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(R)-[(11)C]verapamil is a radiotracer widely used for the evaluation of the P-glycoprotein (P-gp) function at the blood-brain barrier (BBB). Several studies have evaluated the pharmacokinetics of (R)-[(11)C]verapamil in rats and humans under different conditions. However, to the best of our knowledge, the pharmacokinetics of (R)-[(11)C]verapamil have not yet been evaluated in nonhuman primates. Our study aims to establish (R)-[(11)C]verapamil as a reference P-gp tracer for comparison of a newly developed P-gp positron emission tomography (PET) tracer in a species close to humans. Therefore, the study assesses the kinetics of (R)-[(11)C]verapamil and evaluates the effect of scan duration and P-gp inhibition on estimated pharmacokinetic parameters. Three nonhuman primates underwent two dynamic 91 min PET scans with arterial blood sampling, one at baseline and another after inhibition of the P-gp function. The (R)-[(11)C]verapamil data were analyzed using 1-tissue compartment model (1-TCM) and 2-tissue compartment model fits using plasma-corrected for polar radio-metabolites or non-corrected for radio-metabolites as an input function and with various scan durations (10, 20, 30, 60, and 91 min). The preferred model was chosen according to the Akaike information criterion and the standard errors (SE %) of the estimated parameters. 1-TCM was selected as the model of choice to analyze the (R)-[(11)C]verapamil data at baseline and after inhibition and for all scan durations tested. The volume of distribution (V(T)) and the efflux constant k(2) estimations were affected by the evaluated scan durations, whereas the influx constant K(1) estimations remained relatively constant. After P-gp inhibition (tariquidar, 8 mg/kg), in a 91 min scan duration, the whole-brain V(T) increased significantly up to 208% (p < 0.001) and K(1) up to 159% (p < 0.001) compared with baseline scans. The k(2) values decreased significantly after P-gp inhibition in all the scan durations except for the 91 min scans. This study suggests the use of K(1), calculated with 1-TCM and using short PET scans (10 to 30 min), as a suitable parameter to measure the P-gp function at the BBB of nonhuman primates

Abstract Whole-body Patlak images can be obtained from an acquisition of first 6 min of dynamic imaging over the heart to obtain the arterial input function (IF), followed by multiple whole-body sweeps up to 60 min pi. The use of a population-averaged IF (PIF) could exclude the first dynamic scan and minimize whole-body sweeps to 30–60 min pi. Here, the effects of (incorrect) PIFs on the accuracy of the proposed Patlak method were assessed. In addition, the extent of mitigating these biases through rescaling of the PIF to image-derived IF values at 30–60 min pi was evaluated. Methods Using a representative IF and rate constants from the literature, various tumour time-activity curves (TACs) were simulated. Variations included multiplication of the IF with a positive and negative gradual linear bias over 60 min of 5, 10, 15, 20, and 25% (generating TACs using an IF different from the PIF); use of rate constants (K1, k3, and both K1 and k2) multiplied by 2, 1.5, and 0.75; and addition of noise (μ = 0 and σ = 5, 10 and 15%). Subsequent Patlak analysis using the original IF (representing the PIF) was used to obtain the influx constant (Ki) for the differently simulated TACs. Next, the PIF was scaled towards the (simulated) IF value using the 30–60-min pi time interval, simulating scaling of the PIF to image-derived values. Influence of variabilities in IF and rate constants, and rescaling the PIF on bias in Ki was evaluated. Results Percentage bias in Ki observed using simulated modified IFs varied from − 16 to 16% depending on the simulated amplitude and direction of the IF modifications. Subsequent scaling of the PIF reduced these Ki biases in most cases (287 out of 290) to Conclusions Simulations suggest that scaling of a (possibly incorrect) PIF to IF values seen in whole-body dynamic imaging from 30 to 60 min pi can provide accurate Ki estimates. Consequently, dynamic Patlak imaging protocols may be performed for 30–60 min pi making whole-body Patlak imaging clinically feasible.

Purpose Capillary transit time heterogeneity, measured as CTH, may set the upper limit for extraction of substances in brain tissue, e.g., oxygen. The purpose of this study was to investigate the feasibility of dynamic contrast-enhanced T1 weighted MRI (DCE-MRI) at 3 Tesla (T), in estimating CTH based on a gamma-variate model of the capillary transit time distribution. In addition, we wanted to investigate if a subtle increase of the blood–brain barrier permeability can be incorporated into the model, still allowing estimation of CTH. Materials and Methods Twenty-three healthy subjects were scanned at 3.0T MRI system applying DCE-MRI and using a gamma-variate model to estimate CTH as well as cerebral blood flow (CBF), cerebral blood volume (CBV), and permeability of the blood–brain barrier, measured as the influx constant Ki. For proof of principle we also investigated three patients with recent thromboembolic events and a patient with a high grade brain tumor. Results In the healthy subjects, we found a narrow symmetric delta-like capillary transit time distribution in basal ganglia gray matter with median CTH of 0.93 s and interquartile range of 1.33 s. The corresponding residue impulse response function was compatible with the adiabatic tissue homogeneity model. In two patients with complete occlusion of the internal carotid artery and in the patient with a brain tumor CTH was increased with values up to 6 s in the affected brain tissue, with an exponential like residue impulse response function. Conclusion Our results open the possibility of characterizing brain perfusion by the capillary transit time distribution using DCE-MRI, theoretically a determinant of efficient blood to brain transport of important substances. Level of Evidence 2 J. Magn. Reson. Imaging 2016.

KEY POINTS: The blood-brain barrier (BBB) is an important and dynamic structure which contributes to homeostasis in the central nervous system. BBB permeability changes occur in health and disease but measurement of BBB permeability in humans is not straightforward. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) can be used to model the movement of gadolinium contrast into the brain, expressed as the influx constant Ki . Here evidence is provided that Ki as measured by DCE-MRI behaves as expected for a marker of overall BBB leakage. These results support the use of DCE-MRI for in vivo studies of human BBB permeability in health and disease.ABSTRACT: Blood-brain barrier (BBB) leakage can be measured using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) as the influx constant Ki . To validate this method we compared measured Ki with biological expectations, namely (1) higher Ki in healthy individual grey matter (GM) versus white matter (WM), (2) GM/WM cerebral blood volume (CBV) ratio close to the histologically established GM/WM vascular density ratio, (3) higher Ki in visibly enhancing multiple sclerosis (MS) lesions versus MS normal appearing white matter (NAWM), and (4) higher Ki in MS NAWM versus healthy individual NAWM. We recruited 13 healthy individuals and 12 patients with MS and performed whole-brain 3D DCE-MRI at 3 T. Ki and CBV were calculated using Patlak modelling for manual regions of interest (ROI) and segmented tissue masks. Ki was higher in control GM versus WM (P = 0.001). CBV was higher in GM versus WM (P = 0.005, mean ratio 1.9). Ki was higher in visibly enhancing MS lesions versus MS NAWM (P = 0.002), and in MS NAWM versus controls (P = 0.014). Bland-Altman analysis showed no significant difference between ROI and segmentation methods (P = 0.638) and an intra-class correlation coefficient showed moderate single measure consistency (0.610). Ki behaves as expected for a compound marker of permeability and surface area. The GM/WM CBV ratio measured by this technique is in agreement with the literature. This adds evidence to the validity of Ki measured by DCE-MRI as a marker of overall BBB leakage.

The standard uptake value (SUV) has been used for decades to quantify positron emission tomography (PET) tracer uptake (mostly 18F-FDG) in a simple way. It is shown here how this semi-quantitative index relates to the influx constant in the more comprehensive model as proposed by Sokoloff. The limitations of the two techniques are discussed.

A new noninvasive estimation method for the plasma time-activity curve, i.e., input function (IF) of the tracer kinetic model in dynamic 18F-FDG microPET mouse studies, is proposed and validated. This estimation method comprises of four steps. First, a novel constraint nonnegative matrix factorization segmentation algorithm was applied to extract the left ventricle (Lv) and myocardium (Myo) time activity curves (TACs). Second, we modeled the IF as a seven-parameter mathematical equation and constructed a dual-output model of the real TAC in Lv and Myo accounting for the partial-volume and spillover effects. Then, we fit the image-derived Lv and Myo TACs to the dual-output model to estimate the parameters of the IF. Finally, the IF was validated by comparing it to the gold standard IF while considering the delay and dispersion effects. Our method was verified based on 20 mice datasets from the Mouse Quantitation Program database, provided by UCLA. The error of the areas under the curves between the delayed and dispersed estimated IF and the gold standard IF was 7.237% ± 6.742% (r = 0.969), and the error of the 18F-FDG influx constant Ki of the Myo was 4.910% ± 6.810% (r = 0.992). The results demonstrated the effectiveness of the proposed method.

The ability of manganese ions (Mn(2+)) to enter cells through calcium ion (Ca(2+)) channels has been used for depolarization dependent brain functional imaging with manganese-enhanced MRI (MEMRI). The purpose of this study was to quantify changes to Mn(2+) uptake in rat brain using a dynamic manganese-enhanced MRI (dMEMRI) scanning protocol with the Patlak and Logan graphical analysis methods. The graphical analysis was based on a three-compartment model describing the tissue and plasma concentration of Mn. Mn(2+) uptake was characterized by the total distribution volume of manganese (Mn) inside tissue (V(T)) and the unidirectional influx constant of Mn(2+) from plasma to tissue (K(i)). The measurements were performed on the anterior (APit) and posterior (PPit) parts of the pituitary gland, a region with an incomplete blood brain barrier. Modulation of Ca(2+) channel activity was performed by administration of the stimulant glutamate and the inhibitor verapamil. It was found that the APit and PPit showed different Mn(2+) uptake characteristics. While the influx of Mn(2+) into the PPit was reversible, Mn(2+) was found to be irreversibly trapped in the APit during the course of the experiment. In the PPit, an increase of Mn(2+) uptake led to an increase in V(T) (from 2.8±0.3 ml/cm(3) to 4.6±1.2 ml/cm(3)) while a decrease of Mn(2+) uptake corresponded to a decrease in V(T) (from 2.8±0.3 ml/cm(3) to 1.4±0.3 ml/cm(3)). In the APit, an increase of Mn(2+) uptake led to an increase in K(i) (from 0.034±0.009 min(-1) to 0.049±0.012 min(-1)) while a decrease of Mn(2+) uptake corresponded to a decrease in K(i) (from 0.034±0.009 min(-1) to 0.019±0.003 min(-1)). This work demonstrates that graphical analysis applied to dMEMRI data can quantitatively measure changes to Mn(2+) uptake following modulation of neural activity.

Purpose The aim of the study was to estimate normal ranges and test-retest measures for various parameters characterising dopamine metabolism from a prolonged 18F-dopa positron emission tomography (PET) measurement using a reference tissue model and compare their value for the detection of early Parkinson’s disease (PD).

BackgroundDynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) can detect subtle blood-brain barrier (BBB) permeability. We developed a protocol and conducted experiments to validate the technique.Methods12 subjects with relapsing-remitting multiple sclerosis (RRMS) and 13 controls were recruited. Whole-brain 3D DCE-MRI at 3 Tesla was used to calculate the influx constant Ki (Patlak method). Values were derived for manual regions of interest (ROI) as well as segmented tissue masks. In controls, cerebral blood volume (CBV) was measured in grey and white matter.ResultsIn RRMS, Ki in visibly-enhancing lesions was significantly higher than in normal-appearing white matter (NAWM) (p=0.002). Ki in NAWM was significantly higher in RRMS than controls, by both ROI (p=0.014) and segmentation (p=0.019) methods. In controls, Ki was significantly higher in grey than white matter (p=0.001). CBV (and therefore vascular surface area) was also significantly higher in grey matter (p=0.005), with a mean ratio of 1.9.ConclusionsOur method produces results in line with the expected behaviour of a BBB permeability marker, and the grey/white matter CBV ratio is in agreement with the histologically-established value.

The three-compartment model with spillover (SP) and partial volume (PV) corrections has been widely used for noninvasive kinetic parameter studies of dynamic 2-[18F] fluoro-2deoxy-D-glucose (FDG) positron emission tomography images of small animal hearts in vivo. However, the approach still suffers from estimation uncertainty or slow convergence caused by the commonly used optimization algorithms. The aim of this study was to develop an improved optimization algorithm with better estimation performance. Femoral artery blood samples, image-derived input functions from heart ventricles and myocardial time–activity curves (TACs) were derived from data on 16 C57BL/6 mice obtained from the UCLA Mouse Quantitation Program. Parametric equations of the average myocardium and the blood pool TACs with SP and PV corrections in a three-compartment tracer kinetic model were formulated. A hybrid method integrating artificial immune-system and interior-reflective Newton methods were developed to solve the equations. Two penalty functions and one late time-point tail vein blood sample were used to constrain the objective function. The estimation accuracy of the method was validated by comparing results with experimental values using the errors in the areas under curves (AUCs) of the model corrected input function (MCIF) and the 18F-FDG influx constant K i . Moreover, the elapsed time was used to measure the convergence speed. The overall AUC error of MCIF for the 16 mice averaged −1.4 ± 8.2%, with correlation coefficients of 0.9706. Similar results can be seen in the overall K i error percentage, which was 0.4 ± 5.8% with a correlation coefficient of 0.9912. The t-test P value for both showed no significant difference. The mean and standard deviation of the MCIF AUC and K i percentage errors have lower values compared to the previously published methods. The computation time of the hybrid method is also several times lower than using just a stochastic algorithm. The proposed method significantly improved the model estimation performance in terms of the accuracy of the MCIF and K i , as well as the convergence speed.

Sixteen subjects with de novo Parkinson's disease (PD) underwent three 6-[18F]fluoro-L-dopa (Fdopa) positron emission tomography (PET) scans during a follow-up time of 5 years (mean +/- SD 5.5 +/- 0.4 years) to study the progression of striatal dopaminergic hypofunction. Throughout the study, the smallest Fdopa uptake values were found in the dorso-caudal part of the putamen contralateral to the side with dominant motor symptoms. The rate of decline in Fdopa uptake in the contralateral putamen was faster in the beginning of the disease and slowed down as the disease progressed. The annual decline in Fdopa influx constant (Ki, unit x 10(-3) min(-1)) was on average 0.5 during the first 2 years and 0.2 during the subsequent 3 years (P = 0.002) in the contralateral putamen. In caudate, the rate of decline in Fdopa values was slower than in the putamen and did not change significantly during the follow-up time, annual decline in the contralateral caudate being 0.1 between baseline and 2 years and 0.3 between 2 and 5 years (P = 0.4). These results suggest that progression of putaminal dopaminergic hypofuncion in PD follows a nonlinear pattern at least in the contralateral side being faster in the beginning of the disease.

SummaryNon-specific accumulation of 18F-FDG by both tumour and inflammatory lesions can make diagnostic analysis difficult. Our aim was to explore the difference in 18F-FDG uptake kinetics between tumour and inflammatory cells. To this end, we investigated VX2 tumour lesions and inflammatory lesions in rabbits. Methods: Six rabbits with VX2 tumour cells transplanted into one forelimb muscle and inflammatory lesions induced by turpentine oil in the contralateral forelimb were scanned for 60 minutes post 18F-FDG injection. Imaging data was analyzed with the standard 2-tissue-compartment model. Parameters, VB, Ki, K1, k2, k3, k4, were compared between tumour and inflammatory lesions. SUV and dual time scan methods were also compared in the experiment. Results: Time activity curves of VX2 tumour lesions showed a characteristic pattern of gradually increasing 18F-FDG uptake up to 60 min, whereas, 18F-FDG uptake in inflammatory lesions increased more slowly than in tumours. Parameters estimated from the uptake process showed that forward transport constant, K1, and influx constant, Ki, values in VX2 tumour lesions (0.186 ± 0.053 and 0.048 ± 0.014, respectively) was significantly higher than that in inflammatory lesions (0.129 ± 0.024 and 0.022 ± 0.007, respectively) (p < 0.05). In contrast, mean values of VB, k2, k3 and k4 derived from VX2 tumours were not significantly different from that of inflammatory lesions. SUVs at 60 minutes post 18F-FDG injection were also significantly higher in the VX2 tumor lesions than in the inflammatory lesions. Retention index (RI) was not significantly different between VX2 tumours and inflammatory lesions (1.134 ± 0.076 vs. 1.060 ± 0.058, p > 0.05). Conclusion: Different kinetic parameters (Ki, K1, k3) exist between inflammatory and tumour lesions.

Parkinson’s disease is the second neurodegenerative condition worldwide with more than 4.6 million cases. Positron Emission Tomography (PET) in combination with compartmental modeling (CM) has been used to improve clinical diagnosis by providing quantitative parameters for several neurological disorders. In this work, we implemented an acquisition protocol of dynamic images in two periods of time, with data acquired in the early and late postinjection times. We also assessed the graphical methods of Patlak and Logan [1,2] using a reference tissue model for Parkinsonian and atypical Parkinsonian patients to obtain the kinetic influx constant (Ki) and the distribution volume ratio (DVR). The results obtained here were consistent with previous studies and support the usefulness of these methods for medical diagnosis.

The regional distribution of skeletal muscle blood flow was measured during postischemic reactive hyperemia using Gd-DTPA contrast-enhanced (CE) MRI. The release of an occlusive thigh cuff was used to deliver a step-input of contrast concentration that was coincident with the onset of reactive hyperemia. A first-order tracer kinetic equation was used to estimate the unidirectional influx constant, Ki (ml/100 g/min), and the distribution volume of Gd-DTPA in the tissue, v(e), from T1-weighted images acquired with saturation recovery (SR) steady-state free precession (SSFP) and spoiled gradient-echo (SPGR) protocols. The capillary permeability surface (PS) area increased significantly during reactive hyperemia, which facilitated rapid extraction of Gd-DTPA during the first pass. Regional muscle group studies from 11 normal volunteers yielded blood flow (Ki) values of 108.3 +/- 34.1 ml/100 g/min in the gastrocnemius, 184.3 +/- 41.3 ml/100 g/min in the soleus, and 122.4 +/- 34.4 ml/100 g/min in the tibialis anterior. The distribution volumes (v(e)) in the corresponding muscle groups were respectively 8.3% +/- 2.1%, 9.3% +/- 1.9%, and 7.9% +/- 1.8% from the kinetic model, and 8.8% +/- 2.4%, 9.1% +/- 1.9%, and 7.2% +/- 1.4% from tissue relaxometry studies. Bulk blood flow studies in the same volunteers using phase-contrast velocimetry (popliteal artery) yielded significantly lower flow values, but with a correlation coefficient R2 = 0.62 and P = 0.004.

Summary. The aim of the study was to reveal particularities of coupled Na+, K+, 2Cl–-cotransport with erythrocyte β-adrenergic system in bronchial asthma patients. Healthy controls (n = 10) and patients with bronchial asthma (n = 36) were examined. Effect of isoproterenol (10–6 М) on Na+, K+, 2Cl–-cotransport was estimated. Balance of K+, Na+ and Cl– in erythrocyte lysates was studied by the flame emission and radiotracer techniques (spectrophotometer Perkin-Elmer AA 306). In healthy controls, isoproterenol increased activity of Na+, K+, 2Cl–-cotransport up to 75 % according to Rb+ influx constant and up to 113 % according to Na+ efflux constant. In allergic asthma patients, isoproterenol decreased activity of Na+, K+, 2Cl–-cotransport according to Na+ efflux constant and Rb+ influx constant. In nonallergic asthma patients, isoproterenol decreased activity of Na+, K+, 2Cl–-cotransport according to Na+ efflux constant and Rb+ influx constant. Therefore, the influence of β2-adrenergic agonist isoproterenol on Na+, K+, 2Cl–-cotransport in erythrocytes of healthy controls and asthma patients has been estimated. This fact indicates coupling of cotransport with cellular β2-adrenergic system while in allergic asthma patients "paradoxical" influence of isoproterenol was observed which was a decrease in Na+, K+, 2Cl–-cotransport activity.

Background The cerebrospinal fluid (CSF) circulatory system is involved in neuroimmune regulation, cerebral detoxification, and delivery of various endogenous and exogenous substances. In conjunction with the choroid plexuses, which form the main barrier site between blood and CSF, this fluid participates in controlling the environment of the developing brain. The lack of comprehensive data on developmental changes in CSF volume and distribution impairs our understanding of CSF contribution to brain development, and limits the interpretation of blood-CSF permeability data. To address these issues, we describe the evolution of the CSF circulatory system during the perinatal period and have quantified the volume of the different ventricular, cisternal and subarachnoid CSF compartments at three ages in developing rats. Methods Immunohistofluorescence was used to visualize tight junctions in parenchymal and meningeal vessels, and in choroid plexus epithelium of 19-day fetal rats. A quantitative method based on serial sectioning of frozen head and surface measurements at the cutting plane was used to determine the volume of twenty different CSF compartments in rat brain on embryonic day 19 (E19), and postnatal days 2 (P2) and 9 (P9). Blood-CSF permeability constants for sucrose were established at P2 and P9, following CSF sampling from the cisterna magna. Results Claudin-1 and claudin-5 immunohistofluorescence labeling illustrated the barrier phenotype acquired by all blood–brain and blood-CSF interfaces throughout the entire CNS in E19 rats. This should ensure that brain fluid composition is regulated and independent from plasma composition in developing brain. Analysis of the caudo-rostral profiles of CSF distribution and of the volume of twenty CSF compartments indicated that the CSF-to-cranial cavity volume ratio decreases from 30% at E19 to 10% at P9. CSF compartmentalization within the brain changes during this period, with a major decrease in CSF-to-brain volume ratio in the caudal half of the brain. Integrating CSF volume with the measurement of permeability constants, adds to our understanding of the apparent postnatal decrease in blood-CSF permeability to sucrose. Conclusion Reference data on CSF compartment volumes throughout development are provided. Such data can be used to refine blood-CSF permeability constants in developing rats, and should help a better understanding of diffusion, bulk flow, and volume transmission in the developing brain. Electronic supplementary material The online version of this article (doi:10.1186/s12987-015-0001-2) contains supplementary material, which is available to authorized users.

Cancer therapy involving blood-borne macromolecular therapeutic agents often fails, owing to inadequate macromolecule uptake in malignant tissue. The transvascular and interstitial transport of a 19 kDa linear molecule (NC22181 or poly-[Gd-DTPA]-co-[1,6-diaminohexane]) was studied in the present work in an attempt to identify transport barriers limiting the delivery of macromolecules to tumors. Tumors of four human melanoma xenograft lines were included in the study. The uptake of NC22181 was measured by spoiled gradient recalled magnetic resonance imaging (MRI). The effective microvascular permeability constant and the interstitial influx constant of NC22181 were calculated from NC22181 uptake curves by using a three-compartment tissue model. The uptake of NC22181 was limited by the interstitial transport and not by thetransvascular transport in all xenograft lines. If the melanoma xenografts used in this study are representative models of human cancer, our results suggest that strategies for increasing the delivery of macromolecular therapeutic agents to tumors should focus on improving the transport conditions in the interstitium, rather than enhancing the permeability of the microvascular wall. J. Magn. Reson. Imaging 2001;14:608–616. © 2001 Wiley-Liss, Inc.

Useful characterizing parameters have been derived from historical positron emission tomography (PET) standardized uptake values (SUV) and influx constants K. Meta-analysis was performed on 30 multipatient PET oncological studies providing same patient SUVs and K’s. Averaged results for fluorine-18 fluorodeoxyglucose (FDG) and l -methionine respectively were: SUV vs. K correlation coefficients = 0.89 and 0.80; SUV/K ratios = 192 and 63 minutes as average tracer clearance times T in these populations. For cancers, coefficients of variation (CV) for K’s were 0.61 and 0.46, notably larger than the CVs (0.50 and 0.40) for SUVs. A Monte Carlo simulation model, matching these results, represents 1/T as (an effective tracer clearance rate) × (its initial distribution volume). We conclude that T is a characteristic tracer clearance time that is independent of cancer type. A measurement model is introduced that might help improve protocols. The higher CVs of K’s vs. SUVs is worth noting clinically when seeking an effective diagnostic marker. Also, SUV conversions to K can provide some quality assurance in K measurements.

To reduce the variability of the standardized uptake value (SUV) which is widely used to evaluate 2-[18F]fluoro-2-deoxy-d-glucose (FDG) uptake by neoplasms, net influx constant (Ki) was derived from SUV. The relationship Ki=SUV.kp.V0, where kp is the plasma clearance rate and V0 is the initial distribution volume of FDG, was utilized. A total of 71 plasma input functions were measured up to 60 min after intravenous injection of FDG in 55 patients and were analysed to obtain kp and V0. SUV and V0 were calculated based on either body weight or body surface area. To validate the Ki estimation, another group of eight patients with squamous cell carcinoma of the head and neck was included. Parametric images of the net influx constant were obtained by Patlak graphical analysis of dynamic positron emission tomography (PET) data and measured plasma input function. V0 based on body weight was 0.1627+/-0.0329 (ml/g) and showed a weak negative correlation with body weight (y=0.23356-0.00138x, r=0.591). V0 based on body surface area was 5540+/-871 (ml/m2) and had no significant correlation with body weight. kp at 50 min post injection was 0. 03272+/-0.00243 (1/min), and had no correlation with the plasma glucose concentration. A highly significant positive correlation was noted between true Ki and estimated Ki based on both body weight (y=0.0033+1.0371x, r2=0.897), and body surface area (y=0.0033+1. 0351x, r2=0.926). Ki, a better indicator of FDG uptake by tumour than SUV, is derivable non-invasively. Quantification of FDG uptake by Ki will aid standardization of diagnostic criteria of FDG PET oncology.

A noninvasive and repeatable method for assessing mouse myocardial glucose uptake with (18)F-FDG PET and Patlak kinetic analysis was systematically assessed using the vena cava image-derived blood input function (IDIF).Contrast CT and computer modeling was used to determine the vena cava recovery coefficient. Vena cava IDIF (n = 7) was compared with the left ventricular cavity IDIF, with blood and liver activity measured ex vivo at 60 min. The test-retest repeatability (n = 9) of Patlak influx constant K(i) at 10-40 min was assessed quantitatively using Bland-Altman analysis. Myocardial glucose uptake rates (rMGU) using the vena cava IDIF were calculated at baseline (n = 8), after induction of type 1 diabetes (streptozotocin [50 mg/kg] intraperitoneally, 5 d), and after acute insulin stimulation (0.08 mU/kg of body weight intraperitoneally). These changes were analyzed with a standardized uptake value calculation at 20 and 40 min after injection to correlate to the Patlak time interval.The proximal mouse vena cava diameter was 2.54 ± 0.30 mm. The estimated recovery coefficient, calculated using nonlinear image reconstruction, decreased from 0.76 initially (time 0 to peak activity) to 0.61 for the duration of the scan. There was a 17% difference in the image-derived vena cava blood activity at 60 min, compared with the ex vivo blood activity measured in the γ-counter. The coefficient of variability for Patlak K(i) values between mice was found to be 23% with the proposed method, compared with 51% when using the left ventricular cavity IDIF (P0.05). No significant bias in K(i) was found between repeated scans with a coefficient of repeatability of 0.16 mL/min/g. Calculated rMGU values were reduced by 60% in type 1 diabetic mice from baseline scans (P0.03, ANOVA), with a subsequent increase of 40% to a level not significantly different from baseline after acute insulin treatment. These results were confirmed with a standardized uptake value measured at 20 and 40 min.The mouse vena cava IDIF provides repeatable assessment of the blood time-activity curve for Patlak kinetic modeling of rMGU. An expected significant reduction in myocardial glucose uptake was demonstrated in a type 1 diabetic mouse model, with significant recovery after acute insulin treatment, using a mouse vena cava IDIF approach.

Neurotensin (NT) has been suggested to be a neuropeptide with therapeutic potential. We used multiple-time regression analysis to measure the unidirectional influx constant (Ki) of a tritiated analog of NT8-13, NT1, with improved metabolic stability. The Ki of [3H]NT1 across the blood-brain barrier (BBB) was 5.12(10(-4)) ml/g-min and was decreased 66% by unlabeled NT1 system. The amount of NT1 crossing the BBB, 0.087% of the injected dose per gram of brain, is consistent with its exerting central effects after peripheral administration. The stable [3H]NT1 crossed the BBB in intact form as assessed by HPLC and completely crossed the endothelial cells that comprise the BBB as assessed by the capillary depletion method. The presence of a transport system could be important for the development of NT analogs.

To study the precision of repeated 2-[fluorine-18]-fluoro-2-deoxy-D-glucose (FDG) uptake measurements at positron emission tomography (PET) in patients with primary lung cancer.Ten patients with untreated lung cancer underwent two dynamic FDG PET examinations after a 4-hour fast within 1 week. Kinetic modeling of tumor FDG uptake was performed on the basis of a three-compartment model. The tumor concentration of F-18 (standardized uptake value calculated on the basis of predicted lean body mass [SUV-lean]) was also measured 50-60 minutes after injection of a tracer. Blood glucose, insulin, and free fatty acid levels were monitored.SUV-lean and the FDG influx constant Ki were measured with a mean +/- standard deviation difference of 10% +/- 7 and 10% +/- 8, respectively, over repeated PET scans. The mean difference was reduced to 6% +/- 6 and 6% +/- 5 by multiplying SUV-lean and Ki by plasma glucose concentration.SUV-lean and graphical Ki can be measured reproducibly, supporting their use in quantitative FDG PET algorithms.

Endocannabinoid tone has recently been implicated in a number of prevalent neuropsychiatric conditions. [11C]CURB is the first available positron emission tomography (PET) radiotracer for imaging fatty acid amide hydrolase (FAAH), the enzyme which metabolizes the prominent endocannabinoid anandamide. Here, we sought to determine the most suitable kinetic modeling approach for quantifying [11C]CURB that binds selectively to FAAH. Six healthy volunteers were scanned with arterial blood sampling for 90 minutes. Kinetic parameters were estimated regionally using a one-tissue compartment model (TCM), a 2-TCM with and without irreversible trapping, and an irreversible 3-TCM. The 2-TCM with irreversible trapping provided the best identifiability of PET outcome measures among the approaches studied (coefficient of variation ( COV) of the net influx constant Ki and the composite parameter λ k3 (λ = K1/ k2) 3) < 10%). Reducing scan time to 60 minutes did not compromise the identifiability of rate constants. Arterial spin labeling measures of regional cerebral blood flow were only slightly correlated with Ki, but not with k3 or λ k3. Our data suggest that λ k3 is sensitive to changes in FAAH activity, therefore, optimal for PET quantification of FAAH activities with [11C]CURB. Simulations showed that [11C]CURB binding in healthy subjects is far from a flow-limited uptake.

Quantitative evaluation of dynamic Positron Emission Tomography (PET) of mouse heart in vivo is challenging due to the small size of the heart and limited intrinsic spatial resolution of the PET scanner. Here, we optimized a compartment model which can simultaneously correct for spill over and partial volume effects for both blood pool and the myocardium, compute kinetic rate parameters and generate model corrected blood input function (MCBIF) from ordered subset expectation maximization – maximum a posteriori (OSEM-MAP) cardiac and respiratory gated 18F-FDG PET images of mouse heart with attenuation correction in vivo, without any invasive blood sampling. Arterial blood samples were collected from a single mouse to indicate the feasibility of the proposed method. In order to establish statistical significance, venous blood samples from n=6 mice were obtained at 2 late time points, when SP contamination from the tissue to the blood is maximum. We observed that correct bounds and initial guesses for the PV and SP coefficients accurately model the wash-in and wash-out dynamics of the tracer from mouse blood. The residual plot indicated an average difference of about 1.7% between the blood samples and MCBIF. The downstream rate of myocardial FDG influx constant, Ki (0.15±0.03 min−1), compared well with Ki obtained from arterial blood samples (P=0.716). In conclusion, the proposed methodology is not only quantitative but also reproducible.

The authors present an in vivo method for measuring the unidirectional influx constant (Ki) for gadolinium diethylenetriaminepentaacetic acid (DTPA) diffusion across the capillary membrane in the human myocardium with magnetic resonance imaging. Ki, is related to the extraction fraction (E) and the perfusion (F) by the equation Ki = E. F. Ki was obtained by using the longitudinal relaxation rate (R1) as a measure of the myocardial concentration of Gd-DTPA in the mathematical model for transcapillary transport across capillary membranes. Myocardial enhancement after Gd-DTPA injection was followed by using inversion-recovery Turbo-FLASH (fast low-angle shot) images obtained in real time. The results were comparable to those obtained from studies with positron emission tomography in humans and invasive studies in animals. A method for obtaining the input function nonin-vasively is also presented. Comparison with direct arterial blood sampling showed that the noninvasive input function may be even more accurate with regard to timing and curve shape than the invasive input function. The procedure may therefore prove useful in clinical studies.

We present and validate a method to estimate the input function (IF) from dynamic mouse 18F-FDG microPET images and 1 late blood sample. The proposed method is almost entirely noninvasive, and accounts for the spillover, partial-volume, delay and dispersion effects. First, the time-activity curves (TACs) of the left ventricle (LV), the myocardium and the liver were extracted from their respective volumes of interest (VOIs). The liver TAC data points between 35 seconds and 1500 seconds were used to substitute for blood samples since we found they were highly correlated (average correlation coefficient r = 0.989 ± 0.012). The IF to be estimated (EIF) was expressed as a mathematical model in which the parameters were simultaneously estimated by fitting the modeled LV and myocardium TACs to the mouse PET data for these organs. Twenty normal mice data sets from the Mouse Quantitation Program database, which were shared by UCLA, were used to verify our method. The differences of the area under the curves between the EIF and the true IF (blood samples) was 6.9% ± 13.2%, and the difference of the 18F-FDG influx constant K i in myocardium was 4.8% ± 16.7% (r = 0.931). The experimental results demonstrate the effectiveness of the proposed method.

Dynamic FDG-PET imaging was used to study inflammation in lungs of mice following administration of a virulent strain of Klebsiella (K.) pneumoniae. Net whole-lung FDG influx constant (Ki) was determined in a compartment model using an image-derived blood input function. Methods. K. pneumoniae (~3 x 105 CFU) was intratracheally administered to six mice with 6 other mice serving as controls. Dynamic FDG-PET and X-Ray CT scans were acquired 24 hr after K. pneumoniae administration. The experimental lung time activity curves were fitted to a 3-compartment FDG model to obtain Ki. Following imaging, lungs were excised and immunohistochemistry analysis was done to assess the relative presence of neutrophils and macrophages. Results. Mean Ki for control and K. pneumoniae infected mice were (5.1±1.2) ×10-3 versus (11.4±2.0) ×10-3 min−1, respectively, revealing a 2.24 fold significant increase (P=0.0003) in the rate of FDG uptake in the infected lung. Immunohistochemistry revealed that cellular lung infiltrate was almost exclusively neutrophils. Parametric Ki maps by Patlak analysis revealed heterogeneous inflammatory foci within infected lungs. Conclusion. The kinetics of FDG uptake in the lungs of mice can be noninvasively quantified by PET with a 3-compartment model approach based on an image-derived input function.

Positron emission tomography (PET) was carried out, with 18 F-DOPA as a ligand, in normal control monkeys and “parkinsonian” monkeys who had been treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. The following approaches were used in data analysis: ratio of 18 F accumulation in specific to nonspecific brain areas and 18 F-DOPA influx constant obtained using either the actual plasma 18 F-DOPA or the 18 F activity in a nonspecific brain area as the input function. The results from these analyses were compared to one another and to biological parameters relevant to dopaminergic function. The striatum/cortex ratio and the rate constant calculated from plasma 18 F-DOPA appeared to be the most sensitive analytic techniques.

A kinetic modelling method for the determination of influx constant, Ki is given that utilises basis functions derived from plasma input two-tissue compartmental models (BAFPIC). Two forms of the basis functions are given: BAFPICI with k4=0 (no product loss) and BAFPICR with k4 non-zero. Simulations were performed using literature rate constant values for [18F]fluorodeoxyglucose (FDG) in both normal and abnormal brain pathology. Both homogeneous and heterogeneous tissues were simulated and this data was also used as input for other methods commonly used to determine Ki: non-linear least squares compartmental modelling (NLLS), autoradiographic method and Patlak-Gjedde graphical analysis (PGA). The four methods were also compared for real FDG positron emission tomography (PET) data. For both k4=0 and k4 non-zero simulated data BAFPIC had the best bias properties of the four methods. The autoradiographic method was always the best for variability but BAFPICI had lower variability than PGA and NLLS. For non-zero k4 data, the variance of BAFPICR was inferior to PGA but still significantly superior to NLLS. Ki maps calculated from real data substantiate the simulation results, with BAFPICI having lower noise than PGA. Voxel Ki values from BAFPICI correlated well with those from PGA (r2=0.989). BAFPIC is easy to implement and combines low bias with good noise properties for voxel-wise determination of Ki for FDG. BAFPIC is suitable for determining Ki for other tracers well characterised by a serial two-tissue compartment model and has the advantage of also producing values for individual kinetic constants and blood volume.

The purpose of this study was to investigate the kinetic behavior of 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) before and early after initiation of chemoradiation therapy in patients with squamous cell head and neck cancer.A total of 8 patients with head and neck cancer underwent (18)F-FLT PET scans (7 patients at baseline and after 5 d [10 Gy] of radiation therapy given with concomitant chemotherapy and 1 patient only at baseline). Dynamic PET images were obtained with concurrent arterial or venous blood sampling. Kinetic parameters including the flux constant of (18)F-FLT based on compartmental analysis (K-FLT), the Patlak influx constant (K-Patlak), and standardized uptake value (SUV) were calculated for the primary tumor and (18)F-FLT-avid cervical lymph nodes for all scans.Mean pretreatment values of uptake for the primary tumor and cervical nodes were 0.075 +/- 0.006 min(-1), 0.042 +/- 0.004 min(-1), and 3.4 +/- 0.5 (mean +/- SD) for K-FLT, K-Patlak, and SUV, respectively. After 10 Gy of radiation therapy, these values were 0.040 +/- 0.01 min(-1), 0.018 +/- 0.016 min(-1), and 1.8 +/- 1.1 for K-FLT, K-Patlak, and SUV, respectively. For all lesions seen on pretherapy and midtherapy scans, the correlation was 0.90 between K-FLT and K-Patlak, 0.91 between K-FLT and SUV, and 0.99 between K-Patlak and SUV.The initial (18)F-FLT uptake and change early after treatment in squamous head and neck tumors can be adequately characterized with SUV obtained at 45-60 min, which demonstrates excellent correlation with influx parameters obtained from compartmental and Patlak analyses.

A tracer kinetic procedure was developed for the measurement of monoamine oxidase type B (MAO-B) activity using L-[11C]deprenyl and positron emission tomography (PET). The kinetic model consisted of two tissue compartments with irreversible binding to the second compartment (three rate constants). In addition, a blood volume component was included. Special attention was given to the accurate measurement of the plasma and whole blood input functions. The method was applied to the measurement of the dose-response curve of a reversible MAO-B inhibitor (Ro 19–6327). From the results, it followed that the rate constant for irreversible binding ( k3) appeared to be a better index of MAO-B activity than the net influx constant Ki Furthermore, regional analysis demonstrated that Ki but not k3, was flow dependent. This implies that full kinetic analysis is required for an accurate assessment of MAO-B activity.

Objectives: We assessed the reproducibility of the kinetic analysis of 3′-deoxy-3′-[ 18 F]fluorothymidine (FLT) positron emission tomography (PET) in A431 human epidermoid carcinoma and murine Lewis lung carcinoma (LLC) tumor models. Methods: We injected 7.4 MBq of FLT (n=10 for each group) and acquired 2-h dynamic PET images. A second scan was performed 1 day later. We calculated standardized uptake value (SUV), kinetic rate constants, volume of distribution of phosphorylated FLT (Vdm), net influx constant (KFLT-CA) and influx constant by Patlak graphical analysis (KFLT-PA). The percent difference between measurements of a parameter was calculated to compare the reproducibilities of different parameters. Results: FLT phosphorylation was higher in mice with A431 tumors than in mice with LLC tumors (Pb.005). Differences in the standard deviations of the percent differences of parameters were statistically significant (Pb.001) in each model. In mice with A431 tumors, SUV, Vdm, KFLT-CA and KFLT-PA had standard deviations of the percent difference of ≤20%. The most reproducible parameter was KFLT-PA, although the standard deviation (15.6%) was not statistically different from those of Vdm (15.8%), KFLT-CA (17.5%) and SUV (18.9%). In mice with LLC tumors, K1, K1/k2 and k3 had standard deviations of the percent difference of ≤20%. No macroparameters reflecting a total FLT flux had standard deviations of ≤20%. Conclusion: Our results show the reproducibility of the kinetic macroparameters of FLT PETin mouse tumors with high FLT phosphorylation.

We attempted to measure the regional metabolic rate of glucose (MRglc) in sliced spinal cords in vitro. The thoracic spinal cord of a mature Wister rat was cut into 400-μm slices in oxygenated and cooled (1–4°C) Krebs-Ringer solution. After at least 60 min of preincubation, the spinal cord slices were transferred into double polystyrene chambers and incubated in Krebs-Ringer solution at 36°C, bubbled with 5% O 2 /5% CO 2 gas. To measure MRglc, we used the dynamic positron autoradiography technique (dPAT) with F-18-2-fluoro-2-deoxy-d-glucose ([ 18 F]FDG) and the net influx constant of [ 18 F]FDG as an index. Uptake curves of [ 18 F]FDG were well fitted by straight lines for more than 7 h after the slicing of the spinal cord (linear regression coefficient, r =0.99), indicating a constant uptake of glucose by the spinal cord tissue. The slope ( K ), which denotes MRglc, is affected by tetrodotoxin, and high K + (50 mM) or Ca 2+ -free, high Mg 2+ solution. After 10 min of hypoxia, the K value following reoxygenation was similar to the unloaded control value, but after 45 min of hypoxia, the K value was markedly lower than the unloaded control value, and after >90 min of reoxygenation it was nearly 0. Our results indicate that the living spinal cord slices used retained an activity-dependent metabolism to some extent. This technique may provide a new approach for measuring MRglc in sliced living spinal cord tissue in vitro and for quantifying the dynamic changes in MRglc in response to various interventions such as hypoxia.

We present and validate a method to obtain an input function from dynamic image data and 0 or 1 blood sample for smallanimal 18F-FDG PET studies. The method accounts for spillover and partial-volume effects via a physiologic model to yield a model-corrected input function (MCIF). Methods: Imagederived input functions (IDIFs) from heart ventricles and myocardial time–activity curves were obtained from 14 Sprague–Dawley rats and 17 C57BL/6 mice. Each MCIF was expressed as a mathematic equation with 7 parameters, which were estimated simultaneously with the myocardial model parameters by fitting the IDIFs and myocardium curves to a dual-output compartment model. Zero or 1 late blood sample was used in the simultaneous estimation. MCIF was validated by comparison with input measured from blood samples. Validation included computing errors in the areas under the curves (AUCs) and in the 18F-FDG influx constant Ki in 3 types of tissue. Results: For the rat data, the AUC error was 5.3% 6 19.0% in the 0-sample MCIF and 22.3% 6 14.8% in the 1-sample MCIF. When the MCIF was used to calculate the Ki of the myocardium, brain, and muscle, the overall errors were 26.3% 6 27.0% in the 0-sample method (correlation coefficient r 5 0.967) and 3.1% 6 20.6% in the 1-sample method (r 5 0.970). The t test failed to detect a significant difference (P . 0.05) in the Ki estimates from both the 0-sample and the 1-sample MCIF. For the mouse data, AUC errors were 4.3% 6 25.5% in the 0-sample MCIF and 21.7% 6 20.9% in the 1-sample MCIF. Ki errors averaged 28.0% 6 27.6% for the 0-sample method (r 5 0.955) and 22.8% 6 22.7% for the 1-sample method (r 5 0.971). The t test detected significant differences in the brain and muscle in the Ki for the 0-sample method but no significant differences with the 1-sample method. In both rat and mouse, 0-sample and 1-sample MCIFs both showed at least a 10-fold reduction in AUC and Ki errors compared with uncorrected IDIFs. Conclusion: MCIF provides a reliable, noninvasive estimate of the input function that can be used to accurately quantify the glucose metabolic rate in small-animal 18 F-FDG PET

Introduction: 18F-Fluoro-L-thymidine (18F-FLT) has been established as a non-invasive marker for tumor proliferation by positron emission tomography (PET). It has been shown that the uptake of 18F-FLT might correlate to increased transport as well as to S-phase specific thymidine kinase 1 (TK1) activity (Jacobs et al. 2005). Aim of the study was to further characterize 18F-FLT as marker for tumor activity and proliferation in patients with newly diagnosed gliomas. Material and methods: 13 patients (age: from 35 to 71y) with newly diagnosed primary brain tumors underwent 18F-FLT- and 11C-MET-PET, as well as T1- and T2-weighted MRI with and without contrast media on consecutive days. Tracer kinetics (k1, k2, k3, ki) were determined in tumor and in contralateral grey matter. The uptake of 18F-FLT was calculated by the standardized uptake value (SUV) and the tumor-to-background (T/B) ratio. Data of kinetic modelling, SUV and T/B values derived from 18F-FLT-PET were compared to T/B values derived from 11C-MET-PET and histology. Results: In 12 patients the diagnosis of a glioma was confirmed by histology (WHO III: n=6; WHO IV: n=6. In 4/6 patients with anaplastic gliomas no significant k3 value was measured. In contrast, in all patients with glioblastomas (n=6) k3 values ranged between 0,02/min and 0,015/min. The net influx constant ki correlated significantly with the FLT uptake ratio (p=0,002, r=0,78). Moreover, a significant correlation was observed between the SUV and metabolic rate constants ki and k3 with the proliferation index as measured by Ki67 immunostaining (p=0,038, r=0,604; p=0,023, r=0,65; p=0,043, r=0,60). A positive correlation was found between 11C-MET uptake and 18F-FLT uptake indicating the relationship between the increased transport of amino acids and nucleosides into the tumor (p=0,016, r=0,65). Conclusion: FLT uptake is a measure of increased uptake as measured by Ki and increased trapping in proliferating tumor cells as measured by k3at least in patients with glioblastoma. The significant correlation between ki and k3 with the histological proliferation index ki67 demonstrates that FLT uptake might be an indirect measure of tumor proliferation. Moreover, the positive correlation between 11C-MET uptake and k3 indicates, that 18F-FLT uptake is related to cell proliferation in areas with an increased microvessel density.

Purpose To develop an in vivo MR method for evaluation of myocardial calcium channel activity through quantification of apparent unidirectional manganese influx constants following manganese dipyridoxyl-diphosphate (MnDPDP) infusions. Materials and Methods A total of 10 healthy volunteers were divided in two groups, and received 5 μmol of MnDPDP per kg of body weight intravenously in a 1.5 Tesla scanner over five or 30 minutes, respectively. A fast inversion recovery gradient echo sequence was used to estimate pre- and postcontrast R1 values and to measure signal changes following infusions. By assuming equal longitudinal relaxivity (r1) of the contrast in all tissue compartments, signal changes in blood and myocardial tissue yielded temporal input and tissue contrast concentrations respectively. Through a two-tissue compartment model, apparent unidirectional influx constants (Ki) for myocardial manganese accumulation were estimated. Results Consistent values for Ki in left ventricular wall were found, with a mean value of 5.96 mL/100 g/minute (SD = 0.49; N = 10). No statistical significant differences in Ki were found between the two infusion groups. Conclusion Since unidirectional manganese accumulation depends upon intact myocyte membranes with functioning calcium channels, the use of unidirectional manganese influx rates may be a valuable research tool for in vivo studies of myocyte functioning in myocardial disease. J. Magn. Reson. Imaging 2006. © 2006 Wiley-Liss, Inc.

Objectives: To compare the effects of low vs. high tidal volume (Vt) with three positive end-expiratory pressure (PEEP) strategies on activated neutrophil influx into the lung. Design: Prospective, randomized controlled animal study. Setting: Animal laboratory in a university hospital. Subjects: Newborn piglets. Interventions: Surfactant-depleted piglets were randomized in littermate pairs; to PEEP of either 0 (zero end-expiratory pressure [ZEEP]; n = 6), 8 cm H2O (PEEP 8; n = 5), or 1 cm H2O above the lower inflection point (LIP) (PEEP>LIP; n = 6). Within each pair piglets were randomized to a low Vt (5–7 mL/kg) or high Vt strategy (17–19 mL/kg). After 4 hrs of mechanical ventilation, 18-fluorodeoxyglucose (18FDG) was injected and positron emission tomography scanning was performed. Measurements and Main Results: Vt and PEEP changes on influx constants of 18FDG were assessed by analysis of variance. A within-litter comparison of Vt was nonsignificant (p = .50). A between-litter comparison, ordered in linear trend rank, from ZEEP, to PEEP 8, to PEEP>LIP, showed a strong effect of PEEP on influx constant (p = .019). Conclusions: PEEP set above the LIP on the inspiratory limb of the pressure-volume curve affords a stronger lung protection than Vt strategy.

Residual FDG activity in normal tissues, such as blood vessels and the liver, as well as the spilled in background activity can impair the detection of small or modestly tracer-avid tumors in FDG-PET cancer imaging. In order to maximize tumor visualization but minimize background and artifacts, an efficient new method, adapted from the constrained temporal filtering processing widely used for signal detection, is extended to the application of dynamic FDG-PET processing. Comparing with the well-known Patlak analysis and spectral analysis (SA), the proposed method can objectively remove the partial volume effect superimposed onto the TAC as well as the residual blood activities and result in the pixel-by-pixel estimations of the influx constant as the output of the filter. Since the constrained temporal filter is designed to preserve the power of tumor signal, therefore, it is likely to offer a desirable noise canceling result, while make no or minimum distortion on tumor signatures. In contrast, Patlak analysis may fail to classify tumor and normal structures when the tumor is severely interfered by background activity. In this case the tumor present approximately similar time activity curve as that of normal tissue at the later stage of acquisition. The signal-to-noise ratio (SNR) and the contrast-to-noise ratio (CNR) are served as the figure of merit for performance evaluation. Our digital phantom study demonstrates that the proposed method outperforms Patlak and SA methods. With microPET two mouse studies are also dynamically acquired on the 6th day and the 12th day, respectively, after the cancer cell implantation. The proposed method is applied to process the earlier acquired images and the resulting findings are confirmed with the later acquisitions. The results show that the new method can enhance the tumor-to-background ratio at an early stage and is promising for improving lesion detectability.

Fluorine-18 3'-deoxy-3'-fluorothymidine (18FLT) is a tissue proliferation marker which has been suggested as a new tumour-specific imaging tracer in positron emission tomography (PET). The objectives of this study were to investigate the pharmacokinetics of 18FLT in patients with colorectal cancer, defining methodologies for the quantitative analysis of the in vivo 18FLT uptake and subsequently assessing the accuracy of semi-quantitative measures. Dynamic acquisitions over a single field of view of interest identified by computed tomography were carried out for up to 60 min following injection of 18FLT (360 +/- 25 MBq). Dynamic arterial blood sampling was carried out in order to provide a blood input function. Simultaneous venous samples were also taken in order to investigate their potential utilisation in deriving a hybrid input function. Arterial and venous blood samples at 5, 15, 30, 60 and 90 min p.i. were used for metabolite analysis. Eleven patients with primary and/or metastatic colorectal cancer were studied on a lesion by lesion basis (n = 21). All acquired images were reconstructed using ordered subsets expectation maximisation and segmented attenuation correction. Time-activity curves were derived by image region of interest (ROI) analysis and image-based input functions were obtained using abdominal or thoracic aorta ROIs. Standardised uptake values (SUVs) were calculated to provide semi-quantitative indices of uptake, while non-linear regression (NLR) methodology in association with a three-compartment model and Patlak analysis were carried out to derive the net influx constant Ki. The metabolite analysis revealed two radioactive metabolites, with the parent compound representing approximately 80% of the total radioactivity in the 30-min plasma sample. In the case of NLR, better fits were obtained with a 3k model (i.e. k4 = 0) for both lesion and bone marrow time-activity curves. For the same lesions, a high correlation was observed between the Ki derived from either Patlak analysis or NLR(3k) and the corresponding SUVs. Our results also suggest that the quantitative behaviour of 18FLT in vivo (up to 60 min p.i.) may be characterised using a 3k model or Patlak analysis in combination with image-derived input functions. The good correlation found between the SUVs (at 60 min) and Ki values supports the use of semi-quantitative indices to assess the proliferation rate of colorectal cancer lesions in vivo with 18FLT.

Objective To compare positron emission tomography (PET) and magnetic resonance imaging (MRI) in the evaluation of inflammatory proliferation of synovium. Methods Ten patients (mean ± SD age 36 ± 13 years) with inflammatory joint disease and with clinical signs of inflammation of the joint were studied. A new tracer for cellular proliferation, methyl-11C-choline (11C-choline), and a widely used tracer for the detection of inflammation and cancer, 2-18F-fluoro-2-deoxy-D-glucose (18F-FDG), were applied for PET imaging, and the results were compared with the findings from gadolinium diethylenetriaminepentaacetic acid–enhanced MR images. The uptake of 11C-choline and 18F-FDG in the inflamed synovium was measured and expressed as the standardized uptake value (SUV) and the kinetic influx constant (Ki) obtained from graphic analysis, and these values were compared with quantitative values on MRI. Synovial volumes were measured on the coronal contrast-enhanced T1-weighted MR images using the standard software of the MR imager. Results All patients showed high accumulation of both 11C-choline and 18F-FDG at the site of arthritic changes, where quantification of the tracer uptake was performed. The SUV of 11C-choline was 1.5 ± 0.9 gm/ml (mean ± SD; n = 10) and the SUV of 18F-FDG was 1.9 ± 0.9 gm/ml (n = 10) (P = 0.017). The Ki of 11C-choline (mean ± SD 0.048 ± 0.042 minute−1) was 8-fold higher than the Ki of 18F-FDG (0.006 ± 0.003 minute−1) (P = 0.009). Both the uptake of 11C-choline and the uptake of 18F-FDG correlated highly with the volume of synovium; the highest correlation was observed with the Ki of 11C-choline (r = 0.954, P < 0.0001). Conclusion In the use of PET scans,11C-choline can be regarded as a promising tracer for quantitative imaging of proliferative arthritis changes. Nevertheless, subsequent prospective studies with larger numbers of patients are necessary to further characterize the relationship between the findings on PET imaging and the clinical and functional measures of inflammation.

Objective: To compare kinetics and accumulation of 2-[fluorine-18]-fluoro-2-deoxy-D-glucose (FDG) in primary lung cancer between diabetic and non-diabetic patients using positron emission tomography (PET). Methods: Five diabetic patients and 21 non-diabetic patients underwent dynamic FDG-PET to image untreated primary lung cancers. Standardized uptake value normalized for lean body mass (SUL) was determined in tumor, blood, muscle, and lung. A 3-compartment metabolic model was applied to FDG kinetics in tumors in 24 of 26 patients. Results: At the time of PET scans, serum glucose levels were elevated in 5 diabetic patients, while 21 non-diabetic patients showed normal glucose levels. In diabetic patients, tumor SUL, tumor/blood and tumor/muscle SUL ratios were significantly decreased (P < 0.02) and also tumor/lung SUL ratio declined (P = 0.064), as compared to non-diabetic patients. In addition, the rate constant for FDG phosphorylation (k3) and influx constant (Ki) in diabetic patients were significantly lower than those in non-diabetic patients (P < 0.02). Conclusion: In diabetic patients, the rate of FDG accumulation in tumors is decreased, and tumor targeting with FDG is impaired. Diabetes may reduce the sensitivity of FDG-PET for lung cancer detection.

Background: In the usual techniques for intraoperative intact parathyroid hormone (iPTH) monitoring for primary hyperparathyroidism. the normal glands are implicitly considered suppressed. On the contrary, we believe, as do other researchers, that they are not totally suppressed. Methods: For this reason, we considered the introduction of an infusion from the unsuppressed normal glands (UNG), described by an influx constant (IC (pg/ml per min)), into the formulation of a two-compartment model, For the blood compartment, we have: C(t) = A.exp(-at) + B.exp(-bt) + EV, where A + B + EV = iPTH concentration at zero time (clamping), EV (equilibrium value) = IC/k, 'a' and 'b' are reciprocals of the time constants of the two exponentials and k = rate constant of elimination from the blood. The experimental data were obtained using an IRMA standard method, collecting samples in 20 patients, during and following adenomectomy. Results: In spite of the variability among the patients, all fits were very good, thus confirming the importance of the UNG contribution to the shaping of the disappearance curve, For this reason. the relationship between the constant infusion from the UNG and the basal iPTH level at the induction of anaesthesia (BV), was studied. Conclusions: The existence of a negative correlation, together with the determination of a regression curve (IC = 6.5BV((-0.162))), not only confirmed our assumptions. but also revealed the theoretical possibility of a priori knowledge of the iPTH contribution from the UNG. Hence, there is a theoretical possibility of discriminating between this contribution and that of the remaining (if any) affected gland(s).

This positron emission tomography (PET) study was designed to compare 2-[fluorine-18]fluoro-2-deoxy-D-glucose (FDG) kinetic parameters of tumours derived from imaging frames of 0-60 min post FDG injection with those derived from shorter imaging frames of 0-30 min. Dynamic FDG-PET scans were performed on 20 patients with primary lung cancers for 1 h after intravenous injection of FDG. Images were reconstructed with attenuation correction using transmission images obtained with a germanium-68 ring source immediately before FDG injection. A region of interest (ROI) was placed on the plane of the maximal tumour FDG uptake. Arterial input function was estimated from an ROI defined in the left atrium. Based on the standard three-compartment metabolic model, we calculated the rate constants (K1-k3) and influx constant Ki = K1k3/(k2+k3) using the imaging frames for 60 min and 30 min post FDG injection. The standardized uptake value (SUV) of tumour was measured using the imaging frame of 50-60 min post injection. High correlations were observed between kinetic parameters (K1, k2, k3 and Ki) derived from imaging frames of 0-60 min and 0-30 min [0.231+/-0.114 vs 0.260+/-0.174 (r=0.958), 1.149+/-1.038 vs 1.565+/-2.027 (r=0.968), 0.259+/-0.154 vs 0.311+/-0.194 (r=0.886) and 0.044+/-0.022 vs 0.048+/-0.023 (r=0.961), respectively, P0.001]. Ki showed an excellent agreement between the two methods (y=-0.0041+0.9831x). Mean SUV of the lung cancers was 6.58+/-2.85. It is concluded that the briefer 30-min acquisition may yield essentially the same results as the standard 60-min imaging protocol, thus offering a time saving in dynamic PET studies in which the model parameters are desired.

Dynamic changes in the cerebral glucose metabolic rate (CMRglc) before and after thiamine replenishment were investigated in living brain slices obtained from pyrithiamine-treated (PT) and pair-fed control rats by use of a positron autoradiography technique. Fresh rat brain slices (300 microm thick) were incubated with [18F]2-fluoro-2-deoxy-D-glucose ([18F]FDG) in oxygenated Krebs-Ringer solution at 36 degrees C, during which serial two-dimensional images of [18F]FDG uptake in the slices were constructed on the imaging plates. The net influx constant (=K) of [18F]FDG was determined by a Patlak graphical method of the image data. Prior to thiamine pyrophosphate (TPP)-loading, the K value in the neurologically symptomatic PT was higher in all brain regions except the thalamus and mammillary body than the control, suggesting compensatory enhanced glycolysis. The rapid decrease in this heightened net influx constant immediately after TPP-loading was surmised to be due to activation of pyruvate oxidation with lactate as the substrate, with this inhibiting the glycolysis. From > or = 150 min after TPP-loading, the K value continued to show low values in the thalamus and mammillary body, which are regarded as the responsible sites for Korsakoff syndrome, whereas in all other sites recovery to control values was observed. These findings suggest that using this technique the quantitative evaluation of serial local changes in CMRglc from thiamine deficiency to after its replenishment may be useful in elucidating the pathophysiology and prognosis of Wernicke's encephalopathy.