Network-driven anomalous transport is a fundamental component of brain microvascular dysfunction

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.

The glymphatic system: Current understanding and modeling

“…Most studies of perivascular spaces have avoided the complexities of bifurcations and of interactions among the many PVS segments that comprise the glymphatic system. Although the computational costs of simulating those complexities are daunting, flow and transport are surely affected by bifurcations and interactions, which are routinely simulated in studies of blood flow (e.g., see Goirand et al (Goirand et al (2021)). Daversin-Catty et al (2020) simulated flow in a bifurcation, concluding that in vivo flow characteristics could most easily be reproduced via a combination of arterial pulsation and a steady pressure gradient of unknown source.…”

Advances in studying whole mouse brain vasculature using high-resolution 3D light microscopy imaging

“…High-resolution cerebrovascular datasets provide crucial structural information to simulate blood flow using in silico modeling. 52 , 53 Sample collection (e.g., perfusion and fixation) and labeling procedures (e.g., vessel filling with dyes or 3D immunolabeling with tissue clearing) may introduce distortion. Thus, careful validation is needed to confirm that vascular geometry measurements (e.g., vascular diameter, shape, connectivity) from fixed brains are matched or correlated with in vivo conditions.…”

Red blood cell dynamics in extravascular biological tissues modelled as canonical disordered porous media

“…Significant progress in computational modelling has been made over recent years to elucidate the complex behaviour of blood flow in physiological environments, e.g. the small-vessel network in the brain [1][2][3], in the eye [4,5], in tumours [6] and in microaneurysms [7]. However, the flow and transport of blood and solutes in other (e.g.…”