Imaging the accumulation and suppression of tau pathology using multiparametric MRI

Holly Holmes ,Niall Colgan,Emily C Collins,Da Ma,Nick M Powell,Morton Heggenes,Ozama Ismail,Marc Modat,Alice Fisher,Ian F Harrison,Zeshan Ahmed,Jack A Wells,Mark F Lythgoe,Ross A Johnson,Tracey K Murray,M Jorge Cardoso ,Elizabeth Fisher ,James M O’callaghan ,Michael O’neill ,Sébastien Ourselin ,Simon Walker‐Samuel

doi:10.1016/j.neurobiolaging.2015.12.001

Abstract

Mouse models of Alzheimer's disease have served as valuable tools for investigating pathogenic mechanisms relating to neurodegeneration, including tau-mediated and neurofibrillary tangle pathology—a major hallmark of the disease. In this work, we have used multiparametric magnetic resonance imaging (MRI) in a longitudinal study of neurodegeneration in the rTg4510 mouse model of tauopathy, a subset of which were treated with doxycycline at different time points to suppress the tau transgene. Using this paradigm, we investigated the sensitivity of multiparametric MRI to both the accumulation and suppression of pathologic tau. Tau-related atrophy was discernible from 5.5 months within the cortex and hippocampus. We observed markedly less atrophy in the treated rTg4510 mice, which was enhanced after doxycycline intervention from 3.5 months. We also observed differences in amide proton transfer, cerebral blood flow, and diffusion tensor imaging parameters in the rTg4510 mice, which were significantly less altered after doxycycline treatment. We propose that these non-invasive MRI techniques offer insight into pathologic mechanisms underpinning Alzheimer's disease that may be important when evaluating emerging therapeutics targeting one of more of these processes.

Highlights

It has been over a century since Alois Alzheimer first described the symptoms of the presenile dementia that would come to bear his name (Stelzmann et al, 1995); but to date, there is still no disease-modifying or preventative treatment for this devastating disease
We have explored the sensitivity of multiparametric magnetic resonance imaging (MRI) to the accumulation and suppression of pathologic tau
We report the first application of multiparametric MRI biomarkers, including structural MRI, arterial spin labelling (ASL), diffusion tensor imaging (DTI), and amide proton transfer (APT), in a longitudinal study of neurodegeneration in the rTg4510 mouse model of tauopathy

Summary

Introduction

It has been over a century since Alois Alzheimer first described the symptoms of the presenile dementia that would come to bear his name (Stelzmann et al, 1995); but to date, there is still no disease-modifying or preventative treatment for this devastating disease. As the incidence of Alzheimer’s disease (AD) continues to rise to epidemic proportions (Brookmeyer et al, 2007), effective therapies are urgently required to ease both the economic and emotional burdens of this devastating disease. The two key neuropathologic hallmarks of AD are plaques comprised of amyloid-beta (Ab) peptides and neurofibrillary tangles (NFTs) of hyperphosphorylated tau. Emerging therapies targeting the production or clearance of these protein aggregates require robust biomarkers to evaluate and quantify therapeutic efficacy. One approach is to establish and validate biomarkers using mouse models of AD as a surrogate for patient populations

Methods

Results

Discussion

Conclusion