Appendix 6 Use cases Amsterdam Neuroscience 2016-2021

1. Consortia

• ABOARD • Brainscapes • Brainmodel • ProPark • ENIGMA • Don’t be late

2. Research projects

• Genetics & epilepsy • I-pace • Brain networks on cognition • Novel dimensionality-reduction to predictive of behavior • Visual cortical prosthesis to restore vision • Imagine genetics • Deep Brain Stimulation in Obsessive Compulsive Disorders • Causality studies in substance use • EEG controlled triage in the ambulance for acute ischemic stroke

3. Research facilities & support

• SynGO • ADORE • Hersenonderzoek.nl • MeMo lab

4. Cohorts

• NESDA cohort • The Netherlands sleep registry • MS cohort • MeninGene cohort • Amsterdam dementia cohort • COVID-19 biobank • 100-plus study • INCbase

5. Clinical trials

• MR clean study • TETRO trial • Blood test for Alzheimers’ disease • Vanishing White Matter Trial

6. Companies

• Macrobian Biotech • NBT Analytics

7. Communication & society

• Amsterdam Neuroscience MAGAZINE • Communication channnels • Online & hybrid events • Books

1. Consortia

Consortia help us to stay connected, broaden our network and showcase our research and expertise internationally, to show what we can do when we work together. Researchers from the Amsterdam Neuroscience research institute have been participating in or leading many consortia that include partners from all over the world and in various fields.

ABOARD: Stopping Alzheimer’s together before it starts

ABOARD, in full ‘A personalized Medicine Approach for Alzheimer’s Disease’, is a large-scale research project carried out by a national, multidisciplinary consortium. This consortium of more than thirty partners works towards a future with personalized diagnoses, prediction and prevention of AD.

Personalized medicine

ABOARD’s mission is to make a start with personalized medicine for AD by making all the preparations for effective patient-directed diagnosis, prediction, and prevention. The goal is to pave the way for tailor-made treatment for Alzheimer’s so better strategies for diagnosing, predicting, and preventing Alzheimer’s can be created. In this way, patients and relatives feel supported and more in control.

Collaborations

The ABOARD consortium launched in April 2021. The project brings over thirty partners together, among which five Dutch Alzheimer centers, including the Alzheimer Center Amsterdam, a center of expertise of Amsterdam Neuroscience, and patients’ organizations like Alzheimer Nederland. Public and private parties across the entire knowledge chain work together in this consortium, from universities to care and knowledge institutions, civil society organizations and businesses. An overview of all involved partners and more information about ABOARD can be found on the project website.

Support by the Dutch government

ABOARD is the first research project to be launched as part of the National Dementia Strategy 2021-2030 of the Ministry of Health, Welfare and Sport. It also contributes to the Knowledge and Innovation Agenda 2020-2023 of Health~Holland, in which public and private partners collaborate to improve the quality of life of people (Mission IV).

BRAINSCAPES: A roadmap from neurogenetics to neurobiology

The Brainscapes consortium aims to map the biological mechanisms underlying multiple brain disorders. Recent genetic discovery studies have provided more insight into the genes involved in brain disorders. The next step is to use this knowledge for gaining mechanistic disease insight, although this is an extremely complex task to fulfill due to the involvement of many different research fields that all speak their own language. The research group that is coordinated by Professor Danielle Posthuma will develop novel analytic and experimental tools to study the functional consequences of risk genes on the function of specific cells, their circuits and functional output. These insights into the molecular and cellular basis of complex brain disorders can be used to design novel treatments.

Long term funding

On August 30, 2019, the Dutch Research Council (NWO) announced that the Brainscapes consortium was awarded a Gravitation grant to the value of €20 million. The Ministry of Education, Culture and Science provides

this type of funding for long-term (10-year) multidisciplinary projects, with the ambition to stimulate world-leading Dutch research that could potentially lead to international breakthroughs.

Research findings

In May 2020, the Brainscapes consortium published their first review in the journal Biological Psychiatry. In their paper, Emil Uffelmann and Danielle Posthuma reviewed resources and methods used by geneticists to point to the most-likely biological mechanism underlying a psychiatric condition. Their review includes a detailed overview of tools and resources that aid in interpreting GWAS results.

In October 2021, two co-leaders of Brainscapes, Amsterdam Neuroscience Professor Huib Mansvelder and Professor Boudewijn Lelieveldt from Leiden University Medical Centrum, have contributed to successfully map the different cell types of the motor cortex and other cortical areas in the brain. They take part in a major NIH-funded international study called the BRAIN initiative Cell Census Network, worth more than 4 billion dollars, of which the goal is to map all brain cells of several species including humans. Nature has devoted a special 17-paper issue to describe the first BICCN’s findings covering the motor cortex, including two papers to which Mansvelder and Lelieveldt contributed with their specific functional and informatics expertise, respectively.

BRAINMODEL: Precision medicine for brain disorders

A team of researchers from six Dutch knowledge institutions (including Vrije Universiteit Amsterdam as coordinator) is introducing new research methods to improve treatment for developmental disorders of the brain. The scientific team will work together with societal partners, clinical associations, and companies in the BRAINMODEL consortium and will implement new stem cell-based methods to improve diagnostics and therapy decisions and to develop new therapies. ZonMw has allocated a grant of €4 million for this work.

Living nerve cells in a dish

BRAINMODEL’s new approach is based on patient-derived cells with which networks of living nerve cells are produced in a culture dish. These closely resemble the neural networks in our brains. This is known as ‘pluripotent stem cell technology (iPSC)’ and offers new opportunities in terms of understanding human diseases and finding personalized treatments. iPSC-based strategies are particularly promising for understanding developmental brain disorders because they overcome the problem of not having access to brain tissue to study underlying causes.

N=You center

N=You neurodevelopmental precision center, led by Professor Hilgo Bruining, is part of the BRAINMODEL project. The main objective of this project is to use iPSC-based analyses to detect abnormal cellular functions in material from patients with brain disorders and link these to clinical outcome measures, such as EEG biomarkers. The N=You center combines EEG analyses with genetic and cellular diagnostics. Linking the genetic material to the EEG results can show the effect on information processing and brain development. The use of stem cell cultures opens a new framework for rational, mechanism-based treatment. The N=You center of Amsterdam UMC collaborates with the Radboudumc expert center for rare genetic disorders in Nijmegen.

ProPark: Project Profiling Parkinson’s Disease

ProPark stands for ‘Profiling Parkinson’s Disease’ and is a collaboration of Parkinson’s disease (PD) researchers over a timeframe of five years starting in 2019. Wilma van de Berg, Senior Associate Professor at the Department of Anatomy & Neurosciences at Amsterdam UMC, is involved in this national consortium.

The overall aim of ProPark is to (1) evaluate the role of existing and novel quantitative biomarkers in understanding the heterogeneity in the Parkinson’s phenotype (i.e., rate of progression, motor dysfunction, and cognitive and neuropsychiatric impairment), predicting treatment response, and assess the occurrence of adverse drug reactions over a three-year period; (2) develop a ProPark biobank containing comprehensive and uniformly acquired longitudinal clinical data, imaging data and biological samples for identification and validation of biomarker panels and data-driven approaches to unravel heterogeneity in PD phenotype. Together with LUMC, ErasmusMC, and nearby community hospitals, Amsterdam UMC recruits 1,250 PD patients in two years and follows them up for at least three years.

ENIGMA

Researchers from all over the world, including several Principal Investigators and staff of Amsterdam Neuroscience, are part of the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) consortium. This global consortium of over 1,400 scientists across 43 countries, studies the human brain in health and disease and brings together researchers from the fields of imaging genomics, neurology and psychiatry.

ENIGMA on obsessive-compulsive disorders

This worldwide imaging consortium is led from Amsterdam, by Professor Odile van den Heuvel, and appears very strong in connecting OCD imaging experts from the whole world to perform well powered meta- and mega-analyses. In this consortium, the first steps are made towards the link with genetics. The ENIGMA-OCD consortium now also develops task-based functional MRI meta- and mega-analyses.

ENIGMA Parkinson’s disease

Another ENIGMA group led by an Amsterdam Neuroscience researcher is the worldwide working group on Parkinson’s disease led by Professor Ysbrand van der Werf. This Parkinson’s project consists of three major studies, including: A) A meta-analysis of volumetric changes in Parkinsonian versus healthy brains, using previously developed FreeSurfer protocols; B) A shape meta-analysis of deep gray matter structures; and C) A meta-analysis of white matter differences, based on the ENIGMA-DTI protocol.

Collaboration for more than a decade

In March 2020, a review in Translational Psychiatry was published on the last decade of large-scale studies of the brain by the ENIGMA consortium and in parallel an update on the genetic basis of corticavl structures studied by ENIGMA was published in Science.

Don’t be late consortium on multiple sclerosis

A group of MS researchers and supportive organizations, known as the ‘Don’t be late’ consortium, has been awarded €1.6 million in funding within the second round of the Dutch Research Agenda (NWA), called Research along Routes by Consortia (NWA-ORC). Their mission is to postpone cognitive decline and prevent unemployment in patients with MS. Cognitive decline is one of the symptoms of MS, affecting up to 70% of the (young) people with MS. When patients with MS report cognitive and work-related problems, these problems are often too advanced for treatment. Intervening sooner rather than later is crucial, which requires a paradigm shift from symptom management to prevention of symptoms. By focusing on prevention, quality of life and participation in society will be enhanced.

‘Don’t be late’ is led by neuroscientist Hanneke Hulst, who has worked for the MS Center Amsterdam of Amsterdam UMC for many years. Researchers from different organizations throughout The Netherlands are involved, such as: Vrije Universiteit Amsterdam,

Leiden University, Sanofi Genzyme, Merck bv, Personal Fitness Nederland, MS vereniging Nederland, St. Anthonius Hospital Nieuwegein, Hospital Rivierenland Tiel, Medisch Spectrum Twente Enschede, Stichting MS Research, Nationaal MS Fonds, Nederlandse Vereniging voor Verzekeringsgeneeskunde, Nederlandse Vereniging voor Arbeids- en bedrijfsgeneeskunde, MSweb.nl.

Physiological and genetic fingerprints of seizure freedom after epilepsy surgery

The current leading treatment for intractable drug-resistant epilepsy is surgical resection of the responsible brain tissue, but seizures remain in 30% of patients after surgery. Amsterdam Neuroscience researchers Ilse van Straaten, Natalia Goriounova and Linda Douw are looking for ways to better predict the surgery outcome of epilepsy patients. This project’s long-term goal is to improve the selection of epilepsy patients for surgery candidates and to improve neurosurgical resection plans.

First, these women in science aimed to identify morphological and neurophysiological biomarkers related to seizure freedom after surgery. Training random forest algorithms on presurgical neurophysiological and MRI data showed that machine learning outperformed logistic regression models. Neuronal electrophysiological and morphological features in the resected non-pathological tissue from a limited number of eligible patients (n=14) revealed no differences between seizure free and non-seizure free patients after surgery. The next step is to build an individual prediction tool based on the data to better inform patients on the surgery outcome and therefore to better tailor patient selection.

Improving Prognosis by using innovative methods to diagnose Causes of Encephalitis (I-PACE)

Meningitis can be caused by bacteria, viruses, or other microorganisms, but also excessive activation of the immune system as seen in auto-immune diseases can be identified as the cause. During the last two decades, the spectrum of bacteria causing meningitis during childhood has substantially changed due to the introduction of vaccinations. Furthermore, diagnostic methods have improved and new viruses were discovered that can cause meningitis. Because of these changes, we are currently able to identify the cause of meningitis in the majority of cases. However, in a substantial number of the patients (~30%) the cause is still unknown.

I-PACE study

Amsterdam Neuroscience Principal Investigators Matthijs Brouwer and Diederik van de Beek are involved in the I-PACE study whose primary aim is to determine the causes of meningitis and/or encephalitis. Furthermore, the study aims to evaluate the clinical signs and symptoms and cerebrospinal fluid (CSF) laboratory characteristics of patients with a diagnosis of meningitis and/or encephalitis. All patients in whom meningitis is suspected who receive a lumbar puncture can be

2. Research Projects

Our research projects are directed to fulfill the Amsterdam Neuroscience mission (to broaden the fundamental knowledge of the nervous system and to translate this into effective therapies and treatments for the individual patient with a neurological disorder) with an interdisciplinary approach.

included. After informed consent is given by the patient or his/her representative/ caregivers the leftover CSF derived from the diagnostic puncture will be stored and later tested for an extensive panel of known and unknown viruses. Furthermore, additional material (feces, blood and throat swab) will be stored and later tested for the presence of (new) viruses. Clinical data will be stored in an online clinical database.

From single neurons to brain networks of cognition

Temporal lobe epilepsy (TLE) patients are at risk of memory deficits, which have been linked to functional network disturbances, particularly of integration of the default mode network (DMN). However, the cellular substrates of functional network integration are unknown.

Researchers Natalia Goriounova (Vrije Universiteit Amsterdam) and Linda Douw (Amsterdam UMC) leverage a unique cross-scale dataset of drug-resistant TLE patients (n = 31), who underwent pseudo resting-state functional magnetic resonance imaging (fMRI), resting-state magnetoencephalography (MEG) and/or neuropsychological testing before neurosurgery. fMRI and MEG underwent atlas-based connectivity analyses. Functional network centrality of the lateral middle temporal gyrus, part of the DMN, was used as a measure of local network integration. Subsequently, non-pathological cortical tissue from this region was used for single cell morphological and electrophysiological patch-clamp analysis, assessing integration in terms of total dendritic length and action potential rise speed. As hypothesized, greater network centrality is related to better memory performance. Moreover, greater network centrality correlated with more integrative properties at the cellular level across patients. Goriounova and Douw concluded that individual differences in cognitively relevant functional network integration of a DMN region are mirrored by differences in cellular integrative properties of this region in TLE patients.

A novel dimensionality-reduction method for optical and electrophysiological data to identify neural population code predictive of behavior

A collaboration between researchers from Vrije Universiteit Amsterdam and Amsterdam UMC resulted in a study to find out which intricate neural mechanisms drive the cognitive process involved in attention. Aishwarya Parthasarathy, Christiaan de Kock, and Ingo Willuhn join forces in this project.

Attention refers to the process of allocating sufficient cognitive resources to complete a task successfully. While the overall role of the prefrontal cortex (PFC) in attention is well established through fMRI and lesion studies, knowledge about the intricate neural mechanismsdrivingspecificcognitiveprocesses involved in attention (engagement) is lacking. Parthasarathy, de Kock and Willuhn and their teams used a novel dimensionality reduction method on both optical (n = 5 rats) and electrophysiological data (n = 3 rats) recorded from simultaneously rat medial PFC ensembles to predict the animal’s performance during an action control task. They decoded the animal’s behavior from the ensemble activity, which enabled them to predict errors in the task performance up to 1s before the animal failed to engage in the task successfully. This project allowed these researchers to forge a collaboration between AMC and VU Amsterdam researchers and provides a novel data-analysis platform that can be used in both labs.

Shape perception via a high-channel-count neuroprosthesis in monkey visual cortex

Blindness affects 40 million people across the world. One day, a neuroprosthesis could restore functional vision in the blind. Pieter Roelfsema of Vrije Universiteit Amsterdam and his team implanted a 1024-channel prosthesis in areas V1 and V4 of the visual cortex of monkeys and used electrical stimulation to elicit percepts of dots of light (called phosphenes) on hundreds of electrodes, the locations of which matched the receptive fields of the stimulated neurons. Activity in area V4 predicted phosphene percepts that were elicited in V1. Roelfsema simultaneously stimulated multiple electrodes to impose visible patterns composed of several phosphenes. The monkeys immediately recognized them as simple shapes, motions, or letters. These results demonstrate the potential of electrical stimulation to restore functional, life-enhancing vision in the blind.

Imaging Genetics

Several initiatives for imaging genetics substantiate the target expressed in the midterm evaluation of Amsterdam Neuroscience institute. Two and a half years ago, Shu Liu started his PhD project in imaging genetics supervised by Amsterdam Neuroscience Principal Investigators Guido van Wingen (Compulsivity, Impulsivity & Attention) and Karin Verweij (Complex Trait Genetics). He combines information from imaging measures (sMRI and fMRI) with genome-wide genetic data to investigate the underlying biological mechanisms of a broad range of mental health outcomes (including psychiatric disorders and substance use phenotypes). This PhD project is funded by a personal fellowship from a Chinese governmental institute.

Deep Brain Stimulation in Obsessive Compulsive Disorders

A retrospective study showed that individual differences in white matter anatomy could explain differences in deep brain stimulation (DBS) response in patients with OCD (Liebrand et al., 2019). This has resulted in a change in the DBS targeting procedure, which is now done using individual white matter tractography. The initial evaluation of this procedure showed that it did not result in better treatment response, but it had a large effect on reducing side-effects (Graat et al., submitted). This work fits the general aim of Amsterdam Neuroscience to translate neuroscientific knowledge into clinical practice.

Causality studies in substance use

A new line of research is to use a genetic instrumental variable approach (Mendelian Randomization) to investigate causal associations between traits. Over the last years, this method has been successfully applied to investigate (bidirectional) causal associations of substance use with brain volumes, insomnia, ADHD, and loneliness, resulting in four publications. In 2021, a systematic review was performed by Amsterdam UMC researchers Jorien Treur and Karin Verweij, summarizing the findings of all existing Mendelian Randomization studies on the association between substance use and mental health outcomes.

EEG controlled triage in the ambulance for acute ischemic stroke

Endovascular stroke treatment (EVT) is highly effective but can be performed in selected hospitals only. Pre-hospital identification of stroke patients who are eligible for this therapy would allow paramedics to bring patients straight to the right hospital, thus saving valuable time. In ELECTRA-STROKE neurologist Jonathan Coutinho and technical physician Wouter Potters examine whether electroencephalography (EEG) is suitable for this purpose.

ELECTRA-STROKE is an ongoing diagnostic pilot study that consists of four phases that started in October 2018. In phases 1 and 2, technical and logistical feasibility of performing dry electrode EEGs were tested in the outpatient clinic and Neurology ward of the Amsterdam UMC. In phase 3, EEGs were performed on 250 patients wo were presented to the emergency room of Amsterdam UMC with a suspected stroke. In phase 4 of the study, ambulance paramedics will perform EEGs in a pre-hospital setting in 222 suspected stroke patients. The primary goal of the study is to develop an EEG algorithm for prehospital LVO-detection. Phase 4 started in August 2020; the first patient was enrolled on August 25, 2020.

3. Research facilities & support

Amsterdam Neuroscience has scientific knowledge, infrastructure, and state-of-the-art facilities to perform preclinical and clinical studies, often working toward end-to-end research solutions and always in a multidisciplinary setting. These research facilities or support centers help to accelerate scientific developments and share knowledge with research colleagues.

Syngo: Defining the synapse

The Synaptic Gene Ontologies (SynGO) consortium is coordinated by the Center for Neurogenomics and Cognitive Research (CNCR) (Frank Koopmans, Loek van der Kallen, Guus Smit, and Matthijs Verhage) and brings together leading experts in synapse biology on a worldwide level to establish a knowledgebase of the synapse. The CNCR works together with the Stanley Center at the Broad institute in Cambridge, MA, USA on this international gene annotation effort for pre- and postsynaptic genes. SynGO builds on prior initiatives generated in European consortia on synapse research EU-Synapse, EuroSpin, and SynSys. The aim of SynGO is to provide evidence-based annotation of synaptic gene products as a universal reference for synapse research and to facilitate enrichment studies in large scale -omics data.

In previous years, the consortium has built a new ontology for the synapse and annotated more than 1,000 synaptic proteins based exclusively on published experimental evidence. Since launching the SynGO portal and publication of the first analyses by the consortium in Neuron in 2019, the knowledgebase and portal have served many scientists worldwide, with many daily users of the portal and the Neuron paper being in the top 5% of most cited papers in the field (March 1, 2022: 195 citations in <2 years; Google Scholar).

ADORE: Amsterdam Oncology and Neuroscience Research

ADORE, short for Amsterdam Oncology and Neuroscience research, is a new form of medical-scientific research. Their goal is to develop and apply new medicine and treatments for patients with cancer and brain diseases by doing research based on the parallels between oncology and neurology.

Ambitions

Cross-fertilization between cancer researchers and neuroscientists should lead to new diagnostics and therapies. There are differences between these diseases, but also similarities. Therefore, Amsterdam UMC decided to combine cancer and neuroscience research within ADORE to boost breakthroughs. Professor Philip Scheltens, director of Alzheimer Center Amsterdam, is involved in the foundation of this unique concept. Together with doctors and researchers from Amsterdam UMC, the dream and ambition is to find a solution for cancer and brain diseases. Why do cells in one person grow explosively but in the other person die, as happens in diseases such as multiple scleroses?

Location

The city of Amsterdam is providing a subsidy of more than 600.000 euros for the ADORE Research and Diagnostic Center to be built at Amsterdam UMC. The start of the new building of this Research and Diagnostics center will be in spring 2022. ADORE will be a center with offices and laboratories between VU Amsterdam campus and Amsterdam UMC. It will be the biggest neuro-onco campus in the world, where researchers, doctors and patients can come together. The arrival of ADORE attracts companies from the Netherlands and abroad and strengthens the Life Sciences and Health sector in the region.

Vision

ADORE will guarantee a research infrastructure of at least ten years, to ensure that the best of the best researchers and clinicians can work for a longer period on unique and groundbreaking research. Within ADORE, the focus for the next years will be on immunotherapy, imaging, and artificial intelligence.

Hersenonderzoek.nl: Accelerating research into brain diseases

Hersenonderzoek.nl is an online platform that helps researchers find the right participants for their studies. It is a platform where healthy people and patients can register their interest in participating in brain research. Neuroscientists can call on this registry and indicate their search for participants for a specific research project. The platform brings researchers into contact with people who want to participate in their studies.

Renewed funding

Hersenonderzoek.nl received renewed funding in January 2022 from ZonMw, Alzheimer Nederland, Dutch Brain Foundation, and Amsterdam Neuroscience. With this renewed funding they will be able to continue their work, which aims to accelerate research into brain diseases. More research is needed to cure brain diseases such as AD, other forms of dementia, Parkinson’s, or MS. Globally, there is a severe shortage of healthy controls and patients to participate in brain research, which results in research delays.

MeMo lab

The Memory Modification platform for the development of novel smoking cessation methods based on recent insights in the field of neuroscience and psychology. This is an initiative by Taco de Vries and Ysbrand van der Werf in the Department of Anatomy and Neurosciences. The professors De Vries and Van der Werf are currently testing a novel protocol that is based on both Eye Movement Desensitization and Reprocessing (EMDR) and recent insights from animal studies. It is known that deep memory paths in the brain strongly affect the persistence of addictive behavior. By keeping those memory paths preoccupied with other tasks, while simultaneously triggering memories associated with nicotine addiction in a virtual 3D environment, they try to rewire the paths that trigger smoking behavior.

Going forward, De Vries and colleagues want to include neurostimulation in these experiments as well. For that, they see the insular cortex as a promising target based, among others, on their recent preclinical observations. In a translational model of nicotine addiction, Nathan Marchant in the team of De Vries found strong evidence for a role of the anterior insula in relapse to nicotine seeking using chemogenetic intervention and in vivo calcium imaging techniques in rats. His studies also suggest opposing roles of left and right insula in reward seeking, in line with observations in humans. Based on these findings the researchers will now start a clinical trial in smokers and apply deep rTMS to either the left or right insula using a newly designed H-coil in combination with cue-exposure.

Memo-lab is also reaching out to other researchers interested in designing novel procedures to treat pathological behaviors with strong environmental triggers, including those present in OCD, behavioral addictions and eating disorders.

4. Cohorts

As a research institute, Amsterdam Neuroscience stimulates cohort studies and registries. Longitudinal data collection can be a crucial source of information in studying neurodevelopmental disorders over time. Longitudinal cohorts are ideal for understanding and exploring progressive diseases or mental health issues.

NESDA Cohort

The Netherlands Study of Depression and Anxiety (NESDA) was designed to investigate the course of depression and anxiety disorders, in particular the psychological, social, biological and genetic factors that influence the development and the long-term prognosis of anxiety and depression.

The main aim of NESDA is to determine the (psychological, social, biological and genetic) factors that influence the development and the long-term prognosis of anxiety and depression. In 2004, 2981 participants were recruited with and without symptoms from primary care practices and specialized mental health institutions in the regions of Amsterdam and Leiden, and in the provinces of Groningen, Drenthe and Friesland. In January 2019, the 7th measurement took place, 13 years after the first people were included. Current NESDA cohort consists of 3348 subjects. The contact for the NESDA cohort is Professor Brenda Penninx.

The Netherlands Sleep Registry

The Sleep Registry (Slaap register) is an initiative of researchers at the Netherlands Institute for Neuroscience (part of the Royal Netherlands Academy of Arts and Sciences) and Vrije Universiteit Amsterdam. They believe it is time to join forces to help poor sleepers. The Sleep Registry is led by Professor Eus van Someren, an expert in the field of sleep, who works as the head of the Sleep and Cognition Department at the Netherlands Institute for Neuroscience and is a professor of neurophysiology at the Vrije Univeristiteit Amsterdam.

European funding

In 2022, the European Research Council (ERC) of the European Commission awarded its most prestigious grant, the ‘ERC Advanced Grant’ to Van Someren, to study anxiety disorders and chronic insomnia in combination to find a better treatment for insomnia. This is the second time that Professor van Someren receives this prestigious grant. His research team has been trying for years to improve treatment of insomnia to prevent its adverse consequences on mental health. Their discoveries have made the Netherlands the international leader in the field of fundamental research into insomnia.

Combining sleep and anxiety research

Via the Dutch Sleep Registry his team is looking for research participants who, in addition to their poor sleep, also have complaints of anxiety, stress or emotion regulation. Thousands of people can contribute to the research by filling in questionnaires. Hundreds of them can also take measurements of their brain activity before, during and after sleep in the comfort of their own bed. Treatments will also be tried out, including innovative medication. Van Someren expects that people will find it easier to control their anxiety and post-traumatic stress symptoms if they sleep better.

Amsterdam MS Cohort

Clinical progression in MS has a major impact on a patient’s quality of life but can be very difficult to predict. Why do people with MS continue to deteriorate? How can disease progression be stopped? The researchers at the MS Center Amsterdam (MSCA) want to find answers to these questions. Therefore, the MS researchers ask permission to collect clinical data for the Amsterdam MS cohort of all patients who visit the MSCA for regular care, second opinions or research. The Amsterdam MS cohort currently consists of >7,500 people who visited the MSCA. From a good part of them (>1,500) highly detailed longitudinal clinical and research data is collected. With

this extensive database, the MSCA aims to find a way to identify mechanisms and milestones leading to progression, and ultimately find and optimize ways to stop patients from progressing altogether.

MeninGene biobank

The MeninGene study is a nationwide prospective cohort study on genetic risk factors for bacterial meningitis which started in 2006 and has included over 3,000 patients in 2022. All specimens collected in this study and its substudies are stored in the MeninGene biobank. These include leftover cerebrospinal fluid samples from the diagnostic lumbar puncture, DNA from the patients and controls, clinical and radiological data, and the causative bacteria from blood and cerebrospinal fluid. Furthermore, samples from a serial sampling substudy and recalled patients are also stored in this biobank. Finally, as part of the MeninGene biobank samples from brain autopsies were collected, resulting in a large collection of bacterial meningitis brain pathology material (MeninGene-Path). The availability of these samples in the biobank enabled the researchers from the Neuroinfection Center Amsterdam at Amsterdam UMC to study interaction between genetic characteristics of the bacterial and the patient, of which the results were published in Nature communications in 2019 (Lees J et al, Nat comm 2019). This study showed several regions in the human genome that are associated with susceptibility to meningitis or severe outcome of meningitis. In a separate project they found that changes in genetics of Listeria monocytogenes in bacterial meningitis patients caused the pathogen to become less sensitive to disinfectants used in the food industry, and caused more severe disease (Kremer, CMI 2017).

In another study on long-term sequelae after bacterial meningitis Diederik van de Beek, Matthijs Brouwer and their colleagues used the biobank to identify the responsiveness of patient blood to stimulation with pneumococci and provided clues in how overactivation of the immune system affects patient outcome (Kloek AT et al, Acta Neuropath Comm 2021). Recently, they found that neurofilament light, a marker of axonal damage in cerebrospinal fluid, is a strong predictor of poor outcome even after correction for clinical parameters of disease severity (Chekrouni, Neurology: NII 2022). Altogether, the MeninGene biobank proved to be a huge resource for scientific research and enabled multiple international cooperative projects.

Alzheimer Dementia Cohort

The Amsterdam Dementia Cohort was established in 2000, along with the foundation of the Alzheimer Center Amsterdam by Professor Philip Scheltens. In this clinic, top quality patient care and scientific research are performed in parallel. All patients that visit the Alzheimer Center Amsterdam are asked to consent to the use of their clinical data for scientific purposes. This patient population comprises the Amsterdam Dementia Cohort, which currently consists of almost 7000 individuals. The Amsterdam Dementia Cohort forms the basis of much of the research conducted by Alzheimer Center Amsterdam. In addition, it is a starting point for many (inter) national collaborations.

Patients that are referred to the Alzheimer Center Amsterdam undergo an elaborate one-day screening battery. This battery consists of, among others, extensive neuropsychological evaluation, a MRI scan, an EEG, and a lumbar puncture. After their baseline visit, the majority of patients visit the clinic annually for follow-up. The Amsterdam Dementia Cohort has evolved into one of the most elaborate clinical databases in the field of dementia research. Additional information on the set-up, content, and data collection procedures within the Amsterdam Dementia Cohort can be found in the reference below (van der Flier & Scheltens, 2018).

COVID-19 biobank

To support fundamental and clinical research related to COVID-19, Amsterdam UMC initiated the COVID-19 Biobank. This biobank has been initiated by clinical departments, laboratories and the central biobank facility. As of March 20, 2020, employees of Amsterdam UMC are collecting samples of COVID-19 patients, resulting in a database with thousands of samples. The biobank aims to enable as much research as possible in patients with COVID-19 by collecting clinical data, DNA and blood samples, among others, from patients hospitalized in Amsterdam UMC with COVID-19.

Funding

The Corona Research Fund of Amsterdam UMC supports the study of Professor Diederik van de Beek, co-director of Amsterdam Neuroscience and specialized in neurological infectious, who leads the COVID-19 Biobank project since the start of the COVID-19 pandemic in 2020.

Several publications

The relatively young Amsterdam UMC COVID-19 Biobank is a partner in two important studies, published in Science in September 2020. Partly thanks to this biobank, it has become clearer why some people become so seriously ill with COVID-19. An international consortium of researchers, including researchers from Amsterdam UMC, published these findings on September 24, 2020. The first Science paper, entitled ‘Auto-antibodies against type I IFNs in patients with life-threatening COVID-19’, is co-authored by Diederik van de Beek, a neurologist at Amsterdam UMC; over 60 Amsterdam UMC investigators are acknowledged because of their efforts in setting the Amsterdam UMC COVID-19 Biobank.

100-plus study

Repetitions in the DNA-code influence the chance of AD. To increase our understanding of the heritability of AD, researchers from the Alzheimer Center Amsterdam are comparing repetitive sequences in Alzheimer patients and healthy centenarians. This allows them to use individual genomes to predict who should be treated to prevent AD-associated brain damage, and how they can be treated.

Professor Henne Holstege and her colleagues of the 100-plus study aim to identify the characteristics associated with the escape or delay of cognitive decline. The 100-plus study is an ongoing prospective cohort study of Dutch centenarians who self-reported to be cognitively healthy, their first-degree family members and their respective partners. The researchers collect demographics, life history, medical history, genealogy, neuropsychological data and blood samples. Centenarians are followed annually until death.

INCbase: The Inflammatory Neuropathy Consortium Base

Neurologist Filip Eftimov’s specific area of interest is chronic inflammatory demyelinating polyneuropathy (CIDP). Eftimov is combining a translational approach to search for biomarkers of disease activity in CIDP and clinical research that focuses on long-term outcome of the disease. As the Principal Investigator of INCbase, a worldwide registry and biobank to describe CIDP phenotypes and long-term outcome, Eftimov will improve diagnostic criteria and develop biomarkers of disease activity. The main goal is to strengthen international collaboration, improve diagnostic criteria, develop biomarkers of disease activity, and contribute to discovering new treatments for this rare disease.

5. Clinical trials

Amsterdam Neuroscience has integrated the clinical trial expertise from different therapeutic areas within Amsterdam UMC into peer groups of clinical advisors, headed by the Industry Alliance Office. The clinical trial teams of Amsterdam Neuroscience provide support and know-how for organizing and executing industry sponsored clinical trials. The emphasis is on rigorous, academically informed clinical trials, capitalizing on our extensive clinical and academic facilities. This allows us to undertake a broad range of trials, from first-in-patient studies up to large national and international multicenter clinical trials.

MR Clean study

Neurologist Yvo Roos and radiologist Charles Majoie were pioneers of the MR CLEAN study and the endovascular treatment (EVT) of acute ischemic stroke in which a patient receives a thin catheter through an injection in the groin. The catheter is advanced into the occluded blood vessel in the brain. The blood clot is then removed from the body through the catheter. With the MR CLEAN study Roos, Majoie and colleagues demonstrated the effectiveness of cerebral angioplasty, signifying a worldwide breakthrough in the treatment of people who have suffered a major stroke. And they have worked hard on the technology ever since.

Nowadays, patients have much better prospects than five years ago. Patients treated with EVT have less brain damage and fever neurological complaints. Their functioning in society, like walking or getting dressed, is significantly better. A life with severe disabilities can be prevented more often than with the previous treatment. The patients only receive drugs that can dissolve the blood clot. Thanks to the MR CLEAN study, which was published in the New England Journal of Medicine, this type of treatment is now carried out across the globe and became the standard approach for acute ischemic stroke.

On December 17, 2020, Charles Majoie and Yvo Roos of Amsterdam UMC were awarded the prestigious gold Winkler medal for the MR CLEAN study.

TETRO trial

In the Netherlands, at least 100,000 people suffer from obsessive compulsive disorder (OCD). This is characterized by disruptive compulsive thoughts and time-consuming compulsions that can be so disruptive that someone experiences a high level of suffering. They are often unable to work or study and become socially isolated. From a longer-term perspective, roughly 50% of the people with OCD can’t be remedied with existing care (cognitive behavioral therapy and/ or medication). Currently, there is no good alternative for them. The most far-reaching treatment (brain surgery or deep brain stimulation) is only an option for the most extreme cases. In the search for a new, promising treatment for treatment-resistant compulsive disorders, Amsterdam Neuroscience researchers from Amsterdam UMC collaborate with several Dutch hospitals and mental health institutions in the so-called TETRO trial. With a grant of €2.8 million from ZonMw, Professor Odile van den Heuvel leads the trial in which 250 patients will participate in a research study for a new, promising treatment for OCD. This promising treatment is repetitive transcranial magnetic stimulation (rTMS).

“We think that the group that does not benefit sufficiently from cognitive behavioral therapy can be helped with this new rTMS treatment,” says Van den Heuvel. “We generate an electric current in the brain with the help of a magnetic field. This allows us to stimulate the brain circuit that is responsible for controlling emotions and behavior. By this means we will bring the brain into an optimal condition to increase the effects of cognitive behavioral therapy.” Patients will undergo rTMS treatment four times a week for a minimum of five weeks and a maximum of seven weeks. Each session is followed by cognitive behavioral therapy.

Blood test for early diagnosis of Alzheimer’s disease

The diagnosis of Alzheimer’s disease (AD) is a complex process and is usually done at an advanced stage of the disease. However, research on AD-specific blood-based or cerebrospinal fluid biomarkers supports the development of diagnostic tests for early detection of AD. The research group led by Professor of Neurochemistry Charlotte Teunissen of Alzheimer Center Amsterdam studies the blood-based biomarkers for the diagnosis of AD. They published a review in The Lancet Neurology on the current state of the blood test.

The US-based company Quanterix Corporation and the Alzheimer’s Drug Discovery Foundation (ADDF) started investments in the development of a multi-analyte plasma test. The ADDF funds a series of prospective clinical trials to validate the test in collaboration with Amsterdam UMC and Alzheimer Centrum Amsterdam. Charlotte Teunissen Is leading these clinical studies in collaboration with Quanterix.

Teunissen: “We are in a historic moment with plasma-based biomarkers for AD detection nearing clinical implementation. The funding from the ADDF will help further drive the rapid progress in this area just in time for the arrival of new therapeutics. We will be looking to validate the Simoa multi-analyte test for use in both memory care and primary care settings, in persons with worries about their cognition.”

Vanishing White Matter trial

The Amsterdam Leukodystrophy Center at Amsterdam UMC is conducting a clinical trial in children with Vanishing White Matter (VWM). In this trial, the researchers evaluate whether the drug Guanabenz is effective in slowing progression, stabilizing, or even improving the brain white matter abnormalities in VWM. Guanabenz is an old and well-known medicine that has been used for decades for the treatment of high blood pressure. It has been approved by the FDA, the American medicines agency.

Given the mechanism of action of Guanabenz, the researchers of the Amsterdam Leukodystrophy Center led by Professor Marjo van der Knaap estimated it likely to be beneficial in VWM. They had laboratory mice with VWM and treated them with Guanabenz. The results of that study indicate that long-term high-dose Guanabenz treatment ameliorates VWM in these mice and leads to both important improvements in motor function and amelioration of brain pathology. Because it was shown previously that the disease mechanism of VWM and the mode of action of Guanabenz are the same in mice and patients, the researchers expect that long-term treatment with high doses of Guanabenz could also be beneficial in patients with VWM.

6. Companies

Valorization is the utilization of scientific knowledge in practice. Examples include the translation of innovation into developing a product or medicine or applying scientific knowledge to a system or process. Some researchers from the Amsterdam Neuroscience network partnered up and started their own spin-off companies.

Macrobian Biotech

In 2017, Dr. Lars van der Heide and Professor Marten Smidt decided to challenge themselves further by founding Macrobian-Biotech, as a spin-off company from the University of Amsterdam. Macrobian-Biotech aims at performing pre-clinical research that leads to novel treatments for disorders that affect the midbrain dopamine system. The company is currently housed at the Amsterdam Science Park, the heart of academic excellence in the Netherlands.

Within the company, new treatments for neurological disorders of the dopamine system are being researched and developed. By means of patented technology, various substances will be developed that act specifically on the dopamine system and restore the affected system. The specificity of the treatment ensures that the patient has the least possible chance of side effects. The company’s work is aimed at delivering a fully tested preclinical drug, and then entering clinical trials with it.

NBT Analytics

NBT Analytics is a spin-off company from the Vrije Universiteit Amsterdam. The company was founded in August 2015 by Dr. Klaus Linkenkaer-Hansen and Dr. Simon-Shlomo Poil with Professor Hilgo Bruining as Chief Medical Officer. NBT Analytics provides extensive insights on how drugs influence the brain through a comprehensive selection of EEG biomarkers and identification of drug specific indices.

By using machine learning techniques, NBT combines information from multiple biomarkers. Unlike traditional analyses that only focus on one or two spectral biomarkers, NBT Analytics investigates biomarkers from temporal and spatial domains allowing for more comprehensive insights into the effect of an intervention on the brain. NBT combines relevant biomarkers into one integrative index improving statistical power and simplifying the assessment of activity. The integrated index can be used for prediction, stratification, or quantification of effects. The analytic method allows EEG biomarkers to be used as a robust secondary endpoint.

7. Communication & society

To stimulate the alliances within our research institute and pursuit the ability to connect our people, their science and the brain we need communication. Several communication tools have been developed and deployed to increase connections among our researchers and to the outside world.

Amsterdam Neuroscience magazine

The Amsterdam Neuroscience MAGAZINE is an annual publication that celebrates the achievements and hard work of the investigators and colleagues in the neuroscience field. The magazine contains in-depth interviews and short profiles of prominent senior and junior investigators. A must-read for anyone interested in the neuroscience research community in Amsterdam.

• 2021 edition on resilience (online only) • 2020 edition on team science (online and

PDF-version) • 2019 edition (online and PDF-version)

Communication channels

Website

2021 23,200

Total visitors

2020

15,719

Total visitors Social media

Twitter LinkedIn

2021 814

Total followers

2020

397

Total followers

2021 2,604

Total followers

2020

1,398

Total followers Newsletter

2021 3,899

Total reads

2020

3,742

Total reads

Figure 6.1 Infographic on the Amsterdam Neuroscience communication channels in 2020 and 2021. There is an overall growth of the digital channels of Amsterdam Neuroscience. Illustrated is a rise of the unique visitors of the Amsterdam Neuroscience website with more than 30%. In a period of one year, the total amount of followers on the Amsterdam Neuroscience social media channels almost doubled. And there is a small increase of people who read the Amsterdam Neuroscience newsletter.

Online and hybrid events Amsterdam Neuroscience

Annual meeting 2020

On October 2, 2020, the fifth Annual Meeting of the Amsterdam Neuroscience research institute took place. During this day around 500 online participants joined this virtual Annual Meeting. With a variety of sessions Amsterdam Neuroscience wanted to inform participants on the latest research developments in neuroscience all revolving around this year’s theme: team science.

Amsterdam UMC & COVID-19 research event 2020

On December 3, 2020, the research institutes jointly organized the Amsterdam UMC & COVID-19 Research event entitled ‘Unorthodox Teams, Accelerating Science’. With eighteen young researchers, several supporting experts, a brief interview with Anthony Fauci, and nine illustrative videos we showed a brief outline of the COVID-19 research at Amsterdam UMC.

Annual meeting 2021

On September 30 and October 1, 2021, the sixth Annual Meeting of the Amsterdam Neuroscience research institute took place. This year we organized a two-day hybrid event that started with the online poster market in Gather town on Thursday and continued with a plenary program on Friday with 200 attendees live at the Johan Cruijff ArenA and more than 300 participants that joined the Annual Meeting online.

TN2 webinars series

Translational Neuroscience Network (TN2) stands for connecting fundamental and clinical researchers in the field of Translational Neuroscience. In 2020, 2021 and 2022 two TN2 webinar series were organized in which we invited investigators of public and private partners to share their knowledge and explore translational medicine in the field of neurology and psychiatry. With our easily accessible webinars, each time scientists will be updated within less than 1,5 hours and be inspired to continue to foster the integration of basic research and patient-oriented research.

Books Odile van den Heuvel

Parkinson bij de psychiater - Uitgeverij De Geus, 2021

Odile van den Heuvel and Sonja Rutten, both psychiatrists working at Amsterdam UMC, published a book where they write about the mental symptoms many patients with Parkinson’s disease experience, such as anxiety, depression and psychosis: ‘Parkinson’s at the psychiatrist’ (‘Parkinson bij de psychiater’ in Dutch). They see the book as an ode to the resilience and creativity of people with Parkinson’s disease (PD).

The book features twenty personal stories from people with PD, who opened up about their personal experiences in the hope that they can help other patients. For example, to recognize the psychiatric symptoms, being able to talk about difficult topics, to seek help and to find a way to deal with the mental side of PD together with loved ones and therapists. As a reader you get an insight in the perspective of the psychiatrist and you are included in their observations and medical considerations.

Christiaan Vinkers

Hoe zit het nu echt met antidepressiva - Uitgeverij Prometheus, 2021 Psychiatrist and Professor of stress and resilience Christiaan Vinkers and pharmacist Roeland Vis published the Dutch book ‘Hoe zit het nu echt met antidepressiva?’. In this new book, Vinkers discussed the ins and outs of taking antidepressants. There are so many misconceptions about taking these drugs that Vinkers and Vis felt the need to discuss the subject in an accessible way for a wide audience. The book is a revised version of the book ‘Even slikken’ from 2017. They updated the information and added some sections, for instance about the how and why (not) of quitting antidepressants.

Cyriel Pennartz

De code van het bewustzijn - Uitgeverij Prometheus, 2021

“This is not a book for the faint of heart - it is for doubters, puzzlers, worriers, pathfinders and other people curious about what’s going on up there in their head,” says Cyriel Pennartz about his new book. In it, Pennartz takes the reader on an inspiring quest for one of the greatest scientific challenges of the twenty-first century: understanding the relationship between brain and mind. Pennartz, Professor at the Swammerdam Institute for Life Sciences (SILS) at the University of Amsterdam, has written a popular scientific work in Dutch about how the brain shapes our reality. The issue of consciousness, and especially sensory consciousness, is central in it. How is the brain, this remarkable tissue where it literally crackles with electrical activity, able to let us experience the world with its wealth of qualities as if it’s just regular matter? According to Pennartz, studying experience and consciousness is not an impassable road. In fact, over the past thirty years, studies of patients, computer simulations and the electrical behavior of brain cells have paved the way for thorough research into brain mechanisms of consciousness.

Annemiek Dols

Koorddansers - Uitgeverij Boom, 2021 Annemiek Dols and Moniek van Dijk composed a photography book filled with personal stories of people with bipolar disorder, their loved ones and healthcare professionals to show a realistic image of their lives. The book, published by Boom publishers, is called ‘Tightrope Walkers’ (Koorddansers in Dutch).

Bipolar disorder occurs in 2% of people in the Netherlands, just as often in men and women. In the Netherlands many people with bipolar disorder have not yet been correctly diagnosed. People often do not seek help, for example because they are ashamed. Dols: “Now it’s time to break that stigma and illustrate the real lives of people with bipolar disorder and their loved ones.” With this new book Dols and Van Dijk want to open the doors to the lives of people with bipolar disorder and start a new era where psychological problems should not be kept a secret.

Damiaan Denys

Het tekort van het teveel - Uitgeverij: Nijgh & van Ditmar, 2020

In 2020, psychiatrist and philosopher Damiaan Denys published the book ‘The shortage of the excess; (‘Het tekort van het teveel’ in Dutch). In this book, Denys outlines the paradox of mental health care. Denys is known for his honest questions and courageous positions in complex social debates. He thinks and speaks about fear and freedom, (ab)normality, death, and life at the intersection of the disciplines of psychiatry, philosophy and neuroscience.

Something crazy is going on. Western countries have been among the happiest countries in the world for years. Never has prosperity been higher, wealth greater, and quality of life better. These countries are positioned at the top of the world in education, living environment, health, safety and well-being. Yet four out of ten people suffer from a mental disorder in their lifetime and in the Netherlands one million people undergo treatment for mental health problems every year. We are more prosperous than ever, but we also experience more mental health problems than ever before. We are ranked happier but are suffering more than ever. How can we understand these paradoxes? Do we expect too much from life? Does prosperity bring more unhappiness? Why is mental health care failing? Can we still suffer healthily and normally? Are our expectations too high? Can we still be human?