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BrainMicroFlow Report Summary

Project ID: 615102
Funded under: FP7-IDEAS-ERC
Country: France

Mid-Term 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 are developing 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 are validating this methodological framework by direct comparison of in vivo anatomical and functional TPSLM measurements with the simulation results based on mice anatomical data.

These methodologies are exploited in order to identify the logic of the structure/function relationships of brain microcirculation and neurovascular coupling, in human health and disease, with a focus on the role of vascular factors in AD. Specific hypotheses on how vascular changes in AD affect both vascular function and neurovascular coupling can be 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 white blood cells. We are now manipulating the occurrence of such occlusions, and found that the blood flow increases by up to 30% when removed. This large change in blood flow appears to be correlated with a rapid increase in performance in short term memory tests. This result suggests 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 predict a comparable decrease in blood flow when human capillaries are occluded in a similar fashion. Further modeling efforts will help to understand how these AD-induced vascular alterations could affect human patients. Ultimately, it will provide new avenues for design and/or evaluation of improved diagnosis/preventive/treatment strategies based on targeting blood flow in AD.

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