High Circulatory Phosphate Level Is Associated with Cerebral Small-Vessel Diseases

High phosphate is linked to vascular calcification and endothelial dysfunction; however, its relationship with cerebral small-vessel diseases (CSVDs) is still unknown. Study subjects were prospectively recruited from the community-based I-Lan Longitudinal Aging Study. CSVDs including lacunes, white matter hyperintensities (WMHs), and cerebral microbleeds were evaluated using 3T magnetic resonance images. Multivariate analyses were performed to study the associations between circulatory phosphate level and the presence of CSVDs. In vitro experiments included human brain microvascular endothelial cell (HBMEC) studies and western blotting. The present study included 186 subjects (age [mean ± standard deviation, range] 64.7 ± 8.6, 50-86.8 years; 93 men). Multivariate analysis revealed that circulatory phosphate levels > 3.925 mg/dL were associated with severe WMH with an odds ratio of 3.7 (95% confidence interval = 1.3-10.6) independent of age, sex, traditional vascular risk factors, total cholesterol, renal function, or circulatory calcium level. The in vitro study revealed a downregulation of tight junction protein (zona occludens-1, occludin, and claudin-5) expression in HBMECs after 48 h of treatment with high phosphate (2.5/5 mM). We are the first to report a relationship between circulatory phosphate and CSVDs. Our results suggest that high circulatory phosphate level might be a novel risk factor for CSVD, possibly by impairing BBB structures.