Interictal Brain 5-HT1A Receptors Binding in Migraine Without Aura: A 18F-MPPF-PET Study

Cephalalgia ◽  
2008 ◽  
Vol 28 (12) ◽  
pp. 1282-1291 ◽  
Author(s):  
A Lothe ◽  
I Merlet ◽  
G Demarquay ◽  
N Costes ◽  
P Ryvlin ◽  
...  
Keyword(s):  
Cortical Excitability ◽  
Region Of Interest ◽  
Binding Potential ◽  
Resonance Imaging ◽  
Reference Tissue ◽  
Tissue Model ◽  
Positron Emission ◽  
Cortical Regions ◽  
Simplified Reference Tissue Model ◽  
The Brain

In this study we aimed to assess the brain distribution of 5-HT1A receptors in migraine patients without aura. Ten female migraine patients and 24 female healthy volunteers underwent magnetic resonance imaging and positron emission tomography using a radioligand antagonist of 5-HT1A receptors [4-(2'-methoxyphenyl)-1-[2'-( N-2-pirydynyl)-p-fluorobenzamido]-ethylpiperazine (18F-MPPF)]. A simplified reference tissue model was used to generate parametric images of 5-HT1A receptor binding potential (BP) values. Statistical Parametrical Mapping (SPM) analysis showed increased MPPF BP in posterior cortical areas and hippocampi bilaterally in patients compared with controls. Region of interest (ROI) analysis showed a non-significant trend in favour of a BP increase patients in cortical regions identified by the SPM analysis except in hippocampi, left parietal areas and raphe nuclei. During the interictal period of migraine patients without aura, the increase of MPPF BP in posterior cortical and limbic areas could reflect an increase in receptor density or a decrease of endogenous serotonin, which could explain their altered cortical excitability.

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.

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 Long-Term Test–Retest Reliability of Striatal and Extrastriatal Dopamine D2/3 Receptor Binding: Study with [11C]Raclopride and High-Resolution PET

2015 ◽  
Vol 35 (7) ◽  
pp. 1199-1205 ◽  
Author(s):  
Kati Alakurtti ◽  
Jarkko J Johansson ◽  
Juho Joutsa ◽  
Matti Laine ◽  
Lars Bäckman ◽  
...  
Keyword(s):  
High Resolution ◽  
Intraclass Correlation ◽  
Binding Potential ◽  
Reference Tissue ◽  
Retest Reliability ◽  
Positron Emission ◽  
Simplified Reference Tissue Model ◽  
Test Retest Reliability

We measured the long-term test–retest reliability of [11C]raclopride binding in striatal subregions, the thalamus and the cortex using the bolus-plus-infusion method and a high-resolution positron emission scanner. Seven healthy male volunteers underwent two positron emission tomography (PET) [11C]raclopride assessments, with a 5-week retest interval. D2/3 receptor availability was quantified as binding potential using the simplified reference tissue model. Absolute variability (VAR) and intraclass correlation coefficient (ICC) values indicated very good reproducibility for the striatum and were 4.5%/0.82, 3.9%/0.83, and 3.9%/0.82, for the caudate nucleus, putamen, and ventral striatum, respectively. Thalamic reliability was also very good, with VAR of 3.7% and ICC of 0.92. Test-retest data for cortical areas showed good to moderate reproducibility (6.1% to 13.1%). Our results are in line with previous test–retest studies of [11C]raclopride binding in the striatum. A novel finding is the relatively low variability of [11C]raclopride binding, providing suggestive evidence that extrastriatal D2/3 binding can be studied in vivo with [11C]raclopride PET to be verified in future studies.

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.

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.

The simplified reference tissue model for SPECT/PET brain receptor studies

2008 ◽  
Vol 47 (04) ◽  
pp. 167-174 ◽  
Author(s):  
F. Thiele ◽  
R. Buchert
Keyword(s):  
Region Of Interest ◽  
Compartment Model ◽  
Receptor Imaging ◽  
Reference Tissue ◽  
Time Activity ◽  
Tissue Model ◽  
Activity Curve ◽  
Reference Tissue Model ◽  
Simplified Reference Tissue Model ◽  
Brain Receptor

SummaryAim: The SRTM (simplified reference tissue model) of brain receptor imaging assumes that the time activity curve in the receptor-rich region of interest can be fitted satisfactorily by the 1-tissue compartment model. This assumption has been formulated by a rather restrictive constraint on the rate constants. Empirically, the SRTM might well describe also tracers which do not fulfil this constraint, such as [11C]raclopride, for example. However, this has not been justified rigorously. Methods: The requirements for the SRTM to be applicable are analyzed in detail. Results: The SRTM is applicable under a less restrictive constraint than described previously. The interpretation of the SRTM parameters R1 and K2 in physiological terms depends on the constraint, while the interpretation of BPND does not. Conclusion: Correct interpretation of the results of the SRTM is tracer specific. In particular, the parameter R1, which in case of compliance with the original constraint might be used to detect perfusion and/or extraction effects, might not be appropriate for this purpose in case of raclopride-like tracers.

scholarly journals Optimization of Supervised Cluster Analysis for Extracting Reference Tissue Input Curves in (R)-[11C]PK11195 Brain PET Studies

2012 ◽  
Vol 32 (8) ◽  
pp. 1600-1608 ◽  
Author(s):  
Maqsood Yaqub ◽  
Bart NM van Berckel ◽  
Alie Schuitemaker ◽  
Rainer Hinz ◽  
Federico E Turkheimer ◽  
...  
Keyword(s):  
Cluster Analysis ◽  
Binding Potential ◽  
Reference Tissue ◽  
Time Activity ◽  
Positron Emission ◽  
Lower Blood ◽  
Activity Curve ◽  
Simplified Reference Tissue Model ◽  
Significant Concentration ◽  
Brain Positron Emission Tomography

Performance of two supervised cluster analysis (SVCA) algorithms for extracting reference tissue curves was evaluated to improve quantification of dynamic (R)-[11C]PK11195 brain positron emission tomography (PET) studies. Reference tissues were extracted from images using both a manually defined cerebellum and SVCA algorithms based on either four (SVCA4) or six (SVCA6) kinetic classes. Data from controls, mild cognitive impairment patients, and patients with Alzheimer's disease were analyzed using various kinetic models including plasma input, the simplified reference tissue model (RPM) and RPM with vascular correction (RPM V b). In all subject groups, SVCA-based reference tissue curves showed lower blood volume fractions ( V b) and volume of distributions than those based on cerebellum time-activity curve. Probably resulting from the presence of specific signal from the vessel walls that contains in normal condition a significant concentration of the 18 kDa translocation protein. Best contrast between subject groups was seen using SVCA4-based reference tissues as the result of a lower number of kinetic classes and the prior removal of extracerebral tissues. In addition, incorporation of V b in RPM improved both parametric images and binding potential contrast between groups. Incorporation of V b within RPM, together with SVCA4, appears to be the method of choice for analyzing cerebral (R)-[11C]PK11195 neurodegeneration studies.

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 applicability of SRTM in [18F]fallypride PET investigations: Impact of scan durations

2011 ◽  
Vol 31 (9) ◽  
pp. 1958-1966 ◽  
Author(s):  
Ingo Vernaleken ◽  
Lisa Peters ◽  
Mardjan Raptis ◽  
Robert Lin ◽  
Hans-Georg Buchholz ◽  
...  
Keyword(s):  
Temporal Cortex ◽  
Receptor Occupancy ◽  
Binding Potential ◽  
Reference Tissue ◽  
Scan Time ◽  
Positron Emission ◽  
Simplified Reference Tissue Model ◽  
Pet Scans ◽  
Drug Free ◽  
Time Point

The high-affinity radioligand [18F]fallypride (FP) is frequently used for quantification of striatal/extrastriatal D2/3 receptors and the receptor occupancies of antipsychotics (APs). Its 110 minutes half-life allows long scan durations. However, the optimum scan duration is a matter of debate. This investigation focuses on scan-duration-related effects on simplified reference tissue model (SRTM) results and the time point of transient equilibrium in a large sample of dynamic FP positron emission tomography (PET) scans. Fifty drug-free and 50 AP-treated subjects underwent FP-PET scans (180 minutes scan duration). The binding potential ( BPND) of the putamen, thalamus, and temporal cortex were calculated using the SRTM and the transient equilibrium model. Furthermore, receptor occupancies were calculated for AP-treated patients. Transient equilibrium in the unblocked putamen occurred after 121 ± 29.6 minutes. The transient equilibrium occurred much earlier in the extrastriatal regions or under AP treatment. Stepwise scan shortening caused BPND under-estimations of 0.58% for the first 10-minute reduction (putamen, SRTM), finally reaching 5.76% after 1 hour scan-time reduction. We observed preferential extrastriatal AP binding irrespective of the analytical method. [18F]fallypride scan durations of 180 minutes reliably reach equilibrium even in D2/3-receptor-rich regions. Moderate reductions in FP scan durations only caused small changes to SRTM results even in receptor-rich regions. Apparently, the D2/3 receptor occupancy results of APs, especially preferential extrastriatal binding observations, are not relevantly biased by inappropriate scan durations.

Sign in / Sign up

Export Citation Format

Share Document