Measuring cortical mean diffusivity to assess early microstructural cortical change in presymptomatic familial Alzheimer\u2019s disease

Ivor J. A. Simpson,Sebastien Ourselin,Philip S. J. Weston,Natalie S. Ryan,Jonathan M. Schott,Yuying Liang,Nicolas Toussaint,Hui Zhang,Jennifer M. Nicholas,Marc Modat,Nick C. Fox,Teresa Poole,Martin N. Rossor

doi:10.1186/s13195-020-00679-2

Abstract

BackgroundThere is increasing interest in improving understanding of the timing and nature of early neurodegeneration in Alzheimer’s disease (AD) and developing methods to measure this in vivo. Autosomal dominant familial Alzheimer’s disease (FAD) provides the opportunity for investigation of presymptomatic change. We assessed early microstructural breakdown of cortical grey matter in FAD with diffusion-weighted MRI.MethodsDiffusion-weighted and T1-weighed MRI were acquired in 38 FAD mutation carriers (17 symptomatic, 21 presymptomatic) and 39 controls. Mean diffusivity (MD) was calculated for six cortical regions previously identified as being particularly vulnerable to FAD-related neurodegeneration. Linear regression compared MD between symptomatic and presymptomatic carriers and controls, adjusting for age and sex. Spearman coefficients assessed associations between cortical MD and cortical thickness. Spearman coefficients also assessed associations between cortical MD and estimated years to/from onset (EYO). Across mutation carriers, linear regression assessed associations between MD and EYO, adjusting for cortical thickness.ResultsCompared with controls, cortical MD was higher in symptomatic mutation carriers (mean ± SD CDR = 0.88 ± 0.39) for all six regions (p < 0.001). In late presymptomatic carriers (within 8.1 years of predicted symptom onset), MD was higher in the precuneus (p = 0.04) and inferior parietal cortex (p = 0.003) compared with controls. Across all presymptomatic carriers, MD in the precuneus correlated with EYO (p = 0.04). Across all mutation carriers, there was strong evidence (p < 0.001) of association between MD and cortical thickness in all regions except entorhinal cortex. After adjusting for cortical thickness, there remained an association (p < 0.05) in mutation carriers between MD and EYO in all regions except entorhinal cortex.ConclusionsCortical MD measurement detects microstructural breakdown in presymptomatic FAD and correlates with proximity to symptom onset independently of cortical thickness. Cortical MD may thus be a feasible biomarker of early AD-related neurodegeneration, offering additional/complementary information to conventional MRI measures.

Highlights

There is increasing interest in improving understanding of the timing and nature of early neurodegeneration in Alzheimer’s disease (AD) and developing methods to measure this in vivo
We found evidence that late presymptomatic familial Alzheimer’s disease (FAD) mutation carriers have significantly increased cortical Mean diffusivity (MD) compared with controls in both the precuneus and the inferior parietal cortex
We show that MD is higher in those with symptomatic AD compared to healthy individuals, in a group of symptomatic familial AD individuals who on average were only mildly clinically affected

Summary

Introduction

There is increasing interest in improving understanding of the timing and nature of early neurodegeneration in Alzheimer’s disease (AD) and developing methods to measure this in vivo. Autosomal dominant familial Alzheimer’s disease (FAD) provides the opportunity for investigation of presymptomatic change. Neurodegeneration involving cortical grey matter is a recognised feature of both sporadic and familial AD, with structural MRI identifying similar characteristic patterns of macrostructural loss within the cerebral cortex [4, 5].

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