Histochemical visualization and diffusion MRI at 7 Tesla in the TgCRND8 transgenic model of Alzheimer’s disease

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that has been characterized by gross cortical atrophy, cellular neurodegeneration, reactive gliosis, and the presence of microscopic extracellular amyloid plaques and intracellular neurofibrillary tangles. Earlier diagnoses of AD would be in the best interest of managing the patient and would allow for earlier therapeutic intervention. By measuring the apparent diffusion coefficient (ADC) using diffusion-weighted imaging (DWI), a type of magnetic resonance imaging (MRI), one can quantify alterations in water diffusivity resulting from microscopic structural changes in the cell at early stages that are associated with pathophysiological processes of brain injury and/or disease progression. Whether or not this methodology is useful for AD is a question under examination. For example, DWI in suspected AD patients has shown increases in mean ADC values in the hippocampus and diminished diffusion anisotropy in the posterior white matter. However, in some cases, hippocampal ADC values appear not to change in AD patients. Moreover, to our knowledge, all DWI studies in suspected AD patients to date are technically incomplete in experimental design, because corresponding histological sections demonstrating actual plaque deposition are lacking and so it is not clear that ADC changes actually correspond to plaque deposition. In our study, we used DWI in the TgCRND8 transgenic model of Alzheimer's disease in conjunction with histological techniques and found robust plaque deposition in the transgenic strain in older animals (12-16 months old). However, we did not find statistically significant changes (p > 0.05) in ADC values (although ADC values in TgCRND8 mice did decrease in all regions examined) in mice 12-16 months old. Collectively, recent results from human studies and in rodent AD transgenic models support our findings and suggest that amyloid beta plaque load is not likely the major or primary component contributing to diffusional changes, if they occur.

Systematic Evaluation of Magnetic Resonance Imaging and Spectroscopy Techniques for Imaging a Transgenic Model of Alzheimer's Disease (AβPP/PS1)

“…A trend towards higher ADC values is observed in whole brain as well as hippocampus or cortex of the A␤PP/PS1, compared to control mice, but these trends are not statistically significant. Similar findings were reported in other AD mouse model that expresses a double mutant form of hA␤PP 695 (K670 N/M671 L and V717F) [54].…”

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

“…Consistent with this interpretation is the finding of a the lack of DTI differences in the slice containing the entorhinal cortex, in which immunoreactivity for pathological tau was particularly intense in the subiculum, as previously reported [29,44,45]. Using diffusion weighted imaging, however, TgCRND8 mice failed to show altered diffusivity in gray matter regions, including the hippocampus and cerebral cortex [24], regions with robust plaque deposition in the absence of neurofibrillary tangles, suggesting it is the co-occurrence of both A␤ plaques and neurofibrillary tangles that contributes to the altered DTI measures in the present study. One must exercise caution in interpreting results of DTI because changes in DTI metrics reflect differences in the diffusion behavior of water and thus imply some sort of neuropathology.…”

“…In gray matter, the trace of the diffusion tensor was decreased in both hippocampal and cortical tissue [23]. In contrast, in TgCRND8 mice, also characterized by robust A␤ plaque deposition, no differences in diffusivity were detected in hippocampal or cortical tissue using diffusion weighted imaging [24]. Studies of double transgenic APP/PSI mice [25,26], in which both A␤ plaque deposition and neuron loss occur, report elevated diffusivity measures in multiple brain regions, including gray matter-rich hippocampus and cortex.…”

Associations between white matter microstructure and amyloid burden in preclinical Alzheimer's disease: A multimodal imaging investigation

“…Mueggler et al (2004) found reduced diffusivity in neocortex of APP23 transgenic mice that was accompanied by fibrillar amyloid deposits and associated gliosis, suggesting that extracellular deposition of fibrillar amyloid and/or associated glial proliferation restrict diffusion. Still, the contribution of Aβ plaques to diffusional changes remains controversial (Thiessen et al, 2010). To investigate this theory in the present study, nonparametric correlations were performed on the PiB signal and MD value from the region with significant differences in MD.…”