Metabolic dysregulation in cerebral small vessel disease: pathogenesis and therapeutic targets

Cerebral small vessel disease (CSVD) is a leading cause of cognitive impairment and stroke in older adults. Accumulating evidence suggests that systemic metabolic disorders and cellular metabolic alterations within the neurovascular unit (NVU) play key roles in the pathogenesis of CSVD. This review first summarizes the associations between CSVD and systemic metabolic alterations, including dysregulated glucose metabolism, lipid disturbances, and imbalanced amino acid profiles. Age- and hypertension-associated metabolic perturbations further contribute to the heterogeneity and progression of CSVD. We next discuss the metabolic disturbance events within key cellular components of the NVU, such as endothelial cells, pericytes, and glial cells, and discuss potential contributions to blood-brain barrier dysfunction, cerebral hypoperfusion, neuroinflammation, and ultimately, CSVD progression. Furthermore, we highlight the therapeutic potential of targeting abnormal metabolic pathways and discuss how emerging technologies like metabolomics can facilitate biomarker discovery and precision medicine in CSVD. A deeper understanding of CSVD-associated metabolic dysregulation will inform the development of targeted interventions and precision therapies for this increasingly prevalent cerebrovascular disorder.