Research team

Expertise

in vitro and in vivo preclinical research in experimental animal models of neurological and psychiatric diseases including epilepsy (kainic acid, traumatic brain injury), schizophrenia and Alzheimer's, investigation of brain inflammation, autoradiography/histology, behavioral phenotyping (video-EEG monitoring, pre-pulse inhibition), preclinical PET imaging and evaluation of new drugs (functional in vivo readouts).

Long term in vivo follow-up of PET biomarkers in neurological disease models. 01/12/2015 - 19/09/2017

Abstract

The aim of the project is to i) set-up chronic animal models for different neurological diseases, ii) to establish specific, but also common biomarkers for these diseases using in vivo imaging modalities (focusing on small animal PET imaging) and validation with histological techniques, iii) follow-up disease progress using these in vivo biomarkers in conjunction with bio-imaging, and iv) to evaluate treatment response using these in vivo biomarkers with bio-imaging.

Researcher(s)

Research team(s)

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.

Researcher(s)

Research team(s)

The role of the extracellular matrix proteases MMP-9 and uPA in the development of posttraumatic epilepsy following traumatic brain injury. 01/10/2015 - 30/09/2017

Abstract

We propose a novel hypothesis for the development of PTE with a central role for ECM modulating components MMP-9 and uPA. TBI results in blood-brain barrier disruption, hyperexcitability and primary damage triggering repair mechanisms such as modulation of the ECM by proteases MMP-9 and uPA. These alterations in ECM proteases MMP-9 and uPA, followed by brain inflammation, induce abnormal synaptic remodeling and epileptogenesis, ultimately leading to PTE.

Researcher(s)

Research team(s)

The Extracellular Matrix in Epileptogenesis (ECMED). 01/01/2015 - 31/12/2018

Abstract

This project brings together considerable expertise from academic and industry partners in the biology of the extracellular matrix (ECM) with experts in epilepsy research. This, therefore, represents a truly collaborative effort to determine not only the role of the ECM in the development of epilepsy but also novel approaches to treat and to prevent epilepsy.

Researcher(s)

Research team(s)

Prolyl oligopeptidase: partners and pathways in neuronal function and neurodegeneration. 01/01/2015 - 31/12/2018

Abstract

In this project we aim (1) to characterize at the molecular level the role of PREP in hallmark processes of neurodegenerative disease: neuronal death, synapse loss and neuroinflammation; and (2) to investigate whether PREP-inhibitors can be used to modulate these processes.

Researcher(s)

Research team(s)

Translocator protein expression in an animal model of temporal lobe epilepsy: picturing a Janus face? 01/12/2014 - 30/09/2015

Abstract

Epilepsy is a devastating disorder affecting 50 million people worldwide characterised by recurrent seizures and serious psychiatric comorbidities such as anxiety and depression. This research proposal will investigate a novel hypothesis connecting brain inflammation and neurosteriod alterations as protagonists during the development of epilepsy and its comorbidities a process termed epileptogenesis. These former pathways are shown to have bimodal effects on seizure susceptibility, but up till now have only been investigated independently. Our hypothesis of coupling these pathways is supported by the observation that i) the translocator protein (TSPO) a marker of brain inflammation is highly upregulated in epilepsy and ii) the main function of TSPO is cholesterol import, the rate-limiting step in steroidogenesis. Firstly, we will for the first time investigate the brain region and cell specific distribution pattern of TSPO during epileptogenesis and established epilepsy in two rat models of acquired epilepsy. Secondly, pharmacological agents will be used to interfere with TSPO and brain inflammation to investigate a causal relationship between TSPO and epileptogenesis by means of translational techniques namely in vivo TSPO PET imaging, behavioural tests and video-EEG monitoring in a rat model of temporal lobe epilepsy. This innovative project will increase our understanding of the ambiguous complexities related to brain inflammation- and neurosteriod-induced effects on brain excitability potentially revealing an interrelated action. If the proposed hypothesis holds true, this may influence our current thinking regarding the role of brain inflammation in epilepsy and psychiatric conditions.

Researcher(s)

Research team(s)

Development of an in vivo microPET imaging platform for the non-invasive investigation of novel therapeutics in Alzheimer's disease. 01/01/2014 - 31/12/2017

Abstract

This research project aims to improve the predictive value of preclinical animal studies through the implementation of small animal PET imaging (microPET). By employing transgenic mouse models that recapitulate certain pathological hallmarks of Alzheimer Disease we will validate and optimize a number of non-invasive biomarkers for disease monitoring.

Researcher(s)

Research team(s)

    Translocator protein expression in acquired models of epilepsy: picturing a Janus face? 01/01/2014 - 31/12/2016

    Abstract

    Epilepsy is a devastating disorder affecting 50 million people worldwide. This research project will investigate a novel hypothesis connecting brain inflammation and neurosteriod alterations as key processes during epileptogenesis. These two pathways are shown to have bimodal effects on seizure susceptibility, but up till now have only been investigated independently.

    Researcher(s)

    Research team(s)

    Translocator protein expression in temporal lobe epilepsy: picturin a Janus face? 01/01/2014 - 31/12/2014

    Abstract

    Epilepsy is a devastating disorder affecting 50 million people worldwide. This research project will investigate a novel hypothesis connecting brain inflammation and neurosteriod alterations as key processes during epileptogenesis. These two pathways are shown to have bimodal effects on seizure susceptibility, but up till now have only been investigated independently.

    Researcher(s)

    Research team(s)

    The role of the extracellular matrix proteases MMP-9 and uPA in the development of posttraumatic epilepsy following traumatic brain injury. 01/10/2013 - 30/09/2015

    Abstract

    We propose a novel hypothesis for the development of PTE with a central role for ECM modulating components MMP-9 and uPA. TBI results in blood-brain barrier disruption, hyperexcitability and primary damage triggering repair mechanisms such as modulation of the ECM by proteases MMP-9 and uPA. These alterations in ECM proteases MMP-9 and uPA, followed by brain inflammation, induce abnormal synaptic remodeling and epileptogenesis, ultimately leading to PTE.

    Researcher(s)

    Research team(s)

    NEURON II - Proteolytic remodeling of the extracellular matrix in aberrant synaptic plasticity underlying epilepsy evoked by traumatic brain injury (TBI Epilepsy). 01/01/2013 - 31/12/2015

    Abstract

    In the present project we aim at testing a hypothesis that MMP-9 and uPA/uPAR contribute to circuitry remodeling during post-traumatic epileptogenesis. We focus on those two molecular systems, because there is a strong support for their involvement in other models of epileptogenesis, as well as the partners of this consortium have excellent tools and expertise to investigate these molecules.

    Researcher(s)

    Research team(s)

    Immuno-positron emission tomography as a potential biomarker for diagnosis and treatment in Alzheimer disease. 01/07/2012 - 30/06/2014

    Abstract

    This project represents a formal research agreement between UA and on the other hand a private institution. UA provides the private institution research results mentioned in the title of the project under the conditions as stipulated in this contract.

    Researcher(s)

    Research team(s)

    Investigation of functional and structural brain abnormalities utilizing multimodal brain imaging in a neurodevelopmental animal model with relevance to schizophrenia. 01/01/2012 - 31/12/2015

    Abstract

    The current project will follow the development of neuroinflammation together with functional brain integrity and behavioural outcome in a rodent model of maternal immune activation in vivo utilising state-of-the-art multimodal imaging biomarkers.This project will generate highly novel information about the contribution of neuroinflammation to the development of schizophrenia and its consequences for the functional integrity of the brain, and eventually provide a rationale for the implementation of novel disease-modifying strategies.

    Researcher(s)

    Research team(s)

    Characterisation of neuroinflammation in an epilepsy model by means of longitudinal in vivo PET/MRI imaging. 01/01/2012 - 31/12/2014

    Abstract

    Various brain injuries in humans are associated with the acute occurrence of seizures and an increased risk of developing epilepsy after a latent period. An important feature regulating the reorganization of the neuronal network after the occurrence of a neuronal insult is neuroinflammation. Most recently, the hypothesis has been postulated that inflammatory processes within the brain mght constitute a common and crucial mechanism in the pathophysiology of seizures and epilepsy. Advances in small animal imaging allow researchers, for the first time, to study structural and functional changes during the development of epilepsy in living animals. This comprehensive innovative project will develop thorough in vivo methodologies with histological validation in a rodent model for temporal lobe epilepsy. Following, a longitudinal study will allow investigating the development of structural brain abnormalities and neuroinflammation in relation to the occurrence of epileptic seizures utilising in vivo PET/MRI imaging. In a last phase, the project will set a translational framework for evaluating novel anti-inflammatory therapies using a multimodal imaging approach, which will facilitate transferring knowledge from bench to bed. Briefly, this project may lead to novel diagnostic imaging biomarkers for the identification of patients at risk and provide rationale for neuroprotective treatment strategies.

    Researcher(s)

    Research team(s)

    Characterisation of brain inflammation in an epilepsy model by means of longitudinal in vivo PET/MRI imaging. 01/01/2012 - 31/12/2012

    Abstract

    The neurobiological processes that eventually result in epilepsy are still not completely understood. It is well known that brain injuries such as neurotraumata, febrile seizures, infection and status epilepticus are associated with the acute occurrence of seizures and a higher risk of developing epilepsy after a latent period. Recent studies strongly support the hypothesis that brain inflammation plays an important role in the pathophysiology of seizures and epilepsy. The asset of this comprehensive study is that it will employ the recent progress made in non-invasive small animal imaging to characterize brain inflammation in a chronic epilepsy model. First of all the project aims to characterize this process by traditional postmortem techniques. In the following step in vivo methodologies will be developed with histological validation to assess brain inflammation, brain activity and structural brain abnormalities. In the next step, structural changes in the brain together with inflammation will be longitudinally followed up during the development of epilepsy in living animals by PET/MRI imaging. Finally, the effect of different pharmacological interventions on brain inflammation will be investigated by PET/MRI imaging. Thus, this project will lead to a better understanding and characterization of the role of brain inflammation in epilepsy, which will impact development and evaluation of novel treatment strategies in the field.

    Researcher(s)

    Research team(s)

    Longitudinal in vivo follow-up of PET biomarkers in neurological disease models. 01/07/2011 - 31/12/2015

    Abstract

    Chronic neurological diseases such as epilepsy and schizophrenia are difficult to manage and severely disabling disorders. Moreover, they are putting a huge burden on our social health care system. Currently, there is no available therapy that effectively halts or retards the development or progression of these conditions. The more we learn, the more it becomes clear that these neurological diseases are extremely complex as they do not have a well-understood mechanism of action and perhaps diverging dysfunctions, with evolving temporal and spatial aspects, may contribute to the disease. Remarkably, the manifestation of both diseases is preceded by a seemingly "silent" or "latent" period of several years without any apparent symptoms. Interestingly, scientific research suggests that this could be related to a neuronal insult during a critical phase of life, which initiates a series of pathophysiological processes during the latent period. At current, little research has been directed to investigate the latent period. As in patients, the chronic stage of the disease is represented rather than the early stage, the human research endeavour has been limited due to the difficulty to set-up these type of long-term prospective studies. As a consequence, our understanding of the processes occurring during this critical phase of the development of the disorder is incomplete. For instance, it is unknown what factors contribute to the phenomenon that only a subgroup of individuals will eventually be affected by the disorder. A better insight in these events could potentially lead to early identification of patients at risk. It has been speculated that neuroinflammation plays an important role in the reorganisation of the neuronal network after the occurrence of a traumatic event. The current project will follow the development of neuroinflammation together with the investigation of the functional integrity of the brain in laboratory animals utilising imaging biomarkers. The recent advances in dedicated in vivo imaging techniques for small animal brain imaging, such as positron emission tomography (PET), allow scientist for the first time to conduct basic research in a non-invasive and longitudinal manner, facilitating translation of knowledge from bench side to clinical application. This study will add very important new information about the contribution of neuroinflammation to the development of neurological disorders such as epilepsy and schizophrenia, its consequences for the functional integrity of the brain and whether these biomarkers could contribute to the early identification of patients as risk. Non-invasive imaging using biomarkers is an upcoming and promising new approach, which clearly allows for translation of applications to the clinic. The outcomes of this research will inform clinical practice, particularly providing rationale for the implementation of potentially neuroprotective strategies to slow down or halt this degeneration, as well as potentially providing a method to assess the biological efficacy of prospective new therapies prior to the institution of expensive human trials.

    Researcher(s)

    Research team(s)

    Long term in vivo follow-up of PET biomarkers in neurological disease models. 01/12/2010 - 30/11/2015

    Abstract

    The aim of the project is to i) set-up chronic animal models for different neurological diseases, ii) to establish specific, but also common biomarkers for these diseases using in vivo imaging modalities (focusing on small animal PET imaging) and validation with histological techniques, iii) follow-up disease progress using these in vivo biomarkers in conjunction with bio-imaging, and iv) to evaluate treatment response using these in vivo biomarkers with bio-imaging.

    Researcher(s)

    Research team(s)