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J Neurosci. 2017 Dec 13;37(50):12263-12271. doi: 10.1523/JNEUROSCI.1346-17.2017. Epub 2017 Nov 2.

Multimodal Imaging in Rat Model Recapitulates Alzheimer's Disease Biomarkers Abnormalities.

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McGill Centre for Studies in Aging, McGill University, Montreal H4H 1R3, Canada.
Douglas Mental Health University Institute, Montreal H4H 1R3, Canada.
Department of Biochemistry, Federal University of Rio Grande do Sul, Porto Alegre 90035-000, Brazil.
Brain Institute (BraIns) of Rio Grande do Sul, Porto Alegre 90610-000, Brazil.
Montreal Neurological Institute, Montreal H3A 2B4, Canada, and.
Department of Pharmacology and Therapeutics, McGill University, Montreal H3G 1Y6, Canada.
McGill Centre for Studies in Aging, McGill University, Montreal H4H 1R3, Canada,


Imaging biomarkers are frequently proposed as endpoints for clinical trials targeting brain amyloidosis in Alzheimer's disease (AD); however, the specific impact of amyloid-β (Aβ) aggregation on biomarker abnormalities remains elusive in AD. Using the McGill-R-Thy1-APP transgenic rat as a model of selective Aβ pathology, we characterized the longitudinal progression of abnormalities in biomarkers commonly used in AD research. Middle-aged (9-11 months) transgenic animals (both male and female) displayed mild spatial memory impairments and disrupted cingulate network connectivity measured by resting-state fMRI, even in the absence of hypometabolism (measured with PET [18F]FDG) or detectable fibrillary amyloidosis (measured with PET [18F]NAV4694). At more advanced ages (16-19 months), cognitive deficits progressed in conjunction with resting connectivity abnormalities; furthermore, hypometabolism, Aβ plaque accumulation, reduction of CSF Aβ1-42 concentrations, and hippocampal atrophy (structural MRI) were detectable at this stage. The present results emphasize the early impact of Aβ on brain connectivity and support a framework in which persistent Aβ aggregation itself is sufficient to impose memory circuits dysfunction, which propagates to adjacent brain networks at later stages.SIGNIFICANCE STATEMENT The present study proposes a "back translation" of the Alzheimer pathological cascade concept from human to animals. We used the same set of Alzheimer imaging biomarkers typically used in large human cohorts and assessed their progression over time in a transgenic rat model, which allows for a finer spatial resolution not attainable with mice. Using this translational platform, we demonstrated that amyloid-β pathology recapitulates an Alzheimer-like profile of biomarker abnormalities even in the absence of other hallmarks of the disease such as neurofibrillary tangles and widespread neuronal losses.


Alzheimer; MRI; PET; animal model; biomarkers; imaging

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