In vivo imaging biomarkers in mouse models of Alzheimer's disease: are we lost in translation or breaking through?

Abstract

Identification of biomarkers of Alzheimer's Disease (AD) is a critical priority to efficiently diagnose the patients, to stage the progression of neurodegeneration in living subjects, and to assess the effects of disease-modifier treatments. This paper addresses the development and usefulness of preclinical neuroimaging biomarkers of AD. It is today possible to image in vivo the brain of small rodents at high resolution and to detect the occurrence of macroscopic/microscopic lesions in these species, as well as of functional alterations reminiscent of AD pathology. We will outline three different types of imaging biomarkers that can be used in AD mouse models: biomarkers with clear translational potential, biomarkers that can serve as in vivo readouts (in particular in the context of drug discovery) exclusively for preclinical research, and finally biomarkers that constitute new tools for fundamental research on AD physiopathogeny.

Figure 1

Summary of imaging techniques. This figure schematizes the principal methodologies and tools that can be used to image in vivo the brain lesions and functional alterations developed by mouse models of AD. Radioligands analyzed by PET (green dots) can be used to map brain metabolic deficits in APP(xPS1) transgenic mice. Their relevance for plaque detection in mouse models is more controversial. Applications derived from small animal MR-based imaging techniques (red dots) are more versatile. MRI allows the detection of pathological markers at the regional level (e.g., evaluation of brain atrophy) and also at a microscopic resolution (e.g., visualization of amyloid plaques). In vivo MRI is also a tool to assess functional markers of the pathology such as anomalies in brain perfusion. The recent development of manganese-enhanced MRI has opened new opportunities to map in vivo brain connectivity and neuronal activity with an exquisite spatial resolution. The detection of discrete markers at the (sub)cellular level relies today on the use of high resolution, but also more invasive, imaging techniques that require direct access to brain tissues through a craniotomy in anaesthetized animals: with multiphoton microscopy (blue dots) it is for instance possible to detect intraneuronal neurofibrillary tangles as well as dystrophic neurites in APP(xPS1) transgenic mice.