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Stroke is a very common disease which leads to a massive burden of disability in society and causes approximately ten percent of all deaths. Ischemic stroke is the most common subtype followed by intracerebral hemorrhage and subarachnoid hemorrhage. Ischemic stroke is caused by obstruction of blood vessels by clot. These clots can originate in the heart, in vessels leading to the brain (aorta, cervical vessels) and in blood vessels within the brain. Leading causes of emboli are atrial fibrillation and carotid atherosclerosis.
Few therapies are effective in the acute stage, except tissue plasminogen activator. Currently, three therapeutic strategies are investigated. One of the strategies is to salvage the ischemic penumbra by reperfusion, the second strategy aims at protection of the neurovascular unit and the third is geared towards enhancing native recovery mechanisms in the subacute stage after cerebral ischemia. Neuroprotective strategies, including anti-excitotoxic, anti-inflammatory and anti-apoptotic drugs which were successful in animal models failed subsequently in human clinical trials. Multiple reasons for these failures have been proposed, one of which is the extreme rapidity of the ischemic process with ischemia leading to tissue necrosis in minutes to hours. A strategy that targets the native recovery strategies employed by the ischemic brain, a process occurring over days, could therefore have considerable advantages.
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Project 1. The mechanism of recovery from stroke
Investigator: Vincent Thijs
The recovery process following stroke is very variable and involves a complex and dynamic process which is incompletely understood. At the structural level, stroke induces not only a region of cell death and scar formation, but also regions of neural repair, neurogenesis and reorganization. At the cellular level both axonal sprouting and neurogenesis enhance formation of new neural networks which are thought to be essential for functional recovery. Axonal sprouting occurs in peri-infarct and connected cortical areas after stroke. Growth cone proteins like GAP43 are induced in several areas within the peri-infarct cortex, a process followed by increases in synapse formation. New connections, sometimes over distances up to 1 cm between cortical areas have been found in primates. At the same time, the efficacy of axonal sprouting in forming new connections is impeded by formation of a glial scar. In this region, surrounding the infarct, a growth inhibitory program is executed with induction of chondroitin sulphate proteoglycans like neurocan, ephrins, members of the semaphorin class and myelin associated glycoprotein. Finally, stroke induces the migration of newly born immature neurons (neuroblasts) into the areas of ischemic damage. Migration of neuroblasts over long distances to the peri-infarct cortex has been demonstrated. Their survival is however limited as many of these neurons die within a few days after migration. The role of the newly formed neurons in the recovery process is under intense scrutiny.
In this project we investigate the molecular mechanisms that contribute to the recovery of brain ischemia and study the pathways for interference in order to enhance recovery from stroke.
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 Imaging acute cerebral ischemia using diffusion-weighted MRI in humans
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Project 2. Genetics of stroke and stroke recovery
Investigator: Vincent Thijs
Stroke is traditionally considered a sporadic, non inherited disease caused by acquired vascular risk factors like
hypertension and diabetes. Several arguments point towards a genetic contribution to stroke as well. A history
of stroke in siblings or parents predisposes to stroke. Moreover, monogenetic causes of stroke have been identified. CADASIL, an autosomal dominant disorder caused by mutations in the Notch 3 gene manifests as ischemic stroke, white matter disease, migraine and dementia. Genetic studies of functional recovery after ischemic stroke in humans have been rarely performed. One study found that a functional variant in the BDNF gene influenced recovery after subarachnoidal hemorrhage after studies demonstrated that this variant influenced axonal outgrowth and cortical structure. These studies demonstrate that genetic variants may influence recovery within the frame of a complex disease like stroke.
We propose to study risk factors for stroke by performing case control studies in collaboration with the International Stroke Genetics Consortium. The project attempts to confirm the importance of several single nucleotide polymorphisms that have been found in genome wide association studies of risk factors for stroke (hypercholesterolemia, atrial fibrillation, diabetes and myocardial infarction). Furthermore, we study whether SNPs in genes that are involved in axonal regeneration influence the outcome after human stroke.
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Project 3. Treatment of Stroke
Investigator: Vincent Thijs
In collaboration with the University Hospital Leuven and we are investigating new therapeutic avenues for patients with stroke. These studies are done in collaboration with industrial partners. We are currently testing new preventive drugs (in collaboration with Schering Plough) and treatment devices (in collaboration with Coaxia). More information on these trials can be obtained at www.neurology-kuleuven.be.
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Research 
