Multimodal Imaging in Rat Model Recapitulates Alzheimer's Disease Biomarkers Abnormalities.
|Title||Multimodal Imaging in Rat Model Recapitulates Alzheimer's Disease Biomarkers Abnormalities.|
|Publication Type||Journal Article|
|Year of Publication||2017|
|Authors||Parent MJ, Zimmer ER, Shin M, Kang MSu, Fonov VS, Mathieu A, Aliaga A, Kostikov A, Carmo SDo, Dea D, Poirier J, Soucy J-P, Gauthier S, A Cuello C, Rosa-Neto P|
|Date Published||2017 Dec 13|
|Keywords||Alzheimer Disease, Amyloid beta-Peptides, Amyloidosis, Animals, Animals, Genetically Modified, Biomarkers, Brain, Brain Chemistry, Cognitive Dysfunction, Disease Models, Animal, Female, Fluorine Radioisotopes, Fluorodeoxyglucose F18, Magnetic Resonance Imaging, Male, Memory Disorders, Multimodal Imaging, Mutation, Neuroimaging, Plaque, Amyloid, Positron-Emission Tomography, Protein Aggregation, Pathological, Radiopharmaceuticals, Rats, Rats, Transgenic, Rats, Wistar|
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 [F]FDG) or detectable fibrillary amyloidosis (measured with PET [F]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 Aβ 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. 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.
|Alternate Journal||J. Neurosci.|
|PubMed Central ID||PMC5729194|