THE IMPACT OF FIBER-TRACT-SPECIFIC WHITE MATTER HYPERINTENSITIES ON RESTING STATE FUNCTIONAL CONNECTIVITY IN ALZHEIMER'S DISEASE

Abstract

White matter hyperintensities (WMH), a marker of small vessel disease, are common in Alzheimer's disease (AD) and global measures of WMH have been associated with increased neurodegeneration (MRI atrophy, FDG-PET hypometabolism). However, the impact of local WMH onto neural network function in AD remains unclear. The current study aimed to test the association between WMH within particular fiber tracts of the default mode network (DMN) and resting state fMRI based functional connectivity (FC) within the DMN. We hypothesized that higher WMH volume in a particular DMN fiber tract is associated with reduced functional connectivity between those brain areas that the fiber tract connects. Patients with AD dementia (N=22), and subjects at high risk of AD, i.e. mild cognitive impairment (MCI, N=40) and healthy controls (HC, N=14) with abnormally high brain levels of beta-amyloid (as measured by AV45-PET (>1.11)) were included from the data bank of the Alzheimer's Disease Neuroimaging Initiative (ADNI). WMH were segmented in a semi-automated way, from MRI FLAIR images. The ratio of WMH within each tract was determined (WMH-ratio), in selected DMN fiber tracts including the inferior fronto-occipital fasciculus (IFOF), cingulum, cingulum-hippocampal and superior longitudinal fasciculus (plus temporal branch). To identify areas of significant FC within the DMN, independent component analysis (ICA) was applied to the resting state fMRI scans. FC ROI was defined as the overlap between the grey matter area surrounding the specific DMN fiber tract terminal and the ICA-DMN map. In a linear regression analysis, tract specific WMH ratio was tested as a predictor of the tract's FC ROI value, controlled for age, global AV45-PET, diagnosis and education in the pooled group. Higher WMH ratio in the IFOF was associated with decreased FC in the medial prefrontal cortex and the angular gyrus ROIs (t(73) = -2.295, p = .02) across all subjects. The WMH ratios in other tracts of the DMN were not associated with FC. The results suggest that WMH disrupt functional connectivity in a fiber-tract specific way, independent from beta-amyloid. Future research needs to address whether WMH in particular neural networks are associated with specific cognitive deficits.