Early brain connectivity alterations and cognitive impairment in a rat model of Alzheimer’s disease

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.Electronic supplementary materialThe online version of this article (10.1186/s13195-018-0346-2) contains supplementary material, which is available to authorized users.

An MRI-Derived Neuroanatomical Atlas of the Fischer 344 Rat Brain

“…Finally, regarding the generalizability of this Fischer 344 atlas to other rat strains, many studies have successfully applied atlases generated from strains differing from their experimental rats, likely in part due to the lack of an appropriate MRI atlas for their own rat strain and/or research question. 16,42,43,44 In the literature, the general consensus appears to be that any particular atlas, including that designed by Paxinos and Watson, may be applied to both sexes, different strains, etc., provided there are no gross anatomical abnormalities, the age and weight range of the subjects is comparable, and volumes should be within 10% of the template image volume. 2,16,35,42 That said, volume differences in both whole brain and specific structures have been shown between rat strains.…”

Brain connectivity during Alzheimer’s disease progression and its cognitive impact in a transgenic rat model

“…Every three months, working memory was evaluated by DNMS test, following the procedure described in (Muñoz-Moreno et al, 2018). DNMS was carried out in isolated operant chambers (Med Associates, USA), equipped with a pellet dispenser and three retractable levers, two of them in the wall where the pellet is (right and left levers) and the other in the opposite side (center lever).…”

“…Before the first test, animals underwent an habituation and training phase to acquire the required skills. This phase started when the animals were two month old and finished when they achieved an acquisition criteria as explained in (Muñoz-Moreno et al, 2018). After that, animals underwent 15 DNMS sessions (five sessions per week) to evaluate and consolidate the learnt task.…”

“…Indeed, alterations in structural and functional brain network properties have been described in TgF344-AD animals at early ages (5-6 months) (Muñoz-Moreno et al, 2018) as well as differences in functional connectivity of specific regions at several time points from 6 to 18 months (Anckaerts et al, 2019).…”

“…In the present study, we investigated how the disease progression affects both structural and functional brain networks and its effects in cognitive abilities. In this sense, we evaluated how the connectivity impairments observed in young TgF344-AD animals in our previous work (Muñoz-Moreno et al, 2018) evolve during aging. To do this, a longitudinal analysis of brain connectivity was performed based on MRI acquisitions repeated every 3 months from 6 to 18 months of age in a cohort of TgF344-AD rats, which was compared with control animals.…”