AD is a complex and mysterious disease that is already becoming a cause for concern globally due to its lack of cure and the specialized care required to help patients maintain a functional lifestyle. Research efforts are highly varied; from looking into the molecular basis to understand its mechanisms and develop drugs based on these findings, to looking for macroscopic signs in diagnosis and disease progression. The use of neuroimaging with AD animal models provides a way to combine these efforts.
The use of neuroimaging in humans is very different from that in mouse models. and provide a summary of current neuroimaging techniques used to detect various AD pathologies in humans and mouse models, respectively. As previously described, human MRI studies tend to use lower resolution and field of view to encompass the entire brain. This is also done in order to reduce scanning times of patients. In mouse models, the mice are anesthetized, and can be scanned for far longer than would be practical for humans, up to 24hrs. The scope of human studies in structural MRI is to look for macroscopic changes, such as cortical atrophy, to act as biomarkers and measures with which to monitor disease progression and drug efficacy. In mouse models, we look for microscopic features, particularly Aβ plaques, for similar effect but with more emphasis on the molecular mechanisms that cause AD. This is not to say that looking for Aβ plaques in humans is not of interest; PiB-PET and 18F-AV-45-PET were made to look for Aβ in human brains. However, due to the size of Aβ deposits, it is not yet practical to use structural MRI to visualize them in human cohorts. In this sense, mouse models can provide the necessary data, as their Aβ deposits can be monitored over time using MRI. With a mouse model that adequately simulates AD pathology, MRI can then be used to determine the effects of treatment on Aβ plaques, within mice.
Current uses of neuroimaging techniques for imaging AD pathology in vivo in human cohorts (√ indicates successful visualization of pathology, X indicates unsuccessful)
Use of various neuroimaging techniques for imaging AD pathology in vivo and in vitro in mouse models (mouse model name indicates successful visualization of pathology within that model, X indicates unsuccessful)
Unfortunately, microPET results have been largely unsuccessful in finding a tracer that binds to Aβ plaques in mice as effectively as in humans. Perhaps more distressing is the implication that this may be due to an inherent difference between human AD and mouse models of AD. As discussed before, most transgenic mouse models are derived from FAD mutations and may not be applicable to late-onset AD. An example of this can be seen in amyloid vaccination studies, where no serious adverse effects were seen in mouse models, but which resulted in meningoencephalitis for humans [149
]. In light of this, naturally aged non-human primates are being used as a better model of human AD, both to determine the mechanism of these complications and to test other treatments [153
Overall, the main disadvantages of using mouse models in AD research and neuroimaging are that they are sometimes too small to scan properly, as seen in the PET studies, and that the findings obtained from mice are not necessarily transferrable to humans. The definitive cause of AD has yet to be found, but it is clear that it involves interactions between several components, not the single aspect that many transgenic mouse models provide. The question remains as to whether or not mouse models can completely replicate the neuropathological progression of AD. However, these are issues for all animal models, even non-human primates.
Despite the disadvantages, animal models can still be useful in determining the mechanism of AD pathogenesis. Indeed, de la Torre’s CATCH hypothesis [33
] was derived from their studies of mice undergoing chronic brain hypoperfusion. Testing MRI protocols on mouse models can also help develop these concepts for human scanning later on, as demonstrated by Chamberlain et al. [108
]. They were able to determine that fast spin echo techniques were not as good as average multiple echoes and that SWI provided the best contrast for visualizing Aβ plaques in mouse models. In fact, they believe that SWI may be implemented more effectively in human cohorts as the larger brain size reduces the amount of susceptibility interfaces that interfere with the image, as well as the fact that human Aβ plaques contain more iron than APP/PS1 mice [120
], creating even greater contrast.
To conclude, the use of mouse models is still beneficial in AD research, particularly for neuroimaging. They are cheap to maintain, have short lifespans so symptoms appear faster, are much more consistent than humans, and can target a single aspect of AD. Even if this aspect may not be transferrable to humans, it is still useful to form a hypothesis first, based on cellular and molecular findings, before expanding and testing it on more complicated models. They can also be used to test new treatments, using similar neuroimaging techniques that could be transferred to human studies in future.
Neuroimaging is a versatile tool in itself for detecting macroscopic, and potentially microscopic, changes in diseased brains. With the increase in longitudinal, large-scale, multimodal initiatives such as ADNI and AIBL, the search for a new biomarker that can be monitored noninvasively is only just beginning in earnest. This search can be aided when combined with the molecular knowledge obtained from animal studies, as well as complementary neuroimaging information that cannot be tested in humans.