Brain Center Bulletin

October 2019, 16th edition

Editorial

There are many successes to celebrate in this issue of the UMC Utrecht Brain Center bulletin: grants, awards, prizes and much more! You will find many interesting stories on activities from our different focus areas ranging from a public lecture on the influence of stress on the childrens brain, which was part of a broader campaign around the disease area ‘Developmental disorders’, to an app to register relevant bodily functions in ALS patients at home and a new professor, Nicolette Notermans!

While this bulletin is being released, we are busy preparing for the 5-yearly evaluation of our research and teaching at the end of October. In the past months, many people from the Brain Center have contributed to an extensive written overview of all our activities during the past years. For this we are very grateful. This SEP evaluation will not only judge the past years but also provides an opportunity to further strengthen our research and teaching in the future, and to help shape the new UMC Utrecht strategy that is being prepared. In the next bulletin, we will report in more detail on the SEP site visit.

Recently, several things have changed regarding the Brain Center. For example, its name but also the names and focus of different disease areas. We delighted that the new, Neuro-oncology, and re-newed, Precision Psychiatry and Developmental disorders, disease areas are up and running now and that several kick-off and scientific meetings are organized to start collaborations, prepare joint grant applications etc.

This bulletin will change too. It will be released more frequently so that we can share more recent information with you. These new editions of the bulletin will be send to you as a news letter. If you have news that you think should be considered for the bulletin, please contact us at braincenter@umcutrecht.nl.

Finally, I would like to draw your attention to two meetings that are organized by the UMC Utrecht Brain Center in the coming months: the 3rd Utrecht Brain Conference that will be held in December, and our annual Research Day that is scheduled for the end of November. I hope to see you all there!

Jeroen Pasterkamp, ​​chair UMC Utrecht Brain Center

Ynte Ruigrok wants to predict risk of aneurysm

Three percent of the Dutch population develop an aneurysm in their head. If such a bulge in a brain blood vessel bursts, it leads to a stroke with serious consequences. So neurologist Ynte Ruigrok is looking for smart ways to identify risk factors for developing an aneurysm. She has received a European grant of 1.5 million euros for this.

“As a doctor, I see the consequences of brain haemorrhages caused by the rupture of a cerebral aneurysm on a daily basis,” says neurologist/researcher Ynte Ruigrok. “When you know how severe such subarachnoid haemorrhages are, you have a direct awareness of the urgency of research. Thanks to her efforts, more people undergo preventive screening with the help of an MR Angiography, a kind of MRI scan.

Locations on DNA sequence
Previously, Ynte initiated the founding of an international consortium that has put together the genetic profiles of aneurysm patients. “In this way, we want to discover which genes play a role. Both to better predict the risk of aneurysm and subarachnoid bleeding and to better understand how these genes contribute to the disease.”

Genetic material of over 13,000 patients has been analyzed already. Ynte: “Previously we had identified six locations on the DNA sequence, but now we can point to eighteen locations on the DNA. We want to understand how those locations on the DNA sequence contribute to the development of aneurysms. And how we can use genetic material to predict the risk of aneurysm.” Ynte expects to know the results of this research in the short term.

Predictive risk score
One in ten patients have a family history of subarachnoid haemorrhages. There are now increasing indications that each person’s genetic information can be summarized into a single risk score. “We can then compare the risk scores of our 13,000 patients with those of healthy people. Hopefully that will help us to better predict who is at risk of developing the disease.”

Machine learning
As a next step, Ynte now wants to use machine learning for the analysis of the blood vessels in the head, to see if this self-learning software can find differences between patients where the aneurysm was detected in an MR Angiography (MRA scan) and patients where no aneurysm was detected. “With machine learning, we use algorithms to learn from patient data. If we manage to find indications of the development of aneurysms on the MRA scans, we will then examine whether they are genetically determined. If that is the case, we can integrate those data into the consortium’s genetic data set and further analyze them.”

““I love doing both research and practicing medicine”

Prediction model for everyone
“My dream is that we can do a genetic scan for everyone without having to do an MRA scan first. So that we can first look at the genetics to see if you’re at risk before we do an MR Angiography.” Ynte: “My ultimate goal? That we can identify people with an increased risk of developing an aneurysm. Not only relatives of patients, but also other people: a risk chart or prediction model for everyone. Based on the outcome, everyone can then decide for themselves whether they want to be screened with an MRA scan. Screening is obviously not mandatory, but as a doctor I feel it’s my duty to inform people about the risks.”

European grant
The interaction between clinic and research is an important drive for Ynte. “My research allows me to better inform my patients. Conversely, we formulate new research questions because I hear what needs patients have.” For instance, she is now researching whether the family (i.e. genetic) component triggers the development of aneurysms, their rupture, or both.
For her research, Ynte has received an ERC Starting Grant, a European grant of one and a half million euros. “The grant gives me more time to do research. It means I can now dedicate half my time to research for a period of five years and attract a new group of PhD students.” But she will also keep working as a doctor in the clinic: “I love doing both research and practicing medicine.”

New professor: Nicolette Notermans

A detective amidst 600 criminal muscular diseases

In May this year, Nicolette Notermans became professor in neuromuscular diseases (NMD) at UMC Utrecht. Before that, she was already – and still is – medical chief of the unit with the same name (since 2008) and an NMD trainer (since 2006). Her work covers all aspects of the field: care, management, teaching and research. “I’m interested in the diagnosis and treatment of muscular diseases.”

And there are quite a number of those: over 600. Muscular disease is the umbrella term for pathologies of the muscles, neuromuscular junctions, nerves and motor neurons of the anterior horn. Since many of these disorders lead to muscle weakness, the term muscular disease is used, although the cause does not always lie in the muscles as such. The medical term is neuromuscular disease.

Polyneuropathy
The most well-known are probably ALS and SMA for which UMC Utrecht (with its ALS Centre and the Spieren voor Spieren – ‘Muscles for Muscles’ – children’s centre) is the foremost treatment centre in the Netherlands. The neuromuscular disease unit in Utrecht is recognised as a major expertise centre (or referral centre) in Europe. With a 45% market share, Utrecht is also the largest diagnosis and treatment centre for polyneuropathy. Neuropathy is a disease that affects the nerves in the arms and legs, the ‘wiring” so to speak. Polyneuropathy means that nerves in various parts of the body are affected. Muscles and sensations will then no longer function correctly, with complaints including numbness, vibrations, tingling, aches, cramps, muscles becoming thinner, muscle weakness and impaired balance. Since many patients come to Utrecht for ALS, SMA and polyneuropathy, many clinical studies also take place here.

Laughing gas
There are many kinds of polyneuropathies, with a variety of causes. Nicolette does research on all polyneuropathies. “With a third of the patients, diabetes is the cause, and for another third, we don’t know what causes it. For about ten percent, the disease was caused by drug use, and for five percent it’s hereditary. Alcohol and vitamin shortage also play a role. A recent development is the use of laughing gas. Laughing gas provokes an acute lack of vitamin B12, which causes polyneuropathy. We therefore get twenty-year-olds with serious signs of paralysis. If you act fast, the damage is reversible.” Recently she also took part in a study on the link between statins (a frequently used cholesterol-lowering drug) and polyneuropathy. Conclusion: statins will not give you neuropathy.

Detective
The fact that the cause of neuropathy can often not be found makes patients feel uncertain, she says. “But in fact, when the cause is not clear, we do see a strong correlation between complaints and evolution. And since we see so many patients for whom this is true, we can reassure them: you won’t end up in a wheelchair, because this form of the disease evolves slowly.”

Nicolette feels a bit like a detective, surrounded by some 600 ‘criminal’ muscle diseases. And her detective work does not escape notice. The Dutch Interest Group for Neuromuscular Disease (Spierziekten Nederland) for instance refers to her appointment as a professor in neuromuscular disease as good news for research on muscle disorders, “since Dr. Notermans has by now earned her stripes in the field. She has done a lot of research on polyneuropathies in particular. She was for instance responsible for mapping CIAP and MGUS polyneuropathy in the Netherlands.” Nicolette is currently chairing IMAGINE, a global study on the clinical picture, cause and treatment of patients suffering from IgM MGUS neuropathy.

Lounge chairs
Working with patients and colleagues gives her a lot of satisfaction. “The patients are nice, sweet people who are afflicted by a terrible or at best a nasty disease. Most of them are glad to know where they stand and are really grateful for the help you can offer them. And we’ve got a nice group here in the unit: open, straightforward people, with no hidden agendas. Everyone does what they do best, and all of it in the patient’s interest. We also work closely with rehabilitation specialists in and outside UMC Utrecht. Our specialised nurses play a key role here. Plus, we work closely with patients and patient associations. For example with the building of our new outpatient clinic. We quickly got rid of the interior designer who wanted hip lounge chairs; that was totally dysfunctional for our patients. We then built the unit together with the association and wherever we could, gave the patients what they wanted.”

Cover story


What is the story behind the thesis cover?

This time: Irene Huenges Wajer

The dissertation is about the impact of an aneurysmal Subarachnoid Hemorrhage (aSAH) on the life of a patient. An aSAH is a subset of stroke of which the peak age of incidence is between 40 and 60 years. On the cover, the red dot represents the subarachnoid hemorrhage. The patient’s life is visualized in the drawing of the face.

The flower on the cover refers to the story of a 47-year old woman who is gardening at the moment she had an aSAH and is described at the start of the dissertation. A tulip is chosen because of the Dutch background of the author of the dissertation.

ASAH has a high case-fatality rate. Of those patients who survive the aSAH, most show good physical recovery. However, many of these patients cannot regain their pre-morbid level of functioning completely. One of the reasons hereof is that a lot of aSAH patients have cognitive complaints and/or impairments. Moreover, symptoms of depression, anxiety or posttraumatic stress are often present after aSAH.

In the dissertation, factors related to cognitive and psychosocial complaints and impairments are studied. The contrast between the good physical recovery versus the present cognitive and psychosocial problems of the group of patients who were investigated in the thesis, is illustrated by the transition from the pink to the white in the background of the cover.

NWO Gravitation grant to find affected nerve cells via DNA abnormalities

In recent years, many of the genes and DNA abnormalities involved in various brain disorders, such as schizophrenia, dementia and depression, have been identified. The next step is to see what these DNA abnormalities actually do and in which nerve cells. “It’s not until you know exactly what’s going wrong and where that you can you do something about it,” says Jeroen Pasterkamp, professor of Translational Neuroscience at the UMC Utrecht.

Jeroen and Elly Hol are the leaders and researchers of BRAINSCAPES from the UMC Utrecht. The Dutch Research Council (NWO) has granted this partnership a Gravitation grant of more than nineteen million euros for ten years.

Great impact
In Europe around 179 million people suffer from a brain disorder. Many of these conditions have a major impact on patients and their families, are not yet curable and involve substantial social costs. Examples of these disorders are depression, dementia, schizophrenia, autism and addiction.

Many small abnormalities
In recent years great progress has been made in genetic research into brain disorders. Jeroen says, “Some disorders are caused by a single gene defect. Most of them, however, involve very many small abnormalities. We now know better what the genetic basis of certain diseases is. But that doesn’t help us much yet. Simply put, we know the beginning – the DNA abnormalities – and the end – the symptoms of a disease. But the part in between is missing. And precisely that part is needed to be able to develop treatments that tackle the cause. We want to translate the genetic basis into a model in the lab that we can use. For this to happen, geneticists, bioinformatics experts and translational researchers will need to work together more closely and differently; the purpose of BRAINSCAPES.”

Understanding brain circuits
BRAINSCAPES will, on the one hand, attempt to fully map the genetic landscape for a number of psychiatric and neurological disorders and, on the other, yield insight into the brain circuits that are affected in these disorders. “We want to know what a DNA anomaly does to which nerve cells. The brain consists of millions of nerve cells, but it is still virtually unknown which groups of nerve cells are important for which functions and how they are affected in a disease.”

New technique
A new technique called “single cell RNA sequencing” makes it possible to see for each cell which piece of DNA is written off and used. Jeroen says, “We are going to develop this technique further so that with the help of genetic information we can identify groups of cells that are relevant to disorders.” Elly: “Over the last years it became clear that besides neurons also the glial cells are involved in brain disorders. These cells support neuronal communication and are the immune cells of the brain. In BRAINSCAPES, we will further decipher how neurons interact with glial cells, in the health and diseased brain.” The researchers will then dive deeper into the groups of cells found. Jeroen: “We want to know what connections they make in the brain. Both in healthy people and in patients. This will enable us to identify the behavior or function for which they are important. Using brain organoids – mini-brains – and other models in the lab, we can further study the nerve cells and their connections, gain insight into what is actually happening and try to influence it.”

Bringing worlds together
Jeroen and Elly are happy with this Gravitation grant. Not only because of the recognition for the research that this grant entails, but also because it brings together different research worlds. Jeroen: “BRAINSCAPES is a large consortium of different research institutes. However, it also brings together geneticists, molecular biologists and bioinformatics specialists, because a huge amount of computational work is required. I believe it’s necessary to bring these worlds together in order to achieve our goal: to find treatments to cure brain disorders.”

In September the Dutch Research Council (NWO) awarded the so-called Gravitation grants. These grants are intended for top researchers in a discipline who work in a consortium or partnership on excellent and innovative research in one or more disciplines.

Social Talk

Theory and action in family lecture about stress and the children’s brain

“When I’m late for football.” “If I have to go to the doctor.” “When I go to a new school for the first time.” A selection of children’s answers to the question when they suffer from stress. But what is stress anyway? What does it do with your brain? And more importantly, how do you get rid of it? On Sunday September 15th, stress and the children’s brain were the focus of a special family lecture. It caused a lot of young heads in the blue lecture hall.

Dr. Femke Lammertink from the Neonatology Department gives an extensive explanation about how stress originates and also that stress is not necessarily wrong. After Femke, it is neonatologist Jeroen Dudink’s turn to explain sleep. He explains that all animals sleep on earth, although it is sometimes dangerous for animals not to pay attention to their environment. Enough and good sleep must therefore be very important! His tip for the children and parents? “Don’t look at your phone or tablet in the two hours before you have to sleep. Otherwise your brain will not go into sleep mode, because the substances in your head that respond to light remain activated.”

Heidi Lesscher (neurobiologist) and Sanne Nijhof (pediatrician) both know a lot about the effects of playing on the brain. Playing is essential for relaxation, but also for the development of your brain and your ability to deal with all kinds of situations later in life. And Sanne explains how difficult it is for children who are sick to not always be able to play.

After so much theory, children and their parents can put everything into practice immediately. Cycling to blend your own smoothie, with physical therapist Willem Broeders explaining the positive effects of sport and exercise on brain development. Dancing together at the silent disco or measuring brain activity with EEG. Or would you prefer to fight in the nonsense quiz, by researcher Kim Annink of the Neonatology department?

Together with Jeroen Dudink, Freek Hoebeek came up with the design of this program. Freek: “Within developmental disorders, we do a lot of research into the development of the young brain. We can organize a public lecture on a weekday evening for adults, but we find it much more fun to involve those children. We combined it this program. Information and activities for everyone.”

Grant from ZonMW for national implementation of ALS Home Monitoring and Coaching

Anne Visser-Meily and Anita Beelen received a grant from ZonMw for the nationwide implementation of the e-health innovation ALS Home Monitoring & Coaching. Central to this new ALS care is that patients at home record data about their functioning (such as walking, dressing, swallowing and breathing), body weight and how they are doing and transmit these data through a mobile app. The app also allows the patient to chat with the health care professional. Monitoring data is viewed by a nurse specialist who, in consultation with the rehabilitation specialist and the multidisciplinary ALS team, takes action if necessary, such as giving advice, providing information, making an appointment with a member of the ALS team or. With the grant, the new ALS-care can be implemented in ten multidisciplinary ALS teams of the ALS Care Network. With the implementation of ALS Home Monitoring & Coaching in these ten teams, insight will be obtained in the critical success factors for effective implementation of e-health which will facilitate further implementation of ALS Home Measurement & Coaching within the ALS care network.

Grants and Awards

Project ‘Making sense of sensor data for personalized health care’, RAAK Pro honored. CVA (De Hoogstraat en UMC Utrecht): Martijn Pisters, Anne Visser-Meilij, Mirjam Kouwenhoven, Wilma Jentink (Hoogstraat)
ATTRACT: ‘Bridging the epilepsy diagnostic gap: a fast, reliable and cost-effective rapid test (BREEDING)’.
NWA-Ideeëngenerator: ‘Reliable and rapid evaluation of clinical evidence in the public domain’ Wim Otte
ZonMW Translational Research: ‘Blood-brain barrier leakage as a predictive factor for poststroke epilepsy; a translational neuroimaging study’. Jaap Jansen (MUMC), Co-PI: Rick Dijkhuizen, Wim Otte
Elly Hol has been elected for the membership of the Academia Europaea (the European Academy) for her scientific achievements and influence.

Calendar

Oct. 30 – YOUth DataDay

The Utrecht based YOUth cohort aims to be a trailblazer for Open Science. On our YOUth DataDay we will not only share expertise and lessons learned, but also discuss our current challenges in enabling FAIR, open and safe data in the YOUth cohort. Free registration at www.uu.nl/youthdataday

November 22 – Dutch Neuroanatomy Championships

November 29 – Brain Center Research Day

The theme of the research day will be ‘Science in Collaboration’. What is a good collaboration? What are key ingredients for a fruitful collaboration?

December 10- Utrecht Brain Conference

Topic: neuro-oncology. More info in the next Bulletin.

January 20 – Public Event about data, AI and brain

Save the date…More info in the next Bulletin.

Colophon

Editors: Mariken de Krom, Marjolein Sneeboer, Vicki Kurapka, Joanne Karssenberg
braincenter@umcutrecht.nl
www.umcutrecht.nl/braincenter
www.braincenter-bulletin.nl

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