Quantitative assessment of microvasculopathy in arcAβ mice with USPIO-enhanced gradient echo MRI

Abstract

Magnetic resonance imaging employing administration of iron oxide-based contrast agents is widely used to visualize cellular and molecular processes in vivo. In this study, we investigated the ability of R2* and quantitative susceptibility mapping to quantitatively assess the accumulation of ultrasmall superparamagnetic iron oxide (USPIO) particles in the arcAβ mouse model of cerebral amyloidosis. Gradient-echo data of mouse brains were acquired at 9.4 T after injection of USPIO. Focal areas with increased magnetic susceptibility and R2* values were discernible across several brain regions in 12-month-old arcAβ compared to 6-month-old arcAβ mice and to non-transgenic littermates, indicating accumulation of particles after USPIO injection. This was concomitant with higher R2* and increased magnetic susceptibility differences relative to cerebrospinal fluid measured in USPIO-injected compared to non-USPIO-injected 12-month-old arcAβ mice. No differences in R2* and magnetic susceptibility were detected in USPIO-injected compared to non-injected 12-month-old non-transgenic littermates. Histological analysis confirmed focal uptake of USPIO particles in perivascular macrophages adjacent to small caliber cerebral vessels with radii of 2–8 µm that showed no cerebral amyloid angiopathy. USPIO-enhanced R2* and quantitative susceptibility mapping constitute quantitative tools to monitor such functional microvasculopathies.

Quantitative susceptibility mapping (QSM) with an extended physical model for MRI frequency contrast in the brain: a proof‐of‐concept of quantitative susceptibility and residual (QUASAR) mapping

“…Susceptibility map reconstruction issues similar to those observed in the present work with the traditional physical model (Figures and ) may be found also in published rodent work by other authors. For example, susceptibility contrast was absent from the frontal horn of the lateral ventricles on all in vivo images presented by O'Callaghan et al (Figures and therein), Ziser et al (Figures and therein) and Vaas et al (Figure therein), as well as studies to which we have contributed …”

“…For example, susceptibility contrast was absent from the frontal horn of the lateral (Figures 3 and 7 therein), Ziser et al 56 (Figures 1 and 2 therein) and Vaas et al 57 ( Figure 5 therein), as well as studies to which we have contributed. 46,58,59 The present study did not aim to and cannot elucidate the underlying biophysical mechanisms causing this additional frequency contribution, which may comprise contributions of different and contentious strength from macromolecular exchange effects, [14][15][16][17]60 (sub-)cellular magnetic architecture, [20][21][22]61 and temporal frequency variations due to tissue compartmentalization. 62,63 In mathematical terms, the additional local component, here referred to as the residual or non-susceptibility frequency contribution, may simply be understood as a lump sum of the discrepancy between the employed physical model and the physical reality.…”

“…This value was similar to the result of our PWCI experiment in vivo (see Figure 1b,c and Section 3). Considering the relatively weak susceptibility contrast in mouse brain reported previously 46 and the lack of a reliable reference, we decided to assign arbitrary…”

Susceptibility weighted imaging and quantitative susceptibility mapping of the cerebral vasculature using ferumoxytol

“…USPIO particles have been used as an alternative contrast agent since 1990 to detect inflammatory macrophage activities . However, their use as a vascular T2* agent and more specifically as a susceptibility blood pool agent has not been heavily investigated . Among all the USPIOs, ferumoxytol is most commonly used today as an off‐label MRI contrast agent, because it is the only one approved by the U.S. Food and Drug Administration (FDA) for human use (as an iron replacement product) and because it is a blood pool superparamagnetic agent and safe for patients with renal diseases …”

Overview of quantitative susceptibility mapping

“…The value of QSM in the quantification of iron oxide nanoparticles in biological tissue has recently been proven in several preclinical MRI studies , where it may be able to uniquely aid the visualization of cellular and molecular processes in vivo .…”