Compartment Kinetic Model Research Articles

Choice of Inversion Time for Arterial Spin Labeling MRI in the U.S. POINTER Lifestyle Intervention Trial

AbstractBackgroundThe U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) is a 2‐year randomized controlled trial to evaluate the effect of lifestyle interventions in older adults (60‐79 years). The POINTER Imaging ancillary study is collecting Arterial Spin Labeling (ASL) MRI data to map cerebral blood flow (CBF) and evaluate the effect of interventions in the perfusion imaging biomarker. The optimization of timing parameters is essential for robust and efficient acquisition of ASL MRI.MethodA subset (n=83; F/M=51/32; age=69.0±5.5) of POINTER Imaging participants at two imaging sites underwent two ASL MRI scans during the same baseline session. Two 3D Pulsed ASL were obtained with TI1 of 790ms and TI2 values of 2000ms or 2750ms, which provide the delay times (between labeling and imaging) of 1210ms or 1960ms. ASL images were quantified into a physiological unit of CBF, ml/100g/min, using a single compartment kinetic model. CBF maps from two scans were normalized into a standard space and a voxel‐wise paired t‐test was performed after site variations were harmonized and covariates (age and sex) were adjusted. The age and sex effects in the difference of CBF values between two scans were also examined using linear regression. To control false positives, clusters smaller than 41ml were removed based on a simulation with α=0.05.ResultThe CBF values in ASL MRI rely on the timing of image acquisition: only a fraction of label bolus arrives in the tissue with a short delay while images suffer from low signal due to the magnetization decay with a long delay. Figure 1 shows the regions that require a long delay time (red) or a short delay (blue). The difference in CBF is proportional to arterial transit time (ATT) and the analysis shows females have shorter ATT mainly in the peri‐Sylvian region (Figure 2). No cluster survived correction in the analysis of the aging effect.ConclusionThe acquisition of two CBF maps not only offers optimization of acquisition timing but provides an additional perfusion parameter, arterial transit time, which may be a potential biomarker of cerebrovascular pathophysiology.

Non-invasive quantification of acute macrophagic lung inflammation with [11C](R)-PK11195 using a three-tissue compartment kinetic model in experimental acute respiratory distress syndrome.

Imaging of acute lung inflammation is pivotal to evaluate innovative ventilation strategies. We aimed to develop and validate a three-tissue compartment kinetic model (3TCM) of [11C](R)-PK11195 lung uptake in experimental acute respiratory distress syndrome (ARDS) to help quantify macrophagic inflammation, while accounting for the impact of its non-specific and irreversible uptake in lung tissues. We analyzed the data of 38 positron emission tomography (PET) studies performed in 21 swine with or without experimental ARDS, receiving general anesthesia and mechanical ventilation. Model input function was a plasma, metabolite-corrected, image-derived input function measured in the main pulmonary artery. Regional lung analysis consisted in applying both the 3TCM and the two-tissue compartment model (2TCM); in each region, the best model was selected using a selection algorithm with a goodness-of-fit criterion. Regional best model binding potentials (BPND) were compared to lung macrophage presence, semi-quantified in pathology. The 3TCM was preferred in 142 lung regions (62%, 95% confidence interval: 56 to 69%). BPND determined by the 2TCM was significantly higher than the value computed with the 3TCM (overall median with interquartile range: 0.81 [0.44-1.33] vs. 0.60 [0.34-0.94], p < 0.02). Regional macrophage score was significantly associated with the best model BPND (p = 0.03). Regional BPND was significantly increased in the hyperinflated lung compartment, compared to the normally aerated one (median with interquartile range: 0.8 [0.6-1.7] vs. 0.6 [0.3-0.8], p = 0.03). To assess the intensity and spatial distribution of acute macrophagic lung inflammation in the context of experimental ARDS with mechanical ventilation, PET quantification of [11C](R)-PK11195 lung uptake was significantly improved in most lung regions using the 3TCM. This new methodology offers the opportunity to non-invasively evaluate innovative ventilatory strategies aiming at controlling acute lung inflammation.

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.

A Kinetic Model for Blood Biomarker Levels After Mild Traumatic Brain Injury.

Traumatic brain injury (TBI) imposes a significant economic and social burden. The diagnosis and prognosis of mild TBI, also called concussion, is challenging. Concussions are common among contact sport athletes. After a blow to the head, it is often difficult to determine who has had a concussion, who should be withheld from play, if a concussed athlete is ready to return to the field, and which concussed athlete will develop a post-concussion syndrome. Biomarkers can be detected in the cerebrospinal fluid and blood after traumatic brain injury and their levels may have prognostic value. Despite significant investigation, questions remain as to the trajectories of blood biomarker levels over time after mild TBI. Modeling the kinetic behavior of these biomarkers could be informative. We propose a one-compartment kinetic model for S100B, UCH-L1, NF-L, GFAP, and tau biomarker levels after mild TBI based on accepted pharmacokinetic models for oral drug absorption. We approximated model parameters using previously published studies. Since parameter estimates were approximate, we did uncertainty and sensitivity analyses. Using estimated kinetic parameters for each biomarker, we applied the model to an available post-concussion biomarker dataset of UCH-L1, GFAP, tau, and NF-L biomarkers levels. We have demonstrated the feasibility of modeling blood biomarker levels after mild TBI with a one compartment kinetic model. More work is needed to better establish model parameters and to understand the implications of the model for diagnostic use of these blood biomarkers for mild TBI.

Incorporating nonlinear kinetics to improve predictive performance of population pharmacokinetic models for ciclosporin in adult renal transplant recipients: A comparison of modelling strategies

BackgroundCiclosporin has been shown to follow nonlinear pharmacokinetics (PK) in renal transplant recipients who received ciclosporin (NeoralⓇ, Novartis)-based triple immunosuppressive therapy. Some of these nonlinear properties have not been fully considered in population PK (popPK) analysis. Therefore, the aim of this study was to determine the potential influence of nonlinearity and the functional forms of covariates on model predictability as well as to analyse multiple nonlinear factors in the in vivo process. MethodsA total of 2969 ciclosporin whole-blood measurements, including 1328 pre-dose and 1641 2-h post-dose concentrations, were collected from 173 patients who underwent their first renal transplantation. Four popPK models based on different modelling strategies were developed to investigate the discrepancy between empirical and theory-based, linear and nonlinear compartmental kinetic models and empirical formulae on model predictability. Prediction and simulation-based diagnostics (prediction-corrected visual predictive checks) were performed to determine the stability and predictive performance of these four models. ResultsModel predictability improved when nonlinearity was considered. The theory-based nonlinear model which incorporated nonlinear property based on known theoretical relationships performed better than the other two compartmental models. The nonlinear Michaelis-Menten model showed a remarkable improvement in predictive performance compared to the other three compartmental models. The saturated binding of ciclosporin to erythrocytes, auto-inhibition induced by the inhibitory effects of ciclosporin on cytochrome P450 3A4/P-glycoprotein may have contributed to the nonlinearity. Ciclosporin-prednisolone drug interaction should be given serious consideration in clinical settings. ConclusionsIncorporation of nonlinear properties is likely to be a promising approach for improving ciclosporin model predictability. Theory-based modelling is helpful to improve model predictability. However, ciclosporin nonlinear kinetics resources need further investigation.

Infarct size assessment through necrosis biomarker release estimation by kinetic modelling: Toward a new gold standard?

Infarct size, a key prognostic factor in ST-segment elevation myocardial infarction (STEMI), is best assessed by late gadolinium enhancement in cardiac magnetic resonance imaging (MRI). MRI availability being limited, necrosis biomarkers (peak concentration and/or area under the concentration versus time curve (AUC)) are used as surrogate markers of infarct size. These methods, excluding biomarkers kinetic data, may provide inaccurate results. We recently developed and published about compartmental kinetic models allowing estimation of the total amount of necrosis biomarker released in STEMI, A 0 , with reduced blood sampling. We sought to evaluate the correlation between A 0 of necrosis biomarkers and MRI measurements of infarct size in STEMI patients. We retrospectively included all STEMI patients with timely reperfusion and a cardiac MRI in the early recovery period in Tours University Hospital (France) from February 2015 to September 2017. Kinetics of Creatine kinase (CK), troponin I (cTnI) and/or T (cTnT), were described using our models and we compared the maximum concentration (Cmax), estimated AUC and A 0 to MRI measurements of infarct size. Forty-one patients were included; all had CK assays, 16 had cTnI assays and 25 hs-cTnT assays. Our population had similar characteristics to the STEMI population reported in the latest FAST-MI registry. The models described satisfactorily biomarker kinetic data. Infarct size was correlated with all CK and hs-cTnT parameters, particularly cTnT A 0 (R 2 = 67,1%) and CK Cmax (R 2 = 64,8%). The correlation was lower with cTnI parameters ( Fig. 1 ). Our models described accurately necrosis biomarkers kinetics following STEMI. The total amount of hs-cTnT released and estimated CK peak concentration were best correlated to MRI infarct size and may be used as easy and accurate estimators of infarct size. This method may be a major advance for future clinical trials on cardioprotection.

Biological correlates of tumor perfusion and its heterogeneity in newly diagnosed breast cancer using dynamic first-pass 18F-FDG PET/CT.

The aim of this prospective study is to analyze the global tumor blood flow (BF) and its heterogeneity in newly diagnosed breast cancer (BC) according to tumor biological characteristics and molecular subtypes. These perfusion parameters were compared to those classically derived from metabolic studies to investigate links between perfusion and metabolism. Two hundred seventeen newly diagnosed BC patients underwent a 18F-FDG PET/CT exam before any treatment. A 2-min dynamic acquisition, centered on the chest, was performed immediately after intravenous injection of 3 MBq/kg of 18F-FDG, followed by a two-step static acquisition 90 min later. Tumor BF was calculated (in ml/min/g) using a single compartment kinetic model. In addition to standard PET parameters, texture features (TF) describing the heterogeneity of tumor perfusion and metabolism were extracted. Patients were divided into three groups: Luminal (HR+/HER2-), HER2 (HER2+), and TN (HR-/HER2-). Global and TF parameters of BF and metabolism were compared in different groups of patients according to tumor biological characteristics. Tumors with lymph node involvement showed a higher perfusion, whereas no significant differences in SUV_max or SUV_mean were reported. TN tumors had a higher metabolic activity than HER2 and luminal tumors but no significant differences in global BF values were noted. HER2 tumors exhibited a larger tumor heterogeneity of both perfusion and metabolism compared to luminal and TN tumors. Heterogeneity of perfusion appeared well correlated to that of metabolism. The study of breast cancer perfusion shows a higher BF in large tumors and in tumors with lymph node involvement, not paralleled by similar modifications in tumor global metabolism. In addition, the observed correlation between the perfusion heterogeneity and the metabolism heterogeneity suggests that tumor perfusion and consequently the process of tumor angiogenesis might be involved in the metabolism heterogeneity previously shown in BC.

Assessment of myocardial necrosis biomarker release after acute myocardial infarction determined by kinetic modeling and correlation with infarct size determined by magnetic resonance imaging

Infarct size (IS) is a key determinant of cardiovascular events and is ideally assessed by cardiac MRI. MRI availability is limited and many studies used necrosis biomarkers (CK, troponin) as a surrogate marker of IS by determination of their peak concentration and/or their area under the concentration versus time curve (AUC). These biological methods, excluding biomarkers kinetic data may provide inaccurate results. We recently developed a compartmental kinetic model allowing estimation of the total amount of necrosis biomarker released during ST-segment elevation myocardial infarction (STEMI), noted A0. The aim of this study was to determine the correlation level between the amount of biomarkers released in STEMI patients obtained with this kinetic modeling and cardiac MRI measurements of IS. We retrospectively included all patients admitted for STEMI in Tours University Hospital (France) from February 2015 to September 2017, that were treated by primary percutaneous coronary intervention and who had had a cardiac MRI in the days following their admission. CK, troponin I (cTnI) and troponin T (cTnT) concentrations data were collected and kinetics of these biomarkers were described by our kinetic model. For each biomarker, we compared the maximum concentration (Cmax), AUC and A0 determined by the model to cardiac MRI measurements of IS. Among the 41 patients included, all had CK assays available, 16 had cTnI assays (cTnI subgroup) and 25 hadcTnT assays (cTnT subgroup) available. The model described satisfactorily biomarker kinetic data with only 3 values of each biomarker. IS was correlated with all CK and cTnT parameters, particularly with CK Cmax (R2 = 64,8%) and cTnT A0 (R2 = 67,1%). For cTnI, there was no correlation between IS and cTnI Cmax (R2 = 2%). Furthermore, in cTnI subgroup, IS correlation was stronger with CK parameters than with cTnI parameters. This model allows an accurate description of necrosis biomarkers kinetics following STEMI, which only few measurements. Estimated parameters, particularly CK peak concentration and the total amount of cTnT released by the injured myocardium, were highly correlated to IS measured by cardiac MRI. This method may be used in future clinical trials on the assessment of therapies aiming to reduce IS, such as conditioning therapies.

Mechanistic study on hydrodynamics in the mini-scale biphasic dissolution model and its influence on in vitro dissolution and partitioning

Biphasic dissolution models were proposed to provide good predictive power for in vivo absorption kinetics. However, up to date the impact of hydrodynamics in mini-scale models are not well understood. Consequently, the aim of this work was to investigate different setups of a previously published mini-scale biphasic dissolution model (miBIdi-pH-II) to better understand the relevance of hydrodynamics for evaluating kinetic parameters and to simultaneously increase the robustness of the experimental model.As a first step, the hydrodynamics within the aqueous phase were characterized by in silico simulations of the flow patterns. Different settings, such as higher rotation speeds of the paddles, the implementation of a second propeller into the aqueous phase, and different shapes of aqueous stirrers were investigated. Second, to evaluate the results of the in silico simulations, in vitro experiments with glitter were carried out. Last, the same settings were applied in the miBIdi-pH-II using dipyridamole (DPD) as model compound to estimate kinetic parameters by applying a compartment-based modelling approach.Both in vitro experiments with glitter or DPD demonstrated the adequateness of the previous in silico hydrodynamic simulations. The use of higher rotation speeds and a second aqueous propeller resulted in more homogeneous mixing of the aqueous phase. This resulted in faster distribution of dissolved active pharmaceutical ingredient (API) into the octanol phase. A kinetic model was successfully applied to quantify the influence of hydrodynamics on the partitioning rate of the API into the octanol phase.In conclusion, the combination of in silico and in vitro methods was demonstrated to be powerful for investigating the flow patterns within the miBIdi-pH-II. A comprehensive understanding of the hydrodynamics and the respective influence on the dissolution and apparent partitioning into the octanol phase in the biphasic dissolution model was obtained and completed by using a compartmental kinetic model. This model allowed successful quantification of how the hydrodynamics influence the partitioning of API into the octanol phase.

Dynamic 18F-FLT PET imaging of spatiotemporal changes in tumor cell proliferation and vasculature reveals the mechanistic actions of anti-angiogenic therapy

Anti-angiogenic therapies target tumor vasculature and tumor cells, thus a concurrent assessment of these targets would lead to a greater understanding of therapeutic resistance and facilitate development of improved therapeutic strategies. We utilize dynamic 3′-deoxy-3′-18F-fluorothymidine positron emission tomography (18F-FLT PET) scanning to concurrently assess changes in tumor cell proliferation and vasculature during anti-angiogenic therapy, providing insight into how these therapies may be used effectively with combination chemotherapy. Thirty-three patients with advanced solid malignancies underwent treatment with vascular endothelial growth factor receptor inhibitor (VEGFR-TKI) axitinib on an intermittent schedule (two-weeks-on/one-week-off). Patients had up to three dynamic 18F-FLT PET/CT scans: at baseline, after two weeks of continuous VEGFR-TKI treatment, and following a one week treatment break. 18F-FLT kinetics were analyzed using a two-tissue compartment kinetic model. Kinetic parameters Vb and K1 were extracted to quantify changes in tumor vasculature and the 18F-FLT flux constant Ki was calculated to quantify changes in tumor cell proliferation. Two weeks of continuous axitinib exposure led to decreases in Vb (median −21%, P = 0.07), K1 (median −39%, P < 0.01), and Ki (median −37%, P < 0.01), corresponding to diminished tumor vasculature and cell proliferation that may antagonize treatment with concurrent chemotherapy. Axitinib treatment breaks led to significant increases in Vb (median +42%, P < 0.01), K1 (median +46%, P < 0.01), and Ki (median +39%, P < 0.01) that is suggestive of an optimal time to schedule synergistic chemotherapy. Significant negative correlations (rho ⩽ −0.70, P < 0.01) were found between changes in tumor vasculature during axitinib exposure weeks and changes in tumor vasculature during treatment breaks. Imaging with dynamic 18F-FLT PET revealed new insights relating to the interplay of vascular and proliferative pharmacodynamics of axitinib therapy, facilitating a greater understanding of the mechanistic actions of VEGFR-TKIs. Increases in tumor vasculature and cell proliferation during VEGFR-TKI treatment breaks, suggests this period is an optimal time to schedule synergistic chemotherapy and warrants further investigation.

Positron Emission Tomography (PET) and Pharmacokinetics: Classical Blood Sampling Versus Image-Derived Analysis of [18F]FAZA and [18F]FDG in a Murine Tumor Bearing Model.

Pharmacokinetic (PK) data are generally derived from blood samples withdrawn serially over a defined period after dosing. In small animals, blood sampling after dosing presents technical difficulties, particularly when short time intervals and frequent sampling are required. Positron emission tomography (PET) is a non-invasive functional imaging technique that can provide semi-quantitative temporal data for defined volume regions of interest (vROI), to support kinetic analyses in blood and other tissues. The application of preclinical small-animal PET to determine and compare PK parameters for [18F]FDG and [18F]FAZA, radiopharmaceuticals used clinically for assessing glucose metabolism and hypoxic fractions, respectively, in the same mammary EMT6 tumor-bearing mouse model, is reported here. Two study groups were used: normal BALB/c mice under isoflurane anesthesia were intravenously injected with either [18F]FDG or [18F]FAZA. For the first group, blood-sampling by tail artery puncture was used to collect blood samples which were then analyzed with Radio-microTLC. Dynamic PET experiments were performed with the second group of mice and analyzed for blood input function and tumor uptake utilizing a modified two compartment kinetic model. Heart and inferior vena cava vROIs were sampled to obtain image-derived data. PK parameters were calculated from blood samples and image-derived data. Time-activity curves (TACs) were also generated over regions of liver, kidney and urinary bladder to depict clearance profiles for each radiotracer. PK values generated by classical blood sampling and PET image-derived analysis were comparable to each other for both radiotracers. Heart vROI data were suitable for analysis of [18F]FAZA kinetics, but metabolic uptake of radioactivity mandated the use of inferior vena cava vROIs for [18F]FDG analysis. While clearance (CL) and blood half-life (t½) were similar for both [18F]FDG and [18F]FAZA for both sampling methods, volume of distribution yielded larger differences, indicative of limitations such as partial volume effects within quantitative image-derived data. [18F]FDG underwent faster blood clearance and had a shorter blood half-life than [18F]FAZA. Kinetic analysis of tumor uptake from PET image data showed higher uptake and longer tumor tissue retention of [18F]FDG, indicative of the tumor's glucose metabolism rate, versus lower tumor uptake and retention of [18F]FAZA. While [18F]FAZA possesses a somewhat greater hepatobiliary clearance , [18F]FDG clears faster through the renal system which results in faster radioactivity accumulation in the urinary bladder. The present study provides a working example of the applicability of functional PET imaging as a suitable tool to determine PK parameters in small animals. The comparative analysis in the current study demonstrates that it is feasible to use [18F]FDG PET and [18F]FAZA PET in the same model to analyze their blood PK parameters, and to estimate kinetic parameters for these tracers in tumor. This non-invasive imaging-based determination of tissue kinetic parameters facilitates translation from pre-clinical to clinical phases of drug development.This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Parametric mapping using spectral analysis for 11C-PBR28 PET reveals neuroinflammation in mild cognitive impairment subjects

PurposeNeuroinflammation and microglial activation play an important role in amnestic mild cognitive impairment (MCI) and Alzheimer’s disease. In this study, we investigated the spatial distribution of neuroinflammation in MCI subjects, using spectral analysis (SA) to generate parametric maps and quantify 11C–PBR28 PET, and compared these with compartmental and other kinetic models of quantification.MethodsThirteen MCI and nine healthy controls were enrolled in this study. Subjects underwent 11C–PBR28 PET scans with arterial cannulation. Spectral analysis with an arterial plasma input function was used to generate 11C–PBR28 parametric maps. These maps were then compared with regional 11C–PBR28 VT (volume of distribution) using a two-tissue compartment model and Logan graphic analysis. Amyloid load was also assessed with 18F–Flutemetamol PET.ResultsWith SA, three component peaks were identified in addition to blood volume. The 11C–PBR28 impulse response function (IRF) at 90 min produced the lowest coefficient of variation. Single-subject analysis using this IRF demonstrated microglial activation in five out of seven amyloid-positive MCI subjects. IRF parametric maps of 11C–PBR28 uptake revealed a group-wise significant increase in neuroinflammation in amyloid-positive MCI subjects versus HC in multiple cortical association areas, and particularly in the temporal lobe. Interestingly, compartmental analysis detected group-wise increase in 11C–PBR28 binding in the thalamus of amyloid-positive MCI subjects, while Logan parametric maps did not perform well.ConclusionsThis study demonstrates for the first time that spectral analysis can be used to generate parametric maps of 11C–PBR28 uptake, and is able to detect microglial activation in amyloid-positive MCI subjects. IRF parametric maps of 11C–PBR28 uptake allow voxel-wise single-subject analysis and could be used to evaluate microglial activation in individual subjects.

Do Skeletal Dynamics Mediate Sugar Uptake and Transport in Human Erythrocytes?

We explore, herein, the hypothesis that transport of molecules or ions into erythrocytes may be affected and directly stimulated by the dynamics of the spectrin/actin skeleton. Skeleton/actin motions are driven by thermal fluctuations that may be influenced by ATP hydrolysis as well as by structural alterations of the junctional complexes that connect the skeleton to the cell’s lipid membrane. Specifically, we focus on the uptake of glucose into erythrocytes via glucose transporter 1 and on the kinetics of glucose disassociation at the endofacial side of glucose transporter 1. We argue that glucose disassociation is affected by both hydrodynamic forces induced by the actin/spectrin skeleton and by probable contact of the swinging 37-nm-long F-actin protofilament with glucose, an effect we dub the “stickball effect.” Our hypothesis and results are interpreted within the framework of the kinetic measurements and compartmental kinetic models of Carruthers and co-workers; these experimental results and models describe glucose disassociation as the “slow step” (i.e., rate-limiting step) in the uptake process. Our hypothesis is further supported by direct simulations of skeleton-enhanced transport using our molecular-based models for the actin/spectrin skeleton as well as by experimental measurements of glucose uptake into cells subject to shear deformations, which demonstrate the hydrodynamic effects of advection. Our simulations have, in fact, previously demonstrated enhanced skeletal dynamics in cells in shear deformations, as they occur naturally within the skeleton, which is an effect also supported by experimental observations.

Quantification of myocardial perfusion reserve using dynamic SPECT images of patients with chronic kidney disease

BackgroundChronic kidney disease (CKD) is an independent risk factor for cardiovascular disorders. The aim of this study was to examine whether the quantitatively measured myocardial blood flow (MBF) or myocardial perfusion reserve (MPR), calculated by dynamic single photon emission computed tomography (SPECT) analysis using a cardiac cadmium zinc telluride (CZT) gamma camera, was related to renal dysfunction in patients with normal myocardial perfusion imaging (MPI) findings. MethodsThe study population consisted of 46 patients with CKD and 46 individuals without CKD (controls). Their MPR index was quantitatively measured using adenosine MPI with a cardiac CZT gamma camera. All assessments were with a single tissue compartment kinetic model. The K1 value was calculated on stress and at-rest images. To obtain the MPR index we divided K1 stress-by K1 at-rest values. ResultsThe at-rest K1 value was significantly higher and the MPR index was significantly lower in patients with CKD than those without CKD [CKD vs. controls: at-rest K1 value, 0.21 (0.17–0.25) vs. 0.19 (0.16–0.22), p=0.040; MPR index, 1.86 (1.69–2.22) vs. 2.19 (1.93–2.41), p<0.001]. The stress K1 values were not significantly different. ConclusionThe MPR index is significantly lower in CKD patients; this is considered as being mainly due to an increase in the at-rest K1 value.

Validation of Bayesian analysis of compartmental kinetic models in medical imaging

IntroductionKinetic compartmental analysis is frequently used to compute physiologically relevant quantitative values from time series of images. In this paper, a new approach based on Bayesian analysis to obtain information about these parameters is presented and validated. Materials and methodsThe closed-form of the posterior distribution of kinetic parameters is derived with a hierarchical prior to model the standard deviation of normally distributed noise. Markov chain Monte Carlo methods are used for numerical estimation of the posterior distribution. Computer simulations of the kinetics of F18-fluorodeoxyglucose (FDG) are used to demonstrate drawing statistical inferences about kinetic parameters and to validate the theory and implementation. Additionally, point estimates of kinetic parameters and covariance of those estimates are determined using the classical non-linear least squares approach. Results and discussionPosteriors obtained using methods proposed in this work are accurate as no significant deviation from the expected shape of the posterior was found (one-sided P>0.08). It is demonstrated that the results obtained by the standard non-linear least-square methods fail to provide accurate estimation of uncertainty for the same data set (P<0.0001). ConclusionsThe results of this work validate new methods for a computer simulations of FDG kinetics. Results show that in situations where the classical approach fails in accurate estimation of uncertainty, Bayesian estimation provides an accurate information about the uncertainties in the parameters. Although a particular example of FDG kinetics was used in the paper, the methods can be extended for different pharmaceuticals and imaging modalities.

Direct reconstruction in CT-analogous pharmacokinetic diffuse fluorescence tomography: two-dimensional simulative and experimental validations.

We present a generalized strategy for direct reconstruction in pharmacokinetic diffuse fluorescence tomography (DFT) with CT-analogous scanning mode, which can accomplish one-step reconstruction of the indocyanine-green pharmacokinetic-rate images within in vivo small animals by incorporating the compartmental kinetic model into an adaptive extended Kalman filtering scheme and using an instantaneous sampling dataset. This scheme, compared with the established indirect and direct methods, eliminates the interim error of the DFT inversion and relaxes the expensive requirement of the instrument for obtaining highly time-resolved date-sets of complete 360 deg projections. The scheme is validated by two-dimensional simulations for the two-compartment model and pilot phantom experiments for the one-compartment model, suggesting that the proposed method can estimate the compartmental concentrations and the pharmacokinetic-rates simultaneously with a fair quantitative and localization accuracy, and is well suitable for cost-effective and dense-sampling instrumentation based on the highly-sensitive photon counting technique.

Transfusion Therapy and Hydroxyurea Improves Cerebrovascular Reserve and Perfusion in Children with Sickle Cell Anemia: An MRI Study

Introduction: The pathophysiology of overt stroke in children with sickle cell anemia (SCA) is not well understood. However, a compromised cerebral hemodynamic environment, marked by elevated cerebral blood flow (CBF) and impaired cerebrovascular reserve are thought to play a critical role. Currently, stroke prevention is based on chronic transfusion therapy (Tx). However, Tx suffers from several complications including; iron overload, risk of infection, and hyperhemolysis reactions. Hydroxyurea (HU) is a well-tolerated myelosupressive agent, which increases fetal hemoglobin (HbF) and is being tested as an alternative to Tx for primary stroke prevention in children with SCA. However, it is currently not clear how either Tx or HU treatment compare with respect to their effects on the precarious hemodynamic environment in children with SCA. Therefore, we assessed cerebrovascular reserve by obtaining MR-based measures of cerebrovascular reactivity (CVR), defined as the change in blood flow in response to a vasoactive stimulus. Considering that HU and Tx both act to dilute HbS and increase oxygen carrying capacity, we hypothesized that SCA children treated with HU and Tx will exhibit increased CVR and decreased CBF compared to age-matched, non-treated, SCA children.Methods: 21 SCA (HbSS) untreated SCA children (5M/16F; avg age 14.1 ± 2.42), 16 SCA children treated with HU (10M/6F; avg age 14.0 ± 2.49) and 7 patients on Tx (3M/4F ; avg age 13.0 ± 1.81) were recruited from the Haematology Department at The Hospital for Sick Children. Exclusion criteria were; history of overt stroke, vasoocclusive crises, and febrile illness within 30 days of the scan. CVR was obtained using a blood-oxygen level-dependent (BOLD) MRI sequence in combination with a CO2 breathing challenge. CO2 was administered via a re-breathing mask in 4 alternating cycles of 40 mmHg PETCO2 for 60 seconds and 45 mmHg PETCO2 for 45 seconds. BOLD MRI signal changes were aligned and regressed against the CO2 waveform on a voxel-wise bases using FSLv4.1 to yield the raw CVR maps. The CVR maps were then co-registered to anatomical images. CBF measurements were obtained using a pulsed arterial spin labeling (pASL) sequence and were quantified from the mean signal difference between the ASL tag and control images using a single compartment kinetic model. The Student's t-test was used to test for significant differences between CVR, CBF, and blood parameters between the HU, Tx, and No Treatment groups. Blood parameters were obtained from complete blood counts.Results: Blood parameters are shown in Table 1.HU-treated SCA children exhibited significantly higher Hct and CVR in both the gray and white matter compared to the No Treatment group, with no significant differences in CBF. The Tx-treated SCA group exhibited higher Hct, CVR in the gray matter, and decreased CBF in both the grey and white matter compared to the No Treatment group (see Figure 1).Conclusions: Both the HU and Tx-treated SCA groups demonstrated significantly improved cerebrovascular reserve compared to the No Treatment group. The increase vascular reserve may be a result of HU and Tx decreasing the severity of anemia thereby reducing the baseline vessel tone necessary to sufficiently perfuse the cerebral tissue. CBF was significantly reduced in the Tx-treated group compared to the No Treatment group, which may be due to the higher oxygen content provided by Tx. Interestingly, CBF was not significantly different between the HU-treated and No Treatment group despite the HU-treated group having significantly greater hematocrit. This was surprising as a previous study using Doppler ultrasound (TCD) demonstrated that HU significantly reduces blood velocities (TCDv). However, unlike TCDv which are velocity measurements obtained at the large feeding arteries, pASL CBF values reflect perfusion at the tissue level. Further studies are required to fully compare TCDv and pASL measures of CBF as a means to monitor treatment effects in SCA patients.Table 1SCA: No TreatmentSCA: HydroxyureaSCA: TransfusionSample Size (N)21167Gender (M/F)5/1610/6*3/4Age (mean ± SD)14.1 ± 2.4214.0 ± 2.4913.0 ±1.81Hematocrit0.253 ± 0.0370.289 ± 0.034*0.308 ± 0.034¥Hemoglobin (g/L)86.4 ± 10.9101 ± 12.1*105 ± 11.2¥Hemoglobin F (%)-15.8 ± 8.073.01 ± 32.2Reticulocyte (%)9.4 ± 6.17.2 ± 3.6-MCV (fL)80.3 ± 10.894.9 ± 12.3*-SaO20.97 ± 0.030.99 ± 0.01-Neutrophils (K/uL)6.1 ± 3.14.2 ± 1.6*- [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Simulating the effect of venous dispersion on distribution volume measurements from the Logan plot

Measurement of distribution volume with the Logan plot requires an arterial time activity curve (TAC). The gold standard for measuring arterial activity concentrations is arterial blood sampling. Arterial cannulation carries with it several risks. This work simulated the effects of venous dispersion on measured distribution volumes using the Logan plot with a venous TAC. A representative arterial TAC was selected from a patient study. Simulated tissue TACs were generated from a three compartment kinetic model using the representative arterial TAC. Venous TACs were simulated by convolving the arterial TAC with modified transit time spectra derived from an in vivo dynamic contrast enhanced-CT forearm study. Gaussian noise was added to the tissue TACs. Logan analysis was compared using the arterial and venous TACs for a wide range of kinetic parameters. Bland–Altman analysis was performed to assess agreement between the two methods. Good agreement was observed between values calculated with the arterial and simulated venous TACs for both noiseless and noisy cases. Agreement was slightly dependent on the arterio–venous extraction efficiency of the PET tracer. Results suggest that venous sampling may be a feasible alternative to arterial sampling for analysis with the Logan plot. This technique must be clinically validated in future patient studies.

Abstract 4522: Pharmacokinetic evaluation of a novel anti-angiogenic molecule named JFD-WS in Balb/c mice

Abstract JFD is a novel anti-angiogenic compound which mediates its action by blocking Vascular Endothelial Growth Factor Receptors and associated kinase activity, thereby arresting tumor angiogenesis and growth. The original JFD has been modified into a water soluble form (JFD-WS) to increase bioavailability and distribution during the in vivo pre-clinical testing in mouse model. Through both in vitro and in vivo testing, we have confirmed its anti-angiogenic and cytoreductive properties and are currently establishing its pharmacokinetic (PK) properties. The absorption, distribution and elimination of JFD-WS were determined by measuring the plasma and urine concentrations after intraperitoneal (i.p.) and oral administration in Balb/c mice. Following i.p. administration of JFD-WS (100 mg/kg body weight), the plasma samples were collected at 2.5, 5, 10, 15, 30, 60, 120, 1440 mins and the urine samples were collected at 15, 30, 60, 120, 1440 mins. The JFD-WS was extracted using a simple liquid extraction procedure and the concentrations in the plasma and urine were analyzed using HPLC method. Our experiments showed that JFD-WS can reach peak plasma concentration after 15 mins and a maximum elimination in urine was observed after 30 mins of i.p. injection. The compound was undetectable in both plasma and urine after 24 hours. Further analysis of plasma levels of JFD-WS using standard PK parameters has led us to hypothesize that JFD-WS may follow a two compartment kinetic model, according to which the molecule may enter the liver through the portal vein after absorption from the peritoneal cavity. During drug distribution, JFD-WS seems to enter the first compartment, including blood circulation, and then reaches the second compartment i.e., the rest of the body till equilibrium is attained. It is further speculated that the first phase of CYP450 system mediated metabolism may not be very extensive since our compound is in water soluble form. Finally, a majority of the molecule is excreted out by glomerular filtration in urine while a small portion is removed through the feces as well. Derived from an established PK formula, the half-life (t½) of our JFD-WS molecule was found to be around 33 mins. A high volume of distribution calculated for JFD-WS leads us to assume that it may distribute largely in extravascular regions such as muscles and tissues, while a high clearance rate could contribute to the lower toxicity of the compound. This hypothesis is further supported by our observations found in the in vivo systems, wherein JFD-WS is highly effective in causing tumor inhibition with minimal toxicity. Thus, the results of our study confirm that i.p. administration allows for reasonable distribution of JFD-WS to the tumor sites within a shorter duration of time that can produce cytoreductive effect. (The Royal Dames of Cancer Research Inc., Ft. Lauderdale Florida is gratefully acknowledged for their generous financial support). Citation Format: Manasa Subbarao, Sivanesan Dhandayuthapani, Mortatha Albassam, Appu Rathinavelu. Pharmacokinetic evaluation of a novel anti-angiogenic molecule named JFD-WS in Balb/c mice. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4522. doi:10.1158/1538-7445.AM2015-4522

A real-time follow-up of photodynamic therapy during PET imaging

To monitor a real-time follow-up of tumor response to photodynamic therapy (PDT) by dynamic 2-deoxy-2-[(18)F]fluoro-d-glucose ((18)FDG) and positron emission tomography (PET) using two photosensitizing drugs in vivo, and to assess their mechanisms of action. Two types of photosensitizers with different action mechanisms were used in rats implanted with two tumors: AlPcS4 mainly affecting the tumor vascular system, and ZnPcS2 largely inducing direct cell kill. Twenty-four hours after administration of either photosensitizer, one tumor served as control while the other was treated with red light during 30min within the 2h PET imaging by infusion of (18)FDG. The usual two-tissue compartment kinetic model was modified to take into account the perturbation of the treatment during imaging. The illumination of the tumors during PET imaging provoked a net decrease of (18)FDG uptake in tumors treated with AlPcS4 and a near total absence of (18)FDG uptake in tumors treated with ZnPcS2. After the end of illumination, the tumors regained (18)FDG uptake with a more pronounced uptake in the tumors treated with ZnPcS2. The rate constant values of the new (18)FDG kinetic model reflected the response of the tumors to the treatment in both photosensitizers. Dynamic PET imaging can be used to quantitatively assess in vivo and in real-time the response of tumors to treatments. It is demonstrated that the 30min of treatment was not sufficient to reduce the activity of the tumors. The technique could be extended to directly monitor the effects of drugs in vivo.