Identification of Clinically Relevant Brain Endothelial Cell Biomarkers in Plasma

Author:

Cordon Jenifer1,Duggan Michael R.1ORCID,Gomez Gabriela T.2ORCID,Pucha Krishna A.3ORCID,Peng Zhongsheng1,Dark Heather E.1ORCID,Davatzikos Christos4,Erus Guray4ORCID,Lewis Alexandria2ORCID,Moghekar Abhay2ORCID,Candia Julián5ORCID,Ferrucci Luigi5ORCID,Kapogiannis Dimitrios3ORCID,Walker Keenan A.1ORCID

Affiliation:

1. Multimodal Imaging of Neurodegenerative Disease (MIND) Unit (J.C., M.R.D., Z.P., H.E.D., K.A.W.), National Institute on Aging, Baltimore, MD.

2. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD (G.T.G., A.L., A.M.).

3. Human Neuroscience Unit (K.A.P., D.K.), National Institute on Aging, Baltimore, MD.

4. Department of Radiology, University of Pennsylvania School of Medicine, Philadelphia (C.D., G.E.).

5. Translational Gerontology Branch (J.C., L.F.), National Institute on Aging, Baltimore, MD.

Abstract

BACKGROUND: Proteins expressed by brain endothelial cells (BECs), the primary cell type of the blood-brain barrier, may serve as sensitive plasma biomarkers for neurological and neurovascular conditions, including cerebral small vessel disease. METHODS: Using data from the BLSA (Baltimore Longitudinal Study of Aging; n=886; 2009–2020), BEC-enriched proteins were identified among 7268 plasma proteins (measured with SomaScanv4.1) using an automated annotation algorithm that filtered endothelial cell transcripts followed by cross-referencing with BEC-specific transcripts reported in single-cell RNA-sequencing studies. To identify BEC-enriched proteins in plasma most relevant to the maintenance of neurological and neurovascular health, we selected proteins significantly associated with 3T magnetic resonance imaging–defined white matter lesion volumes. We then examined how these candidate BEC biomarkers related to white matter lesion volumes, cerebral microhemorrhages, and lacunar infarcts in the ARIC study (Atherosclerosis Risk in Communities; US multisite; 1990–2017). Finally, we determined whether these candidate BEC biomarkers, when measured during midlife, were related to dementia risk over a 25-year follow-up period. RESULTS: Of the 28 proteins identified as BEC-enriched, 4 were significantly associated with white matter lesion volumes (CDH5 [cadherin 5], CD93 [cluster of differentiation 93], ICAM2 [intracellular adhesion molecule 2], GP1BB [glycoprotein 1b platelet subunit beta]), while another approached significance (RSPO3 [R-Spondin 3]). A composite score based on 3 of these BEC proteins accounted for 11% of variation in white matter lesion volumes in BLSA participants. We replicated the associations between the BEC composite score, CDH5, and RSPO3 with white matter lesion volumes in ARIC, and further demonstrated that the BEC composite score and RSPO3 were associated with the presence of ≥1 cerebral microhemorrhages. We also showed that the BEC composite score, CDH5, and RSPO3 were associated with 25-year dementia risk. CONCLUSIONS: In addition to identifying BEC proteins in plasma that relate to cerebral small vessel disease and dementia risk, we developed a composite score of plasma BEC proteins that may be used to estimate blood-brain barrier integrity and risk for adverse neurovascular outcomes.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Advanced and Specialized Nursing,Cardiology and Cardiovascular Medicine,Neurology (clinical)

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