Evaluation of four postprocessing methods for determination of cerebral blood volume and mean transit time by dynamic susceptibility contrast imaging.

Four different postprocessing methods to determine cerebral blood volume (CBV) and contrast agent mean transit time (MTT) by dynamic susceptibility contrast (DSC) MRI were compared. CBV was determined by two different methods that integrate tracer concentration-time curves numerically and by two other methods that take recirculation into account. For the two methods that use numerical integration, one method cuts the integration after the first pass while the other method integrates over the whole time series. For the two methods that account for recirculation, one method uses a gamma-variate fit, whereas the other method utilizes tissue impulse response. All four methods determine MTT as the ratio of CBV and cerebral blood flow (CBF). In each case, CBF was obtained as the height of the impulse response obtained by deconvolving the tissue concentration-time curves with a noninvasively determined arterial input function. Monte Carlo simulations were performed to determine the reliability of the methods and the validity of the simulations was supported by observation of similar trends in 13 acute stroke patients. The method of determining CBV and subsequently MTT was found to affect the measured value especially in areas where MTT is prolonged, but had no apparent effect on the visually determined hypoperfusion volumes.     

Noninvasive method to obtain input function for measuring tissue glucose utilization of thoracic and abdominal organs

We have developed a method for the noninvasive estimation of regional tissue glucose utilization in humans that employs positron emission tomography (PET) and 2-(18F)fluoro-2-deoxy-d-glucose (FDG). Unlike other methods, the input function used in this method is obtained from the corrected time-activity curve of the descending aorta, not the left ventricle, because the descending aorta is relatively free of spillover from other organs and extends from the upper thorax to the lower abdomen. With this method the time-activity curve of the descending aorta must be corrected for the partial volume effect and the difference in counts between plasma and whole blood. Using the noninvasively obtained input function, regional tissue glucose utilization was calculated by Patlak graphic analysis. k1k3/(k2 + k3) was in good agreement with k1k3/(k2 + k3) calculated from the plasma input function by arterial sampling (r = 0.9995). These results suggest that the input function and regional tissue glucose utilization (not only of myocardium but also of other thoracic and abdominal organs) can be determined noninvasively.     

Regional lung water measurements with PET: accuracy, reproducibility, and linearity

We evaluated the accuracy, reproducibility, and linearity of lung water concentration (LWC) measurements using positron emission tomography (PET) in anesthetized supine dogs. First, we evaluated whether errors in attenuation correction, which might occur during the development of pulmonary edema, significantly affect LWC and pulmonary blood flow (PBF) measurements obtained with PET. In 10 animals, PET scans of LWC and PBF were obtained before and after oleic acid induced lung injury. Changes in LWC and PBF after injury were underestimated by 12%-25% if the postinjury LWC scan was reconstructed using attenuation data obtained prior to injury, before lung density had changed, instead of attenuation data obtained after lung injury. Next, in four other dogs, we did not administer oleic acid, but instead instilled progressive amounts of autologous plasma into the left caudal lobe and obtained LWC measurements after each. Changes in LWC were linearly related to the amount of plasma instilled (r = 0.99). The average coefficient of variation for LWC in the control right lobe was 4 +/- 2% and the average percent change between measurements was 1.5% +/- 5.8%. The correlation of regional LWC determined gravimetrically after the last scan, when corrected for differences in regional lung density, with LWC determined by PET, was excellent (r = 0.92). We conclude that when the correct attenuation scan is used for emission scan reconstruction. PET measurements of LWC are accurate, linear, and reproducible.     

The effects of regional pulmonary blood flow on protein flux measurements with PET.

We used PET to evaluate whether changes in regional pulmonary blood flow (PBF) or plasma volume (PV) affect calculations of the pulmonary transcapillary escape rate (PTCER) for 68Ga-labeled transferrin. We reduced PBF in five dogs by inflating a right atrial balloon. Regional PBF decreased 25% to 174 +/- 40 ml/min/100 ml lung without a change in PV or PTCER. In eight other dogs, we decreased PBF and PV via controlled arterial hemorrhage. PBF decreased 45% to 110 +/- 33 ml/min/100 ml lung and PV decreased 22% without a change in PTCER. We also used a series of computer simulations to evaluate the effect of even greater reductions in regional PBF on PTCER calculations. These simulations showed, in support of the experimental data, that if PBF was greater than 40 ml/min/100 ml lung, PTCER could be accurately measured. However, below this level, PV was increasingly under-estimated and PTCER overestimated. The results indicate the sensitivity of the PTCER calculation to errors in the PV measurement, especially in regions of markedly reduced regional PBF.     

Radionuclide determination of right- and left-ventricular mixing

Previous models for the dynamics of the transit of the bolus of activity of labeled red cells through the chambers of the heart have assumed the complete and instantaneous mixing of tracer with the cardiac blood pool. This assumption can be conveniently tested with a radionuclide procedure. We present a model of the bolus transit through the right and left ventricle that allows the quantitation of the mixing of labeled cells with the residual blood of the cardiac chambers. This model was used to analyze the time-activity curves obtained from a variety of patients undergoing first-pass dynamic scans of the heart. It is shown that technetium-labeled red blood cells and technetium pertechnetate have indistinguishable mixing properties, and the blood in the left ventricle is more thoroughly mixed than that in the right ventricle.     

Radionuclide determination of right- and left-ventricular mixing

Previous models for the dynamics of the transit of the bolus of activity of labeled red cells through the chambers of the heart have assumed the complete and instantaneous mixing of tracer with the cardiac blood pool. This assumption can be conveniently tested with a radionuclide procedure. We present a model of the bolus transit through the right and left ventricle that allows the quantitation of the mixing of labeled cells with the residual blood of the cardiac chambers. This model was used to analyze the time-activity curves obtained from a variety of patients undergoing first-pass dynamic scans of the heart. It is shown that technetium-labeled red blood cells and technetium pertechnetate have indistinguishable mixing properties, and the blood in the left ventricle is more thoroughly mixed than that in the right ventricle.     

Superscan-like Hypermetabolic Lesions on Delayed FDG PET/CT Imaging in a Patient With Lung Cancer

ABSTRACT: A 69-year-old man with a lung mass underwent multiple-time-point FDG PET/CT imaging for diagnostic evaluation. The initial PET imaging (performed at 1 hour after tracer injection) revealed equivocal bone marrow uptake in the right iliac bone and proximal femurs in addition to lung and mediastinal lesions. The 3-hour delayed PET imaging, however, demonstrated widespread bone marrow metastases. Biopsies of the right lung mass and right iliac bone marrow were later performed and revealed a poorly differentiated squamous cell carcinoma in both sites. This case indicates the value of delayed FDG PET in detecting superscan-like hypermetabolic bone marrow lesions in patients with lung cancer.     

Gradient effects in extravascular water determination using 15O-labelled water under steady state conditions: Theory and error sensitivity

Steady state tracer measurements with short-lived isotopes allow the determination of dynamic and static physiological functions and parameters. Both types of measurements are affected by the gradient effects which result from the decay of the tracer through the volume observed. Using ¹⁵O-labelled compounds and positron emission tomography (PET), dynamic functions like flow are quite sensitive to variations in extraction fraction and distribution coefficient. In the operational equation for the determination of distribution volumes the gradient effect can be reduced to correction terms which are governed by the mean transit time of the tracer through the observed volume. Because mean transit times can be measured independently they allow a reasonable correction of gradient effects in distribution volume determinations, even if deviations of extraction fraction and distribution coefficient from unity must be considered.     

Quantification of pulmonary blood flow (PBF): Validation of perfusion MRI and nonlinear contrast agent (CA) dose correction with HO positron emission tomography (PET)

Validation of quantification of pulmonary blood flow (PBF) with dynamic, contrast‐enhanced MRI is still missing. A possible reason certainly lies in difficulties based on the nonlinear dependence of signal intensity (SI) from contrast agent (CA) concentration. Both aspects were addressed in this study. Nine healthy pigs were examined by first‐pass perfusion MRI using gadolinium diethylenetriamine pentaacetic acid (Gd‐DTPA) and HO positron emission tomography (PET) imaging. Calculations of hemodynamic parameters were based on a one‐compartment model (MR) and a two‐compartment model (PET). Simulations showed a significant error when assuming a linear relation between MR SI and CA dose in the arterial input function (AIF), even at low doses of 0.025 mmol/kg body weight (BW). To correct for nonlinearity, a calibration curve was calculated on the basis of the signal equation. The required accuracy of equation parameters (like longitudinal relaxation time) was evaluated. Error analysis estimates <5% over‐/underestimation of the corrected SI. Comparison of PET and MR flow values yielded a significant correlation (P < 0.001) in dorsal regions where signal‐to‐noise ratio (SNR) was sufficient. Changes in PBF due to the correction method were significant (P < 0.001) and resulted in a better agreement: mean values (standard deviation) in units of ml/min/100 ml lung tissue were 59 (15) for PET, 112 (28) for uncorrected MRI, and 80 (21) for corrected MRI. Magn Reson Med, 2009. © 2009 Wiley‐Liss, Inc.     

A new method of imaging the right ventricle using peripheral vein infusion of xenon 127

We report the development of a new method for obtaining right ventriculograms using the peripheral intravenous infusion of a new tracer, ¹²⁷Xe dissolved in saline. This tracer has a half life of 36 days, emits 172 keV and 203 keV photons, and is completely cleared by the lungs during pulmonary transit. The right ventricle can therefore be imaged free from interfering activity in the systemic circulation. The technique was used in 11 normal subjects and the results compared with those obtained using first pass and gated equilibrium blood pool angiography with ^99mTc. Excellent images of the right ventricle were obtained and the tricuspid and pulmonary valve planes could be easily identified. This imaging technique has significant advantages over existing methods for the noninvasive assessment of right ventricular function.     

Cis-4-[(18)F]fluoro-L-proline PET imaging of pulmonary fibrosis in a rabbit model.

A fluorinated analog of proline amino acid, cis-4-[(18)F]fluoro-L-proline (FP), was tested for potential use in PET for detection and evaluation of pulmonary response to respirable crystalline silica. The purpose of the study was to determine whether PET imaging with FP is sensitive for detection of pulmonary fibrosis. METHODS: Experimental silicosis was produced in rabbits by airway instillation of 300 mg respirable silica in 0.9% sterile saline; control rabbits received only saline. After 1, 2, 4, or 5 mo, animals were injected with 37 MBq (1 mCi) FP, and imaged in sets of 2 to 3 in a PET scanner using a dynamic scanning protocol over a 3-h period. Each imaging set contained at least 1 control rabbit. FP uptake in each lung was scored from 0 to 5 (PET score) by consensus of 3 readers blinded to animals' exposure status. Animals were humanely killed 2 d after the last imaging, and tissue sections from each lung lobe were graded from 0 to 5 by histopathology examination (histopathology score) for severity and distribution of fibrosis. RESULTS: Silicotic animals had significantly higher (P < 0.05) PET scores at each time point than did control animals. Repeated-measures ANOVA showed significant differences in PET scores between silicotic and control animals for the total lung field, but there were no statistically significant time trends for either group. Presence of fibrosis (i.e., histopathology score > 1) showed a significant association with elevated PET score (i.e., PET score > 1) using Fisher's exact test (P < 0.05). PET scores also showed excellent predictive ability, as all animals (18/18) with fibrosis also had elevated PET scores, and 95% (18/19) of animals with PET scores > 1 showed evidence of fibrosis. Localization of activity to specific lung areas was less exact, perhaps due in part to the small animal size for the resolution of the clinical PET imager used. PET scores were elevated (>1) for 67% (10/15) of silicotic right lungs and 75% (12/16) of silicotic left lungs; fibrosis scores > 1 were measured in 91% (10/11) of right lungs with PET scores > 1, and in 92% (12/13) of such left lungs. CONCLUSION: The FP tracer provided sensitive and specific identification of silicotic animals in early stages of the disease. This suggests that FP PET imaging has the potential sensitivity to detect active fibrosis in silicosis and other lung diseases. Additional studies are needed to determine the specificity of the FP tracer for fibrosis versus inflammatory processes.     

Gradient effects in extravascular water determination using 15O-labelled water under steady state conditions: theory and error sensitivity

Steady state tracer measurements with short-lived isotopes allow the determination of dynamic and static physiological functions and parameters. Both types of measurements are affected by the gradient effects which result from the decay of the tracer through the volume observed. Using 15O-labelled compounds and positron emission tomography (PET), dynamic functions like flow are quite sensitive to variations in extraction fraction and distribution coefficient. In the operational equation for the determination of distribution volumes the gradient effect can be reduced to correction terms which are governed by the mean transit time of the tracer through the observed volume. Because mean transit times can be measured independently they allow a reasonable correction of gradient effects in distribution volume determinations, even if deviations of extraction fraction and distribution coefficient from unity must be considered.     

Quantitative assessment of regional pulmonary perfusion in the entire lung using three-dimensional ultrafast dynamic contrast-enhanced magnetic resonance imaging: Preliminary experience in 40 subjects

PURPOSE: To assess regional differences in quantitative pulmonary perfusion parameters, i.e., pulmonary blood flow (PBF), mean transit time (MTT), and pulmonary blood volume (PBV) in the entire lung on a pixel-by-pixel basis in normal volunteers and pulmonary hypertension patients. MATERIALS AND METHODS: Three-dimensional ultrafast dynamic contrast-enhanced MR imaging was performed in 15 normal volunteers and 25 patients with pulmonary hypertension. From the signal intensity-time course curves, PBF, MTT and PBV maps were generated using deconvolution analysis, indicator dilution theories, and the central volume principle, on a pixel-by-pixel basis. From pulmonary perfusion parameter maps of normal volunteers and pulmonary hypertension patients, regional PBF, MTT, and PBV were statistically evaluated. RESULTS: Regional PBF, MTT, and PBV showed significant differences in the gravitational and isogravitational directions (P < 0.05). The quantitative pulmonary perfusion parameter maps demonstrated significant differences between normal volunteers and pulmonary hypertension patients (P < 0.05). CONCLUSION: Three-dimensional ultrafast dynamic contrast-enhanced MR imaging is feasible for the assessment of regional quantitative pulmonary perfusion parameters in the entire lung on a pixel-by-pixel basis in normal volunteers and pulmonary hypertension patients.     

Evaluation of62Cu labeled diacetyl-bis(N 4-methylthiosemicarbazone) as a hypoxic tissue tracer in patients with lung cancer

62Cu labeled diacetyl-bis(N4-methylthiosemicarbazone) (62Cu-ATSM) has been proposed as a generator-produced, positron-emitting tracer for hypoxic tissue imaging. From basic studies, the retention mechanism of 62Cu-ATSM is considered to be closely related to cytosolic/microsomal bioreduction, a possible system for hypoxic bioreductive drug activation. In order to evaluate the characteristics of 62Cu-ATSM, PET studies were performed in 4 normal subjects and 6 patients with lung cancer. 62Cu-ATSM cleared rapidly from the blood with little lung uptake (0.43+/-0.09, uptake ratio; divided by the arterial input function) in normal subjects. Intense tumor uptake of 62Cu-ATSM was observed in all patients with lung cancer (3.00+/-1.50). A negative correlation was observed between blood flow and flow-normalized 62Cu-ATSM uptake in three of four patients. In contrast, 62Cu-ATSM uptake was not related to that of 18F-fluorodeoxyglucose. The negative correlation between blood flow and flow normalized 62Cu-ATSM uptake suggests an enhancement of retention of 62Cu-ATSM by low flow. 62Cu-ATSM is a promising PET tracer for tumor imaging, which might bring new information for chemotherapeutic treatment as well as radiotherapy of hypoxic tumors.     

A new method of imaging the right ventricle using peripheral vein infusion of xenon 127

We report the development of a new method for obtaining right ventriculograms using the peripheral intravenous infusion of a new tracer, 127Xe dissolved in saline. This tracer has a half life of 36 days, emits 172 keV and 203 keV photons, and is completely cleared by the lungs during pulmonary transit. The right ventricle can therefore be imaged free from interfering activity in the systemic circulation. The technique was used in 11 normal subjects and the results compared with those obtained using first pass and gated equilibrium blood pool angiography with 99mTc. Excellent images of the right ventricle were obtained and the tricuspid and pulmonary valve planes could be easily identified. This imaging technique has significant advantages over existing methods for the noninvasive assessment of right ventricular function.     

Evidence for reduced arterial plasma input, prolonged lung retention and reduced lung monoamine oxidase in smokers

We have previously found that smokers have reduced brain monoamine oxidase (MAO) A and B using positron emission tomography (PET) and the irreversible mechanism-based radiotracers [(11)C]-labeled clorgyline (CLG) and deprenyl (DEP) and their deuterated analogs (D CLG, D DEP). More recently, we have estimated MAO A and B activity in other organs using the deuterium isotope effect to determine binding specificity for MAO and a three-compartment model to estimate k(3), the model term proportional to MAO A activity. Here, we have investigated the robustness of the model term k(3) for estimating lung MAO A and B in light of our unexpected finding that lung MAO activity (k(3)) was reduced for smokers relative to nonsmokers, although radiotracer uptake in the lungs was similar at peak and plateau for the two groups. METHODS: Time-activity data from lung and arterial plasma were used from seven nonsmokers and seven smokers scanned previously with CLG and D CLG, and five nonsmokers and nine smokers scanned previously with DEP and D DEP. The measured time-activity curves for lung and plasma and the integrals for the arterial plasma time-activity curves were compared at an early time point (2.5 min) and at the end of the study (55 min). A three-compartment irreversible model was used to estimate the differences between smokers and nonsmokers, and the stability of the parameter (k(3)) while varying model assumptions for the relative fractions of lung tissue, blood and air in the PET voxel. RESULTS: The peak in the arterial plasma input function and the integral of the arterial plasma time-activity curve over the first 2.5 min after radiotracer injection were significantly lower for smokers relative to nonsmokers for all four tracers. However, although the peak and plateau of the lung time-activity curves were similar for smokers and nonsmokers, the decline in radioactivity from peak to plateau was slower for smokers for all tracers. Using a three-compartment irreversible model, we estimated the ratio of MAO subtypes A and B in normal lung tissue to be on the order of 3 to 1 (MAO A to B) and that smokers have reduced MAO levels for both subtypes as measured by the model parameter, k(3). The values of k(3) are insensitive to model assumptions of variations in air and tissue fraction in the PET voxel. Most of the effects of changes in these fractions are absorbed into the parameter K(1), which governs the plasma-to-tissue transfer of tracer and is a function of blood flow. K(1) was found to be larger in smokers, although the values depend upon model assumptions of air and tissue fractions. k(3) was found to be significantly lower in smokers; for CLG, a 50% reduction in MAO A for both CLG and D CLG was observed. For DEP, k(3) was also significantly lower in smokers with a reduction of approximately 80% in lung MAO B, although there was a very large coefficient of variation in the smoker's k(3). We also found larger values of lambda (K(1)/k(2)) for smokers relative to nonsmokers for all tracers consistent with a longer lung retention of the nonenzyme-bound tracer, which explains the slower decline in uptake from peak radioactivity for smokers. CONCLUSIONS: The measured arterial input function values for smokers and nonsmokers are significantly different for these two tracer pairs for nonsmokers and smokers particularly for the first few minutes after radiotracer injection. Model estimates of k(3) that indicate that smokers have lower lung MAO A and B activity than nonsmokers are robust and insensitive to variations in model assumptions for relative fractions of lung tissue, blood and air in the PET voxel. Although we have only investigated the behavior of [(11)C]clorgyline and [(11)C]l-deprenyl and their deuterium-substituted analogs in this report, the extent to which reduced arterial input and longer lung retention also hold for other tracers for subjects who smoke merits investigation.     

Atypical metastatic lung cancer of the right ventricle on FDG PET/CT

Although primary cardiac tumours are extremely uncommon, secondary tumours or cardiac metastasis are not. We present a 68-year-old gentleman with squamous cell carcinoma of the right lower lobe with bony metastasis to the right clavicle who was treated with radiotherapy to the lung and clavicle as well as combination immunotherapy (Pembrolizumab) and chemotherapy (Carboplatin/Paclitaxel). Despite completing the above treatment regime, ¹⁸F-FDG PET/CT scan showed progression with two new sites of metastasis including a focus in the lateral wall of the right ventricle which correlate to a soft tissue density mass on CT as well as a FDG avid mass in the left masseter. Identification of cardiac lesions with ¹⁸F-FDG PET/CT maybe challenging with routine preparation due high physiological FDG uptake in the myocardium and significant variability, nevertheless, focal FDG uptake in the heart should be carefully assessed for the possibility of cardiac metastasis.     

Noninvasive measurement of cardiovascular function in mice with high-temporal-resolution small-animal PET.

The aim of this study was to explore the feasibility of determining parameters of cardiovascular function in mice noninvasively by high-temporal-resolution imaging with a dedicated small-animal PET system. METHODS: Twenty-five anesthetized mice (28.8 +/- 4.6 g) were injected via an intravenous catheter with a 30-microL bolus of (18)F-FDG (8-44 MBq). The first 9 s of data were reconstructed into 30 frames of 0.3 s using filtered backprojection. The time-activity curve derived from a left ventricle volume of interest was corrected for tracer recirculation and partial volume. Cardiac output was calculated by the Stewart-Hamilton method, in which cardiac output is total injected activity divided by the area under the left ventricle time-activity curve. Cardiac output divided by body weight was defined as cardiac index; cardiac output divided by heart rate yielded the stroke volume. In 5 mice, measurements were repeated 2-4 times to assess reproducibility. In 4 mice, the hemodynamic response to dobutamine was examined by measuring heart rate, cardiac output, and stroke volume. RESULTS: The cardiac output averaged 20.4 +/- 3.4 mL/min; in the repeated measurements, the parameter displayed a mean percentage SD per mouse of 10% +/- 6%. The cardiac index averaged 0.73 +/- 0.19 mL/min/g and the stroke volume 45.0 +/- 6.9 microL, and both correlated with heart rate (r = 0.53, P = 0.007, and r = 0.49, P = 0.01, respectively). During dobutamine stress, heart rate increased from 423 +/- 50 to 603 +/- 30 beats/min (P = 0.002) and cardiac output increased from 18.5 +/- 1.9 to 32.0 +/- 4.2 mL/min (P = 0.008). CONCLUSION: Parameters of cardiovascular function can be measured in mice noninvasively by radionuclide angiography using high-temporal-resolution small-animal PET. Measured values of cardiac output and stroke volume are reproducible and comparable to those obtained with MRI. The approach permits the monitoring of changes in cardiovascular function in response to pharmacologic intervention.     

基于人工免疫网络的小动物PET分子影像动力学参数估计方法

目的基于人工免疫网络提出无需设定初值的示踪剂动力学模型参数估计算法,以提高PET分子影像动力学模型分析方法的可靠性。方法对18F—FDG小鼠PET显像实验中有关数据,用ROI技术获取肝和左心室示踪剂的时间一放射性曲线（TAC）,同时经小鼠尾静脉多点采血获取尾静脉血TAC。对动物实验数据进行示踪剂药代动力学建模,设计人工免疫网络算法估计模型参数,并计算小鼠肝葡萄糖代谢率参数Ki。结果获得肝、左心室和尾静脉血TAC。对小动物实验数据建模,应用基于人工免疫网络的药代动力学参数优化方法（PKAIN）求解模型参数,实现无需设定初始值的模型参数估计,并计算3只小鼠K值,平均值分别为0．0024,0．0417和0．0047。PKAIN算法求出对输出模型参数估计的最大加权残差平方和的平均值小于0．0745,标准差最大为0．0084,表明能够获得准确稳定的模型参数。结论人工免疫网络智能计算方法可提高PET分子影像动力学建模方法的可靠性、实用性提供了新型的智能信息处理技术。