White matter disorders
Multiple sclerosis [MS] is widely-considered to be an autoimmune, demyelinating and neurodegenerative disease of the central nervous system [CNS], leading to the accumulation of significant motor, sensory and cognitive disabilities. MS affects about 2,500,000 people worldwide and is more common in high-income countries. The pathophysiology of MS is reportedly complex, involving different and distinct disease processes that probably require fundamentally different treatments modalities. For example whilst the disease affects both the white matter and the gray matter differences in the pathology are observed that may reflect differences in the mechanisms underlying damage.
The MS research line is thus directed at elucidating the pathogenetic mechanisms underlying both white and gray matter lesions in MS. In addition we aim to correlate the pathology with in vivo imaging i.e. MRI and PET, to better correlate disease mechanisms operating during disease progression.
Our main topics include:
a) differences in the mechanisms contributing to gray matter versus white matter lesions
b) the role of autoimmunity to neuronal antigens and white matter antigens (including heat shock proteins) arising as a consequence of inflammation and damage in the CNS in MS
c) the characterization of early lesion formation (preactive lesion) with a specific focus on the cross-talk of microglia and astrocytes with oligodendrocytes
d) the role of Epstein-Barr virus in induction of the (auto)immune responses , specifically the generation of pathogenic anti-CNS antibodies
e) the impact of ageing in the CNS and specifically of how ageing influences disease progression in MS
f) investigating the role of TSPO including the use of TSPO as a novel treatment regimen to control innate immune responses in the CNS
To investigate these research lines we use human post-mortem tissue from MS and control cases, (in collaboration with the Netherlands Brainbank). To examine aspects of the mechanisms underlying the pathology we have developed novel animal models of MS, and have established in vitro human CNS cultures. These models in conjunction with neuropathological studies of MS allow translation to the clinic.
Genetic White Matter Disorders (the leukodystrophies)
There is a large number of genetic white matter disorders, all characterized by abnormal white matter and all rare. These disorders, also called leukodystrophies, are due to structural or functional defects in the white matter structural components, including oligodendrocytes, astrocytes, microglia, axons and blood vessels. Prof. M. van der Knaap (Amsterdam university medical centers, department of pediatric neurology) has a unique expertise in this field and has characterized at numerous disease entities. The pathological characterization of these has focused on a variety of aspects, i.e. the genetics and the cellular pathophysiology. The genes for these diseases have been characterized and (conditional) knock-out mice for many of these disorders have been generated. The characterization of the pathology of these mice, spontaneous and after interventions has been performed (M. Bugiani). At this moment this project is directed by Prof. van der Knaap, in collaboration with dr. M. Bugiani positioned at the department of Pathology. The exact mechanisms of damage to the cells involved and of the myelin sheath are in progress and often surprising findings come to the fore, for instance that defects in cells that are in strict sense not involved in myelination, such as astrocytes, do cause dysfunction of myelinating cells (oligodendrocytes) and with that the actual disease. This findings often open to treatment options such as transplantation of the cell type detrimental in the single disease.
Paul van der Valk MD PhD - White Matter Group Leader
Sandra Amor PhD - Program leader of Multiple Sclerosis
Marianna Bugiani MD PhD - Program leader of Genetic White Matter Diseases
Jodie Stephenson - (post-doctoral researcher, MS group)
Erik Nutma - PhD student (MS group)
Rianne Gorter - PhD student (MS group)
Claudia Stella Denise Nyamoya (MS group)
Joy De Bruin (MS group)