scholarly journals Longitudinal mouse-PET imaging: a reliable method for estimating binding parameters without a reference region or blood sampling

2020 ◽  
Vol 47 (11) ◽  
pp. 2589-2601 ◽  
Author(s):  
Catriona Wimberley ◽  
Duc Loc Nguyen ◽  
Charles Truillet ◽  
Marie-Anne Peyronneau ◽  
Zuhal Gulhan ◽  
...  
Keyword(s):  
Spatial Resolution ◽  
Pet Imaging ◽  
Ex Vivo ◽  
Input Function ◽  
Blood Sampling ◽  
Whole Body ◽  
Reference Region ◽  
Resolution Recovery ◽  
Arterial Blood ◽  
Pet Scans

Abstract Longitudinal mouse PET imaging is becoming increasingly popular due to the large number of transgenic and disease models available but faces challenges. These challenges are related to the small size of the mouse brain and the limited spatial resolution of microPET scanners, along with the small blood volume making arterial blood sampling challenging and impossible for longitudinal studies. The ability to extract an input function directly from the image would be useful for quantification in longitudinal small animal studies where there is no true reference region available such as TSPO imaging. Methods Using dynamic, whole-body 18F-DPA-714 PET scans (60 min) in a mouse model of hippocampal sclerosis, we applied a factor analysis (FA) approach to extract an image-derived input function (IDIF). This mouse-specific IDIF was then used for 4D-resolution recovery and denoising (4D-RRD) that outputs a dynamic image with better spatial resolution and noise properties, and a map of the total volume of distribution (VT) was obtained using a basis function approach in a total of 9 mice with 4 longitudinal PET scans each. We also calculated percent injected dose (%ID) with and without 4D-RRD. The VT and %ID parameters were compared to quantified ex vivo autoradiography using regional correlations of the specific binding from autoradiography against VT and %ID parameters. Results The peaks of the IDIFs were strongly correlated with the injected dose (Pearson R = 0.79). The regional correlations between the %ID estimates and autoradiography were R = 0.53 without 4D-RRD and 0.72 with 4D-RRD over all mice and scans. The regional correlations between the VT estimates and autoradiography were R = 0.66 without 4D-RRD and 0.79 with application of 4D-RRD over all mice and scans. Conclusion We present a FA approach for IDIF extraction which is robust, reproducible and can be used in quantification methods for resolution recovery, denoising and parameter estimation. We demonstrated that the proposed quantification method yields parameter estimates closer to ex vivo measurements than semi-quantitative methods such as %ID and is immune to tracer binding in tissue unlike reference tissue methods. This approach allows for accurate quantification in longitudinal PET studies in mice while avoiding repeated blood sampling.

scholarly journals Assessment of population-based input functions for Patlak imaging of whole body dynamic 18F-FDG PET

2020 ◽  
Vol 7 (1) ◽  
Author(s):  
Mika Naganawa ◽  
Jean-Dominique Gallezot ◽  
Vijay Shah ◽  
Tim Mulnix ◽  
Colin Young ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Gold Standard ◽  
Fdg Pet ◽  
Time Windows ◽  
Input Function ◽  
Population Based ◽  
Blood Sampling ◽  
Whole Body ◽  
Arterial Blood Sampling ◽  
Arterial Blood

Abstract Background Arterial blood sampling is the gold standard method to obtain the arterial input function (AIF) for quantification of whole body (WB) dynamic 18F-FDG PET imaging. However, this procedure is invasive and not typically available in clinical environments. As an alternative, we compared AIFs to population-based input functions (PBIFs) using two normalization methods: area under the curve (AUC) and extrapolated initial plasma concentration (CP*(0)). To scale the PBIFs, we tested two methods: (1) the AUC of the image-derived input function (IDIF) and (2) the estimated CP*(0). The aim of this study was to validate IDIF and PBIF for FDG oncological WB PET studies by comparing to the gold standard arterial blood sampling. Methods The Feng 18F-FDG plasma concentration model was applied to estimate AIF parameters (n = 23). AIF normalization used either AUC(0–60 min) or CP*(0), estimated from an exponential fit. CP*(0) is also described as the ratio of the injected dose (ID) to initial distribution volume (iDV). iDV was modeled using the subject height and weight, with coefficients that were estimated in 23 subjects. In 12 oncological patients, we computed IDIF (from the aorta) and PBIFs with scaling by the AUC of the IDIF from 4 time windows (15–45, 30–60, 45–75, 60–90 min) (PBIFAUC) and estimated CP*(0) (PBIFiDV). The IDIF and PBIFs were compared with the gold standard AIF, using AUC values and Patlak Ki values. Results The IDIF underestimated the AIF at early times and overestimated it at later times. Thus, based on the AUC and Ki comparison, 30–60 min was the most accurate time window for PBIFAUC; later time windows for scaling underestimated Ki (− 6 ± 8 to − 13 ± 9%). Correlations of AUC between AIF and IDIF, PBIFAUC(30–60), and PBIFiDV were 0.91, 0.94, and 0.90, respectively. The bias of Ki was − 9 ± 10%, − 1 ± 8%, and 3 ± 9%, respectively. Conclusions Both PBIF scaling methods provided good mean performance with moderate variation. Improved performance can be obtained by refining IDIF methods and by evaluating PBIFs with test-retest data.

scholarly journals In vitro and In vivo Assessment of Suitable Reference Region and Kinetic Modelling for the mGluR1 Radioligand [11C]ITDM in Mice

2019 ◽  
Vol 22 (4) ◽  
pp. 854-863 ◽  
Author(s):  
Daniele Bertoglio ◽  
Jeroen Verhaeghe ◽  
Špela Korat ◽  
Alan Miranda ◽  
Leonie wyffels ◽  
...  
Keyword(s):  
Mouse Brain ◽  
Pet Imaging ◽  
Metabotropic Glutamate Receptor ◽  
Kinetic Modelling ◽  
Input Function ◽  
Dependent Manner ◽  
Reference Region ◽  
Suitable Reference

Abstract Purpose This study aimed at investigating binding specificity, suitability of reference region-based kinetic modelling, and pharmacokinetics of the metabotropic glutamate receptor 1 (mGluR1) radioligand [11C]ITDM in mice. Procedures We performed in vivo blocking as well as displacement of [11C]ITDM during positron emission tomography (PET) imaging using the specific mGluR1 antagonist YM-202074. Additionally, we assessed in vitro blocking of [3H]ITDM at two different doses of YM-202074. As an alternative to reference region models, we validated the use of a noninvasive image-derived input function (IDIF) compared to an arterial input function measured with an invasive arteriovenous (AV) shunt using a population-based curve for radiometabolite correction and characterized the pharmacokinetic modelling of [11C]ITDM in the mouse brain. Finally, we also assessed semi-quantitative approaches. Results In vivo blocking with YM-202074 resulted in a decreased [11C]ITDM binding, ranging from − 35.8 ± 8.0 % in pons to − 65.8 ± 3.0 % in thalamus. Displacement was also markedly observed in all tested regions. In addition, in vitro [3H]ITDM binding could be blocked in a dose-dependent manner. The volume of distribution (VT) based on the noninvasive IDIF (VT (IDIF)) showed excellent agreement with the VT values based on the metabolite-corrected plasma input function regardless of the metabolite correction (r2 > 0.943, p < 0.0001). Two-tissue compartmental model (2TCM) was found to be the preferred model and showed optimal agreement with Logan plot (r2 > 0.960, p < 0.0001). A minimum scan duration of 80 min was required for proper parameter estimation. SUV was not reliable (r2 = 0.379, p = 0.0011), unlike the SUV ratio to the SUV of the input function, which showed to be a valid approach. Conclusions No suitable reference region could be identified for [11C]ITDM as strongly supported by in vivo and in vitro evidence of specific binding in all brain regions. However, by applying appropriate kinetic models, [11C]ITDM PET imaging represents a promising tool to visualize mGluR1 in the mouse brain.

scholarly journals Quantitative PET imaging of PD-L1 expression in xenograft and syngeneic tumour models using a site-specifically labelled PD-L1 antibody

2019 ◽  
Vol 47 (5) ◽  
pp. 1302-1313 ◽  
Author(s):  
Camilla Christensen ◽  
Lotte K. Kristensen ◽  
Maria Z. Alfsen ◽  
Carsten H. Nielsen ◽  
Andreas Kjaer
Keyword(s):  
Pet Imaging ◽  
Predictive Value ◽  
Ex Vivo ◽  
Response To Therapy ◽  
Whole Body ◽  
Therapeutic Monitoring ◽  
Non Invasive ◽  
Tumour Bearing ◽  
Quantitative Pet

Abstract Purpose Despite remarkable clinical responses and prolonged survival across several cancers, not all patients benefit from PD-1/PD-L1 immune checkpoint blockade. Accordingly, assessment of tumour PD-L1 expression by immunohistochemistry (IHC) is increasingly applied to guide patient selection, therapeutic monitoring, and improve overall response rates. However, tissue-based methods are invasive and prone to sampling error. We therefore developed a PET radiotracer to specifically detect PD-L1 expression in a non-invasive manner, which could be of diagnostic and predictive value. Methods Anti-PD-L1 (clone 6E11, Genentech) was site-specifically conjugated with DIBO-DFO and radiolabelled with 89Zr (89Zr-DFO-6E11). 89Zr-DFO-6E11 was optimized in vivo by longitudinal PET imaging and dose escalation with excess unlabelled 6E11 in HCC827 tumour-bearing mice. Specificity of 89Zr-DFO-6E11 was evaluated in NSCLC xenografts and syngeneic tumour models with different levels of PD-L1 expression. In vivo imaging data was supported by ex vivo biodistribution, flow cytometry, and IHC. To evaluate the predictive value of 89Zr-DFO-6E11 PET imaging, CT26 tumour-bearing mice were subjected to external radiation therapy (XRT) in combination with PD-L1 blockade. Results 89Zr-DFO-6E11 was successfully labelled with a high radiochemical purity. The HCC827 tumours and lymphoid tissue were identified by 89Zr-DFO-6E11 PET imaging, and co-injection with 6E11 increased the relative tumour uptake and decreased the splenic uptake. 89Zr-DFO-6E11 detected the differences in PD-L1 expression among tumour models as evaluated by ex vivo methods. 89Zr-DFO-6E11 quantified the increase in PD-L1 expression in tumours and spleens of irradiated mice. XRT and anti-PD-L1 therapy effectively inhibited tumour growth in CT26 tumour-bearing mice (p < 0.01), and the maximum 89Zr-DFO-6E11 tumour-to-muscle ratio correlated with response to therapy (p = 0.0252). Conclusion PET imaging with 89Zr-DFO-6E11 is an attractive approach for specific, non-invasive, whole-body visualization of PD-L1 expression. PD-L1 expression can be modulated by radiotherapy regimens and 89Zr-DFO-6E11 PET is able to monitor these changes and predict the response to therapy in an immunocompetent tumour model.

scholarly journals Kinetic Analysis of [11C]MP4A Using a High-Radioactivity Brain Region That Represents an Integrated Input Function for Measurement of Cerebral Acetylcholinesterase Activity without Arterial Blood Sampling

2001 ◽  
Vol 21 (11) ◽  
pp. 1354-1366 ◽  
Author(s):  
Shin-Ichiro Nagatsuka ◽  
Kiyoshi Fukushi ◽  
Hitoshi Shinotoh ◽  
Hiroki Namba ◽  
Masaomi Iyo ◽  
...  
Keyword(s):  
Kinetic Analysis ◽  
Least Squares ◽  
Ache Activity ◽  
Input Function ◽  
Blood Sampling ◽  
Linear Least Squares ◽  
Reference Tissue ◽  
Arterial Blood Sampling ◽  
Arterial Blood ◽  
The Brain

N-[11C]methylpiperidin-4-yl acetate ([11C]MP4A) is an acetylcholine analog. It has been used successfully for the quantitative measurement of acetylcholinesterase (AChE) activity in the human brain with positron emission tomography (PET). [11C]MP4A is specifically hydrolyzed by AChE in the brain to a hydrophilic metabolite, which is irreversibly trapped locally in the brain. The authors propose a new method of kinetic analysis of brain AChE activity by PET without arterial blood sampling, that is, reference tissue-based linear least squares (RLS) analysis. In this method, cerebellum or striatum is used as a reference tissue. These regions, because of their high AChE activity, act as a biologic integrator of plasma input function during PET scanning, when regional metabolic rates of [11C]MP4A through AChE (k3; an AChE index) are calculated by using Blomqvist's linear least squares analysis. Computer simulation studies showed that RLS analysis yielded k3 with almost the same accuracy as the standard nonlinear least squares (NLS) analysis in brain regions with low (such as neocortex and hippocampus) and moderately high (thalamus) k3 values. The authors then applied these methods to [11C]MP4A PET data in 12 healthy subjects and 26 patients with Alzheimer disease (AD) using the cerebellum as the reference region. There was a highly significant linear correlation in regional k3 estimates between RLS and NLS analyses (456 cerebral regions, [RLS k3] = 0.98 × [NLS k3], r = 0.92, P < 0.001). Significant reductions were observed in k3 estimates of frontal, temporal, parietal, occipital, and sensorimotor cerebral neocortices ( P < 0.001, single-tailed t-test), and hippocampus ( P = 0.012) in patients with AD as compared with controls when using RLS analysis. Mean reductions (19.6%) Fin these 6 regions by RLS were almost the same as those by NLS analysis (20.5%). The sensitivity of RLS analysis for detecting cortical regions with abnormally low k3 in the 26 patients with AD (138 of 312 regions, 44%) was somewhat less than NLS analysis (52%), but was greater than shape analysis (33%), another method of [11C]MP4A kinetic analysis without blood sampling. The authors conclude that RLS analysis is practical and useful for routine analysis of clinical [11C]MP4A studies.

scholarly journals Modelling [18F]LW223 PET data using simplified imaging protocols for quantification of TSPO expression in the rat heart and brain

2021 ◽  
Author(s):  
Mark G. MacAskill ◽  
Catriona Wimberley ◽  
Timaeus E. F. Morgan ◽  
Carlos J. Alcaide-Corral ◽  
David E. Newby ◽  
...  
Keyword(s):  
Outcome Measures ◽  
Pet Imaging ◽  
Kinetic Modelling ◽  
Input Function ◽  
Binding Potential ◽  
Coronary Artery Ligation ◽  
Systematic Bias ◽  
Arterial Blood ◽  
The Brain ◽  
Tspo Expression

Abstract Purpose To provide a comprehensive assessment of the novel 18 kDa translocator protein (TSPO) radiotracer, [18F]LW223, kinetics in the heart and brain when using a simplified imaging approach. Methods Naive adult rats and rats with surgically induced permanent coronary artery ligation received a bolus intravenous injection of [18F]LW223 followed by 120 min PET scanning with arterial blood sampling throughout. Kinetic modelling of PET data was applied to estimated rate constants, total volume of distribution (VT) and binding potential transfer corrected (BPTC) using arterial or image-derived input function (IDIF). Quantitative bias of simplified protocols using IDIF versus arterial input function (AIF) and stability of kinetic parameters for PET imaging data of different length (40–120 min) were estimated. Results PET outcome measures estimated using IDIF significantly correlated with those derived with invasive AIF, albeit with an inherent systematic bias. Truncation of the dynamic PET scan duration to less than 100 min reduced the stability of the kinetic modelling outputs. Quantification of [18F]LW223 uptake kinetics in the brain and heart required the use of different outcome measures, with BPTC more stable in the heart and VT more stable in the brain. Conclusion Modelling of [18F]LW223 PET showed the use of simplified IDIF is acceptable in the rat and the minimum scan duration for quantification of TSPO expression in rats using kinetic modelling with this radiotracer is 100 min. Carefully assessing kinetic outcome measures when conducting a systems level as oppose to single-organ centric analyses is crucial. This should be taken into account when assessing the emerging role of the TSPO heart-brain axis in the field of PET imaging.

scholarly journals Substitution of venous for arterial blood sampling in the determination of regional rates of cerebral protein synthesis with L-[1-11C]leucine PET: A validation study

2018 ◽  
Vol 39 (9) ◽  
pp. 1849-1863 ◽  
Author(s):  
Giampaolo Tomasi ◽  
Mattia Veronese ◽  
Alessandra Bertoldo ◽  
Carolyn B Smith ◽  
Kathleen C Schmidt
Keyword(s):  
Protein Synthesis ◽  
Healthy Volunteers ◽  
Venous Blood ◽  
Blood Sampling ◽  
Adult Males ◽  
Arterial Blood ◽  
Arterial Input Functions ◽  
Pet Scans ◽  
Cerebral Protein Synthesis

We developed and validated a method to estimate input functions for determination of regional rates of cerebral protein synthesis (rCPS) with L-[1-11C]leucine PET without arterial sampling. The method is based on a population-derived input function (PDIF) approach, with venous samples for calibration. Population input functions were constructed from arterial blood data measured in 25 healthy 18–24-year-old males who underwent L-[1-11C]leucine PET scans while awake. To validate the approach, three additional groups of 18–27-year-old males underwent L-[1-11C]leucine PET scans with both arterial and venous blood sampling: 13 awake healthy volunteers, 10 sedated healthy volunteers, and 5 sedated subjects with fragile X syndrome. Rate constants of the L-[1-11C]leucine kinetic model were estimated voxel-wise with measured arterial input functions and with venous-calibrated PDIFs. Venous plasma leucine measurements were used with venous-calibrated PDIFs for rCPS computation. rCPS determined with PDIFs calibrated with 30–60 min venous samples had small errors (RMSE: 4–9%), and no statistically significant differences were found in any group when compared to rCPS determined with arterial input functions. We conclude that in young adult males, PDIFs calibrated with 30–60 min venous samples can be used in place of arterial input functions for determination of rCPS with L-[1-11C]leucine PET.

scholarly journals Investigation of the new non-invasive semi-quantitative method of 123I-IMP pediatric cerebral perfusion SPECT

PLoS ONE ◽  
2020 ◽  
Vol 15 (11) ◽  
pp. e0241987
Author(s):  
Yasuharu Wakabayashi ◽  
Mayuki Uchiyama ◽  
Hiromitsu Daisaki ◽  
Makoto Matsumoto ◽  
Masafumi Sakamoto ◽  
...  
Keyword(s):  
Cerebral Perfusion ◽  
Quantitative Method ◽  
Brain Perfusion ◽  
Blood Sampling ◽  
Whole Body ◽  
Whole Body Scan ◽  
Brain Perfusion Spect ◽  
Non Invasive ◽  
Arterial Blood ◽  
Perfusion Spect

In pediatric cases requiring quantification of cerebral blood flow (CBF) using 123I-N-isopropyl-p-iodoamphetamine (123I-IMP) single-photon emission computed tomography (SPECT), arterial blood sampling is sometimes impossible due to issues such as movement, crying, or body motion. If arterial blood sampling fails, quantitative diagnostic assessment becomes impossible despite radiation exposure. We devised a new easy non-invasive microsphere (e-NIMS) method using whole-body scan data. This method can be used in conjunction with autoradiography (ARG) and can provide supportive data for invasive CBF quantification. In this study, we examined the usefulness of e-NIMS for pediatric cerebral perfusion semi-quantitative SPECT and compared it with the invasive ARG. The e-NIMS estimates cardiac output (CO) using whole-body acquisition data after 123I-IMP injection and the body surface area from calculation formula. A whole-body scan was performed 5 minutes after the 123I-IMP injection and CO was estimated by region of interest (ROI) counts measured for the whole body, lungs, and brain using the whole-body anterior image. The mean CBF (mCBF) was compared with that acquired via ARG in 115 pediatric patients with suspected cerebrovascular disorders (age 0–15 years). Although the mCBF estimated by the e-NIMS indicated a slight deviation in the extremely low- or high-mCBF cases when compared with the values acquired using the invasive ARG, there was a good correlation between the two methods (r = 0.799; p < 0.001). There were no significant differences in the mCBF values based on physical features, such as patients’ height, weight, and age. Our findings suggest that 123I-IMP brain perfusion SPECT with e-NIMS is the simplest semi-quantitative method that can provide supportive data for invasive CBF quantification. This method may be useful, especially in pediatric brain perfusion SPECT, when blood sampling or identifying pulmonary arteries for CO estimation using the graph plot method is difficult.

scholarly journals Reliable quantification of 18F-GE-180 PET neuroinflammation studies using an individually scaled population-based input function or late tissue-to-blood ratio

2020 ◽  
Vol 47 (12) ◽  
pp. 2887-2900 ◽  
Author(s):  
Ralph Buchert ◽  
Meike Dirks ◽  
Christian Schütze ◽  
Florian Wilke ◽  
Martin Mamach ◽  
...  
Keyword(s):  
Blood Sample ◽  
Whole Blood ◽  
Input Function ◽  
Population Based ◽  
Blood Sampling ◽  
Tracer Activity ◽  
Arterial Blood Sampling ◽  
Arterial Blood ◽  
The Individual ◽  
Individual Input

Abstract Purpose Tracer kinetic modeling of tissue time activity curves and the individual input function based on arterial blood sampling and metabolite correction is the gold standard for quantitative characterization of microglia activation by PET with the translocator protein (TSPO) ligand 18F-GE-180. This study tested simplified methods for quantification of 18F-GE-180 PET. Methods Dynamic 18F-GE-180 PET with arterial blood sampling and metabolite correction was performed in five healthy volunteers and 20 liver-transplanted patients. Population-based input function templates were generated by averaging individual input functions normalized to the total area under the input function using a leave-one-out approach. Individual population-based input functions were obtained by scaling the input function template with the individual parent activity concentration of 18F-GE-180 in arterial plasma in a blood sample drawn at 27.5 min or by the individual administered tracer activity, respectively. The total 18F-GE-180 distribution volume (VT) was estimated in 12 regions-of-interest (ROIs) by the invasive Logan plot using the measured or the population-based input functions. Late ROI-to-whole-blood and ROI-to-cerebellum ratio were also computed. Results Correlation with the reference VT (with individually measured input function) was very high for VT with the population-based input function scaled with the blood sample and for the ROI-to-whole-blood ratio (Pearson correlation coefficient = 0.989 ± 0.006 and 0.970 ± 0.005). The correlation was only moderate for VT with the population-based input function scaled with tracer activity dose and for the ROI-to-cerebellum ratio (0.653 ± 0.074 and 0.384 ± 0.177). Reference VT, population-based VT with scaling by the blood sample, and ROI-to-whole-blood ratio were sensitive to the TSPO gene polymorphism. Population-based VT with scaling to the administered tracer activity and the ROI-to-cerebellum ratio failed to detect a polymorphism effect. Conclusion These results support the use of a population-based input function scaled with a single blood sample or the ROI-to-whole-blood ratio at a late time point for simplified quantitative analysis of 18F-GE-180 PET.

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