstruction showed more variability. Although R1 values present noise, using the spatiotemporal kernel reconstruction, accurate estimates of binding potential could be obtained with mouse injected activities as low as 0.26–0.518 MBq. This is desirable in order to maintain the tracer kinetics principle in mouse studies.

Improving contrast between gray and white matter of Logan graphical analysis’ parametric images in positron emission tomography through least-squares cubic regression and principal component analysis

Logan graphical analysis (LGA) is a method for in vivo quantification of tracer kinetics in positron emission tomography (PET). The shortcoming of LGA is the presence of a negative bias in the estimated parameters for noisy data. Various approaches have been proposed to address this issue. We recently applied an alternative regression method called least-squares cubic (LSC), which considers the errors in both the predictor and response variables to estimate the LGA slope. LSC reduced the bias in non-displaceable binding potential estimates while causing slight increases in the variance. In this study, we combined LSC with a principal component analysis (PCA) denoising technique to counteract the effects of variance on parametric image quality, which was assessed in terms of the contrast between gray and white matter. Tissue time–activity curves were denoised through PCA, prior to estimating the regression parameters using LSC. We refer to this approach as LSC–PCA. LSC–PCA was assessed against OLS–PCA (PCA with ordinary least-squares (OLS)), LSC, and conventional OLS-based LGA. Comparisons were made for simulated 11 C-carfentanil and 11C Pittsburgh compound B (11C-PiB) data, and clinical 11 C-PiB PET images. PCA-based methods were compared over a range of principal components, varied by the percentage variance they account for in the data. The results showed reduced variances in distribution volume ratio estimates in the simulations for LSC–PCA compared to LSC, and lower bias compared to OLS–PCA and OLS. Contrasts were not significantly improved in clinical data, but they showed a significant improvement in simulation data —indicating a potential advantage of LSC–PCA over OLS–PCA. The effects of bias reintroduction when many principal components are used were also observed in OLS–PCA clinical images. We therefore encourage the use of LSC–PCA. LSC–PCA can allow the use of many principal components with minimal risk of bias, thereby strengthening the interpretation of PET parametric images.

Development of a Compartmental Model to Investigate the Influence of Inflammation on Predictions of Vitamin A Total Body Stores by Retinol Isotope Dilution in Theoretical Humans

BackgroundInflammation, both acute and chronic, is associated with reductions in the synthesis of retinol-binding protein (RBP) and the concentration of retinol in plasma. Consequently, it is currently recommended that the retinol isotope dilution (RID) method not be used to estimate vitamin A total body stores (TBS) in subjects with inflammation. ObjectivesTo apply compartmental analysis to study the effects of inflammation on hepatic apo-RBP input, plasma retinol pool size, and RID-predicted TBS in theoretical subjects with known steady state values for these parameters. MethodsWe selected 6 previously generated hypothetical subjects who ingested a dose of stable isotope–labeled vitamin A (day 0). Starting with each subject’s published steady state model for retinol tracer kinetics, we developed a parallel model for unlabeled retinol and RBP that incorporated links between these entities and tied liver retinol secretion to RBP availability. Then we perturbed the steady state model by initiating chronic or acute inflammation on day 0 or acute inflammation on day 3 or 9 and simulating results for RBP, plasma retinol, and TBS. ResultsChronic inflammation led to substantial reductions in RID-predicted TBS for at least 2 weeks after tracer administration. In contrast, acute inflammation induced on day 0 or 3 resulted in less dramatic impacts on TBS (37% or 20% reduction, respectively, from steady state levels, with levels rebounding by 14 days). When inflammation was induced 9 days after administration of the tracer, the effects on predicted TBS were minimal. Overall, for acute inflammation initiated at 0, 3, or 9 days, accurate predictions of TBS were obtained by 2 weeks. ConclusionsCompartmental analysis can be applied in the novel way described here to study the influence of perturbations such as inflammation on predictions of vitamin A status using RID. Such an approach has potential value for studying other perturbations and different nutrients.

Parametric Mapping for TSPO PET Imaging with Spectral Analysis Impulsive Response Function

PurposeThe aim of this study was to investigate the use of spectral analysis (SA) for voxel-wise analysis of TSPO PET imaging studies. TSPO PET quantification is methodologically complicated by the heterogeneity of TSPO expression and its cell-dependent modulation during neuroinflammatory response. Compartmental models to account for this complexity exist, but they are unreliable at the high noise typical of voxel data. On the contrary, SA is noise-robust for parametric mapping and provides useful information about tracer kinetics with a free compartmental structure.ProceduresSA impulse response function (IRF) calculated at 90 min after tracer injection was used as main parameter of interest in 3 independent PET imaging studies to investigate its sensitivity to (1) a TSPO genetic polymorphism (rs6971) known to affect tracer binding in a cross-sectional analysis of healthy controls scanned with [11C]PBR28 PET; (2) TSPO density with [11C]PBR28 in a competitive blocking study with a TSPO blocker, XBD173; and (3) the higher affinity of a second radiotracer for TSPO, by using data from a head-to-head comparison between [11C]PBR28 and [11C]ER176 scans.ResultsSA-IRF produced parametric maps of visually good quality. These were sensitive to TSPO genotype (mean relative difference between high- and mixed-affinity binders = 25 %) and TSPO availability (mean signal displacement after 90 mg oral administration of XBD173 = 39 %). Regional averages of voxel-wise IRF estimates were strongly associated with regional total distribution volume (VT) estimated with a 2-tissue compartmental model with vascular compartment (Pearson’s r = 0.86 ± 0.11) but less strongly with standard 2TCM-VT (Pearson’s r = 0.76 ± 0.32). Finally, SA-IRF estimates for [11C]ER176 were significantly higher than [11C]PBR28 ones, consistent with the higher amount of specific binding of the former tracer.ConclusionsSA-IRF can be used for voxel-wise quantification of TSPO PET data because it generates high-quality parametric maps, it is sensitive to TSPO availability and genotype, and it accounts for the complexity of TSPO tracer kinetics with no additional assumptions.

Penalized Parametric PET Image Estimation Using Local Linear Fitting

Positron emission tomography (PET) is a powerful imaging tool for quantifying physiological information. Particularly, parametric PET imaging has been increasingly investigated because the voxel-wise spatial distribution of tracer kinetics can be achieved, which is suitable for identifying heterogeneous tracer uptake. Our goal is to provide a fast and accurate parametric imaging method by utilizing the full-dose image. In this article, we propose a novel penalized parametric imaging in which dynamic images are reconstructed frame by frame, and then voxel-wise kinetic parameters are iteratively estimated by a kinetic-domain penalty using a local linear fitting (LLF) that utilizes a full-dose static image as a prior in the penalty. In our optimization, a dual-domain approximation is derived to efficiently split suboptimizations for image and kinetic parameter separately, which can simplify suboptimizations including the nonlinear fitting of the two-tissue compartment model (2-TCM). In addition, we further investigate the feasibility of image-driven input function extraction by comparing with the standard blood sampling. We evaluated the performance of the proposed method using simulation and patient study with [18F]MK6240 tau scan data of two subjects, and results are compared with the conventional method and the Logan graphical model. We demonstrate that the proposed method outperforms the conventional parametric imaging methods.

Modeling dynamic radial contrast enhanced MRI with linear time invariant systems for motion correction in quantitative assessment of kidney function.

Early identification of kidney function deterioration is essential to determine which newborn patients with congenital kidney disease should be considered for surgical intervention as opposed to observation. Kidney function can be measured by fitting a tracer kinetic (TK) model onto a series of Dynamic Contrast Enhanced (DCE) MR images and estimating the filtration rate parameter from the model. Unfortunately, breathing and large bulk motion events due to patient movement in the scanner create outliers and misalignments that introduce large errors in the TK model parameter estimates even when using a motion-robust dynamic radial VIBE sequence for DCE-MR imaging. The misalignments between the series of volumes are difficult to correct using standard registration due to 1) the large differences in geometry and contrast between volumes of the dynamic sequence and 2) the requirement of fast dynamic imaging to achieve high temporal resolution and motion deteriorates image quality. These difficulties reduce the accuracy and stability of registration over the dynamic sequence. An alternative registration approach is to generate noise and motion free templates of the original data from the TK model and use them to register each volume to its contrast-matched template. However, the TK models used to characterize DCE-MRI are tissue specific, non-linear and sensitive to the same motion and sampling artifacts that hinder registration in the first place. Hence, these can only be applied to register accurately pre-segmented regions of interest, such as kidneys, and might converge to local minima under the presence of large artifacts. Here we introduce a novel linear time invariant (LTI) model to characterize DCE-MR data for different tissue types within a volume. We approximate the LTI model as a sparse sum of first order LTI functions to introduce robustness to motion and sampling artifacts. Hence, this model is well suited for registration of the entire field of view of DCE-MR data with artifacts and outliers. We incorporate this LTI model into a registration framework and evaluate it on both synthetic data and data from 20 children. For each subject, we reconstructed the sequence of DCE-MR images, detected corrupted volumes acquired during motion, aligned the sequence of volumes and recovered the corrupted volumes using the LTI model. The results show that our approach correctly aligned the volumes, provided the most stable registration in time and improved the tracer kinetic model fit.

Quantitative Assessment of Blood Lactate in Shock: Measure of Hypoxia or Beneficial Energy Source.

Blood lactate concentration predicts mortality in critically ill patients and is clinically used in the diagnosis, grading of severity, and monitoring response to therapy of septic shock. This paper summarizes available quantitative data to provide the first comprehensive description and critique of the accepted concepts of the physiology of lactate in health and shock, with particular emphasis on the controversy of whether lactate release is simply a manifestation of tissue hypoxia versus a purposeful transfer (“shuttle”) of lactate between tissues. Basic issues discussed include (1) effect of nonproductive lactate-pyruvate exchange that artifactually enhances flux measurements obtained with labeled lactate, (2) heterogeneous tissue oxygen partial pressure (Krogh model) and potential for unrecognized hypoxia that exists in all tissues, and (3) pathophysiology that distinguishes septic from other forms of shock. Our analysis suggests that due to exchange artifacts, the turnover rate of lactate and the lactate clearance are only about 60% of the values of 1.05 mmol/min/70 kg and 1.5 L/min/70 kg, respectively, determined from the standard tracer kinetics. Lactate turnover reflects lactate release primarily from muscle, gut, adipose, and erythrocytes and uptake by the liver and kidney, primarily for the purpose of energy production (TCA cycle) while the remainder is used for gluconeogenesis (Cori cycle). The well-studied physiology of exercise-induced hyperlactatemia demonstrates massive release from the contracting muscle accompanied by an increased lactate clearance that may occur in recovering nonexercising muscle as well as the liver. The very limited data on lactate kinetics in shock patients suggests that hyperlactatemia reflects both decreased clearance and increased production, possibly primarily in the gut. Our analysis of available data in health and shock suggests that the conventional concept of tissue hypoxia can account for most blood lactate findings and there is no need to implicate a purposeful production of lactate for export to other organs.

Copper-64-immunoPET imaging: bench to bedside.

Positron emission tomography (PET) is a growing non-invasive diagnostic and molecular imaging tool in nuclear medicine, that is used to identify several diseases including cancer. The immunoPET probe is made up of monoclonal antibodies (mAbs) or its fragments or similar molecules that tagged with positron radioisotopes (68Ga, 64Cu, 89Zr) bound together by a bifunctional chelator (BFC). This probe is designed to identify a specific disease. Currently, several immunoPET probes are being developed for preclinical as well as for clinical applications. These studies are showing promising results, both in preclinical and patients, using mostly 64Cu, 89Zr isotopes. This review elucidates the 64Cu based immunoPET applications, their pipelines and the emerging scope of this technique within the nuclear medicine and molecular imaging clinics from bench to bedside. Recently, immunoPET research have sharply increased especially after a big surge in approval of oncology antibodies by the FDA for immune checkpoint-blockade cancer immunotherapies. Currently, preclinical to clinical translations of immunoPET has several challenges, including designing probes, choice of radioisotopes, selection of stable BFC, and size of antibody and its tracer kinetics. All these obstacles will be addressed eventually by improving PET scanner sensitivity, designing appropriate size of imaging probe, and combining immunoPET with specific targeting antibodies. These improvements should contribute to the immunoPET becoming more applicable in clinics, which, in turn, will provide critical information for correct patient selection, for right dosing, and for the right time/staging of treatment.

Imaging of dopamine transporters in Parkinson disease: a meta-analysis of 18 F/123 I-FP-CIT studies.

Objective 18F‐FP‐CIT and 123I‐FP‐CIT are widely used radiotracers in molecular imaging for Parkinson’s disease (PD) diagnosis. Compared with 123I‐FP‐CIT, 18F‐FP‐CIT has superior tracer kinetics. We aimed to conduct a meta‐analysis to assess the efficacy of using 18F‐FP‐CIT positron emission tomography (PET) and 123I‐FP‐CIT single‐photon emission computed tomography (SPECT) of dopamine transporters in patients with PD in order to provide evidence for clinical decision‐making.MethodsWe searched the PubMed, Embase, Wanfang Data, and China National Knowledge Infrastructure databases to identify the relevant studies from the time of inception of the databases to 30 April 2020. We identified six PET studies, including 779 patients with PD and 124 healthy controls, which met the inclusion criteria. Twenty‐seven SPECT studies with 1244 PD patients and 859 controls were also included in this meta‐analysis.ResultsOverall effect‐size analysis indicated that patients with PD showed significantly reduced 18F‐FP‐CIT uptake in three brain regions [caudate nucleus: standardized mean difference (SMD) = −1.71, Z = −3.31, P = 0.0009; anterior putamen: SMD = −3.71, Z = −6.26, P < 0.0001; and posterior putamen: SMD = −5.49, Z = −5.97, P < 0.0001]. Significant decreases of 123I‐FP‐CIT uptake were also observed in the caudate (SMD = −2.31, Z = −11.49, P < 0.0001) and putamen (SMD = −3.25, Z = −14.79, P < 0.0001).InterpretationIn conclusion, our findings indicate that both 18F‐FP‐CIT PET and 123I‐FP‐CIT SPECT imaging of dopamine transporters can provide viable biomarkers for early PD diagnosis.

Dynamic 18F-FDOPA-PET/MRI for the preoperative evaluation of gliomas: correlation with stereotactic histopathology.

MRI alone has limited accuracy for delineating tumor margins and poorly predicts the aggressiveness of gliomas, especially when tumors do not enhance. This study evaluated simultaneous 3,4-dihydroxy-6-[18F]fluoro-L-phenylalanine (FDOPA)-PET/MRI to define tumor volumes compared to MRI alone more accurately, assessed its role in patient management, and correlated PET findings with histopathology. Ten patients with known or suspected gliomas underwent standard of care surgical resection and/or stereotactic biopsy. FDOPA-PET/MRI was performed prior to surgery, allowing for precise co-registration of PET, MR, and biopsies. The biopsy sites were modeled as 5-mm spheres, and the local FDOPA uptake at each site was determined. Correlations were performed between measures of tumor histopathology, and static and dynamic PET values: standardized uptake values (SUVs), tumor to brain ratios, metabolic tumor volumes, and tracer kinetics at volumes of interest (VOIs) and biopsy sites. Tumor FDOPA-PET uptake was visualized in 8 patients. In 2 patients, tracer uptake was similar to normal brain reference with no histological findings of malignancy. Eight biopsy sites confirmed for glioma had FDOPA uptake without T1 contrast enhancement. The PET parameters were highly correlated only with the cell proliferation marker, Ki-67 (SUVmax: r = 0.985, P = .002). In this study, no statistically significant difference between high-grade and low-grade tumors was demonstrated. The dynamic PET analysis of VOIs and biopsy sites showed decreasing time-activity curves patterns. FDOPA-PET imaging directly influenced patient management. Simultaneous FDOPA-PET/MRI allowed for more accurate visualization and delineation of gliomas, enabling more appropriate patient management and simplified validation of PET findings with histopathology.

Vitamin A Absorption Efficiency Determined by Compartmental Analysis of Postprandial Plasma Retinyl Ester Kinetics in Theoretical Humans

ABSTRACTBackgroundBetter methods are needed for determining vitamin A absorption efficiency in humans to support development of dietary recommendations and to improve the accuracy of predictions of vitamin A status.ObjectivesWe developed and evaluated a method for estimating vitamin A absorption efficiency based on compartmental modeling of theoretical data on postprandial plasma retinyl ester (RE) kinetics.MethodsWe generated data on plasma RE and retinol kinetics (30 min to 8 h or 56 d, respectively) after oral administration of labeled vitamin A for 12 theoretical adults with a range of values assigned for vitamin A absorption (55–90%); we modeled all data to obtain best-fit values for absorption and other parameters using Simulation, Analysis, and Modeling software. We then modeled RE data only (16 or 10 samples), with or without added random error, and compared assigned to predicted absorption values. We also compared assigned values to areas under RE response curves (RE AUCs).ResultsWe confirmed that a unique value for vitamin A absorption cannot be identified by modeling plasma retinol tracer kinetics. However, when RE data were modeled, predicted vitamin A absorptions were within 1% of assigned values using data without error and within 12% when 5% error was included. When the sample number was reduced, predictions were still within 13% for 10 of the 12 subjects and within 23% overall. Assigned values for absorption were not correlated with RE AUC (P = 0.21).ConclusionsWe describe a feasible and accurate method for determining vitamin A absorption efficiency that is based on compartmental modeling of plasma RE kinetic data collected for 8 h after a test meal. This approach can be used in a clinical setting after fasting subjects consume a fat-containing breakfast meal with a known amount of vitamin A or a stable isotope label.

Flexible numerical simulation framework for dynamic PET-MR data

This paper presents a simulation framework for dynamic PET-MR. The main focus of this framework is to provide motion-resolved MR and PET data and ground truth motion information. This can be used in the optimisation and quantitative evaluation of image registration and in assessing the error propagation due to inaccuracies in motion estimation in complex motion-compensated reconstruction algorithms. Contrast and tracer kinetics can also be simulated and are available as ground truth information. To closely emulate medical examination, input and output of the simulation are files in standardised open-source raw data formats. This enables the use of existing raw data as a template input and ensures seamless integration of the output into existing reconstruction pipelines.The proposed framework was validated in PET-MR and image registration applications. It was used to simulate a FDG-PET-MR scan with cardiac and respiratory motion. Ground truth motion information could be utilised to optimise parameters for PET and synergistic PET-MR image registration. In addition, a free-breathing dynamic contrast enhancement (DCE) abdominal scan of a patient with hepatic lesions was simulated. In order to correct for breathing motion, a motion-corrected image reconstruction scheme was used and a Toft’s model was fit to the DCE data to obtain quantitative DCE-MRI parameters. Utilising the ground truth motion information, the dependency of quantitative DCE-MR images on the accuracy of the motion estimation was evaluated. We demonstrated that respiratory motion had to be available with an average accuracy of at least the spatial resolution of the DCE-MR images in order to ensure an improvement in lesions visualisation and quantification compared to no motion correction.The proposed framework provides a valuable tool with a wide range of scientific PET and MR applications and will be available as part of the open-source project Synergistic Image Reconstruction Framework (SIRF).

In vivo Characterization of Four 18F-Labeled S1PR1 Tracers for Neuroinflammation.

The sphingosine-1-phosphate receptor 1 (S1PR1) is an important biomarker for imaging inflammation in the central nervous system (CNS). Herein, we report our recent evaluation of four 18F-labeled S1PR1 tracers (18F-TZ43113, 18F-TZ35104, 18F-TZ4877, and 18F-TZ4881) in a rat model of multiple sclerosis (MS). MicroPET studies of each tracer's uptake and kinetics were performed in an experimental autoimmune encephalomyelitis (EAE) rat model of MS to quantify upregulated S1PR1 expression in the lumbar spinal cord of EAE rats. Western blot analysis was conducted to confirm the differences in the expression of S1PR1 protein level between EAE and sham rats. Radiometabolite analysis was performed for the most promising candidate in rats. All four S1PR1 tracers detected increased S1PR1 levels in response to neuroinflammation in the lumbar spinal cord of EAE rats, which was supported by western blot results. The ranked order of tracer uptake in rat spinal cord was 18F-TZ4877 > 18F-TZ4881 > 18F-TZ35104 > 18F-TZ43113. 18F-TZ4877 had the highest uptake of the four tracers and showed good kinetic modeling fits in rat spinal cord using an image-based method of arterial blood input function. Radiometabolite analysis of 18F-TZ4877 showed good in vivo stability with no major radiometabolite accumulation in the ratbrain. Among these four new PET tracers, 18F-TZ4877 showed the most favorable profile for assessing S1PR1 expression in the EAE rat model of MS. Further characterization of these radiotracers in other models of neuroinflammation is warranted to identify a promising 18F-labeled tracer for imaging S1PR1 in vivo.

Human biodistribution and internal dosimetry of 4-[ 18F]fluorobenzyl-dexetimide: a PET radiopharmaceutical for imaging muscarinic acetylcholine receptors in the brain and heart

Background4-[18F] fluorobenzyl dexetimide (F-DEX) is the first non-subtype selective fluorine-18 labelled tracer for muscarinic receptors (mAChR) used in humans. A recent first-in-human study found high regional brain uptake with low variation in normal subjects. Disturbance of mAChR has been reported in Alzheimer’s and Parkinson’s disease, schizophrenia and depression and various cardiac diseases. The following work assesses the biodistribution, organ tracer kinetics and radiation dose associated with F-DEX.MethodDose calculations were based on activity uptake derived from multiple time point whole body PET CT imaging and the organ-specific dosimetric S-factors derived from the ICRP 133 standard man and woman mathematical phantoms. Effective doses were calculated using the latest ICRP tissue weighting factors.ResultsSerial images and time activity curves demonstrate high brain and left ventricular myocardial uptake (5% and 0.65% of injected activity, respectively) with greater retention in brain than myocardium. The mean effective dose was in concordance with other 18F labelled tracers at 19.70 ± 2.27 μSv/MBq. The largest absorbed doses were in the liver (52.91 ± 1.46 μGy/MBq) and heart wall (43.94 ± 12.88 μGy/MBq) for standard man and the liver (61.66 ± 13.61 μGy/MBq) and lungs (40.93 ± 3.11 μGy/MBq) for standard woman. The absorbed dose to all organs, most notably, the red bone marrow (20.03 ± 2.89 μGy/MBq) was sufficiently low to ensure no toxicity after numerous follow-up procedures.ConclusionsThe radiation dose associated with an administration of F-DEX is comparable to that of other 18F labelled tracers such as FDG (19.0 μSv/MBq) and lower than tracers used for SPECT imaging of muscarinic receptors (I-DEX 28.5 μSv/MBq). Clinical use would likely result in an effective dose less than 4 mSv for the ICRP 133 standard phantoms after dose optimisation allowing justification for numerous follow-up procedures. Recent results from first in-human studies and a comparatively low radiation dose make F-DEX an attractive option for future applications of imaging muscarinic receptors in the brain. Further investigation of the potential of F-DEX for imaging parasympathetic innervation of the heart may be warranted.