Biomarkers.

Background: The association between platelet endothelial cell adhesion molecule-1 (PECAM-1) with cerebral small vessel disease (CSVD) and cognition in non-demented subjects remains un-investigated.

Method: A longitudinal, prospective cohort of subjects recruited from memory clinics was followed-up for 5 years. Non-demented subjects were included and classified as no cognitive impairment (NCI) or mild cognitive impairment (MCI). Annual neuropsychological assessments and 2-yearly magnetic resonance imaging (MRI) scans were performed. The associations of baseline circulating plasma PECAM-1 levels with neuroimaging markers of CSVD, cognitive decline (Montreal Cognitive Assessment [MoCA] scores and executive function Z-scores), and conversion to dementia were evaluated.

Result: Of 213 subjects (age 70.2±7.7 years, 51.2% male, 122 (57.3%) NCI, and 91 (42.7%) MCI), median PECAM-1 levels were 0.790 [IQR 0.645-0.955] ng/ml). Compared with the highest tertile, subjects within the lowest PECAM-1 tertile had higher age-related white matter changes scores (first tertile: β 1.50, 95% C.I. 0.23-2.77, p=0.02) and cerebral microbleeds (first tertile: Adjusted risk ratio [ARR] 2.59, 95% C.I. 1.81-3.72, p<0.0001). PECAM-1 levels were not associated with baseline MOCA and executive function. Of the 204 participants with follow-up data (median 60.0 [IQR 60.0-60.0] months), 24 (11.8) had incident dementia. Compared with the highest tertile, subjects within the lower tertiles of PECAM-1 were independently associated with higher risk of incident dementia (first tertile: Adjusted Hazard Ratio [AHR] 4.18, 95% C.I. 1.26-13.93, p=0.020; second tertile: AHR 3.45, 95% C.I. 1.07-11.14, p=0.038, Figure 1). The lowest PECAM-1 tertile was associated with greater 4-year progression of cerebral microbleeds (Incident Relative Risk [IRR] 2.44, 95% C.I. 1.20-4.98, p=0.014), and decline in executive function (β -0.43, 95% C.I. -0.73, -0.14, p=0.004), and MoCA (β -1.32, 95% C.I. -2.30, -0.35, p=0.008) scores.

Conclusion: In non-demented subjects, lower circulating PECAM-1 levels are associated with greater CSVD progression, cognitive decline, and incident dementia. PECAM-1 may be a potential therapeutic target for CSVD and cognitive decline.