Blood Input Function Research Articles

PL - 031 Skeletal muscle blood flow determination using gold standard invasive arterial input function and non-invasive image-based input function by positron emission tomography (PET)

Objective Skeletal muscle is unique among organs in that its blood flow, thus oxygen supply that is critical for muscular function, can change over a remarkably large range. Compared to the rest, muscle blood flow can increase over 20-fold during intense exercise. Positron emission tomography (PET) and [15O]-H2O tracer provide a unique tool for the direct measurement of muscle blood flow in specific muscle regions. Quantification of PET blood flow requires knowledge of the arterial input function, which is usually provided by arterial blood sampling. However, arterial sampling is an invasive approach requiring arterial cannulation. In the current study, we aimed to explore the analysis and error estimation based on non-invasive, PET image-based input function for skeletal muscle blood flow in PET [15O]-labeled radiowater study.
 Methods Thirty healthy untrained men volunteered to participate in this study. [15O]-labeled radio water PET perfusion scans were performed at rest and right after cycling exercise. GE Discovery PET-CT scanner was used for image acquisition. The 15O isotope was produced with a Cyclone 3 cyclotron (IBA Molecular, Belgium). After 455 MBq of 15O-H2O was injected intravenously and after 20 seconds, dynamic scanning images were performed in following frames: 6x5 seconds, 12x10 seconds, 7x30 seconds and 12x10 seconds. Arterial blood was sampled continuously from radial artery during imaging for radioactivity with a detector during PET scanning. All the data analysis was performed using all in-house developed programs. Arterial input function was preprocessed with delay correction. Image-based input function was defined based on sum image of dynamic images. Blood flow was calculated using the 1-tissue compartment model, k1 is considered as blood flow without any further correction. All data analysis was performed by Carimas software (http://www.turkupetcentre.fi/carimas).
 Data analysis was performed in five parts: 1) Modelling data using input function from artery. 2) By defining femoral artery Volume Of Interest (VOI) on PET images. 3) Modelling data using image-based input function. 4) Calculating the correlation for blood flow between artery (blood) input function and image-based input function. 5) Predicted true blood flow was calculated based on correlation based on the initial linear relationship between blood and image-based input functions.
 Results Skeletal muscle blood flow had a good linear relationship calculated by femoral artery VOI and by arterial (blood) input function (y = 2,9587x - 0,096, R² = 0,8852, p<0.0001).
 Further, by using the prediction equation obtained by the linear relationship between VOI-determined (femoral) artery blood flow and direct gold standard (radial) artery input function determined blood flow, image-based input function determined blood flow was well predicted using this non-invasive approach (y = 1,1812x + 0,1219, R² = 0,9259, p<0.0001).
 Conclusions It is concluded that there is a strong linear correlation between gold standard invasive approach and non-invasive image-based approach to measure skeletal muscle blood flow by PET, but if no further corrections are made, image-based approach overestimates correct blood flow. However, this can be corrected by linear prediction equation, suggesting that invasive arterial input function may not always be needed in the future when measuring skeletal muscle blood flow by PET. This will be of benefit particularly for exercise studies.

Practical Clinical Measurement of Radiotracer Concentration in Blood: Initial Device Concept and Feasibility Testing.

Kinetic analysis of PET data requires continuous measurement of radioactivity in the arterial blood throughout the acquisition time, termed the arterial input function. The arterial input function is used as an input to compartmental modeling, which can be a better predictor of disease progression than SUV measurements from static PET images. Current common methods of measuring blood concentrations include image-derived, population-based, and manual sampling. These all have challenges due to logistical and technologic issues, as well as patient burden. The aim of this study was to design, develop, and assess a device that is practical and effective for the routine measurement of β-emitting radiotracer concentration in blood without the drawbacks of current methods and for which metabolite analysis is not required. Methods: Designs that integrated a scintillating fiber and a silicon photomultiplier with a general-purpose venous access catheter for in vivo measurement were considered. Other design requirements included miniaturization, high sampling rates, and stopping power for β-particles. Preliminary prototypes were designed to test the feasibility of the concept. Phantom tests were developed to mimic human vasculature. Tests of linearity, sensitivity, signal-to-noise ratios, the impact of vein diameter, and the influence of γ-radiation were conducted. Results: Prototype sensors were constructed using 2 different diameters of polystyrene-based scintillating fibers. Fibers were custom-polished and fixed to a silicon photomultiplier. Sensor output was linear, with R 2 = 0.999 over the range from 0.037 to 9.25 MBq/mL. Absolute sensitivity was approximately 450 counts per second per MBq/mL. Measured signal-to-noise ratios ranged from 1.2:1 to 3.2:1 using a blood-to-tissue concentration ratio of 1:1. Sensor output increased with vein diameter and showed no sensitivity to γ-radiation. Conclusion: In experiments with phantom models, the prototype provided accurate measurements of β-emitting radiotracer concentration. The design will be refined for in vivo testing. The ability to routinely gather blood input function data would facilitate the adoption of kinetic modeling of PET data.

Comparison of two different methods of image analysis for the assessment of microglial activation in patients with multiple sclerosis using (R)-[N-methyl-carbon-11]PK11195

Chronic active multiple sclerosis (MS) lesions have a rim of activated microglia/macrophages (m/M) leading to ongoing tissue damage, and thus represent a potential treatment target. Activation of this innate immune response in MS has been visualized and quantified using PET imaging with [11C]-(R)-PK11195 (PK). Accurate identification of m/M activation in chronic MS lesions requires the sensitivity to detect lower levels of activity within a small tissue volume. We assessed the ability of kinetic modeling of PK PET data to detect m/M activity in different central nervous system (CNS) tissue regions of varying sizes and in chronic MS lesions. Ten patients with MS underwent a single brain MRI and two PK PET scans 2 hours apart. Volume of interest (VOI) masks were generated for the white matter (WM), cortical gray matter (CGM), and thalamus (TH). The distribution volume (VT) was calculated with the Logan graphical method (LGM-VT) utilizing an image-derived input function (IDIF). The binding potential (BPND) was calculated with the reference Logan graphical method (RLGM) utilizing a supervised clustering algorithm (SuperPK) to determine the non-specific binding region. Masks of varying volume were created in the CNS to assess the impact of region size on the various metrics among high and low uptake regions. Chronic MS lesions were also evaluated and individual lesion masks were generated. The highest PK uptake occurred the TH and lowest within the WM, as demonstrated by the mean time activity curves. In the TH, both reference and IDIF based methods resulted in estimates that did not significantly depend on VOI size. However, in the WM, the test-retest reliability of BPND was significantly lower in the smallest VOI, compared to the estimates of LGM-VT. These observations were consistent for all chronic MS lesions examined. In this study, we demonstrate that BPND and LGM-VT are both reliable for quantifying m/M activation in regions of high uptake, however with blood input function LGM-VT is preferred to assess longitudinal m/M activation in regions of relatively low uptake, such as chronic MS lesions.

The Impact of Ageing on 11C-Hydroxyephedrine Uptake in the Rat Heart

We aimed to explore the impact of ageing on 11C-hydroxyephedrine (11C-HED) uptake in the healthy rat heart in a longitudinal setting. To investigate a potential cold mass effect, the influence of specific activity on cardiac 11C-HED uptake was evaluated: 11C-HED was synthesized by N-methylation of (−)-metaraminol as the free base (radiochemical purity >95%) and a wide range of specific activities (0.2–141.9 GBq/μmol) were prepared. 11C-HED (48.7 ± 9.7MBq, ranged 0.2–60.4 μg/kg cold mass) was injected in healthy Wistar Rats. Dynamic 23-frame PET images were obtained over 30 min. Time activity curves were generated for the blood input function and myocardial tissue. Cardiac 11C-HED retention index (%/min) was calculated as myocardial tissue activity at 20–30 min divided by the integral of the blood activity curves. Additionally, the impact of ageing on myocardial 11C-HED uptake was investigated longitudinally by PET studies at different ages of healthy Wistar Rats. A dose-dependent reduction of cardiac 11C-HED uptake was observed: The estimated retention index as a marker of norepinephrine function decreased at a lower specific activity (higher amount of cold mass). This observed high affinity of 11C-HED to the neural norepinephrine transporter triggered a subsequent study: In a longitudinal setting, the 11C-HED retention index decreased with increasing age. An age-related decline of cardiac sympathetic innervation could be demonstrated. The herein observed cold mass effect might increase in succeeding scans and therefore, 11C-HED microPET studies should be planned with extreme caution if one single radiosynthesis is scheduled for multiple animals.

Noninvasive PK11195-PET Image Analysis Techniques Can Detect Abnormal Cerebral Microglial Activation in Parkinson's Disease.

ABSTRACTBACKGROUND AND PURPOSENeuroinflammation has been implicated in the pathophysiology of Parkinson's disease (PD), which might be influenced by successful neuroprotective drugs. The uptake of [11C](R)‐PK11195 (PK) is often considered to be a proxy for neuroinflammation, and can be quantified using the Logan graphical method with an image‐derived blood input function, or the Logan reference tissue model using automated reference region extraction. The purposes of this study were (1) to assess whether these noninvasive image analysis methods can discriminate between patients with PD and healthy volunteers (HVs), and (2) to establish the effect size that would be required to distinguish true drug‐induced changes from system variance in longitudinal trials.METHODSThe sample consisted of 20 participants with PD and 19 HVs. Two independent teams analyzed the data to compare the volume of distribution calculated using image‐derived input functions (IDIFs), and binding potentials calculated using the Logan reference region model.RESULTSWith all methods, the higher signal‐to‐background in patients resulted in lower variability and better repeatability than in controls. We were able to use noninvasive techniques showing significantly increased uptake of PK in multiple brain regions of participants with PD compared to HVs.CONCLUSIONAlthough not necessarily reflecting absolute values, these noninvasive image analysis methods can discriminate between PD patients and HVs. We see a difference of 24% in the substantia nigra between PD and HV with a repeatability coefficient of 13%, showing that it will be possible to estimate responses in longitudinal, within subject trials of novel neuroprotective drugs.

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

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

Kinetic modeling of [18 F]VAT, a novel radioligand for positron emission tomography imaging vesicular acetylcholine transporter in non-human primate brain.

Molecular imaging of vesicular acetylcholine transporter (VAChT) in the brain provides an important cholinergic biomarker for the pathophysiology and treatment of dementias including Alzheimer's disease. In this study, kinetics modeling methods were applied and compared for quantifying regional brain uptake of the VAChT-specific positron emission tomography radiotracer, ((-)-(1-(-8-(2-fluoroethoxy)-3-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)piperidin-4-yl)(4-fluorophenyl)-methanone) ([18 F]VAT) in macaques. Total volume distribution (VT ) estimates were compared for one-tissue compartment model (1TCM), two-tissue compartment model (2TCM), Logan graphic analysis (LoganAIF) and multiple linear analysis (MA1) with arterial blood input function using data from three macaques. Using the cerebellum-hemispheres as the reference region with data from seven macaques, three additional models were compared: reference tissue model (RTM), simplified RTM (SRTM), and Logan graphic analysis (LoganREF). Model selection criterion indicated that a) 2TCM and SRTM were the most appropriate kinetics models for [18 F]VAT; and b) SRTM was strongly correlated with 2TCM (Pearson's coefficients r>0.93, p<0.05). Test-retest studies demonstrated that [18 F]VAT has good reproducibility and reliability (TRV <10%, ICC >0.72). These studies demonstrate [18 F]VAT is a promising VAChT positron emission tomography tracer for quantitative assessment of VAChT levels in the brain of living subjects.

Optimally Repeatable Kinetic Model Variant for Myocardial Blood Flow Measurements with 82Rb PET.

Purpose. Myocardial blood flow (MBF) quantification with 82Rb positron emission tomography (PET) is gaining clinical adoption, but improvements in precision are desired. This study aims to identify analysis variants producing the most repeatable MBF measures. Methods. 12 volunteers underwent same-day test-retest rest and dipyridamole stress imaging with dynamic 82Rb PET, from which MBF was quantified using 1-tissue-compartment kinetic model variants: (1) blood-pool versus uptake region sampled input function (Blood/Uptake-ROI), (2) dual spillover correction (SOC-On/Off), (3) right blood correction (RBC-On/Off), (4) arterial blood transit delay (Delay-On/Off), and (5) distribution volume (DV) constraint (Global/Regional-DV). Repeatability of MBF, stress/rest myocardial flow reserve (MFR), and stress/rest MBF difference (ΔMBF) was assessed using nonparametric reproducibility coefficients (RPCnp = 1.45 × interquartile range). Results. MBF using SOC-On, RVBC-Off, Blood-ROI, Global-DV, and Delay-Off was most repeatable for combined rest and stress: RPCnp = 0.21 mL/min/g (15.8%). Corresponding MFR and ΔMBF RPCnp were 0.42 (20.2%) and 0.24 mL/min/g (23.5%). MBF repeatability improved with SOC-On at stress (p < 0.001) and tended to improve with RBC-Off at both rest and stress (p < 0.08). DV and ROI did not significantly influence repeatability. The Delay-On model was overdetermined and did not reliably converge. Conclusion. MBF and MFR test-retest repeatability were the best with dual spillover correction, left atrium blood input function, and global DV.

Assessment of myocardial metabolic rate of glucose by means of Bayesian ICA and Markov Chain Monte Carlo methods in small animal PET imaging

Abstract In dynamic cardiac PET FDG studies the assessment of myocardial metabolic rate of glucose (MMRG) requires the knowledge of the blood input function (IF). IF can be obtained by manual or automatic blood sampling and cross calibrated with PET. These procedures are cumbersome, invasive and generate uncertainties. The IF is contaminated by spillover of radioactivity from the adjacent myocardium and this could cause important error in the estimated MMRG. In this study, we show that the IF can be extracted from the images in a rat heart study with 18F-fluorodeoxyglucose (18F-FDG) by means of Independent Component Analysis (ICA) based on Bayesian theory and Markov Chain Monte Carlo (MCMC) sampling method (BICA). Images of the heart from rats were acquired with the Sherbrooke small animal PET scanner. A region of interest (ROI) was drawn around the rat image and decomposed into blood and tissue using BICA. The Statistical study showed that there is a significant difference (p &lt; 0.05) between MMRG obtained with IF extracted by BICA with respect to IF extracted from measured images corrupted with spillover.

Impact of contamination with long-lived radionuclides on PET kinetics modelling in multitracer studies.

An important issue in multitracer studies is the separation of signals from the different radiotracers. This is especially the case when an early tracer has a long physical half-life and kinetic modelling has to be performed, because the early tracer can confer a long-lived contaminating background not only to images but also to a measured input function derived from blood samples. In this study, we examined data from a sequential multitracer infection study involving In (t1/2=2.8 days), investigating the influence on gamma counting of blood samples and on the kinetic modelling of subsequent PET tracers. Blood sample counts were corrected by recounting the samples a few days later. A more optimal choice of energy window was also explored. The effect of correction versus noncorrection was investigated using a two-tissue kinetic model with irreversible uptake (K1, k2, k3). K1 was least affected and k3 was most affected by the contamination, corresponding to the effect being relatively larger on the late part of the blood input function. A narrower energy window reduced the problem, but this will not be possible for all types of contaminating background. Gamma counting of blood samples can lead to a contaminating background not observed in PET imaging and this background can affect kinetic modelling. If the contaminating tracer has a much longer half-life than the foreground tracer, then the problem can be solved by late recounting of the samples.

Kinetics modeling and occupancy studies of a novel C-11 PET tracer for VAChT in nonhuman primates

IntroductionDeficits in cholinergic function have been found in the aged brain and in neurodegenerative diseases including Alzheimer's disease (AD) and Parkinson's disease (PD). The vesicular acetylcholine transporter (VAChT) is a reliable biomarker for the cholinergic system. We previously reported the initial in vitro and ex vivo characterization of (−)-[11C]TZ659 as a VAChT specific ligand. Here, we report the in vivo specificity, tracer kinetics, and dose-occupancy studies in the nonhuman primate brain. MethodsMicroPET brain imaging of (−)-[11C]TZ659 was performed under baseline conditions in two male macaques. Tracer kinetic modeling was carried out using a two-tissue compartment model (2TCM) and Logan plot with arterial blood input function and using a simplified reference tissue model (SRTM) and Logan plot (LoganREF) without blood input. Specificity for VAChT was demonstrated by pretreatment with (+)-pentazocine, (−)-vesamicol, or S-(−)-eticlopride. Target occupancy (Occ) was calculated following pretreatment with escalating doses of (−)-vesamicol. ResultsBaseline PET imaging revealed selective retention in the striatum with rapid clearance from the cerebellar hemispheres as a reference region. Total volume of distribution (VT) values derived from both 2TCM and Logan analysis with blood input revealed ~3-fold higher levels of (−)-[11C]TZ659 in the striatum than the cerebellar hemispheres. Injection of (−)-vesamicol either as a blocking or displacing agent significantly reduced striatal uptake of (−)-[11C]TZ659. In contrast, pretreatment with the sigma-1 ligand (+)-pentazocine had no impact. Pretreatment with the S-(−)-eticlopride, a dopamine D2–like receptor antagonist, increased striatal uptake of (−)-[11C]TZ659. Striatal binding potential (BPND, range of 0.33–1.6 with cerebellar hemispheres as the reference region) showed good correlation (r2=0.97) between SRTM and LoganREF. Occupancy studies found that ~0.0057mg/kg of (−)-vesamicol produced 50% VAChT occupancy in the striatum. Conclusion(−)-[11C]TZ659 demonstrated specific and reversible VAChT binding and favorable pharmacokinetic properties for assessing the density of VAChT in the living brain.

Determination of Fatty Acid Metabolism with Dynamic [ 11 C]Palmitate Positron Emission Tomography of Mouse Heart In Vivo

The goal of this study was to establish a quantitative method for measuring fatty acid (FA) metabolism with partial volume (PV) and spill-over (SP) corrections using dynamic [(11)C]palmitate positron emission tomographic (PET) images of mouse heart in vivo. Twenty-minute dynamic [(11)C]palmitate PET scans of four 18- to 20-week-old male C57BL/6 mice under isoflurane anesthesia were performed using a Focus F-120 PET scanner. A model-corrected blood input function, by which the input function with SP and PV corrections and the metabolic rate constants (k1-k5) are simultaneously estimated from the dynamic [(11)C]palmitate PET images of mouse hearts in a four-compartment tracer kinetic model, was used to determine rates of myocardial fatty acid oxidation (MFAO), myocardial FA esterification, myocardial FA use, and myocardial FA uptake. The MFAO thus measured in C57BL/6 mice was 375.03 ± 43.83 nmol/min/g. This compares well to the MFAO measured in perfused working C57BL/6 mouse hearts ex vivo of about 350 nmol/g/min and 400 nmol/min/g. FA metabolism was measured for the first time in mouse heart in vivo using dynamic [(11)C]palmitate PET in a four-compartment tracer kinetic model. MFAO obtained with this model was validated by results previously obtained with mouse hearts ex vivo.

How to Perform Translocator Protein PET-CT Scanning for Microglial Activation in Schizophrenia Patients.

Introduction Activated microglia express translocator protein (TSPO) on the outer mitochondrial membrane. PET ligands targeting TSPO allow in vivo non-invasive visualization and quantification of neuroinflammation. Whereas inflammation in schizophrenia was previously studied using 11 C-PK11195, 18 F-PBR111 is a novel second-generation tracer, with high specific TSPO binding and longer half-life. Objective To establish a protocol for 18 F-PBR111 TSPO PET in schizophrenia. Methods A pilot study on a Siemens Biograph mCT PET-scanner in healthy controls and schizophrenia patients (n=9). Results Subjects underwent a 90-minute dynamic brain PET-CT, following i.v. bolus injection of 214±13 MBq 18 F-PBR111. An arterial input function was measured using continuous blood sampling (Twilite, Switzerland) with discrete samples for metabolite analysis. The metabolite corrected plasma input function (IPF) was calculated from the whole blood input function, individual plasma to whole blood and parent fraction data as determined by a SEP-PAK procedure. Dynamic PET data were reconstructed and a post-reconstruction motion correction was applied. Regional tissue time activity curves (TACs) were extracted from the PET images for regions of interest determined from individual MRI images. Total volume of distribution (V T ) was then calculated from fitting a reversible two-tissue compartmental model to the measured TACs using the individual IPF. Prior genotyping for TSPO receptor polymorphism (rs6971) allowed to exclude low-affinity binders (estimated 10% of European population). The procedure was well tolerated. Conclusions We established a protocol for 18 F-PBR111 TSPO PET in healthy subjects and schizophrenia patients, thereby providing useful information for others considering 18 F-PBR111 TSPO PET imaging for evaluation of neuroinflammation.

11C]-Acetoacetate PET imaging: a potential early marker for cardiac heart failure

The ketone body acetoacetate could be used as an alternate nutrient for the heart, and it also has the potential to improve cardiac function in an ischemic–reperfusion model or reduce the mitochondrial production of oxidative stress involved in cardiotoxicity. In this study, [11C]-acetoacetate was investigated as an early marker of intracellular damage in heart failure. MethodsA rat cardiotoxicity heart failure model was induced by doxorubicin, Dox(+). [14C]-Acetoacetate, a non-positron (β−) emitting radiotracer, was used to characterize the arterial blood input function and myocardial mitochondrial uptake. Afterward, [11C]-acetoacetate (β+) myocardial PET images were obtained for kinetic analysis and heart function assessment in control Dox(−) (n=15) and treated Dox(+) (n=6) rats. The uptake rate (K1) and myocardial clearance rate (k2or kmono) were extracted. Results[14C]-Acetoacetate in the blood was increased in Dox(+), from 2min post-injection until the last withdrawal point when the heart was harvested, as well as the uptake in the heart and myocardial mitochondria (unpaired t-test, p <0.05). PET kinetic analysis of [11C]-acetoacetate showed that rate constants K1, k2 and kmono were decreased in Dox(+) (p <0.05) combined with a reduction of 24% of the left ventricular ejection fraction (p <0.001). ConclusionRadioactive acetoacetate ex vivo analysis [14C], and in vivo kinetic [11C] studies provided evidence that [11C]-acetoacetate can assess heart failure Dox(+). Contrary to myocardial flow reserve (rest–stress protocol), [11C]-acetoacetate can be used to assess reduced kinetic rate constants without requirement of hyperemic stress response. The proposed [11C]-acetoacetate cardiac radiotracer in the investigation of heart disease is novel and paves the way to a potential role for [11C]-acetoacetate in cardiac pathophysiology.

Impact of point spread function modeling and time-of-flight on myocardial blood flow and myocardial flow reserve measurements for rubidium-82 cardiac PET

BackgroundMyocardial flow reserve (MFR) obtained from dynamic cardiac positron emission tomography (PET) with rubidium-82 (Rb-82) has been shown to be a useful measurement in assessing coronary artery disease. Advanced PET reconstructions with point spread function modeling and time-of-flight have been shown to improve image quality but also have an impact on kinetic analysis of dynamic data. This study aims to determine the impact of these algorithms on MFR data. MethodsDynamic Rb-82 cardiac PET images from 37 patients were reconstructed with standard and advanced reconstructions. Area under curve (AUC) of the blood input function (BIF), myocardial blood flow (MBF) and MFR were compared with each reconstruction. ResultsNo significant differences were seen in MFR for the two reconstructions. A relatively small mean difference in MBF data of +11.9% was observed with advanced reconstruction compared with the standard reconstruction but there was considerable variability in the degree of change (95% confidence intervals of −16.2% to +40.0%). Small systematic relative differences were seen for AUC BIF (mean difference of −6.3%; 95% CI −17.5% to +5.4%). Conclusion:MFR results from Rb-82 dynamic PET appear to be robust when generated by standard or advanced PET reconstructions. Considerable increases in MBF values may occur with advanced reconstructions, and further work is required to fully understand this.

An analysis of whole body tracer kinetics in dynamic PET studies with application to image-based blood input function extraction.

In a positron emission tomography (PET) study, the local uptake of the tracer is dependent on vascular delivery and retention. For dynamic studies the measured uptake time-course information can be best interpreted when knowledge of the time-course of tracer in the blood is available. This is certainly true for the most established tracers such as 18F-Fluorodeoxyglucose (FDG) and 15O-Water (H2O). Since direct sampling of blood as part of PET studies is increasingly impractical, there is ongoing interest in image-extraction of blood time-course information. But analysis of PET-measured blood pool signals is complicated because they will typically involve a combination of arterial, venous and tissue information. Thus, a careful appreciation of these components is needed to interpret the available data. To facilitate this process, we propose a novel Markov chain model for representation of the circulation of a tracer atom in the body. The model represents both arterial and venous time-course patterns. Under reasonable conditions equilibration of tracer activity in arterial and venous blood is achieved by the end of the PET study-consistent with empirical measurement. Statistical inference for Markov model parameters is a challenge. A penalized nonlinear least squares process, incorporating a generalized cross-validation score, is proposed. Random effects analysis is used to adaptively specify the structure of the penalty function based on historical samples of directly measured blood data. A collection of arterially sampled data from PET studies with FDG and H2O is used to illustrate the methodology. These data analyses are highly supportive of the overall modeling approach. An adaptation of the model to the problem of extraction of arterial blood signals from imaging data is also developed and promising preliminary results for cerebral and thoracic imaging studies with FDG and H2O are obtained.

Optimization of a Model Corrected Blood Input Function from Dynamic FDG-PET Images of Small Animal Heart In Vivo.

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.

Assessing Lung Inflammation After Nanoparticle Inhalation Using 2-deoxy-2-[18F]fluoro-d-glucose Positron Emission Tomography Imaging

The aim of the present study was to evaluate the use of 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]FDG) as a noninvasive strategy to assess the time course of inflammatory processes after inhalation of ZnO nanoparticles (NPs) in rats. Healthy, male Sprague-Dawley rats (n = 30) were divided in two groups of 15 animals each. Animals from one group (n = 15) were submitted to ZnO NPs inhalation in a chamber (10 nm to 4 μm particle size; maximum in number concentration, ∼ 200 nm; concentration = 245 mg/m(3)). Animals from the other group (n = 15, sham group) were also exposed following the same procedure, but no NPs were introduced into the chamber. Six animals per group were submitted to [(18)F]FDG-positron emission tomography (PET) studies at days 1, 7, and 28 after exposition, and the [(18)F]FDG influx constant (K i ) for the lungs was calculated using Patlak graphical analysis and an image derived blood input function. Nine animals per group were killed at 1, 7 and 28 days after exposure (n = 3 per group and time point), and the lungs were harvested and submitted to immunohistochemical and histological analysis. Significantly higher mean whole-lung K i values were obtained for animals exposed to NPs at days 1 and 7 after exposure (0.0045 ± 0.0016 min(-1) and 0.0047 ± 0.0015 min(-1), respectively) compared to controls (0.0024 ± 0.0010 min(-1) and 0.0019 ± 0.0011 min(-1) at 1 and 7 days, respectively). The K i value for exposed animals dropped to 0.0023 ± 0.0010 min(-1) at day 28. This value was not significantly different from the values obtained at 1, 7, and 28 days for the control group. Immunofluorescence staining on lung tissue slices from animals exposed to ZnO NPs showed an increase in CD11b reactivity at days 1 and 7, followed by a decrease in CD11b positive cells at 28 days. Hematoxylin-eosin staining showed histological alterations in the exposed lungs to ZnO NPs at days 1 and 7 that recovered at 28 days postexposure. The [(18)F]FDG influx rate constant (K i ) could be determined by PET using Patlak analysis and a corrected image derived input function. Higher K i values were obtained for animals exposed to ZnO NPs at days 1 and 7 after exposition. These results were in good concordance with immunohistochemical assays performed on harvested tissue samples.

Repeatable Noninvasive Measurement of Mouse Myocardial Glucose Uptake with 18F-FDG: Evaluation of Tracer Kinetics in a Type 1 Diabetes Model

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 (P < 0.05). 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 (P < 0.03, 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.

Fast direct estimation of the blood input function and myocardial time activity curve from dynamic SPECT projections via reduction in spatial and temporal dimensions

Reconstruction of parametric images from dynamic single photon emission computed tomography (SPECT) data acquired with slow rotating cameras is a challenge because the estimation of the time-activity curves (TACs) may involve fitting data to an inconsistent underdetermined system of equations. This work presents a novel algorithm for the estimation of the blood input function and myocardial TAC with high accuracy and high efficiency directly from these projections. In the proposed dynamic reconstruction method, the information from the segmentation of functional regions from the static reconstructed image was used as a prior to construct a sparse matrix, through which the spatial distribution of the radioactive tracer was represented. Then the temporal distribution of the radioactive tracer was modeled by nonuniform B-spline basis functions which were determined according to a new selection rule. With reduction in both the spatial and temporal dimensions of the reconstructed image, the blood input function and myocardial TAC were estimated using the 4D maximum likelihood expectation maximization algorithm. The method was validated using data from both digital phantom simulations and an experimental rat study. Compared with the conventional dynamic SPECT reconstruction method without the reduction in spatial dimensions, the proposed method provides more accurate TACs with less computation time in both phantom simulation studies and a rat experimental study. The proposed method is promising in both providing more accurate time-activity curves and reducing the computation time, which makes it practical for small animal studies using clinical systems with slow rotating cameras.