White Matter Abnormalities and Structural Hippocampal Disconnections in Amnestic Mild Cognitive Impairment and Alzheimer’s Disease

Jared Rowley,Amir Shmuel,Laksanun Cheewakriengkrai,Pedro Rosa-Neto,Vladimir Fonov,Alain Dagher,Simon Fristed Eskildsen,Serge Gauthier,Liyong Wu,Dorothee Schoemaker,Ona Wu,Viviane Sziklas,Sara Mohades,Monica Shin,Hideyuki Sawada

doi:10.1371/journal.pone.0074776

Abstract

The purpose of this project was to evaluate white matter degeneration and its impact on hippocampal structural connectivity in patients with amnestic mild cognitive impairment, non-amnestic mild cognitive impairment and Alzheimer’s disease. We estimated white matter fractional anisotropy, mean diffusivity and hippocampal structural connectivity in two independent cohorts. The ADNI cohort included 108 subjects [25 cognitively normal, 21 amnestic mild cognitive impairment, 47 non-amnestic mild cognitive impairment and 15 Alzheimer’s disease]. A second cohort included 34 subjects [15 cognitively normal and 19 amnestic mild cognitive impairment] recruited in Montreal. All subjects underwent clinical and neuropsychological assessment in addition to diffusion and T1 MRI. Individual fractional anisotropy and mean diffusivity maps were generated using FSL-DTIfit. In addition, hippocampal structural connectivity maps expressing the probability of connectivity between the hippocampus and cortex were generated using a pipeline based on FSL-probtrackX. Voxel-based group comparison statistics of fractional anisotropy, mean diffusivity and hippocampal structural connectivity were estimated using Tract-Based Spatial Statistics. The proportion of abnormal to total white matter volume was estimated using the total volume of the white matter skeleton. We found that in both cohorts, amnestic mild cognitive impairment patients had 27-29% white matter volume showing higher mean diffusivity but no significant fractional anisotropy abnormalities. No fractional anisotropy or mean diffusivity differences were observed between non-amnestic mild cognitive impairment patients and cognitively normal subjects. Alzheimer’s disease patients had 66.3% of normalized white matter volume with increased mean diffusivity and 54.3% of the white matter had reduced fractional anisotropy. Reduced structural connectivity was found in the hippocampal connections to temporal, inferior parietal, posterior cingulate and frontal regions only in the Alzheimer’s group. The severity of white matter degeneration appears to be higher in advanced clinical stages, supporting the construct that these abnormalities are part of the pathophysiological processes of Alzheimer’s disease.

Highlights

Alzheimer’s disease (AD) has been conceptualized by a succession of pathophysiological events beginning with progressive extracellular accumulation of amyloid followed by a variety of neurodegenerative changes such as intracellular accumulation of neurofibrillary inclusions, brain atrophy and cell depletion [1]
In the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort a 1-way ANOVA of the ADNI demographics showed the cognitively normal (CN), amnestic mild cognitive impairment (aMCI), non-amnestic mild cognitive impairment (naMCI) and AD groups did not differ in terms of gender, age, and education
Average fractional anisotropy (FA) and Mean diffusivity (MD) were significantly different between cohorts (FA CNMCSA=0.41 vs CNADNI=0.36)

Summary

Introduction

Alzheimer’s disease (AD) has been conceptualized by a succession of pathophysiological events beginning with progressive extracellular accumulation of amyloid followed by a variety of neurodegenerative changes such as intracellular accumulation of neurofibrillary inclusions, brain atrophy and cell depletion [1]. In AD, neurodegenerative changes (i.e. tau hyperphosphorylation and cell depletion) follows a typical 6stage topographic pattern starting in the entorhinal cortex, propagating to the limbic cortex and subsequently to the polymodal association cortex [2]. The asymptomatic AD, mild cognitive impairment (MCI) and dementia stages nearly correspond to the severity of AD neuropathology propagation [2,3]. There is a growing consensus that white matter (WM) abnormalities in MCI constitute an integral part of the degenerative process associated with AD pathophysiology. WM structural changes such as myelin breakdown, loss of myelin basic protein [5], neuroinflammation as well as abnormal axonal transport have been recognized as part of AD WM neuropathological features [6,7,8]

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