Nobuyuki Kudomi

Non-invasive estimation of hepatic blood perfusion from H2 15O PET images using tissue-derived arterial and portal input functions

PurposeThe liver is perfused through the portal vein and the hepatic artery. When its perfusion is assessed using positron emission tomography (PET) and 15O-labeled water (H215O), calculations require a dual blood input function (DIF), i.e., arterial and portal blood activity curves. The former can be generally obtained invasively, but blood withdrawal from the portal vein is not feasible in humans. The aim of the present study was to develop a new technique to estimate quantitative liver perfusion from H215O PET images with a completely non-invasive approach.MethodsWe studied normal pigs (nu2009=u200914) in which arterial and portal blood tracer concentrations and Doppler ultrasonography flow rates were determined invasively to serve as reference measurements. Our technique consisted of using model DIF to create tissue model function and the latter method to simultaneously fit multiple liver time–activity curves from images. The parameters obtained reproduced the DIF. Simulation studies were performed to examine the magnitude of potential biases in the flow values and to optimize the extraction of multiple tissue curves from the image.ResultsThe simulation showed that the error associated with assumed parameters was <10%, and the optimal number of tissue curves was between 10 and 20. The estimated DIFs were well reproduced against the measured ones. In addition, the calculated liver perfusion values were not different between the methods and showed a tight correlation (ru2009=u20090.90).ConclusionIn conclusion, our results demonstrate that DIF can be estimated directly from tissue curves obtained through H215O PET imaging. This suggests the possibility to enable completely non-invasive technique to assess liver perfusion in patho-physiological studies.

Myocardial blood flow and its transit time, oxygen utilization, and efficiency of highly endurance-trained human heart

Highly endurance-trained athlete’s heart represents the most extreme form of cardiac adaptation to physical stress, but its circulatory alterations remain obscure. In the present study, myocardial blood flow (MBF), blood mean transit time (MTT), oxygen extraction fraction (OEF) and consumption (MVO2), and efficiency of cardiac work were quantified in highly trained male endurance athletes and control subjects at rest and during supine cycling exercise using [15O]-labeled radiotracers and positron emission tomography. Heart rate and MBF were lower in athletes both at rest and during exercise. OEF increased in response to exercise in both groups, but was higher in athletes (70xa0±xa021 vs. 63xa0±xa011xa0% at rest and 86xa0±xa013 vs. 73xa0±xa010xa0% during exercise). MTT was longer and vascular resistance higher in athletes both at rest and during exercise, but arterial content of 2,3-diphosphoglycerate (oxygen affinity) was unchanged. MVO2 per gram of myocardium trended (pxa0=xa00.08) lower in athletes both at rest and during exercise, while myocardial efficiency of work and MVO2 per beat were not different between groups. Arterial levels of free fatty acids were ~twofold higher in athletes likely leading to higher myocardial fatty acid oxidation and hence oxygen cost, which may have blunted the bradycardia-induced decrease in MVO2. Finally, the observed group differences in MBF, OEF, MTT and vascular resistance remained significant also after they were controlled for differences in MVO2. In conclusion, in highly endurance-trained human heart, increased myocardial blood transition time enables higher oxygen extraction levels with a lower myocardial blood flow and higher vascular resistance. These physiological adaptations to exercise training occur independently of the level of oxygen consumption and together with training-induced bradycardia may serve as mechanisms to increase functional reserve of the human heart.

Non-invasive estimation of hepatic glucose uptake from [18F]FDG PET images using tissue-derived input functions

PurposeThe liver is perfused through the portal vein and hepatic artery. Quantification of hepatic glucose uptake (HGU) using PET requires the use of an input function for both the hepatic artery and portal vein. The former can be generally obtained invasively, but blood withdrawal from the portal vein is not practical in humans. The aim of this study was to develop and validate a new technique to obtain quantitative HGU by estimating the input function from PET images.MethodsNormal pigs (nu2009=u200912) were studied with [18F]FDG PET, in which arterial and portal blood time-activity curves (TAC) were determined invasively to serve as reference measurements. The present technique consisted of two characteristics, i.e. using a model input function and simultaneously fitting multiple liver tissue TACs from images by minimizing the residual sum of square between the tissue TACs and fitted curves. The input function was obtained from the parameters determined from the fitting. The HGU values were computed by the estimated and measured input functions and compared between the methods.ResultsThe estimated input functions were well reproduced. The HGU values, ranging from 0.005 to 0.02xa0ml/min per ml, were not significantly different between the two methods (ru2009=u20090.95, pu2009<u20090.001). A Bland-Altman plot demonstrated a small overestimation by the image-derived method with a bias of 0.00052xa0ml/min per g for HGU.ConclusionThe results presented demonstrate that the input function can be estimated directly from the PET image, supporting the fully non-invasive assessment of liver glucose metabolism in human studies.

Parametric renal blood flow imaging using [15O]H2O and PET.

PurposeThe quantitative assessment of renal blood flow (RBF) may help to understand the physiological basis of kidney function and allow an evaluation of pathophysiological events leading to vascular damage, such as renal arterial stenosis and chronic allograft nephropathy. The RBF may be quantified using PET with H215O, although RBF studies that have been performed without theoretical evaluation have assumed the partition coefficient of water (p, ml/g) to be uniform over the whole region of renal tissue, and/or radioactivity from the vascular space (VA. ml/ml) to be negligible. The aim of this study was to develop a method for calculating parametric images of RBF (K1, k2) as well as VA without fixing the partition coefficient by the basis function method (BFM).MethodsThe feasibility was tested in healthy subjects. A simulation study was performed to evaluate error sensitivities for possible error sources.ResultsThe experimental study showed that the quantitative accuracy of the present method was consistent with nonlinear least-squares fitting, i.e. K1,BFM=0.93K1,NLF−0.11xa0ml/min/g (r=0.80, p<0.001), k2,BFM=0.96k2,NLF−0.13xa0ml/min/g (r=0.77, p<0.001), and VA,BFM=0.92VA,NLF−0.00xa0ml/ml (r=0.97, p<0.001). Values of the Akaike information criterion from this fitting were the smallest for all subjects except two. The quality of parametric images obtained was acceptable.ConclusionThe simulation study suggested that delay and dispersion time constants should be estimated within an accuracy of 2xa0s. VA and p cannot be neglected or fixed, and reliable measurement of even relative RBF values requires that VA is fitted. This study showed the feasibility of measurement of RBF using PET with H215O.

Quantification of liver perfusion with [15O]H2O-PET and its relationship with glucose metabolism and substrate levels

BACKGROUND/AIMSnHepatic perfusion plays an important role in liver physiology and disease. This study was undertaken to (a) validate the use of Positron Emission Tomography (PET) and oxygen-15-labeled water ([(15)O]H(2)O) to quantify hepatic and portal perfusion, and (b) examine relationships between portal perfusion and liver glucose and lipid metabolism.nnnMETHODSnLiver [(15)O]H(2)O-PET images were obtained in 14 pigs during fasting or hyperinsulinemia. Carotid arterial and portal venous blood were sampled for [(15)O]H(2)O activity; Doppler ultrasonography was used invasively as the reference method. A single arterial input compartment model was developed to estimate portal tracer kinetics and liver perfusion. Endogenous glucose production (EGP) and insulin-mediated whole body glucose uptake (wbGU) were determined by standard methods.nnnRESULTSnHepatic arterial and portal venous perfusions were 0.15+/-0.07 and 1.11+/-0.34 ml/min/ml of tissue, respectively. The agreement between ultrasonography and [(15)O]H(2)O-PET was good for total and portal liver perfusion, and poor for arterial perfusion. Portal perfusion was correlated with EGP (r=or+0.62, p=0.03), triglyceride (r=or+0.66, p=0.01), free fatty acid levels (r=or+0.76, p=0.003), and plasma lactate levels (r=or-0.81, p=0.0009).nnnCONCLUSIONSnEstimates of liver perfusion by [(15)O]H(2)O-PET compared well with those by ultrasonography. The method allowed to predict portal tracer concentrations which is essential in human studies. Portal perfusion may affect liver nutrient handling.

Extraction of Input Function from Rat [18F]FDG PET Images

PurposeSmall animal positron emission tomography (PET) with 2-deoxy-2-[18F]fluoro-d-glucose ([18F]FDG) facilitates the visualization and quantification of glucose uptake in rats and mice. The quantification of glucose uptake requires an input function, which is generally obtained by measuring radioactivity in arterial plasma withdrawn during PET imaging; however, this approach is not always feasible because abundant blood sampling may affect the physiological process being measured. The purpose of the present study was to develop a new model-based technique (K-Model) and compare it to the previous F-Model.Materials and MethodsThe study material consisted of two separate groups of rats having different physiological conditions. Each group was scanned by different PET cameras, i.e., HRRT and Inveon-PET/CT, and blood samples were drawn during imaging. Two kinds of model functions, i.e., F-Model and K-Model, were used for estimating input functions by an optimization procedure, applying restrictions on boundary conditions. To validate the method, glucose influx rate, Ki, was computed from the estimated and measured input functions for comparison.ResultsThe input functions were well reproduced when single-point blood count data were used for both models. The difference in Ki values between the model-based and blood sampling methods was 1.1u2009±u200915.1% by K-Model which showed the most feasible in the study. The regression analysis showed a tight correlation between the image-based and blood sampling methods, and the slope was close to unity and the intercept close to zero.ConclusionIt is possible to estimate the input function from rat [18F]FDG PET images, thus facilitating the assessment of glucose metabolism without affecting the physiological conditions of the animal as a result of abundant blood sampling.

Non-invasive diagnosis of acute mesenteric ischaemia using PET.

PurposeAcute mesenteric ischaemia (AMI) is a lethal disease with an increasing incidence. Despite the availability of effective treatment, AMI remains a vascular emergency with over 60% mortality rate mainly due to late diagnosis. The difficulty in diagnosing this fatal condition stems from non-specific clinical and laboratory findings and lack of appropriate imaging study. Our aim was to test a non-invasive method of identifying AMI using PET.MethodsThe study was conducted in normal pigs (nu2009=u200914), sham-operated pigs (nu2009=u20094) and pigs undergoing ischaemia and reperfusion of intestine (nu2009=u20096). Liver blood flow was imaged by H215O PET and liver blood content by C15O PET. Both scans were performed during intestinal ischaemia and during reperfusion.ResultsAMI was identified by PET imaging of hepatic perfusion and blood pool. The H215O PET scan during AMI detected a 40% decrease in total liver perfusion, which was caused by a 45% reduction of portal blood flow and no alteration in arterial blood flow. Compromised hepatic perfusion during AMI was accompanied by a 75% decrease in hepatic blood pool recognized by the C15O PET scan. The striking reduction of liver blood flow and blood content persisted during reperfusion of intestine.ConclusionOur results demonstrate that AMI can be readily recognized by PET imaging of liver blood flow and blood content. Moreover, PET can be used in detection of perfusion abnormalities after revascularization. This non-invasive imaging tool could represent a novel approach to diagnose AMI.

Cross-validation of Input Functions Obtained by H215O PET Imaging of Rat Heart and a Blood Flow-through Detector

PurposePositron emission tomography (PET) with 15O-labeled water (H215O) facilitates the visualization and quantification of blood flow in clinical investigations and also in small animals. The quantification of blood flow requires an input function, which is generally obtained by measuring radioactivity in arterial blood withdrawn during PET scanning. However, this approach is not always feasible, because abundant blood sampling may affect the physiological process being measured. The purpose of the present study was to develop and cross-validate two methods, namely, a blood- and an image-based method for obtaining the input function for blood flow studies from rat H215O PET.MethodsThe study material consisted of two separate groups of rats. Group 1 rats were imaged twice by a high-resolution research tomograph PET camera at resting condition for a test–retest study (nu2009=u20094), and group 2 rats were imaged with and without adenosine infusion for a rest–stress study (nu2009=u20094). In group 1, radioactivity concentration in arterial blood was measured with a new flow-through detector during imaging and a blood-based input function was obtained. The image-based input function was estimated using time-activity curves from the left ventricle and myocardial regions. To validate the two input function methods, myocardial blood flow (MBF) and cerebral blood flow (CBF) were computed, and the methods were tested for reproducibility (test–retest study) and changes (rest–stress study).ResultsThe blood- and image-based input functions were similar, and the corresponding CBF values differed only by −6.9u2009±u20098.1%. In the test–retest study, both MBF and CBF showed good reproducibility, and in the rest–stress study, adenosine significantly increased both MBF (Pu2009=u20090.035) and CBF (Pu2009=u20090.029), compared with the resting condition.ConclusionIt is possible both to measure the input function from rat arteria femoralis during H215O PET imaging and to estimate the input function from rat H215O PET images, thereby facilitating the assessment of blood flow in organs visible in PET images.

Estimation of input function for rapid dual table ARG method

Measurements of the oxygen consumption in brain have been studied by PET. Autoradiographic method(ARG) was suggested (Mintum et al.) to yield CMRO2. This method required separately obtained information about CBF, CBV, thus time of 30-60 min. is required for three separate scans. We developed a rapid dual table method, in which water and oxygen are continuously administrated with the 90-180 sec of water and 180 sec of oxygen scan. In order to derive the quantitative CMRO2 in PET scan, it is necessary to obtain the arterial blood time activity curve. In this study, a method to estimate the input functions corresponds to [/sup 15/O] water injection and [/sup 15/O] oxygen inhalation, in a continuously administration study, was developed. A method developed was model-based, employing a fitting method. In order to estimate the reliability of developed method, input functions of [/sup 15/O] water injection and [/sup 15/O]oxygen inhalation obtained separately in a clinical study was combined with time lag of 90 seconds and 180 seconds. The reproducibility was examined by comparing the blood input functions obtained from present method and from original input functions obtained in clinical study. After fitting the combined input function with model function, each input function of [/sup 15/O] water injection and [/sup 15/O] oxygen inhalation was derived. The whole shapes were in agreement with each other. This method could be used for estimation of each input function in continuously water and oxygen administrated study.

Noninvasive estimation of cerebral blood flow using image-derived carotid input function in H/sub 2//sup 15/O dynamic PET

For the quantitation of cerebral blood flow (CBF) using H/sub 2//sup 15/O PET, the measurement of arterial input function (AIF) is essential. In this study, for the simplified quantitation, we present a method for the blind and noninvasive extraction of carotid input function (CIF) from dynamic PET images. On 8 healthy volunteers, the PET scans of C/sup 15/O and H/sub 2//sup 15/O were sequentially performed with arterial blood sampling using detector. With the inhalation of C/sup 15/O gas, dynamic PET data was acquired. And then after the injection of H/sub 2//sup 15/O, dynamic PET scans of H/sub 2//sup 15/O was perform. For 4 subjects, PET data for both rest and Acetazolamide (ACZ)-induced stress states were acquired, respectively. In the transverse dynamic images of C/sup 15/O and H/sub 2//sup 15/O, the regions of dynamic images including carotid artery were selected by masking. Non-negative matrix factorization (NMF) algorithm was used to extract the CIF from the selected dynamic images. The partial volume correction estimated from dynamic C/sup 15/O image, was applied to the extracted CIF. Whole brain CBF was estimated by kinetic analysis based on single compartment model. The error was analyzed using the area under the curve (AUC) and estimated CBF. NMF provided the good separation of the component of CIF from others in both images of C/sup 15/O and H/sub 2//sup 15/O. The shape of estimated CIF by NMF was similar with AIF measured by blood sampling. The AUC between the measured AIF and the estimated CIF was not so different at both rest and ACZ states. The difference of CBF before and after the injection of ACZ was also same between the measured AIF and the estimated CIF. These results show that NMF technique may be a tool for the noninvasive extraction of carotid input function, and this carotid input function might be used in the noninvasive quantitation of CBF using H/sub 2//sup 15/O PET.