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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Available from: Alexandra Badea
    • "Yet only a handful of MRI volumetry studies have been performed on mouse models of brain amyloidosis, with mixed results [20] [21] [22] [23] [24] [25] [26] [27]. However, it is worth noticing that some studies were performed after A plaque accumulation had already started [21] [22] [25], some both before and after the start of A plaque accumulation [20] [26] [27], while in one study there was no A plaque accumulation whatsoever [24]. Postmortem histological analyses were included in some of these studies [24] [25] [26] [27], but none of them analyzed layer specificity of these changes. "
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    ABSTRACT: Magnetic resonance imaging (MRI) volumetry is widely used in Alzheimer's disease (AD) research and diagnostics alongside clinical assessment. Yet few MRI volumetry studies have been conducted in AD model mice with mixed results. We performed in vivo and ex vivo MRI and extensive postmortem histological analysis in transgenic mice derived from crossing amyloid plaque producing AβPP/PS1 mice with brain-derived neurotrophic factor (BDNF)+/- mice. This allowed us to compare developmental volumetric changes due to BDNF deficiency with progressive changes due to amyloid accumulation. We found decreased whole brain volume at 3 months and decreased cortical volume at both 3 and 8 months in vivo in BDNF+/- Tg mice but increased whole brain and cortical volumes at 8 months in AβPP/PS1 mice. Consistent with this, the postmortem histological analysis showed decreased brain parenchymal area in BDNF+/- mice but an increase in AβPP/PS1 mice. BDNF gene deficiency did not affect brain amyloid load or astrogliosis, but led to decreased dentate gyrus length, whereas AβPP/PS1 mice had significantly increased amyloid load, astrogliosis, and decreased neurogenesis. Distinct and layer-specific effects were found in the hippocampus of AβPP/PS1 and BDNF+/- mice. In contrast to human AD patients, brain atrophy in amyloid producing mice appears to be masked by volume increase due to amyloid accumulation and especially accompanying astrogliosis. Our results indicate that cortical MRI volumetry can be used to some extent as a proxy to progressive brain amyloidosis in preclinical studies.
    No preview · Article · Jun 2015 · Journal of Alzheimer's disease: JAD
    • "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.
    No preview · Article · May 2015 · NeuroImage
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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.
    Full-text · Article · Sep 2014 · Neurobiology of Aging
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