Abstract
Gadolinium (Gd)-stained MRI is based on Gd contrast agent (CA) administration into the brain parenchyma. The strong signal increase induced by Gd CA can be converted into resolution enhancement to record microscopic MR images. Moreover, inhomogeneous distribution of the Gd CA in the brain improves the contrast between different tissues and provides new contrasts in MR images. Gd-stained MRI detects amyloid plaques, one of the microscopic lesions of Alzheimer’s disease (AD), in APPSL/PS1M146L mice or in primates. Numerous transgenic mice with various plaque typologies have been developed to mimic cerebral amyloidosis and comparison of plaque detection between animal models and humans with new imaging methods is a recurrent concern. Here, we investigated detection of amyloid plaques by Gd-stained MRI in five mouse models of amyloidosis (APPSL/PS1M146L, APP/PS1dE9, APP23, APPSwDI, and 3xTg) presenting with compact, diffuse and intracellular plaques as well as in post mortem human-AD brains. The brains were then evaluated by histology to investigate the impact of size, compactness, and iron load of amyloid plaques on their detection by MRI. We show that Gd-stained MRI allows detection of compact amyloid plaques as small as 25 µm, independently of their iron load, in mice as well as in human-AD brains.
Highlights
Amyloid plaques are one of the earliest hallmarks of Alzheimer’s disease (AD), occurring up to 20 years before clinical diagnosis[1]
Gd-stained magnetic resonance imaging (MRI) was performed on five mouse models of amyloidosis (APPSL/PS1M146L, APP/PS1dE9, APP23, APPSwDI and 3xTg) and C57Bl/6 amyloid-free control animals
Amyloid plaques were detected in vivo and ex vivo in APPSL/PS1M146L, APP/PS1dE9, APP23 and to a lesser extent in 3xTg mice but never in APPSwDI mice
Summary
Amyloid plaques are one of the earliest hallmarks of Alzheimer’s disease (AD), occurring up to 20 years before clinical diagnosis[1]. ® The second option uses non-targeted gadolinium (Gd) contrast agents such as gadoterate meglumine (Dotarem , Guerbet, France) that is administered in cerebral ventricles after stereotaxic injection[26] or intravenously in association with a non-invasive and safe permeation of the blood-brain barrier using ultrasound[27] With this method, called Gd-stained MRI, once the contrast agent has reached the brain, amyloid plaques appear as black spots since the hydrophilic Gd-contrast agent increases the signal of tissues surrounding the plaques but do not access their hydrophobic core[28]. We explored the capacity of Gd-stained MRI to detect amyloid plaques in post mortem human-AD brains. Amyloid plaques from APPSL/PS1M146L, APP/PS1dE9 and human-AD brains had the most similar histological characteristics and could be detected by Gd-stained MRI. We found that the key features associated to amyloid plaque detection by Gd-stained MRI are their size, compactness but not their iron load
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