From Structure to Function: Cognitive Impairment and Its Heterogeneity in Cerebral Small Vessel Disease.

Abstract

Cerebral small vessel disease (CSVD) is a common, age-related microvascular brain disorder and a major vascular cause of cognitive impairment. However, individuals with similar magnetic resonance imaging (MRI) lesion burdens often follow different cognitive trajectories, indicating that conventional imaging captures only late-stage manifestations of a broader pathological cascade. This review focuses on cognitive heterogeneity in CSVD through a heterogeneity-oriented conceptual framework, discussing how divergent cognitive trajectories may arise through the interaction of lesion-related factors, network-mediated consequences, biological and pathological modifiers, and individual susceptibility factors. We highlight the importance of lesion topography, particularly damage to strategic network hubs and connections. Beyond focal lesions, structural network disruption and remote structural and functional abnormalities beyond MRI-visible lesions further shape clinical heterogeneity. We additionally examine biological and pathological modifiers, including molecular biomarkers, heterogeneous neuropathological substrates, and mixed pathology, as well as individual susceptibility factors, such as life-course influences, brain reserve, and resilience. Together, these interacting mechanisms help explain why individuals with comparable structural lesion burdens may experience divergent cognitive trajectories. By reframing CSVD-related cognitive impairment beyond a simple lesion-burden model, this review highlights implications for diagnosis, prognostication, and future individualized approaches to cognitive impairment in CSVD.