Comparison of In Vivo and Ex Vivo MRI for the Detection of Structural Abnormalities in a Mouse Model of Tauopathy

Abstract

With increasingly large numbers of mouse models of human disease dedicated to MRI studies, compromises between in vivo and ex vivo MRI must be fully understood in order to inform the choice of imaging methodology. We investigate the application of high resolution in vivo and ex vivo MRI, in combination with tensor-based morphometry (TBM), to uncover morphological differences in the rTg4510 mouse model of tauopathy. The rTg4510 mouse also offers a novel paradigm by which the overexpression of mutant tau can be regulated by the administration of doxycycline, providing us with a platform on which to investigate more subtle alterations in morphology with morphometry. Both in vivo and ex vivo MRI allowed the detection of widespread bilateral patterns of atrophy in the rTg4510 mouse brain relative to wild-type controls. Regions of volume loss aligned with neuronal loss and pathological tau accumulation demonstrated by immunohistochemistry. When we sought to investigate more subtle structural alterations in the rTg4510 mice relative to a subset of doxycycline-treated rTg4510 mice, ex vivo imaging enabled the detection of more regions of morphological brain changes. The disadvantages of ex vivo MRI may however mitigate this increase in sensitivity: we observed a 10% global shrinkage in brain volume of the post-mortem tissues due to formalin fixation, which was most notable in the cerebellum and olfactory bulbs. However, many central brain regions were not adversely affected by the fixation protocol, perhaps due to our “in-skull” preparation. The disparity between our TBM findings from in vivo and ex vivo MRI underlines the importance of appropriate study design, given the trade-off between these two imaging approaches. We support the utility of in vivo MRI for morphological phenotyping of mouse models of disease; however, for subtler phenotypes, ex vivo offers enhanced sensitivity to discrete morphological changes.

Comparison between diffusion MRI tractography and histological tract-tracing of cortico-cortical structural connectivity in the ferret brain

“…High resolution MRI were acquired ex vivo using a small animal 7 Tesla Bruker MRI scanner (Neurospin, Saclay, France). The acquisitions were performed post mortem in order to improve sensitivity (Holmes et al, 2017) . The brain was obtained from a 2 month old ferret.…”

Progressive Pathological Changes in Neurochemical Profile of the Hippocampus and Early Changes in the Olfactory Bulbs of Tau Transgenic Mice (rTg4510)

“…MRS studies on several transgenic mouse models of AD demonstrated the reliable longitudinal assessment of neurochemical changes associated with AD pathology [24–26,10]. MR imaging studies of rTg4510 transgenic mice showed extensive brain atrophy [10,27,28] alterations in white matter water diffusion [29,30,27], axonal transport deficit [31], vascular reactivity [32], glutamate and chemical exchange saturation transfer (CEST) signals [27] in rTg4510 mice. Elevated mI concentrations in rTg4510 than wild type (wt) mice have also been reported [10].…”

In vivo diffusion MRI detects early spinal cord axonal pathology in a mouse model of amyotrophic lateral sclerosis

“…[44][45][46] Moreover, recent studies have indicated that significant structural differences in nervous tissues can be seen between ex vivo and in vivo preparations with a clear trade-off between these two imaging approaches. 46 Specifically, we analyzed SC microstructural changes in animal ALS using a different animal model (YFP,G93A-SOD1 mice). Results from our MRI segmentation analysis showed that macrostructural alterations in WM can be detected at the symptomatic stage of the disease, demonstrating the particular susceptibility of this CNS tissue to the SOD1 mutation (Figure 1).…”

“…This study is a continuation of our previous work using a new line of mice (C57 mice) with a fluorescent reporter in vivo . A growing number of published studies have pointed to differences between ex vivo models and the need to choose the best model for the purpose of each study: ex vivo for precision; in vivo for time course . Moreover, recent studies have indicated that significant structural differences in nervous tissues can be seen between ex vivo and in vivo preparations with a clear trade‐off between these two imaging approaches .…”

“…A growing number of published studies have pointed to differences between ex vivo models and the need to choose the best model for the purpose of each study: ex vivo for precision; in vivo for time course. [44][45][46] Moreover, recent studies have indicated that significant structural differences in nervous tissues can be seen between ex vivo and in vivo preparations with a clear trade-off between these two imaging approaches. 46 Specifically, we analyzed SC microstructural changes in animal ALS using a different animal model (YFP,G93A-SOD1 mice).…”