Research team

Neurochemistry and behaviour

Expertise

1) Metabolic and neurochemical analyses 2) Behavioural phenotyping of mouse models and preclinical evaluation of symptomatic and preventive therapeutic interventions in validated transgenic mouse models for Alzheimer's disease 3) Diagnostic reference centre for biomarkers in dementia 4) Scientific consulting 5) Brain banking

Prediction of conversion to Alzheimer's disease in Down syndrome: a behavioural and neurochemical approach. 01/01/2018 - 31/12/2021

Abstract

Alzheimer's disease (AD) and related dementias are degenerative and irreversible brain illnesses characterized by memory loss, behavioral and psychological signs and symptoms of dementia (BPSD), and an (over)activated neuroimmune response. Interestingly, people with Down syndrome (DS), a congenital disorder, face accelerated aging and are at high risk to develop AD over time; 50- 70% of the DS individuals develop AD. Earlier AD diagnosis and/or prediction of conversion to AD is essential for adaptive caretaking and adequate treatment interventions. BPSD in AD patients are diagnosed using validated rating scales. However, no BPSD scales are available for DS. Therefore, our first aim is to validate and longitudinally apply our recently developed BPSD scale specifically adapted for DS in cohorts of DS patients with and without dementia. Concentration changes in biogenic amines, i.e. neurotransmitters and their metabolites, have been associated with BPSD. We previously discovered that the serum concentration of the monoaminergic neurotransmitter metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) can predict the development of AD in DS. The current project aims to investigate the biological functionality of the monoaminergic neurotransmitter system in human brain, blood and CSF samples. We will also study in detail how brain pathology typical for AD, develops in DS, whether locus coeruleus pathology is observed and how these link to neurotransmitter changes and patients' symptoms.

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Monoaminergic and neuroinflammatory markers in dementia with Lewy bodies to improve differential dementia diagnosis. 01/11/2019 - 30/11/2020

Abstract

Due to overlapping clinical and pathological features, the differential diagnosis between dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) becomes extremely difficult. Besides, there still is no approved treatment for DLB. The current application, therefore, aims at identifying neurochemical markers in blood (serum) and cerebrospinal fluid (CSF) to improve the diagnostic accuracy among these syndromes. Based on our previous data, DLB-specific alterations in the locus coeruleus, a small noradrenergic brainstem nucleus, may provide rationale to address these challenges. The same goes for the neuroinflammatory marker lipocalin-2 (LCN2), of which expression levels in the substantia nigra are increased. Overall, this proposal intends to (i) analyze various neurochemical compounds in serum/CSF as potential disease-specific biomarkers with a demonstrated link to underlying brain pathology. Here, our main focus will be on the noradrenergic neurotransmitter system (3-methoxy-4-hydroxyphenylglycol; noradrenaline) and LCN2. We will also study in detail (ii) if these marker alterations are associated with the clinical follow-up diagnosis and measured noradrenergic tracer uptake values after MIBG-scintigraphy. Finally, this study will (iii) meticulously process and analyze brain material, allowing us an in-depth evaluation of the regional distribution of alfa-synuclein and AD-related pathology, linked to the monoaminergic and neuroinflammatory markers previously determined.

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GPCR dimerization in AD: From brain expression to therapeutic potential. 01/05/2018 - 30/04/2019

Abstract

GPCR targets are considered highly "druggable" and a growing interest in GPCRs forming hetero- or homodimers as possible new pharmacological targets in a variety of diseases, including AD and related dementias, has been expressed. The translation of GPCR heterodimers and mosaics to pharmaceutical drug discovery and development is however in its infancy and hampered by the lack of appropriate tools to study these bioconjugates, as well as insufficient understanding of which interactions are important and (patho)physiologically relevant. This project will provide a systematic screening of GPCR expression and subcellular localisation in human brain tissue, as well as in a valid amyloidosis mouse model. Latter model will be applied to provide the very first proof-of-concept that targeting an AD-relevant GPCR heterodimer with a bivalent ligand may provide a novel therapeutic approach that could cause a major shift in AD treatment.

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Financial support for animal-based research of dementia. 01/12/2016 - 30/11/2017

Abstract

Operating grant financed by the Institute Born-Bunge for conducting animal-based research on dementia and other brain disorders. The operating grant will mainly finance the necessary staff (and possibly limited research-related costs).

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Unravelling monoaminergic alterations in Alzheimer's disease in Down Syndrome. 01/01/2016 - 31/12/2017

Abstract

Down syndrome (DS), or trisomy 21, is the most common genetic cause of intellectual disability in humans. In addition, 50-70% of the DS individuals develops dementia due to AD before the age of 70. Studying mechanisms in DS does not only contribute to unravelling the pathophysiology in DS, but may also substantially aid to the understanding of AD. Predicting the progression of AD in DS is a major challenge in clinical practice and essential for adaptive caretaking and therapeutic interventions. We hypothesize that accurate recognition of behavioural and psychological symptoms of dementia (BPSD) may improve early identification of those at risk, and provide a non-invasive way to monitor the course to dementia. Elucidating the underlying neurobiological mechanisms further aids novel target identification for goal-directed drug development. While cognitive decline in AD cannot be prevented, specific behavioural symptoms can be reduced, thus improving the quality of life. BPSD in AD patients are diagnosed using validated questionnaires, but unfortunately, no BPSD scales are available for DS. Concentration changes in monoaminergic systems have been associated with BPSD (for example in AD). To that end, we previously quatified the levels of eight biogenic amines and their metabolites in serum of DS subjects with AD, without AD and a non-demented group that converted to AD over time. Our observations indicate that serum MHPG levels might serve a predictive biomarker for conversion to AD in DS. The major aims are therefore to (1) develop a scale for BPSD in DS, which takes DS-specific circumstances into account, (2) validate our previously reported findings on altered serum concentrations of monoaminergic neurotransmitters in relation to the status of dementia and behavioural correlates in DS, and, (3) unravel the central cause(s) of the altered monoaminergic concentrations, and MHPG in particular, in selected post mortem DS brain regions (with/without AD).

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D-SCOPE: Detection - Support and Care of Older People in their Environment. 01/01/2015 - 31/12/2018

Abstract

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

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Unravelling the pharmaceutical potential of receptor heterodimers for therapeutic intervention in CNS disorders. 01/01/2015 - 31/12/2017

Abstract

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

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Research in the field of neurochemistry. 01/10/2012 - 30/09/2013

Abstract

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

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An integrated approach towards understanding the pathogenesis of neurodegeneration (NEUROBRAINNET). 01/04/2012 - 31/12/2017

Abstract

We aim to establish an integrated network to identify genes and proteins involved in neurodegenerative disorders, determine their biological functions, establish their role in the pathophysiological processes, identify modifiers of the function by genetic screens, The network meets the prerequisites for such a project: frontline research in functional genomics related to human health, creating synergies with and between research efforts, teaming up with clinical groups through translational research for providing novel avenues for diagnosis, prevention, treatment and providing training and mobility to improve the skills of our young researchers.

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Models of cerebellar disease: preclinical and clinical. 01/10/2011 - 30/09/2016

Abstract

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

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Pathophysiological mechanisms in amyloidosis mouse models. 01/10/2011 - 30/09/2014

Abstract

Alzheimer's disease (AD) is the most frequent form of neurodegenerative disease resulting in progressive loss of memory and cognitive abilities. AD is vastly becoming a major medical and social-economical problem in our ageing society. In Europe alone, approximately 7 million people suffer from AD. Despite intense research, pathophysiological mechanisms underlying AD and related disorders are still insufficiently documented. Valid animal models are essential in research ensuing elucidation of human disease processes and testing of potential therapeutic strategies. The valid APP23 transgenic mouse model will be used to further study underlying pathophysiological mechanisms related to soluble aggregates of the amyloid-beta peptide and reactivation of the cell cycle in neurons, with presumed effects at the neurochemical, electrophysiological, morphological and behavioural level. In addition, a model for vascular dementia will be developed by crossing APP23 mice with atherogenic ApoE knockout mice. Based on parallel genetic and environmental risk factors, pathophysiological aspects, and response to therapeutic interventions, it is assumed that convergent disease processes are the basis of AD and atherosclerosis. Behavioural, biochemical and pathological assessments will shed more light onto the link between AD and atherosclerosis, as well as the role of the amyloid precursor protein in atherosclerosis.

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Biobanking and mib dementia of Alzheimer's and glaucoma. 15/09/2011 - 30/09/2018

Abstract

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

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Multiple Sclerosis, a multidisciplinary approach. 01/01/2010 - 31/12/2019

Abstract

The FWO WOG Multiple Sclerosis is a network that brings together Flemish scientists and clinicians researching multiple sclerosis (MS) and other neurodegenerative diseases. MS is a demyelinating disorder of the central nervous system with an inflammatory and neurodegenerative component. It is the most common neurological disorder in young people in Western Europe that affects about 1 in 1000 people. The disease is incurable and has a major medical and socio-economic impact. Current medication remains ineffective and often has serious side effects. Given the complexity of the disease, and the disappointing progress in the development of efficacious medication, a drastic change is required in the scientific approach. In this context, teams with scientific expertise in multidisciplinary aspects must work together in a multi- and interdisciplinary way to gain insight into the disease mechanism and to develop better treatments. Although there was already a strong network of MS research groups in neighboring countries, this was not the case in Flanders until the establishment of the FWO WOG-MS, although several excellent Flemish research groups work on different aspects of MS. To promote cooperation and interaction between these groups, the WOG-MS was established in 2010 using FWO funding. This has led to a strong growth of cooperation among the participating research groups. This is evident from the joint project applications, publications and the multiple exchange of pre- and postdoctoral researchers. In addition, this has led to increased interaction with Flemish clinical centers, foreign MS networks and MS patients. The establishment of the FWO WOG-MS has ensured that MS research in Flanders currently has a greater international reputation. The FWO funding for the research community enables us to strengthen the network by expanding the collaboration between the partner groups and increasing the national and international visibility of the network. It is becoming increasingly clear that proper insight into all aspects of MS is essential for the development of more effective therapies. Consultation between groups that investigate different aspects of the disease through a multidisciplinary approach will therefore lead to innovative insights and efficient development of more targeted therapies.

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Characterisation of new targets for the treatment of the fragile X syndrome. 01/01/2010 - 31/12/2011

Abstract

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

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Characterization and validation of biological markers of dementia and mild cognitive impairment 01/10/2009 - 30/09/2011

Abstract

Mild cognitive impairment (MCI) is a clinical heterogeneous syndrome that is characterised by memory problems or other cognitive complaints that are not severe enough to fulfil the diagnostic criteria of dementia. The diagnosis of MCI refers to a state intermediate between normal ageing and dementia. Yearly, approximately 12% of the MCI patients convert to dementia, mostly AD, although a number of MCI patients remain stable or even improve and do not convert to dementia at all. Development of biological markers as an early diagnostic tool for the diagnosis of dementia (in particular Alzheimer's disease) is of increasing importance given the future availability of disease-modifying drugs. This research project aims at the identification of genetic (APOE) and biological markers (proteins such as ß-amyloïd, tau and phospho-tau in easily accessible body fluids like cerebrospinal fluid and blood plasma) with a predictive value for conversion to dementia in MCI patients. Furthermore, the discriminatory power of these biomarkers for the differential diagnosis of dementia will be investigated. Patients will undergo thorough behavioural, genetic, neurochemical and neuropathological testing, providing us with a well-characterized study population.

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Neurochemical characterization of behavioral disturbances in dementia. 01/10/2009 - 30/09/2010

Abstract

Behavioral disturbances (Behavioral and psychological signs and symptoms of dementia, BPSD) are an indispensable part of dementia and consist of delusions, hallucinations, aggressiveness, activity disturbances, diurnal rhythm disturbances, affective disorders and anxieties/phobias. Research has repeatedly confirmed that there is a neurochemical basis underlying BPSD although the pathophysiology remains unclear. In this project ante-mortem behavioral data will be correlated with neurotransmitter concentrations from regional dissection of post-mortem brain tissue of patients with various forms of dementia. Changes in different neurotransmitter systems will be mutually compared between different diagnostic categories of dementia in order to unravel possible neurochemical changes that predispose to certain behavioral profiles.

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An integrated approach towards understanding the pathogenesis of CNS and PNS disorders. 01/01/2008 - 31/12/2014

Abstract

The research activity in the research excellence centre NEURO focuses on molecular genetics and clinical neurology of neurodegenerative diseases comprising diseases of the central nervous system such as Alzheimer disease, Parkinson disease, frontotemporal dementia, amyotrophic lateral sclerosis, multiple sclerosis and related diseases; and of the peripheral nervous system such as motor- and/or sensory neuropathies and related disorders. The centre brings together basic and clinical researchers from the Department of Molecular Genetics, VIB, and the Institute Born Bunge, representing two major neuroresearch activities at the University of Antwerp. The general aim of the excellence centre aims at clarifying a series of fundamental questions related to the pathophysiological processes underlying neurodegenerative diseases. More specifically, the elucidation of biological disease pathways by identifying novel genes and genetic risk factors and modifiers of genetic function, by analysing the functional networks in which proteins encoded by these genes are operating, and ultimately, by providing novel avenues for early diagnosis, prognosis, prevention and treatment.

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Identification of clinical characteristics and biomarkers with a predictive value for conversion to dementia in patients with mild cognitive impairment. 01/01/2008 - 31/12/2009

Abstract

Mild cognitive impairment (MCI) is a heterogeneous clinically syndrome. Patients suffering from MCI have an increased risk to develop dementia. The aim of this research project is the identification of clinical characteristics (behavioural profiles) and biomarkers (APOE genotype and ¿-amyloïd1-42, total tau and tau phosphorylated at serine 181 in cerebrospinal fluid) with a predictive value for conversion to dementia in MCI patients.

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Biochemical, electrophysiological and ultrastructural analysis of neurotoxic APP cleavage products in transgenic mouse models for amyloidosis. 01/10/2007 - 30/09/2011

Abstract

This is a fundamental research project financed by the Research Foundation - Flanders (FWO). The project was subsidized after selection by the FWO-expert panel.

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Characterization and validation of biological markers of dementia and mild cognitive impairment. 01/10/2007 - 30/09/2009

Abstract

Mild cognitive impairment (MCI) is a clinical heterogeneous syndrome that is characterised by memory problems or other cognitive complaints that are not severe enough to fulfil the diagnostic criteria of dementia. The diagnosis of MCI refers to a state intermediate between normal ageing and dementia. Yearly, approximately 12% of the MCI patients convert to dementia, mostly AD, although a number of MCI patients remain stable or even improve and do not convert to dementia at all. Development of biological markers as an early diagnostic tool for the diagnosis of dementia (in particular Alzheimer's disease) is of increasing importance given the future availability of disease-modifying drugs. This research project aims at the identification of genetic (APOE) and biological markers (proteins such as ß-amyloïd, tau and phospho-tau in easily accessible body fluids like cerebrospinal fluid and blood plasma) with a predictive value for conversion to dementia in MCI patients. Furthermore, the discriminatory power of these biomarkers for the differential diagnosis of dementia will be investigated. Patients will undergo thorough behavioural, genetic, neurochemical and neuropathological testing, providing us with a well-characterized study population.

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Biobank (Antwerp) of the Born Bunge Institute: supporting core facilities. 01/05/2007 - 31/12/2015

Abstract

The primary research projects of the different laboratories of the IBB study Alzheimer's disease and related conditions, Parkinson's disease, frontotemporal dementias, Creutzfeld-Jacob disease, epilepsy, peripheral neuropathies and muscle disorders. The IBB focuses at a better integration and correlation of fundamental, clinical and neuropathological data concerning neurological conditions employing molecular genetics, biochemistry, experimental analyses of behavioural alterations and computational neurosciences. The IBB Biobank is a mutual initiative of the research units of the IBB department Neurology that is based upon the original brain bank.

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An integrated approach to the unraveling of the pathogenesis of CNS and PNS neurodegenerative disorders. 01/01/2007 - 31/12/2011

Abstract

This project is designed to apply the unique information provided by sequencing of the human genome to further the understanding of and to develop treatments for these devastating diseases. The association in the proposed network of research groups in clinical research, human genetics and genomics, cell biology, proteomics, bioinformatics, and model organisms (mice, zebrafish and Drosophila), will create an integrated network to identify disease genes, determine their biological functions, establish their role in the pathophysiological processes and identify novel avenues for early diagnosis, treatment and prevention.

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Transplantation of embryonic stem cell-derived neural stem cells after spinal cord injury and traumatic brain injury. 01/01/2007 - 31/12/2010

Abstract

This project will investigate whether transplantation of defined embryonic stem cell-derived neural stem cells (ES-NSC), genetically modified to secrete neurotrophic factors, can support or improve recovery after TBI and SCI. An improved recovery can be due to: A) a decreased secondary neural loss due to secretion of neurotrophic factors, and/or B) an enhanced neural recovery due to functional integration of transplanted ES-NSC and/or recruited endogenous NSC.

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    Histopathological validation and characterisation of biological markers of dementia. 01/01/2007 - 31/12/2010

    Abstract

    This research project aims at a histopathological validation and a better characterisation of neurchemical markers of dementia. This will lead to improved insights in biomarkers of dementia and their relation to the pathophysiology of dementia. The study design allows us to perform neuropathological and neurochemical analyses in different neurotransmitter nuclei of the CNS, moreover, the different neurochemical substances are analysed in CSF as well.

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    Is the GABA (A) receptor a therapeutic target for treatment of the fragile X syndrome? 01/01/2007 - 31/12/2008

    Abstract

    The fragile X syndrome is the most frequent form of hereditary mental retardation. Recently, our group found consistent underexpression of the delta subunit of the gamma-aminobutyric acid receptor type A in brains of fragile X knock out mice, a validated animal model for the fragile X syndrome. GABAA receptors are the principal inhibitory receptors of the brain and are involved in anxiety, depression, epilepsy, insomnia and learning and memory, processes disturbed in fragile X patients. This project attempts to increase our insights in the role of the GABAA receptor in the fragile X syndrome using a variety of molecular techniques. Furthermore we want to investigate whether the GABAA receptor is an appropriate target for treatment of this syndrome. A number of drugs specific for the GABAA receptor are already available on the market.

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    The predictive value of biochemical parameters among which amino acids and amino acid analogues in the prognosis of an acute ischemic cerebrovascular accident. 01/10/2006 - 30/09/2008

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    Functional peptidomics. 01/03/2006 - 28/02/2010

    Abstract

    Novel candidate bioactive peptides will be extracted from selected mouse tissues and identified by a combination of liquid chromatography and advanced mass spectrometry. We will try to assign a function to the peptides via a systematic series of analysis steps, supported by advanced data mining on a comprehensive peptide database that will include relevant public domain information as well as all project results. Thus peptides will be prioritized dynamically for experimental testing based on the best evidence available. Bioinformatics analysis will look for known hallmarks of bioactive peptides (precursor with signal peptide, flanking motifs for cleavage, sequence conservation across species, etc.) as well as newly derived properties. Such novel features may be derived from relational data mining. The bioinformatics and relational data mining tools will be developed for the peptidomics data but in such a way that they can be applied more generally to other ¿omics projects, i.e. research programmes that can be phrased in terms of a set of relevant genes. Promising peptides will be synthesized and tested on a panel of approximately 60 cell lines representative of major cell types using a method such as microphysiometry that can detect cellular activation independent of the type of activated signal transduction cascade. Because the gut is (together with the brain) the richest source of bioactive peptides, all novel peptides will also be tested in organ assays of various segments of the gastro-intestinal tract. Peptide expression will be mapped by in situ hybridization of the precursor mRNA. Peptides of sufficient interest will be radio-labeled for binding studies on tissue sections and for pharmacokinetic studies (including whole animal PET and SPECT). The pharmacokinetic studies will reveal the time-course of the peptide concentration in various compartments of interest (blood, CNS) as well as the organs where a peptide preferentially localizes. Competition with unlabeled competitors will help to distinguish whether such localization is due to the peptide binding to a specific receptor or being concentrated e.g., in an excretory system. If sufficient indications for a CNS action are found (mENA expression, peptide binding on brain sections, penetration of blood brain barrier, etc.), behavioural studies will be initiated. These again will use a multi- tiered strategy, starting with simple tests covering a variety of behavioural functions and gradually zooming in on specific functions with more specialized tests.

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    Center of excellence NEURO. 01/01/2006 - 31/12/2007

    Abstract

    The research activity in the research excellence centre NEURO focuses on molecular genetics and clinical neurology of neurodegenerative diseases comprising diseases of the central nervous system such as Alzheimer disease, Parkinson disease, frontotemporal dementia, amyotrophic lateral sclerosis, multiple sclerosis and related diseases; and of the peripheral nervous system such as motor- and/or sensory neuropathies and related disorders. The centre brings together basic and clinical researchers from the Department of Molecular Genetics, VIB, and the Institute Born-Bunge, representing two major neuroresearch activities at the University of Antwerp. The general aim of the excellence centre aims at clarifying a series of fundamental questions related to the pathophysiological processes underlying neurodegenerative diseases. More specifically, the elucidation of biological disease pathways by identifying novel genes and genetic risk factors and modifiers of genetic function, by analysing the functional networks in which proteins encoded by these genes are operating, and ultimately, by providing novel avenues for early diagnosis, prognosis, prevention and treatment.

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    Identification and characterisation of neurochemical markers for dementia. 01/01/2006 - 31/12/2006

    Abstract

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    Characterisation and validation of biological markers of dementia and mild cognitive impairment. 01/10/2005 - 30/09/2008

    Abstract

    This research project wil! establish the role and value of BAP, tau, P-tau and APOE as biomarkers in the diagnostic work up of MCI and dementia in a large population of patients of which a substantial number wil! get neuropathological confirmation of clinical diagnosis of dementia. The research project wil! moreover lead to a better characterisation of the several disease groups studied and wil! probably identify subgroups of patients with common biochemica! and/or behavioural features.

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    Molecular biological, pharmacological, neurochemical and behavioral genotyping of mice for dementia. 01/10/2005 - 30/09/2007

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    Behavioural phenotyping of transgenic mouse models for human disorders with cognitive deficits : aetiological research and innovating therapies. 01/01/2005 - 31/12/2008

    Abstract

    In the research project, different transgenic mouse lines will be studied. Behavioural phenotyping will be accomplished in collaboration with (inter)national research groups that have the indispensable experience and willingness for the construction and genotypic support of transgenic mouse lines.

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    Is the GABA (A) receptor a therapeutic target for treatment of the fragile X syndrome? 01/01/2005 - 31/12/2006

    Abstract

    The fragile X syndrome is the most frequent form of hereditary mental retardation. Recently, our group found consistent underexpression of the delta subunit of the gamma-aminobutyric acid receptor type A in brains of fragile X knock out mice, a validated animal model for the fragile X syndrome. GABAA receptors are the principal inhibitory receptors of the brain and are involved in anxiety, depression, epilepsy, insomnia and learning and memory, processes disturbed in fragile X patients. This project attempts to increase our insights in the role of the GABAA receptor in the fragile X syndrome using a variety of molecular techniques. Furthermore we want to investigate whether the GABAA receptor is an appropriate target for treatment of this syndrome. A number of drugs specific for the GABAA receptor are already available on the market.

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    Clinical and animal-experimental research of the neurochemical and behavioural aspects of 'Behavioural and Psychological Signs and Symptoms of Dementia" (BPSD). 01/10/2004 - 30/09/2006

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    01/10/2004 - 31/12/2004

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    Support of neurological and cardiovascular scientific investigation conducted by the UA by/or in association with Born-Bunge Foundation. 01/01/2004 - 31/12/2007

    Abstract

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    Identification of genetic factors involved in mild mental retardation. 01/01/2004 - 31/12/2007

    Abstract

    In contrast to severe mental retardation that is usually caused by defects in a single gene, mild mental retardation is caused by a multitude of genetic factors or QTLs. This project aims to aims to identify one QTL responsible for mild mental retardation in a mouse model. A 'dull' and a 'bright' colony will be bred starting from a single colony of outbred HS mice by repeated backcrossing while selecting for extreme learning performance. Genetic mapping will subsequently be used to identify the QTL.

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    Design and validation of a neurophysiological test of cognition in multiple sclerose. 01/10/2002 - 30/09/2006

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    Neurochemical correlates of behavioral and psychological signs and symptoms of Dementia of the Alzheimer Typen and Frontal Lobe Dementia. 01/10/2002 - 30/09/2004

    Abstract

    The aim of the present study is to trace for neurochemical correlates of BPSD in a population of DAT and FLD patients. We will focus on paranoid and delusional ideations, hallucinations, aggressiveness, affective distrubances and anxiety. Rating scales for BPSD will be used for reasons of standardization and quantification of observations. Especially serotonergic and catecholaminergic neurotransmitter systems will be studied as a physiopathological link with psychosis, aggressive behavior, depression and anxiety is presumed. As amino acid neurotransmitters have not systematically been studied in these patients related tot BPSD, we will trace for possible correlations in this field as well. Patients will be compared with age-matched controls in order to determine the disease specificity of the correlations revealed.

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    Phosphomannomutases in human and mouse : characterization of a novel gene family and establisment of a mouse model for Carbohydrate-Deficient-Glycoprotein Syndrome Type I (CDG1) 01/01/2002 - 31/12/2003

    Abstract

    Congenital disorders of glycosylation constitute a group of inborn errors of metabolism characterized by defects in N-glycosylation of cellular and serum proteins. Different types of such disorders have been described, however, the phosphomanomutase deficiency, CDG-Ia, remains the most frequent form. The human disorder CDG-Ia, which causes severe deficits of the central nervous system and other organ systems, appeared to be due to mutations in the PMM2 gene. The purposes of the present project are the study of the expression and characteristics of the PMMs, as well as the construction of transgenic murine models to examine the fuctions of the PMMs. The recently available PMM1 knockout mice have been tested in a battery of behavioral tests, and appeared to be indistinguishable from controls on all of the neurobehavioural functions tested. Construction of a PMM2 knockout is one of the main purposes of the present project, and the model will also be tested on different functions. In the behavioural study of these models, tests of different aspect of mouse behaviour will be used (locomotor activity, exploration, motor coordination, emotional responses, different forms of learning and conditioning, etc.).

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    Determination and validation of mouse models for mixed-type dementia: Alzheimer-type vascular dementia and post-traumatic dementia 01/10/2001 - 30/09/2003

    Abstract

    Dementia (including Alzheimer's disease) (AD) is the fourth most important cause of death in the developed world. Alzheimer's disease is characterized by cognitive impairment and profound behavioural changes leading to death after several years of progressive illness. At the neurochemical level, AD is characterized by a considerable loss of cholinergic neurons leading to a decrease of acetylcholine concentration in the temporal cortex and the cerebrospinal fluid. Other neurotransmitter systems (monoamines, neuropeptides, excitatory and inhibitory amino acids) also exhibit abnormalities. A conclusive diagnosis is only possible after post-mortem brain examination revealing senile plaques, neurofibrillary tangles, dystrophic neurites and neuronal cell loss in specific regions of the brain. Because of the growing group of elderly in our society, AD is a continuously growing medical and socio-economical problem. Unfortunately the exact ethiology of AD still remains unknown. The major goal of AD research is to produce animal models that exhibit pathologic and/or phenotypic features of the humans affected by the disease to learn more about its pathophysiology and to create new treatment opportunities. Mutations in different genes are thought to be related to an increased risk of developping AD. It is one of our goals to validate a mouse model that expresses a mutated 751-amino acid isoform of hAPP under the control of the neuron-specific enolase promotor of the rat. A base substitution on chromosome 21 causes a missense mutation (Val717 ? Ile717) that can be found in patients with familial AD. Behavioural testing examines possible cognitive impairment in an animal model to search for similarities between the deficits in the animals and the cognitive impairment in the human condition. Behavioural testing will be performed on 3, 6 and 12 month old mice. The model expresses low levels of hAPP and does not develop ?-amyloid deposits, and therefore it might be possible to provoke these pathological features. Recent literature states a possible connection between cholesterol, the deposition of A?, and AD. A chronic provocation will be established by putting the mice on a high fat diet (constitution: 15% cacaobutter, 0.5% cholate, 1% cholesterol, 40.5% sucrose, 10% cornstarch, 1% corn oil, and 4.7% cellulose) during 24 weeks. Head injuries cause brain damage leading to physical, cognitive, and behavioural disturbances in humans. In order to further examine this hypothesis a traumatic model of closed head injury for mice will be developed. The effects of these two provocations will be examined at the level of behaviour and cognition, and histopathological examinations will be performed as well. An important motive to generate transgenic (mouse) models is the possibility to test new therapeutic strategies. Prophylactic drugs and drugs used in the symptomatic treatment of human AD patients will be administered to the animals. Whether these drugs can prevent or diminish cognitive deficits should show up during behavioural testing following or during treatment. Since no earlier neurochemical research has been performed, the concentration of neurotransmitters in the brain of the NSE-hAPP751m-model is not known. If behavioural testing of the models reveals cognitive deficits, neurochemical testing will be carried out. Determinations will be performed electrochemically on homogenates of brain tissue after separation of substances by high pressure liquid chromatography (HPLC). The different sections of the research proposal should make it possible for us to validate the different mouse models, and if this turns out possitive these new models could be used for the testing of new pharmaceuticals.

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      01/01/2001 - 30/09/2001

      Abstract

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        Correlative behavioural studies of some animal models of dementia syndromes 01/10/2000 - 30/09/2003

        Abstract

        The proposed project will focus on a few animal models for neurocognitive disorders. The project will comprise the study of three groups of models: (1) transgenic mice expressing mutant human amyloid precursor proteïn (hAPP), a possible murine model for Alzheimer's disease; (2) transgenic mice with inactivation of the arylsulfatase A (ASA) gene (model for metachromatic leukodystrophy); (3) mice with surgically induced renal insufficiency (model for uremic encephalopathy). The behavioural assessment of these models will include tests of different aspects of mouse behaviour (incl. locomotor activity, exploration, motor coordination, emotional responses, different forms of learning and conditioning). Where possible, the behavioral observations will be related to electrophysiological (cellular electrophysiology and electro-encephalography), neuro-chemical (chromatographic analysis of amino acids, amino acid derivatives and neurotransmitters in tissues and biological fluids), & histopathological (in collaboration with workers of Janssen Research Foundation) measurements.

        Researcher(s)

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          Neurochemical correlates of behavioral and psychological signs and symptoms of Dementia of the Alzheimer Typen and Frontal Lobe Dementia. 01/10/2000 - 30/09/2002

          Abstract

          The aim of the present study is to trace for neurochemical correlates of BPSD in a population of DAT and FLD patients. We will focus on paranoid and delusional ideations, hallucinations, aggressiveness, affective distrubances and anxiety. Rating scales for BPSD will be used for reasons of standardization and quantification of observations. Especially serotonergic and catecholaminergic neurotransmitter systems will be studied as a physiopathological link with psychosis, aggressive behavior, depression and anxiety is presumed. As amino acid neurotransmitters have not systematically been studied in these patients related tot BPSD, we will trace for possible correlations in this field as well. Patients will be compared with age-matched controls in order to determine the disease specificity of the correlations revealed.

          Researcher(s)

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            Evaluation of uremic retention solutes as candidate neurotoxines. 01/01/2000 - 31/12/2003

            Abstract

            This project is characterized by a multidisciplinary approach to the study of uremic neurotoxines. In a first phase we will attempt to identify the accumulated substances by fractionation of a variety of biological fluids of renal insufficient individuals. The different fractions will consequently be tested in different in vitro and in-vivo settings (respectively on neurones in culture and in experimental animals after ICV or more localized application. Effects on neurotransmission, excitotoxicity and behavioral manifestations (e.g. epilepsy and cognition) will be investigated. In a second phase, we will study the protein binding of the identified uremic neurotoxins and will thereafter attempt to optimize the dialysability of the identified substances.

            Researcher(s)

            Research team(s)

            Studies on the fragile X gene in man and transgenic mice. 01/01/2000 - 31/12/2001

            Abstract

            By constructing new lines of transgenic mice, the physiological function of the fragile X gene and the pathogenesis of the fragile X syndrome, the most frequent form of inherited mental retardation, will be studied. A mouse fine with a point mutation (lle 304 Asn) and a mouse fine with an unstable CGG repeat in the fragile X gene will be constructed by microinjection. The mouse fine with the pointmutation is anticipated to have a more severe phenotype than the knockout mouse that we already generated and studied. The line with the elongated CGG repeats enables studies of the mechanism and timing of repeat amplification in a mouse model. In addition, biochemical studies will be performed to study the possibility that FMR1 is involved in transcription. Moreover, the effect of selected drugs on the cognitive function and behaviour of the transgenic mice will be tested.

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              Realization of simultaneous recording of electroencephalography (EEG) and Nuclear Magnetic Resonance Imaging (MRI) in epilepsy animal models in view of source localisation and detection of brain damage. 01/10/1999 - 30/09/2001

              Abstract

              The most powerful use of MRI may come from the combination of anatomic and functional MRI data with EEG information acquired simultaneously. The fMRI data can then be analyzed as a function of brain state and the EEG can serve as a trigger for acquiring fMRI-data. In the framework of this project we will develop a setup which allows to acquire simultaneous fMRI and EEG data. Also the novel Mn++ MRI technique will be combined with simultaneous recorded EEG. These simultaneous techniques will be developed on known animal models of epilepsy. Afterwards the techniques will be used to allow source allocation in new models for epilepsy.

              Researcher(s)

              Research team(s)

                Determination and validation of mouse models for mixed-type dementia: Alzheimer-type vascular dementia and post-traumatic dementia 01/10/1999 - 30/09/2001

                Abstract

                Dementia (including Alzheimer's disease) (AD) is the fourth most important cause of death in the developed world. Alzheimer's disease is characterized by cognitive impairment and profound behavioural changes leading to death after several years of progressive illness. At the neurochemical level, AD is characterized by a considerable loss of cholinergic neurons leading to a decrease of acetylcholine concentration in the temporal cortex and the cerebrospinal fluid. Other neurotransmitter systems (monoamines, neuropeptides, excitatory and inhibitory amino acids) also exhibit abnormalities. A conclusive diagnosis is only possible after post-mortem brain examination revealing senile plaques, neurofibrillary tangles, dystrophic neurites and neuronal cell loss in specific regions of the brain. Because of the growing group of elderly in our society, AD is a continuously growing medical and socio-economical problem. Unfortunately the exact ethiology of AD still remains unknown. The major goal of AD research is to produce animal models that exhibit pathologic and/or phenotypic features of the humans affected by the disease to learn more about its pathophysiology and to create new treatment opportunities. Mutations in different genes are thought to be related to an increased risk of developping AD. It is one of our goals to validate a mouse model that expresses a mutated 751-amino acid isoform of hAPP under the control of the neuron-specific enolase promotor of the rat. A base substitution on chromosome 21 causes a missense mutation (Val717 ? Ile717) that can be found in patients with familial AD. Behavioural testing examines possible cognitive impairment in an animal model to search for similarities between the deficits in the animals and the cognitive impairment in the human condition. Behavioural testing will be performed on 3, 6 and 12 month old mice. The model expresses low levels of hAPP and does not develop ?-amyloid deposits, and therefore it might be possible to provoke these pathological features. Recent literature states a possible connection between cholesterol, the deposition of A?, and AD. A chronic provocation will be established by putting the mice on a high fat diet (constitution: 15% cacaobutter, 0.5% cholate, 1% cholesterol, 40.5% sucrose, 10% cornstarch, 1% corn oil, and 4.7% cellulose) during 24 weeks. Head injuries cause brain damage leading to physical, cognitive, and behavioural disturbances in humans. In order to further examine this hypothesis a traumatic model of closed head injury for mice will be developed. The effects of these two provocations will be examined at the level of behaviour and cognition, and histopathological examinations will be performed as well. An important motive to generate transgenic (mouse) models is the possibility to test new therapeutic strategies. Prophylactic drugs and drugs used in the symptomatic treatment of human AD patients will be administered to the animals. Whether these drugs can prevent or diminish cognitive deficits should show up during behavioural testing following or during treatment. Since no earlier neurochemical research has been performed, the concentration of neurotransmitters in the brain of the NSE-hAPP751m-model is not known. If behavioural testing of the models reveals cognitive deficits, neurochemical testing will be carried out. Determinations will be performed electrochemically on homogenates of brain tissue after separation of substances by high pressure liquid chromatography (HPLC). The different sections of the research proposal should make it possible for us to validate the different mouse models, and if this turns out possitive these new models could be used for the testing of new pharmaceuticals.

                Researcher(s)

                Research team(s)

                  Collective behavioural studies of transgenic mouse. 01/10/1997 - 30/09/2000

                  Abstract

                  The project will aim at the characterisation of putative models of dementia an/or retarded cognitive development. A large number of behavioural assessment techniques will be employed, including test for active and passive avoidence learning, maze escape learning, reward conditioning, activity and neuromotor testing, social exploration, etc. The main focus will beon transgenic mouse models expressing human amyloid precursor proteins. Efforts will be directed towards the understanding of behavioural (including neurocognitive) deficits, and correlation with neurochemical alterations in neurotranmitter systems, using, amongst other things, microdialysis and HPLC.

                  Researcher(s)

                  Research team(s)

                    Realization of simultaneous recording of electroencephalography (EEG) and Nuclear Magnetic Resonance Imaging (MRI) in epilepsy animal models in view of source localisation and detection of brain damage. 01/10/1997 - 30/09/1999

                    Abstract

                    The most powerful use of MRI may come from the combination of anatomic and functional MRI data with EEG information acquired simultaneously. The fMRI data can then be analyzed as a function of brain state and the EEG can serve as a trigger for acquiring fMRI-data. In the framework of this project we will develop a setup which allows to acquire simultaneous fMRI and EEG data. Also the novel Mn++ MRI technique will be combined with simultaneous recorded EEG. These simultaneous techniques will be developed on known animal models of epilepsy. Afterwards the techniques will be used to allow source allocation in new models for epilepsy.

                    Researcher(s)

                    Research team(s)

                      Behavioural and neurochemical validation of models of cognitive retardation and deterioration . 01/01/1997 - 31/12/2002

                      Abstract

                      The project involves the behavioural and neurochemical assessment of the characteristics and possible validity of recently developped transgenic and surgical mouse models of Alzheimer's disease, HIV1-associated dementia, metachromatic leukodystrophy, fragile X mental retardation and uremic encephalopathy. Behavioural assessment techniques include several test procedures and systems for reflexes, motor coordination, muscle strength, cage and open field activity, and spatial, reversal and avoidance learning. Neurochemical techniques involve HPLC, ELISA and enzyme activity analysis of neurotransmitters and associated compounds in tissue or microdialysis samples.

                      Researcher(s)

                      Research team(s)

                        Vision: dynamic processing, plasticity and memory. 01/01/1997 - 31/12/2001

                        Abstract

                        The UIA team will record the activity of tens of neurons in the rat cerebellum and develop methods to analyze this multi-unit data. This study is part of the investigation of cerebellar function by the Laboratory of Theoretical Neurobiology (Prof. E. De Schutter) and complements the development of neural network simulations. The Laboratory of Theoretical Neurobiology will also support the analysis of multi-unit data obtained in monkey visual cortex by the group of Prof. Orban (KUL).

                        Researcher(s)

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                          Further study of the neurochemical and behavioural alterations in uremic encephalopathy. 01/10/1995 - 31/12/1996

                          Abstract

                          The project aims at clarifying the pathofysiological basis of neurological complications related to renal failure. Neurochemical and behavioral alterations are investigated in vivo and correlated with post-mortem neuropathological findings. GSA-induced encephalopathy model as well as the genetically determined polycistic renal failure model and the nephrectomy induced chronic renal failure model are studied. A microdialysis system is applied for sampling of cerebrospinal fluid and interstitial fluid for neurochemical analysis.

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                            Guanidino compounds and brain function on the neurochemical, neurophysical and behavioral effects of uremic and hyperargininemic guanidino compounds. 01/10/1993 - 30/09/1995

                            Abstract

                            The project further studies the neurotoxicity of low-molecular toxins (LMTs) and aims to elucidate the mechanisms of action of these compounds in the pathogenesis of the uremic and hyperargininemic encefalopathy. Behavioral, (electro) fysiological, cytotoxicological and neurochemical (analyses, receptor bindings studies) investigations are performed.

                            Researcher(s)

                            Research team(s)

                              Neurotoxicity and mechanisms of action of low-molecular toxins (LMTs) in metabolic encephalopathies. 01/01/1993 - 31/12/1996

                              Abstract

                              The project further studies the neurotoxicity of low-molecular toxins (LMTs) and aims to elucidate the mechanisms of action ofthese compounds in the pathogenesis of the uremic and hyperargininemic encefalopathy. Behavioral, (electro)fysiological, cytotoxicological and neurochemical (analyses, receptor bindings studies) investigations are performed.

                              Researcher(s)

                              Research team(s)

                                Guanidino compounds and brain function on the neurochemical, neurophysical and behavioral effects of uremic and hyperargininemic guanidino compounds. 01/10/1992 - 30/09/1993

                                Abstract

                                The project further studies the neurotoxicity of low-molecular toxins (LMTs) and aims to elucidate the mechanisms of action of these compounds in the pathogenesis of the uremic and hyperargininemic encefalopathy. Behavioral, (electro) fysiological, cytotoxicological and neurochemical (analyses, receptor bindings studies) investigations are performed.

                                Researcher(s)

                                Research team(s)

                                  01/01/1991 - 31/12/1991

                                  Abstract

                                  Researcher(s)

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