David Zahra
Australian Nuclear Science and Technology Organisation
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Publication
Featured researches published by David Zahra.
Nature Communications | 2014
Richard B. Banati; Ryan J. Middleton; Ronald Chan; Claire R. Hatty; Winnie Wai-Ying Kam; Candice Quin; Manuel B. Graeber; Arvind Parmar; David Zahra; Paul D. Callaghan; Sandra Fok; Nicholas R. Howell; Marie Claude Gregoire; Alexander M Szabo; Tien Pham; Emma Davis; Guo Jun Liu
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.
The Journal of Nuclear Medicine | 2013
Filomena Mattner; Maria Staykova; Paula Berghofer; Heng Jian Wong; Susan Fordham; Paul D. Callaghan; Timothy Jackson; Tien Pham; Marie-Claude Gregoire; David Zahra; Gita Rahardjo; David Liñares; Andrew Katsifis
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. 18F-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 18F-PBR111. Methods: RR EAE was induced by immunization with PLP139–151 peptide in complete Freunds adjuvant. Naive female SJL/J mice and mice immunized with saline–complete Freunds adjuvant were used as controls. The biodistribution of 18F-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 18F-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 18F-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.
International Journal of Molecular Imaging | 2011
Mathieu Verdurand; Vu Nguyen; Daniela Stark; David Zahra; Marie-Claude Gregoire; Ivan Greguric; Katerina Zavitsanou
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(1,109)=5.0, P = 0.02) 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(10,99)=140.1, P < 0.0001). 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.
Computerized Medical Imaging and Graphics | 2010
Di Xiao; David Zahra; Pierrick Bourgeat; Paula Berghofer; Oscar Acosta Tamayo; Catriona Wimberley; Marie Claude Gregoire; Olivier Salvado
3D shape context is a method to define matching points between similar shapes. It can be used as a pre-processing 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.
Scientific Reports | 2016
Vincent Raoult; Victor M. Peddemors; David Zahra; Nicholas R. Howell; Daryl L. Howard; Martin D. de Jonge; Jane E. Williamson
Determining the age of sharks using vertebral banding is a vital component of management, but the causes of banding are not fully understood. Traditional shark ageing is based on fish otolith ageing methods where growth bands are assumed to result from varied seasonal calcification rates. Here we investigate these assumptions by mapping elemental distribution within the growth bands of vertebrae from six species of sharks representing four different taxonomic orders using scanning x-ray fluorescence microscopy. Traditional visual growth bands, determined with light microscopy, were more closely correlated to strontium than calcium in all species tested. Elemental distributions suggest that vertebral strontium bands may be related to environmental variations in salinity. These results highlight the requirement for a better understanding of shark movements, and their influence on vertebral development, if confidence in age estimates is to be improved. Analysis of shark vertebrae using similar strontium-focused elemental techniques, once validated for a given species, may allow more successful estimations of age on individuals with few or no visible vertebral bands.
Physics in Medicine and Biology | 2013
Frederic Boisson; Catriona Wimberley; Wencke Lehnert; David Zahra; Pham T; Perkins G; Hasar Hamze; Marie Claude Gregoire; Anthonin Reilhac
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 & 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 ([(11)C]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.
Brain Research Bulletin | 2012
Vu Nguyen; Mathieu Verdurand; Stefanie Dedeurwaerdere; Hongqin Wang; David Zahra; Marie-Claude Gregoire; Katerina Zavitsanou
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) 15 min (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 (100 μg/kg, n=7) or vehicle (n=5) on Day 1. Approximately 1mCi of (18)F-FDG was injected intravenously into each animal at 15 min (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 40 min 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 24 h later.
Experimental Neurology | 2014
Mathieu Verdurand; Victoria S. Dalton; Vu Nguyen; Marie-Claude Gregoire; David Zahra; Naomi Wyatt; Leena Burgess; Ivan Greguric; Katerina Zavitsanou
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 [(18)F]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) (4mg/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.
Proceedings of SPIE | 2011
Di Xiao; David Zahra; Pierrick Bourgeat; Paula Berghofer; Oscar Acosta Tamayo; Heather Green; Marie Claude Gregoire; Olivier Salvado
Automatic small animal whole-body organ registration is challenging because of subjects joint structure, posture and position difference and loss of reference features. In this paper, an improved 3D shape context based non-rigid registration method is applied for mouse whole-body skeleton registration and lung registration. A geodesic path based non-rigid registration method is proposed for mouse torso skin registration. Based on the above registration methods, a novel non-rigid registration framework is proposed for mouse whole-body organ mapping from an atlas to new scanned CT data. A preliminary experiment was performed to test the method on lung and skin registration. A whole-body organ mapping was performed on three target data and the selected organs were compared with the manual outlining results. The robust of the method has been demonstrated.
Proceedings of SPIE | 2010
Di Xiao; David Zahra; Pierrick Bourgeat; Paula Berghofer; Oscar Acosta Tamayo; Catriona Wimberley; Marie Claude Gregoire; Olivier Salvado
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.
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Commonwealth Scientific and Industrial Research Organisation
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View shared research outputsCommonwealth Scientific and Industrial Research Organisation
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