Deep white matter injury and cognitive decline in cerebral small vessel disease: Mediation by a unified atrophy network

Background In cerebral small vessel disease (CSVD), the burden of white matter hyperintensities (WMH) does not fully account for cognitive impairment, suggesting the involvement of intermediary mechanisms. Objective We investigated whether a gray matter atrophy network acts as the key mediator linking topologically specific (deep) WMH to multidomain cognitive dysfunction. Methods In this retrospective study, 260 patients with CSVD (62 cognitively normal, 125 with mild impairment, 73 with dementia) were included. Cognitive status was assessed neuropsychologically. 3.0 T MRI identified an atrophy network. We then conducted pre-specified mediation analyses and a primary confirmatory analysis using structural equation modeling (SEM) to test whether this atrophy network mediated the effect of deep WMH on cognitive performance. Results A 41-region atrophy network was identified , primarily involving the medial temporal lobe and thalamus, that was significantly associated with cognitive status. The final SEM demonstrated excellent fit, showing that higher deep WMH burden was associated with greater network atrophy ( β = 0.145, p < 0.05), which in turn was strongly associated with poorer executive function ( β = −0.64, p < 0.001) and memory ( β = −0.572, p < 0.001). The direct effect of WMH on cognition was not statistically significant in the model. Conclusions Our findings suggest that in CSVD, a unified network of gray matter atrophy acts as a powerful statistical mediator in the effect of deep white matter injury on cognitive decline. This atrophy pattern may represent a more direct biomarker of the neurodegenerative process underlying cognitive impairment than WMH burden alone.