Abstract
Knowledge of the three-dimensional (3D) architecture of blood vessels in the brain is crucial because the progression of various neuropathologies ranging from Alzheimer's disease to brain tumors involves anomalous blood vessels. The challenges in obtaining such data from patients, in conjunction with development of mouse models of neuropathology, have made the murine brain indispensable for investigating disease induced neurovascular changes. Here we describe a novel method for “whole brain” 3D mapping of murine neurovasculature using magnetic resonance microscopy (μMRI). This approach preserves the vascular and white matter tract architecture, and can be combined with complementary MRI contrast mechanisms such as diffusion tensor imaging (DTI) to examine the interplay between the vasculature and white matter reorganization that often characterizes neuropathologies. Following validation with micro computed tomography (μCT) and optical microscopy, we demonstrate the utility of this method by: (i) combined 3D imaging of angiogenesis and white matter reorganization in both, invasive and non-invasive brain tumor models; (ii) characterizing the morphological heterogeneity of the vascular phenotype in the murine brain; and (iii) conducting “multi-scale” imaging of brain tumor angiogenesis, wherein we directly compared in vivo MRI blood volume measurements with ex vivo vasculature data.
Highlights
The neurovasculature plays a critical role in a wide range of neuropathological processes from dementia to stroke to tumors [1]
We demonstrate the potential of our mMRI technique via several applications that include combined 3D imaging of angiogenesis-induced vascular remodeling and white matter reorganization in both, invasive and non-invasive brain tumor models; characterization of the morphological heterogeneity of the neurovasculature; and ‘‘multi-scale’’ imaging of brain tumor angiogenesis
We validated the fidelity of the mMRI-derived vasculature by comparing it to that acquired using micro computed tomography (mCT) and whole-mount optical microscopy
Summary
The neurovasculature plays a critical role in a wide range of neuropathological processes from dementia to stroke to tumors [1]. The physiological underpinnings of image contrast in functional MRI (fMRI) critically involves the neurovasculature [2], and is central to understanding drug delivery and pharmacokinetics of novel therapies in the brain [3,4]. The challenges in obtaining high-resolution vascular data from patients, combined with new pre-clinical models of neuropathology, have made the mouse brain indispensable to investigations of these areas [5,6]. 3D reconstruction of 2D tissue slices generates high resolution imaging data, the practical limit as to the number of adjacent tissue slices that can be obtained limits the region of brain that can be interrogated. Corrosion casts allow extensive brain regions to be analyzed but require dissolving of tissues to visualize cast vessels, and precludes simultaneous assessment of the vasculature and neuroanatomy
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