scholarly journals Kinetic Modeling without Accounting for the Vascular Component Impairs the Quantification of [11C]PBR28 Brain PET Data

2014 ◽  
Vol 34 (6) ◽  
pp. 1060-1069 ◽  
Author(s):  
Gaia Rizzo ◽  
Mattia Veronese ◽  
Matteo Tonietto ◽  
Paolo Zanotti-Fregonara ◽  
Federico E Turkheimer ◽  
...  
Keyword(s):  
Arterial Input Function ◽  
Compartment Model ◽  
Input Function ◽  
Translocator Protein ◽  
Brain Vessels ◽  
Data Set ◽  
Potential Marker ◽  
Positron Emission ◽  
Vascular Component ◽  
The Impact

The positron emission tomography radioligand [11C]PBR28 targets translocator protein (18 kDa) (TSPO) and is a potential marker of neuroinflammation. [11C]PBR28 binding is commonly quantified using a two-tissue compartment model and an arterial input function. Previous studies with [11C]HRJ-PK11195 demonstrated a slow irreversible binding component to the TSPO proteins localized in the endothelium of brain vessels, such as venous sinuses and arteries. However, the impact of this component on the quantification of [11C]PBR28 data has never been investigated. In this work we propose a novel kinetic model for [11C]PBR28. This model hypothesizes the existence of an additional irreversible component from the blood to the endothelium. The model was tested on a data set of 19 healthy subjects. A simulation was also performed to quantify the error generated by the standard two-tissue compartmental model when the presence of the irreversible component is not taken into account. Our results show that when the vascular component is included in the model the estimates that include the vascular component (2TCM-1K) are more than three-fold smaller, have a higher time stability and are better correlated to brain mRNA TSPO expression than those that do not include the model (2TCM).

scholarly journals Kinetic modeling and parameter estimation of TSPO PET imaging in the human brain

2021 ◽  
Author(s):  
Catriona Wimberley ◽  
Sonia Lavisse ◽  
Ansel Hillmer ◽  
Rainer Hinz ◽  
Federico Turkheimer ◽  
...  
Keyword(s):  
Human Brain ◽  
Input Function ◽  
Translocator Protein ◽  
Alternative Methods ◽  
Brain Diseases ◽  
Brain Vessels ◽  
Non Invasive ◽  
Positron Emission ◽  
The Brain ◽  
Tspo Imaging

Abstract Purpose Translocator protein 18-kDa (TSPO) imaging with positron emission tomography (PET) is widely used in research studies of brain diseases that have a neuro-immune component. Quantification of TSPO PET images, however, is associated with several challenges, such as the lack of a reference region, a genetic polymorphism affecting the affinity of the ligand for TSPO, and a strong TSPO signal in the endothelium of the brain vessels. These challenges have created an ongoing debate in the field about which type of quantification is most useful and whether there is an appropriate simplified model. Methods This review focuses on the quantification of TSPO radioligands in the human brain. The various methods of quantification are summarized, including the gold standard of compartmental modeling with metabolite-corrected input function as well as various alternative models and non-invasive approaches. Their advantages and drawbacks are critically assessed. Results and conclusions Researchers employing quantification methods for TSPO should understand the advantages and limitations associated with each method. Suggestions are given to help researchers choose between these viable alternative methods.

scholarly journals Region- and voxel-based quantification in human brain of [18F]LSN3316612, a radioligand for O-GlcNAcase

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jae-Hoon Lee ◽  
Mattia Veronese ◽  
Jeih-San Liow ◽  
Cheryl L. Morse ◽  
Jose A. Montero Santamaria ◽  
...  
Keyword(s):  
Human Brain ◽  
Arterial Input Function ◽  
Impulse Response Function ◽  
Standardized Uptake Value ◽  
Compartment Model ◽  
Input Function ◽  
Strongly Correlated ◽  
Parametric Images ◽  
Logan Plot ◽  
Positron Emission

Abstract Background Previous studies found that the positron emission tomography (PET) radioligand [18F]LSN3316612 accurately quantified O-GlcNAcase in human brain using a two-tissue compartment model (2TCM). This study sought to assess kinetic model(s) as an alternative to 2TCM for quantifying [18F]LSN3316612 binding, particularly in order to generate good-quality parametric images. Methods The current study reanalyzed data from a previous study of 10 healthy volunteers who underwent both test and retest PET scans with [18F]LSN3316612. Kinetic analysis was performed at the region level with 2TCM using 120-min PET data and arterial input function, which was considered as the gold standard. Quantification was then obtained at both the region and voxel levels using Logan plot, Ichise's multilinear analysis-1 (MA1), standard spectral analysis (SA), and impulse response function at 120 min (IRF120). To avoid arterial sampling, a noninvasive relative quantification (standardized uptake value ratio (SUVR)) was also tested using the corpus callosum as a pseudo-reference region. Venous samples were also assessed to see whether they could substitute for arterial ones. Results Logan and MA1 generated parametric images of good visual quality and their total distribution volume (VT) values at both the region and voxel levels were strongly correlated with 2TCM-derived VT (r = 0.96–0.99) and showed little bias (up to − 8%). SA was more weakly correlated to 2TCM-derived VT (r = 0.93–0.98) and was more biased (~ 16%). IRF120 showed a strong correlation with 2TCM-derived VT (r = 0.96) but generated noisier parametric images. All techniques were comparable to 2TCM in terms of test–retest variability and reliability except IRF120, which gave significantly worse results. Noninvasive SUVR values were not correlated with 2TCM-derived VT, and arteriovenous equilibrium was never reached. Conclusions Compared to SA and IRF, Logan and MA1 are more suitable alternatives to 2TCM for quantifying [18F]LSN3316612 and generating good-quality parametric images.

scholarly journals Quantification of human brain PDE4 occupancy by GSK356278: A [11C](R)-rolipram PET study

2017 ◽  
Vol 38 (11) ◽  
pp. 2033-2040 ◽  
Author(s):  
Jasper van der Aart ◽  
Cristian Salinas ◽  
Rahul Dimber ◽  
Sabina Pampols-Maso ◽  
Ashley A Weekes ◽  
...  
Keyword(s):  
Human Brain ◽  
Arterial Input Function ◽  
Compartment Model ◽  
Input Function ◽  
Post Dose ◽  
Emission Data ◽  
Pet Tracer ◽  
Positron Emission ◽  
Tolerability Data

We characterized the relationship between the plasma concentration of the phospodiesterase (PDE)-4 inhibitor GSK356278 and occupancy of the PDE4 enzyme in the brain of healthy volunteers, using the positron emission tomography (PET) tracer [11C](R)-rolipram. To this end, PET scans were acquired in eight male volunteers before and at 3 and 8 h after a single 14 mg oral dose of GSK356278. A metabolite-corrected arterial input function was used in conjunction with the dynamic PET emission data to estimate volumes of distribution (VT) from a two-tissue compartment model. The administration of GSK356278 reduced [11C](R)-rolipram whole brain VT by 17% at 3 h post-dose (p = 0.01) and by 4% at 8 h post-dose. The mean plasma Cmax was 42.3 ng/ml, leading to a PDE4 occupancy of 48% at Tmax. The in vivo affinity of GSK356278 was estimated as EC50 = 46 ± 3.6 ng/ml. We present the first report of a direct estimation of PDE4 blockade in the living human brain. In vivo affinity of GSK356278 for the PDE4, estimated in this early phase study, was combined with GSK356278 safety and tolerability data to decide on a therapeutic dose for future clinical development.

scholarly journals Population Pharmacokinetics of Fluconazole in Young Infants

2008 ◽  
Vol 52 (11) ◽  
pp. 4043-4049 ◽  
Author(s):  
K. C. Wade ◽  
D. Wu ◽  
D. A. Kaufman ◽  
R. M. Ward ◽  
D. K. Benjamin ◽  
...  
Keyword(s):  
Fixed Effects ◽  
Compartment Model ◽  
Volume Of Distribution ◽  
Relative Standard Error ◽  
Data Set ◽  
Mixed Effect ◽  
Young Infants ◽  
Relative Standard ◽  
Population Pk ◽  
The Impact

ABSTRACT Fluconazole is being increasingly used to prevent and treat invasive candidiasis in neonates, yet dosing is largely empirical due to the lack of adequate pharmacokinetic (PK) data. We performed a multicenter population PK study of fluconazole in 23- to 40-week-gestation infants less than 120 days of age. We developed a population PK model using nonlinear mixed effect modeling (NONMEM) with the NONMEM algorithm. Covariate effects were predefined and evaluated based on estimation precision and clinical significance. We studied fluconazole PK in 55 infants who at enrollment had a median (range) weight of 1.02 (0.440 to 7.125) kg, a gestational age at birth (BGA) of 26 (23 to 40) weeks, and a postnatal age (PNA) of 2.3 (0.14 to 12.6) weeks. The final data set contained 357 samples; 217/357 (61%) were collected prospectively at prespecified time intervals, and 140/357 (39%) were scavenged from discarded clinical specimens. Fluconazole population PK was best described by a one-compartment model with covariates normalized to median values. The population mean clearance (CL) can be derived for this population by the equation CL (liter/h) equals 0.015 · (weight/1)0.75 · (BGA/26)1.739 · (PNA/2)0.237 · serum creatinine (SCRT)−4.896 (when SCRT is >1.0 mg/dl), and using a volume of distribution (V) (liter) of 1.024 · (weight/1). The relative standard error around the fixed effects point estimates ranged from 3 to 24%. CL doubles between birth and 28 days of age from 0.008 to 0.016 and from 0.010 to 0.022 liter/kg/h for typical 24- and 32-week-gestation infants, respectively. This population PK model of fluconazole discriminated the impact of BGA, PNA, and creatinine on drug CL. Our data suggest that dosing in young infants will require adjustment for BGA and PNA to achieve targeted systemic drug exposures.

scholarly journals Different preprocessing strategies lead to different conclusions: A [11C]DASB-PET reproducibility study

2019 ◽  
Vol 40 (9) ◽  
pp. 1902-1911
Author(s):  
Martin Nørgaard ◽  
Melanie Ganz ◽  
Claus Svarer ◽  
Vibe G Frokjaer ◽  
Douglas N Greve ◽  
...  
Keyword(s):  
Motion Correction ◽  
Positive Association ◽  
Sequential Data ◽  
Double Blind ◽  
Data Set ◽  
Reproducibility Study ◽  
Positron Emission ◽  
The Impact ◽  
Data Analytic

Positron emission tomography (PET) neuroimaging provides unique possibilities to study biological processes in vivo under basal and interventional conditions. For quantification of PET data, researchers commonly apply different arrays of sequential data analytic methods (“preprocessing pipeline”), but it is often unknown how the choice of preprocessing affects the final outcome. Here, we use an available data set from a double-blind, randomized, placebo-controlled [11C]DASB-PET study as a case to evaluate how the choice of preprocessing affects the outcome of the study. We tested the impact of 384 commonly used preprocessing strategies on a previously reported positive association between the change from baseline in neocortical serotonin transporter binding determined with [11C]DASB-PET, and change in depressive symptoms, following a pharmacological sex hormone manipulation intervention in 30 women. The two preprocessing steps that were most critical for the outcome were motion correction and kinetic modeling of the dynamic PET data. We found that 36% of the applied preprocessing strategies replicated the originally reported finding ( p < 0.05). For preprocessing strategies with motion correction, the replication percentage was 72%, whereas it was 0% for strategies without motion correction. In conclusion, the choice of preprocessing strategy can have a major impact on a study outcome.

scholarly journals Evaluation of Simplified Kinetic Analyses for Measurement of Brain Acetylcholinesterase Activity Using N-[11C]Methylpiperidin-4-yl Propionate and Positron Emission Tomography

2004 ◽  
Vol 24 (6) ◽  
pp. 600-611 ◽  
Author(s):  
Koichi Sato ◽  
Kiyoshi Fukushi ◽  
Hitoshi Shinotoh ◽  
Shinichiro Nagatsuka ◽  
Noriko Tanaka ◽  
...  
Keyword(s):  
Ache Activity ◽  
Arterial Input Function ◽  
Acetylcholinesterase Activity ◽  
Input Function ◽  
Previous Method ◽  
Target Tissue ◽  
Standard Analysis ◽  
Reference Tissue ◽  
Arterial Blood ◽  
Positron Emission

The applicability of two reference tissue-based analyses without arterial blood sampling for the measurement of brain regional acetylcholinesterase (AChE) activity using N-[11C]methylpiperidin-4-yl propionate ([11C]MP4P) was evaluated in 12 healthy subjects. One was a linear least squares analysis derived from Blomqvist's equation, and the other was the analysis of the ratio of target-tissue radioactivity relative to reference-tissue radioactivity proposed by Herholz and coworkers. The standard compartment analysis using arterial input function provided reliable quantification of k3 (an index of AChE activity) estimates in regions with low (neocortex and hippocampus), moderate (thalamus), and high (cerebellum) AChE activity with a coefficient of variation (COV) of 12% to 19%. However, the precise k3 value in the striatum, where AChE activity is the highest, was not obtained. The striatum was used as a reference because its time-radioactivity curve was proportional to the time integral of the arterial input function. Reliable k3 estimates were also obtained in regions with low-to-moderate AChE activity with a COV of less than 21% by striatal reference analyses, though not obtained in the cerebellum. Shape analysis, the previous method of direct k3 estimation from the shape of time-radioactivity data, gave k3 estimates in the cortex and thalamus with a somewhat larger COV. In comparison with the standard analysis, a moderate overestimation of k3 by 9% to 18% in the linear analysis and a moderate underestimation by 2% to 13% in the Herholz method were observed, which were appropriately explained by the results of computer simulation. In conclusion, simplified kinetic analyses are practical and useful for the routine analysis of clinical [11C]MP4P studies and are nearly as effective as the standard analysis for detecting regions with abnormal AChE activity.

scholarly journals Quantitation of Translocator Protein Binding in Human Brain with the Novel Radioligand [18F]-FEPPA and Positron Emission Tomography

2011 ◽  
Vol 31 (8) ◽  
pp. 1807-1816 ◽  
Author(s):  
Pablo M Rusjan ◽  
Alan A Wilson ◽  
Peter M Bloomfield ◽  
Irina Vitcu ◽  
Jeffrey H Meyer ◽  
...  
Keyword(s):  
Positron Emission Tomography ◽  
Human Brain ◽  
Specific Binding ◽  
Compartment Model ◽  
Distribution Volume ◽  
Translocator Protein ◽  
Emission Tomography ◽  
Binding Potential ◽  
Specific Distribution ◽  
Positron Emission

This article describes the kinetic modeling of [18F]-FEPPA binding to translocator protein 18 kDa in the human brain using high-resolution research tomograph (HRRT) positron emission tomography. Positron emission tomography scans were performed in 12 healthy volunteers for 180 minutes. A two-tissue compartment model (2-CM) provided, with no exception, better fits to the data than a one-tissue model. Estimates of total distribution volume ( VT), specific distribution volume ( VS), and binding potential ( BPND) demonstrated very good identifiability (based on coefficient of variation ( COV)) for all the regions of interest (ROIs) in the gray matter ( COV VT < 7%, COV VS < 8%, COV BPND < 11%). Reduction of the length of the scan to 2 hours is feasible as VS and VT showed only a small bias (6% and 7.5%, respectively). Monte Carlo simulations showed that, even under conditions of a 500% increase in specific binding, the identifiability of VT and VS was still very good with COV<10%, across high-uptake ROIs. The excellent identifiability of VT values obtained from an unconstrained 2-CM with data from a 2-hour scan support the use of VT as an appropriate and feasible outcome measure for [18F]-FEPPA.

scholarly journals Arterial Input Function Derived from Pairwise Correlations Between PET-image Voxels

2013 ◽  
Vol 33 (7) ◽  
pp. 1058-1065 ◽  
Author(s):  
Martin Schain ◽  
Simon Benjaminsson ◽  
Katarina Varnäs ◽  
Anton Forsberg ◽  
Christer Halldin ◽  
...  
Keyword(s):  
Arterial Input Function ◽  
Pearson Correlation ◽  
Invasive Procedure ◽  
Compartmental Analysis ◽  
Input Function ◽  
Time Activity ◽  
Pairwise Correlation ◽  
Positron Emission ◽  
Using Data ◽  
Suitable Reference

A metabolite corrected arterial input function is a prerequisite for quantification of positron emission tomography (PET) data by compartmental analysis. This quantitative approach is also necessary for radioligands without suitable reference regions in brain. The measurement is laborious and requires cannulation of a peripheral artery, a procedure that can be associated with patient discomfort and potential adverse events. A non invasive procedure for obtaining the arterial input function is thus preferable. In this study, we present a novel method to obtain image-derived input functions (IDIFs). The method is based on calculation of the Pearson correlation coefficient between the time-activity curves of voxel pairs in the PET image to localize voxels displaying blood-like behavior. The method was evaluated using data obtained in human studies with the radioligands [ 11 C]flumazenil and [ 11 C]AZ10419369, and its performance was compared with three previously published methods. The distribution volumes ( VT) obtained using IDIFs were compared with those obtained using traditional arterial measurements. Overall, the agreement in VT was good (~3% difference) for input functions obtained using the pairwise correlation approach. This approach performed similarly or even better than the other methods, and could be considered in applied clinical studies. Applications to other radioligands are needed for further verification.

scholarly journals A Two-Compartment Mathematical Model of Neuroglial Metabolism Using [1-11C] Acetate

2011 ◽  
Vol 32 (3) ◽  
pp. 548-559 ◽  
Author(s):  
Bernard Lanz ◽  
Kai Uffmann ◽  
Matthias T Wyss ◽  
Bruno Weber ◽  
Alfred Buck ◽  
...  
Keyword(s):  
Brain Metabolism ◽  
Arterial Input Function ◽  
Tca Cycle ◽  
Compartment Model ◽  
Metabolic Model ◽  
Input Function ◽  
Resonance Spectroscopy ◽  
Uptake Curve ◽  
Metabolic Fluxes ◽  
Good Agreement

The purpose of this study was to develop a two-compartment metabolic model of brain metabolism to assess oxidative metabolism from [1-11C] acetate radiotracer experiments, using an approach previously applied in 13C magnetic resonance spectroscopy (MRS), and compared with an one-tissue compartment model previously used in brain [1-11C] acetate studies. Compared with 13C MRS studies, 11C radiotracer measurements provide a single uptake curve representing the sum of all labeled metabolites, without chemical differentiation, but with higher temporal resolution. The reliability of the adjusted metabolic fluxes was analyzed with Monte-Carlo simulations using synthetic 11C uptake curves, based on a typical arterial input function and previously published values of the neuroglial fluxes Vtcag, Vx, Vnt, and Vtcan measured in dynamic 13C MRS experiments. Assuming Vxg=10 × Vtcag and Vxn= Vtcan, it was possible to assess the composite glial tricarboxylic acid (TCA) cycle flux Vgtg ( Vgtg= Vxg × Vtcag/( Vxg+ Vtcag)) and the neurotransmission flux Vnt from 11C tissue-activity curves obtained within 30 minutes in the rat cortex with a beta-probe after a bolus infusion of [1-11C] acetate ( n=9), resulting in Vgtg=0.136±0.042 and Vnt=0.170±0.103 μmol/g per minute (mean±s.d. of the group), in good agreement with 13C MRS measurements.

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