scholarly journals Estimation of Local Cerebral Protein Synthesis Rates with L-[1-11C]Leucine and PET: Methods, Model, and Results in Animals and Humans

1989 ◽  
Vol 9 (4) ◽  
pp. 446-460 ◽  
Author(s):  
Randall A. Hawkins ◽  
Sung-Cheng Huang ◽  
Jorge R. Barrio ◽  
Randy E. Keen ◽  
Dagan Feng ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Compartment Model ◽  
Input Function ◽  
Model Parameters ◽  
Positron Emission ◽  
Human Volunteers ◽  
Normal Human ◽  
Three Compartment Model ◽  
Computer Simulation Studies ◽  
Cerebral Protein Synthesis

We have estimated the cerebral protein synthesis rates (CPSR) in a series of normal human volunteers and monkeys using l-[1-11C]leucine and positron emission tomography (PET) using a three-compartment model. The model structure, consisting of a tissue precursor, metabolite, and protein compartment, was validated with biochemical assay data obtained in rat studies. The CPSR values estimated in human hemispheres of about 0.5 nmol/min/g agree well with hemispheric estimates in monkeys. The sampling requirements (input function and scanning sequence) for accurate estimates of model parameters were investigated in a series of computer simulation studies.

scholarly journals In Vivo Measurement of Glucose Utilization in Rats using a β-Microprobe: Direct Comparison with Autoradiography

2004 ◽  
Vol 24 (9) ◽  
pp. 1015-1024 ◽  
Author(s):  
Philippe Millet ◽  
Marcelle Moulin Sallanon ◽  
Jean-Marie Petit ◽  
Yves Charnay ◽  
Philippe Vallet ◽  
...  
Keyword(s):  
Kinetic Parameters ◽  
Animal Studies ◽  
Correlation Coefficients ◽  
Compartment Model ◽  
Input Function ◽  
In Vivo Measurement ◽  
Positron Emission ◽  
Three Compartment Model ◽  
Concentration Curves

A new β-microprobe (βP) has been used to locally measure the time–concentration curve of a radiolabeled substance. The βP, analogous to positron emission tomography methodology, is useful for in vivo animal studies because it can acquire time–concentration curves with high temporal and spatial resolution. Using [18F]fluoro-2-deoxy-d-glucose and βP, we evaluated the reliability of the biologic parameters and we compared this method with the [14C]2-deoxy-d-glucose autoradiography. βP time–concentration curves in three regions of the brain were obtained from 24 rats. Four kinetic parameters (K1-k4) were estimated from 60-minute experimental periods using a three-compartment model. Best fits were obtained when the vascular fraction (Fv) was estimated simultaneously with the four kinetic parameters (K1-k4). The mean estimated Fv values were about 5.5% for the frontal cortex regions and 8.0% for the cerebellum. Correlation coefficients higher than 0.830 were observed between regional cerebral metabolic rates for glucose (rCMRglc) values obtained by βP and autoradiography. In addition, the βP-derived input function was similar to that obtained by manual sampling. Our findings show that reliable rCMRglc values can be obtained using βP.

scholarly journals Voxel-Based Estimation of Kinetic Model Parameters of the l-[1-11C]Leucine PET Method for Determination of Regional Rates of Cerebral Protein Synthesis: Validation and Comparison with Region-of-Interest-Based Methods

2009 ◽  
Vol 29 (7) ◽  
pp. 1317-1331 ◽  
Author(s):  
Giampaolo Tomasi ◽  
Alessandra Bertoldo ◽  
Shrinivas Bishu ◽  
Aaron Unterman ◽  
Carolyn Beebe Smith ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Kinetic Model ◽  
Region Of Interest ◽  
Nonlinear Least Squares ◽  
Measured Data ◽  
Parameter Estimates ◽  
Model Parameters ◽  
Time Activity ◽  
Positron Emission ◽  
Cerebral Protein Synthesis

We adapted and validated a basis function method (BFM) to estimate at the voxel level parameters of the kinetic model of the l-[1-11C]leucine positron emission tomography (PET) method and regional rates of cerebral protein synthesis (rCPS). In simulation at noise levels typical of voxel data, BFM yielded low-bias estimates of rCPS; in measured data, BFM and nonlinear least-squares parameter estimates were in good agreement. We also examined whether there are advantages to using voxel-level estimates averaged over regions of interest (ROIs) in place of estimates obtained by directly fitting ROI time-activity curves (TACs). In both simulated and measured data, fits of ROI TACs were poor, likely because of tissue heterogeneity not taken into account in the kinetic model. In simulation, rCPS determined from fitting ROI TACs was substantially overestimated and BFM-estimated rCPS averaged over all voxels in an ROI was slightly underestimated. In measured data, rCPS determined by regional averaging of voxel estimates was lower than rCPS determined from ROI TACs, consistent with simulation. In both simulated and measured data, intersubject variability of BFM-estimated rCPS averaged over all voxels in a ROI was low. We conclude that voxelwise estimation is preferable to fitting ROI TACs using a homogeneous tissue model.

scholarly journals Measurement of Regional Cerebral pH in Human Subjects Using Continuous Inhalation of 11CO2 and Positron Emission Tomography

1984 ◽  
Vol 4 (3) ◽  
pp. 458-465 ◽  
Author(s):  
David J. Brooks ◽  
Adriaan A. Lammertsma ◽  
Ronald P. Beaney ◽  
Klaus L. Leenders ◽  
Peter D. Buckingham ◽  
...  
Keyword(s):  
Positron Emission Tomography ◽  
Human Subjects ◽  
Compartment Model ◽  
Emission Tomography ◽  
Inhalation Technique ◽  
Positron Emission ◽  
Brain Ph ◽  
Normal Human ◽  
Uptake Data ◽  
Arterial Plasma

The cerebral pH of four normal human subjects has been measured using continuous inhalation of 11CO2 and positron emission tomography (PET). 11CO2 was administered to each subject at a constant rate for 15 min, during which time serial arterial plasma 11C levels were determined and serial 11C cerebral uptake PET scans were performed at a fixed axial tomographic level. 11C uptake kinetics were analysed using a three-compartment model. Rate constants have been estimated for the free exchange of 11CO2 between plasma and cerebral compartments for each subject, and their cerebral pH calculated. Whole brain pH values ranged from 6.96 to 7.05, and no significant pH difference between regions containing predominantly grey or white matter was noted. Best fits to 11C uptake data were achieved by effectively neglecting the metabolic fixation of 11C by cerebral tissue. The purpose of this study was to test the feasibility of pH measurement using the 11CO2 continuous inhalation technique. It is concluded from the results and the error analysis that continuous 11CO2 inhalation combined with PET is potentially a simple and useful method for determining regional cerebral pH.

scholarly journals In vivo Cerebral Protein Synthesis Rates with Leucyl-Transfer RNA Used as a Precursor Pool: Determination of Biochemical Parameters to Structure Tracer Kinetic Models for Positron Emission Tomography

1989 ◽  
Vol 9 (4) ◽  
pp. 429-445 ◽  
Author(s):  
Randy E. Keen ◽  
Jorge R. Barrio ◽  
Sung-Cheng Huang ◽  
Randall A. Hawkins ◽  
Michael E. Phelps
Keyword(s):  
Positron Emission Tomography ◽  
Protein Synthesis ◽  
Bolus Injection ◽  
Emission Tomography ◽  
Precursor Pool ◽  
Leucine Oxidation ◽  
Positron Emission ◽  
Tissue Compartments ◽  
Cerebral Protein Synthesis

Leucine oxidation and incorporation into proteins were examined in the in vivo rat brain to determine rates and compartmentation of these processes for the purpose of structuring mathematical compartmental models for the noninvasive estimation of in vivo human cerebral protein synthesis rates (CPSR) using positron emission tomography (PET). Leucine specific activity (SA) in arterial plasma and intracellular free amino acids, leucyl-tRNA, α-ketoisocaproic acid (KIC), and protein were determined in whole brain of the adult rat during the first 35 min after intravenous bolus injection of l-[1-14C]leucine. Incorporation of leucine into proteins accounted for 90% of total brain radioactivity at 35 min. The lack of [14C]KIC buildup indicates that leucine oxidation in brain is transaminase limited. Characteristic specific activities were maximal between 0 to 2 min after bolus injection with subsequent decline following the pattern: plasma leucine ≥ leucyl-tRNA ≈ KIC > intracellular leucine. The time integral of leucine SA in plasma was about four times that of tissue leucine and twice those of leucyl-tRNA and KIC, indicating the existence of free leucine, leucyl-tRNA, and KIC tissue compartments, communicating directly with plasma, and separate secondary free leucine, leucyl-tRNA, and KIC tissue compartments originating in unlabeled leucine from proteolysis. Therefore, a relatively simple model configuration based on the key assumptions that (a) protein incorporation and catabolism proceed from a precursor pool communicating with the plasma space, and (b) leucine catabolism is transaminase limited is justified for the in vivo assessment of CPSR from exogenous leucine sources using PET in humans.

scholarly journals Quantification of [18F]afatinib using PET/CT in NSCLC patients, a feasibility study

2020 ◽  
Author(s):  
Eveline Annette van de Stadt ◽  
Maqsood Yaqub ◽  
Adriaan Lammertsma ◽  
Alex Poot ◽  
Patrick Schober ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Information Criterion ◽  
Compartment Model ◽  
Input Function ◽  
Pet Scan ◽  
Time Interval ◽  
Tumour Uptake ◽  
Positron Emission ◽  
Nsclc Patients

Abstract Introduction: Only a subgroup of non-small cell lung cancer (NSCLC) patients benefit from treatment using epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) such as afatinib. Tumour uptake of [18F]afatinib using positron emission tomography (PET) may identify those patients that respond to afatinib therapy. Therefore, the aim of this study was to find the optimal tracer kinetic model for quantification of [18F]afatinib uptake in NSCLC tumours.Methods: [18F]afatinib PET scans were performed in 10 NSCLC patients. The first patient was scanned for the purpose of dosimetry. Subsequent patients underwent a 20 minutes dynamic [15O]H2O PET-scan (370 MBq) followed by a dynamic [18F]afatinib PET-scan (342 ± 24 MBq) of 60 or 90 minutes. Using the Akaike information criterion (AIC), three pharmacokinetic plasma input models were evaluated with both metabolite corrected plasma sampler input and image-derived (IDIF) input functions in combination with discrete blood samples. Correlation analysis of arterial on-line sampling versus IDIF was performed. In addition, perfusion dependency and simplified measures were assessed.Results: Ten patients were included. The injected dose of [18F]afatinib was 341 ± 37 MBq. 15 tumours could be identified in the field of view of the scanner. Based on AIC, tumour kinetics were best described using an irreversible two-tissue compartment model and a metabolite corrected arterial plasma input function (Akaike 37%). Correlation of plasma-based input functions with metabolite-corrected IDIF was very good (r2=0.93). The preferred simplified uptake parameter was the tumour-to-blood ratio over the 60 to 90 minutes time interval (TBR60-90). Tumour uptake of [18F]afatinib was independent of perfusion.Conclusion: The preferred pharmacokinetic model for quantifying [18F]afatinib uptake in NSCLC tumours was the 2T3K_vb model. TBR60-90 showed excellent correlation with this model and is the best candidate simplified method.

Cardiopulmonary Bypass Has Minimal Effects on the Pharmacokinetics of Fentanyl in Adults

2003 ◽  
Vol 99 (4) ◽  
pp. 847-854 ◽  
Author(s):  
Robert J. Hudson ◽  
Ian R. Thomson ◽  
Rajive Jassal ◽  
David J. Peterson ◽  
Aaron D. Brown ◽  
...  
Keyword(s):  
Cardiopulmonary Bypass ◽  
Prediction Error ◽  
Predictive Accuracy ◽  
Predictive Ability ◽  
Compartment Model ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Model Parameters ◽  
Final Model ◽  
Three Compartment Model

Background Although fentanyl has been widely used in cardiac anesthesia, no complete pharmacokinetic model that has assessed the effect of cardiopulmonary bypass (CPB) and that has adequate predictive accuracy has been defined. The aims of this investigation were to determine whether CPB had a clinically significant impact on fentanyl pharmacokinetics and to determine the simplest model that accurately predicts fentanyl concentrations during cardiac surgery using CPB. Methods Population pharmacokinetic modeling was applied to concentration-versus-time data from 61 patients undergoing coronary artery bypass grafting using CPB. Predictive ability of models was assessed by calculating bias (prediction error), accuracy (absolute prediction error), and measured:predicted concentration ratios versus time. The predictive ability of a simple three-compartment model with no covariates was initially compared to models with premedication (lorazepam vs. clonidine), sex, or weight as covariates. This simple model was then compared to 18 CPB-adjusted models that allowed for step changes in pharmacokinetic parameters at the start and/or end of CPB. The predictive ability of the final model was assessed prospectively in a second group of 29 patients. Results None of the covariate (premedication, sex, weight) models nor any of the CPB-adjusted models significantly improved prediction error or absolute prediction error, compared to the simple three-compartment model. Thus, the simple three-compartment model was selected as the final model. Prospective assessment of this model yielded a median prediction error of +3.8%, with a median absolute prediction error of 15.8%. The model parameters were as follows: V1, 14.4 l; V2, 36.4 l; V3, 169 l; Cl1, 0.82 l. min-1; Cl2, 2.31 l x min-1; Cl3, 1.35 l x min-1. Conclusions Compared to other factors that cause pharmacokinetic variability, the effect of CPB on fentanyl kinetics is clinically insignificant. A simple three-compartment model accurately predicts fentanyl concentrations throughout surgery using CPB.

scholarly journals A Spectral Analysis Approach for Determination of Regional Rates of Cerebral Protein Synthesis with the L-[1-11C]leucine PET Method

2010 ◽  
Vol 30 (8) ◽  
pp. 1460-1476 ◽  
Author(s):  
Mattia Veronese ◽  
Alessandra Bertoldo ◽  
Shrinivas Bishu ◽  
Aaron Unterman ◽  
Giampaolo Tomasi ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Spectral Analysis ◽  
Count Rate ◽  
Volume Fraction ◽  
Analysis Approach ◽  
Model Parameters ◽  
Time Activity ◽  
Influx Rate ◽  
Precursor Pool ◽  
Cerebral Protein Synthesis

A spectral analysis approach was used to estimate kinetic model parameters of the L-[1-11C]leucine positron emission tomography (PET) method and regional rates of cerebral protein synthesis (rCPS) in predefined regions of interest (ROIs). Unlike analyses based on the assumption that tissue ROIs are kinetically homogeneous, spectral analysis allows for heterogeneity within a region. To improve estimation performance, a new approach was developed—spectral analysis with iterative filter (SAIF). In simulation SAIF produced low bias, low variance estimates of the influx rate constant for leucine ( K1), blood volume fraction ( V b), fraction of unlabeled leucine in the tissue precursor pool for protein synthesis derived from arterial plasma (λ), and rCPS. Simulation of normal count rate studies showed that SAIF applied to ROI time-activity curves (TACs) performed comparably to the basis function method (BFM) applied to voxel TACs when voxelwise estimates were averaged over all voxels in the ROI. At low count rates, however, SAIF performed better. In measured L-[1-11C]leucine PET data, there was good agreement between ROI-based SAIF estimates and average voxelwise BFM estimates of K1, V b, λ, and rCPS. We conclude that SAIF sufficiently addresses the problem of tissue heterogeneity in ROI data and provides a valid tool for estimation of rCPS, even in low count rate studies.

scholarly journals Quantification of Cerebral Nicotinic Acetylcholine Receptors by PET Using 2-[18F]Fluoro-A-85380 and the Multiinjection Approach

2007 ◽  
Vol 28 (1) ◽  
pp. 172-189 ◽  
Author(s):  
Jean-Dominique Gallezot ◽  
Michel A Bottlaender ◽  
Jacques Delforge ◽  
Héric Valette ◽  
Wadad Saba ◽  
...  
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Compartment Model ◽  
Input Function ◽  
Graphical Analysis ◽  
Dissociation Rate ◽  
Model Parameters ◽  
Nicotinic Acetylcholine ◽  
Arterial Blood

The multiinjection approach was used to study in vivo interactions between α4β2* nicotinic acetylcholine receptors and 2-[18F]fluoro-A-85380 in baboons. The ligand kinetics was modeled by the usual nonlinear compartment model composed of three compartments (arterial plasma, free and specifically bound ligand in tissue). Arterial blood samples were collected to generate a metabolite-corrected plasma input function. The experimental protocol, which consisted of three injections of labeled or unlabeled ligand, was aiming at identifying all parameters in one experiment. Various parameters, including B'max (the binding sites density) and Kd VR (the apparent in vivo affinity of 2-[18F]fluoro-A-85380) could then be estimated in thalamus and in several receptor-poor regions. B'max estimate was 3.0±0.3 pmol/mL in thalamus, and ranged from 0.25 to 1.58 pmol/ml_ in extrathalamic regions. Although Kd VR could be precisely estimated, the association and dissociation rate constants kon/ VR and koff could not be identified separately. A second protocol was then used to estimate koff more precisely in the thalamus. Having estimated all model parameters, we performed simulations of 2-[18F]fluoro-A-85380 kinetics to test equilibrium hypotheses underlying simplified approaches. These showed that a pseudo-equilibrium is quickly reached between the free and bound compartments, a favorable situation to apply Logan graphical analysis. In contrast, the pseudo-equilibrium between the plasma and free compartments is only reached after several hours. The ratio of radioligand concentration in these two compartments then overestimates the true equilibrium value, an unfavorable situation to estimate distribution volumes from late images after a bolus injection.

scholarly journals Propofol Anesthesia Does Not Alter Regional Rates of Cerebral Protein Synthesis Measured with l-[1-11C]Leucine and PET in Healthy Male Subjects

2009 ◽  
Vol 29 (5) ◽  
pp. 1035-1047 ◽  
Author(s):  
Shrinivas Bishu ◽  
Kathleen C Schmidt ◽  
Thomas V Burlin ◽  
Michael A Charming ◽  
Lisa Horowitz ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Coefficient Of Variation ◽  
Regional Variation ◽  
Precursor Pool ◽  
Young Males ◽  
Positron Emission ◽  
Variation Range ◽  
Arterial Plasma ◽  
Mean Differences ◽  
Cerebral Protein Synthesis

We report regional rates of cerebral protein synthesis (rCPS) in 10 healthy young males, each studied under two conditions: awake and anesthetized with propofol. We used the quantitative l-[1-11C]leucine positron emission tomography (PET) method to measure rCPS. The method accounts for the fraction (1) of unlabeled leucine in the precursor pool for protein synthesis that is derived from arterial plasma; the remainder comes from proteolysis of tissue proteins. Across 18 regions and whole brain, mean differences in rCPS between studies ranged from 5% to 5% and were within the variability of rCPS in awake studies (coefficient of variation range: 7% to 14%). Similarly, differences in Λ (range: 1% to 4%) were typically within the variability of Λ (coefficient of variation range: 3% to 6%). Intersubject variances and patterns of regional variation were also similar under both conditions. In propofol-anesthetized subjects, rCPS varied regionally from 0.98 ± 0.12 to 2.39 ± 0.23 nmol g−1 min−1 in the corona radiata and in the cerebellum, respectively. Our data indicate that the values, variances, and patterns of regional variation in rCPS and Λ measured by the l-[1-11C]leucine PET method are not significantly altered by anesthesia with propofol.

scholarly journals Measurement of Regional Rates of Cerebral Protein Synthesis with L-[1-11C]leucine and PET with Correction for Recycling of Tissue Amino Acids: II. Validation in Rhesus Monkeys

2005 ◽  
Vol 25 (5) ◽  
pp. 629-640 ◽  
Author(s):  
Carolyn Beebe Smith ◽  
Kathleen C Schmidt ◽  
Mei Qin ◽  
Thomas V Burlin ◽  
Michelle P Cook ◽  
...  
Keyword(s):  
Amino Acids ◽  
Protein Synthesis ◽  
Excellent Agreement ◽  
Kinetic Modeling ◽  
Precursor Pool ◽  
Modeling Approach ◽  
Positron Emission ◽  
Arterial Plasma ◽  
Cerebral Protein Synthesis

The confounding effect of recycling of amino acids derived from tissue protein breakdown into the precursor pool for protein synthesis has been an obstacle to adapting in vivo methods for determination of regional rates of cerebral protein synthesis (rCPS) to positron emission tomography (PET). We used a kinetic modeling approach to estimate λ, the fraction of the precursor pool for protein synthesis derived from arterial plasma, and to measure rCPS in three anesthetized adult monkeys dynamically scanned after a bolus injection of L-[1-11C]leucine. In the same animals, λ was directly measured in a steady-state terminal experiment, and values showed excellent agreement with those estimated in the PET studies. In three additional monkeys rCPS was determined with the quantitative autoradiographic L-[1-14C]leucine method. In whole brain and cerebellum, rates of protein synthesis determined with the autoradiographic method were in excellent agreement with those determined with PET, and regional values were in good agreement when differences in spatial resolution of the two methods were taken into account. Low intrasubject variability was found on repeated PET studies. Our results in anesthetized monkey indicate that, by using a kinetic modeling approach to correct for recycling of tissue amino acids, quantitatively accurate and reproducible measurement of rCPS is possible with L-[1-11C]leucine and PET.

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