IC‐P1‐049: Direct visualization of β‐amyloid plaques in hypercholesterolemic rabbits using clinical field‐strength magnetic resonance imaging

Definitive diagnosis of Alzheimer's disease (AD) requires postmortem pathologic demonstration of beta-amyloid (Aβ) plaques. The ability to non-invasively image Aβ plaque burden would markedly improve the diagnosis and treatment of AD patients. This has been accomplished in several transgenic mouse models using animal-dedicated high-field (7 or 9.4 T) MRI scanners. However, to determine the translational potential of MR techniques, it is important to visualize plaques using clinical field-strength (3T) scanners in larger animal models. Rabbits fed high (2%) cholesterol (CH) diets form Aβ plaques, but plaque progression is hard to track due to a high mortality rate (liver failure). Here we show that low-level CH-feeding in rabbits resulted in a low mortality rate whilst still promoting the formation of Aβ plaques. In addition, we developed a state-of-the-art clinical field MR technique allowing direct visualization of these plaques. Rabbits were fed a low (0.25%) CH (n=5) or normal (n=4) diet for 27 months. Ex vivo MRI of half brains was performed on a 3T MR scanner interfaced with customized gradient and RF coils. 66x66x100 μm3 MR images were acquired in 96 minutes. Aβ-42 immunostaining and Prussian blue iron staining were performed on matched brain sections. MR images revealed distinct signal voids throughout the brains of the CH-fed animals, located primarily in the hippocampus and adjacent cortex, striatum and thalamus (Fig. 1A). Voids correlated directly to small clusters of Aβ-42-positive plaques, which were also consistently identified as iron-loaded (the presumed source of MR contrast) (Fig. 2). Minimal voids and plaques were seen in control brains (Fig. 1B). Our findings combine for the first time a large animal model of AD with clinical field MRI, and demonstrate direct visualization of Aβ plaques. The low CH diet used resulted in both significant Aβ plaque burden and a survivable model, allowing treatment effects after disease establishment to be assessed in the future. Extension of these technologies to an in vivo setting is practical, and should allow the study of AD pathogenesis in animals over time. These exciting results also hint at the promise of clinical MRI-based detection of Aβ plaques in humans.

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