Cerebral Small Vessel Disease and Blood-Brain Barrier Disruption: Mechanisms and Therapeutic Strategies in Cognitive Impairment.

To evaluate the molecular and cellular mechanisms underlying cerebral small vessel disease (CSVD) pathophysiology, the blood-brain barrier (BBB) dysfunction, and emerging therapeutic strategies for cognitive impairment. We conducted a comprehensive review of recent literature examining the relationship between CSVD and BBB disruption, focusing on pathophysiological mechanisms and therapeutic approaches. Key databases were searched for relevant studies investigating inflammatory responses, lipid metabolism, endothelial dysfunction, and their impact on cognitive function in CSVD. BBB disruption plays a central role in CSVD pathogenesis, characterized by increased permeability that triggers neuroinflammatory cascades and subsequent cognitive deterioration. Neuroinflammation, oxidative stress, and disrupted lipid metabolism synergistically contribute to BBB breakdown, creating a detrimental feedback loop. Therapeutic strategies targeting these pathways, including vascular risk factor management, anti-inflammatory interventions, and non-pharmacological approaches such as cognitive training and physical exercise, show promising results in preserving cognitive function in CSVD patients. This review provides critical insights into the complex interplay between CSVD and BBB integrity, emphasizing BBB disruption as both a consequence and amplifier of CSVD-related pathology. Understanding these mechanisms offers novel perspectives for developing targeted interventions to mitigate cognitive decline in affected individuals and addresses a significant public health challenge in our aging global population. We also integrate recent evidence connecting BBB leakage to lipid dysmetabolism, EndMT, and impaired perivascular clearance, and propose a BBB-centered framework for CSVD-related cognitive impairment.