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Cellular mechanisms of critical illness-induced cognitive dysfunction

04/2016-03/2018

This third-party funded project is conducted in the framework of the BfR research programme on alternatives to animal experiments.

Einstein Foundation grant number: A-2014-223

Project homepage: http://www.einsteinfoundation.de/en/people-projects/einstein-research-projects/

Project description:

There is compelling evidence that survivors of critical illness who enter medical care with no evidence of cognitive impairment are often discharged with severe de novo neurocognitive decline that is long-lasting and likely permanent. More than one in three patients have profound cognitive impairments for at least one year after release from an intensive care unit (ICU) and as medical care is improving, the number of survivors of critical illness is growing worldwide.

Sepsis, a potentially life-threatening systemic inflammation, is a leading cause of ICU admission and commonly precipitates severe long-term cognitive impairment. Recent studies aiming to elucidate the neuronal correlate of cognitive demise have found neuroinflammation (i.e. activation of microglia, the immune cells of the central nervous system) and neuronal death to be responsible for diffuse cerebral damage and eventually brain atrophy. However, the underlying pathophysiology remains poorly understood.

Based on mounting evidence that phagocytosis (i.e. engulfment and degradation of a target) can eliminate functional neurons and/or synapses during brain inflammation, it is conceivable that neuronal and/or synaptic loss following sepsis is executed by microglial phagocytosis. Using an animal model of sepsis, the primary aim of this project is to investigate whether phagocytosis of neurons and/or synapses is beneficial or detrimental for cognitive outcome following sepsis. These studies will determine whether anti-phagocytic treatment may be a therapeutic option for preventing cognitive deficits in sepsis survivors.

The detection of subtle cognitive deficits in rodent models of sepsis using conventional behavioural tests is highly challenging and large cohorts of animals are often required. The second aim of this project is to assess the respective merits of common manual and automated behavioural tests to improve the detection of subtle cognitive alterations and thus facilitate the implementation of the principles of reduction and refinement in behavioural analyses to improve animal welfare.

Project partners:

• Charité - Universitätsmedizin Berlin, Germany
• Eberhard Karls Universität Tübingen, Germany

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