Abstract
Blood microcirculation supplies neurons with oxygen and nutrients, and contributes to clearing their neurotoxic waste, through a dense capillary network connected to larger tree-like vessels. This complex microvascular architecture results in highly heterogeneous blood flow and travel time distributions, whose origin and consequences on brain pathophysiology are poorly understood. Here, we analyze highly-resolved intracortical blood flow and transport simulations to establish the physical laws governing the macroscopic transport properties in the brain micro-circulation. We show that network-driven anomalous transport leads to the emergence of critical regions, whether hypoxic or with high concentrations of amyloid-β, a waste product centrally involved in Alzheimer’s Disease. We develop a Continuous-Time Random Walk theory capturing these dynamics and predicting that such critical regions appear much earlier than anticipated by current empirical models under mild hypoperfusion. These findings provide a framework for understanding and modelling the impact of microvascular dysfunction in brain diseases, including Alzheimer’s Disease.
Highlights
Blood microcirculation supplies neurons with oxygen and nutrients, and contributes to clearing their neurotoxic waste, through a dense capillary network connected to larger treelike vessels
Understanding the links between the microvascular architecture, reduced blood flow, and impaired oxygen delivery and metabolic waste clearance is a key challenge to decipher the role of microvascular dysfunction in brain disease
The microvascular architecture is structured by tree-like arterioles and venules that connect to a dense capillary network[3,12,13]
Summary
Blood microcirculation supplies neurons with oxygen and nutrients, and contributes to clearing their neurotoxic waste, through a dense capillary network connected to larger treelike vessels. We develop a Continuous-Time Random Walk theory capturing these dynamics and predicting that such critical regions appear much earlier than anticipated by current empirical models under mild hypoperfusion These findings provide a framework for understanding and modelling the impact of microvascular dysfunction in brain diseases, including Alzheimer’s Disease. The progressive appearance of abnormal vessel architectures, including reduced capillary diameters or stalling, and the decrease in regulation efficiency together reduce blood flow and the availability of oxygen[2,5,7,8,9,10,11] This alters the clearance of metabolic waste, including neurotoxic forms of amyloid-β centrally involved in the pathogenesis of Alzheimer’s Disease (AD)[4,9,10]. Since reduced capillary flow compromises metabolic waste clearance, critical vessels with abnormally high intravascular concentrations of amyloid-β may be expected
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