Research team

Molecular Imaging and Radiology (MIRA)

Expertise

Molecular imaging using positron emission tomography and single photon emission tomography. With these techniques we can image molecular and functional processes in humans and rodents through the use of radioactive tracers that are injected into the body and will visualise specific targets and processes in the living body. The technique is used in preclinical and clinical research and in the clinic (nuclear medicine). I’m particularly interested in methodological aspects of the technique to ensure the most optimal imaging results. This includes study design, image reconstruction, motion correction, imaging awake animals, tracer and therapy evaluation, pharmacokinetic modelling as well as translational aspects ensuring a cross-fertilization between pre-clinical and clinical research. Currently I’m applying these techniques for the neurosciences and pathologies such as Alzheimer's disease, Huntington’s disease schizophrenia.

IMARK. Network for image-based biomarker discovery and evaluation 01/01/2021 - 31/12/2026

Abstract

IMARK capitalizes on the deeply rooted expertise in biomedical imaging at the University of Antwerp to push the boundaries of precision medicine. By resolving molecular and structural patterns in space and time, IMARK aims at expediting biomarker discovery and development. To this end, it unites research groups with complementary knowledge and tools that cover all aspects of imaging-centred fundamental research, preclinical validation and clinical evaluation. IMARK harbours high-end infrastructure for electron and light microscopy, mass spectrometry imaging, magnetic resonance imaging, computed tomography, positron emission tomography and single-photon emission computed tomography. Moreover, IMARK members actively develop correlative approaches that involve multiple imaging modalities to enrich information content, and conceive dedicated image analysis pipelines to obtain robust, quantitative readouts. This unique blend of technologies places IMARK in an excellent position as preferential partner for public-private collaborations and offers strategic advantage for expanding the flourishing IP portfolio. The major application fields of the consortium are neuroscience and oncology. With partners from the Antwerp University Hospital and University Psychiatric Centre Duffel, there is direct access to patient data/samples and potential for translational studies.

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Preclinical PET imaging of allele-selective mHTT lowering as candidate treatment for Huntington's Disease. 01/10/2020 - 30/09/2023

Abstract

Huntington's Disease (HD) is a progressive autosomal dominant neurodegenerative disorder caused by a genetic mutation in the huntingtin gene (HTT), which encodes for mutant huntingtin (mHTT), the causative agent of the disorder. Since lowering the levels of toxic mHTT is postulated to halt disease progression, the use of engineered zinc finger protein transcription repressors (ZFP-TR) to selectively suppress the mutant HTT allele represents a novel candidate treatment for HD. A major limitation in the assessment of therapeutic efficacy is the lack of objective non-invasive markers. We recently validated the first-ever radioligand to image in vivo mHTT levels using positron emission tomography (PET) imaging in mice. The aim of this project is to assess the preclinical relevance of the use of ZFP-TR at different disease stages as candidate therapeutic intervention. This work will provide proof of efficacy for an mHTT lowering HD therapy in the living (rodent) brain by measuring mHTT in parallel to molecular targets for phenotypic recovery in wellcharacterized mouse models of HD. This multi-modal approach consisting of non-invasive in vivo PET imaging in combination with magnetic resonance imaging (MRI) and post-mortem techniques will represent a strategic multi-disciplinary platform to assess the efficacy of the ZFP-TR therapeutic efficacy providing a key contribution on the timing of intervention, ultimately leading to clinical translation in the future. GENERAL -

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Translational molecular imaging studies 01/01/2017 - 31/07/2022

Abstract

Huntington's disease (HD) is a dominantly inherited disorder characterized by a progressive neurodegeneration of the striatum that also involves other regions, primarily the cerebral cortex. Patients display progressive motor, cognitive, and psychiatric impairment. Symptoms usually start at midlife. The mutation responsible for this fatal disease is an abnormally expanded and unstable CAG repeat within the coding region of the gene encoding huntingtin. The pathogenic mechanisms by which mutant huntingtin cause neuronal dysfunction and cell death remain uncertain (Menalled, 2005). The mechanism underlying HD-related suppression of inhibition has been shown to include tonic activity of metabotropic glutamate receptor subtype 5 (mGluR5) as a pathophysiological hallmark (Dvorzhak, Semtner, Faber, & Grantyn, 2013) and inhibition of glutamate neurotransmission via specific interaction with mGluRs might be interesting for both inhibition of disease progression as well as early symptomatic treatment (Scheifer et al., 2004). With the objective to elucidate the role of glutamatergic pathways using small animal PET imaging, this study aims to use several PET imaging agents as tracers in a knock-in model of Huntington's disease.

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Remote controlled miniaturized radiotracer injection device for dynamic PET imaging in free running small animals. 01/04/2019 - 30/03/2020

Abstract

In this project, a miniaturized injection device will be developed. The injection device will be carried by a rat and will be operated by remote control to perform an intravenous bolus injection (0.5 ml / min) in the rat via a catheter in the jugular vein. The injection device will be used for the injection of a radio-tracer into the animal while being in the scanner during the dynamic brain imaging of awake, free-running animals. Since access to the scanner is limited due to the small bore size, the injection must be delivered through a miniature injection device that can be carried by the rat. The aim of the project is to be able to extend our previously developed methodology of brain imaging in free-running animals to dynamic scans where the animal is injected while it is in the scanner. Previously, our imaging in awake animals was only performed after the animals were injected outside the scanner. However, these post-injection scans are less useful for quantitative biomedical research in neuroscience. By developing the automated injection device, we will be able to perform the more relevant dynamic PET scans in free-running animals. In this way we can scan free running animals and we can avoid the influence of anesthesia (as used for PET imaging of small animals) on the brain and thus the measurement results. The usability of the injection device will be demonstrated in a dynamic PET test-retest study in rat in which dopamine receptors will be visualized using [11C]raclopride, a D2 receptor antagonist.

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Imaging synaptic plasticity in therapeutic sleep deprivation for major depression (SleepLess). 01/05/2018 - 30/04/2021

Abstract

Patients with major depression benefit from therapeutic sleep deprivation. The causality of this clinically effective therapeutic measure is unknown; there is particularly only rare information about the underlying molecular mechanisms. We hypothesize that prolonged wakefulness is associated with an increase in synaptic strength, and that the synaptic dysregulation is affecting long term potentiation in patients with major depression. The aim of the project is to examine the synaptic basis of the antidepressant effect of therapeutic sleep deprivation by Positron Emission Tomography (PET) imaging of the synaptic vesicle protein 2A (SV2A) as a measure of synaptic density in patients and healthy subjects as well as animal models of depression. Since both anesthesia and sleep are subject to compromise biologically valid outcomes when studying the synaptic basis of therapeutic sleep deprivation, a fully quantitative PET imaging method for awake animals will be developed. We are convinced that synaptic density determined with PET has the power to become an indicator for the success of therapeutic sleep deprivation and thus providing means for future stratifications of different therapies in major depression. Identifying and understanding the mechanisms that mediate the effects of sleep restriction is necessary to develop effective interventions. This project will test a model that can be used to improve schedule design.

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Translocator protein expression in animal models of temporal lobe epilepsy and Huntington's Disease. 01/10/2017 - 30/09/2019

Abstract

Epilepsy is a devastating disorder affecting 65 million people worldwide characterized by recurrent seizures. This research project will investigate a novel hypothesis connecting translocator protein (TSPO) overexpression, a hallmark of brain inflammation, and spontaneous seizure outcome during the development of epilepsy (epileptogenesis). Our hypothesis is supported by the observation that i) TSPO is highly up-regulated in epilepsy and ii) our preliminary data suggest a relationship between TSPO overexpression and spontaneous seizure outcome. Unraveling this relationship will enable us to assess TSPO as a biomarker for maladaptive neuroplasticity during epileptogenesis. Firstly, by means of translational techniques, we will investigate longitudinally the pattern of TSPO expression during epileptogenesis in vivo in the kainic acid-induced status epilepticus (KASE) model. Secondly, the role of TSPO in epileptogenesis will be investigated by the study of the effects of the absence of TSPO in the TSPO knockout mouse, and by pharmacological stimulation of TSPO in the KASE model. This innovative project will increase our understanding of brain excitability during epileptogenesis offering a biomarker to identify patients at risk and moving the field forward giving a contribution to the development of therapies to prevent acquired epilepsy.

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    Non-invasive motion tracking and motion adaptive resolution modeling for awake rat brain positron emission tomography. 01/01/2017 - 31/12/2020

    Abstract

    Small animal positron emission tomography (PET) imaging is an indispensible tool for basic research, drug discovery and development. However, in contrast to clinical scanning, animals need to be immobilized during the scan using anesthetics. Unfortunately, in neuroscience experiments, these anesthetics can alter and obscure the outcome of the PET study. Therefore, we are developing techniques to enable PET scanning of awake and unrestrained rats. The technique will measure the position and motion of the rat's head during the PET scan so that a PET image can be formed as if the rat did not move. We will develop minimally and non-invasive techniques to measure this motion. Compared to the current invasive method that uses a large checkerboard marker these methods have many advantages: it does not introduce animal stress, is less prone to errors due to skin motion and can be used in scanners with small scanner bores. These novelties will boost the practicality and relevance of awake rat brain PET. Secondly, we will develop motion adaptive correction methods that will improve the resolution of the PET images. By doing so the image quality of the motion corrected image will have a resolution that is comparable to the resolution that can be obtained from a scan without motion. Finally, we will extend our method to measure head motion of two rats simultaneously while being scanned. This will, for the first time, let us investigate live animal interaction with PET imaging.

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      Non-invasive motion tracking for awake rat brain positron emission tomography with in vivo validation. 01/01/2017 - 31/12/2019

      Abstract

      Small animal positron emission tomography (PET) imaging is an indispensible tool for basic research, drug discovery and development. However, in contrast to clinical scanning, animals need to be immobilized during the scan using anesthetics. Unfortunately, in neuroscience experiments, these anesthetics can alter and obscure the outcome of the PET study. Therefore, we are developing techniques to enable PET scanning of awake and unrestrained rats. The technique will measure the position and motion of the rat's head during the PET scan so that a PET image can be formed as if the rat did not move. We will develop minimally and non-invasive techniques to measure this motion. One method is based on miniscule radioactive point sources that are pasted on the animal's head; the other makes use of a 3D optical camera. These novelties will boost the practicality and relevance of awake rat brain PET. Compared to the current invasive method that uses a large checkerboard marker these methods have many advantages: it does not introduce animal stress, is less prone to errors due to skin motion and can be used in scanners with small scanner bores. A full- scale small animal experiment visualizing the brain response to amphetamine will demonstrate the practicality of the method and show the impact of awake versus anesthetized scanning. The new tracking techniques and the in vivo validation will finally establish awake and unrestrained small animal PET imaging as a valid imaging protocol.

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        PET imaging of free running rats with a high resolution human scanner for simultaneous behavioral neuroscience and imaging 01/04/2016 - 31/03/2017

        Abstract

        The feasibility to perform brain PET imaging in free running rats on the high resolution research tomograph (HRRT) is investigated. With its high resolution (2.5 mm) and large field-of-view (FOV) (31x25 cm transaxial x axial) this dedicated human brain scanner would be particularly suited to image free running rats in a large FOV. This study will open the way, for the first time, to simultaneous behavioral and PET imaging experiments in rat. We will make use of our rat brain tracking and motion correction technology that was developed to scan awake rats on small animal PET scanners with much smaller FOV. We will adapt this technology to enable the methodology to work with scanners with a larger FOV where the animals have much more movement freedom.

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          Translocator protein expression in an animal model of temporal lobe epilepsy. 01/10/2015 - 30/09/2017

          Abstract

          Epilepsy is a devastating disorder affecting 65 million people worldwide characterized by recurrent seizures. This research project will investigate a novel hypothesis connecting translocator protein (TSPO) overexpression, a hallmark of brain inflammation, and spontaneous seizure outcome during the development of epilepsy (epileptogenesis). Our hypothesis is supported by the observation that i) TSPO is highly up-regulated in epilepsy and ii) our preliminary data suggest a relationship between TSPO overexpression and spontaneous seizure outcome. Unraveling this relationship will enable us to assess TSPO as a biomarker for maladaptive neuroplasticity during epileptogenesis. Firstly, by means of translational techniques, we will investigate longitudinally the pattern of TSPO expression during epileptogenesis in vivo in the kainic acid-induced status epilepticus (KASE) model. Secondly, the role of TSPO in epileptogenesis will be investigated by the study of the effects of the absence of TSPO in the TSPO knockout mouse, and by pharmacological stimulation of TSPO in the KASE model. This innovative project will increase our understanding of brain excitability during epileptogenesis offering a biomarker to identify patients at risk and moving the field forward giving a contribution to the development of therapies to prevent acquired epilepsy.

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          Research team(s)

          Prototyping and validation of a system for unrestrained awake brain PET imaging of small laboratory animals. 01/10/2015 - 30/09/2016

          Abstract

          Molecular imaging of small laboratory animals typically involves a restraining procedure to avoid movement during the imaging scan. To reduce the impact of stress, animals are anesthetized, but the latter largely influences brain physiology. The current project aims to develop a prototype for awake unrestrained small animal brain positron emission tomography (PET) imaging to better mimic the clinicalsituation where human patients are seldom sedated.

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            Standardized SUV quantification methods in 18F-FDG microPET imaging of rat brains 01/02/2014 - 31/12/2014

            Abstract

            A simplified FDG-uptake measure for small animal brain PET imaging that correlates with metabolic glucose consumption irrespective of body weight is investigated. It is an alternative to the widely used standardized uptake value (SUV) for which we observe a (unwanted) correlation with animal weight. The investigated measure does not require dynamic imaging or excessive blood sampling and is therefore practical feasible for longitudinal imaging.

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              Functional imaging and analysis of tumors (FIAT). 01/01/2014 - 31/12/2015

              Abstract

              The FIAT consortium will make concrete improvements to quantitative functional imaging of tumours, which will be incorporated in clinical and preclinical application packages, clinical software modules, image analyses and ultimately routine clinical procedures.

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                Development of Temporal Separation Methods for Simultaneous Dual Tracer PET Imaging with in vivo Validation for Applications in Oncology and Neurology. 01/01/2013 - 31/12/2015

                Abstract

                In this project we will develop new methods to be able to image two PET tracers at the same time during a single acquisition. The method uses the temporal changes of the tracer distribution to decode the two images formed by the two different tracers.

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