Functional connectivity of white matter as a biomarker of cognitive decline in Alzheimer's disease.

Yurui Gao,Zhongliang Zu,Adam W Anderson,Anirban Sengupta,John C Gore,Baxter P Rogers,Zhaohua Ding,Muwei Li,Alzheimer’s Disease Neuroimaging Initiative

doi:10.1371/journal.pone.0240513

Yurui Gao, Zhongliang Zu + Show 7 more

Open Access

https://doi.org/10.1371/journal.pone.0240513

Copy DOI

Abstract

ObjectiveIn vivo functional changes in white matter during the progression of Alzheimer’s disease (AD) have not been previously reported. Our objectives are to measure changes in white matter functional connectivity (FC) in an elderly population undergoing cognitive decline as AD develops, to establish their relationship to neuropsychological scores of cognitive abilities, and to assess the performance in prediction of AD using white matter FC measures as features.MethodsAnalyses were conducted using resting state functional MRI and neuropsychological data from 383 ADNI participants, including 136 cognitive normal (CN) controls, 46 with significant memory concern, 83 with early mild cognitive impairment (MCI), 37 with MCI, 46 with late MCI, and 35 with AD dementia. FC metrics between segregated white matter tracts and discrete gray matter volumes or between white matter tracts were quantitatively analyzed and characterized, along with their relationships to 6 cognitive measures. Finally, supervised machine learning was implemented on white matter FCs to classify the participants and performance of the classification was evaluated.ResultsSignificant decreases in FC measures were found in white matter with prominent, specific, regional deficits appearing in late MCI and AD dementia patients from CN. These changes significantly correlated with neuropsychological measurements of impairments in cognition and memory. The sensitivity and specificity of distinguishing AD dementia and CN using white matter FCs were 0.83 and 0.81 respectively.Conclusions and relevanceThe white matter FC decreased in late MCI and AD dementia patients compared to CN participants, and this decrease was correlated with cognitive measures. White matter FC is valuable in the prediction of AD. All these findings suggest that white matter FC may be a promising avenue for understanding functional impairments in white matter tracts during AD progression.

Highlights

Alzheimer’s disease (AD) is the most common progressive neurodegenerative disorder, which begins at a pre-symptomatic stage before subjects exhibit increasingly severe cognitive impairments and dementia [1, 2]
Significant decreases in functional connectivity (FC) measures were found in white matter with prominent, specific, regional deficits appearing in late mild cognitive impairment (MCI) and AD dementia patients from cognitive normal (CN)
The white matter FC decreased in late MCI and AD dementia patients compared to CN participants, and this decrease was correlated with cognitive measures

Summary

Introduction

Alzheimer’s disease (AD) is the most common progressive neurodegenerative disorder, which begins at a pre-symptomatic stage before subjects exhibit increasingly severe cognitive impairments and dementia [1, 2]. While there has been considerable emphasis on GM changes, pathological alterations of WM post mortem have been reported in late stages of AD (associated with loss of axons and oligodendrocytes [5] and concomitant with vascular abnormalities [6, 7]), and in earlier, pre-clinical stages, probably related to amyloid toxicity [8]. Atrophy has been found to be even more prominent in WM than in GM in early stage disease [3]. Structural changes of WM have been intensively investigated [9,10,11], there have been no studies investigating functional changes in WM, which presumably link structure and behavioral performance, in the progression towards AD dementia (ADD)

Methods

Results

Discussion

Conclusion