The capability of detecting small vessels beyond the conventional MRI sensitivity using iron‐based contrast agent enhanced susceptibility weighted imaging

Abstract

Imaging brain microvasculature is important in cerebrovascular diseases. However, there is still a lack of non-invasive, non-radiation, and whole-body imaging techniques to investigate them. The aim of this study is to develop an ultra-small superparamagnetic iron oxide (USPIO) enhanced susceptibility weighted imaging (SWI) method for imaging micro-vasculature in both animal (~10 μm in rat) and human brain. We hypothesized that the USPIO-SWI technique could improve the detection sensitivity of the diameter of small subpixel vessels 10-fold compared with conventional MRI methods.Computer simulations were first performed with a double-cylinder digital model to investigate the theoretical basis for this hypothesis. The theoretical results were verified using in vitro phantom studies and in vivo rat MRI studies (n = 6) with corresponding ex vivo histological examinations. Additionally, in vivo human studies (n = 3) were carried out to demonstrate the translational power of the USPIO-SWI method.By directly comparing the small vessel diameters of an in vivo rat using USPIO-SWI with the small vessel diameters of the corresponding histological slide using laser scanning confocal microscopy, 13.3-fold and 19.9-fold increases in SWI apparent diameter were obtained with 5.6 mg Fe/kg and 16.8 mg Fe/kg ferumoxytol, respectively. The USPIO-SWI method exhibited its excellent ability to detect small vessels down to about 10 μm diameter in rat brain. The in vivo human study unveiled hidden arterioles and venules and demonstrated its potential in clinical practice. Theoretical modeling simulations and in vitro phantom studies also confirmed a more than 10-fold increase in the USPIO-SWI apparent diameter compared with the actual small vessel diameter size.It is feasible to use SWI blooming effects induced by USPIO to detect small vessels (down to 10 μm in diameter for rat brain), well beyond the spatial resolution limit of conventional MRI methods. The USPIO-SWI method demonstrates higher potential in cerebrovascular disease investigations.Abbreviations: 3D, three dimensional; CA, contrast agent; CNR, contrast-to-noise ratio; FITC-dextran, fluorescein isothiocyanate-dextran; FOV, field of view; IV, intravenous; LSCM, laser scanning confocal microscopy; MRA, magnetic resonance angiography; PVS, para-vascular space; SNR, signal-to-noise ratio; SWI, susceptibility weighted imaging; T 2 *W, T 2 * weighted; USPIO, ultra-small superparamagnetic iron oxide; Δχ, susceptibility difference of adjacent materials.

A Review of Translational Magnetic Resonance Imaging in Human and Rodent Experimental Models of Small Vessel Disease

“…We did find a few studies where assessment tools developed to assess SVD features in humans, such as the Fazekas scale for WMH [56], Brain Observer MicroBleed Scale (BOMBS) for cerebral microbleeds [57] and several image analysis methods such as segmentation and voxel-based morphometry, have been adapted for use in animal models [22,54]. We also found one example of a novel imaging approach developed to assess perivascular space fluid uptake in rodents that had been translated to human use [53].…”

“…Of the 15 relevant papers that addressed any aspect of rodent-human MRI, seven were narrative reviews [42][43][44][45][46][47][48], one was an editorial [49] and seven were original research [22,[50][51][52][53][54][55] (Table 1). Of these, six focused on AD (four reviews [42][43][44][45], one editorial [49] and one original paper [52]), one review [47] on stroke, two original papers on Huntington's disease [51,54], one original paper each on ageing [50] and hypertension [55], two original papers [22,53] and one review on SVD [48] and one review briefly summarised functional MRI (fMRI) applications in several diseases [46], including stroke and neurodegeneration.…”

“…All studies were cross-sectional [22,50,[52][53][54][55] with the exception of the preclinical component of [51] which was longitudinal.…”

4D Flat Panel Conebeam CTA for In Vivo Imaging of the Microvasculature of the Human Cortex with a Novel Software Prototype

“…1,2 In animal experiments, MR imaging with SWI and iron-based contrast agents could visualize intracortical vessels of .10 mm. 3 For optimal display of vessels, section thicknesses between 6 and 9.5 mm were chosen. Thinner slices could improve the detection of small branches.…”

“…SWI has the potential to show the microvasculature at 7T or with the use of iron-based contrast agents. 3 Until now, the clinical interest in imaging of the microvasculature of the human cortex was limited, but this may change due to research demonstrating the importance of the microcirculation in patients with cerebral ischemia or smallvessel disease. [4][5][6][7] It was shown that flat panel conebeam CTA (FPCBCTA) derived from 3D rotational angiography (3DRA) datasets is able to demonstrate small perforating branches of proximal parts of the cerebral arteries.…”