Abstract
BackgroundAnimal models of Alzheimer’s disease (AD) are essential to understanding the disease progression and to development of early biomarkers. Because AD has been described as a disconnection syndrome, magnetic resonance imaging (MRI)-based connectomics provides a highly translational approach to characterizing the disruption in connectivity associated with the disease. In this study, a transgenic rat model of AD (TgF344-AD) was analyzed to describe both cognitive performance and brain connectivity at an early stage (5 months of age) before a significant concentration of β-amyloid plaques is present.MethodsCognitive abilities were assessed by a delayed nonmatch-to-sample (DNMS) task preceded by a training phase where the animals learned the task. The number of training sessions required to achieve a learning criterion was recorded and evaluated. After DNMS, MRI acquisition was performed, including diffusion-weighted MRI and resting-state functional MRI, which were processed to obtain the structural and functional connectomes, respectively. Global and regional graph metrics were computed to evaluate network organization in both transgenic and control rats.ResultsThe results pointed to a delay in learning the working memory-related task in the AD rats, which also completed a lower number of trials in the DNMS task. Regarding connectivity properties, less efficient organization of the structural brain networks of the transgenic rats with respect to controls was observed. Specific regional differences in connectivity were identified in both structural and functional networks. In addition, a strong correlation was observed between cognitive performance and brain networks, including whole-brain structural connectivity as well as functional and structural network metrics of regions related to memory and reward processes.ConclusionsIn this study, connectivity and neurocognitive impairments were identified in TgF344-AD rats at a very early stage of the disease when most of the pathological hallmarks have not yet been detected. Structural and functional network metrics of regions related to reward, memory, and sensory performance were strongly correlated with the cognitive outcome. The use of animal models is essential for the early identification of these alterations and can contribute to the development of early biomarkers of the disease based on MRI connectomics.
Highlights
Animal models of Alzheimer’s disease (AD) are essential to understanding the disease progression and to development of early biomarkers
AD has been described as a disconnection syndrome, and, in this study, connectivity disruption was identified in structural and functional networks of young adult TgF344-AD rats at as early a period as 5 months of age
Structural connectivity differences did not lead to changes in global functional metrics, probably because of changes induced in the resting-state connectivity by the long cognitive training phase the animals underwent before magnetic resonance imaging (MRI) scanning
Summary
Animal models of Alzheimer’s disease (AD) are essential to understanding the disease progression and to development of early biomarkers. The late appearance of symptoms makes it difficult to identify subjects in early stages of the disease In this regard, transgenic animal models of AD can contribute to a great degree to the identification of early biomarkers of the disease [4,5,6,7]. Other reasons to use rats instead of murine models are based on the fact that rats are physiologically, genetically, and morphologically closer to humans than mice, and their bigger brain size facilitates neuroimaging procedures. Their postnatal neurodevelopment leads to more complex synaptic organization, allowing better behavioral characterization [4]
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