Peripheral Microvascular and Endothelial Dysfunction as Predictors of Cognitive Decline and Small Vessel Disease: A...

Background: Endothelial and microvascular dysfunction play a central role in the pathogenesis of both cardiovascular and neurodegenerative disorders. However, whether impaired peripheral endothelial function independently predicts cognitive decline, cerebral small-vessel disease (SVD) progression, or stroke remains uncertain. Methods: We conducted a systematic review and meta-analysis of prospective cohort studies assessing the prognostic value of non-invasive peripheral endothelial tests-flow-mediated dilation (FMD), peripheral arterial tonometry (PAT/EndoPAT), and sublingual microcirculatory imaging-for cognitive or cerebrovascular outcomes. Databases (PubMed, Embase, Scopus, Web of Science) were searched from inception through 30 September 2025. Study quality was appraised using the Newcastle-Ottawa Scale (NOS), and evidence certainty was graded via GRADE. Random-effects models (DerSimonian-Laird or REML) pooled hazard ratios (HRs) using inverse-variance weighting. PROSPERO-registered (CRD42025211876). Results: Fifteen prospective cohorts (n = 13,972 participants; median follow-up 4.3 years) met inclusion criteria. Across all modalities, impaired endothelial or microvascular function predicted cognitive decline, SVD progression, or cerebrovascular events (pooled HR = 1.72, 95% CI 1.38-2.14, p < 0.001; I² = 57%). Subgroup analyses confirmed consistent associations for FMD (HR = 1.59, 95% CI 1.27-1.98) and PAT/EndoPAT (HR = 1.84, 95% CI 1.40-2.41). Evidence certainty was rated moderate-to-high according to GRADE. Conclusions: Peripheral endothelial dysfunction, measured by validated non-invasive techniques, independently predicts future cognitive and cerebrovascular events. These findings support the concept of a vascular-neural continuum, suggesting that endothelial health represents a modifiable biomarker for early neurovascular risk stratification. Routine assessment of endothelial function may help identify high-risk individuals and guide preventive interventions aimed at preserving brain and vascular health.