[Cerebrovaskuläre Erkrankungen][Neuroinflammation][Störungen funktioneller Netzwerkstrukturen]

(Die deutsche Übersetzung folgt demnächst)
Disorders of the central nervous system (CNS) have long been seen as diseases with little therapeutic potential. However, due to recent progress in our understanding of pathophysiological processes and the generation of novel ideas for interventions arising from basic as well as clinical studies, the prospects for successful prevention and treatment of neurological disorders have been vastly improved. NeuroCure will focus on cerebro-vascular and neuroinflammatory diseases as well as on disorders of network formation with stroke, multiple sclerosis, and focal epilepsies as well as brain malformations due to mitochondrial dysfunction as prototypical diseases. These neurological disorders share common mechanisms of damage, endogenous neuroprotection, and repair mechanisms. It is our vision that significant progress in the treatment of these disease complexes will result from the understanding and eventual therapeutic modulation of damage processes, endogenous neuroprotection, regeneration, crosstalk between nervous and immune system, developmental disturbances, and pathogenic plasticity. For this progress to ultimately benefit the patient, we in addition need to understand the effects on these mechanisms by confounding factors, such as age, gender, and comorbidities.

Cerebro-vascular diseases (CVD)

Cerebro-vascular diseases (CVD) are the most common neurological disorders. Stroke, the most prominent CVD, has an incidence of about 200,000 cases each year in Germany alone and is the number one cause of disability in the European Union. Indeed, about 25% of men and 20% of women can expect to suffer a stroke if they live to be 85 years old. This sex difference also applies to rodents such as the stroke prone rats. Although stroke is a major cause of death, mortality data underestimate the true burden of stroke. Since stroke causes disability more often than death, stroke patients frequently require long hospital stays followed by ongoing support. Stroke is consequently a major drain on health-care funding and resources. Because of the rapid increase in the elderly population, the total incidence of stroke is projected to increase considerably over the next two decades. Fortunately, the last decades have seen remarkable progress in the understanding of the pathophysiology of stroke. In addition, new avenues for the treatment of stroke utilizing strategies to induce the brain's own mechanisms of protection and regeneration have been opened. However, experiences in translating this knowledge into clinical interventions to combat acute stroke have been mixed. It is NeuroCure 's vision that by blocking subacute mechanisms of cell death, by utilizing endogenous mechanisms of protection and repair, by further understanding the complex bidirectional interactions of the ischemic brain with the immune system, and by applying novel strategies in clinical trial design, we will be able to protect or partially recover lost neurological function of stroke patients in the near future.

Neuroinflammation

Neuroinfl ammation has been recently shown to play an important role in the etiology of a variety of neurological disorders. Our understanding of principal mechanisms of the crosstalk between two research areas, the nervous and the immune system has been mostly derived from studies focusing on multiple sclerosis (MS), the most common neuroinflammatory disease of the CNS and the major cause of neurological disability in young adults in developed countries. For example, in Germany , more than 120,000 young people suffer from MS. Clinical manifestation of MS is typically characterized by recurrent episodes of neurological deficits such as, e.g., optic neuritis or paresis of the legs, and periods of remission. The relapsing-remitting disease course can then turn into a chronic progressive phase. Current disease models indicate that MS is a T-cell-mediated autoimmune disease and that the target is not only the myelin sheath of the CNS, but also neuronal structures including the axon and the neuronal cell body. This concept is based on data from human studies as well as the animal model of MS, experimental autoimmune encephalitis (EAE). In MS, physicians use magnetic resonance imaging (MRI) of the brain and the spinal cord to localize the lesions and to measure progression of the disease. Based on progress in the understanding of the underlying pathophysiology of the disease, novel therapeutic concepts have been already translated into the clinic. However, understanding the mechanisms leading to neuroprotection, e.g. blocking autoaggression and preserving protective and regenerative immune responses, is among the key challenges faced by neuroscientists today.

Disorders of network formation

Disorders of network formation are not yet attributed as a disease complex in classical neurological textbooks such as CVD and neuroinfl ammation. Nevertheless, it is becoming accepted that failure in structural and functional connectivity is the common denominator of various neurological syndromes. The human CNS harbors about 10 12 neurons which form around 10 15 specifi c connections. Proper function of this network depends on an orchestrated process of cell proliferation, migration, and differentiation. Genetic programs as well as activity dependent mechanisms act in combination, and alteration of this by mutations or traumatic insults in critical phases result in disorders of network formation. These disorders are often manifest in newborn and children, but may also become apparent only in adulthood. We are beginning to understand that the molecular machinery which governs this process is also in use during mechanisms of reorganization after damage in the adult brain, and may lead to maladaptive reorganization. An important example of such a complex disturbance of network formation is the induction of focal epilepsies, affecting approximately 250,000 people in Germany . More than 50% of these are pharmacoresistant. A small number of patients can be cured by surgical intervention, offering the potential to study disease processes in resected tissues. In Berlin, between 50 and 70 patients per year undergo surgical treatment of epilepsy. Focal epilepsies frequently are caused by disturbances of neuronal development, lesions and ischemia. Another set of disorders derive from the mutation of genes important for mitochondrial energy metabolism. The Department of Pediatric Neurology at the Charité provides a national center for medical care for these patients having specifi c phenotypes of cortical network malformations. The ultimate aim of our research on this topic is to understand the major steps which lead from selective alterations to specific disorders of network formation, and consequently, to therapeutically target these processes of malformation.  NeuroCure is geared to exploit the synergies created by the collaborative basic and clinical investigation of these prototypical CNS disorders. In the following, we will sketch our aims and hypotheses arranged by approaches and concepts, rather than grouping them by disease. This structure also demonstrates that NeuroCure is open to research into other pathologies of the nervous system such as chronic neurodegeneration in Alzheimer's or Parkinson's disease, also sharing molecular processes with the diseases focussed on in NeuroCure, but so far not as strongly represented in Berlin . Therefore, the current focus on the prototypical diseases described above may - with time - be supplemented or even replaced by other diseases of the nervous system.