Browsing by Author "Zahra, D"

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    Central nervous system expression and PET imaging of the translocator protein in relapsing–remitting experimental autoimmune encephalomyelitis
    (Society of Nuclear Medicine and Molecular Imaging, 2013-01-15) Mattner, F; Staykova, M; Berghofer, PJ; Wong, HJ; Fordham, S; Callaghan, PD; Jackson, T; Pham, TQ; Grégoire, MC; Zahra, D; Rahardjo, GL; Linares, D; Katsifis, A
    Glial neuroinflammation is associated with the development and progression of multiple sclerosis. PET imaging offers a unique opportunity to evaluate neuroinflammatory processes longitudinally in a noninvasive and clinically translational manner. (18)F-PBR111 is a newly developed PET radiopharmaceutical with high affinity and selectivity for the translocator protein (TSPO), expressed on activated glia. This study aimed to investigate neuroinflammation at different phases of relapsing-remitting (RR) experimental autoimmune encephalomyelitis (EAE) in the brains of SJL/J mice by postmortem histologic analysis and in vivo by PET imaging with (18)F-PBR111. METHODS: RR EAE was induced by immunization with PLP(139-151) peptide in complete Freund's adjuvant. Naive female SJL/J mice and mice immunized with saline-complete Freund's adjuvant were used as controls. The biodistribution of (18)F-PBR111 was measured in 13 areas of the central nervous system and compared with PET imaging results during different phases of RR EAE. The extents of TSPO expression and glial activation were assessed with immunohistochemistry, immunofluorescence, and a real-time polymerase chain reaction. RESULTS: There was significant TSPO expression in all of the central nervous system areas studied at the peak of the first clinical episode and, importantly, at the preclinical stage. In contrast, only a few TSPO-positive cells were observed at the second episode. At the third episode, there was again an increase in TSPO expression. TSPO expression was associated with microglial cells or macrophages without obvious astrocyte labeling. The dynamics of (18)F-PBR111 uptake in the brain, as measured by in vivo PET imaging and biodistribution, followed the pattern of TSPO expression during RR EAE. CONCLUSION: PET imaging with the TSPO ligand (18)F-PBR111 clearly reflected the dynamics of microglial activation in the SJL/J mouse model of RR EAE. The results are the first to highlight the discrepancy between the clinical symptoms of EAE and TSPO expression in the brain, as measured by PET imaging at the peaks of various EAE episodes. The results suggest a significant role for PET imaging investigations of neuroinflammation in multiple sclerosis and allow for in vivo follow-up of antiinflammatory treatment strategies. © 2013 Society of Nuclear Medicine and Molecular Imaging, Inc.
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    Comparison of cannabinoid CB1 receptor binding in adolescent and adult rats: a positron emission tomography study using [18F]MK-947
    (Hindawi Publishing Corporation, 2011-01-01) Verdurand, M; Nguyen, VH; Stark, D; Zahra, D; Grégoire, MC; Greguric, I; Zavitsanou, K
    Despite the important role of cannabinoid CB1 receptors (CB1R) in brain development, little is known about their status during adolescence, a critical period for both the development of psychosis and for initiation to substance abuse. In the present study, we assessed the ontogeny of CB1R in adolescent and adult rats in vivo using positron emission tomography with [18F]MK-9470. Analysis of covariance (ANCOVA) to control for body weight that would potentially influence [18F]MK-9470 values between the two groups revealed a main effect of age ( 𝐹 ( 1 , 1 0 9 ) = 5 . 0 , 𝑃 = 0 . 0 2 ) on [18F]MK-9470 absolute binding (calculated as percentage of injected dose) with adult estimated marginal means being higher compared to adolescents amongst 11 brain regions. This finding was confirmed using in vitro autoradiography with [3H]CP55,940 ( 𝐹 ( 1 0 , 9 9 ) = 1 4 0 . 1 , 𝑃 < 0 . 0 0 0 1 ). This ontogenetic pattern, suggesting increase of CB1R during the transition from adolescence to adulthood, is the opposite of most other neuroreceptor systems undergoing pruning during this period. Copyright © 2011 Mathieu Verdurand et al.
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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, I; 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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    Feasibility of imaging the ontogeny of CB1 receptors in adolescent and adult rats in vivo with [18F]MK 9470 and PET: a pilot study
    (Royal Australian and New Zealand College of Psychiatrists (RANZCP), 2010-09-23) Verdurand, M; Nguyen, VH; Stark, D; Zahra, D; Grégoire, MC; Greguric, I; Zavitsanou, K
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    Fluorine-18 radiolabelling and in vitro / in vivo metabolism of [18F]D4-PBR111
    (John Wiley & Sons, Inc, 2019-05-26) Wyatt, NA; Safavi-Naeini, M; Wotherspoon, ATL; Arthur, A; Nguyen, AP; Parmar, A; Hamze, H; Day, CM; Zahra, D; Matesic, L; Davis, E; Rahardjo, GL; Yepuri, NR; Shepherd, R; Murphy, RB; Pham, TQ; Nguyen, VH; Callaghan, PD; Holden, PJ; Grégoire, MC; Darwish, TA; Fraser, BH
    Objectives The purinergic receptor P2X ligand-gated ion channel type 7 (P2X7R) is an adenosine triphosphate (ATP)-gated ion-channel, and P2X7R is a key player in inflammation. P2X7R is an emerging therapeutic target in central nervous system (CNS) diseases including Alzheimer's disease (AD) and Parkinson's disease (PD), because P2X7R also plays a pivotal role in neuroinflammation. P2X7R represents a potential molecular imaging target for neuroinflammation via biomedical imaging technique positron emission tomography (PET), and several radioligands targeting P2X7R have been developed and evaluated in animals. In our previous work, we have developed and characterized [11C]GSK1482160 as a P2X7R radioligand for neuroinflammation,2 clinical evaluation of [11C]GSK1482160 in healthy controls and patients is currently underway, and the estimation of radiation dosimetry for [11C]GSK1482160 in normal human subjects has been reported.3 Since the half-life (t1/2) of radionuclide carbon-11 is only 20.4 min, it is attractive for us to develop derivatives of [11C]GSK1482160, which can be labeled with the radionuclide fluorine-18 (t1/2, 109.7 min), and a fluorine-18 ligand would be ideal for widespread use.4 To this end, a series of [18F]fluoroalkyl including [18F]fluoromethyl (FM), [18F]fluoroethyl (FE), and [18F]fluoropropyl (FP) derivatives of GSK1482160 have been prepared and examined as new potential P2X7R radioligands. © 2019 The Authors
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    Fossil barnacles from the Antarctic Peninsula: refining ways of exploring the nature of rare and/or delicate specimens employing X-ray Computer Tomography (CT)
    (Cambridge University Press, 2020-06-03) Stilwell, JD; Buckeridge, JSJS; Bevitt, JJ; Zahra, D
    Assessment of unique and potentially significant fossils may be considerably compromised by surrounding matrix. This paper assesses a fossil barnacle group from the mid to late Eocene of Seymour Island, off the Antarctic Peninsula, that potentially has very significant phylogenetic importance. It discusses why the specimen could be significant, and describes and applies as a proof of concept an advanced imaging technique, using X-ray Computed Tomography (CT), that was effectively employed to confirm systematic taxonomy with virtual 3-D sections through the specimen. In this case, the Antarctic barnacle's complex internal plate morphologies were resolved by advanced 3-D imaging, such that a taxonomic attribution could be made to either the Archaeobalanidae or Austrobalanidae, excluding the initial assessment of Coronulidae, which would have otherwise been allusive. © 2020, The Paleontological Society.
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    Hybrid non-rigid registration method for registering rat skeletons from micro-CT images
    (Society of Nuclear Medicine and Molecular Imaging, 2009-05) Xiao, D; Zahra, D; Bourgeat, P; Tamayo, OA; Berghofer, PJ; Fripp, J; Grégoire, MC; Salvado, O
    Objectives: A hybrid non-rigid registration method for automatic rat spine detection and registration and further rat limbs registration was proposed. Methods: We first developed an automatic algorithm to extract the rat spine from its whole-body skeleton and then detect top point on the spinous process of each vertebra starting from the first vertebra at thoracic vertebrae towards the tail. The extracted points were matched to the predefined corresponding points of the spine in a rat atlas. Their correspondences field was used to perform skeletons registration by thin-plate-spline (TPS). Further, we extend 3D shape context algorithm for landmarks matching for rat limbs between the atlas and the newly extracted skeletons. The correspondences found were used to perform the rat limb skeletons registration by TPS. Results: Experiments were described using phantoms and actual rat skeletons. Mean square errors decrease was observed during registration process. Visually, the skeletons were successfully registered. Conclusions: The method can improve the robustness of rat skeleton registration, even in the case of large variation in some postures and this first step work can be extended to further improve rat organs registration guided by the correspondences found from the skeletons.© 2009 by Society of Nuclear Medicine
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    Imaging capabilities of the Inveon SPECT system using single-and multipinhole collimators
    (Society of Nuclear Medicine and Molecular Imaging, 2013-09-05) Boisson, F; Zahra, D; Parmar, A; Grégoire, MC; Meikle, SR; Hamze, H; Reilhac, A
    The Inveon small-animal SPECT system comes with several types of multipinhole collimator plates. We evaluate here the performance measurements of the Inveon SPECT system using 6 different collimators: 3 dedicated for mouse imaging and 3 for rat imaging. Methods: The measured performance parameters include the sensitivity, the spatial resolution using line sources, the ultra-micro Derenzo phantom, the recovery coefficient and the noise measurements using the National Electrical Manufacturers Association NU-4 image quality phantom, obtained with the 2 reconstruction algorithms available with the Inveon Acquisition Workplace, version 1.5—the 3-dimensional ordered-subset expectation maximization (3DOSEM) and the 3-dimensional maximum a posteriori (3DMAP). Further, the overall performance of the system is illustrated by an animal experiment. Results: The results show that the Inveon SPECT scanner offers a spatial resolution, measured at the center of the field of view, ranging from 0.6 to 1 mm with the collimator plates dedicated to mouse imaging and from 1.2 to less than 2 mm with rat collimator plates. The system sensitivity varies from 29 to 404 cps/MBq for mouse collimators and from 53 to 175 cps/MBq for rat collimators. The image quality study showed that 3DMAP allows better noise reduction while preserving the recovery coefficient, compared with other regularization strategies such as the premature termination of the 3DOSEM reconstruction or 3DOSEM followed by gaussian filtering. Conclusion: The acquisition parameters, such as the collimator set and the radius of rotation, offer a wide range of possibilities to apply to a large number of biologic studies. However, special care must be taken because this increase in sensitivity can be offset by image degradation, such as image artifacts caused by projection overlap and statistical noise due to a higher number of iterations required for convergence. 3DMAP allowed better noise reduction while maintaining relatively constant recovery coefficients, as compared with other reconstruction strategies. © 2013 by the Society of Nuclear Medicine and Molecular Imaging, 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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    Increased brain metabolism after acute administration of the synthetic cannabinoid HU210: A small animal PET imaging study with (18)F-FDG
    (Elsevier, 2012-02-10) Nguyen, VH; Verdurand, M; Dedeurwaerdere, S; Wang, HQ; Zahra, D; Grégoire, MC; Zavitsanou, K
    Cannabis use has been shown to alter brain metabolism in both rat models and humans although the observations between both species are conflicting. In the present study, we examined the short term effects of a single-dose injection of the synthetic cannabinoid agonist HU210 on glucose metabolism in the rat brain using small animal (18)F-2-fluoro-deoxyglucose (FDG) Positron Emission Tomography (PET) 15min (Day 1) and 24h (Day 2) post-injection of the agonist in the same animal. Young adult male Wistar rats received an intra-peritoneal injection of HU210 (100μg/kg, n=7) or vehicle (n=5) on Day 1. Approximately 1mCi of (18)F-FDG was injected intravenously into each animal at 15min (Day 1) and 24h (Day 2) post-injection of HU210. A 5-min Computer Tomography (CT) scan followed by a 20-min PET scan was performed 40min after each (18)F-FDG injection. Standardised Uptake Values (SUVs) were calculated for 10 brain regions of interest (ROIs). Global increased SUVs in the whole brain, hence global brain metabolism, were observed following HU210 treatment on Day 1 compared to the controls (21%, P<0.0001), but not in individual brain regions. On Day 2, however, no statistically significant differences were observed between the treated and control groups. At the 24h time point (Day 2), SUVs in the HU210 treated group returned to control levels (21-30% decrease compared to Day 1), in all ROIs investigated (P<0.0001). In the control group, SUVs did not differ between the two acquisition days in all brain regions. The present results suggest that high-dose HU210 increases brain glucose metabolism in the rat brain shortly after administration, in line with normalised human in vivo studies, an effect that was no longer apparent 24h later. Copyright © 2011 Elsevier Inc. All rights reserved.
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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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    Peformance evaluation of preclinical PET scanners with the NEMA NU-4 image quality phantom using a collection of radioisotopes
    (John Wiley & Sons, Inc., 2013-04-13) Nezich, R; Reilhac, A; Zahra, D; Price, R
    Background: The radioisotopes 18F, 11C, 124I, 68Ga, 89Zr and 64Cu have found numerous applications in small animal PET imaging, and this entire subset of isotopes will soon be available to Australian preclinical researchers. The suitability of an isotope for a given imaging application is determined largely by its radioactive half-life. However, other characteristic physical properties of the isotope such as the branching fraction and positron energy can severely impact image quality and the ability to accurately quantify uptake of the radio-labelled molecule. Furthermore, the specific acquisition parameters and reconstruction algorithms employed to generate the image can significantly affect the image quality and quantification accuracy. The NEMA NU-4 2008 standards describe a method to evaluate the performance of small animal PET scanners. The information gathered through the NEMA Image Quality phantom scanning experiment is valuable for optimising the scanner usage, because it allows for the best selection of acquisition/reconstruction protocols and provides knowledge of the resolution limits of the system. Method: NEMA NU-4 image quality phantom performance testing was performed on the Siemens Inveon with 18F, 124I and 64Cu, using default acquisition parameters and each of the available reconstruction algorithms. Further testing will be performed using 11C, 68Ga and 89Zr. The Bioscan NanoPET scanner will be tested with all of the mentioned isotopes. Results: The figure shows NU-4 phantom images obtained for 18F, 64Cu and 124I; using the Inveon preclinical scanner and FBP2D reconstruction. The relatively poor image quality obtained with 124I is mainly caused by single gamma-photon contamination. Due to a higher positron range, recovery coefficients obtained with 124I are well below the values measured with 18F. Conclusion: NEMA NU-4 performance testing provides valuable information about the image quality achievable for a given PET scanner and radioisotope. © 2003 John Wiley & Sons, Inc.
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    Positron emission tomography and functional characterization of a complete PBR/TSPO knockout
    (Springer Nature, 2014-11-19) Banati, RB; Middleton, RJ; Chan, RHY; Hatty, CR; Wai-Ying Kam, W; Quin, C; Graeber, MB; Parmar, A; Zahra, D; Callaghan, PD; Fok, S; Howell, NR; Grégoire, MC; Szabo, A; Pham, TQ; Davis, E; Liu, GJ
    The evolutionarily conserved peripheral benzodiazepine receptor (PBR), or 18-kDa translocator protein (TSPO), is thought to be essential for cholesterol transport and steroidogenesis, and thus life. TSPO has been proposed as a biomarker of neuroinflammation and a new drug target in neurological diseases ranging from Alzheimer’s disease to anxiety. Here we show that global C57BL/6-Tspotm1GuWu(GuwiyangWurra)-knockout mice are viable with normal growth, lifespan, cholesterol transport, blood pregnenolone concentration, protoporphyrin IX metabolism, fertility and behaviour. However, while the activation of microglia after neuronal injury appears to be unimpaired, microglia from GuwiyangWurraTSPO knockouts produce significantly less ATP, suggesting reduced metabolic activity. Using the isoquinoline PK11195, the ligand originally used for the pharmacological and structural characterization of the PBR/TSPO, and the imidazopyridines CLINDE and PBR111, we demonstrate the utility of GuwiyangWurraTSPO knockouts to provide robust data on drug specificity and selectivity, both in vitro and in vivo, as well as the mechanism of action of putative TSPO-targeting drugs. Copyright © 2014, Springer Nature
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    Prenatal poly I:C age-dependently alters cannabinoid type 1 receptors in offspring: a longitudinal small animal PET study using [18F]MK-9470
    (Elsevier, 2014-05-10) Verdurand, M; Dalton, VS; Nguyen, VH; Grégoire, MC; Zahra, D; Wyatt, NA; Burgess, L; Greguric, I; Zavitsanou, K
    Evidence suggests that there is a link between the endocannabinoid system (ECS) and neuropsychiatric illnesses, including schizophrenia. Whilst the ECS has been shown to be involved in immune system regulation in various ways, it is known that infections during pregnancy can modulate the immune system of the mother and increase the risk for schizophrenia in offspring. In animal studies, maternal immune activation following administration of viral or bacterial mimics has been shown to reproduce many key structural, behavioural, and pharmacological abnormalities in offspring that resemble schizophrenia. In the present study, we used Positron Emission Tomography (PET) and [18F]MK-9470, a selective high-affinity inverse agonist radioligand for cannabinoid type 1 receptors (CB1R), to longitudinally assess CB1R expression in the progeny of female rats exposed to the viral mimic polyriboinosinic–polyribocytidilic acid (poly I:C) (4 mg/kg i.v.) or vehicle at gestational day 15 (GD 15). PET scans were performed in offspring at postnatal days (PND) 32–42 (adolescence) and in the same animals again at PNDs 75–79 (adulthood). Sixteen regions of interest were assessed, encompassing the whole rat brain. At adolescence, offspring exposed prenatally to poly I:C had significantly lower CB1R relative Standard Uptake Values (rSUV) compared to controls in the globus pallidus (p = 0.046). In adulthood, however, poly I:C exposed offspring had higher levels of CB1R rSUV in sensory cortex (p = 0.034) and hypothalamus (p = 0.032) compared to controls. Our results suggest that prenatal poly I:C leads to long term alterations in the integrity of the ECS that are age and region-specific. The increased CB1R expression in adulthood following poly I:C mirrors the increased CB1R observed in patients with schizophrenia in post-mortem and in vivo PET studies. © Elsevier
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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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    The role of earthquakes and climate in the formation of diamictic sediments in a New Zealand mountain lake
    (Elsevier, 2018-03-03) Woodward, CA; Slee, A; Gadd, PS; Zawadzki, A; Hamze, H; Parmar, A; Zahra, D
    We used Itrax XRF, magnetic susceptibility, grain size, and micro-CT scanning to provide a facies classification for a Late Holocene sediment sequence from Lake Chappa'ai in the Southern Alps, New Zealand. The record contained multiple diamictic layers and our objective was to determine the environmental significance of these deposits. Clast fabric analysis indicated that the diamicts comprise dropstones transported to the centre of the lake by ice rafting. Diamicts belonging to Facies 1 represent rock falls onto lake ice triggered by earthquakes that produced MMI (Modified Mercalli Intensity) > 8 shaking in the catchment. MMI >8 earthquakes may need to occur when the lake has ice cover to produce Facies 1 diamicts. MMI >8 earthquakes in the ice free season or MMI 7–8 earthquakes may also result in an increased flux of large (>1 mm) clasts to the centre of the lake, but may not produce a Facies 1 diamict. More work is required to establish the role of climate related processes on the formation of non-Facies 1 diamicts in Lake Chappa'ai. Climate change may directly lead to diamict formation by changing lake ice cover and facilitating transport of large clasts by anchor ice, or increasing the likelihood of rain on snow events in the spring. Changing ice cover conditions will also affect how mountain lakes record past earthquake events. Lakes that are ice free will not produce earthquake diamicts and lakes that have perennial ice cover may produce a single diamict representing multiple earthquakes if the lake becomes ice free. A reduction in the duration of winter ice cover will also decrease the probability of capturing primary rockfall deposits from earthquakes. Additional data, such as a diatom or chironomid record from Lake Chappa'ai may help to resolve the contribution of climate processes to diamict formation. We should consider the Lake Chappa'ai record as an indicator of minimum earthquake activity until we can disentangle the effects of climate change on non-Facies 1 diamict formation. This study highlights the multiple mechanisms that can lead to diamict formation in mountain lake sediments. These processes should always be considered before attributing the presence of diamict deposits to ice-rafted debris in a pro-glacial lake. This is particularly true in seismically active settings where earthquake triggered rockfalls may lead to diamict formation. Crown Copyright ©2017 Published by Elsevier Ltd
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    Selective, high-contrast detection of syngeneic glioblastoma in vivo
    (Springer Nature, 2020-06-19) Banati, RB; Wilcox, P; Xu, R; Yin, G; Si, E; Son, ET; Shimizu, M; Holsinger, RMD; Parmar, A; Zahra, D; Arthur, A; Middleton, RJ; Liu, GJ; Charil, A; Graeber, MB
    Glioblastoma is a highly malignant, largely therapy-resistant brain tumour. Deep infiltration of brain tissue by neoplastic cells represents the key problem of diffuse glioma. Much current research focuses on the molecular makeup of the visible tumour mass rather than the cellular interactions in the surrounding brain tissue infiltrated by the invasive glioma cells that cause the tumour’s ultimately lethal outcome. Diagnostic neuroimaging that enables the direct in vivo observation of the tumour infiltration zone and the local host tissue responses at a preclinical stage are important for the development of more effective glioma treatments. Here, we report an animal model that allows high-contrast imaging of wild-type glioma cells by positron emission tomography (PET) using [18 F]PBR111, a selective radioligand for the mitochondrial 18 kDa Translocator Protein (TSPO), in the Tspo−/− mouse strain (C57BL/6-Tspotm1GuMu(GuwiyangWurra)). The high selectivity of [18 F]PBR111 for the TSPO combined with the exclusive expression of TSPO in glioma cells infiltrating into null-background host tissue free of any TSPO expression, makes it possible, for the first time, to unequivocally and with uniquely high biological contrast identify peri-tumoral glioma cell invasion at preclinical stages in vivo. Comparison of the in vivo imaging signal from wild-type glioma cells in a null background with the signal in a wild-type host tissue, where the tumour induces the expected TSPO expression in the host’s glial cells, illustrates the substantial extent of the peritumoral host response to the growing tumour. The syngeneic tumour (TSPO+/+) in null background (TSPO−/−) model is thus well suited to study the interaction of the tumour front with the peri-tumoral tissue, and the experimental evaluation of new therapeutic approaches targeting the invasive behaviour of glioblastoma. © 2020, The Author(s).
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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