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


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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    • "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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    ABSTRACT: Manganese Enhanced MRI (MEMRI) was used to detect specific laminar changes in the olfactory bulb (OB) to follow the progression of amyloid precursor protein (APP)-induced neuronal pathology and its recovery in a reversible olfactory based Alzheimer's disease (AD) mouse model. Olfactory dysfunction is an early symptom of AD, which suggests that olfactory sensory neurons (OSNs) may be more sensitive to AD related factors than neurons in other brain areas. Previously a transgenic mouse model was established that causes degeneration of OSNs by overexpressing humanized APP (hAPP), which results in a disruption of olfactory circuitry with changes in glomerular structure. In the present work, OB volume and manganese enhancement of the glomerular layer in OB were decreased in mutant mice. Turning off APP overexpression with doxycycline produced a significant increase in manganese enhancement of the glomerular layer after only 1 week, and further recovery after 3 weeks, while treatment with Aβ antibody produced modest improvement with MRI measurements. Thus, MEMRI enables a direct tracking of laminar specific neurodegeneration through a non-invasive in vivo measurement. The use of MRI will enable assessment of the ability of different pharmacological reagents to block olfactory neuronal loss and can serve as a unique in vivo screening tool to both identify potential therapeutics and test their efficacy. Copyright © 2015. Published by Elsevier Inc.
    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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    ABSTRACT: Mouse models of Alzheimer’s disease (AD) have been used to draw associations between atrophy of neural tissue and underlying pathology. In this study, the early-onset TgCRND8 mouse model of AD and littermate controls were scanned longitudinally with in-vivo manganese-enhanced MRI (MEMRI) before and after the onset of amyloid plaque deposition at 12 weeks of age. Separate cohorts of mice were scanned at 1 week (ex-vivo imaging) and 4 weeks (MEMRI) of age to investigate early life alterations in the brain. Contrary to our expectations, differences in neuroanatomy were found in early post-natal life, preceding plaque deposition by as much as 11 weeks. Many of these differences remained at all imaging time points, suggesting that they were programmed early in life and were unaffected by the onset of pathology. Furthermore, rather than showing atrophy, many regions of the TgCRND8 brain grew at a faster rate compared to controls. These regions contained the greatest density of amyloid plaques and reactive astrocytes. Our findings suggest that pathological processes as well as an alteration in brain development influence the TgCRND8 neuroanatomy throughout the lifespan.
    Neurobiology of Aging 09/2014; 36(2). DOI:10.1016/j.neurobiolaging.2014.08.032 · 5.01 Impact Factor
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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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    ABSTRACT: Magnetic resonance imaging (MRI) of rodent brains enables study of the development and the integrity of the brain under certain conditions (alcohol, drugs etc.). However, these images are difficult to analyze for biomedical researchers with limited image processing experience. In this paper we present an image processing pipeline running on a Midas server, a web-based data storage system. It is composed of the following steps: rigid registration, skull-stripping, average computation, average parcellation, parcellation propagation to individual subjects, and computation of region-based statistics on each image. The pipeline is easy to configure and requires very little image processing knowledge. We present results obtained by processing a data set using this pipeline and demonstrate how this pipeline can be used to find differences between populations.
    Frontiers in Neuroinformatics 08/2013; 7:15. DOI:10.3389/fninf.2013.00015 · 3.26 Impact Factor
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