Dataset Information

In Vivo Detection of Amyloid Plaques by Gadolinium-Stained MRI Can Be Used to Demonstrate the Efficacy of an Anti-amyloid Immunotherapy.

ABSTRACT: Extracellular deposition of ? amyloid plaques is an early event associated to Alzheimer's disease. Here, we have used in vivo gadolinium-stained high resolution (29(?)29(?)117 ?m(3)) magnetic resonance imaging (MRI) to follow-up in a longitudinal way individual amyloid plaques in APP/PS1 mice and evaluate the efficacy of a new immunotherapy (SAR255952) directed against protofibrillar and fibrillary forms of A?. APP/PS1 mice were treated for 5 months between the age of 3.5 and 8.5 months. SAR255952 reduced amyloid load in 8.5-months-old animals, but not in 5.5-months animals compared to mice treated with a control antibody (DM4). Histological evaluation confirmed the reduction of amyloid load and revealed a lower density of amyloid plaques in 8.5-months SAR255952-treated animals. The longitudinal follow-up of individual amyloid plaques by MRI revealed that plaques that were visible at 5.5 months were still visible at 8.5 months in both SAR255952 and DM4-treated mice. This suggests that the amyloid load reduction induced by SAR255952 is related to a slowing down in the formation of new plaques rather than to the clearance of already formed plaques.

SUBMITTER: Santin MD

PROVIDER: S-EPMC4802995 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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In Vivo Detection of Amyloid Plaques by Gadolinium-Stained MRI Can Be Used to Demonstrate the Efficacy of an Anti-amyloid Immunotherapy.

Santin Mathieu D MD Vandenberghe Michel E ME Herard Anne-Sophie AS Pradier Laurent L Cohen Caroline C Debeir Thomas T Delzescaux Thierry T Rooney Thomas T Dhenain Marc M

Frontiers in aging neuroscience 20160322

Extracellular deposition of β amyloid plaques is an early event associated to Alzheimer's disease. Here, we have used in vivo gadolinium-stained high resolution (29(∗)29(∗)117 μm(3)) magnetic resonance imaging (MRI) to follow-up in a longitudinal way individual amyloid plaques in APP/PS1 mice and evaluate the efficacy of a new immunotherapy (SAR255952) directed against protofibrillar and fibrillary forms of Aβ. APP/PS1 mice were treated for 5 months between the age of 3.5 and 8.5 months. SAR2559 ...[more]

PMID: 27047372

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Project description:Two significant barriers have limited the development of effective treatment of Alzheimer's disease. First, for many cases the aetiology is unknown and likely multi-factorial. Among these factors, hypercholesterolemia is a known risk predictor and has been linked to the formation of beta-amyloid plaques, a pathological hallmark this disease. Second, standardized diagnostic tools are unable to definitively diagnose this disease prior to death; hence new diagnostic tools are urgently needed. Magnetic resonance imaging (MRI) using high field-strength scanners has shown promise for direct visualization of beta-amyloid plaques, allowing in vivo longitudinal tracking of disease progression in mouse models. Here, we present a new rabbit model for studying the relationship between cholesterol and Alzheimer's disease development and new tools for direct visualization of beta-amyloid plaques using clinical field-strength MRI. New Zealand white rabbits were fed either a low-level (0.125-0.25% w/w) cholesterol diet (n = 5) or normal chow (n = 4) for 27 months. High-resolution (66 x 66 x 100 microm(3); scan time = 96 min) ex vivo MRI of brains was performed using a 3-Tesla (T) MR scanner interfaced with customized gradient and radiofrequency coils. Beta-amyloid-42 immunostaining and Prussian blue iron staining were performed on brain sections and MR and histological images were manually registered. MRI revealed distinct signal voids throughout the brains of cholesterol-fed rabbits, whereas minimal voids were seen in control rabbit brains. These voids corresponded directly to small clusters of extracellular beta-amyloid-positive plaques, which were consistently identified as iron-loaded (the presumed source of MR contrast). Plaques were typically located in the hippocampus, parahippocampal gyrus, striatum, hypothalamus and thalamus. Quantitative analysis of the number of histologically positive beta-amyloid plaques (P < 0.0001) and MR-positive signal voids (P < 0.05) found in cholesterol-fed and control rabbit brains corroborated our qualitative observations. In conclusion, long-term, low-level cholesterol feeding was sufficient to promote the formation of extracellular beta-amyloid plaque formation in rabbits, supporting the integral role of cholesterol in the aetiology of Alzheimer's disease. We also present the first evidence that MRI is capable of detecting iron-associated beta-amyloid plaques in a rabbit model of Alzheimer's disease and have advanced the sensitivity of MRI for plaque detection to a new level, allowing clinical field-strength scanners to be employed. We believe extension of these technologies to an in vivo setting in rabbits is feasible and that our results support future work exploring the role of MRI as a leading imaging tool for this debilitating and life-threatening disease.

Dataset Information

In Vivo Detection of Amyloid Plaques by Gadolinium-Stained MRI Can Be Used to Demonstrate the Efficacy of an Anti-amyloid Immunotherapy.

Publications

In Vivo Detection of Amyloid Plaques by Gadolinium-Stained MRI Can Be Used to Demonstrate the Efficacy of an Anti-amyloid Immunotherapy.

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