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 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 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 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 Characterisation of the Contribution of the GABA-Benzodiazepine α1 Receptor Subtype to [11C]Ro15-4513 PET Images

2012 ◽  
Vol 32 (4) ◽  
pp. 731-744 ◽  
Author(s):  
James FM Myers ◽  
Lula Rosso ◽  
Ben J Watson ◽  
Sue J Wilson ◽  
Nicola J Kalk ◽  
...  
Keyword(s):  
Spectral Analysis ◽  
A Priori ◽  
Benzodiazepine Receptor ◽  
Brain Regions ◽  
Complex Model ◽  
Receptor Subtype ◽  
Receptor Subtypes ◽  
Time Activity ◽  
Positron Emission ◽  
The Impact

This positron emission tomography (PET) study aimed to further define selectivity of [11C]Ro15-4513 binding to the GABARα5 relative to the GABARα1 benzodiazepine receptor subtype. The impact of zolpidem, a GABARα1-selective agonist, on [11C]Ro15-4513, which shows selectivity for GABARα5, and the nonselective benzodiazepine ligand [11C]flumazenil binding was assessed in humans. Compartmental modelling of the kinetics of [11C]Ro15-4513 time-activity curves was used to describe distribution volume ( VT) differences in regions populated by different GABA receptor subtypes. Those with low α5 were best fitted by one-tissue compartment models; and those with high α5 required a more complex model. The heterogeneity between brain regions suggested spectral analysis as a more appropriate method to quantify binding as it does not a priori specify compartments. Spectral analysis revealed that Zolpidem caused a significant VT decrease (~10%) in [11C]flumazenil, but no decrease in [11C]Ro15-4513 binding. Further analysis of [11C]Ro15-4513 kinetics revealed additional frequency components present in regions containing both α1 and α5 subtypes compared with those containing only α1. Zolpidem reduced one component (mean ± s.d.: 71% ± 41%), presumed to reflect α1-subtype binding, but not another (13% ± 22%), presumed to reflect α5. The proposed method for [11C]Ro15-4513 analysis may allow more accurate selective binding assays and estimation of drug occupancy for other nonselective ligands.

scholarly journals 11C-Diprenorphine Binding in Huntington's Disease: A Comparison of Region of Interest Analysis with Statistical Parametric Mapping

1997 ◽  
Vol 17 (9) ◽  
pp. 943-949 ◽  
Author(s):  
Robert A. Weeks ◽  
Vincent J. Cunningham ◽  
Paola Piccini ◽  
Simon Waters ◽  
Anita E. Harding ◽  
...  
Keyword(s):  
Spectral Analysis ◽  
Statistical Parametric Mapping ◽  
Region Of Interest ◽  
Emission Tomography ◽  
Z Score ◽  
Parametric Images ◽  
Positron Emission ◽  
Opioid Binding ◽  
Static Images ◽  
Analytical Approaches

We compare region of interest (ROI) analytical approaches with statistical parametric mapping (SPM) of 11C-diprenorphine positron emission tomography findings in five patients with Huntington's disease (HD) and nine age-matched controls. The ROI were placed on caudate, putamen, and an occipital reference area. Ratios of striatal–occipital uptake from averaged static images centered at 60 minutes showed a mean 20% reduction in caudate ( P = 0.034) and 15% reduction in putamen ( P = 0.095) receptor binding in the HD patients. Dynamic data from caudate and putamen ROI, together with a plasma tracer input function, were analyzed using spectral analysis to give regional impulse response functions. Regional data at 60 minutes after impulse showed a mean 29% decrease in caudate ( P = 0.006) and 23% decrease in putamen ( P = 0.029) opioid binding in the HD cohort. Parametric images of tracer binding also were produced with spectral analysis on a voxel basis. The images of the unit impulse response function at 60 minutes showed a mean 31 % decrease in caudate ( P = 0.005) and a 26% decrease in putamen binding ( P = 0.011) in HD. The voxel-based parametric images were transformed into standard stereotactic space, and a between-group comparison (patient versus controls) was performed with SPM. This approach revealed symmetrical decreases in caudate (peak 40% decrease, z score = 4.38) and putamen opioid binding (peak 24% decrease, z score = 4.686) with additional nonhypothesized changes in cingulate, prefrontal, and thalamic areas. The significance and precision of changes measured with spectral analysis applied to dynamic data sets were superior to ROI-based ratio analysis on static images. The SPM replicated the striatal reductions in opioid binding in HD and detected additional nonpredicted changes. This study suggests that SPM is a valid alternative to conventional ROI analytical approaches for determining binding changes with positron emission tomography and may have advantages over region-based analyses in exploratory studies.

scholarly journals Striatal Kinetic Modeling of FDOPA with a Cerebellar-Derived Constraint on the Distribution Volume of 3OMFD: A PET Investigation using Non-Human Primates

2000 ◽  
Vol 20 (7) ◽  
pp. 1134-1148 ◽  
Author(s):  
Kooresh Shoghi-Jadid ◽  
Sung-Cheng Huang ◽  
David B. Stout ◽  
Randa E. Yee ◽  
Eric L. Yeh ◽  
...  
Keyword(s):  
Compartmental Model ◽  
Squirrel Monkeys ◽  
Distribution Volume ◽  
Reliable Estimate ◽  
Parameter Estimates ◽  
Large Neutral Amino Acid ◽  
Vervet Monkeys ◽  
Intersubject Variability ◽  
Time Activity ◽  
Positron Emission

The peripherally born metabolite of FDOPA, 3-O-Methyl-FDOPA (3OMFD), crosses the blood-brain barrier, thus complicating positron emission tomography-FDOPA (PET-FDOPA) data analysis. In previous reports the distribution volume (DV) of 3OMFD was constrained to unity. We have recently shown that the forward transport rate-constant of FDOPA ( KS1) and the cerebellum-to-plasma ratio ( Cb/ Cp), a measure for the DV of 3OMFD, are functions of plasma large neutral amino acid (LNAA) concentration. Given large interstudy and intersubject differences in plasma LNAA levels, variations in the DV of 3OMFD are significant. In this report, the authors propose a constraint on the DV of 3OMFD that accounts for these variations. Dynamic PET-FDOPA scans were performed on 12 squirrel monkeys and 12 vervet monkeys. Two sets of constraints were employed on the compartmental model—M1 or M2. In M1, the striatal DV of 3OMFD was constrained to unity; in M2, the striatal DV of 3OMFD was constrained to an estimate derived from the cerebellum. Striatal and cerebellar time-activity curves were fitted using FDOPA and 3OMFD plasma input functions. The estimate of KS1 and that of the compartmental FDOPA uptake-constant ( Ki), both obtained using M2, were adjusted to values corresponding to average LNAA levels. Finally, Ki was compared with the graphical uptake-constant ( PKi). With the use of constraint M2, intersubject variability of squirrel monkey kS3 and Ki was reduced by 45% and 53%, respectively; and for vervet monkeys, by 54% and 44%, respectively. Intersubject variability of Kl and Ki was further reduced after correction for variations in intersubject plasma LNAA levels (for squirrel monkeys, by 67% and 41%; for vervet monkeys, by 40% and 36%, respectively). Ki correlation to PKi was enhanced to identity. Finally, average cerebellar kC2 estimates were more than 2.5-fold higher than striatal kS2 estimates ( P < 0.0001). In modeling of PET-FDOPA data, it cannot be assumed that the DV of 3OMFD is unity. The cerebellar-derived constraint furnishes a reliable estimate for the DV of 3OMFD. Invoking the constraint and correcting for variations in plasma LNAA significantly reduced interstudy and intersubject variations in parameter estimates.

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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