Diffusion and Functional MRI Monitoring of Therapy Response in Alzheimer’s Disease Mouse Model

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Project Summary Despite extensive research, effective therapies for Alzheimer's disease (AD) are still unavailable. One important contributing factor for this is a lack of sensitive tools for assessing AD pathology progression at its earliest stages when interventions are most likely to succeed. Both positron emission tomography and anatomical magnetic resonance imaging (MRI) have been applied for this purpose in many prior AD studies, but the information they provide is limited. In particular, they are insensitive to brain tissue microstructure and functional connectivity, which are known to be altered by AD pathology. Therefore, alternative imaging methods with sensitivity to microstructure and function could help in monitoring response to potential therapeutic interventions as well as support studies of the underlying causes of AD, which are still not fully understood. For quantifying brain microstructure, diffusion MRI (dMRI) is the pre-eminent noninvasive imaging modality, while for brain functional connectivity, resting-state functional MRI (rs-fMRI) is the leading approach. In our first funding period, we have shown, for the 3xTg-AD mouse model of the AD pathology, that a specific dMRI method called diffusional kurtosis imaging (DKI) is able to detect microstructural brain abnormalities as early as 2 months of age, which precedes the deposition of amyloid plaques and neurofibrillary tangles, the two classic histological markers of AD. In addition, DKI measures are found to be extremely sensitive to further changes in microstructure occurring throughout the progression of AD pathology up to 21 months of age. In Aim 1 of this renewal application, we propose to extend this work by determining the ability of DKI to monitor, from 2 to 18 months of age, the response of AD pathology to a promising drug treatment known as neurotrophic factor peptide mimetic (P021), which is known to inhibit neurodegeneration and prevent the deposition of amyloid plaques and neurofibrillary tangles in 3xTg-AD mice. The goal is to demonstrate the utility of both standard DKI and a novel extension known as double-pulsed DKI as tools for monitoring therapy response in AD. Since DKI is easily implemented on clinical MRI scanners, translation to human drug trials would be straightforward. In Aim 2, we will acquire rs-fMRI data in this same mouse model to determine the ability of rs- fMRI to monitor response to P021 treatment. In Aim 3, both our DKI and rs-fMRI data will be correlated with biochemical, morphological, and behavioral measures in order to investigate the biological significance of the observed imaging changes. The successful completion of this project will support the application of DKI and rs-fMRI as valuable imaging tools for the assessment of AD drug therapies and for improving our understanding of the mechanisms underlying AD.