The Simplified Reference Tissue Model with
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            F-Fallypride Positron Emission Tomography: Choice of Reference Region

[11C]physostigmine, an acetylcholinesterase inhibitor, has been shown to be a promising positron emission tomography ligand to quantify the cerebral concentration of the enzyme in animals and humans in vivo. Here, a quantitative and noninvasive method to measure the regional acetylcholinesterase concentration in the brain is presented. The method is based on the observation that the ratio between regions rich in acetylcholinesterase and white matter, a region almost entirely deprived of this enzyme, was found to become approximately constant after 20 to 30 minutes, suggesting that at late time points the uptake mainly contains information about the distribution volume. Taking the white matter as the reference region, a simplified reference tissue model, with effectively one reversible tissue compartment and three parameters, was found to give a good description of the data in baboons. One of these parameters, the ratio between the total distribution volumes in the target and reference regions, showed a satisfactory correlation with the acetylcholinesterase concentration measured postmortem in two baboon brains. Eight healthy male subjects were also analyzed and the regional enzyme concentrations obtained again showed a good correlation with the known acetylcholinesterase concentrations measured in postmortem studies of human brain.

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Noise Reduction in the Simplified Reference Tissue Model for Neuroreceptor Functional Imaging

Journal of Cerebral Blood Flow & Metabolism ◽

10.1097/01.wcb.0000033967.83623.34 ◽

2002 ◽

Vol 22 (12) ◽

pp. 1440-1452 ◽

Cited By ~ 177

Author(s):

Yanjun Wu ◽

Richard E. Carson

Keyword(s):

Noise Reduction ◽

Compartment Model ◽

Binding Potential ◽

Reference Region ◽

Reference Tissue ◽

Tissue Model ◽

Tissue Compartment ◽

Functional Images ◽

Reference Tissue Model ◽

Simplified Reference Tissue Model

The Simplified Reference Tissue Model (SRTM) produces functional images of receptor binding parameters using an input function derived from a reference region and assuming a model with one tissue compartment. Three parameters are estimated: binding potential ( BP), relative delivery ( R1), and the reference region clearance constant k′2 Since k′2 should not vary across brain pixels, the authors developed a two-step method (SRTM2) using a global value of k′2. Whole-brain simulations were performed using human input functions and rate constants for [18F]FCWAY, [11C]flumazenil, and [11C]raclopride, and parameter SD and bias were determined for SRTM and SRTM2. The global mean of k′2 was slightly biased (2% to 6%), but the median was unbiased (<1%) and was used as the global value. Binding potential noise reductions with SRTM2 were 4% to 14%, 20% to 53%, and 10% to 30% for [18F]FCWAY, [11C]flumazenil, and [11C]raclopride, respectively, with larger reductions for shorter scans. R1 noise reduction was larger than that of BP. Simulations were also performed to assess bias when the reference and/or tissue regions followed a two-tissue compartment model. Owing to the constrained k′2, SRTM2 showed somewhat larger biases due to violations of the one-compartment model assumption. These studies demonstrate that SRTM2 should be a useful method to improve the quality of neuroreceptor functional images.

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The Simplified Reference Tissue Model: Model Assumption Violations and Their Impact on Binding Potential

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2014.202 ◽

2014 ◽

Vol 35 (2) ◽

pp. 304-311 ◽

Cited By ~ 43

Author(s):

Cristian A Salinas ◽

Graham E Searle ◽

Roger N Gunn

Keyword(s):

Input Function ◽

Binding Potential ◽

Model Assumption ◽

Reference Tissue ◽

Tissue Model ◽

Positron Emission ◽

Assumption Violations ◽

Quantitative Accuracy ◽

Reference Tissue Model ◽

Simplified Reference Tissue Model

Reference tissue models have gained significant traction over the last two decades as the methods of choice for the quantification of brain positron emission tomography data because they balance quantitative accuracy with less invasive procedures. The principal advantage is the elimination of the need to perform arterial cannulation of the subject to measure blood and metabolite concentrations for input function generation. In particular, the simplified reference tissue model (SRTM) has been widely adopted as it uses a simplified model configuration with only three parameters that typically produces good fits to the kinetic data and a stable parameter estimation process. However, the model's simplicity and its ability to generate good fits to the data, even when the model assumptions are not met, can lead to misplaced confidence in binding potential (BPND) estimates. Computer simulation were used to study the bias introduced in BPND estimates as a consequence of violating each of the four core SRTM model assumptions. Violation of each model assumption led to bias in BPND (both over and underestimation). Careful assessment of the bias in SRTM BPND should be performed for new tracers and applications so that an appropriate decision about its applicability can be made.

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Tracer Kinetic Modeling of [11C]AFM, a New PET Imaging Agent for the Serotonin Transporter

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2013.134 ◽

2013 ◽

Vol 33 (12) ◽

pp. 1886-1896 ◽

Cited By ~ 8

Author(s):

Mika Naganawa ◽

Nabeel Nabulsi ◽

Beata Planeta ◽

Jean-Dominique Gallezot ◽

Shu-Fei Lin ◽

...

Keyword(s):

Positron Emission Tomography ◽

Serotonin Transporter ◽

Emission Tomography ◽

Binding Potential ◽

Reference Tissue ◽

Time Activity ◽

Tissue Model ◽

Positron Emission ◽

Arterial Input Functions ◽

Tissue Models

[11C]AFM, or [11C]2-[2-(dimethylaminomethyl)phenylthio]-5-fluoromethylphenylamine, is a new positron emission tomography (PET) radioligand with high affinity and selectivity for the serotonin transporter (SERT). The purpose of this study was to determine the most appropriate kinetic model to quantify [11C]AFM binding in the healthy human brain. Positron emission tomography data and arterial input functions were acquired from 10 subjects. Compartmental modeling and the multilinear analysis-1(MA1) method were tested using the arterial input functions. The one-tissue model showed a lack of fit in low-binding regions, and the two-tissue model failed to estimate parameters reliably. Regional time–activity curves were well described by MA1. The rank order of [11C]AFM binding potential ( BPND) matched well with the known regional SERT densities. For routine use of [11C]AFM, several noninvasive methods for quantification of regional binding were evaluated, including simplified reference tissue models (SRTM and SRTM2), and multilinear reference tissue models (MRTM and MRTM2). The best methods for region of interest (ROI) analysis were MA1, MRTM2, and SRTM2, with fixed population kinetic values ( k′2 or b′) for the reference methods. The MA1 and MRTM2 methods were best for parametric imaging. These results showed that [11C]AFM is a suitable PET radioligand to image and quantify SERT in humans.

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Comparative Assessment of Parametric Neuroreceptor Mapping Approaches Based on the Simplified Reference Tissue Model Using [11C]ABP688 PET

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2015.190 ◽

2015 ◽

Vol 35 (12) ◽

pp. 2098-2108 ◽

Cited By ~ 6

Author(s):

Seongho Seo ◽

Su J Kim ◽

Yu K Kim ◽

Jee-Young Lee ◽

Jae M Jeong ◽

...

Keyword(s):

Least Squares ◽

Nuclear Imaging ◽

Volume Ratio ◽

Parametric Image ◽

Reference Tissue ◽

Tissue Model ◽

Positron Emission ◽

Reference Tissue Model ◽

Image Production ◽

Simplified Reference Tissue Model

In recent years, several linearized model approaches for fast and reliable parametric neuroreceptor mapping based on dynamic nuclear imaging have been developed from the simplified reference tissue model (SRTM) equation. All the methods share the basic SRTM assumptions, but use different schemes to alleviate the effect of noise in dynamic-image voxels. Thus, this study aimed to compare those approaches in terms of their performance in parametric image generation. We used the basis function method and MRTM2 (multilinear reference tissue model with two parameters), which require a division process to obtain the distribution volume ratio (DVR). In addition, a linear model with the DVR as a model parameter (multilinear SRTM) was used in two forms: one based on linear least squares and the other based on extension of total least squares (TLS). Assessment using simulated and actual dynamic [11C]ABP688 positron emission tomography data revealed their equivalence with the SRTM, except for different noise susceptibilities. In the DVR image production, the two multilinear SRTM approaches achieved better image quality and regional compatibility with the SRTM than the others, with slightly better performance in the TLS-based method.

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Comparison of Plasma Input and Reference Tissue Models for Analysing [11C]flumazenil Studies

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/sj.jcbfm.9600554 ◽

2007 ◽

Vol 28 (3) ◽

pp. 579-587 ◽

Cited By ~ 40

Author(s):

Ursula MH Klumpers ◽

Dick J Veltman ◽

Ronald Boellaard ◽

Emile F Comans ◽

Cassandra Zuketto ◽

...

Keyword(s):

White Matter ◽

Rejection Rate ◽

Compartment Model ◽

Reference Tissue ◽

Tissue Model ◽

Arterial Blood ◽

Positron Emission ◽

Reference Tissue Model ◽

Simplified Reference Tissue Model ◽

Tissue Models

A single-tissue compartment model with plasma input is the established method for analysing [11C]flumazenil ([11C]FMZ) studies. However, arterial cannulation and measurement of metabolites are time-consuming. Therefore, a reference tissue approach is appealing, but this approach has not been fully validated for [11C]FMZ. Dynamic [11C]FMZ positron emission tomography scans with arterial blood sampling were performed in nine drug-free depressive patients and eight healthy subjects. Regions of interest were defined on co-registered magnetic resonance imaging scans and projected onto dynamic [11C]FMZ images. Using a Hill-type metabolite function, single (1T) and reversible two-tissue (2T) compartmental models were compared. Simplified reference tissue model (SRTM) and full reference tissue model (FRTM) were investigated using both pons and (centrum semiovale) white matter as reference tissue. The 2T model provided the best fit in 59% of cases. Two-tissue VT values were on average 1.6% higher than 1T VT values. Owing to the higher rejection rate of 2T fits (7.3%), the 1T model was selected as plasma input method of choice. SRTM was superior to FRTM, irrespective whether pons or white matter was used as reference tissue. BPND values obtained with SRTM correlated strongly with 1T VT ( r = 0.998 and 0.995 for pons and white matter, respectively). Use of white matter as reference tissue resulted in 5.5% rejected fits, primarily in areas with intermediate receptor density. No fits were rejected using pons as reference tissue. Pons produced 23% higher BPND values than white matter. In conclusion, for most clinical studies, SRTM with pons as reference tissue can be used for quantifying [11C]FMZ binding.

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Defining the hypoxic target volume based on positron emission tomography for image guided radiotherapy – the influence of the choice of the reference region and conversion function

Acta Oncologica ◽

10.1080/0284186x.2017.1293289 ◽

2017 ◽

Vol 56 (6) ◽

pp. 819-825 ◽

Cited By ~ 8

Author(s):

Emely Lindblom ◽

Alexandru Dasu ◽

Johan Uhrdin ◽

Aniek Even ◽

Wouter van Elmpt ◽

...

Keyword(s):

Positron Emission Tomography ◽

Target Volume ◽

Emission Tomography ◽

Conversion Function ◽

Reference Region ◽

Image Guided Radiotherapy ◽

Image Guided ◽

Positron Emission

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Kinetic Modeling of the Serotonin 5-HT1B Receptor Radioligand [11C]P943 in Humans

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2009.195 ◽

2009 ◽

Vol 30 (1) ◽

pp. 196-210 ◽

Cited By ~ 44

Author(s):

Jean-Dominique Gallezot ◽

Nabeel Nabulsi ◽

Alexander Neumeister ◽

Beata Planeta-Wilson ◽

Wendol A Williams ◽

...

Keyword(s):

Positron Emission Tomography ◽

Arterial Input Function ◽

Human Subjects ◽

Emission Tomography ◽

Binding Potential ◽

Noninvasive Methods ◽

Reference Tissue ◽

Positron Emission ◽

Tissue Models

[11C]P943 is a new radioligand recently developed to image and quantify serotonin 5-Hydroxytryptamine (5-HT1B) receptors with positron emission tomography (PET). The purpose of this study was to evaluate [11C]P943 for this application in humans, and to determine the most suitable quantification method. Positron emission tomography data and arterial input function measurements were acquired in a cohort of 32 human subjects. Using arterial input functions, compartmental modeling, the Logan graphical analysis, and the multilinear method MA1 were tested. Both the two tissue-compartment model and MA1 provided good fits of the PET data and reliable distribution volume estimates. Using the cerebellum as a reference region, BPND binding potential estimates were computed. [11C]P943 BPND estimates were significantly correlated with in vitro measurements of the density of 5-HT1B receptors, with highest values in the occipital cortex and pallidum. To evaluate noninvasive methods, two- and three-parameter graphical analyses, Simplified Reference Tissue Models (SRTM and SRTM2), and Multilinear Reference Tissue Models (MRTM and MRTM2) were tested. The MRTM2 model provided the best correlation with MA1 binding-potential estimates. Parametric images of the volume of distribution or binding potential of [11C]P943 could be computed using both MA1 and MRTM2. The results show that [11C]P943 provides quantitative measurements of 5-HT1B binding potential.

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Linearized Reference Tissue Parametric Imaging Methods: Application to [11C]DASB Positron Emission Tomography Studies of the Serotonin Transporter in Human Brain

Journal of Cerebral Blood Flow & Metabolism ◽

10.1097/01.wcb.0000085441.37552.ca ◽

2003 ◽

Vol 23 (9) ◽

pp. 1096-1112 ◽

Cited By ~ 403

Author(s):

Masanori Ichise ◽

Jeih-San Liow ◽

Jian-Qiang Lu ◽

Akihiro Takano ◽

Kendra Model ◽

...

Keyword(s):

Positron Emission Tomography ◽

Human Brain ◽

Positron Emission Tomography Imaging ◽

Emission Tomography ◽

Binding Potential ◽

Parametric Imaging ◽

Reference Tissue ◽

Parametric Images ◽

Positron Emission ◽

Tissue Models

The authors developed and applied two new linearized reference tissue models for parametric images of binding potential ( BP) and relative delivery ( R1) for [11C]DASB positron emission tomography imaging of serotonin transporters in human brain. The original multilinear reference tissue model (MRTMO) was modified (MRTM) and used to estimate a clearance rate ( k′2) from the cerebellum (reference). Then, the number of parameters was reduced from three (MRTM) to two (MRTM2) by fixing k′2. The resulting BP and R1 estimates were compared with the corresponding nonlinear reference tissue models, SRTM and SRTM2, and one-tissue kinetic analysis (1TKA), for simulated and actual [11C]DASB data. MRTM gave k′2 estimates with little bias (<1%) and small variability (<6%). MRTM2 was effectively identical to SRTM2 and 1TKA, reducing BP bias markedly over MRTMO from 12–70% to 1–4% at the expense of somewhat increased variability. MRTM2 substantially reduced BP variability by a factor of two or three over MRTM or SRTM. MRTM2, SRTM2, and 1TKA had R1 bias <0.3% and variability at least a factor of two lower than MRTM or SRTM. MRTM2 allowed rapid generation of parametric images with the noise reductions consistent with the simulations. Rapid parametric imaging by MRTM2 should be a useful method for human [11C]DASB positron emission tomography studies.

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