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

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.

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

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2015.53 ◽

2015 ◽

Vol 35 (7) ◽

pp. 1199-1205 ◽

Cited By ~ 30

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.

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Kinetics and 28-day test–retest repeatability and reproducibility of [11C]UCB-J PET brain imaging

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x20964248 ◽

2020 ◽

pp. 0271678X2096424

Author(s):

Hayel Tuncel ◽

Ronald Boellaard ◽

Emma M Coomans ◽

Erik FJ de Vries ◽

Andor WJM Glaudemans ◽

...

Keyword(s):

Grey Matter ◽

Volume Of Distribution ◽

Reference Tissue ◽

Positron Emission ◽

Tracer Kinetic ◽

Repeatability And Reproducibility ◽

Simplified Reference Tissue Model ◽

Tissue Models ◽

Pet Scans ◽

Brain Positron Emission Tomography

[11C]UCB-J is a novel radioligand that binds to synaptic vesicle glycoprotein 2A (SV2A). The main objective of this study was to determine the 28-day test–retest repeatability (TRT) of quantitative [11C]UCB-J brain positron emission tomography (PET) imaging in Alzheimer’s disease (AD) patients and healthy controls (HCs). Nine HCs and eight AD patients underwent two 60 min dynamic [11C]UCB-J PET scans with arterial sampling with an interval of 28 days. The optimal tracer kinetic model was assessed using the Akaike criteria (AIC). Micro-/macro-parameters such as tracer delivery (K1) and volume of distribution (VT) were estimated using the optimal model. Data were also analysed for simplified reference tissue model (SRTM) with centrum semi-ovale (white matter) as reference region. Based on AIC, both 1T2k_VB and 2T4k_VB described the [11C]UCB-J kinetics equally well. Analysis showed that whole-brain grey matter TRT for VT, DVR and SRTM BPND were –2.2% ± 8.5, 0.4% ± 12.0 and –8.0% ± 10.2, averaged over all subjects. [11C]UCB-J kinetics can be well described by a 1T2k_VB model, and a 60 min scan duration was sufficient to obtain reliable estimates for both plasma input and reference tissue models. TRT for VT, DVR and BPND was <15% (1SD) averaged over all subjects and indicates adequate quantitative repeatability of [11C]UCB-J PET.

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

Nuklearmedizin ◽

10.3413/nukmed-0153 ◽

2008 ◽

Vol 47 (04) ◽

pp. 167-174 ◽

Cited By ~ 4

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.

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

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2011.73 ◽

2011 ◽

Vol 31 (9) ◽

pp. 1958-1966 ◽

Cited By ~ 28

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.

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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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Cerebral grey matter density is associated with neuroreceptor and neurotransporter availability: A combined PET and MRI study

10.1101/2020.01.29.924530 ◽

2020 ◽

Cited By ~ 1

Author(s):

Sandra Manninen ◽

Tomi Karjalainen ◽

Lauri J. Tuominen ◽

Jarmo Hietala ◽

Valtteri Kaasinen ◽

...

Keyword(s):

Grey Matter ◽

Magnetic Resonance Images ◽

Matter Density ◽

Binding Potential ◽

Reference Tissue ◽

Grey Matter Density ◽

Positron Emission ◽

Simplified Reference Tissue Model ◽

Mri Study

AbstractPositron emission tomography (PET) can be used for in vivo measurement of specific neuroreceptors and transporters using radioligands, while voxel-based morphometric analysis of magnetic resonance images allows automated estimation of local grey matter densities. However, it is not known how regional neuroreceptor or transporter densities are reflected in grey matter densities. Here, we analyzed brain scans retrospectively from 325 subjects and compared grey matter density estimates with three different neuroreceptors and transporter availabilities. µ-opioid receptors (MORs) were measured with [11C]carfentanil (162 scans), dopamine D2 receptors with [11C]raclopride (91 scans) and serotonin transporters (SERT) with [11C]MADAM (72 scans). The PET data were modelled with simplified reference tissue model. Voxel-wise correlations between binding potential and grey matter density images were computed. Regional binding of all the used radiotracers was associated with grey matter density in region and ligand-specific manner independently of subjects’ age or sex. These data show that grey matter density and MOR and D2R neuroreceptor / SERT availability are correlated, with effect sizes (r2) ranging from 0.04 to 0.69. This suggests that future studies comparing PET outcome measure different groups (such as patients and controls) should take grey matter density differences between the groups into account.

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

Cephalalgia ◽

10.1111/j.1468-2982.2008.01677.x ◽

2008 ◽

Vol 28 (12) ◽

pp. 1282-1291 ◽

Cited By ~ 26

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.

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Voxelwise Principal Component Analysis of Dynamic [S-Methyl-11C]Methionine PET Data in Glioma Patients

Cancers ◽

10.3390/cancers13102342 ◽

2021 ◽

Vol 13 (10) ◽

pp. 2342

Author(s):

Corentin Martens ◽

Olivier Debeir ◽

Christine Decaestecker ◽

Thierry Metens ◽

Laetitia Lebrun ◽

...

Keyword(s):

Principal Component Analysis ◽

Principal Component ◽

Component Analysis ◽

Added Value ◽

Time Activity ◽

Positron Emission ◽

Activity Curve ◽

The Mean ◽

Mean Time ◽

Met Pet

Recent works have demonstrated the added value of dynamic amino acid positron emission tomography (PET) for glioma grading and genotyping, biopsy targeting, and recurrence diagnosis. However, most of these studies are based on hand-crafted qualitative or semi-quantitative features extracted from the mean time activity curve within predefined volumes. Voxelwise dynamic PET data analysis could instead provide a better insight into intra-tumor heterogeneity of gliomas. In this work, we investigate the ability of principal component analysis (PCA) to extract relevant quantitative features from a large number of motion-corrected [S-methyl-11C]methionine ([11C]MET) PET frames. We first demonstrate the robustness of our methodology to noise by means of numerical simulations. We then build a PCA model from dynamic [11C]MET acquisitions of 20 glioma patients. In a distinct cohort of 13 glioma patients, we compare the parametric maps derived from our PCA model to these provided by the classical one-compartment pharmacokinetic model (1TCM). We show that our PCA model outperforms the 1TCM to distinguish characteristic dynamic uptake behaviors within the tumor while being less computationally expensive and not requiring arterial sampling. Such methodology could be valuable to assess the tumor aggressiveness locally with applications for treatment planning and response evaluation. This work further supports the added value of dynamic over static [11C]MET PET in gliomas.

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Quantification of Ligand PET Studies using a Reference Region with a Displaceable Fraction: Application to Occupancy Studies with [11C]-DASB as an Example

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2011.108 ◽

2011 ◽

Vol 32 (1) ◽

pp. 70-80 ◽

Cited By ~ 21

Author(s):

Federico E Turkheimer ◽

Sudhakar Selvaraj ◽

Rainer Hinz ◽

Venkatesha Murthy ◽

Zubin Bhagwagar ◽

...

Keyword(s):

Specific Binding ◽

Normal Subjects ◽

Volume Of Distribution ◽

Binding Potential ◽

Accurate Estimation ◽

Data Sets ◽

Reference Region ◽

Reference Tissue ◽

Positron Emission ◽

Definition Of

This paper aims to build novel methodology for the use of a reference region with specific binding for the quantification of brain studies with radioligands and positron emission tomography (PET). In particular: (1) we introduce a definition of binding potential BPD = DVR–1 where DVR is the volume of distribution relative to a reference tissue that contains ligand in specifically bound form, (2) we validate a numerical methodology, rank-shaping regularization of exponential spectral analysis (RS-ESA), for the calculation of BPD that can cope with a reference region with specific bound ligand, (3) we demonstrate the use of RS-ESA for the accurate estimation of drug occupancies with the use of correction factors to account for the specific binding in the reference. [11C]-DASB with cerebellum as a reference was chosen as an example to validate the methodology. Two data sets were used; four normal subjects scanned after infusion of citalopram or placebo and further six test—retest data sets. In the drug occupancy study, the use of RS-ESA with cerebellar input plus corrections produced estimates of occupancy very close the ones obtained with plasma input. Test-retest results demonstrated a tight linear relationship between BPD calculated either with plasma or with a reference input and high reproducibility.

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