scholarly journals Region- and voxel-based quantification in human brain of [18F]LSN3316612, a radioligand for O-GlcNAcase

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jae-Hoon Lee ◽  
Mattia Veronese ◽  
Jeih-San Liow ◽  
Cheryl L. Morse ◽  
Jose A. Montero Santamaria ◽  
...  
Keyword(s):  
Human Brain ◽  
Arterial Input Function ◽  
Impulse Response Function ◽  
Standardized Uptake Value ◽  
Compartment Model ◽  
Input Function ◽  
Strongly Correlated ◽  
Parametric Images ◽  
Logan Plot ◽  
Positron Emission

Abstract Background Previous studies found that the positron emission tomography (PET) radioligand [18F]LSN3316612 accurately quantified O-GlcNAcase in human brain using a two-tissue compartment model (2TCM). This study sought to assess kinetic model(s) as an alternative to 2TCM for quantifying [18F]LSN3316612 binding, particularly in order to generate good-quality parametric images. Methods The current study reanalyzed data from a previous study of 10 healthy volunteers who underwent both test and retest PET scans with [18F]LSN3316612. Kinetic analysis was performed at the region level with 2TCM using 120-min PET data and arterial input function, which was considered as the gold standard. Quantification was then obtained at both the region and voxel levels using Logan plot, Ichise's multilinear analysis-1 (MA1), standard spectral analysis (SA), and impulse response function at 120 min (IRF120). To avoid arterial sampling, a noninvasive relative quantification (standardized uptake value ratio (SUVR)) was also tested using the corpus callosum as a pseudo-reference region. Venous samples were also assessed to see whether they could substitute for arterial ones. Results Logan and MA1 generated parametric images of good visual quality and their total distribution volume (VT) values at both the region and voxel levels were strongly correlated with 2TCM-derived VT (r = 0.96–0.99) and showed little bias (up to − 8%). SA was more weakly correlated to 2TCM-derived VT (r = 0.93–0.98) and was more biased (~ 16%). IRF120 showed a strong correlation with 2TCM-derived VT (r = 0.96) but generated noisier parametric images. All techniques were comparable to 2TCM in terms of test–retest variability and reliability except IRF120, which gave significantly worse results. Noninvasive SUVR values were not correlated with 2TCM-derived VT, and arteriovenous equilibrium was never reached. Conclusions Compared to SA and IRF, Logan and MA1 are more suitable alternatives to 2TCM for quantifying [18F]LSN3316612 and generating good-quality parametric images.

scholarly journals Quantification of human brain PDE4 occupancy by GSK356278: A [11C](R)-rolipram PET study

2017 ◽  
Vol 38 (11) ◽  
pp. 2033-2040 ◽  
Author(s):  
Jasper van der Aart ◽  
Cristian Salinas ◽  
Rahul Dimber ◽  
Sabina Pampols-Maso ◽  
Ashley A Weekes ◽  
...  
Keyword(s):  
Human Brain ◽  
Arterial Input Function ◽  
Compartment Model ◽  
Input Function ◽  
Post Dose ◽  
Emission Data ◽  
Pet Tracer ◽  
Positron Emission ◽  
Tolerability Data

We characterized the relationship between the plasma concentration of the phospodiesterase (PDE)-4 inhibitor GSK356278 and occupancy of the PDE4 enzyme in the brain of healthy volunteers, using the positron emission tomography (PET) tracer [11C](R)-rolipram. To this end, PET scans were acquired in eight male volunteers before and at 3 and 8 h after a single 14 mg oral dose of GSK356278. A metabolite-corrected arterial input function was used in conjunction with the dynamic PET emission data to estimate volumes of distribution (VT) from a two-tissue compartment model. The administration of GSK356278 reduced [11C](R)-rolipram whole brain VT by 17% at 3 h post-dose (p = 0.01) and by 4% at 8 h post-dose. The mean plasma Cmax was 42.3 ng/ml, leading to a PDE4 occupancy of 48% at Tmax. The in vivo affinity of GSK356278 was estimated as EC50 = 46 ± 3.6 ng/ml. We present the first report of a direct estimation of PDE4 blockade in the living human brain. In vivo affinity of GSK356278 for the PDE4, estimated in this early phase study, was combined with GSK356278 safety and tolerability data to decide on a therapeutic dose for future clinical development.

scholarly journals Kinetic Modeling without Accounting for the Vascular Component Impairs the Quantification of [11C]PBR28 Brain PET Data

2014 ◽  
Vol 34 (6) ◽  
pp. 1060-1069 ◽  
Author(s):  
Gaia Rizzo ◽  
Mattia Veronese ◽  
Matteo Tonietto ◽  
Paolo Zanotti-Fregonara ◽  
Federico E Turkheimer ◽  
...  
Keyword(s):  
Arterial Input Function ◽  
Compartment Model ◽  
Input Function ◽  
Translocator Protein ◽  
Brain Vessels ◽  
Data Set ◽  
Potential Marker ◽  
Positron Emission ◽  
Vascular Component ◽  
The Impact

The positron emission tomography radioligand [11C]PBR28 targets translocator protein (18 kDa) (TSPO) and is a potential marker of neuroinflammation. [11C]PBR28 binding is commonly quantified using a two-tissue compartment model and an arterial input function. Previous studies with [11C]HRJ-PK11195 demonstrated a slow irreversible binding component to the TSPO proteins localized in the endothelium of brain vessels, such as venous sinuses and arteries. However, the impact of this component on the quantification of [11C]PBR28 data has never been investigated. In this work we propose a novel kinetic model for [11C]PBR28. This model hypothesizes the existence of an additional irreversible component from the blood to the endothelium. The model was tested on a data set of 19 healthy subjects. A simulation was also performed to quantify the error generated by the standard two-tissue compartmental model when the presence of the irreversible component is not taken into account. Our results show that when the vascular component is included in the model the estimates that include the vascular component (2TCM-1K) are more than three-fold smaller, have a higher time stability and are better correlated to brain mRNA TSPO expression than those that do not include the model (2TCM).

scholarly journals Evaluation of Simplified Kinetic Analyses for Measurement of Brain Acetylcholinesterase Activity Using N-[11C]Methylpiperidin-4-yl Propionate and Positron Emission Tomography

2004 ◽  
Vol 24 (6) ◽  
pp. 600-611 ◽  
Author(s):  
Koichi Sato ◽  
Kiyoshi Fukushi ◽  
Hitoshi Shinotoh ◽  
Shinichiro Nagatsuka ◽  
Noriko Tanaka ◽  
...  
Keyword(s):  
Ache Activity ◽  
Arterial Input Function ◽  
Acetylcholinesterase Activity ◽  
Input Function ◽  
Previous Method ◽  
Target Tissue ◽  
Standard Analysis ◽  
Reference Tissue ◽  
Arterial Blood ◽  
Positron Emission

The applicability of two reference tissue-based analyses without arterial blood sampling for the measurement of brain regional acetylcholinesterase (AChE) activity using N-[11C]methylpiperidin-4-yl propionate ([11C]MP4P) was evaluated in 12 healthy subjects. One was a linear least squares analysis derived from Blomqvist's equation, and the other was the analysis of the ratio of target-tissue radioactivity relative to reference-tissue radioactivity proposed by Herholz and coworkers. The standard compartment analysis using arterial input function provided reliable quantification of k3 (an index of AChE activity) estimates in regions with low (neocortex and hippocampus), moderate (thalamus), and high (cerebellum) AChE activity with a coefficient of variation (COV) of 12% to 19%. However, the precise k3 value in the striatum, where AChE activity is the highest, was not obtained. The striatum was used as a reference because its time-radioactivity curve was proportional to the time integral of the arterial input function. Reliable k3 estimates were also obtained in regions with low-to-moderate AChE activity with a COV of less than 21% by striatal reference analyses, though not obtained in the cerebellum. Shape analysis, the previous method of direct k3 estimation from the shape of time-radioactivity data, gave k3 estimates in the cortex and thalamus with a somewhat larger COV. In comparison with the standard analysis, a moderate overestimation of k3 by 9% to 18% in the linear analysis and a moderate underestimation by 2% to 13% in the Herholz method were observed, which were appropriately explained by the results of computer simulation. In conclusion, simplified kinetic analyses are practical and useful for the routine analysis of clinical [11C]MP4P studies and are nearly as effective as the standard analysis for detecting regions with abnormal AChE activity.

scholarly journals Quantitation of Translocator Protein Binding in Human Brain with the Novel Radioligand [18F]-FEPPA and Positron Emission Tomography

2011 ◽  
Vol 31 (8) ◽  
pp. 1807-1816 ◽  
Author(s):  
Pablo M Rusjan ◽  
Alan A Wilson ◽  
Peter M Bloomfield ◽  
Irina Vitcu ◽  
Jeffrey H Meyer ◽  
...  
Keyword(s):  
Positron Emission Tomography ◽  
Human Brain ◽  
Specific Binding ◽  
Compartment Model ◽  
Distribution Volume ◽  
Translocator Protein ◽  
Emission Tomography ◽  
Binding Potential ◽  
Specific Distribution ◽  
Positron Emission

This article describes the kinetic modeling of [18F]-FEPPA binding to translocator protein 18 kDa in the human brain using high-resolution research tomograph (HRRT) positron emission tomography. Positron emission tomography scans were performed in 12 healthy volunteers for 180 minutes. A two-tissue compartment model (2-CM) provided, with no exception, better fits to the data than a one-tissue model. Estimates of total distribution volume ( VT), specific distribution volume ( VS), and binding potential ( BPND) demonstrated very good identifiability (based on coefficient of variation ( COV)) for all the regions of interest (ROIs) in the gray matter ( COV VT < 7%, COV VS < 8%, COV BPND < 11%). Reduction of the length of the scan to 2 hours is feasible as VS and VT showed only a small bias (6% and 7.5%, respectively). Monte Carlo simulations showed that, even under conditions of a 500% increase in specific binding, the identifiability of VT and VS was still very good with COV<10%, across high-uptake ROIs. The excellent identifiability of VT values obtained from an unconstrained 2-CM with data from a 2-hour scan support the use of VT as an appropriate and feasible outcome measure for [18F]-FEPPA.

scholarly journals Arterial Input Function Derived from Pairwise Correlations Between PET-image Voxels

2013 ◽  
Vol 33 (7) ◽  
pp. 1058-1065 ◽  
Author(s):  
Martin Schain ◽  
Simon Benjaminsson ◽  
Katarina Varnäs ◽  
Anton Forsberg ◽  
Christer Halldin ◽  
...  
Keyword(s):  
Arterial Input Function ◽  
Pearson Correlation ◽  
Invasive Procedure ◽  
Compartmental Analysis ◽  
Input Function ◽  
Time Activity ◽  
Pairwise Correlation ◽  
Positron Emission ◽  
Using Data ◽  
Suitable Reference

A metabolite corrected arterial input function is a prerequisite for quantification of positron emission tomography (PET) data by compartmental analysis. This quantitative approach is also necessary for radioligands without suitable reference regions in brain. The measurement is laborious and requires cannulation of a peripheral artery, a procedure that can be associated with patient discomfort and potential adverse events. A non invasive procedure for obtaining the arterial input function is thus preferable. In this study, we present a novel method to obtain image-derived input functions (IDIFs). The method is based on calculation of the Pearson correlation coefficient between the time-activity curves of voxel pairs in the PET image to localize voxels displaying blood-like behavior. The method was evaluated using data obtained in human studies with the radioligands [ 11 C]flumazenil and [ 11 C]AZ10419369, and its performance was compared with three previously published methods. The distribution volumes ( VT) obtained using IDIFs were compared with those obtained using traditional arterial measurements. Overall, the agreement in VT was good (~3% difference) for input functions obtained using the pairwise correlation approach. This approach performed similarly or even better than the other methods, and could be considered in applied clinical studies. Applications to other radioligands are needed for further verification.

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

2003 ◽  
Vol 23 (9) ◽  
pp. 1096-1112 ◽  
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.

scholarly journals A Two-Compartment Mathematical Model of Neuroglial Metabolism Using [1-11C] Acetate

2011 ◽  
Vol 32 (3) ◽  
pp. 548-559 ◽  
Author(s):  
Bernard Lanz ◽  
Kai Uffmann ◽  
Matthias T Wyss ◽  
Bruno Weber ◽  
Alfred Buck ◽  
...  
Keyword(s):  
Brain Metabolism ◽  
Arterial Input Function ◽  
Tca Cycle ◽  
Compartment Model ◽  
Metabolic Model ◽  
Input Function ◽  
Resonance Spectroscopy ◽  
Uptake Curve ◽  
Metabolic Fluxes ◽  
Good Agreement

The purpose of this study was to develop a two-compartment metabolic model of brain metabolism to assess oxidative metabolism from [1-11C] acetate radiotracer experiments, using an approach previously applied in 13C magnetic resonance spectroscopy (MRS), and compared with an one-tissue compartment model previously used in brain [1-11C] acetate studies. Compared with 13C MRS studies, 11C radiotracer measurements provide a single uptake curve representing the sum of all labeled metabolites, without chemical differentiation, but with higher temporal resolution. The reliability of the adjusted metabolic fluxes was analyzed with Monte-Carlo simulations using synthetic 11C uptake curves, based on a typical arterial input function and previously published values of the neuroglial fluxes Vtcag, Vx, Vnt, and Vtcan measured in dynamic 13C MRS experiments. Assuming Vxg=10 × Vtcag and Vxn= Vtcan, it was possible to assess the composite glial tricarboxylic acid (TCA) cycle flux Vgtg ( Vgtg= Vxg × Vtcag/( Vxg+ Vtcag)) and the neurotransmission flux Vnt from 11C tissue-activity curves obtained within 30 minutes in the rat cortex with a beta-probe after a bolus infusion of [1-11C] acetate ( n=9), resulting in Vgtg=0.136±0.042 and Vnt=0.170±0.103 μmol/g per minute (mean±s.d. of the group), in good agreement with 13C MRS measurements.

scholarly journals Quantification of [18F]afatinib using PET/CT in NSCLC patients, a feasibility study

2020 ◽  
Author(s):  
Eveline Annette van de Stadt ◽  
Maqsood Yaqub ◽  
Adriaan Lammertsma ◽  
Alex Poot ◽  
Patrick Schober ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Information Criterion ◽  
Compartment Model ◽  
Input Function ◽  
Pet Scan ◽  
Time Interval ◽  
Tumour Uptake ◽  
Positron Emission ◽  
Nsclc Patients

Abstract Introduction: Only a subgroup of non-small cell lung cancer (NSCLC) patients benefit from treatment using epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) such as afatinib. Tumour uptake of [18F]afatinib using positron emission tomography (PET) may identify those patients that respond to afatinib therapy. Therefore, the aim of this study was to find the optimal tracer kinetic model for quantification of [18F]afatinib uptake in NSCLC tumours.Methods: [18F]afatinib PET scans were performed in 10 NSCLC patients. The first patient was scanned for the purpose of dosimetry. Subsequent patients underwent a 20 minutes dynamic [15O]H2O PET-scan (370 MBq) followed by a dynamic [18F]afatinib PET-scan (342 ± 24 MBq) of 60 or 90 minutes. Using the Akaike information criterion (AIC), three pharmacokinetic plasma input models were evaluated with both metabolite corrected plasma sampler input and image-derived (IDIF) input functions in combination with discrete blood samples. Correlation analysis of arterial on-line sampling versus IDIF was performed. In addition, perfusion dependency and simplified measures were assessed.Results: Ten patients were included. The injected dose of [18F]afatinib was 341 ± 37 MBq. 15 tumours could be identified in the field of view of the scanner. Based on AIC, tumour kinetics were best described using an irreversible two-tissue compartment model and a metabolite corrected arterial plasma input function (Akaike 37%). Correlation of plasma-based input functions with metabolite-corrected IDIF was very good (r2=0.93). The preferred simplified uptake parameter was the tumour-to-blood ratio over the 60 to 90 minutes time interval (TBR60-90). Tumour uptake of [18F]afatinib was independent of perfusion.Conclusion: The preferred pharmacokinetic model for quantifying [18F]afatinib uptake in NSCLC tumours was the 2T3K_vb model. TBR60-90 showed excellent correlation with this model and is the best candidate simplified method.

scholarly journals Noninvasive Measurement of [11C]PiB Distribution Volume Using Integrated PET/MRI

Diagnostics ◽  
2020 ◽  
Vol 10 (12) ◽  
pp. 993
Author(s):  
Hidehiko Okazawa ◽  
Masamichi Ikawa ◽  
Tetsuya Tsujikawa ◽  
Akira Makino ◽  
Tetsuya Mori ◽  
...  
Keyword(s):  
Standardized Uptake Value ◽  
Input Function ◽  
Distribution Volume ◽  
Mri Segmentation ◽  
Reference Tissue ◽  
Pittsburgh Compound B ◽  
Quantitative Measurements ◽  
Logan Plot ◽  
Static Data ◽  
Early Alzheimer’S Disease

A noninvasive image-derived input function (IDIF) method using PET/MRI was applied to quantitative measurements of [11C] Pittsburgh compound-B (PiB) distribution volume (DV) and compared with other metrics. Fifty-three patients suspected of early dementia (71 ± 11 y) underwent 70 min [11C]PiB PET/MRI. Nineteen of them (68 ± 11 y) without head motion during the scan were enrolled in this study and compared with 16 age-matched healthy controls (CTL: 68 ± 11 y). The dynamic frames reconstructed from listmode PET data were used for DV calculation. IDIF with metabolite correction was applied to the Logan plot method, and DV was normalized into DV ratio (DVR) images using the cerebellar reference (DVRL). DVR and standardized uptake value ratio (SUVR) images were also calculated using the reference tissue graphical method (DVRr) and the 50–70 min static data with cerebellar reference, respectively. Cortical values were compared using the 3D-T1WI MRI segmentation. All patients were assigned to the early Alzheimer’s disease (eAD) group because of positive [11C]PiB accumulation. The correlations of regional values were better for DVRL vs. DVRr (r2 = 0.97) than for SUVR vs. DVRr (r2 = 0.88). However, all metrics clearly differentiated eAD from CTL with appropriate thresholds. Noninvasive quantitative [11C]PiB PET/MRI measurement provided equivalent DVRs with the two methods. SUVR images showed acceptable results despite inferior variability and image quality to DVR images.

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