Ongoing projects

Neurophysiological Markers of Cognition in Healthy Ageing & Neurodegeneration. 01/10/2022 - 30/09/2026

Abstract

Early and reliable diagnosis of neurodegenerative diseases such as Alzheimer's Disease (AD) and Frontotemporal Degeneration (FTD) is paramount from a clinical point of view, to provide accurate information about the cause of a patient's symptoms and their prognosis. Fluid- and PET-based biomarkers are reliable tools for early diagnosis of AD, but they entail invasive, costly procedures and are not easily accessible to all clinicians. Here, we advocate the development of a new and reliable neurophysiological marker as a suitable triage tool to identify patients with cognitive complaints who are at high risk for AD or FTD. Functional changes, which can be measured using high-density Electroencephalography (hd-EEG), precede structural changes of the brain. Our focus is on characterizing functional changes related to higher-order cognitive abilities which are relevant for the activities of daily living such as mental flexibility, reasoning and communication. We here introduce a novel hd-EEG approach to assess the early functional changes at the individual level. Studying neurophysiological changes at the individual level is necessary for clinical implementation, where markers need to be reliable at the single-patient level. Theoretically, the impact of interindividual differences on cognitive decline has received much attention in the past decade. The concept of cognitive reserve reflects the flexibility of cognitive processes that helps to explain the differential susceptibility of day-to-day-function to the effects of neurodegenerative diseases on the brain. Fluid intelligence (correlating with one's capacity for mental flexibility and reasoning) has been proposed as a proxy for cognitive reserve. In this proposal, we will acquire hd-EEG during paradigms testing fluid intelligence and language in a cohort of patients with neurodegenerative disease (biomarker-proven AD, and non-AD pathologies such as FTD) as well as controls. We previously demonstrated in older adults that larger task-related neurophysiological signal changes measured using magnetoencephalography are linked to better cognitive performance. In this project, we validate our approach using hd-EEG and test whether we can identify patients with neurodegenerative disease using single-case statistics to validate our neurophysiological marker for use in clinical practice. The scientific innovation of this project firstly lies in the translation of recent discoveries in cognitive neuroscience to clinical practice for use at the level of a single individual, combined with methodological advances regarding the acquisition and analysis of hd-EEG. Our goal is ultimately to optimize the clinical diagnostic pathway for neurodegeneration, by identifying some individuals as low-risk and providing reassurance to these patients, while prioritizing patients with a high risk of neurodegeneration for more invasive diagnostic procedures. In the future, neurophysiological markers could help to efficiently identify individuals who may benefit from disease-modifying therapy in a clinical trial.

Researcher(s)

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Project type(s)

  • Research Project

Het begrijpen van hersencircuits vanuit de oorsprong van neuronale embryonale progenitors. 01/10/2022 - 30/09/2026

Abstract

The brain's ability to process information and guide behaviour is reliant on diverse neurons forming complex neuronal circuits. In this PhD project proposal, we set out to explore how such diversity in neurons and synaptic circuits arises with a focus on embryonic progenitor origin and using mouse as a model organism. Recently data from my lab and others suggest that key aspects of neuronal identity and synaptic specificity in both cortex and striatum are controlled by their embryonic progenitor origin. In this proposal we will explore this further and focus on the striatum, but the tools and approaches generated will be universally applicable. The PhD project proposal has four main Objectives. Firstly, we will use RNA sequencing approaches to genetically parse the different embryonic progenitors that generate striatal spiny projection neurons (SPNs) and generate tools for their fate mapping from embryo to adulthood. Secondly, we will use a variety of techniques on adult SPNs to determine what 'types' of neurons arise from different progenitor pools. Thirdly, we will use novel viral tracing approaches to observe the synaptic integration of striatal SPNs within larger brain circuits. Lastly, we will reveal the molecular recognition systems that different embryonic progenitor-derived SPNs employ to achieve synapse specificity within these larger circuits. Together they will provide new insights how the vast complexity of neurons and circuits in the striatum arises and open avenues for future study of the roles for embryonic progenitor origin in neurological and neurodevelopmental disorders.

Researcher(s)

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Project type(s)

  • Research Project

Collen-Francqui Start-up Grant (Rose Bruffaerts). 01/10/2022 - 30/09/2025

Abstract

Early and reliable diagnosis of neurodegenerative diseases such as Alzheimer's Disease (AD) and Frontotemporal Degeneration (FTD) is paramount from a clinical point of view, to provide accurate information about the cause of a patient's symptoms and their prognosis. Fluid- and PET-based biomarkers are reliable tools for early diagnosis of AD, but they entail invasive, costly procedures and are not easily accessible to all clinicians. Here, we advocate the development of a new and reliable neurophysiological marker as a suitable triage tool to identify patients with cognitive complaints who are at high risk for AD or FTD. Functional changes, which can be measured using high-density Electroencephalography (hd-EEG), precede structural changes of the brain. In this proposal, we examine hd-EEG in a cohort of patients with neurodegenerative disease (biomarker-proven AD, and non-AD pathologies such as FTD) as well as controls. We previously demonstrated in older adults using multivariate analysis that larger task-related neurophysiological signal changes measured using magnetoencephalography are linked to better cognitive performance. In this project, we validate our approach using hd-EEG and we will develop a multivariate marker reflecting the dynamic neural pattern across the whole brain at the individual level. Using this "neural fingerprint" we test whether we can identify patients with neurodegenerative disease using single-case statistics to validate our multivariate neurophysiological marker for use in clinical practice. The scientific innovation of this project firstly lies in the translation of recent discoveries in cognitive neuroscience to clinical practice for use at the level of a single individual, combined with methodological advances regarding the acquisition and analysis of hd-EEG. Our goal is ultimately to optimize the clinical diagnostic pathway for neurodegeneration, by identifying some individuals as low-risk and providing reassurance to these patients, while prioritizing patients with a high risk of neurodegeneration for more invasive diagnostic procedures. In the future, neurophysiological markers could help to efficiently identify individuals who may benefit from disease-modifying therapy in a clinical trial.

Researcher(s)

Research team(s)

Project type(s)

  • Research Project

Towards therapies for epilepsy: Probing the potential of NMDA receptor allosteric modulation. 01/04/2022 - 31/03/2023

Abstract

Epilepsy is one of the most debilitating brain disorders and to date there is a shortage of drugs to combat it effectively. This is in part the result of the complexity of epileptic seizures, which arise from interactions amongst diverse excitatory and inhibitory neurons expressing numerous ion channels and receptors as well as relevant models. Here we propose to establish two in vitro models of seizure activity, based on mouse hippocampal brain slices and neurons derived from human induced pluripotent stem cells, to investigate the efficacy of novel modulators at one key brain receptor - the glutamatergic NMDA receptor – in controlling seizure activity. In this pilot project we will investigate both positive and negative allosteric NMDA receptor modulators using a combination of electrophysiological techniques including field potential recordings, multi-neuron patch-clamp electrophysiology and multi-electrode array recordings to understand the locus of action of these drugs at the excitatory and inhibitory neurons of the brain and their ability to control seizure activity. This will allow a deeper appreciation of the balance of excitation and inhibition in the generation of seizure activity, reveal the potential of allosteric modulation in controlling seizures and provide the preliminary data for future grant applications to study their effect in vivo.

Researcher(s)

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Project type(s)

  • Research Project

Lab animal based cognitive and behavioural research 01/01/2022 - 31/12/2023

Abstract

Support of collective laboratory animal-based neuroscience research via the funding of an ATP employee with extensive expertise in behavioral and cognitive analysis of rodent models, therapeutic interventions, neurochemical and neuropathological analyses.

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  • Research Project

Support maintenance scientific equipment (ENU). 01/01/2022 - 31/12/2022

Abstract

Financial support towards maintenance of scientific equipment in the Experimental Neurobiology Unit (ENU). This includes various electrophysiological setups, behavioural setups, molecular biolology setups and EEG equipment amongst others.

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  • Research Project

The medium is the memory, the support the souvenir. 01/12/2020 - 30/11/2024

Abstract

At the beginning of 2018 I started the research project Sculpture as a flexible ephemerality. My question concerned the meaning of sculpture as a static medium in a rapidly changing world. As a methodology I used the changing conditions between creation and destruction. In the course of the research the term destruction changed into transformation, because the new form still carries the old one, but in a paradoxical way. This transformation of the images took place on the basis of happenings or events. In a later step, the work of art was literally fragmented to be distributed as a souvenir among the visitors of the exhibition. This led to the following question: Can a work of art be stripped of its static character by inscribing it in a cyclical system of recovery and recycling? Each work of art has a metamorphosis in the viewer's memory, does it still exist in its original physical form? In the PhD I want to go deeper into the memory that functions as a medium and the physical work of art that is reduced to the technical carrier of the concept. Is the artwork the packaging of an idea, just as our economic system stimulates the consumer with evocative packaging? The content is processed and the packaging is temporary and seductive. In this way I question the material character of a work of art by viewing it as a changeable carrier of an immaterial message that is shaped and reformed by the viewer's memory. I want to connect this system in art to our daily world of consumption, recycling and our related economic system. My artistic practice functions as a case study.

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  • Research Project

The effect of Alzheimer's disease on cognitive decline after an ischemic stroke and the role of neurogenesis. 01/11/2020 - 31/10/2024

Abstract

Ischemic stroke (IS) and Alzheimer's disease (AD) are both common neurological diseases. IS can be defined as the sudden onset of a focal neurological deficit due to loss of regional blood supply. AD manifests by core features of progressive memory impairment, visuospatial decline and loss of executive functions. Cognitive worsening in general and an increased rate of cognitive decline in AD patients after stroke has already been reported. In both AD and IS, neurogenesis seems to play an important role. After IS, aberrant neurogenesis seems to interfere with the existing hippocampal circuitry and can therefore influence cognitive functioning. We hypothesize that stroke-induced cognitive decline is more pronounced in AD mice than in WT controls as a result of aberrant neurogenesis. This hypothesis will be tested in an animal study using a well-established AD (3xTg) mouse model, a stroke mouse model by middle cerebral artery occlusion (MCAO) and a combined model. We will investigate the role of neurogenesis after stroke in AD mice and how their cognitive performance in memory tasks is influenced. To this purpose, temozolomide (TMZ, inhibitor of neurogenesis) and memantine (MEM, stimulator of neurogenesis) will be administered. We will assess the effect of both treatments on cognitive performance and various markers of AD progression, neurodegeneration, inflammation and neurogenesis. If successful, a future similar clinical investigation could be set up.

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Project type(s)

  • Research Project

A zebrafish model system to assess pathogenicity of genetic variants in patients with cardiac arrhythmias. 01/01/2020 - 31/12/2023

Abstract

Inherited Cardiac Arrhythmia (ICA) refers to a group of genetic disorders in which patients present with abnormal and potentially harmful heart rhythm. These episodes often go unnoticed, but can lead to fainting and sudden cardiac death. At present, over 50 ICA genes have been identified. With the advent of next generation sequencing technology it is possible to test all of these genes simultaneously in multiple ICA patients with a single test. This method proficiently identifies clear disease causing genetic alterations. However, as the number of genes involved increases through better mechanistic insight into disease modifier genes and polymo hisms, we are confronted with a high number of genetic alterations for which causality is unsure. These pose a major challenge for the management of ICA patients. Therefore, the aim of this project is to develop a functional tool that will allow to test the functional impact of variants of unknown significance. We will develop a zebrafish assay in which the electrical dynamics of the heart are reported by fluorescent light signals. As zebrafish are translucent in early development, this model lends itself perfectly to visualize these signals 'in vivo' and at an exceptional resolution. After validating this tool with known pathogenic alterations, we will apply this method to evaluate variants of unknown significance. This innovative approach will allow the clinicians to deliver true personalized medicine.

Researcher(s)

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  • Research Project

Detailed characterizing and phenotyping of patients with Alzheimer's disease in order to identify modifying of prognostic factors and biomarkers. 20/12/2019 - 31/12/2022

Abstract

In this project we will perform detailed characterizing and phenotyping of patients with a clinical diagnosis of Alzheimer's disease (AD), including presymptomatic patients carrying a monogenic cause of AD, patients with mild cognitive impairment due to AD and patients with AD dementia. New participants will be included but we will also build on already existing research cohorts of MCI patients with valuable retrospective data. Prospective characterizing and phenotyping will be performed at several time points using (a) a systematic questionary on origin, region of residence, education level, profession, comorbidity, life style factors, exposion to toxic substances and familial history; (b) a systematic (hetero)anamnesis of cognitive symptoms; (c) a systematic standard clinical neurological examination; (d) a neuropsychological testing; (e) an MRI of the brain and (f) a sober blood sampling in order to determine markers of glucose metabolism and inflammation as well as APOE 4 status and monogenic causes of AD. Each 12 months neuropsychological testing and a sober blood sampling for markers of glucose metabolism and inflammation will be repeated. In case of progression from asymptomatic to MCI stage or from MCI stage to dementia stage, an MRI of the brain will be repeated. By using statistical comparative analyses between patients and between different time points within one patient, we will search for (1) associations of certain comorbidity, demographic, lifestyle or environmental factors with specific phenotype characteristics of patients with AD; (2) associations of blood markers of glucose metabolism and inflammation with stages of the disease; (3) associations of blood markers of glucose metabolism and inflammation with specific phenotype characteristics of patients with AD. Identified associations can then lead to the development of prognostic or etiological factors for the disease and biomarkes for progression. At their turn those findings might lead to targets for disease delaying, disease modifying, or even disease curing therapies. Furthermore, our aim is to expand a detailed clinically characterized and longitudinally followed cohort of patients with AD, which would be very valuable in other (future) research projects such as genetic modifying studies.

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Project type(s)

  • Research Project

Molecular elucidation of the unique gating behavior of cardiac ion channels thanks to their interaction with conopeptides. 01/01/2019 - 31/12/2022

Abstract

Venoms from cone snails (genus Conus) can be seen as an untapped cocktail of biologically active compounds, being increasingly recognized as new emerging source of peptide-based therapeutics. Cone snails are considered to be specialized predators that have evolved the most sophisticated peptide chemistry and neuropharmacology for their own biological purposes by producing venoms which contains a structural and functional diversity of neurotoxins. These neurotoxins or conopeptides are small cysteine-rich peptides which have shown to be highly selective ligands for a wide range of ion channels and receptors. The gamma- and omega-conopeptides their structurefunction activity relationships (QSARs) will be investigated by site-directed mutagenesis on both toxin and target in order to elucidate the molecular mechanisms involved.

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  • Research Project

Can antiepileptogenic treatments slow down the progression of Alzheimer's disease? 01/01/2019 - 31/12/2022

Abstract

Alzheimer's disease (AD) is the most frequent global cause of severe cognitive impairment. Epileptic seizures have always been thought to be a late complication in a minority of AD patients. We hypothesise that subclinical epileptic phenomena do however occur in a considerable part of AD patients much earlier in the disease course which aggravates cognitive decline. We will test this hypothesis in a prospective, longitudinal observational clinical study. Moreover, we will investigate the onset and frequency of epileptiform discharges in well-established transgenic AD mouse models and how their cognitive performance in memory tasks is influenced. Next we propose an early intervention with antiseizure drugs as a possible disease modifying therapy. To this end, AD mice will be chronically treated with a clinically used antiseizure drug levetiracetam or with a ghrelin receptor agonist in development. Levetiracetam was previously shown to exhibit antiepileptogenic properties, while ghrelin receptor agonism inhibits cognitive deficits in AD models and reduces seizures in epilepsy mouse models. We will assess the effect of both treatments on epileptiform biomarkers, cognitive performance and various markers indicative of AD progression. If successful, we could set up future clinical investigations with chronic treatment of levetiracetam in patients with mild cognitive impairment due to AD.

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  • Research Project

Past projects

Monoaminergic and neuroinflammatory markers in dementia with Lewy bodies to improve differential dementia diagnosis. 01/11/2019 - 31/10/2022

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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  • Research Project

Genetic-manipulation-free photothermal stimulation and enhanced photothermal ablation of cardiomyocytes; new and safer tool to cure cardiac arrhythmias. 01/11/2019 - 30/10/2022

Abstract

Cardiac arrhythmias are the result of disorganised electrical signalling in the heart, affecting up to 33.5 million people worldwide and about 1-3% of the Belgian population. Moreover, as the prevalence of atrial fibrillation is expected to double the next 20 years, the clinical and economic impact of the disease is huge. The goal of the project is two-fold: (1) Establish a new and innovative tool for the synchronous stimulation of cardiomyocytes using light and circumventing the need for genetic manipulation and (2) Provide a proof of concept and initial protocol for a safer alternative for RF/cryo balloon cathether ablation. Both aims will be achieved by using a gold nanoparticle label, which specifically targets a cardiomyocyte surface marker. The gold nanoparticle will absorb LASER/LED light and produce heat. Depending on the rate of change in temperature, either photothermal stimulation or photothermal ablation is accomplished.

Researcher(s)

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    Project type(s)

    • Research Project

    Development of a functional assay to determine the pathogenicity of genetic variants with unknown significance identified in patients with cardiac arrhythmia. 01/10/2018 - 30/09/2022

    Abstract

    Inherited Cardiac Arrhythmia (ICA) refers to a group of genetic disorders in which patients present with abnormal and potentially harmful heart rhythm. These episodes often go unnoticed, but can lead to fainting and sudden cardiac death. At present, over 50 ICA genes have been identified. With the advent of next generation sequencing technology it is possible to test all of these genes simultaneously in multiple ICA patients with a single test. This method proficiently identifies clear disease causing genetic alterations. However, as the number of genes involved increases through better mechanistic insight into disease modifier genes and polymorphisms, we are confronted with a high number of genetic alterations for which causality is unsure. These pose a major challenge for the management of ICA patients. Therefore, the aim of this project is to develop a functional tool that will allow to test the functional impact of variants of unknown significance. We have developed a zebrafish assay in which the electrical dynamics of the heart are reported by fluorescent light signals. As zebrafish are translucent in early development, this model lends itself perfectly to visualize these signals 'in vivo' and at an exceptional resolution. After validating this tool with known pathogenic alterations, we will apply this method to evaluate variants of unknown significance and test the possible arrhythmogenic side effects of some drugs. This innovative approach will allow the clinicians to deliver true personalized medicine.

    Researcher(s)

    Research team(s)

    Project type(s)

    • Research Project

    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.

    Researcher(s)

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    • Research Project