Ex vivo molecular imaging in transgenic mouse models of Alzheimer’s disease
ALZHEIMER’S ASSOCIATION
Background: The recent upsurge in the development of novel diseasemodifying therapeutic agents for the treatment of Alzheimer’s disease (AD) requires efficient and robust methods of determining pre-clinical therapeutic efficacy in transgenic mouse models. While measuring the effects of therapy on AD-type pathological changes on post-mortem tissue remains the gold-standard, conventional methods of evaluation are time-consuming, operator-biased, and limited to specific regionsof- interest. Objective: The objective is to develop and evaluate a state-of-the-art technology platform called “ex vivo molecular imaging” which allows for fully-automated, whole-brain, quantitative analysis of AD-type pathology in transgenic mice. Methods: The technology platform consists of four major components, (1) specialized preparation and ultra-high resolution digitization of whole-brain histology and immunohistochemistry (IHC) sections, (2) analysis ex-vivo data at the cellular level to generate of quantitative 2D “ex vivo molecular images”, (3) 3D reconstruction of serial 2D images for 3D quantitative maps, and (4) generation of population averages in stereotaxic space and anatomical structure-based statistical analysis of 3D data. For evaluation of this new technique, ex vivo molecular imaging volumes were produced using brains from transgenic AD mice and wild-type littermates, as well as from treated and control mice. Results: Ex vivo molecular imaging volumes demonstrating -amyloid burden, gliosis, and neuronal density were produced from each mouse brain. Figure 1 depicts a typical coronal view of a -amyloid ex vivo molecular image from a 16 month-old APP transgenic mouse. Our analyses show significant regional differences between transgenic and wild-type mice, and clearly demonstrates the efficacy of the therapeutic agents evaluated. Conclusions: Ex vivo molecular imaging is a novel strategy for rapid, highthroughput analysis of the natural evolution of AD-type pathology and assessment of the therapeutic efficacy of disease-modifying agents in transgenic mice. The image processing and analysis components are fully-automated, while our specialized techniques for preparation of histology and IHC sections are as automated as possible to maximize efficiency and minimize operator-related variability. We believe that the seamless integration of ex vivo molecular imaging data with non-invasive, in vivo imaging measures of structure and function will, ultimately, allow for a comprehensive analysis of AD in animal models.
3 (3)
2007
S183
Chakravarty M.M., Collins D.L., Zehntner S.P., Hemmings K., Chan C., Zijdenbos A.P., Hamel E., Evans A.C. & Bedell B.J.
Alzheimer's Association 2007 International Conference on Prevention of Dementia
Alzheimer’s Association
Platform Presentation
Washington, DC, USA (June9 - 12, 2007)
O2-01-05
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