Magnetic Resonance Q Mapping Reveals a Decrease in Microvessel Density in the arcAβ Mouse Model of Cerebral Amyloidosis

Abstract

Alterations in density and morphology of the cerebral microvasculature have been reported to occur in Alzheimer's disease patients and animal models of the disease. In this study we compared magnetic resonance imaging (MRI) techniques for their utility to detect age-dependent changes of the cerebral vasculature in the arcAβ mouse model of cerebral amyloidosis. Dynamic susceptibility contrast (DSC)-MRI was performed by tracking the passage of a superparamagnetic iron oxide nanoparticle in the brain with dynamic gradient echo planar imaging (EPI). From this measurements relative cerebral blood volume [rCBV(DSC)] and relative cerebral blood flow (rCBF) were estimated. For the same animal maps of the relaxation shift index Q were computed from high resolution gradient echo and spin echo data that were acquired before and after superparamagnetic iron oxide (SPIO) nanoparticle injection. Q-values were used to derive estimates of microvessel density. The change in the relaxation rates [Formula: see text] obtained from pre- and post-contrast gradient echo data was used for the alternative determination of rCBV [rCBV([Formula: see text])]. Linear mixed effects modeling found no significant association between rCBV(DSC), rCBV([Formula: see text]), rCBF, and Q with genotype in 13-month old mice [compared to age-matched non-transgenic littermates (NTLs)] for any of the evaluated brain regions. In 24-month old mice there was a significant association for rCBV(DSC) with genotype in the cerebral cortex, and for rCBV([Formula: see text]) in the cerebral cortex and cerebellum. For rCBF there was a significant association in the cerebellum but not in other brain regions. Q-values in the olfactory bulb, cerebral cortex, striatum, hippocampus, and cerebellum in 24-month old mice were significantly associated with genotype. In those regions Q-values were reduced between 11 and 26% in arcAβ mice compared to age-matched NTLs. Vessel staining with CD31 immunohistochemistry confirmed a reduction of microvessel density in the old arcAβ mice. We further demonstrated a region-specific association between parenchymal and vascular deposition of β-amyloid and decreased vascular density, without a correlation with the amount of Aβ deposition. We found that Q mapping was more suitable than the hemodynamic read-outs to detect amyloid-related degeneration of the cerebral microvasculature.

Keywords: Alzheimer's disease; cerebral amyloid angiopathy; cerebral amyloidosis; dynamic susceptibilty contrast MRI; microvessel density; relaxation rate shift index; superparamagnetic iron oxide nanoparticles.

Figure 1

Representative axial images of a mouse brain at different anatomical locations. Images were acquired with a TrueFISP sequence (A) before injection of SPIOs. Corresponding rCBV(DSC) (B) and rCBF (C) maps obtained from the dynamic GE EPI sequence. Region-of-interests were drawn over the cerebral cortex (CC), hippocampus (HC), and cerebellum (CB) as indicated.

Figure 2

Box plots of rCBV(DSC) (A,B) and rCBF (C,D) from DSC-MRI. Values were measured in the cerebral cortex (CC), hippocampus (HC), and cerebellum (CB) in 13-months (A,C) and 24-months (B,D) old arcAβ mice and non-transgenic littermates (NTL). Center lines show the medians; box limits indicate the 25th and 75th percentiles; whiskers extend 1.5 times the interquartile range from the 25th and 75th percentiles, outliers are represented by dots.

Figure 3

Coronal spin echo images (A) before injection of SPIOs and corresponding ${\Delta \text{R}}_2^{*}$ (B) and Q maps (C) from steady-state measurements. Illustration of region-of-interests are delineated for the olfactory bulb (OB), cerebral cortex (CC), striatum (ST), hippocampus (HC), thalamus (TH), and cerebellum (CB).

Figure 4

Box plots of the rCBV(${\Delta \text{R}}_2^{*}$) (A,B), relaxation shift index Q (C,D), and microvessel density N (E,F) in the olfactory bulb (OB), cerebral cortex (CC), striatum (ST), hippocampus (HC), thalamus (TH), and cerebellum (CB) in 13-months (A,C,E) and 24-months (B,D,F) old arcAβ mice and non-transgenic littermates (NTL). Center lines show the medians; box limits indicate the 25th and 75th percentiles; whiskers extend 1.5 times the interquartile range from the 25th and 75th percentiles, outliers are represented by dots.

Figure 5

Immunohistochemistry for vessel staining (CD31) and β-amyloid comparing 13- and 24-month old non-transgenic littermates. Overviews (scale bars = 200 μm) of the corpus callosum (CC), thalamus (TH), and cerebellum (CB). Insets show the regions with higher magnification (scale bar = 50 μm).

Figure 6

Immunohistochemistry for vessel staining (CD31) and β-amyloid comparing 13- and 24-month old arcAβ mice. Overviews (scale bars = 200 μm) of the corpus callosum (CC), thalamus (TH), and cerebellum (CB). Insets show the regions with higher magnification (scale bar = 50 μm).