Early Stage Alterations in White Matter and Decreased Functional Interhemispheric Hippocampal Connectivity in the 3xTg Mouse Model of Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is characterized in the late stages by amyloid-β (Aβ) plaques and neurofibrillary tangles. Nevertheless, recent evidence has indicated that early changes in cerebral connectivity could compromise cognitive functions even before the appearance of the classical neuropathological features. Diffusion tensor imaging (DTI), resting-state functional magnetic resonance imaging (rs-fMRI) and volumetry were performed in the triple transgenic mouse model of AD (3xTg-AD) at 2 months of age, prior to the development of intraneuronal plaque accumulation. We found the 3xTg-AD had significant fractional anisotropy (FA) increase and radial diffusivity (RD) decrease in the cortex compared with wild-type controls, while axial diffusivity (AD) and mean diffusivity (MD) were similar. Interhemispheric hippocampal connectivity was decreased in the 3xTg-AD while connectivity in the caudate putamen (CPu) was similar to controls. Most surprising, ventricular volume in the 3xTg-AD was four times larger than controls. The results obtained in this study characterize the early stage changes in interhemispheric hippocampal connectivity in the 3xTg-AD mouse that could represent a translational biomarker to human models in preclinical stages of the AD.

Progression of Alzheimer's disease and effect of scFv‐h3D6 immunotherapy in the 3xTg‐AD mouse model: An in vivo longitudinal study using Magnetic Resonance Imaging and Spectroscopy

“…The ADC levels were ambiguous, the only differences being the higher values shown by the 3xTg‐AD at 7‐mo in both the hippocampus and cortex. No statistical differences in the mean diffusivities were observed either in other studies using the 3xTg‐AD mouse model although a tendency to increased ADC values in 3xTg‐AD mice could be noticed at 12–14‐mo in the cortex region . Thus, it was likely that neither significant inflammation processes nor vasogenic edemas occurred .…”

“…The triple transgenic mouse model (3xTg‐AD) is extensively used in AD research and reproduces both amyloid and tau pathologies in a regional and temporal pattern analogous to AD patients, which makes it very valuable for longitudinal studies . In vivo magnetic resonance imaging (MRI) and proton spectroscopy ( 1 H‐MRS) have recently begun to be used for the characterization of the triple transgenic Alzheimer's Disease mouse model . MRI not only provides structural information but also relevant functional evidence when acquiring multiparametric MRI maps.…”

“…In this study, different MRI/MRS parameters were analyzed at 5, 7, 9, and 12‐mo. MRI was used to determine the volume of different cerebral regions involved in the disease, as a reduction in cerebral volume is associated with atrophy and neurodegeneration due to neuron loss in humans and mice . We have also quantified the T 2 value, whose changes are associated with the appearance of amyloid plaques, neuroinflammation, and neurodegeneration .…”

Loss and Reorganisation of Superficial White Matter in Alzheimer’s disease: A Diffusion MRI study

“…For example, previous FA increases have been observed in asymptomatic amyloid positive individuals 57 and transgenic mouse models of Alzheimer's disease prior to intraneuronal plaque accumulation. 58 Alternatively, previous work has attributed increased anisotropy to a degeneration of crossing fibres and sparing of motor-related projection fibres. 59 However, with no corresponding NDI or ODI changes in these regions that met our our FDR-corrected threshold for multiple comparisons, the specific microstructural changes driving DTI here are unclear.…”

Diffusion Tensor Imaging-Based Studies at the Group-Level Applied to Animal Models of Neurodegenerative Diseases

“…Further investigation of the APP model has confirmed abnormalities in DTI metrics both in gray and in white matter (Bitner et al, 2012 ; Qin et al, 2013 ; Shu et al, 2013 ; Shen et al, 2018 ; Liu L. et al, 2020 ). Gray and white matter degeneration was detected by DTI in an unbiased approach in cohort studies of APP transgenic mice (Müller et al, 2013 ) and 3× Tg-AD model mice (Manno et al, 2019 ) or after Aβ injections (Sun et al, 2014 ; Nishioka et al, 2019 ). Ex-vivo DTI was used to identify vulnerable brain networks in mouse models for late onset AD (Hara et al, 2017 ; Badea et al, 2019 ).…”