Association Between White Matter Hyperintensity and Cognitive Impairment in Cerebral Small Vessel Disease: The Frequency-dependent Role of Brain Functional Activity

Background: Cognitive dysfunction in cerebral small vessel disease (CSVD) patients is associated with white matter hyperintensity (WMH), which demonstrates frequency-dependent correlations with brain functional activities. However, the neural mechanisms underlying the relationship between these structural and functional abnormalities and cognitive impairment remain unclear. Methods: We recruited 34 CSVD patients (mean age 63.74 ± 4.85 years, 19 males) and 45 age-matched healthy controls (mean age 63.69 ± 6.15 years, 15 males). All participants underwent magnetic resonance imaging (MRI) scanning and comprehensive cognitive assessments, including three behavioral tasks and a cognitive questionnaire battery. Regional brain activity and network topological properties were separately compared between the two groups for each of the three frequency bands (slow-4, slow-5, and typical band) using two-sample t-tests. Simple and multiple mediation analyses were performed to examine the relationships among WMH, functional brain measures, and global cognition. Results: CSVD patients exhibited frequency-specific alterations in regional activity and reduced global functional organization in the slow-4 band. Frequency-dependent functional measures in the slow-4 band significantly mediated the relationship between deep WMH and cognitive performance. Conclusion: Our findings demonstrate the frequency-specific mediating role of abnormal brain functions in the pathophysiological pathway linking WMHs to cognitive impairment. This study provides new insight into the pathological mechanisms underlying WMH-related cognitive dysfunction.