Article

Remote sites of structural atrophy predict later amyloid formation in a mouse model of Alzheimer's disease

Center for In Vivo Microscopy, Duke University Medical Center, Durham, NC, USA.
NeuroImage (Impact Factor: 6.36). 04/2010; 50(2):416-27. DOI: 10.1016/j.neuroimage.2009.12.070
Source: PubMed

ABSTRACT Magnetic resonance (MR) imaging can provide a longitudinal view of neurological disease through repeated imaging of patients at successive stages of impairment. Until recently, the difficulty of manual delineation has limited volumetric analyses of MR data sets to a few select regions and a small number of subjects. Increased throughput offered by faster imaging methods, automated segmentation, and deformation-based morphometry have recently been applied to overcome this limitation with mouse models of neurological conditions. We use automated analyses to produce an unbiased view of volumetric changes in a transgenic mouse model for Alzheimer's disease (AD) at two points in the progression of disease: immediately before and shortly after the onset of amyloid formation. In addition to the cortex and hippocampus, where atrophy has been well documented in AD patients, we identify volumetric losses in the pons and substantia nigra where neurodegeneration has not been carefully examined. We find that deficits in cortical volume precede amyloid formation in this mouse model, similar to presymptomatic atrophy seen in patients with familial AD. Unexpectedly, volumetric losses identified by MR outside of the forebrain predict locations of future amyloid formation, such as the inferior colliculus and spinal nuclei, which develop pathology at very late stages of disease. Our work provides proof-of-principle that MR microscopy can expand our view of AD by offering a complete and unbiased examination of volumetric changes that guide us in revisiting the canonical neuropathology.

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Available from: Alexandra Badea, Sep 05, 2015
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    • "An earlier MRI study used a double-transgenic APP/tTa mouse model that overexpressed hAPP under the control of CaMKII promoter which is expressed more broadly throughout the brain. The hAPP overexpression was suppressed until 6 weeks of age and then allowed to reactivate which resulted in volume reduction in various brain areas such as hippocampus and cortex that serve as a measure for degeneration (Badea et al., 2010). However, this study lacked any laminar analysis that could provide important insight into the specific cell types that are affected and the resulting loss in connectivity. "
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    NeuroImage 05/2015; 118. DOI:10.1016/j.neuroimage.2015.05.045 · 6.36 Impact Factor
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    • "Previous longitudinal MRI studies in murine models of AD have found conflicting results regarding the trajectory of brain volume over time, with some investigators describing an atrophy between imaging sessions (Badea et al., 2010; Delatour et al., 2006) and others an increase in cortical and hippocampal volume (Grand'maison et al., 2013; Lau et al., 2008). However, these conflicting results may depend on when the brain is imaged during pathogenesis and what transgenic line used. "
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    • "One common method is to perform a region-based analysis of the MR Images. The average and standard deviation of properties, such as the volume or the intensity of each region, is used to compare the different populations (Harms et al., 2006; Stone et al., 2008; Wang et al., 2008; Chan et al., 2009; Fatemi et al., 2009; Lodygensky et al., 2009; Zahr et al., 2009; Badea et al., 2010; Hui et al., 2010). Structural Magnetic Resonance Imaging (sMRI) and Diffusion Tensor MRI (DTI) can be used in such studies. "
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