Progressive degeneration of white matter functional connectivity in Alzheimer’s disease

Background: Alzheimer’s Disease (AD) is a progressive neurodegenerative disorder, in which pathological alterations are seen in both gray matter (GM) and white matter (WM). To date functional MRI (fMRI) studies of AD have been exclusively focused on GM, since blood oxygenation level dependent (BOLD) signals in WM are relatively weak and thus ignored in practice. Our recent work provides compelling evidence that BOLD fluctuations in brain WM are reliably detectable and reflect neural activities, offering the potential of investigating the functional connectivity in WM. Purpose: In this study, we aim to apply our fMRI analysis method to the investigation of functional alterations in WM during the progression of AD. Method: Raw resting state fMRI data of normal subjects and patients (total n=290, 5 diagnostic groups) were obtained from the Alzheimer’s Disease Neuroimaging Initiative database. Each fMRI image was parcellated into 82 GM regions and 48 WM bundles. Temporal correlation between each pair of GM and WM was calculated and the correlations of all pairs constituted a functional correlation matrix (FCM) for each subject. The FCMs were averaged within each diagnostic group, and differences in the averaged FCMs between the normal group and each disease group were sought. Result: Differences in functional correlations progressively enlarge as the disease evolves, and fornix and ventral entorhinal cortices exhibited most pronounced differences between the normal and disease groups. Conclusion: Functional connectivity in WM may serve as a novel neuroimaging biomarker for the progression of AD.