ApoE influences regional white-matter axonal density loss in Alzheimer's disease

Catherine F Slattery,Jiaying Zhang,Ross W Paterson,Alexander J.M Foulkes,Amelia Carton,Kirsty Macpherson,Laura Mancini,David L Thomas,Marc Modat,Nicolas Toussaint,David M Cash,John S Thornton,Susie M.D Henley,Sebastian J Crutch,Daniel C Alexander,Sebastien Ourselin,Nick C Fox,Hui Zhang,Jonathan M Schott

doi:10.1016/j.neurobiolaging.2017.04.021

Abstract

Mechanisms underlying phenotypic heterogeneity in young onset Alzheimer disease (YOAD) are poorly understood. We used diffusion tensor imaging and neurite orientation dispersion and density imaging (NODDI) with tract-based spatial statistics to investigate apolipoprotein (APOE) ε4 modulation of white-matter damage in 37 patients with YOAD (22, 59% APOE ε4 positive) and 23 age-matched controls. Correlation between neurite density index (NDI) and neuropsychological performance was assessed in 4 white-matter regions of interest. White-matter disruption was more widespread in ε4+ individuals but more focal (posterior predominant) in the absence of an ε4 allele. NODDI metrics indicate fractional anisotropy changes are underpinned by combinations of axonal loss and morphological change. Regional NDI in parieto-occipital white matter correlated with visual object and spatial perception battery performance (right and left, both p = 0.02), and performance (nonverbal) intelligence (WASI matrices, right, p = 0.04). NODDI provides tissue-specific microstructural metrics of white-matter tract damage in YOAD, including NDI which correlates with focal cognitive deficits, and APOEε4 status is associated with different patterns of white-matter neurodegeneration.

Highlights

The biological underpinnings of phenotypic expression in neurodegenerative disease are poorly understood
neurite orientation dispersion and density imaging (NODDI), a multishell diffusion technique implemented on standard 3T clinical magnetic resonance (MR) scanners, provided further insights into the commonalities and differences in white-matter change associated with ε4 genotype; namely more widespread neurite density index (NDI) reduction in ε4þ individuals and more focal posterior reductions in patients without an ε4 allele
Reduction in regional NDIdspecifically modeling axonal loss in white matterdcorrelated with patterns of focal cognitive impairment, suggesting that NODDI metrics provide insights into regional white-matter vulnerability and have relevant clinical correlates

Summary

Introduction

The biological underpinnings of phenotypic expression in neurodegenerative disease are poorly understood. Clinical heterogeneity is apparent in patients with sporadic young onset AD (YOAD), defined as symptom onset at less than 65 years (Rossor et al, 2010). These individuals are more likely to present with nonamnestic phenotypes, including posterior cortical atrophy (Tang-Wai et al, 2004), logopenic progressive aphasia (GornoTempini et al, 2011) and a dysexecutive/behavioural syndrome (Ossenkoppele et al, 2015b).

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