Associations of Circulating Platelet Endothelial Cell Adhesion Molecule-1 Levels With Progression of Cerebral Small-Vessel Disease, Cognitive Decline, and Incident Dementia

Abstract

Background: The association between platelet endothelial cell adhesion molecule-1 (PECAM-1) with cerebral small-vessel disease and cognition in dementia-free subjects remains uninvestigated.

Methods and results: A prospective cohort of dementia-free subjects was recruited from memory clinics and followed up for 5 years. Annual neurocognitive assessments and twice-yearly brain magnetic resonance imaging scans were performed. Associations of baseline plasma PECAM-1 levels with cerebral small-vessel disease, cognitive decline (Montreal Cognitive Assessment scores and executive function Z scores), and incident dementia were evaluated. Of 213 subjects (aged 70.2±7.7 years, 51.2% men), median PECAM-1 levels were 0.790 (interquartile range, 0.645-0.955 ng/mL). Compared with the highest tertile, subjects within the lowest PECAM-1 tertile had greater cross-sectional white matter hyperintensity volume (β=4.84 [95% CI, 0.67-9.01]; P=0.023), age-related white matter change scores (β=1.39 [95% CI, 0.12-2.67]; P=0.033), and cerebral microbleeds (Adjusted risk ratio, 2.59 [95% CI, 1.19-5.62]; P=0.016). Of the 204 participants with follow-up data (median, 60.0 [interquartile range, 60.0-60.0] months), 24 (11.8%) developed incident dementia. Compared with the highest tertile, subjects within the lower tertiles of PECAM-1 had a higher risk of incident dementia (first tertile: adjusted hazard ratio [AHR], 4.52 [95% CI, 1.35-15.13]; P=0.024; second tertile: AHR, 3.28 [95% CI, 1.02-10.60]; P=0.047). The lowest PECAM-1 tertile was associated with greater progression of white matter hyperintensity volume (β=4.15 [95% CI, 0.06-8.24]; P=0.047), cerebral microbleeds (incident relative risk [IRR], 2.21 [95% CI, 1.05-4.65]; P=0.036), and decline in executive function (β=-0.45 [95% CI, -0.76 to -0.14]; P=0.004), and Montreal Cognitive Assessment (β=-1.32 [95% CI, -2.30 to -0.35]; P=0.008) scores.

Conclusions: In dementia-free subjects, lower circulating PECAM-1 levels are associated with greater cerebral small-vessel disease progression and cognitive decline, thus warranting future study as a potential therapeutic target.

Keywords: PECAM‐1; cerebral small‐vessel disease; cognition.

Figure 1. Flowchart of subject recruitment and follow‐up.

Created with biorender.com. ARWMC indicates age‐related white matter changes; CSVD, cerebral small‐vessel disease; MoCA, Montreal Cognitive Assessment; and PECAM‐1, platelet endothelial cell adhesion molecule‐1.

Figure 2. Nelson–Aalen cumulative hazard estimates for conversion to dementia stratified by PECAM‐1 levels (tertiles).

PECAM‐1 indicates platelet endothelial cell adhesion molecule‐1.

Figure 3. Cross‐sectional associations of PECAM‐1 levels (stratified by tertiles), with MRI and plasma biomarkers of amyloid burden and neurodegeneration.

Regression coefficient plots present regression coefficients, 95% CIs, and P values derived from linear regressions adjusted for age and sex, with reference to the third (highest) PECAM‐1 tertile. Regression models for gray matter and hippocampal volume were additionally adjusted for intracranial volume. MRI indicates magnetic resonance imaging; NfL, neurofilament light; PECAM‐1, platelet endothelial cell adhesion molecule‐1; and p‐tau181, phosphorylated tau181.