The potential role of leukoaraiosis in remodeling the brain network to buffer cognitive decline: a Leukoaraiosis And Disability study from Alzheimer's Disease Neuroimaging Initiative

Abstract

Background: Leukoaraiosis (LA) is a phenomenon of the brain that is often observed in elderly people. However, little is known about the role of LA in cognitive impairment in neurodegeneration and disease. This cross-sectional, retrospective Leukoaraiosis And Disability (LADIS) study aimed to characterize the relationship between brain white matter connectivity properties with LA ratings in patients with Alzheimer's disease (AD) as compared with age-matched cognitively normal controls.

Methods: Patients with AD (n=76) and elderly individuals with normal cognitive (NC) function (n=82) were classified into 3 groups, LA1, LA2, and LA3, according to the rating of their white matter changes (WMCs). Diffusion tensor imaging (DTI) data were analyzed by quantifying and comparing the white matter connectivity properties and gray matter (GM) volume of brain regions of interest (ROIs).

Results: The rich-club network properties in the AD LA1 and LA2 groups showed significant patterns of disrupted peripheral regions and reduced connectivity compared to those in the NC LA1 and LA2 groups, respectively. However, the rich-club network properties in the AD LA3 group showed similar patterns of disrupted peripheral regions and reduced connectivity compared to those in the NC LA3 group, despite there being significant hippocampal and amygdala atrophic differences between AD patients and NC elders. Compared to the NC LA1 group, the characteristic path length of white matter fiber connectivity in the NC LA3 group was significantly increased, and the brain's global efficiency, clustering coefficient, and network connectivity strength were significantly reduced (P<0.05, respectively). However, no significant differences (P>0.05) were observed in characteristic path length, reduced global efficiency, or the clustering coefficient between the NC LA3 and AD LA1 groups, or between the NC LA3 and AD LA2 groups.

Conclusions: Our findings offer some insights into a potential role of LA in cognitive impairment that may predict the development of disability in older adults. The occurrence of LA, an intermediate degenerative change, during neurodegeneration and disease may potentially lead to the remodeling of the brain network through brain plasticity. LA, therefore, representing a possible compensatory mechanism to buffer cognitive decline.

Keywords: White matter hyperintensities (WMH); brain plasticity; network-based statistic (NBS); quantitative magnetic resonance imaging (qMRI); rich club; voxel-based morphometry (VBM).

Figure 1

The representative LA1 to LA3 in AD patients and NC adults. The red arrow showed examples of LA.

Figure 2

Global metrics in different LA rating scale. Global metrics defined by fractional anisotropy connection weight in AD LA1-3 and NC LA1-3 show unadjusted values for (A) characteristic path length, (B) global efficiency and (C) clustering coefficient. Values are presented as mean ± standard deviation, the symbols (* and N.S.) indicate being and not being significant, respectively. (*, P<0.05).

Figure 3

Rich-club membership in AD and NC. The difference in the composition of the rich club between groups was coded in three colors: blue, red, and green. Nodes in blue represent the rich club members common to all AD participants. Nodes in red represent rich-club structures present in the AD group, not in the NC group. Nodes in green indicate structures absent in the rich-club in the AD group. Size of sphere relates to rich-club structures common to 60% of participants, larger spheres common to 95–100% of participants. (A) AD group vs. NC group without LA classification; (B) AD group vs. NC group with LA1 rating; (C) AD group vs. NC group with LA2 rating; (D) AD group vs. NC group with LA3 rating. AL, angular gyrus; ORBsup, superior orbital gyrus; SFGdor, dorsolateral superior frontal gyrus; Put, putamen; THA, Thalamus; STG, superior temporal gyrus; MTG, middle temporal gyrus; PCUN, precuneus; SOG, superior occipital gyrus; MOG, middle occipital gyrus; L, left; R, right.

Figure 4

Group differences in rich club network properties are displayed. Bar graphs display the mean (standard deviation) connectivity strengths for (A) rich club, (B) feeder, and (C) local (N=158). *, P<0.05, N.S. representative has no significant significance.

Figure 5

Rich club functions of FA-weighted group networks. The figures show (A) rich club coefficients and (B) normalized rich club coefficients for a range of ks. The graph shows the association between the mean (standard error) Ønorm as a function of node degree (k) for each of the groups. The differences between NC and patient groups emerge as the node degree increases (N=158). *, P<0.05; **, P<0.01; ***, P<0.001. Normalized rich club coefficients were larger than 1, suggesting rich club organization in all groups.

Figure 6

The aberrant connections in AD groups and NC groups. Red edges indicate affected rich club connections, purple edges indicate affected feeder connections, and green edges indicate affected local connections. The classification of rich club nodes and non-rich club nodes is depicted by the inner ring (gray palette, with black squares indicating rich club nodes and gray ones indicating non-rich club nodes). (D) Proportion (%, y-axis) of significantly altered connections (100% × observed/expected) illustrated by rich club, feeder and local edges.

Figure 7

Whole-brain structural connectivity of nodes with the highest number of aberrant connections in AD individuals relative to NC. (A-C) Nodes in the red triangle (DCG.R, PHG.R, PCUN.R, PCUN.L, etc.) were those with the highest number of aberrant connections in AD individuals relative to NC. Nodes in red means rich club regions. Nodes in blue means peripheral regions. The connections displayed were those that connect with the nodes in the red Triangle. ORBsup, superior orbital gyrus; SFGdor, dorsolateral superior frontal gyrus; Put, putamen; THA, Thalamus; STG, superior temporal gyrus; MTG, middle temporal gyrus; ITG, inferior temporal gyrus; PCUN, precuneus; SOG, superior occipital gyrus; IOG, inferior occipital gyrus; IFGtriang, inferior frontal triangular gyrus; DCG, median cingulate and paracingulate gyri; PHG, parahipppocampal gyrus; HIP, hippocampus; SPG, superior parietal gyrus; LING, Lingual gyrus; L, left; R, right.

Figure 8

Density of nodal connections in AD and NC groups determined by network-based statistic (NBS) analysis. Nodal alterations identified in NBS toolbox, with color and size of sphere indicating increasing t-statistic thresholds. Dark blue nodes indicate Automated Anatomical Labeling (AAL) nodes without significantly difference at any threshold. Light blue nodes (T=3) identify a reduction in density of connections in the AD group compared with the NC group. Similarly, yellow nodes (T=4) and red nodes (T=5) represent reduced density of connections in the AD group at higher thresholds. (I) Axial orientation; (II) coronal orientation; (III) left sagittal orientation; (IV) right sagittal orientation. (A) AD LA1 vs. NC LA1; (B) AD LA2 vs. NC LA2; (C) AD LA3 vs. NC LA3.

Figure 9

The relationship among network metrics and cognitive function. The relationship among network metrics and MMSE or MoCA score after Bonferroni corrections in AD patients and NC adults was plotted by R package “corplot”. Rich_club_connection, Rich club connectivity strength; clustering_coef, clustering coefficient; Feeder connection, Feeder connectivity strength; Local connection, Local connectivity strength; MMSE, Mini-Mental State Examination; MoCA, Montreal Cognitive Assessment Scale.