In Vivo Detection of Gray Matter Neuropathology in the 3xTg Mouse Model of Alzheimer’s Disease with Diffusion Tensor Imaging

Abstract

Abstract.A diagnosis of Alzheimer's disease (AD), a neurodegenerative disorder accompanied by severe functional and cognitive decline, is based on clinical findings, with final confirmation of the disease at autopsy by the presence of amyloid-␤ (A␤) plaques and neurofibrillary tangles. Given that microstructural brain alterations occur years prior to clinical symptoms, efforts to detect brain changes early could significantly enhance our ability to diagnose AD sooner. Diffusion tensor imaging (DTI), a type of MRI that characterizes the magnitude, orientation, and anisotropy of the diffusion of water in tissues, has been used to infer neuropathological changes in vivo. Its utility in AD, however, is still under investigation. The current study used DTI to examine brain regions susceptible to AD-related pathology; the cerebral cortex, entorhinal cortex, and hippocampus, in 12-14-month-old 3xTg AD mice that possess both A␤ plaques and neurofibrillary tangles. Mean diffusivity did not differ between 3xTg and control mice in any region. Decreased fractional anisotropy (p < 0.01) and axial diffusivity (p < 0.05) were detected only in the hippocampus, in which both congophilic A␤ plaques and hyperphosphorylated tau accumulation, consistent with neurofibrillary tangle formation, were detected. Pathological tau accumulation was seen in the cortex. The entorhinal cortex was largely spared from AD-related neuropathology. This is the first study to demonstrate DTI abnormalities in gray matter in a mouse model of AD in which both pathological hallmarks are present, suggesting the feasibility of DTI as a non-invasive means of detecting brain pathology in vivo in early-stage AD.

Increased Neurite Orientation-Dispersion and Density in the TgCRND8 Mouse Model of Amyloidosis: Inverse Relation with Functional Connectome Clustering and Modulation by Interleukin-6

“…The latter results were highly consistent with those of Shu et al (2013) (Shu et al, 2013). In the triple transgenic (3xTgFAD) mouse model, reduced FA and AD was measured only in the hippocampus (Snow et al, 2017). Results similar to those obtained here were reported by Sun et al, who observed reduced relative anisotropy along with reduced AD and increased RD in the Tg2576 mouse model (Sun et al, 2005).…”

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 .…”

“…In fact, this is not a good model for causing vasogenic edema as this pathology is related to cerebral amyloid angiopathy (CAA) and the 3xTg‐AD does not develop it . Analysis of other DTI neurodegeneration related parameters like fractional anisotropy or axial and radial diffusivities may provide additional information about microstructural anomalies, which may be worth considering to include them in future studies.…”

“…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.…”

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

“…However, these findings were not confirmed in ex-vivo DTI measurements, which revealed no loss in white matter integrity (Harms et al, 2006 ), raising questions about the source of the signal actually lost upon formalin fixation. More recently, DTI abnormalities have been confirmed in multiple white matter tracts as well as in the hippocampus in different mouse models for AD (Kerbler et al, 2013 ; Snow et al, 2017 ) and imaged in vivo at different field strengths, for example, 7 T (Whittaker et al, 2018 ) or 11.7 T (Zerbi et al, 2013 ). 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 ).…”