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Brain Microcirculation : Numerical simulation for inter-species translation with applications in human health

Final Report Summary - BRAINMICROFLOW (Brain Microcirculation : Numerical simulation for inter-species translation with applications in human health)

The cerebral microvascular system is essential to a large variety of physiological processes in the brain, including blood delivery and blood flow regulation as a function of neuronal activity (neuro-vascular coupling). It plays a major role in the associated mechanisms leading to disease (stroke, neurodegenerative diseases, ...).

In the last decade, cutting edge technologies, including two-photon scanning laser microscopy (TPSLM) and optical manipulation of blood flow, have produced huge amounts of anatomic and functional experimental data in normal and Alzheimer Disease (AD) mice. These require accurate, highly quantitative, physiologically informed modeling and analysis for any coherent understanding and for translating results between species.

In this context, we have developed a general methodological framework for physiologically informed microvascular fluid dynamics modeling, understood in a broad meaning, i.e. blood flow, molecule transport and resulting functional imaging signals or signal surrogates. By using multi-scale model reduction strategies, we are already able to simulate blood flow in regions with millions of vessels.

We have validated this methodological framework by direct comparison of in vivo anatomical and functional TPSLM measurements with simulation results based on mouse anatomical data.

These methodologies have been exploited in order to identify the role of vascular factors in AD. Specific hypotheses on how vascular changes in AD affect function have been experimentally tested in animal models of AD. For example, we discovered that blood flow reduction in the AD mouse brain is caused by the occlusion of individual capillary segments by neutrophils, a specific type of white blood cells. We have manipulated the occurrence of such occlusions, and found that the blood flow increases by up to 30% when removed. This large change in blood flow is correlated with a rapid increase of performance in short term memory tests. This result demonstrates that, at least early in the disease, neural performance deficits are caused primarily by blood flow.

For obvious ethical reasons, similar experiments cannot be done in human patients. However, using anatomical data acquired post-mortem in humans and the simulation tools developed in the present project, we predicted a comparable decrease in blood flow when human capillaries are occluded in a similar fashion. In both humans and mice, we predicted that this decrease in blood flow induces a decrease in nutrient and oxygen delivery, despite an increased extraction fraction. These results provide new insights for the design and/or evaluation of improved diagnosis/preventive/treatment strategies based on targeting blood flow in AD.