Net Influx Research Articles

Functional asymmetry of the urea transporter UT-B in human red blood cells.

We studied urea, thiourea, and methylurea transport and interaction in human red blood cells (RBCs) under conditions of self-exchange (SE), net efflux (NE), and net influx (NI) at pH 7.2. We combined four methods, a four-centrifuge technique, the Millipore-Swinnex filtering technique, the continuous flow tube method, and a continuous pump method to measure the transport of the 14C-labeled compounds. Under SE conditions, both urea and thiourea show perfect Michaelis-Menten kinetics with half-saturation constants, K½,SE (mM), of ≈300 (urea) and ≈20 (thiourea). The solutes show no concentration-dependent saturation under NE conditions. Under NI conditions, transport displays saturation or self-inhibition kinetics with a K½,NI (mM) of ≈210 (urea) and ≈20 (thiourea). Urea, thiourea, and methylurea are competitive inhibitors of the transport of analog solutes. This study supports the hypothesis that the three compounds share the same urea transport system (UT-B). UT-B functions asymmetrically as it saturates from the outside only under SE and NI conditions, whereas it functions as a high-capacity channel-like transporter under NE conditions. When the red blood cell enters the urea-rich kidney tissue, self-inhibition reduces the urea uptake in the cell. When the cell leaves the kidney, the channel-like function of UT-B implies that intracellular urea rapidly equilibrates with external urea. The net result is that the cell during the passage in the kidney capillaries carries urea to the kidney to be excreted while the urea transfer from the kidney via the bloodstream is minimized.NEW & NOTEWORTHY The kinetics of urea transport in red blood cells was determined by means of a combination of four methods that ensures a high time resolution. In the present study, we disclose that the urea transporter UT-B functions highly asymmetric being channel-like with no saturation under conditions of net efflux and saturable under conditions of net influx and self-exchange in the concentration range 1-1,000 mM (pH 7.2 and 25-38 °C).

A short 18F-FDG imaging window triple injection neuroimaging protocol for parametric mapping in PET.

In parametric PET, kinetic parameters are extracted from dynamic PET images. It is not commonly used in clinical practice because of long scan times and the requirement for an arterial input function (AIF). To address these limitations, we designed an 18F-fluorodeoxyglucose (18F-FDG) triple injection dynamic PET protocol for brain imaging with a standard field of view PET scanner using a 24-min imaging window and an input function modeled using measurements from a region of interest placed over the left ventricle. To test the protocol in 6 healthy participants, we examined the quality of voxel-based maps of kinetic parameters in the brain generated using the two-tissue compartment model and compared estimated parameter values with previously published values. We also utilized data from a 36-min validation imaging window to compare (1) the modeled AIF against the input function measured in the validation window; and (2) the net influx rate ([Formula: see text]) computed using parameter estimates from the short imaging window against the net influx rate obtained using Patlak analysis in the validation window. Compared to the AIF measured in the validation window, the input function estimated from the short imaging window achieved a mean area under the curve error of 9%. The voxel-wise Pearson's correlation between [Formula: see text] estimates from the short imaging window and the validation imaging window exceeded 0.95. The proposed 24-min triple injection protocol enables parametric 18F-FDG neuroimaging with noninvasive estimation of the AIF from cardiac images using a standard field of view PET scanner.

Full kinetic modeling analysis of [18F]fluorocholine Positron Emission Tomography (PET) at initial diagnosis of high-grade glioma

PurposeThe main objective was to characterize the tracer uptake kinetics of [18F]fluoromethylcholine ([18F]F-CHO) in high-grade gliomas (HGG) through a full PET kinetic modeling approach. Secondarily, we aimed to explore the relationship between the PET uptake measures and the HGG molecular features. Materials and methodsTwenty-four patients with a suspected diagnosis of HGG were prospectively included. They underwent a dynamic brain [18F]F-CHO-PET/CT, from which a tumoral time-activity curve was extracted. The plasma input function was obtained through arterial blood sampling with metabolite correction. These data were fitted to 1- and 2-tissue-compartment models, the best of which was selected through the Akaike information criterion. We assessed the correlation between the kinetic parameters and the conventional static PET metrics (SUVmax, SUVmean and tumor-to-background ratio TBR). We explored the association between the [18F]F-CHO-PET quantitative parameters and relevant molecular biomarkers in HGG. ResultsTumoral time-activity curves in all patients showed a rapid rise of [18F]F-CHO uptake followed by a plateau-like shape. Best fits were obtained with near-irreversible 2-tissue-compartment models. The perfusion-transport constant K1 and the net influx rate Ki showed strong correlation with SUVmax (r = 0.808–0.861), SUVmean (r = 0.794–0.851) and TBR (r = 0.643–0.784), p < 0.002. HGG was confirmed in 21 patients, of which those with methylation of the O-6-methylguanine-DNA methyltransferase (MGMT) gene promoter showed higher mean Ki (p = 0.020), K1 (p = 0.025) and TBR (p = 0.001) than the unmethylated ones. Conclusion[18F]F-CHO uptake kinetics in HGG is best explained by a 2-tissue-compartment model. The conventional static [18F]F-CHO-PET measures have been validated against the perfusion-transport constant (K1) and the net influx rate (Ki) derived from kinetic modeling. A relationship between [18F]F-CHO uptake rate and MGMT methylation is suggested but needs further confirmation.

Dynamic Human Brain Imaging with a Portable PET Camera: Comparison to a Standard Scanner.

Portable, cost-effective PET cameras can radically expand the applicability of PET. We present here a within-participant comparison of fully quantified [18F]FDG dynamic scans in healthy volunteers using the standard Biograph mCT scanner and portable CerePET scanner. Methods: Each of 20 healthy volunteers underwent dynamic [18F]FDG imaging with both scanners (1-154 d apart) and concurrent arterial blood sampling. Tracer SUV, net influx rate (Ki), and the corresponding cerebral metabolic rate of glucose (CMRglu) were quantified at regional and voxel levels. Results: At the regional level, CerePET outcome measure estimates within participants robustly correlated with Biograph mCT estimates in the neocortex, wherein the average Pearson correlation coefficients across participants ± SD were 0.83 ± 0.07 (SUV) and 0.85 ± 0.08 (Ki and CMRglu). There was also strong agreement between CerePET and Biograph mCT estimates, wherein the average regression slopes across participants were 0.84 ± 0.17 (SUV), 0.83 ± 0.17 (Ki), and 0.85 ± 0.18 (CMRglu). There was similar bias across participants but higher correlation and less variability in subcortical regions than in cortical regions. Pearson correlation coefficients for subcortical regions equaled 0.97 ± 0.02 (SUV) and 0.97 ± 0.03 (Ki and CMRglu), and average regression slopes equaled 0.79 ± 0.14 (SUV), 0.83 ± 0.11 (Ki), and 0.86 ± 0.11 (CMRglu). In voxelwise assessment, CerePET and Biograph mCT estimates across outcome measures were significantly different only in a cluster of left frontal white matter. Conclusion: Our results indicate robust correlation and agreement between semi- and fully quantitative brain glucose metabolism measurements from portable CerePET and standard Biograph mCT scanners. The results obtained with a portable PET scanner in this comparison in humans require follow-up but lend confidence to the feasibility of more flexible and portable brain imaging with PET.

Single time point quantitation of cerebral glucose metabolism by FDG-PET without arterial sampling

BackgroundUntil recently, quantitation of the net influx of 2-[18F]fluorodeoxyglucose (FDG) to brain (Ki) and the cerebrometabolic rate for glucose (CMRglc) required serial arterial blood sampling in conjunction with dynamic positron emission tomography (PET) recordings. Recent technical innovations enable the identification of an image-derived input function (IDIF) from vascular structures, but are frequently still encumbered by the need for interrupted sequences or prolonged recordings that are seldom available outside of a research setting. In this study, we tested simplified methods for quantitation of FDG-Ki by linear graphic analysis relative to the descending aorta IDIF in oncology patients examined using a Biograph Vision 600 PET/CT with continuous bed motion (Aarhus) or using a recently installed Biograph Vision Quadra long-axial field-of-view (FOV) scanner (Bern).ResultsCorrelation analysis of the coefficients of a tri-exponential decomposition of the IDIFs measured during 67 min revealed strong relationships among the total area under the curve (AUC), the terminal normalized arterial integral (theta(52–67 min)), and the terminal image-derived arterial FDG concentration (Ca(52–67 min)). These relationships enabled estimation of the missing AUC from late recordings of the IDIF, from which we then calculated FDG-Ki in brain by two-point linear graphic analysis using a population mean ordinate intercept and the single late frame. Furthermore, certain aspects of the IDIF data from Aarhus showed a marked age-dependence, which was not hitherto reported for the case of FDG pharmacokinetics.ConclusionsThe observed interrelationships between pharmacokinetic parameters in the IDIF measured during the PET recording support quantitation of FDG-Ki in brain using a single averaged frame from the interval 52–67 min post-injection, with minimal error relative to calculation from the complete dynamic sequences.

Changes in tumor-to-blood ratio as a prognostic marker for progression-free survival and overall survival in neuroendocrine tumor patients undergoing PRRT

BackgroundHistorically, patient selection for peptide receptor radionuclide therapy (PRRT) has been performed by virtue of somatostatin receptor scintigraphy (SRS). In recent years, somatostatin receptor positron emission tomography (SSTR-PET) has gradually replaced SRS because of its improved diagnostic capacity, creating an unmet need for SSTR-PET-based selection criteria for PRRT. Tumor-to-blood ratio (TBR) measurements have shown high correlation with the net influx rate Ki, reflecting the tumor somatostatin receptor expression, to a higher degree than standardized uptake value (SUV) measurements. TBR may therefore predict treatment response to PRRT. In addition, changes in semiquantitative SSTR-PET parameters have been shown to predate morphological changes, making them a suitable metric for response assessment.MethodsThe institutional database of the Department of Nuclear Medicine (University Hospital Essen) was searched for NET patients undergoing ≥ 2 PRRT cycles with available baseline and follow-up SSTR-PET. Two blinded independent readers reported the occurrence of new lesions quantified tumor uptake of up to nine lesions per patient using SUV and TBR. The association between baseline TBR and changes in uptake/occurrence of new lesions with progression-free survival (PFS) and overall survival (OS) was tested by use of a Cox regression model and log-rank test.ResultsPatients with baseline TBR in the 1st quartile had a shorter PFS (14.4 months) than those in the 3rd (23.7 months; p = 0.03) and 4th (24.1 months; p = 0.02) quartile. Similarly, these patients had significantly shorter OS (32.5 months) than those with baseline TBR in the 2nd (41.8 months; p = 0.03), 3rd (69.2 months; p < 0.01), and 4th (42.7 months; p = 0.03) quartile. Baseline to follow-up increases in TBR were independently associated with shorter PFS when accounting for prognostic markers, e.g., RECIST response (hazard ratio = 2.91 [95%CI = 1.54–5.50]; p = 0.01). This was confirmed with regard to OS (hazard ratio = 1.64 [95%CI = 1.03–2.62]; p = 0.04). Changes in SUVmean were not associated with PFS or OS.ConclusionsBaseline TBR as well as changes in TBR were significantly associated with PFS and OS and may improve patient selection and morphological response assessment. Future trials need to assess the role of TBR for therapy monitoring also during PRRT and prospectively explore TBR as a predictive marker for patient selection.

Assessing dynamic metabolic heterogeneity in prostate cancer patients via total-body [68Ga]Ga-PSMA-11 PET/CT imaging: quantitative analysis of [68Ga]Ga-PSMA-11 uptake in pathological lesions and normal organs.

This study aimed to quantitatively assess [68Ga]Ga-PSMA-11 uptake in pathological lesions and normal organs in prostate cancer using the total-body [68Ga]Ga-PSMA-11 PET/CT and to characterize the dynamic metabolic heterogeneity of prostate cancer. Dynamic total-body [68Ga]Ga-PSMA-11 PET/CT scans were performed on ten prostate cancer patients. Manual delineation of volume-of-interests (VOIs) was performed on multiple normal organs displaying high [68Ga]Ga-PSMA-11 uptake, as well as pathological lesions. Time-to-activity curves (TACs) were generated, and the four compartment models including one-tissue compartmental model (1T1k), reversible one-tissue compartmental model (1T2k), irreversible two-tissue compartment model (2T3k) and reversible two-tissue compartmental model (2T4k) were fitted to each tissue TAC. Various rate constants, including K1 (forward transport rate from plasma to the reversible compartment), k2 (reverse transport rate from the reversible compartment to plasma), k3 (tracer binding on the PSMA-receptor and its internalization), k4 (the externalization rate of the tracer) and Ki (net influx rate), were obtained. The selection of the optimal model for describing the uptake of both lesions and normal organs was determined using the Akaike information criteria (AIC). Receiver operating characteristic (ROC) curve analysis was performed to determine the cut-off values for differentiating physiological and pathological [68Ga]Ga-PSMA-11 uptake. Both 1T1k and 1T2k models showed relatively high AIC values compared to the 2T3k and 2T4k models in both pathological lesions and normal organs. The kinetic behavior of pathological lesions was better described by the 2T3k model compared to the 2T4k model, while the normal organs were better described by the 2T4k model. Significant variations in kinetic metrics, such as K1, k2, and k3, and Ki, were observed among normal organs with high [68Ga]Ga-PSMA-11 uptake and pathological lesions. The high Ki value in normal organs was primarily determined by elevated K1 and low k3, rather than k2. Conversely, the high Ki value in pathological lesions, ranking second to the kidney and similar to salivary glands and spleen, was predominantly determined by the highest k3 value. Notably, k3 exhibited the highest performance in distinguishing between physiological and pathological [68Ga]Ga-PSMA-11 uptake, with an area under the curve (AUC) of 0.844 (95% CI, 0.773-0.915), sensitivity of 82.9%, and specificity of 74.1%. The k3 values showed better performance than SUVmean (AUC, 0.659), SUVmax (AUC, 0.637), and other kinetic parameter including K1 (AUC, 0.604), k2 (AUC, 0.634), and Ki (AUC, 0.651). Significant discrepancies in kinetic metrics were detected between pathological lesions and normal organs, despite their shared high uptake of [68Ga]Ga-PSMA-11. Notably, the k3 value exhibits a noteworthy capability to distinguish between pathological lesions and normal organs with elevated [68Ga]Ga-PSMA-11 uptake. This discovery implies that k3 holds promise as a prospective imaging biomarker for distinguishing between pathologic and non-specific [68Ga]Ga-PSMA-11 uptake in patients with prostate cancer.

Optimization of Q.Clear reconstruction for dynamic 18F PET imaging

BackgroundQ.Clear, a Bayesian penalized likelihood reconstruction algorithm, has shown high potential in improving quantitation accuracy in PET systems. The Q.Clear algorithm controls noise during the iterative reconstruction through a β penalization factor. This study aimed to determine the optimal β-factor for accurate quantitation of dynamic PET scans.MethodsA Flangeless Esser PET Phantom with eight hollow spheres (4–25 mm) was scanned on a GE Discovery MI PET/CT system. Data were reconstructed into five sets of variable acquisition times using Q.Clear with 18 different β-factors ranging from 100 to 3500. The recovery coefficient (RC), coefficient of variation (CVRC) and root-mean-square error (RMSERC) were evaluated for the phantom data. Two male patients with recurrent glioblastoma were scanned on the same scanner using 18F-PSMA-1007. Using an irreversible two-tissue compartment model, the area under curve (AUC) and the net influx rate Ki were calculated to assess the impact of different β-factors on the pharmacokinetic analysis of clinical PET brain data.ResultsIn general, RC and CVRC decreased with increasing β-factor in the phantom data. For small spheres (< 10 mm), and in particular for short acquisition times, low β-factors resulted in high variability and an overestimation of measured activity. Increasing the β-factor improves the variability, however at a cost of underestimating the measured activity. For the clinical data, AUC decreased and Ki increased with increased β-factor; a change in β-factor from 300 to 1000 resulted in a 25.5% increase in the Ki.ConclusionIn a complex dynamic dataset with variable acquisition times, the optimal β-factor provides a balance between accuracy and precision. Based on our results, we suggest a β-factor of 300–500 for quantitation of small structures with dynamic PET imaging, while large structures may benefit from higher β-factors.Trial registrationClinicaltrials.gov, NCT03951142. Registered 5 October 2019, https://clinicaltrials.gov/ct2/show/NCT03951142. EudraCT no 2018-003229-27. Registered 26 February 2019, https://www.clinicaltrialsregister.eu/ctr-search/trial/2018-003229-27/NO.

First-in-human immunoPET imaging of COVID-19 convalescent patients using dynamic total-body PET and a CD8-targeted minibody.

With most of the T cells residing in the tissue, not the blood, developing noninvasive methods for in vivo quantification of their biodistribution and kinetics is important for studying their role in immune response and memory. This study presents the first use of dynamic positron emission tomography (PET) and kinetic modeling for in vivo measurement of CD8+ T cell biodistribution in humans. A 89Zr-labeled CD8-targeted minibody (89Zr-Df-Crefmirlimab) was used with total-body PET in healthy individuals (N = 3) and coronavirus disease 2019 (COVID-19) convalescent patients (N = 5). Kinetic modeling results aligned with T cell-trafficking effects expected in lymphoid organs. Tissue-to-blood ratios from the first 7 hours of imaging were higher in bone marrow of COVID-19 convalescent patients compared to controls, with an increasing trend between 2 and 6 months after infection, consistent with modeled net influx rates and peripheral blood flow cytometry analysis. These results provide a promising platform for using dynamic PET to study the total-body immune response and memory.

Comparison of parametric imaging and SUV imaging with [68Ga]Ga-PSMA-11 using dynamic total-body PET/CT in prostate cancer.

Standardized uptake value (SUV) has been prevalently used to measure [68Ga]Ga-PSMA-11 activity in prostate cancer, but it is susceptible to multiple factors. Parametric imaging allows for absolute quantification of tracer uptake and provides a better diagnostic accuracy that is crucial for lesion detection. However, the clinical significance of total-body parametric imaging of [68Ga]Ga-PSMA-11 remains to be fully assessed. Therefore, the aim of our study is to delve into the diagnostic implications of total-body parametric imaging of [68Ga]Ga-PSMA-11 PET/CT for patients with prostate cancer. Twenty prostate cancer patients were included and underwent a dynamic total-body [68Ga]Ga-PSMA-11 PET/CT scan. An irreversible two-tissue compartment model (2T3k) was fitted for each tissue time-to-activity curve, and the net influx rate (Ki) was obtained. The image quality and semi-quantitative analysis of lesion-to-background ratio (LBR), signal-to-noise ratio (SNR), and contrast-to-noise ratio (CNR) were compared between parametric images and SUV images. Kinetic modeling using 2T3k demonstrated favorable model fitting in both normal organs and lesions. All of the lesions detected on SUV images (55-60min) could be detected on Ki images. The correlation between Ki, SUVmean, and SUVmax in both normal organs and pathological lesions was found to be positive and statistically significant. Conversely, a moderate positive correlations were found between Ki and K1 (R = 0.69, P < 0.001; R = 0.61, P < 0.001) and Ki and k3 (R = 0.69, P < 0.001; R = 0.62, P < 0.001), in normal organs and pathological lesions, respectively. Visual assessment in Ki images showed less image noise and higher lesions conspicuity compared to SUV images. Ki image-derived LBR, SNR, and CBR of pathological lesions including primary tumors (PTs), lymph node metastases (LNMs) and bone metastases (BMs), exhibited remarkably higher folds (1.4-3.6 folds) compared to those derived from SUV of corresponding lesions. Total-body parametric imaging of [68Ga]Ga-PSMA-11 enhanced lesion contrast and improved lesion detectability compared to SUV images. This may potentially serve as an imaging biomarker and theranostic tool for precise diagnosis and treatment evaluation in prostate cancer patients.

Characteristics of clustered heavy precipitation events at Northeast China and associated atmospheric circulations

AbstractHeavy precipitation events can exert greater impact than general precipitation on the economy, ecology, and people’s livelihoods. Based on CN05.1 daily precipitation data and the NCEP/NCAR global daily reanalysis dataset, this study analyzes the characteristics of clustered heavy precipitation (CHP) events during summer in Northeast China (NEC) during 1961–2020, with consideration of associated atmospheric circulations and moisture transport. Results indicate that CHP events occurred mainly during midsummer, especially in July. Both the frequency and the intensity of CHP events decrease after the mid-1970s, increase after the early 1980s, and then diminish again after the 2000s. The CHP events occur in association with an anomalous lower-tropospheric cyclone centered over NEC, northward and westward shifts of the western North Pacific subtropical high in the middle troposphere, and northward shift of an intensified westerly jet in the upper troposphere, in conjunction with strengthened local convective motion. Additionally, the net moisture budget begins to increase 2 days before the occurrence of CHP and peaks 6 h earlier than the CHP. Further results indicate that net moisture influx across the southern boundary of NEC made a dominant contribution to the net moisture budget. The results of this study have importance regarding the prediction of CHP events over NEC.

The feasibility of quantitative assessment of dynamic 18F-fluorodeoxyglucose PET in Takayasu's arteritis: a pilot study.

PET has been demonstrated to be sensitive for detecting active inflammation in Takayasu's arteritis (TAK) patients, but semi-quantitative-based assessment may be susceptible to various biological and technical factors. Absolute quantification via dynamic PET (dPET) may provide a more reliable and quantitative assessment of TAK-active arteries. The purpose of this study was to investigate the feasibility and efficacy of dPET in quantifying TAK-active arteries compared to static PET. This prospective study enrolled 10 TAK-active patients (fulfilled the NIH criteria) and 5 control participants from March to October 2022. One-hour dPET scan (all TAK and control participants) and delayed static PET scan at 2-h (all TAK patients) were acquired. For 1-h static PET, summed images from 50 to 60min of the dPET were extracted. PET parameters derived from 1- and 2-h static PET including SUV (SUV1H and SUV2H), target-to-background ratio (TBR) (TBR1H and TBR2H), net influx rate (Ki), and TBRKi extracted from dPET were obtained. The detectability of TAK-active arteries was compared among different scanning methods using the generalized estimating equation (GEE) with a logistic regression with repeated measures, and the GEE with gamma distribution and log link function was used to evaluate the different study groups or scanning methods. Based on the disease states, 5 cases of TAK were classified as untreated and relapsed, respectively. The SUVmax on 2-h PET was higher than that on 1-h PET in the untreated patients (P < 0.05). However, no significant differences were observed in the median SUVmax between 1-h PET and 2-h PET in the relapsed patients (P > 0.05). The TBRKi was significantly higher than both TBR1H and TBR2H (all P < 0.001). Moreover, the detectability of TAK-active arteries by dPET-derived Ki was significantly higher than 1-h and 2-h PET (all P < 0.001). Significant differences were observed in Kimax, SUVmax-1H, TBR1H, and TBRKi among untreated, relapsed, and control groups (all P < 0.05). Absolute quantitative assessment by dPET provides an improved sensitivity and detectability in both visualization and quantification of TAK-active arteries. This elucidates the clinical significance of dPET in the early detection of active inflammation and monitoring recurrence.

Dynamic 68Ga-DOTA0-Tyr3-octreotate positron emission tomography-computed tomography for the evaluation of pancreatic neuroendocrine tumors: a pilot study.

68Ga-DOTA0-Tyr3-octreotate (68Ga-DOTATATE) is a radiolabeled somatostatin analog used for the diagnosis of pancreatic neuroendocrine tumors (pNETs), and standardized uptake value (SUV) measurements for therapeutic monitoring is recommended. However, changes in net influx rate (Ki) may better reflect treatment effects than may those of the SUV. The aim of this study was to investigate the value of dynamic 68Ga-DOTATATE positron emission tomography-computed tomography (PET-CT) in the evaluation of pNETs. Dynamic PET-CT scans over 60 min were acquired for 7 patients with localized pancreatic mass before surgery. Maximal and mean SUV (SUVmax and SUVmean) were measured in tumors and normal pancreatic body as reference tissue (RT). Time-activity curves (TACs) were extracted from tumors and RT. A 2-tissue compartment model was used to calculate the rate constants K1, k2, and k3 (min-1); Ki (mL/g/min); and K1:k2 ratio. The following statistical tests were used to evaluate the results: the Shapiro-Wilk, Student t test, Mann-Whitney, Spearman, and Pearson rank correlation tests. Among 6 patients, 8 primary tumors were histopathologically proven to be pNETs. Moreover, 6 lesions with high uptake of 68Ga-DOTATATE showed an ascending TAC pattern, while 2 lesions with no or low uptake showed a descending TAC pattern. The mean SUVmax and SUVmean of pNETs were 46.4±40.2 (range, 3.9-109.9) and 21.9±16.0 (range, 0.5-42.8), respectively, which were significantly higher than the SUVmax of 4.2±0.6 (range, 3.1-4.9) and the SUVmean of 2.7±1.0 (range, 1.4-3.6) for the RT (P=0.021 and P=0.036), respectively. The Ki of pNETs was statistically higher than that of the RT [pNET: 0.366±0.372 (range, 0.019-0.992); RT: 0.060±0.017 (range, 0.04-0.08); P=0.036]. The mean K1:k2 ratio in pNETs was 12-fold higher than that of RT (6.06 vs. 0.50). In pNETs, there was a positive correlation between SUVmax and Ki (r=0.952; P<0.001) and between SUVmean and Ki (r=0.905; P=0.002). Another patient was diagnosed with intrapancreatic accessory spleen. The uptake of 68Ga-DOTATATE by pNETs can be explained by its high Ki value and K1:k2 ratio. Dynamic 68Ga-DOTATATE PET-CT can serve as a potential tool for evaluating pNETs and support the further assessment of a larger cohort of patients.

Total-Body Multiparametric PET Quantification of 18F-FDG Delivery and Metabolism in the Study of Coronavirus Disease 2019 Recovery.

Conventional whole-body static 18F-FDG PET imaging provides a semiquantitative evaluation of overall glucose metabolism without insight into the specific transport and metabolic steps. Here we demonstrate the ability of total-body multiparametric 18F-FDG PET to quantitatively evaluate glucose metabolism using macroparametric quantification and assess specific glucose delivery and phosphorylation processes using microparametric quantification for studying recovery from coronavirus disease 2019 (COVID-19). Methods: The study included 13 healthy subjects and 12 recovering COVID-19 subjects within 8 wk of confirmed diagnosis. Each subject had a 1-h dynamic 18F-FDG scan on the uEXPLORER total-body PET/CT system. Semiquantitative SUV and the SUV ratio relative to blood (SUVR) were calculated for different organs to measure glucose utilization. Tracer kinetic modeling was performed to quantify the microparametric blood-to-tissue 18F-FDG delivery rate [Formula: see text] and the phosphorylation rate k 3, as well as the macroparametric 18F-FDG net influx rate ([Formula: see text]). Statistical tests were performed to examine differences between healthy subjects and recovering COVID-19 subjects. The effect of COVID-19 vaccination was also investigated. Results: We detected no significant difference in lung SUV but significantly higher lung SUVR and [Formula: see text] in COVID-19 recovery, indicating improved sensitivity of kinetic quantification for detecting the difference in glucose metabolism. A significant difference was also observed in the lungs with the phosphorylation rate k 3 but not with [Formula: see text], which suggests that glucose phosphorylation, rather than glucose delivery, drives the observed difference of glucose metabolism. Meanwhile, there was no or little difference in bone marrow 18F-FDG metabolism measured with SUV, SUVR, and [Formula: see text] but a significantly higher bone marrow [Formula: see text] in the COVID-19 group, suggesting a difference in glucose delivery. Vaccinated COVID-19 subjects had a lower lung [Formula: see text] and a higher spleen [Formula: see text] than unvaccinated COVID-19 subjects. Conclusion: Higher lung glucose metabolism and bone marrow glucose delivery were observed with total-body multiparametric 18F-FDG PET in recovering COVID-19 subjects than in healthy subjects, implying continued inflammation during recovery. Vaccination demonstrated potential protection effects. Total-body multiparametric PET of 18F-FDG can provide a more sensitive tool and more insights than conventional whole-body static 18F-FDG imaging to evaluate metabolic changes in systemic diseases such as COVID-19.

Feasibility of [18F]fluoropivalate hybrid PET/MRI for imaging lower and higher grade glioma: a prospective first-in-patient pilot study

PurposeMRI and PET are used in neuro-oncology for the detection and characterisation of lesions for malignancy to target surgical biopsy and to plan surgical resections or stereotactic radiosurgery. The critical role of short-chain fatty acids (SCFAs) in brain tumour biology has come to the forefront. The non-metabolised SCFA radiotracer, [18F]fluoropivalate (FPIA), shows low background signal in most tissues except eliminating organs and has appropriate human dosimetry. Tumour uptake of the radiotracer is, however, unknown. We investigated the uptake characteristics of FPIA in this pilot PET/MRI study.MethodsTen adult glioma subjects were identified based on radiological features using standard-of-care MRI prior to any surgical intervention, with subsequent histopathological confirmation of glioma subtype and grade (lower-grade – LGG – and higher-grade – HGG – patients). FPIA was injected as an intravenous bolus injection (range 342–368 MBq), and dynamic PET and MRI data were acquired simultaneously over 66 min.ResultsAll patients tolerated the PET/MRI protocol. Three patients were reclassified following resection and histology. Tumour maximum standardised uptake value (SUVmax,60) increased in the order LGG (WHO grade 2) < HGG (WHO grade 3) < HGG (WHO grade 4). The net irreversible solute transfer, Ki, and influx rate constant, K1, were significantly higher in HGG (p < 0.05). Of the MRI variables studied, DCE-MRI-derived extravascular-and-extracellular volume fraction (ve) was high in tumours of WHO grade 4 compared with other grades (p < 0.05). SLC25A20 protein expression was higher in HGG compared with LGG.ConclusionTumoural FPIA PET uptake is higher in HGG compared to LGG. This study supports further investigation of FPIA PET/MRI for brain tumour imaging in a larger patient population.Clinical trial registrationClinicaltrials.gov, NCT04097535.

The SLC38A5/SNAT5 amino acid transporter: from pathophysiology to pro-cancer roles in the tumor microenvironment.

SLC38A5/SNAT5 is a system N transporter that can mediate net inward or outward transmembrane fluxes of neutral amino acids coupled with Na+ (symport) and H+ (antiport). Its preferential substrates are not only amino acids with side chains containing amide (glutamine and asparagine) or imidazole (histidine) groups, but also serine, glycine, and alanine are transported by the carrier. Expressed in the pancreas, intestinal tract, brain, liver, bone marrow, and placenta, it is regulated at mRNA and protein levels by mTORC1 and WNT/β-catenin pathways, and it is sensitive to pH, nutritional stress, inflammation, and hypoxia. SNAT5 expression has been found to be altered in pathological conditions such as chronic inflammatory diseases, gestational complications, chronic metabolic acidosis, and malnutrition. Growing experimental evidence shows that SNAT5 is overexpressed in several types of cancer cells. Moreover, recently published results indicate that SNAT5 expression in stromal cells can support the metabolic exchanges occurring in the tumor microenvironment of asparagine-auxotroph tumors. We review the functional role of the SNAT5 transporter in pathophysiology and propose that, due to its peculiar operational and regulatory features, SNAT5 may play important pro-cancer roles when expressed either in neoplastic or in stromal cells of glutamine-auxotroph tumors.NEW & NOTEWORTHY The transporter SLC38A5/SNAT5 provides net influx or efflux of glutamine, asparagine, and serine. These amino acids are of particular metabolic relevance in several conditions. Changes in transporter expression or activity have been described in selected types of human cancers, where SNAT5 can mediate amino acid exchanges between tumor and stromal cells, thus providing a potential therapeutic target. This is the first review that recapitulates the characteristics and roles of the transporter in physiology and pathology.

Poorer aging trajectories are associated with elevated serotonin synthesis capacity.

The dorsal raphe nucleus (DRN) is one of the earliest targets of Alzheimer's disease-related tau pathology and is a major source of brain serotonin. We used [18F]Fluoro-m-tyrosine ([18F]FMT) PET imaging to measure serotonin synthesis capacity in the DRN in 111 healthy adults (18-85 years-old). Similar to reports in catecholamine systems, we found elevated serotonin synthesis capacity in older adults relative to young. To establish the structural and functional context within which serotonin synthesis capacity is elevated in aging, we examined relationships among DRN [18F]FMT net tracer influx (Ki) and longitudinal changes in cortical thickness using magnetic resonance imaging, longitudinal changes in self-reported depression symptoms, and AD-related tau and β-amyloid (Aβ) pathology using cross-sectional [18F]Flortaucipir and [11C]Pittsburgh compound-B PET respectively. Together, our findings point to elevated DRN [18F]FMT Ki as a marker of poorer aging trajectories. Older adults with highest serotonin synthesis capacity showed greatest temporal lobe cortical atrophy. Cortical atrophy was associated with increasing depression symptoms over time, and these effects appeared to be strongest in individuals with highest serotonin synthesis capacity. We did not find direct relationships between serotonin synthesis capacity and AD-related pathology. Exploratory analyses revealed nuanced effects of sex within the older adult group. Older adult females showed the highest DRN synthesis capacity and exhibited the strongest relationships between entorhinal cortex tau pathology and increasing depression symptoms. Together these findings reveal PET measurement of the serotonin system to be a promising marker of aging trajectories relevant to both AD and affective changes in older age.

Mitochondria-Endoplasmic Reticulum Contact Sites Dynamics and Calcium Homeostasis Are Differentially Disrupted in PINK1-PD or PRKN-PD Neurons.

It is generally believed that the pathogenesis of PINK1/parkin-related Parkinson's disease (PD) is due to a disturbance in mitochondrial quality control. However, recent studies have found that PINK1 and Parkin play a significant role in mitochondrial calcium homeostasis and are involved in the regulation of mitochondria-endoplasmic reticulum contact sites (MERCSs). The aim of our study was to perform an in-depth analysis of the role of MERCSs and impaired calcium homeostasis in PINK1/Parkin-linked PD. In our study, we used induced pluripotent stem cell-derived dopaminergic neurons from patients with PD with loss-of-function mutations in PINK1 or PRKN. We employed a split-GFP-based contact site sensor in combination with the calcium-sensitive dye Rhod-2 AM and applied Airyscan live-cell super-resolution microscopy to determine how MERCSs are involved in the regulation of mitochondrial calcium homeostasis. Our results showed that thapsigargin-induced calcium stress leads to an increase of the abundance of narrow MERCSs in wild-type neurons. Intriguingly, calcium levels at the MERCSs remained stable, whereas the increased net calcium influx resulted in elevated mitochondrial calcium levels. However, PINK1-PD or PRKN-PD neurons showed an increased abundance of MERCSs at baseline, accompanied by an inability to further increase MERCSs upon thapsigargin-induced calcium stress. Consequently, calcium distribution at MERCSs and within mitochondria was disrupted. Our results demonstrated how the endoplasmic reticulum and mitochondria work together to cope with calcium stress in wild-type neurons. In addition, our results suggests that PRKN deficiency affects the dynamics and composition of MERCSs differently from PINK1 deficiency, resulting in differentially affected calcium homeostasis. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

North Atlantic Ocean Circulation and Related Exchange of Heat and Salt Between Water Masses

AbstractThe meridional transport of mass, heat, and salt in the North Atlantic Ocean is often described for separate regions and parts, but rarely are all components of the circulation followed at once. Lagrangian trajectories have here been used to divide the North Atlantic Ocean circulation into four different pathways. In the boundary between the Subpolar and Subtropical Gyres, we show that the northward flowing waters exchange heat and salt with the water originating from the subpolar regions. This subsurface water mass exchange takes place in the first 1,000 m and is a key piece of the puzzle of how the Atlantic Meridional Overturning Circulation transports heat and salt. Between 30° and 60°N the northward flowing water loses 8.8 Gg/s salt to the Subpolar Gyre and an equivalent loss of only 1.7 Gg/s to the atmosphere due to the net fresh water influx.

Glucose uptake and distribution across the human skeleton using state-of-the-art total-body PET/CT

A growing number of studies have demonstrated that the skeleton is an endocrine organ that is involved in glucose metabolism and plays a significant role in human glucose homeostasis. However, there is still a limited understanding of the in vivo glucose uptake and distribution across the human skeleton. To address this issue, we aimed to elucidate the detailed profile of glucose uptake across the skeleton using a total-body positron emission tomography (PET) scanner. A total of 41 healthy participants were recruited. Two of them received a 1-hour dynamic total-body 18F-fluorodeoxyglucose (18F-FDG) PET scan, and all of them received a 10-minute static total-body 18F-FDG PET scan. The net influx rate (Ki) and standardized uptake value normalized by lean body mass (SUL) were calculated as indicators of glucose uptake from the dynamic and static PET data, respectively. The results showed that the vertebrae, hip bone and skull had relatively high Ki and SUL values compared with metabolic organs such as the liver. Both the Ki and SUL were higher in the epiphyseal, metaphyseal and cortical regions of long bones. Moreover, trends associated with age and overweight with glucose uptake (SULmax and SULmean) in bones were uncovered. Overall, these results indicate that the skeleton is a site with significant glucose uptake, and skeletal glucose uptake can be affected by age and dysregulated metabolism.