Objective:

Identify plasma protein biomarkers of brain endothelial cells (BEC) that are related to clinically meaningful neurologic outcomes.

Background:

BECs are important components of the blood-brain-barrier, and their dysfunction has been associated with cognitive impairment and dementia. However, these cells lack established blood biomarkers relevant for brain health. 

Design/Methods:

We used data from the Baltimore Longitudinal Study of Aging (BLSA) (n = 886) to identify BEC plasma biomarkers. Among the 7,268 plasma proteins measured on the SomaLogic ® platform, BEC proteins were identified using an automated annotation algorithm that filtered endothelial cell proteins form the Human Protein Atlas and cross-referenced previously published BEC-specific markers. We next identified a subset of BEC proteins associated with 3T MRI-defined white matter lesions; we then related this set of candidate proteins to white matter hyperintensities, lacunar infarcts, cerebral microhemorrhages and dementia risk in the Atherosclerosis Risk in Communities (ARIC) study. 

Results:

Of the 4,268 proteins examined, 28 proteins were categorized as BEC-specific, and four were significantly associated with white matter lesion volume (ICAM2, CDH5, CD93, GP1BB; p < 0.05), while another approached significance (RSPO3; p = 0.05). Of the three proteins measured in ARIC, two (CDH5, RSPO3) were related to white matter hyperintensities, cerebral microhemorrhages and dementia risk. Notably, the direction of association between CDH5 and RSPO3 with each outcome was consistent across studies. 

Conclusions:

We identified novel plasma biomarkers of BECs that are associated with cerebral small vessel disease and dementia risk, particularly CDH5 (Cadherin 5) and RSPO3 (R-Spondin 3). Functional validation of these findings is warranted to further characterize the mechanisms underlying these relationships, and replication in additional external cohorts may support their use as blood biomarkers for brain health.