A reference tissue forward model for improved PET accuracy using within-scan displacement studies

2021 ◽  
pp. 0271678X2110652
Author(s):  
Joseph B Mandeville ◽  
Michael A Levine ◽  
John T Arsenault ◽  
Wim Vanduffel ◽  
Bruce R Rosen ◽  
...  
Keyword(s):  
Radioactive Decay ◽  
Forward Model ◽  
Binding Potential ◽  
Reference Tissue ◽  
Primate Model ◽  
Tissue Model ◽  
Pet Tracer ◽  
Reference Tissue Model ◽  
Simplified Reference Tissue Model ◽  
Improved Accuracy

We report a novel forward-model implementation of the full reference tissue model (fFTRM) that addresses the fast-exchange approximation employed by the simplified reference tissue model (SRTM) by incorporating a non-zero dissociation time constant from the specifically bound compartment. The forward computational approach avoided errors associated with noisy and nonorthogonal basis functions using an inverse linear model. Compared to analysis by a multilinear single-compartment reference tissue model (MRTM), fFTRM provided improved accuracy for estimation of binding potentials at early times in the scan, with no worse reproducibility across sessions. To test the model’s ability to identify small focal changes in binding potential using a within-scan challenge, we employed a nonhuman primate model of focal dopamine release elicited by deep brain microstimulation remote to ventral striatum (VST) during imaging by simultaneous PET and fMRI. The new model reported an unambiguously lateralized response in VST consistent with fMRI, whereas the MRTM-derived response was not lateralized and was consistent with simulations of model bias. The proposed model enabled better accuracy in PET [11C]raclopride displacement studies and may also facilitate challenges sooner after injection, thereby recovering some sensitivity lost to radioactive decay of the PET tracer.

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

2002 ◽  
Vol 22 (12) ◽  
pp. 1440-1452 ◽  
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.

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

2014 ◽  
Vol 35 (2) ◽  
pp. 304-311 ◽  
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.

scholarly journals Dual time-point imaging for post-dose binding potential estimation applied to a [11C]raclopride PET dose occupancy study

2016 ◽  
Vol 37 (3) ◽  
pp. 866-876
Author(s):  
Isadora L Alves ◽  
Antoon TM Willemsen ◽  
Rudi A Dierckx ◽  
Ana Maria M da Silva ◽  
Michel Koole
Keyword(s):  
Receptor Occupancy ◽  
Standard Uptake Value ◽  
Binding Potential ◽  
Post Dose ◽  
Reference Tissue ◽  
Tissue Model ◽  
Reference Tissue Model ◽  
Dual Time Point ◽  
Simplified Reference Tissue Model ◽  
Time Point

Receptor occupancy studies performed with PET often require time-consuming dynamic imaging for baseline and post-dose scans. Shorter protocol approximations based on standard uptake value ratios have been proposed. However, such methods depend on the time-point chosen for the quantification and often lead to overestimation and bias. The aim of this study was to develop a shorter protocol for the quantification of post-dose scans using a dual time-point approximation, which employs kinetic parameters from the baseline scan. Dual time-point was evaluated for a [11C]raclopride PET dose occupancy study with the D2 antagonist JNJ-37822681, obtaining estimates for binding potential and receptor occupancy. Results were compared to standard simplified reference tissue model and standard uptake value ratios-based estimates. Linear regression and Bland–Altman analysis demonstrated excellent correlation and agreement between dual time-point and the standard simplified reference tissue model approach. Moreover, the stability of dual time-point-based estimates is shown to be independent of the time-point chosen for quantification. Therefore, a dual time-point imaging protocol can be applied to post-dose [11C]raclopride PET scans, resulting in a significant reduction in total acquisition time while maintaining accuracy in the quantification of both the binding potential and the receptor occupancy.

An extended simplified reference tissue model for the quantification of dynamic PET with amphetamine challenge

NeuroImage ◽  
2006 ◽  
Vol 33 (2) ◽  
pp. 550-563 ◽  
Author(s):  
Yun Zhou ◽  
Ming-Kai Chen ◽  
Christopher J. Endres ◽  
Weiguo Ye ◽  
James R. Brašić ◽  
...  
Keyword(s):  
Dynamic Pet ◽  
Reference Tissue ◽  
Tissue Model ◽  
Reference Tissue Model ◽  
Simplified Reference Tissue Model

scholarly journals Validity and reliability of extrastriatal [11C]raclopride binding quantification in the living human brain

2019 ◽  
Author(s):  
Jonas E Svensson ◽  
Martin Schain ◽  
Pontus Plavén-Sigray ◽  
Simon Cervenka ◽  
Mikael Tiger ◽  
...  
Keyword(s):  
Temporal Cortex ◽  
Binding Potential ◽  
Validity And Reliability ◽  
Reference Tissue ◽  
Pet Tracer ◽  
Binding Data ◽  
Healthy Control ◽  
The Mean ◽  
Cortical Regions ◽  
Simplified Reference Tissue Model

Abstract[11C]raclopride is a well established PET tracer for the quantification of dopamine 2/3 receptors (D2/3R) in the striatum. Outside of the striatum the receptor density is up to two orders of magnitude lower. In contrast to striatal binding, the characteristics of extrastriatal [11C]raclopride binding quantification has not been thoroughly described. Still, binding data for e.g., neocortex is frequently reported in the scientific literature. Here we evaluate the validity and reliability of extrastriatal [11C]raclopride binding quantification. Two sets of healthy control subjects were examined with HRRT and [11C]raclopride: i) To assess the validity of extrastriatal [11C]raclopride binding estimates, eleven subjects were examined at baseline and after dosing with quetiapine, a D2/3R antagonist. ii) To assess test-retest repeatability, nine subjects were examined twice. Non displaceable binding potential (BPND) was quantified using the simplified reference tissue model. Quetiapine dosing was associated with decrease in [11C]raclopride BPND in temporal cortex (18±17% occupancy) and thalamus (20±17%), but not in frontal cortex. Extrastriatal occupancy was lower than in putamen (51±4%). The mean absolute variation was 4-7% in the striatal regions, 17% in thalamus, and 13-59% in cortical regions. Our data indicate that [11C]raclopride PET is not a suitable tool for D2/3R binding quantification in extrastriatal regions.

scholarly journals The importance of small polar radiometabolites in molecular neuroimaging: A PET study with [11C]Cimbi-36 labeled in two positions

2017 ◽  
Vol 38 (4) ◽  
pp. 659-668 ◽  
Author(s):  
Annette Johansen ◽  
Hanne D Hansen ◽  
Claus Svarer ◽  
Szabolcs Lehel ◽  
Sebastian Leth-Petersen ◽  
...  
Keyword(s):  
Receptor Agonist ◽  
Binding Potential ◽  
Reference Tissue ◽  
Tissue Model ◽  
Background Ratio ◽  
Significant Difference ◽  
Methoxy Groups ◽  
Simplified Reference Tissue Model ◽  
Pet Scans ◽  
The Brain

[11C]Cimbi-36, a 5-HT2A receptor agonist PET radioligand, contains three methoxy groups amenable to [11C]-labeling. In pigs, [11C]Cimbi-36 yields a polar (M1) and a less polar (M2) radiometabolite fraction, while changing the labeling to [11C]Cimbi-36_5 yields only the M1 fraction. We investigate whether changing the labeling position of [11C]Cimbi-36 eliminates M2 in humans, and if this changes the signal-to-background ratio. Six healthy volunteers each underwent two dynamic PET scans; after injection of [11C]Cimbi-36, both the M1 and M2 fraction appeared in plasma, whereas only the M1 appeared after [11C]Cimbi-36_5 injection. [11C]Cimbi-36_5 generated higher uptake than [11C]Cimbi-36 in both neocortex and cerebellum. With the simplified reference tissue model mean neocortical non-displaceable binding potential for [11C]Cimbi-36 was 1.38 ± 0.07, whereas for [11C]Cimbi-36_5, it was 1.18 ± 0.14. This significant difference can be explained by higher non-displaceable binding caused by demethylation products in the M1 fraction such as [11C]formaldehyde and/or [11C]carbon dioxide/bicarbonate. Although often considered without any impact on binding measures, we show that small polar radiometabolites can substantially decrease the signal-to-background ratio of PET radioligands for neuroimaging. Further, we find that [11C]Cimbi-36 has a better signal-to-background ratio than [11C]Cimbi-36_5, and thus will be more sensitive to changes in 5-HT2A receptor levels in the brain.

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