Comparison of brain vasculature network characteristics between wild type and Alzheimer’s disease mice using topological metrics

There is a strong clinical correlation between Alzheimer’s disease (AD) and microvascular disorders. In mouse models of AD, our lab has found blood flow dysfunction in brain capillaries, suggesting the need to study the function of vascular networks at the capillary level. However, the ability to deliver blood flow continuously to all neurons also depends on connections between vessels, requiring that we also characterize the topology of brain vascular networks. Here, we use graph theory and topological metrics to characterize the connectivity of brain capillary networks in AD and control mice

Brain capillary networks across species : a few simple organizational requirements are sufficient to reproduce both structure and function

International audienceDespite the key role of the capillaries in neurovascular function, a thorough characterization of cerebral capillary network properties is currently lacking. Here, we define a range of metrics (geometrical, topological, flow, mass transfer, and robustness) for quantification of structural differences between brain areas, organs, species, or patient populations and, in parallel, digitally generate synthetic networks that replicate the key organizational features of anatomical networks (isotropy, connectedness, space-filling nature, convexity of tissue domains, characteristic size). To reach these objectives, we first construct a database of the defined metrics for healthy capillary networks obtained from imaging of mouse and human brains. Results show that anatomical networks are topologically equivalent between the two species and that geometrical metrics only differ in scaling. Based on these results, we then devise a method which employs constrained Voronoi diagrams to generate 3D model synthetic cerebral capillary networks that are locally randomized but homogeneous at the network-scale. With appropriate choice of scaling, these networks have equivalent properties to the anatomical data, demonstrated by comparison of the defined metrics. The ability to synthetically replicate cerebral capillary networks opens a broad range of applications, ranging from systematic computational studies of structure-function relationships in healthy capillary networks to detailed analysis of pathological structural degeneration, or even to the development of templates for fabrication of 3D biomimetic vascular networks embedded in tissue-engineered constructs

How do capillary occlusions impact brain microcirculation in Alzheimer's disease ? Numerical Simulations and Experimental validation

The most common form of dementia is Alzheimer's disease, making it a major health problem. While studied intensively, no cure or even clear diagnostic procedures have been found yet (Nelson JNEEN 2012). A recent study (Iturria-Medina Nat Com 2016) has shown that a significant decrease in blood flow arises in the onset of Alzheimer's disease. In vivo two photon microscopy of cortical vasculature in APP/PS1 mouse models suggests that the mechanism underlying this blood flow reduction is capillary occlusions due to leucocytes adhering to inflamed blood vessel walls (Cruz-Hernandez Neuroscience meeting 2016). However, these techniques generate massive amounts of anatomical and functional data that are difficult to interpret without proper theoretical and numerical frameworks. Here, we develop a model describing blood flow in large microvascular networks that accounts for complex blood rheology (hematocrit-dependent viscosity and non-linear phase separation at bifurcations, Pries Microvasc Res 1989). We validate it by comparison with in vivo measurements in mice and extrapolate the model to humans. We then quantify the impact of capillary occlusions on regional perfusion for both species. The numerical simulations, based on an iterative algorithm derived from Newton's fixed point method (Lorthois, Neuroimage 2011) are run in 4 postmortem mice anatomical networks with more than 10,000 vessels each acquired by two-photon imaging (Tsai J Neuroscience 2009). For human we use a dataset composed of 300 μm thick slices (over 20,000 vessels per slice) acquired by confocal microscopy (Cassot Microcirculation 2006). We correct post-mortem vessel variations in both dataset using shape-preserving transformations based on available in vivo measurements. We validate our model and corrections by direct comparison with in vivo red blood cell velocity measurements performed in mice (Santisakultarm AJPHCP 2012, Taylor JCBFM 2016). We then investigate, for both humans and mice, the impact of an increasing percentage of capillary occlusions on regional perfusion, defined as the sum of flows in all arterioles supply the studied domain. We observe a clear linear dependence in both species, with similar slopes and no threshold effect. Our results imply that even a small percentage of occluded vessels (2-4%) yield a drastic reduction of regional perfusion (5-12 % in mice and humans), which is of the same order of magnitude as observed experimentally in APP/PS1 mice. Finally, we show that these slopes are controlled by the capillary network connectivity and spatial distribution of occlusions across the network, while only slightly affected by uncertainties on vessel diameters