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 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 Use of Spectral Analysis with Iterative Filter for Voxelwise Determination of Regional Rates of Cerebral Protein Synthesis with L-[1-11C]leucine PET

2012 ◽  
Vol 32 (6) ◽  
pp. 1073-1085 ◽  
Author(s):  
Mattia Veronese ◽  
Kathleen C Schmidt ◽  
Carolyn Beebe Smith ◽  
Alessandra Bertoldo
Keyword(s):  
Protein Synthesis ◽  
Spectral Analysis ◽  
Kinetic Parameters ◽  
Region Of Interest ◽  
Parameter Estimates ◽  
Time Activity ◽  
Positron Emission ◽  
Highly Correlated ◽  
Tissue Compartments ◽  
Cerebral Protein Synthesis

A spectral analysis approach was used to estimate kinetic parameters of the L-[1-11C]leucine positron emission tomography (PET) method and regional rates of cerebral protein synthesis ( rCPS) on a voxel-by-voxel basis. Spectral analysis applies to both heterogeneous and homogeneous tissues; it does not require prior assumptions concerning number of tissue compartments. Parameters estimated with spectral analysis can be strongly affected by noise, but numerical filters improve estimation performance. Spectral analysis with iterative filter (SAIF) was originally developed to improve estimation of leucine kinetic parameters and rCPS in region-of-interest (ROI) data analyses. In the present study, we optimized SAIF for application at the voxel level. In measured L-[1-11C]leucine PET data, voxel-level SAIF parameter estimates averaged over all voxels within a ROI (mean voxel-SAIF) generally agreed well with corresponding estimates derived by applying the originally developed SAIF to ROI time-activity curves (ROI-SAIF). Region-of-interest-SAIF and mean voxel-SAIF estimates of rCPS were highly correlated. Simulations showed that mean voxel-SAIF rCPS estimates were less biased and less variable than ROI-SAIF estimates in the whole brain and cortex; biases were similar in white matter. We conclude that estimation of rCPS with SAIF is improved when the method is applied at voxel level than in ROI analysis.

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 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.

scholarly journals Regional Rates of Cerebral Protein Synthesis Measured with l-[1-11C]Leucine and PET in Conscious, Young Adult Men: Normal Values, Variability, and Reproducibility

2008 ◽  
Vol 28 (8) ◽  
pp. 1502-1513 ◽  
Author(s):  
Shrinivas Bishu ◽  
Kathleen C Schmidt ◽  
Thomas Burlin ◽  
Michael Channing ◽  
Shielah Conant ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
White Matter ◽  
Human Subjects ◽  
Intersubject Variability ◽  
Precursor Pool ◽  
Arterial Blood ◽  
Positron Emission ◽  
Mean Differences ◽  
Cortical Regions ◽  
Cerebral Protein Synthesis

We report regional rates of cerebral protein synthesis (rCPS) measured with the fully quantitative l-[1-11C]leucine positron emission tomography (PET) method. The method accounts for the fraction (Λ) of unlabeled amino acids in the precursor pool for protein synthesis derived from arterial plasma; the remainder (1-Λ) comes from tissue proteolysis. We determined rCPS and Λ in 18 regions and whole brain in 10 healthy men (21 to 24 years). Subjects underwent two 90-min dynamic PET studies with arterial blood sampling at least 2 weeks apart. Rates of cerebral protein synthesis varied regionally and ranged from 0.97 ± 0.70 to 2.25 ± 0.20 nmol/g per min. Values of rCPS were in good agreement between the two PET studies. Mean differences in rCPS between studies ranged from 9% in cortical regions to 15% in white matter. The Λ value was comparatively more uniform across regions, ranging from 0.63 ± 0.03 to 0.79 ± 0.02. Mean differences in Λ between studies were 2% to 8%. Intersubject variability in rCPS was on average 6% in cortical areas, 9% in subcortical regions, and 12% in white matter; intersubject variability in Λ was 2% to 8%. Our data indicate that in human subjects low variance and highly reproducible measures of rCPS can be made with the l-[1-11C]leucine PET method.

Rates of local cerebral protein synthesis in the rat during normal postnatal development

1995 ◽  
Vol 268 (2) ◽  
pp. R549-R561 ◽  
Author(s):  
Y. Sun ◽  
G. E. Deibler ◽  
J. Jehle ◽  
J. Macedonia ◽  
I. Dumont ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
White Matter ◽  
Brain Regions ◽  
Leucine Incorporation ◽  
Protein Breakdown ◽  
Precursor Pool ◽  
The Times ◽  
Cerebral Protein Synthesis ◽  
The Brain ◽  
Supraoptic Nuclei

The degree of recycling of leucine derived from protein breakdown into the precursor pool for protein synthesis was measured in rat brain at different postnatal ages, and age-specific values were used in the calculation of regional (local) rates of cerebral leucine incorporation into protein (lCPSleu) in 44 brain regions and the brain as a whole. Early in development, a greater fraction of the precursor leucine pool is derived from protein breakdown, indicating that protein degradation is higher in young rats compared with adults. In whole brain and in most regions, values for lCPSleu were highest at 10 days and gradually decreased with age. By 60 days of age, values in cortex were approximately 60% of those at 10 days of age. In the paraventricular and supraoptic nuclei of the hypothalamus, however, lCPSleu increased during development, reaching peak values in adults. In white matter of the cerebellum and the cerebrum, peaks of lCPSleu were reached at 14 and 21 days, respectively, approximately at the times of maximum rates of myelination.

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: I. Kinetic Modeling Approach

2005 ◽  
Vol 25 (5) ◽  
pp. 617-628 ◽  
Author(s):  
Kathleen C Schmidt ◽  
Michelle P Cook ◽  
Mei Qin ◽  
Julia Kang ◽  
Thomas V Burlin ◽  
...  
Keyword(s):  
Amino Acids ◽  
Protein Synthesis ◽  
Kinetic Model ◽  
Kinetic Modeling ◽  
Specific Activity ◽  
Data Simulation ◽  
Precursor Pool ◽  
Modeling Approach ◽  
Arterial Plasma ◽  
Cerebral Protein Synthesis

Measurements of regional rates of cerebral protein synthesis (rCPS) require correction for the effect of recycling of tissue amino acids back into the precursor pool for protein synthesis. The fraction of the precursor pool derived from arterial plasma, λ, can be evaluated as the steady-state ratio of the specific activity of leucine in the tissue tRNA-bound fraction to that in arterial plasma. While λ can be directly measured in terminal experiments in animals, an alternative method is required for use with PET. We report a method to estimate λ based on a kinetic model of labeled and unlabeled leucine and labeled CO2 in the tissue. The kinetic model is also used to estimate the amount of labeled protein and rCPS. We measured time courses of [14C]leucine, [14C]protein, and 14CO2 in the blood and brain of anesthetized rats and estimated parameters of the kinetic model from these data. Simulation studies based on the kinetic parameters were then performed to examine the feasibility of this approach for use with L-[1-11C]leucine and PET. λ and rCPS were estimated with low bias, which suggests that PET can be used for quantitative measurement of rCPS with L-[1-11C]leucine and a kinetic modeling approach for correction for recycling of tissue amino acids.

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.

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