Ming Ann Sim, Saima Hilal, Jasper Tromp, Eugene S J Tan, James Doecke, Oi Wah Liew, Vera Yuan Cai, Siew Pang Chan, Eddie Jun Yi Chong, Anqi Toh, Tan Boon Yeow, Narayanaswamy Venketasubramanian, Natasha Barascuk-Michaelsen, David Sim, Gerard Kui Toh Leong, Daniel Poh Shuan Yeo, Hean Yee Ong, Lieng Hsi Ling, Carolyn Lam, Mitchell K P Lai, Hyungwon Choi, Arthur Mark Richards, Christopher L H Chen
We report distinct and overlapping plasma proteins for baseline and longitudinal CeVD, representing diverse biological processes. Four proteins were prioritized as mediators of CeVD-associated cognitive decline, and predictors of MACCE. These proteins were validated for incident mortality across both cohorts: neurofilament light chain (NEFL), latent-transforming growth factor beta-binding protein 2 (LTBP2), cysteine-rich motor neuron 1 protein (CRIM1), and urokinase plasminogen activator surface receptor (PLAUR).
INTRODUCTION: The plasma proteomic signatures underlying cerebrovascular disease (CeVD) remains poorly understood.
METHODS: A total of N = 2534 participants across two independent longitudinal Southeast-Asian cohorts were included. We profiled 1441 baseline plasma proteins in a memory-clinic cohort (N = 518), followed-up for 4 years. Proteins associating with baseline and longitudinal CeVD lesions (i.e., white matter hyperintensity volume, lacunes, cerebral microbleeds, and cortical infarcts) were reported. The prognostic value of CeVD-associated proteins was evaluated for incident major cardiovascular/cerebrovascular events (MACCE) and mortality. External validation of key proteins for mortality was performed in the plasma proteome of an independent cardiovascular cohort (N = 2016).
RESULTS: We report distinct and overlapping plasma proteins for baseline and longitudinal CeVD, representing diverse biological processes. Four proteins were prioritized as mediators of CeVD-associated cognitive decline, and predictors of MACCE. These proteins were validated for incident mortality across both cohorts: neurofilament light chain (NEFL), latent-transforming growth factor beta-binding protein 2 (LTBP2), cysteine-rich motor neuron 1 protein (CRIM1), and urokinase plasminogen activator surface receptor (PLAUR).
DISCUSSION: The prognostic proteins prioritized in our study provide robust signals in two cohorts, representing potential mechanistic targets for CeVD and health outcomes.