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

Alexandra Badea1, G. Allan Johnson1, 2, Joanna L. Jankowsky3

1Center for In Vivo Microscopy, 2Departments of Radiology, Biomedical Engineering, and Physics Duke University Medical Center, Durham, NC, 3Departments of Neuroscience, Neurology, and Neurosurgery, Baylor College of Medicine, Houston, TX

Neuroimage 50: 416-427, 2010. PMCID: PMC2823970

Magnetic resonance (MR) imaging provides 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 datasets 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 longitudinal view of volumetric changes in a transgenic mouse model for Alzheimer's disease (AD). 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 pre-symptomatic 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 very late in disease. We further show that MR microscopy can detect amyloid deposits shortly after they are formed, when the cortex and hippocampus are only modestly involved in pathology. We show histology-confirmed plaques in T2* images of fixed brains at the earliest stage of disease yet studied by MR. Our work provides proof-of-principle that MR microscopy can expand our view of AD, from the earliest amyloid deposits to the most remote volumetric changes.

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