Abstract 96: Integrated Genomic and Proteomic Profiling Support Cathepsin-B as a Drug Repurposing Target in Cerebral Small Vessel Disease

Stroke, Volume 56, Issue Suppl_1, Page A96-A96, February 1, 2025. Background:White Matter Hyperintensities (WMH) are a radiographic manifestation of cerebral small vessel disease (CSVD), representing myelin and axonal loss. Currently, no drugs specifically target or reduce the burden of WMH. Integrating genomic and proteomic data may identify proteins as potential targets to slow WMH progression. Particularly promising are proteins that serve as pathway-level hubs through which polygenic effects converge.Methods:We analyzed data from 53,014 participants enrolled in the UK Biobank. The analytical pipeline involved (Figure 1): 1) linear regression analyses between a polygenic risk score of WMH (from 27 independent variants) and normalized levels of 2,923 proteins ascertained at baseline, adjusting for age, sex, and genetic principal components; 2) evaluation of proteins selected in step 1 for association with WMH volume, ascertained through dedicated research MRIs; 3) mediation analyses to confirm that proteins with significant and directionally concordant associations with both the polygenic score and WMH are indeed mediators of the polygenic score-WMH relationship; 4) Mendelian Randomization using cis-protein quantitative trait loci as instruments to evaluate the causality between selected proteins and WMH and other clinical manifestation of CSVD. Each step was adjusted for multiple testing using Bonferroni correction.Results:Our analyses identified two proteins (Cathepsin B and ECHDC3) that met all the criteria to mediate the polygenic effect of CSVD on WMH. However, only one of these, Cathepsin B, was confirmed by Mendelian Randomization (Beta: -0.092, SE: 0.003, P

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Gennaio 2025

Abstract 96: Temporal Trends in Vascular Risk Factor Burden Among Young Adults With Ischemic Stroke: The Florida Stroke Registry

Stroke, Volume 55, Issue Suppl_1, Page A96-A96, February 1, 2024. Introduction:While ischemic stroke (IS) in the young (18-55) is thought to have different etiologies than in older patients, a rise in vascular risk factors (VRFs) among young adults may translate to an IS risk profile similar to the older population. We aimed to examine the prevalence of VRFs and temporal trends in VRF burden among young patients presenting with IS.Methods:Data was prospectively collected by Get With the Guidelines-Stroke® hospitals participating in the Florida Stroke Registry between January 2010 and December 2022. Patients aged 18-55 with a diagnosis of IS were included and separated into two age groups: 18-35 and 36-55. VRFs included hypertension, dyslipidemia, obesity, smoking, atrial fibrillation, coronary artery disease, heart failure, diabetes, and sleep apnea. Multimorbidity was defined as having ≥4 VRFs.Results:47,792 patients with IS were included (43% female, median age 49, 51% white), comprising 4,275 patients aged 18-35 (8.9%) and 43,517 aged 36-55 (91.1%). The prevalence of each VRF was higher among patients aged 36-55 vs 18-35 (all p values

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Febbraio 2024