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Imprint
Mechanisms of Critical Illness-induced Cognitive Dysfunction
Project
Project code: BfR-ZEBET-08-1336-105, A-2014-223
Contract period: 01.04.2016
- 31.12.2018
Purpose of research: Experimental development
There is compelling evidence that survivors of critical illness that 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 if 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.
The results showed that, under certain conditions and subject to further results, a deficiency in phagocytosis can increase the survival of neurons and improve long-term cognitive functions after sepsis. Research of refinement measures in animal based biomedical science was successful as well. Body temperature of animals should be used in this model as an additional criterion to define humane endpoints, the more so as even simple and non-invasive methods achieved sufficient accuracy. Machine learning applied to data from this and another animal disease model showed that the combination of body temperature data with other welfare indicators improved prediction accuracy of the individual mortality risk. This can be used to prevent unnecessary harm and suffering for the animals by early termination. Automation of behavioural tests, allowing animals to participate voluntarily according to their biorhythm, showed their potential to generate relevant data within a short time and with reduced stress for the animals. Such systems should be used in the future as part of the 3R-strategy in basic research. Publications: Mei J, Riedel N, Grittner U, Endres M, Banneke S, Emmrich JV. Body temperature measurement in mice during acute illness: implantable temperature transponder versus surface infrared thermometry. Sci Rep. 2018 Feb 23;8(1):3526. doi: 10.1038/s41598-018-22020-6. Emmrich JV, Neher JJ, Boehm-Sturm P, Endres M, Dirnagl U, Harms C. Stage 1 Registered Report: Effect of deficient phagocytosis on neuronal survival and neurological outcome after temporary middle cerebral artery occlusion (tMCAo). F1000Res. 2018 May 6:1827. doi: 10.12688/f1000research.12537.3. Mei J, Banneke S, Lips J, Kuffner MTC, Hoffmann CJ, Dirnagl U, Endres M, Harms C, Emmrich JV. Refining humane endpoints in mouse models of disease using body weight, temperature or sickness scores: a systematic review and approach to machine learning-based endpoint definition. ALTEX. 2019 Apr 18. doi: 10.14573/altex.1812231. [Epub ahead of print]
Section overview
Subjects
- Animal health
Framework programme
Funding programme
Excutive institution
BfR - Centre for Documentation and Evaluation of Alternatives to Animal Experiments (BfR - ZEBET)
