Almost 65 million people suffer from epilepsy, making it to one of the most common neurological diseases worldwide. Epilepsy is a chronic disease affecting all ages, but the peak incidence is higher in the older population, rising from the age of 65. This may be explained by the predominance of brain diseases with epileptogenic potential (e.g. dementia and cerebrovascular diseases) and by the effects of the aging process through a number of molecular mechanisms, including vascular and inflammatory factors which are implicated in the aging process and can explain cognitive dysfunction in people with epilepsy. Recent findings show that older persons with epilepsy are more likely to suffer from cognitive dysfunction and that there might be an important bidirectional relationship between epilepsy and dementia. Since the world population is steadily growing and the number of older adults with epilepsy is set to rise substantially, the burden of epilepsy for the society is expected to be enormous in future. Therefore, measures must thus be taken to prevent seizures and epilepsy through the reduction of preventable epileptogenic factors. However, current anti-epileptic drug treatment does not adequately suppress seizures in 30% of all patients. Therefore, there is a pressing need for new therapeutic treatments.
We will test the hypothesis that age-associated cerebrovascular changes play an essential role in progressive blood-brain barrier dysfunction and contribute significantly to epileptogenesis and cognitive decline.
Almost 65 million people suffer from epilepsy, making it to one of the most commonneurological diseases worldwide. Intractable epilepsy has a life-long effect on social and cognitive functioning and quality of life of patients. One of the major challenges in epilepsy research is the identification of reliable biomarkers that can be measured routinely in easily accessible samples, such as blood. Biomarkers could substantially improve the management of people with epilepsy and could lead to prevention in the right person at the right time. We propose that circulating isomiRs (recently discovered disease modified small non-coding RNA molecules) in blood reflect pathological changes in brain and can be used as biomarkers for epilepsy. To test this hypothesis, we will use an innovative and translational experimental approach. To identify biomarkers we will study changes of circulating isomiRs in the model in two cohorts (developing epilepsy or no epilepsy) using state-of-the-art techniques. The approach outlined here has recently delivered biomarkers in cancer research, however, this has never been attempted in epilepsy.
EPITARGET, a new FP7 Health project, started on 1 November 2013. The consortium is led by the University of Lund with Prof. Merab Kokaia as coordinator and includes members from Sweden, Germany, France, Finland, Italy, United Kingdom, Poland, the Netherlands and Israel. The work will be funded by the EC with nearly 12 million Euros in the course of the next five years.
Epilepsy is a devastating condition affecting over 50 million people worldwide. Current antiepileptic drugs provide only symptomatic relief but cannot cure the condition. This is why EPITARGET is focused on identifying novel biomarkers for epileptogenesis to be able to explore new ways of how to treat epilepsy.
Epilepsy affects 1% of the world’s population. In Europe, 6 million people have epilepsy (World Health Organization, 2010). In more than 65% of patients, epilepsy begins in childhood and the incidence of epilepsy is highest in the first year of life (Hauser, 1993). In children, the problem of epilepsy is far beyond seizures, as about 50% of children with epilepsy suffer from psychiatric and behavioural comorbidities, including developmental delay, learning disabilities, and autism spectrum disorder (Ono, 2012).
About Tuberous Sclerosis Complex
Tuberous Sclerosis Complex (TSC) is a genetically determined neurocutaneous syndrome affecting 1 child in 6,000 (Curatolo, 2008). Molecular genetic studies have shown that there are two genes that cause TSC, TSC1 and TSC2, both of which are subject to heterozygous inactivating mutations in TSC. TSC is often considered an excellent clinical model of severe focal epilepsy, as 70 to 90% of patients are affected by epilepsy and in most cases the seizures are drug-resistant. In the majority of patients epilepsy manifests in the first months of life and half of patients develop cognitive impairment, autism spectrum disorder or other neurodevelopmental disturbances (Jozwiak, 1998). Epilepsy in TSC is often focal initially, but in many cases infantile spasms follow or coexist with focal seizures. Thirty-eight percent of TSC patients experience infantile spasms, and TSC accounts for 10% of all infantile spasms cases (Osborne, 2010). Therefore TSC is an excellent model for both focal epilepsy and infantile spasms. Although there is definite clinical heterogeneity, TSC represents a relatively homogenous group of patients for the studies of epileptogenesis,who are at high risk of this disease.
About prevention of epileptogenesis
It is now widely accepted that clinical seizures are preceded by a latent period of epileptogenesis (Pitkanen, 2011, Rakhade, 2009). This cascade of cellular and molecular events may be triggered by diverse brain insults, including trauma, infection or genetic predisposition, and leads to the formation of hyperexcitable neural networks ultimately resulting in spontaneous epileptiform activity. This process continues with onset of clinical seizures, leading to the development of established, drug-resistant epilepsy, and secondary comorbidities. In humans, epileptogenesis studies are difficult because the patients usually present after seizures and little is known about the earlier stages of the disease. The molecular changes occurring during epileptogenesis in animal models are still not fully understood, but are known to include changes in gene expression, activation of several immune and inflammatory processes, and others. It has been shown in multiple animal models of epilepsy that interventions applied prior to the onset of clinical epilepsy can prevent or delay the development of seizures. Even if seizures occur, they may be seen at reduced frequency, may be of shorter duration, or of milder severity (Galanopoulou, 2012, Zeng, 2008). Attempts at preventative treatment for epilepsy in humans have been inconsistent, mainly due to the extreme heterogeneity of epilepsy mechanisms in different patients and the difficulty of identifying patients at risk. However, two recent studies of children with epileptiform activity recorded on electroencephalography (EEG) indicate that patients treated with standard antiepileptic drugs before the onset of clinical seizures may benefit from this approach (Jozwiak, 2011, van Rooij, 2010). Our study showed that treatment before onset of clinical seizures appeared to not only reduce the risk of clinical seizures, but also to modify the later phases of epileptogenesis, reducing the risk of both drug-resistance and neurodevelopmental delay associated with epilepsy (Jozwiak, 2011). Increasing numbers of TSC patients are diagnosed prenatally or soon after birth, through increasing awareness of this syndrome, and early detection of cardiac rhabdomyomas which are often detected on routine prenatal echocardiography. These tumours are present in over 80% of foetuses with TSC. When cardiac rhabdomyomas are detected, prenatal or neonatal brain MRI can be performed to confirm the diagnosis of TSC. This early diagnosis enables serial clinical observation BEFORE the onset of epilepsy, which usually starts at the age of 4-6 months. A prospective study of TSC infants before clinical seizures has been published by the Coordinating Investigator, Professor Sergiusz Jóźwiak, proving the feasibility of this approach. This study showed that 71% of all TSC infants develop epilepsy in the first 24 months of life.
Over 50 million people worldwide have epilepsy and 30% are resistant to our present therapies. Epilepsy, therefore, comprises a major burden to society and so there is a pressing need for new approaches to treatment.
The brain extracellular matrix (ECM) plays a critical role in governing brain excitability and function. This project brings together considerable expertise from academic and industry partners. 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.
to understand the key mechanisms of epileptogenesis mediated by activity dependent remodelling of extracellular matrix
to detect and prevent changes in the ECM during early epileptogenesis
to develop ECM-targeting treatment strategies for “opening a window” for persistent structural normalisation of neural circuitries in late stages of epileptogenesis as well as in established epilepsy.
to understand remodelling of ECM during epileptogenesis,
to identify ECM components or their degradation products that can serve as biomarkers for early diagnostics of epileptogenesis,
to identify targets for prevention of epilepsy-related ECM alterations,
to identify targets prompting restoration of neural connectivity during established epilepsy,
to validate biomarkers and treatment targets.
Evidence is accumulating supporting the contribution of dysregulation in expression or activity of ECM molecules to pathological plasticity in the brain of patients with developmental epileptogenic lesions, as well as in patients with acquired forms of epilepsy. MicroRNAs (miRNAs) represent new class of post-transcriptional regulators of numerous biological processes within the central nervous system. miRNAs regulating different components of the ECM have been recently identified.
Investigation and characterization at the cellular level of ECM expression-regulating miRNAs deregulated in different human epileptic disorders.
Identification of ECM expression-regulating miRNAs as peripheral biomarkers.
The characterization of the expression pattern and the cellular distribution of miRNAs acting as potential regulators of ECM molecules will be performed using both real-time quantitative PCR analysis and combined in situ hybridization-immunohistochemistry in human specimens from patients who died after injury (status epilepticus or traumatic brain injury), as well as from patients with established epilepsy (hippocampal sclerosis and focal malformations of cortical development). microRNA overexpression and loss of function studies will be performed in vitro to further identify the exact role of selected miRNAs in the modulation of ECM signalling pathways in human astrocytes in culture.
The brain is the most complex, but also the most vulnerable part of our body. “How does the brain work?” has been among the most frequently asked questions for more than centuries. Elucidation of molecular and cellular mechanisms of brain function is a prerequisite to understand its pathologies and to develop novel and better therapies. Therefore, training and education of neuroscientists will be of paramount importance to the future prosperous development of the European countries.
The EU-GliaPhD consortium has defined the following aims in a novel European Training Network funded by EU Horizon 2020:
Research on brain function is of paramount importance to develop better therapies. It is essential to disseminate research results, but also to learn more about patients’ priorities and to help them and their families in understanding the disease burden.
To address these aims established European neuroscientists joint forces with two industrial partners to form the innovative European Training Network EU-GliaPhD. Our network is complemented by four associated partner organisations from the private sector contributing to training, dissemination, outreach and management. Thereby, the training-by-research programme of the EU-GliaPhD early-stage researchers will be highly inter-sectorial, addressing academic AND industrial research requirements as well as bidirectional interactions with the public via social media and face-to-face with patients’ organisations.
The research of the EU-GliaPhD principal investigators addresses mechanisms of cell-cell communication in the healthy and the diseased brain. The technical expertise covers mouse and human genetics, immunohistochemistry, molecular and cellular biology, advanced microscopy and electrophysiology in vivo and in situ, large neuronal ensemble recordings in freely moving animals, high throughput drug screening and development of novel research instrumentation.
Objectives: To examine the non-coding (nc) RNA expression profile of intracellular and extracellular miRNAs upon exposure to inflammatory molecules in human astrocytes. To study the ncRNA expression profile of glial enriched/ inflammation-associated miRNAs in selected hippocampal subregions and in blood samples after induction of status epilepticus in animal models.
Methodology: To study the effect of silencing or overexpression of ncRNAs involved in the regulation of astrocyte-mediated inflammatory response on ictogenesis in vitro (hippocampal slices) and in vivo (experimental models of acute and chronic seizures). In this proposal the translational regulation of astroglial proteins involved in inflammatory responses will be investigated using human astrocyte cultures. In particular the effect of inhibition or overexpression of specific short ncRNAs (microRNAs; miRNAs) and long ncRNA on the production of inflammatory mediators in cultured human astrocytes will be evaluated.
Current therapies in epilepsy are aimed at pharmacologically suppressing seizures in the chronic epileptic phase; however they are not aimed at preventing epilepsy or modifying epileptogenesis. To prevent the latter constitute the main challenge in epilepsy research and disease management.
Recent advances suggest that matrix metalloproteinases (MMPs), a specific class of extracellular matrix proteins, may be a novel target.
Our hypothesis builds upon these advances and we hypothesize that increased expression and activation of MMPs after brain injury play an essential role in persistent blood-brain barrier dysfunction and contribute significantly to epileptogenesis. Therefore, we will study the role of MMPs in relation to blood-brain barrier dysfunction and epileptogenesis. Furthermore, we aim to target MMPs using inhibitors in order to restore the blood-brain barrier and modify epileptogenesis. This innovative approach will lead to novel insights into the role of MMPs during epileptogenesis and will help to develop new anti-epileptogenic treatments.
Mesial Temporal Lobe Epilepsy (MTLE) is a progressive neurological disorder and the most frequent type of epilepsy in adults. MTLE is often preceded by an initial insult that after a latent period leads to recurrent seizures. The main aim is to characterize mechanisms of seizure progression in epilepsy. Recent studies indicate that the blood-brain barrier (BBB; a defense mechanism that protects the brain against blood components) may be a new target. BBB leakage has been shown in epileptic humans and animals and is associated with epileptic activity and inflammation. We recently showed that artificial opening of the BBB increased seizure frequency.
However, the precise factors that contribute to progression of epilepsyare not known. It is also not known whether restoration of the BBB could lead to a milder form of epilepsy or even prevent the development of epilepsy. First, we will study whether the extent of BBB disruption during the early epileptogenic phase is predictive of seizure outcome during the chronic epileptic phase using Magnetic Resonance Imaging (MRI). Since BBB disruption leads to intrusion of (white) blood cells and plasma derived substances, we will also use cellular imaging techniques (MR, confocal and voltage sensitive dye imaging) to determine the effects of these compounds on neuronal and glial network dynamics and on seizure progression. Finally, we will study whether anti-inflammatory therapies have disease modifying therapeutic effects in epilepsy.
De Harry Meinardi proefschriftprijs is dit jaar tijdens het Nationaal Epilepsie Symposium op vrijdag 28 mei uitgereikt aan Dr. Erwin van Vliet van de Universiteit van Amsterdam. Van Vliet ging in zijn proefschrift in op temporaalkwabepilepsie. Door deze ernstige vorm van epilepsie blijft ruim 30 procent van de mensen met epilepsie last houden van aanvallen, ondanks het gebruik van medicijnen.
Onderzoek naar de rol van bloedhersenbarrière
De hersenen worden goed beschermd tegen vreemde stoffen die via de bloedbaan naar binnen willen dringen. Dat is goed voor de hersenen, maar een groot probleem voor farmacotherapie. Op de bloedvatwand bevinden zich drugtransporters die de hersenen beschermen door actief ongewenste stoffen en medicijnen terug te pompen naar de bloedbaan. Uit van Vliet's onderzoek blijkt dat het toedienen van een transporterremmer een goede strategie is om farmacoresistentie te omzeilen.
Van Vliet en zijn collega's hebben ook aangetoond dat de bloedvaten die de bloedhersenbarrière vormen, beschadigd worden door een zware epileptische aanval. Hierdoor dringen bloedeiwitten en witte bloedcellen de hersenen binnen. Die vreemde stoffen verergeren op hun beurt de ontstekingsreactie in het brein waardoor zowel de epileptische activiteit als de activiteit van de drugtransporters toeneemt.
Harry Meinardi proefschriftprijs
De Harry Meinardi proefschriftprijs is een nieuw initiatief en wordt voortaan eens in de twee jaar uitgereikt voor het meest baanbrekende of veelbelovende proefschrift over epilepsie. Aan deze proefschriftprijs is een oorkonde en een geldbedrag van € 2.500 verbonden.
Mesial Temporal Lobe Epilepsy is a severe form of epilepsy in adults that often cannot be controlled with antiepileptic drugs. Considering the fact that epilepsy is one of the most common neurological disorders, pharmacoresistance is a major health issue. Insights into the mechanisms that are involvedin pharmacoresistance may ultimately lead to a therapy for pharmacoresistant epilepsy patients. The aim of the research described in my thesis is to investigate the role of the blood-brain barrier and multidrug transporters in pharmacoresistant epilepsy. My thesis provides evidence that multidrug transporters play an important role in pharmacoresistance by reducing antiepileptic drug levels in specific brain regions and shows that seizures can be controlled by pharmacological inhibition of multidrug transporters.
Alternatively, an anti-epileptic drug that is not transported by multidrug transporters (levetiracetam) also initially controlled seizures. However, the effects of both these therapeutic approaches were transient.
The development of tolerance indicates that, in addition to overexpression of multidrug transporters, other mechanisms of pharmacoresistance are relevant. Future research should therefore not be limited to multidrug transporters but should also include anti-epileptic drug properties and their targets.
In 2013 wordt voor de 21e keer de Publieksdag over de hersenen gehouden.
Donderdag 10 oktober 2013 vertellen weer diverse wetenschappers over hun onderzoek. Het thema in 2013 is: Gezonde hersenen?
Brain Awareness Week 2012 @ The British School in The Netherlands, Voorschoten.
The Brain Awareness Week campaign unites families, schools, and communities in a worldwide celebration of the brain. The Dana Alliance for Brain Initiatives founded the now-global campaign in 1996. Since its start, more than 2,800 partners in 82 countries have participated in the campaign. The Society for Neuroscience and many others serve as partners.
In 2019, assistant professor Erwin van Vliet was awarded a Grassroots grant for developing the UvA application of the online learning platform Perusall. Now, there are over 250 courses making use of this tool, and their number is still growing. See whole story via link below.
See blog about the Grassroot program "Perusall-FNWI" (project leader Erwin van Vliet):
reading assignment, confusion report, automated analysis, social learning platform
For best practice see:
flipped classroom, interaction in the classroom, large groups, methods to enhance interaction, student activation, voting, team based learning
In flipped-class pedagogy, students prepare themselves at home before lectures, often by watching short video clips of the course contents. The aim of this study was to investigate the effects of flipped classes on motivation and learning strategies in higher education using a controlled, pre- and posttest approach. The same students were followed in a traditional course and in a course in which flipped classes were substituted for part of the traditional lectures. On the basis of the validated Motivated Strategies for Learning Questionnaire (MSLQ), we found that flipped-class pedagogy enhanced the MSLQ components critical thinking, task value, and peer learning. However, the effects of flipped classes were not long-lasting. We therefore propose repeated use of flipped classes in a curriculum to make effects on metacognition and collaborative-learning strategies sustainable.
In january 2013 Erwin van Vliet recieved the education award: most innovative teacher of the year, University of Amsterdam, Swammerdam Institute for Life Sciences
Till Zimmer - The epileptogenic trinity: oxidative stress, brain inflammation and iron in epilepsy (2021)
Diede Broekaart - Breaking the vicious cycle of epileptogenesis: focus on brain inflammation and matrix metalloproteinases (2020)
Anatoly Korotkov - The role of microRNAs in epileptogenesis: modulation of brain inflammation and the extracellular matrix (2020)
Jackelien van Scheppingen - Astrocytes as mediators of inflammation in epilepsy: focus on tuberous sclerosis complex (2018)