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.

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 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 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.

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 Use of Acute Hyperphenylalaninemia in Rhesus Monkeys to Examine Sensitivity and Stability of the l-[1-11C]Leucine Method for Measurement of Regional Rates of Cerebral Protein Synthesis with Pet

2008 ◽  
Vol 28 (7) ◽  
pp. 1388-1398 ◽  
Author(s):  
Carolyn B Smith ◽  
Kathleen C Schmidt ◽  
Shrinivas Bishu ◽  
Michael A Channing ◽  
Jeff Bacon ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Competitive Inhibition ◽  
Precursor Pool ◽  
Plasma Phenylalanine ◽  
Positron Emission ◽  
The Face ◽  
Arterial Plasma ◽  
Tomography Method ◽  
Plasma Leucine ◽  
Cerebral Protein Synthesis

We have previously shown by direct comparison with autoradiographic and biochemical measurements that the l-[1-11C]leucine positron emission tomography method provides accurate determinations of regional rates of cerebral protein synthesis (rCPS) and the fraction (Λ) of unlabeled leucine in the precursor pool for protein synthesis derived from arterial plasma. In this study, we examine sensitivity of the method to detect changes in Λ and stability of the method to measure rCPS in the face of these changes. We studied four isoflurane-anesthetized monkeys dynamically scanned with the high resolution research tomograph under control and mild hyperphenylalaninemic conditions. Hyperphenylalaninemia was produced by an infusion of phenylalanine that increased plasma phenylalanine concentrations three- to five-fold. In phenylalanine-infused monkeys, plasma leucine concentrations remained relatively constant, but values of Λ were statistically significantly decreased by 11% to 15%; rCPS was unaffected. Effects on Λ are consistent with competitive inhibition of leucine transport by increased plasma phenylalanine. The effect on Λ shows that competition for the transporter results in a reduction in the fraction of leucine in the precursor pool for protein synthesis coming from plasma. Even under these hyperphenylalaninemic conditions, rCPS remains unchanged due to the compensating increased contribution of leucine from protein degradation to the precursor pool.

scholarly journals Altered Cerebral Protein Synthesis in Fragile X Syndrome: Studies in Human Subjects and Knockout Mice

2013 ◽  
Vol 33 (4) ◽  
pp. 499-507 ◽  
Author(s):  
Mei Qin ◽  
Kathleen C Schmidt ◽  
Alan J Zametkin ◽  
Shrinivas Bishu ◽  
Lisa M Horowitz ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Fragile X Syndrome ◽  
Fragile X ◽  
Human Subjects ◽  
Brain Regions ◽  
Synaptic Activity ◽  
Whole Brain ◽  
Propofol Sedation ◽  
Positron Emission ◽  
Cerebral Protein Synthesis

Dysregulated protein synthesis is thought to be a core phenotype of fragile X syndrome (FXS). In a mouse model ( Fmr1 knockout (KO)) of FXS, rates of cerebral protein synthesis (rCPS) are increased in selective brain regions. We hypothesized that rCPS are also increased in FXS subjects. We measured rCPS with the L-[1-11C]leucine positron emission tomography (PET) method in whole brain and 10 regions in 15 FXS subjects who, because of their impairments, were studied under deep sedation with propofol. We compared results with those of 12 age-matched controls studied both awake and sedated. In controls, we found no differences in rCPS between awake and propofol sedation. Contrary to our hypothesis, FXS subjects under propofol sedation had reduced rCPS in whole brain, cerebellum, and cortex compared with sedated controls. To investigate whether propofol could have a disparate effect in FXS subjects masking usually elevated rCPS, we measured rCPS in C57Bl/6 wild-type (WT) and KO mice awake or under propofol sedation. Propofol decreased rCPS substantially in most regions examined in KO mice, but in WT mice caused few discrete changes. Propofol acts by decreasing neuronal activity either directly or by increasing inhibitory synaptic activity. Our results suggest that changes in synaptic signaling can correct increased rCPS in FXS.

Determination of protein synthesis in human rectal cancer in situ by continuous [1-13C]leucine infusion

1997 ◽  
Vol 272 (5) ◽  
pp. E796-E802 ◽  
Author(s):  
W. H. Hartl ◽  
H. Demmelmair ◽  
K. W. Jauch ◽  
H. L. Schmidt ◽  
B. Koletzko ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Rectal Cancer ◽  
Protein Synthesis ◽  
Tumor Tissue ◽  
Normal Mucosa ◽  
Constant Infusion ◽  
Precursor Pool ◽  
Arterial Blood

Previous studies on human colorectal tumor protein synthesis in situ relied on techniques that required intra- or perioperative sampling to obtain a sufficient biopsy size. The purpose of the present study was to develop a new technique by use of new mass spectrometry equipment [capillary gas chromatography (GC)-combustion isotope ratio mass spectrometry (IRMS)], which allows reduction of the necessary sampling size. Thereby, tumor sampling could be done via conventional rectosigmoidoscopy, excluding the need for further disturbing invasive measures. Fifteen postabsorptive patients with localized rectal cancer received a primed-constant infusion of [1-13C]leucine (0.16 mumol.kg-1.min-1 constant, 9.6 mumol/kg prime). Forceps biopsies were taken after 3 and 6 h. In five subjects, tumor tissue and normal mucosa were studied simultaneously. Determination of protein-bound leucine enrichment was done by GC-IRMS, and GC-quadrupole MS was used to determine tracer-to-tracee ratios (tracer/tracee) for free intracellular leucine. GC-MS data demonstrated achievement of a steady state in the precursor pool enrichment after 3 h of isotope infusion (tracer/tracee at 3 h: 6.34 +/- 0.46%, at 6 h: 6.58 +/- 0.38%). Calculation of tumor protein synthesis yielded a fractional synthetic rate (FSR) of 1.06 +/- 0.11%/h or 25.5 +/- 2.6%/day (range 12.0-37.1%/day). At any time, protein-bound leucine enrichment was significantly higher in tumor tissue than in normal mucosa of the same subject. However, protein synthetic rates were comparable (tumor: 1.09 +/- 0.20%/h, mucosa: 1.29 +/- 0.28%/h). Thus combined GC-combustion IRMS and GC-/quadrupole MS provide a simple, reliable, and minimally invasive method to determine tumor FSR in situ, thereby excluding interferences common to previous methods. Tumor and mucosa tissues are similar with respect to protein synthesis, but they apparently differ with respect to leucine extraction from the arterial blood.

scholarly journals Cerebral Blood Flow with the Continuous Infusion of Oxygen-15-Labeled Water

1985 ◽  
Vol 5 (4) ◽  
pp. 566-575 ◽  
Author(s):  
S. C. Jones ◽  
J. H. Greenberg ◽  
R. Dann ◽  
G. D. Robinson ◽  
M. Kushner ◽  
...  
Keyword(s):  
White Matter ◽  
Continuous Infusion ◽  
Human Subjects ◽  
Recovery Coefficient ◽  
Whole Brain ◽  
Positron Emission ◽  
Arterial Concentration ◽  
Normal Human

This work describes the determination of CBF in eight normal human subjects with positron emission tomographic (PET) imaging using the continuous intravenous infusion of H215O. A whole-brain CBF model is described that permits the comparison of the CBF values determined using PET with those obtained using other methods. This model includes a correction for whole-brain recovery coefficient, a correction for the underestimation of flow due to the nonlinearity of the CBF model when considering tissue that includes both gray and white matter, the use of in vitro-determined brain–blood partition coefficients for gray and white matter, and a variation of the equilibrium model that permits the arterial concentration to vary. CBF values using this method compare well with values determined previously. Regional determinations using a brain overlay atlas are presented. Radiation dosimetry for the continuous infusion of H215O is also included.

scholarly journals Kinetic Compartment Modeling of [11C]-5-Hydroxy-L-Tryptophan for Positron Emission Tomography Assessment of Serotonin Synthesis in Human Brain

2002 ◽  
Vol 22 (11) ◽  
pp. 1352-1366 ◽  
Author(s):  
Gisela E. Hagberg ◽  
Richard Torstenson ◽  
Ina Marteinsdottir ◽  
Mats Fredrikson ◽  
Bengt Långström ◽  
...  
Keyword(s):  
Positron Emission Tomography ◽  
White Matter ◽  
Tissue Concentration ◽  
Compartment Model ◽  
Anterior Cingulate ◽  
Emission Tomography ◽  
Serotonin Synthesis ◽  
Compartment Modeling ◽  
Arterial Blood ◽  
Positron Emission

The substrate for the second enzymatic step in serotonin synthesis, 5-hydroxy-L-tryptophan, labeled in the β-position ([11C]-HTP), was used for positron emission tomography (PET) measurements in six healthy human participants, examined on two occasions. One- and two-tissue kinetic compartment modeling of time-radioactivity curves was performed, using arterial, metabolite-corrected [11C]-HTP values as input function. The availability of unchanged tracer in arterial blood plasma was ⩽ 80% up to 60 minutes after injection, while [11C]-hydroxyindole acetic acid and [11C]-serotonin accounted for the remaining radioactivity, amounting to ⩽16% and ⩽4%, respectively. Compartment modeling was performed for brain stem, putamen, caudate nucleus, anterior cingulate, white matter, and superior occipital, occipitotemporal, and temporal cortices. The average biologic half-life for plasma-to-tissue equilibrium was 7 to 12 minutes, and the volume of distribution was 0.2 to 0.5 μL·mL−1. In all regions except white matter, the kinetic compartment model that included irreversible [11C]-HTP trapping showed significantly improved model fits with respect to a one-tissue compartment model. The [11C]-HTP trapping rate constant depended on the estimated tissue availability of the serotonin precursor tryptophan, known to reflect serotonin synthesis in healthy individuals, and correlated with serotonin tissue concentration and synthesis rates reported previously in literature. These findings suggest the use of [11C]-HTP PET measurements to investigate serotonin synthesis.

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.

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