Long-range connections damage in white matter hyperintensities affects information processing speed

Abstract

White matter hyperintensities, one of the major markers of cerebral small vessel disease, disrupt the integrity of neuronal networks and ultimately contribute to cognitive dysfunction. However, a deeper understanding of how white matter hyperintensities related to the connectivity patterns of brain hubs at the neural network level could provide valuable insights into the relationship between white matter hyperintensities and cognitive dysfunction. A total of 36 patients with moderate to severe white matter hyperintensities (Fazekas score ≥ 3) and 34 healthy controls underwent comprehensive neuropsychological assessments and resting-state functional MRI scans. The voxel-based graph-theory approach-functional connectivity strength was employed to systematically investigate the topological organization of the whole-brain networks. The white matter hyperintensities patients performed significantly worse than the healthy controls in episodic memory, executive function and information processing speed. Additionally, we found that white matter hyperintensities selectively affected highly connected hub regions, predominantly involving the medial and lateral prefrontal, precuneus, inferior parietal lobule, insula and thalamus. Intriguingly, this impairment was connectivity distance-dependent, with the most prominent disruptions observed in long-range connections (e.g. 100-150 mm). Finally, these disruptions of hub connectivity (e.g. the long-range functional connectivity strength in the left dorsolateral prefrontal cortex) positively correlated with the cognitive performance in white matter hyperintensities patients. Our findings emphasize that the disrupted hub connectivity patterns in white matter hyperintensities are dependent on connection distance, especially longer-distance connections, which in turn predispose white matter hyperintensities patients to worse cognitive function.

Keywords: cerebral small vessel disease; cognitive impairment; connectome; functional connectivity; white matter hyperintensities.

Graphical Abstract

Figure 1

Between-group differences in full-range FCS. Compared with the HC subjects, the WMHs patients showed significantly decreased FCS mainly located in the bilateral superior/middle frontal gyrus (SFG/MFG), dorsal medial prefrontal cortex (dMPFC), precuneus (PCUN), inferior parietal lobule (IPL), insula, thalamus, calcarine fissure and surrounding cortex and superior/middle occipital gyrus. FCS, functional connectivity strength; HC, healthy control; WMHs, white matter hyperintensities.

Figure 2

Distance-dependent FCS patterns in WMHs. (A) Between-group differences in different distance bins. The between-group FCS maps exhibited similar patterns in neighbouring distance bins, but were very different between very short and long distances. The reduced FCS values in WMHs were predominantly observed in the bilateral dorsolateral prefrontal cortex, medial prefrontal cortex, precuneus (PCUN), inferior parietal lobule (IPL), insula, thalamus and occipital lobe. Of note, the most prominent WMHs-related FCS decreases were observed within the 100–150 mm range, indicating that WMHs were primarily associated with longer-distance disconnections. (B) The number of voxels exhibiting significant group differences in FCS in different distance bins. (C) Difference maps between groups for short- and long-range FCS. We grouped the 18 FCS bins into two categories: 0–100 mm (short-range FCS) and 100–180 mm (long-range FCS). FCS, functional connectivity strength; WMHs, white matter hyperintensities.

Figure 3

Relationships between the cognitive performance and short/long-range FCS values in the WMHs group. For IPS, we observed positive correlations in the left dorsolateral prefrontal cortex with long-range FCS, and in the right precuneus with short-range FCS. Warm colours represent positive correlations. FCS, functional connectivity strength; WMHs, white matter hyperintensities; IPS, information processing speed.