Identification of novel cerebral small vessel disease biomarkers in blood using proteomics

Abstract

Introduction: Identifying novel cerebral small vessel disease (cSVD) biomarkers in blood is critical to advance therapeutic and preventive strategies for Vascular Contributions to Cognitive Impairment and Dementia (VCID). This exploratory analysis aimed to identify novel blood-based markers of cSVD using proteomics in a Hispanic sample. This is critical, as most biomarker discovery has focused on non-Hispanic Whites, despite increased cardiometabolic risk and cognitive impairment among minoritized populations. Methods: We included 107 dementia-free Mexican American participants from the MarkVICD-1 San Antonio site (73% women, mean age 70 ±7 years, Table 1). Participants provided fasting blood samples and underwent a comprehensive clinical and neuroimaging evaluation. Serum aliquots were shipped to Olink for proteomic profiling with the Explore 3072 panel. Normalized protein levels were related to cSVD markers, including White Matter Hyperintensities (WMH), Peak-with of Skeletonized Mean Diffusivity (PSMD), and Free Water (FW), using linear regression models adjusting for age, age2, sex, and total intracranial volume. P-values were corrected using False Discovery Rate (FDR) to account for multiple testing. Results: We identified 36, and 128 proteins significantly associated with PSDM, and FW, respectively (Figure 1). The strongest associations were seen for elevated neurogranin with higher PSMD (Beta ±SE, 0.20 ±0.04, FDR=0.005) and FW (0.23 ±0.04, FDR=0.002), and Cartilage Intermediate Layer Protein (CILP) with higher PSMD (0.07 ±0.014, FDR=0.005). Neurogranin is a marker of synaptic dysfunction and CSF levels have shown potential as a predictor of cognitive decline. CILP may antagonize TGFB1 and IGF1 and has been related to mortality in patients with heart failure. Discussion: Our results uncovered multiple novel blood-based cSVD biomarkers for risk stratification in VCID studies, including neurogranin and CILP. Further studies are needed to confirm these findings in larger samples.