Browsing by Author "Wimberley, CA"

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    4D PET iterative deconvolution with spatiotemporal regularization for quantitative dynamic PET imaging
    (Elsevier, 2015-09-01) Reilhac, A; Charil, A; Wimberley, CA; Angelis, GI; Hamze, H; Callaghan, PD; Garcia, MP; Boisson, F; Ryder, W; Meikle, SR; Grégoire, MC
    Quantitative measurements in dynamic PET imaging are usually limited by the poor counting statistics particularly in short dynamic frames and by the low spatial resolution of the detection system, resulting in partial volume effects (PVEs). In this work, we present a fast and easy to implement method for the restoration of dynamic PET images that have suffered from both PVE and noise degradation. It is based on a weighted least squares iterative deconvolution approach of the dynamic PET image with spatial and temporal regularization. Using simulated dynamic [11C] Raclopride PET data with controlled biological variations in the striata between scans, we showed that the restoration method provides images which exhibit less noise and better contrast between emitting structures than the original images. In addition, the method is able to recover the true time activity curve in the striata region with an error below 3% while it was underestimated by more than 20% without correction. As a result, the method improves the accuracy and reduces the variability of the kinetic parameter estimates calculated from the corrected images. More importantly it increases the accuracy (from less than 66% to more than 95%) of measured biological variations as well as their statistical detectivity. © 2015 Elsevier Inc.
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    Comparison of in vivo binding properties of the 18-kDa translocator protein (TSPO) ligands [18F]PBR102 and [18F]PBR111 in a model of excitotoxin-induced neuroinflammation
    (Springer Link, 2015-01) Callaghan, PD; Wimberley, CA; Rahardjo, GL; Berghofer, PJ; Pham, TQ; Jackson, TW; Zahra, D; Bourdier, T; Wyatt, N; Greguric, ID; Howell, NR; Siegele, R; Pastuovic, Z; Mattner, F; Loc'h, C; Grégoire, MC; Katsifis, A
    The in vivo binding parameters of the novel imidazopyridine TSPO ligand [18F]PBR102 were assessed and compared with those of [18F]PBR111 in a rodent model of neuroinflammation. The validity of the key assumptions of the simplified reference tissue model (SRTM) for estimation of binding potential (BP) was determined, with validation against a two-tissue compartment model (2TC). Methods Acute neuroinflammation was assessed 7 days after unilateral stereotaxic administration of (R,S)-α-amino-3-hydroxy-5-methyl-4-isoxazolopropionique (AMPA) in anaesthetized adult Wistar rats. Anaesthetized rats were implanted with a femoral arterial cannula then injected with a low mass of [18F]PBR102 or [18F]PBR111 and dynamic images were acquired over 60 min using an INVEON PET/CT camera. Another population of rats underwent the same PET protocol after pretreatment with a presaturating mass of the same unlabelled tracer (1 mg/kg) to assess the validity of the reference region for SRTM analysis. Arterial blood was sampled during imaging, allowing pharmacokinetic determination of radiotracer concentrations. Plasma activity concentration–time curves were corrected for unchanged tracer based on metabolic characterization experiments in a separate cohort of Wistar rats. The stability of neuroinflammation in both imaging cohorts was assessed by [125I] CLINDE TSPO quantitative autoradiography, OX42/GFAP immunohistochemistry, Fluoro-Jade C histology, and elemental mapping using microparticle-induced x-ray emission spectroscopy. The BP of each ligand were assessed in the two cohorts of lesioned animals using both SRTM and a 2TC with arterial parent compound concentration, coupled with the results from the presaturation cohort for comparison and validation of the SRTM. Results The BPs of [18F]PBR102 [18F]PBR111 were equivalent, with improved signal-to-noise ratio and sensitivity compared with [11C]PK11195. The presaturation study showed differences in the volume of distribution between the ipsilateral striatum and the striatum contralateral to the injury (0.7) indicating that an assumption of the SRTM was not met. The modelling indicated that the BPs were consistent for both ligands. Between the SRTM and 2TC model, the BPs were highly correlated, but there was a bias in BP. Conclusion [18F]PBR102 and [18F]PBR111 have equivalent binding properties in vivo, displaying significantly greater BPs with lower signal-to-noise ratio than [11C]PK11195. While an assumption of the SRTM was not met, this modelling approach was validated against 2TC modelling for both ligands, facilitating future use in longitudinal PET imaging of neuroinflammation.© 2014, Springer Nature
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    A data driven method for estimation of Bavail and appKD using a single injection protocol with [11C]raclopride in the mouse
    (Elsevier Inc., 2014-10-01) Wimberley, CA; Fischer, K; Reilhac, A; Pichler, BJ; Grégoire, MC
    Purpose The partial saturation approach (PSA) is a simple, single injection experimental protocol that will estimate both Bavail and appKD without the use of blood sampling. This makes it ideal for use in longitudinal studies of neurodegenerative diseases in the rodent. The aim of this study was to increase the range and applicability of the PSA by developing a data driven strategy for determining reliable regional estimates of receptor density (Bavail) and in vivo affinity (1/appKD), and validate the strategy using a simulation model. Methods The data driven method uses a time window guided by the dynamic equilibrium state of the system as opposed to using a static time window. To test the method, simulations of partial saturation experiments were generated and validated against experimental data. The experimental conditions simulated included a range of receptor occupancy levels and three different Bavail and appKD values to mimic diseases states. Also the effect of using a reference region and typical PET noise on the stability and accuracy of the estimates was investigated. Results The investigations showed that the parameter estimates in a simulated healthy mouse, using the data driven method were within 10±30% of the simulated input for the range of occupancy levels simulated. Throughout all experimental conditions simulated, the accuracy and robustness of the estimates using the data driven method were much improved upon the typical method of using a static time window, especially at low receptor occupancy levels. Introducing a reference region caused a bias of approximately 10% over the range of occupancy levels. Conclusions Based on extensive simulated experimental conditions, it was shown the data driven method provides accurate and precise estimates of Bavail and appKD for a broader range of conditions compared to the original method. © 2014 Elsevier Inc.
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    An improved 3D shape context based non-rigid registration method and its application to small animal skeletons registration
    (Pergamon-Elsevier Science Ltd, 2010-06-01) Xiao, D; Zahra, D; Bourgeat, P; Berghofer, PJ; Tamayo, OA; Wimberley, CA; Grégoire, MC; Salvado, O
    3D shape context is a method to define matching points between similar shapes. It can be used as a preprocessing step in a non-rigid registration. The main limitation of the method is point mismatching, which includes long geodesic distance mismatch causing wrong topological structure, and neighbors crossing mismatch between two adjacent points. In this paper, we propose a topological structure verification method to correct the long geodesic distance mismatch and a correspondence field smoothing method to correct the neighbors crossing mismatch. A robust 3D shape context model is generated and further combined with thin-plate spline model for non-rigid registration. The method was tested on phantoms and applied to rat hind limb and mouse hind limb skeletons registration from micro-CT images. Errors between the registered surfaces were reduced by using the proposed method. The robustness of the method is demonstrated. © 2010, Elsevier Ltd.
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    An improved 3D shape context registration method for non-rigid surface registration.
    (Society of Photo-optical Instrumentation Engineers (SPIE), 2010-02-14) Xiao, D; Zahra, D; Bourgeat, P; Berghofer, PJ; Tamayo, AO; Wimberley, CA; Grégoire, MC; Salvado, O
    3D shape context is a method to define matching points between similar shapes as a pre-processing step to non-rigid registration. The main limitation of the approach is point mismatching, which includes long geodesic distance mismatch and neighbors crossing mismatch. In this paper, we propose a topological structure verification method to correct the long geodesic distance mismatch and a correspondence field smoothing method to correct the neighbors crossing mismatch. A robust 3D shape context model is proposed and further combined with thin-plate spline model for non-rigid surface registration. The method was tested on phantoms and rat hind limb skeletons from micro CT images. The results from experiments on mouse hind limb skeletons indicate that the approach is robust.
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    In vivo measurement of hippocampal GABAA/cBZR density with [18F]-Flumazenil PET for the study of disease progression in an animal model of temporal lobe epilepsy
    (Public Library of Science, 2014-01-21) Vivash, L; Grégoire, MC; Bouilleret, V; Berard, A; Wimberley, CA; Binns, D; Roselt, P; Katsifis, A; Myers, DE; Hicks, RJ; O'Brien, TJ; Dedeurwaerdere, S
    Purpose Imbalance of inhibitory GABAergic neurotransmission has been proposed to play a role in the pathogenesis of temporal lobe epilepsy (TLE). This study aimed to investigate whether [18F]-flumazenil ([18F]-FMZ) PET could be used to non-invasively characterise GABAA/central benzodiazepine receptor (GABAA/cBZR) density and affinity in vivo in the post-kainic acid status epilepticus (SE) model of TLE. Methods Dynamic [18F]-FMZ -PET scans using a multi-injection protocol were acquired in four male wistar rats for validation of the partial saturation model (PSM). SE was induced in eight male Wistar rats (10 weeks of age) by i.p. injection of kainic acid (7.5–25 mg/kg), while control rats (n = 7) received saline injections. Five weeks post-SE, an anatomic MRI scan was acquired and the following week an [18F]-FMZ PET scan (3.6–4.6 nmol). The PET data was co-registered to the MRI and regions of interest drawn on the MRI for selected structures. A PSM was used to derive receptor density and apparent affinity from the [18F]-FMZ PET data. Key Findings The PSM was found to adequately model [18F]-FMZ binding in vivo. There was a significant decrease in hippocampal receptor density in the SE group (p<0.01), accompanied by an increase in apparent affinity (p<0.05) compared to controls. No change in cortical receptor binding was observed. Hippocampal volume reduction and cell loss was only seen in a subset of animals. Histological assessment of hippocampal cell loss was significantly correlated with hippocampal volume measured by MRI (p<0.05), but did not correlate with [18F]-FMZ binding. Significance Alterations to hippocampal GABAA/cBZR density and affinity in the post-kainic acid SE model of TLE are detectable in vivo with [18F]-FMZ PET and a PSM. These changes are independent from hippocampal cell and volume loss. [18F]-FMZ PET is useful for investigating the role that changes GABAA/cBZR density and binding affinity play in the pathogenesis of TLE. © 2014 Vivash et al.
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    NEMA NU 4-2008 validation and applications of the PET-SORTEO Monte Carlo simulations platform for the geometry of the Inveon PET preclinical scanner
    (IOP Publishing, 2013-09-10) Boisson, F; Wimberley, CA; Lehnert, W; Zahra, D; Pham, TQ; Perkins, G; Hamze, H; Grégoire, MC; Reilhac, A
    Monte Carlo-based simulation of positron emission tomography (PET) data plays a key role in the design and optimization of data correction and processing methods. Our first aim was to adapt and configure the PET-SORTEO Monte Carlo simulation program for the geometry of the widely distributed Inveon PET preclinical scanner manufactured by Siemens Preclinical Solutions. The validation was carried out against actual measurements performed on the Inveon PET scanner at the Australian Nuclear Science and Technology Organisation in Australia and at the Brain and Mind Research Institute and by strictly following the NEMA NU 4-2008 standard. The comparison of simulated and experimental performance measurements included spatial resolution, sensitivity, scatter fraction and count rates, image quality and Derenzo phantom studies. Results showed that PET-SORTEO reliably reproduces the performances of this Inveon preclinical system. In addition, imaging studies showed that the PET-SORTEO simulation program provides raw data for the Inveon scanner that can be fully corrected and reconstructed using the same programs as for the actual data. All correction techniques (attenuation, scatter, randoms, dead-time, and normalization) can be applied on the simulated data leading to fully quantitative reconstructed images. In the second part of the study, we demonstrated its ability to generate fast and realistic biological studies. PET-SORTEO is a workable and reliable tool that can be used, in a classical way, to validate and/or optimize a single PET data processing step such as a reconstruction method. However, we demonstrated that by combining a realistic simulated biological study ([11C]Raclopride here) involving different condition groups, simulation allows one also to assess and optimize the data correction, reconstruction and data processing line flow as a whole, specifically for each biological study, which is our ultimate intent. © 2017 IOP Publishing
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    Non-rigid registration method for mouse whole body skeleton registration.
    (Society of Photo-optical Instrumentation Engineers (SPIE), 2010-02-14) Xiao, D; Zahra, D; Bourgeat, P; Berghofer, PJ; Tamayo, AO; Wimberley, CA; Grégoire, MC; Salvado, O
    Micro-CT/PET imaging scanner provides a powerful tool to study tumor in small rodents in response to therapy. Accurate image registration is a necessary step to quantify the characteristics of images acquired in longitudinal studies. Small animal registration is challenging because of the very deformable body of the animal often resulting in different postures despite physical restraints. In this paper, we propose a non-rigid registration approach for the automatic registration of mouse whole body skeletons, which is based on our improved 3D shape context non-rigid registration method. The whole body skeleton registration approach has been tested on 21 pairs of mouse CT images with variations of individuals and time-instances. The experimental results demonstrated the stability and accuracy of the proposed method for automatic mouse whole body skeleton registration. © 2012, SPIE.
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    Optimisation of PET data processing for a single injection experiment with [11C]Raclopride using a simulations based approach
    (Society of Nuclear Medicine, 2014-11-05) Wimberley, CA; Angelis, GI; Boisson, F; Callaghan, PD; Fischer, K; Pichler, BJ; Meikle, SR; Grégoire, MC; Reilhac, A
    Objectives Positron emission tomography (PET) with [11C]Raclopride is an important tool for studying dopamine D2 receptor expression in vivo. [11C]Raclopride PET binding experiments conducted using the Partial Saturation Approach (PSA) (a simple, single injection experiment, Delforge 1995) allow the estimation of receptor density (Bavail) and the in vivo affinity 1/(KD). To achieve accurate and stable parameter estimates, and the ability to detect small changes in these parameters, the impact of the data processing chain should be investigated and optimised. Methods Two groups of PET scans were generated for a Partial Saturation Approach (PSA) experiment using Monte Carlo simulation software with a biological phenomenon inferred between the groups. The kinetic parameters Bavail and KD were estimated and the impact of spatial smoothing, temporal denoising and image resolution recovery on the statistical detectability of change in the estimates was investigated. Results Before optimisation, the inferred Bavail difference between the two groups was underestimated by 42% and detected in 66% of cases (at p<0.05), while a false decrease of KD by 13% was detected in more than 11% of cases. After optimisation, the calculated Bavail difference was underestimated by only 3.7% and detected in 89% of cases, while a false slight increase of KD by 3.7 % was detected in only 2% of cases. Conclusions The use of Monte Carlo generated PET scans allowed the optimisation of the data processing chain in order to reliably estimate and detect changes in the parameters Bavail and KD.
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    OSSI-PET: open-access database of simulated [11C]raclopride scans for the inveon preclinical PET scanner: application to the optimization of reconstruction methods for dynamic studies
    (IEEE, 2016-07) Garcia, MP; Charil, A; Callaghan, PD; Wimberley, CA; Busso, F; Grégoire, MC; Bardiès, M; Reilhac, A
    A wide range of medical imaging applications benefits from the availability of realistic ground truth data. In the case of positron emission tomography (PET), ground truth data is crucial to validate processing algorithms and assessing their performances. The design of such ground truth data often relies on Monte-Carlo simulation techniques. Since the creation of a large dataset is not trivial both in terms of computing time and realism, we propose the OSSI-PET database containing 350 simulated [ 11 C]Raclopride dynamic scans for rats, created specifically for the Inveon pre-clinical PET scanner. The originality of this database lies on the availability of several groups of scans with controlled biological variations in the striata. Besides, each group consists of a large number of realizations (i.e., noise replicates). We present the construction methodology of this database using rat pharmacokinetic and anatomical models. A first application using the OSSI-PET database is presented. Several commonly used reconstruction techniques were compared in terms of image quality, accuracy and variability of the activity estimates and of the computed kinetic parameters. The results showed that OP-OSEM3D iterative reconstruction method outperformed the other tested methods. Analytical methods such as FBP2D and 3DRP also produced satisfactory results. However, FORE followed by OSEM2D reconstructions should be avoided. Beyond the illustration of the potential of the database, this application will help scientists to understand the different sources of noise and bias that can occur at the different steps in the processing and will be very useful for choosing appropriate reconstruction methods and parameters. © 2016 IEEE
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    Quantification of dopamine d2 receptor density and apparent affinity can be used to longitudinally assess transient striatal variations during adolescence using [11c]raclopride pet imaging
    (John Wiley & Sons, Inc., 2017-04-11) Callaghan, PD; Sobbi, PF; Safavi-Naeini, M; Wimberley, CA; Davis, E; Zahra, D; Arthur, A; Rahardjo, GL; Perkins, G; Pascali, G; Reilhac-Laborde, A; Grégoire, MC
    Background Transient increases in striatal dopamine D2 receptors occur during adolescence in rats, correlating with a developmental epoch where synaptic pruning occurs. Alteration of these processes with external stresses during adolescence may lead to affective disorders later in life. Longitudinal PET imaging with [11C]raclopride using a partial saturation design allows assessment of density (Bavail) and affinity changes (appKd) to map neurodevelopmental changes in D2 expression, which necessitates a significant level of receptors occupancy during the PET study. Aims Validate that repeated transient partial saturation of D2 receptors does not bias measures of D2 Bavail and appKd assessed using PET/CT imaging with [11C]raclopride. Methods Three cohorts of male Sprague-Dawley rats (n=6-7/group) underwent a single session of PET/CT imaging (INVEON, Siemens, USA) with [11C]raclopride (5 nmol injected i.v.) as naïve or after repeated partial saturation of D2 receptors: Cohort A received 5nmol raclopride (i.v) weekly from PND35 (postnatal day) to PND96 with PET imaging session at PND96, cohort B was scanned at PND96; Cohort C was scanned at PND35 Datasets were reconstructed (2D-FBP), coregistered with CT and time-activity data extracted using age matched atlas-based volumes of interest (striatum, cerebellum). in vivo receptor density and appKd were derived using kinetic modelling (comparisons used 1-way ANOVA follow by post hoc test). Results Expected differences in Bavail and appKd were seen between the adolescent (PND35) and the adult (PND96) cohorts, corresponding with increases in D2 receptor consistently reported in the literature using post mortem methods. No significant difference was observed in both Bavail and appKd in cohort A, exposed to repeated D2 partial saturation, compared to the naïve cohort B. Conclusion Longitudinal quantification of dopamine D2 receptor density and apparent affinity in vivo using [11C]raclopride PET imaging with partial saturation can be used to map changes in adolescent and adult rats.
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    Simulation-based optimisation of the PET data processing for partial saturation approach protocols
    (Elsevier B.V., 2014-08-15) Wimberley, CA; Angelis, GI; Boisson, F; Callaghan, PD; Fischer, K; Pichler, BJ; Meikle, SR; Grégoire, MC; Reilhac, A
    Positron emission tomography (PET) with [11C]Raclopride is an important tool for studying dopamine D2 receptor expression in vivo. [11C]Raclopride PET binding experiments conducted using the Partial Saturation Approach (PSA) allow the estimation of receptor density (Bavail) and the in vivo affinity appKD. The PSA is a simple, single injection, single scan experimental protocol that does not require blood sampling, making it ideal for use in longitudinal studies. In this work, we generated a complete Monte Carlo simulated PET study involving two groups of scans, in between which a biological phenomenon was inferred (a 30% decrease of Bavail), and used it in order to design an optimal data processing chain for the parameter estimation from PSA data. The impact of spatial smoothing, noise removal and image resolution recovery technique on the statistical detection was investigated in depth. We found that image resolution recovery using iterative deconvolution of the image with the system point spread function associated with temporal data denoising greatly improves the accuracy and the statistical reliability of detecting the imposed phenomenon. Before optimisation, the inferred Bavail variation between the two groups was underestimated by 42% and detected in 66% of cases, while a false decrease of appKD by 13% was detected in more than 11% of cases. After optimisation, the calculated Bavail variation was underestimated by only 3.7% and detected in 89% of cases, while a false slight increase of appKD by 3.7% was detected in only 2% of cases. We found during this investigation that it was essential to adjust a factor that accounts for difference in magnitude between the non-displaceable ligand concentrations measured in the target and in the reference regions, for different data processing pathways as this ratio was affected by different image resolutions. © 2014 Elsevier B.V..
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    Simultaneous scanning of two mice in a small-animal PET scanner: a simulation-based assessment of the signal degradation
    (IOP science publishing, 2016-01-21) Reilhac, A; Boisson, F; Wimberley, CA; Parmar, A; Zahra, D; Hamze, H; Davis, E; Arthur, A; Bouillot, C; Charil, A; Grégoire, MC
    In PET imaging, research groups have recently proposed different experimental set ups allowing multiple animals to be simultaneously imaged in a scanner in order to reduce the costs and increase the throughput. In those studies, the technical feasibility was demonstrated and the signal degradation caused by additional mice in the FOV characterized, however, the impact of the signal degradation on the outcome of a PET study has not yet been studied. Here we thoroughly investigated, using Monte Carlo simulated [18F]FDG and [11C]Raclopride PET studies, different experimental designs for whole-body and brain acquisitions of two mice and assessed the actual impact on the detection of biological variations as compared to a single-mouse setting. First, we extended the validation of the PET-SORTEO Monte Carlo simulation platform for the simultaneous simulation of two animals. Then, we designed [18F]FDG and [11C]Raclopride input mouse models for the simulation of realistic whole-body and brain PET studies. Simulated studies allowed us to accurately estimate the differences in detection between single- and dual-mode acquisition settings that are purely the result of having two animals in the FOV. Validation results showed that PET-SORTEO accurately reproduced the spatial resolution and noise degradations that were observed with actual dual phantom experiments. The simulated [18F]FDG whole-body study showed that the resolution loss due to the off-center positioning of the mice was the biggest contributing factor in signal degradation at the pixel level and a minimal inter-animal distance as well as the use of reconstruction methods with resolution modeling should be preferred. Dual mode acquisition did not have a major impact on ROI-based analysis except in situations where uptake values in organs from the same subject were compared. The simulated [11C]Raclopride study however showed that dual-mice imaging strongly reduced the sensitivity to variations when mice were positioned side-by-side while no sensitivity reduction was observed when they were facing each other. This is the first study showing the impact of different experimental designs for whole-body and brain acquisitions of two mice on the quality of the results using Monte Carlo simulated [18F]FDG and [11C]Raclopride PET studies. © 2016 Institute of Physics and Engineering in Medicine
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    Test-retest reliability and inter scanner variability of 11C-raclopride striatal binding potentials between two INVEON PET/CT imaging systems for naïve Sprague Dawley rats
    (Wiley, 2014-04-16) Callaghan, PD; Zahra, D; Wimberley, CA; Arthur, A; Rahardjo, GL; Hamze, H; Davis, E; Nguyen, A; Boisson, F; Perkins, G; Pascali, G; Reilhac, A; Grégoire, MC
    Background: 11C-raclopride is a routine tracer for quantification of dopamine D2 receptors in neurological and psychiatric disease. D2 imaging in key longitudinal models has significant utility of understanding mechanisms and therapeutic interventions. Aims: Optimisation of preclinical imaging and data analysis protocols for 11C-raclopride in rat brain. Methods: a) Test-retest reliability: Naïve male Sprague Dawley rats (n = 6) underwent test-retest assessment of binding potential variability, with two scans, 1 week apart. Rats were anaesthetised (1–5% isoflurane) and received 11C-raclopride (>0.1 nmol, 20–40 MBq) during 1 hour image acquisition (Siemens Inveon PET/CT), followed by a 10 minute CT scan. b) Assessment of the intersystem variability of the INVEON scanners (n = 12). Test-retest experiments were performed on a second INVEON system. c) Assessment of inter system variability with arterial blood sampling (n = 5). Acquisitions were performed (as above) with prior femoral artery cannulation: 23 blood samples (∼30 ul) were collected during PET acquisition, and plasma metabolite corrected input functions generated. PET list mode data were histogrammed (23 frames) and reconstructed with 2D filtered backprojection algorithm. The impact of some post-reconstruction image processing techniques, such iterative deconvolution of the image and data denoising techniques, onto the accuracy and reliability of the computed parameter of interest were also investigated. Binding potential parametric maps were calculated from the dynamic PET data (using either a standard reference tissue modelling using the cerebellum TAC (test-retest), and or a 2 compartment kinetic modelling with input function). Preliminary results: Significant improvements were seen for tissue activity data after denoising /iterative deconvolution (see figure). Analysis of binding potential data are currently in progress. Conclusion: Assessment of within and intersystem variability will aid the appropriate statistical design of future longitudinal 11C-raclopride imaging studies. Improvements from post-reconstruction image processing techniques show significant benefits. © 1999-2022 John Wiley & Sons, Inc.