White Matter Diseases

Program Committee

Theme 1: Multiple sclerosis and other neuroinflammatory diseases
Chris Polman (program leader and theme leader)
Christien Dijkstra (theme leader)
Frederik Barkhof (theme leader)
Bernard Uitdehaag (vice theme leader)
Elga de Vries
Paul van der Valk
Annette van der Goes (program coordinator)


Theme 2: Childhood white matter diseases
Marjo van der Knaap (program leader and theme leader)  
Cornelis Jakobs (theme leader)
Gajja Salomons
Jeroen Vermeulen (theme leader)

Rationale

Within the program white matter diseases two strong themes, ‘multiple sclerosis (MS) and other neuroinflammatory diseases’ and ‘childhood white matter diseases’ (CWMD), are united. The two themes both have an excellent international reputation. Although there are many differences between white matter diseases in children and adults, the same substrate is affected (CNS white matter) and the neurological consequences are similar. The close interaction between the two themes further enforces this program. For instance, it may well be that ultimately, from what is learned about the monogenetic CWMDs, a better understanding emerges of the pathogenesis of (certain types of) MS. Both themes are aimed at a well defined patient population, and results have been gathered for several decades. Thereby well defined cohorts are available, with a wealth of clinical and research data, for both MS and CWMD.

Theme 1: Multiple sclerosis and other neuroimflammatory diseases
The MS research at the VUmc is assembled in the multidisciplinary MS Center Amsterdam. The center is a reliable source of scientific information about MS for both neurologists and patients. About 50 percent of all newly diagnosed MS patients in the Netherlands visit the center for a consultation. The center is one of the top five MS research groups in the world. It includes more than 60 researchers of different disciplines who collaborate to answer questions regarding the cause and cure of MS. The center’s combination of fundamental and clinical research allows it to quickly apply new research developments in diagnostics and treatment of MS. In addition, clinical questions can be answered in collaboration with basic scientists. The interdisciplinary interaction between neurology, radiology, pathology and immunology within one center is quite unique worldwide. An independent national (CWTS) analysis revealed that the center has a very high number of top publications. The theme leaders are among the most frequently cited scientists in the field of MS.

Theme 2: Childhood white matter diseases
The Center for CWMD at the VUmc integrates patient care, diagnostics, research, and education. It has a widely recognized national and international position with patient referrals from all other university medical centers in The Netherlands, as well as many MRI second opinions and numerous consultations for metabolic and genetic evaluation from all over the world. The research is truly translational. It is based on clinical issues, includes basic laboratory experiments, and involves application of the research results to the development of therapeutic approaches. We focus on optimization of diagnostic processes, elucidation of disease mechanisms and development of treatment. The research group is multidisciplinary, including physicians and basic scientists of different disciplines. Our research has been extremely successful with publications in top journals and prestigious prizes. In 2008 the research on CWMD has been awarded the Spinoza prize, the highest research award in The Netherlands.

Background

In the program ‘White matter diseases’ we aim at understanding pathogenic mechanisms of typical white matter diseases. Also we wish to obtain insight into mechanisms that contribute to disease progression in order to define new targets and strategies for possible therapeutic interventions. The cooperation between the two themes concerns MR imaging of white matter defects and lesions, neuropathological analysis, and cell biological approaches to study pathophysiological mechanisms in in vitro models (such as astroglia and oligodendrocyte cultures).

Theme 1: Multiple sclerosis and other neuroimflammatory diseases
MS is an immune mediated white matter disease with unknown aetiology mainly occurring in adults with onset between the ages of 20–40. Probably endogenous (genetic) factors and environmental factors both contribute to disease susceptibility and possibly also to the type of disease.
The MS Center Amsterdam has three important aims: research of MS, care for people with MS and education of MS-specialized researchers, neurologists and radiologists. Our key theme, ‘Early and Targeted’, aims at generating knowledge on early disease events and inter-individual heterogeneity. The center performs multidisciplinary, basic to bedside and vice versa research closely linked to an important patient group at VUmc. The research plan furthermore includes research of innovative techniques and translational research.

Theme 2: Childhood white matter diseases
For children, white matter diseases constitute a heterogeneous category of disorders with many different underlying causes, most often genetic. Individual CWMDs are rare, but together they form a substantial group with more or less the same incidence as MS. A major problem of CWMDs is that in a large proportion of the patients no specific diagnosis can be established, despite extensive laboratory work-up. The Center for CWMD has four important aims: 1) optimization of the MRI diagnosis of white matter disorders and MRI second opinions; 2) definition of novel white matter disorders, identification of their basic defects and insight into their pathophysiology; 3) care for children with white matter disorders and their families; and 4) development of new therapies, both symptomatic and curative.

Executive summary

Theme 1: Multiple sclerosis and other neuroimflammatory diseases
The primary goal of the MS Center Amsterdam is to perform internationally distinctive MS research that allows better understanding and treatment of MS. The 5-year (2005-2010) strategic plan defined as main motto of the center ‘Early and targeted’. By identifying the different disease subtypes we can design targeted treatment strategies. Starting a targeted treatment at an early stage of MS, when there is still limited damage, will lead to better quality of life for patients. In this respect we distinguish different research lines divided up into three categories:

CAUSE

• Pathogenesis (lesion formation and neuroimmunology)
• Pathogenesis (dendritic cell immunobiology)
• Pathogenesis (astrogliosis-remyelination)
• Biomarkers
• Neuropathology
• Neuropathology - MRI correlation
• MRI pattern recognition
• Genomics and genetics

CURE

• Target finding
• Outcome measurements
• Clinical  trials
• Research infrastructure

CARE

• MRI diagnosis and prognosis
• Treatment protocols

Theme 2: Childhood white matter diseases
The primary goal of the Center for Childhood White Matter Disorders is to improve the diagnosis and understanding of CWMD in order to find openings for better treatment.
CWMDs can be divided into acquired damage and genetic disorders. The genetic CWMDs can be divided in metabolic and non-metabolic.

For all three CWMD subcategories, the following major research tools are used:

• MR imaging (pattern recognition, quantitative parameters)
• MR spectroscopy
• Neuropathology

For the genetic CWMDs, the focus is on identification of novel disease genes, understanding of disease mechanisms and development of better treatments. In doing so we will apply

• Genetics
• Biochemistry / metabolomics
• Molecular biology
• Cell biology
• Genotype-phenotype correlation
• Neuropathology and immunohistochemistry
• Experimental neurophysiology
• Mouse models
• Stem cell biology
• Compound screening

For all three CWMD subcategories, optimization of symptomatic treatment is an important target, especially treatment of spasticity and loss of communication.

Future perspectives

Theme 1: Multiple sclerosis and other neuroimflammatory diseases
We still need to know more about MS if we are to provide optimal support for MS patients and to achieve our goal of finding a cure for the disease in the future. The MS Center Amsterdam wants to raise the quality of life of people with MS by diagnosing the disease early and providing effective treatment.

We know a lot more about the blood-brain barrier regulation under neuro-inflammatory conditions now than we did ten years ago. Thanks to the various advanced cell-culture systems in a human and rodent setting at our disposal, we will be able during the coming years to investigate which substances or molecules reinforce the blood-brain barrier and limit cell migration. We will also be studying whether antioxidants can help to protect the blood-brain barrier and which biological processes play a role in enabling leukocytes to pass through the barrier. Newly established MR and PET imaging modalities techniques offer the possibility to differentiate between the various pathological processes ongoing during the animal model for MS and assess protective effects of blood-brain barrier reinforcing agents. In addition the newly obtained multiphoton (NWO grant) will be used to visualize in vivo cell migration in varying circumstances (eg with and without Tysabri). It is hoped that these various studies will form the basis for new therapies.

Macrophages play a crucial role in axonal degeneration, but also in the prevention and possibly recovery of early axonal damage. This could be dependent on the phenotype of macrophages during different phases of lesion formation. We want to be able to modulate the phenotypes of macrophages to enable prevention of progression of axonal damage into extensive irreversible damage.
The brain material of MS patients allows us to investigate mechanisms that contribute to lesion formation. The MRI guided sampling of MS lesions provides us with lesion material that cannot be sampled with the naked eye. More importantly it facilitates neuropathological characterization of MRI detected abnormalities. We want to expand these correlative studies, in order to define the pathological substrate for subtle MRI changes (normal appearing white matter, preactive lesions, gray matter changes). Furthermore we want to check if the findings in the basic research (eg on blood brain barrier and neurodegeneration) are reflected in MS lesion pathology. Approaches will include immunohistochemistry, cell culture from autopsy material, and genomics/proteomics of dissected lesion (areas).

Although the early detection of MS has improved by the new MRI-techniques, there is still more progress to be made. Furthermore, the correlation of MRI scans with our pathological findings will bring more knowledge on how MS lesions develop. We want to reduce the time needed to analyze MRI scans, not only for monitoring of lesion activity, but also in terms of MRI markers for neurodegeneration (normal appearing brain tissue and brain volume).

By using genomics we hope to identify the typical differences in gene activity between the different subtypes of MS, and thereby to discover which biological processes are disturbed in MS. In addition, we hope that this technique will help us to predict whether MS patients will respond to particular therapies.

In addition, we are searching for suitable biomarkers to distinguish between different subtypes of MS, to determine the activity of the disease and to predict its future course. We will discover such new biomarkers by proteomics of CSF and serum, and then validate these findings in larger cohorts. For identified suitable biomarkers, assays will be developed and validated. Such biomarkers could also be used to monitor the effect of a given treatment.

Over time more and more important decisions affecting patients, practice, policy, and public funds will be based on results generated by rating scales. It is critical that these scales are rigorous measures but so far, the majority of the scales that are used to define disease severity in MS are far from satisfying this requirement. Major weaknesses are: a lack of conceptual clarity, a poor scientific base, and limited flexibility. Future research will focus on developing a series of scales for MS that measure the most important constructs for clinical trials and clinical practice and to develop these as “item banks” rather than as fixed length-rating scales.

The MS Center Amsterdam is currently developing an online system operating in the Netherlands, where both patients and the health professionals responsible for their treatment can view and (subject to quite stringent safeguards) modify clinical data on the patient in question. This provides very useful background information each time the patient consults his or her specialist and when the latter needs to advise the patient concerning various details of the treatment. The MS patient portal will improve patient care, promote communication between the various health professionals involved, help patients to manage their own case more effectively, make it possible for patients to receive information tailored to their needs, support online care and facilitate doctor-patient consultation by E-mail.

In the past years we started to develop formal programs to better share our knowledge. We started a course for Dutch neurologists and we have in cooperation with the pharmaceutical company Bayer Schering Health an MS-fellowship for MS researchers. We would like to broaden these possibilities for more young scientists and clinicians.

Theme 2: Childhood white matter diseases
Most research efforts of the Center are on genetic white matter disorders, both metabolic and non-metabolic. In the last 15 years, the definition of novel diseases by both biochemical and MRI techniques has been highly successful and numerous novel diseases have been identified. The search for the basic genetic defects has been equally successful. Subsequently, multiple studies on the pathophysiology of the diseases have been initiated.

The search for novel diseases and disease genes will be continued. We have a huge database of unsolved CWMDs and we will continue to apply clinical, biochemical/metabolic and MRI techniques to identify novel disease entities. We have ongoing genetic linkage studies and expect to be able to continue to start new genetic linkage studies in the future. Considering the high number of unclassified CWMDs, we still have a long way to go.

We have found that most of the newly identified CWMDs are not demyelinating disorders but are disorders of glia (astrocytes and oligodendrocytes). Consequently, our therapeutic strategies need to target glia. We are working on the exploration of glia progenitor transplantation for several disorders. The question if we could provide the brain with healthy glia progenitors in an early stage, when the brain structure is still preserved or relatively preserved, is whether we could prevent the development of the CWMD or whether we could halt the progression of the disease.

For several newly identified gene defects we have an eligible cell system (lymphoblasts, fibroblasts) for testing treatment options. For some of these disorders we will apply compound screening to select drugs with potential beneficial effects. We are working on high throughput screening tests to allow screening of thousands of compounds in a short time.

Some mutant mouse models have been developed for the diseases we study and some are under development. These mouse models are necessary for in-depth studies on the pathophysiology of the disease; they are indispensible for the testing of the potential beneficial effects of glial progenitor transplantation and eligible compounds.

The most common cause of acquired white matter damage is perinatal asphyxia. Worldwide, great efforts are dedicated to the prevention of hypoxic-ischemic brain damage around birth, especially for the most vulnerable: the prematurely born infants. Our research efforts are mainly dedicated to the assessment of the brain damage (clinical handicap, MRI abnormalities), long-term outcome (with implications for the understanding of brain plasticity) and most of all the optimization of treatment (with again implications for brain plasticity). Major therapeutic targets are spasticity and loss of communication skills.

The neurological consequences of cerebral white matter damage related to either a genetic disease or acquired damage are the same: motor problems dominate and affect ambulation, manual skills and communication. This implicates that therapeutic strategies developed for acquired white matter damage can be applied to all types of CWMDs. 

We are working on the set-up for a therapeutic center for CWMDs, in which both symptomatic and curative treatment can be offered. We aim at patients within The Netherlands and within Europe. We will offer novel therapies, developed in the center in Amsterdam, but we will also offer participation in international trials for the Dutch patients.

The focus on CWMD is unique world-wide. Consequently, we have a unique collection of body fluid samples, cell lines, DNA, MRIs and neuropathological specimen. We participate in courses on MRI interpretation & pattern recognition and neuropathology of CWMDs around the world. Training of fellows and young specialists in metabolic research, MRI interpretation and neuropathology of CWMDs will also be a focus in the coming years.