Non-invasive Standardised Uptake Value for Verification of the Use of Previously Validated Reference Region for [18F]Flortaucipir and [18F]Florbetapir Brain PET Studies

Abstract Purpose The simplified reference tissue model (SRTM) is commonly applied for the quantification of brain positron emission tomography (PET) studies, particularly because it avoids arterial cannulation. SRTM requires a validated reference region which is obtained by baseline-blocking or displacement studies. Once a reference region is validated, the use should be verified for each new subject. This verification normally requires volume of distribution (VT) of a reference region. However, performing dynamic scanning and arterial sampling is not always possible, specifically in elderly subjects and in advanced disease stages. The aim of this study was to investigate the use of non-invasive standardised uptake value (SUV) approaches, in comparison to VT, as a verification of the previously validated grey matter cerebellum reference region for [18F]flortaucipir and [18F]florbetapir PET imaging in Alzheimer’s disease (AD) patients and controls. Procedures Dynamic 130-min [18F]flortaucipir PET scans obtained from nineteen subjects (10 AD patients) and 90-min [18F]florbetapir dynamic scans obtained from fourteen subjects (8 AD patients) were included. Regional VT’s were estimated for both tracers and were considered the standard verification of the previously validated reference region. Non-invasive SUVs corrected for body weight (SUVBW), lean body mass (SUL), and body surface area (SUVBSA) were obtained by using later time intervals of the dynamic scans. Simulations were also performed to assess the effect of flow and specific binding (BPND) on the SUVs. Results A low SUV corresponded well with a low VT for both [18F]flortaucipir and [18F]florbetapir. Simulation confirmed that SUVs were only slightly affected by flow changes and that increases in SUV were predominantly determined by the presence of specific binding. Conclusions In situations where dynamic scanning and arterial sampling is not possible, a low SUV(80–100 min) for [18F]flortaucipir and a low SUV(50–70 min) for [18F]florbetapir may be used as indication for absence of specific binding in the grey matter cerebellum reference region.

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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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Measuring Drug Occupancy in the Absence of a Reference Region: The Lassen Plot Re-Visited

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2009.190 ◽

2009 ◽

Vol 30 (1) ◽

pp. 46-50 ◽

Cited By ~ 138

Author(s):

Vincent J Cunningham ◽

Eugenii A Rabiner ◽

Mark Slifstein ◽

Marc Laruelle ◽

Roger N Gunn

Keyword(s):

Graphical Method ◽

Quantitative Estimation ◽

Specific Binding ◽

Volume Of Distribution ◽

Distribution Volume ◽

Emission Tomography ◽

Reference Region ◽

Site Specific ◽

Positron Emission ◽

Regional Estimates

Quantitative estimation of neuroreceptor occupancy by exogenous drugs using positron emission tomography is based on the reduction in the total volume of distribution ( VT) of site-specific radioligands after drug administration. An estimate of the distribution volume of free and nonspecifically bound radioligand ( VND) is also required to distinguish specific from total binding. However, a true reference region, devoid of specific binding, is often not available. We present a transformation of a graphical method, originally introduced by Lassen, using regional estimates of VT alone to determine occupancy, together with an extension that does not require baseline data.

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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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Assessment of a white matter reference region for 11C-UCB-J PET quantification

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x19879230 ◽

2019 ◽

Vol 40 (9) ◽

pp. 1890-1901 ◽

Cited By ~ 12

Author(s):

Samantha Rossano ◽

Takuya Toyonaga ◽

Sjoerd J Finnema ◽

Mika Naganawa ◽

Yihuan Lu ◽

...

Keyword(s):

Gray Matter ◽

Specific Binding ◽

Region Of Interest ◽

Volume Of Distribution ◽

Reference Region ◽

Synaptic Density ◽

Positron Emission ◽

The Difference ◽

Density Marker

11C-UCB-J is a positron emission tomography (PET) radioligand that has been used in humans for synaptic vesicle glycoprotein 2A (SV2A) imaging and as a potential synaptic density marker. The centrum semiovale (CS) is a proposed reference region for noninvasive quantification of 11C-UCB-J, due to negligible concentrations of SV2A in this region in baboon brain assessed by in vitro methods. However, in displacement scans with SV2A-specific drug levetiracetam in humans, a decrease in 11C-UCB-J concentration was observed in the CS, consistent with some degree of specific binding. The current study aims to validate the CS as a reference region by (1) optimizing CS region of interest (ROI) to minimize spill-in from gray matter with high radioactivity concentrations; (2) investigating convergence of CS ROI values using ordered subset expectation maximization (OS-EM) reconstruction, and (3) comparing baseline CS volume of distribution ( VT) to nondisplaceable uptake in gray matter, VND. Improving ROI definition and increasing OS-EM iterations during reconstruction decreased the difference between CS VT and VND. However, even with these corrections, CS VT overestimated VND by ∼35–40%. These measures showed significant correlation, suggesting that, though biased, the CS may be a useful estimate of nondisplaceable uptake, allowing for noninvasive quantification for SV2A PET.

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The pharmacokinetics of [18F]UCB-H revisited in the healthy non-human primate brain

EJNMMI Research ◽

10.1186/s13550-021-00777-8 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Sébastien Goutal ◽

Martine Guillermier ◽

Guillaume Becker ◽

Mylène Gaudin ◽

Yann Bramoullé ◽

...

Keyword(s):

Slow Component ◽

Specific Binding ◽

Compartment Model ◽

Brain Regions ◽

Volume Of Distribution ◽

Pharmacokinetic Data ◽

Limited Information ◽

Positron Emission ◽

Human Primate

Abstract Background Positron Emission Tomography (PET) imaging of the Synaptic Vesicle glycoprotein (SV) 2A is a new tool to quantify synaptic density. [18F]UCB-H was one of the first promising SV2A-ligands to be labelled and used in vivo in rodent and human, while limited information on its pharmacokinetic properties is available in the non-human primate. Here, we evaluate the reliability of the three most commonly used modelling approaches for [18F]UCB-H in the non-human cynomolgus primate, adding the coupled fit of the non-displaceable distribution volume (VND) as an alternative approach to improve unstable fit. The results are discussed in the light of the current state of SV2A PET ligands. Results [18F]UCB-H pharmacokinetic data was optimally fitted with a two-compartment model (2TCM), although the model did not always converge (large total volume of distribution (VT) or large uncertainty of the estimate). 2TCM with coupled fit K1/k2 across brain regions stabilized the quantification, and confirmed a lower specific signal of [18F]UCB-H compared to the newest SV2A-ligands. However, the measures of VND and the influx parameter (K1) are similar to what has been reported for other SV2A ligands. These data were reinforced by displacement studies using [19F]UCB-H, demonstrating only 50% displacement of the total [18F]UCB-H signal at maximal occupancy of SV2A. As previously demonstrated in clinical studies, the graphical method of Logan provided a more robust estimate of VT with only a small bias compared to 2TCM. Conclusions Modeling issues with a 2TCM due to a slow component have previously been reported for other SV2A ligands with low specific binding, or after blocking of specific binding. As all SV2A ligands share chemical structural similarities, we hypothesize that this slow binding component is common for all SV2A ligands, but only hampers quantification when specific binding is low.

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Noninvasive Estimation of Normalized Distribution Volume: Application to the Muscarinic-2 Ligand [18F]FP-TZTP

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/sj.jcbfm.9600530 ◽

2007 ◽

Vol 28 (2) ◽

pp. 420-430 ◽

Cited By ~ 10

Author(s):

Masanori Ichise ◽

Robert M Cohen ◽

Richard E Carson

Keyword(s):

Statistical Significance ◽

Free Fraction ◽

Cholinergic Receptor ◽

Distribution Volume ◽

Reference Region ◽

Reference Tissue ◽

Apoe Ε4 ◽

Arterial Blood ◽

Noninvasive Estimation ◽

Input Region

Reference tissue methods to estimate neuroreceptor binding are not applicable to [18F]FP-TZTP (a muscarinic-2 cholinergic receptor ligand), because there is no suitable receptor-free reference region. We evaluated a new method to estimate, without using arterial data or a receptor-free reference region, a receptor parameter called the normalized distribution volume, V*T, using a region containing receptors as the input tissue. V*T is defined as VT /K′1 (distribution volume ( VT) normalized by K′1 of the input region). We used a two-parameter multilinear reference tissue model (MRTM2) to generate parametric images of V*T and R1 ( R1 = K1/ K′1) from [18F]FP-TZTP PET data of healthy aged subjects (10 with apolipoprotein E-ε4 alleles (APOE-ε4(+)) and nine without (APOE-ε4(–)). VT and VT were normalized by plasma-free fraction, fP. By one-tissue kinetic analysis (1TKA) with metabolite-corrected plasma data, VT was previously reported as higher in the APOE-ε4(+) group. The noise magnitude of MRTM2 V*T and R1 images were nearly identical to those of 1TKA VT and K1 images. K′1 or fP was not different between the two groups. V*T (mins) (1,659 ± 497) and VT (mL/cm3) (701 ± 99) in APOE-ε4(+) were higher by 38 and 22% than those (1,209 ± 233 and 577 ± 112) in APOE-ε4(–), respectively. The statistical significance for V*T (0.041) was lower than that for VT (0.025), due to the higher intersubject variability of V*T (25%) than that of VT (17%). We conclude that MRTM2 V*T allows detection of group differences in receptor binding without arterial blood or a receptor-free reference region.

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Test–retest variability and reference region-based quantification of 18F-BCPP-EF for imaging mitochondrial complex I in the human brain

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x20928149 ◽

2020 ◽

pp. 0271678X2092814 ◽

Cited By ~ 1

Author(s):

Ayla Mansur ◽

Eugenii A Rabiner ◽

Hideo Tsukada ◽

Robert A Comley ◽

Yvonne Lewis ◽

...

Keyword(s):

Complex I ◽

Compartment Model ◽

Mitochondrial Complex I ◽

Reference Region ◽

Mitochondrial Complex ◽

Time Activity ◽

Non Invasive ◽

Arterial Blood ◽

Absolute Test ◽

Highly Correlated

Mitochondrial complex I (MC-I) is an essential regulator of brain bioenergetics and can be quantified in the brain using PET radioligand 18F-BCPP-EF. Here we evaluate the test–retest reproducibility of 18F-BCPP-EF in humans, and assess the use of a non-invasive quantification method (standardised uptake value ratio – SUVR). Thirty healthy volunteers had a 90-min dynamic 18F-BCPP-EF scan with arterial blood sampling, five of which received a second scan to be included in the test–retest analysis. Time-activity curves (TAC) were analysed using multilinear analysis 1 (MA1) and the two-tissue compartment model (2TC) to estimate volumes of distribution (VT). Regional SUVR-1 values were calculated from the 70 to 90-min TAC data using the centrum semiovale as a pseudo reference region, and compared to kinetic analysis-derived outcome measures. The mean absolute test–retest variability of VT ranged from 12% to 18% across regions. Both DVR-1and SUVR-1 had improved test–retest variability in the range 2%–7%. SUVR-1 was highly correlated with DVR-1 (r2 = 0.97, n = 30). In conclusion, 18F-BCPP-EF has suitable test–retest reproducibility and can be used to quantify MC-I in clinical studies.

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Simulating the effect of cerebral blood flow changes on regional quantification of [18F]flutemetamol and [18F]florbetaben studies

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x20918029 ◽

2020 ◽

pp. 0271678X2091802

Author(s):

Fiona Heeman ◽

Maqsood Yaqub ◽

Isadora Lopes Alves ◽

Kerstin Heurling ◽

Santiago Bullich ◽

...

Keyword(s):

Blood Flow ◽

Cerebral Blood Flow ◽

Time Window ◽

Standardized Uptake Value ◽

Volume Of Distribution ◽

Reference Tissue ◽

Time Activity ◽

Amyloid Load ◽

Flow Changes ◽

Simplified Reference Tissue Model

Global and regional changes in cerebral blood flow (CBF) can result in biased quantitative estimates of amyloid load by PET imaging. Therefore, the current simulation study assessed effects of these changes on amyloid quantification using a reference tissue approach for [18F]flutemetamol and [18F]florbetaben. Previously validated pharmacokinetic rate constants were used to simulate time-activity curves (TACs) corresponding to full dynamic and dual-time-window acquisition protocols. CBF changes were simulated by varying the tracer delivery ( K1) from +25 to −25%. The standardized uptake value ratio (SUVr) was computed and TACs were fitted using reference Logan (RLogan) and the simplified reference tissue model (SRTM) to obtain the relative delivery rate ( R1) and volume of distribution ratio (DVR). RLogan was least affected by CBF changes ( χ2 = 583 p < 0.001, χ2 = 81 p < 0.001, for [18F]flutemetamol and [18F]florbetaben, respectively) and the extent of CBF sensitivity generally increased for higher levels of amyloid. Further, SRTM-derived R1 changes correlated well with simulated CBF changes ( R2 > 0.95) and SUVr’s sensitivity to CBF changes improved for later uptake-times, with the exception of [18F]flutemetamol cortical changes. In conclusion, RLogan is the preferred method for amyloid quantification of [18F]flutemetamol and [18F]florbetaben studies and SRTM could be additionally used for obtaining a CBF proxy.

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