Tissue magnetic susceptibility mapping as a marker of tau pathology in Alzheimer's disease

J O'Callaghan,H Holmes,N Powell,J.A Wells,O Ismail,I.F Harrison,B Siow,R Johnson,Z Ahmed,A Fisher,S Meftah,M.J O'Neill,T.K Murray,E.C Collins,K Shmueli,M.F Lythgoe

doi:10.1016/j.neuroimage.2017.08.003

Abstract

Alzheimer's disease is connected to a number of other neurodegenerative conditions, known collectively as ‘tauopathies’, by the presence of aggregated tau protein in the brain. Neuroinflammation and oxidative stress in AD are associated with tau pathology and both the breakdown of axonal sheaths in white matter tracts and excess iron accumulation grey matter brain regions. Despite the identification of myelin and iron concentration as major sources of contrast in quantitative susceptibility maps of the brain, the sensitivity of this technique to tau pathology has yet to be explored. In this study, we perform Quantitative Susceptibility Mapping (QSM) and T2* mapping in the rTg4510, a mouse model of tauopathy, both in vivo and ex vivo. Significant correlations were observed between histological measures of myelin content and both mean regional magnetic susceptibility and T2* values. These results suggest that magnetic susceptibility is sensitive to tissue myelin concentrations across different regions of the brain. Differences in magnetic susceptibility were detected in the corpus callosum, striatum, hippocampus and thalamus of the rTg4510 mice relative to wild type controls. The concentration of neurofibrillary tangles was found to be low to intermediate in these brain regions indicating that QSM may be a useful biomarker for early stage detection of tau pathology in neurodegenerative diseases.

Highlights

Alzheimer's disease (AD) is defined by the presence of amyloid-β plaque and neurofibrillary tangle (NFT) tau pathology found primarily in grey matter regions of the brain
These findings suggest that tissue magnetic susceptibility provided by Quantitative Susceptibility Mapping (QSM) may be useful as a non-invasive marker of tau pathology in its early stages
T2* mapping and QSM were conducted in a mouse model of AD exhibiting tau pathology for the first time

Summary

Introduction

Alzheimer's disease (AD) is defined by the presence of amyloid-β plaque and neurofibrillary tangle (NFT) tau pathology found primarily in grey matter regions of the brain. These insoluble plaques and tangles have both been found to contain iron (Lovell et al, 1998; Good et al, 1992). Numerous white matter changes in AD have been reported in post mortem studies including decreased myelin density (Sjo€beck et al, 2005), decreased myelin basic protein (Wang et al, 2004), loss of oligodendrocytes (Sjo€beck et al, 2006), activation of microglia (Gouw et al, 2008), as well as denudation of the ventricular ependyma, gliosis and the loss of myelinated axons (Scheltens et al, 1995). In-vivo biomarkers sensitive to tissue neuroinflammatory processes and the concentration of iron and myelin in brain tissue, may play a key role in tracking the progressive pathology of AD and provide a means by which to measure the efficacy of therapeutics

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Discussion

Conclusion