Ultra High-Resolution In vivo Computed Tomography Imaging of Mouse Cerebrovasculature Using a Long Circulating Blood Pool Contrast Agent

Abstract

Abnormalities in the cerebrovascular system play a central role in many neurologic diseases. The on-going expansion of rodent models of human cerebrovascular diseases and the need to use these models to understand disease progression and treatment has amplified the need for reproducible non-invasive imaging methods for high-resolution visualization of the complete cerebral vasculature. In this study, we present methods for in vivo high-resolution (19 μm isotropic) computed tomography imaging of complete mouse brain vasculature. This technique enabled 3D visualization of large cerebrovascular networks, including the Circle of Willis. Blood vessels as small as 40 μm were clearly delineated. ACTA2 mutations in humans cause cerebrovascular defects, including abnormally straightened arteries and a moyamoya-like arteriopathy characterized by bilateral narrowing of the internal carotid artery and stenosis of many large arteries. In vivo imaging studies performed in a mouse model of Acta2 mutations demonstrated the utility of this method for studying vascular morphometric changes that are practically impossible to identify using current histological methods. Specifically, the technique demonstrated changes in the width of the Circle of Willis, straightening of cerebral arteries and arterial stenoses. We believe the use of imaging methods described here will contribute substantially to the study of rodent cerebrovasculature.

Micro-computed tomography in murine models of cerebral cavernous malformations as a paradigm for brain disease

“…Finally, the micro-CT technique was validated using two observers and demonstrated high reliability. While there exist techniques for imaging cerebral vasculature using micro-CT (Ghanavati et al, 2014; Starosolski et al, 2015) as well as techniques to preserve tissue for histological analysis (Dobrivojevic et al, 2013; Hopkins et al, 2015), this study is the first to implement, optimize and validate a quantitative volumetric assessment of a model of cerebral vascular disease, in comparison to classical morphometry.…”

First-in-Human Study of Acoustic Angiography in the Breast and Peripheral Vasculature

“…Of note, the sensitivity and spatial resolution of the current system used in this study allowed acquisition of images with vessels as small as 100–200 μm (Figure 3), similar to the resolution provided by pre-clinical MRI and CT systems (Herrmann, et al 2012, Jansen, et al 2009, Starosolski, et al 2015). Improvements in sensitivity would require either improved transducer sensitivity or increased microbubble dose.…”

“…Even with the use of contrast agents, the ability to both detect and resolve the microvessels of clinical interest remains challenging, as typical spatial resolutions for clinical imaging systems are ~700 μm for MRI (Pinker, et al 2014), ~600 μm for CT (Reiner, et al 2013), and 300–500 μm for conventional ultrasound (Rissanen, et al 2008). Special small animal imaging systems have demonstrated higher resolutions in all modalities, including as high as 100–200 μm in MRI (Herrmann, et al 2012, Jansen, et al 2009), as high as 40 μm in CT (for scan times >50 min) (Starosolski, et al 2015), and 30–200 μm for high-frequency ultrasound (Foster, et al 2009, Foster, et al 2002). …”

Opportunities for new CT contrast agents to maximize the diagnostic potential of emerging spectral CT technologies

“…These include polymeric constructs[100, 123] (including dendrimers[124]), emulsions[125, 126], micelles[127], liposomes[122] and nanoparticles[128–130] One variant employs a liposomal iodinated agent for high-resolution imaging with a blood pool contrast agent[131]. A coated version of polymeric iohexol has also been employed to exploit the longer retention in the body[129].…”