ABSTRACT NUMBER: ESOC2026A2062 WHITE MATTER MICROSTRUCTURAL DAMAGE IS ASSOCIATED WITH A PRO-INFLAMMATORY CIRCULATING IMMUNE CELL COMPOSITION IN CEREBRAL SMALL VESSEL DISEASE

Abstract Background and aims This study examined the cross-sectional association between white matter microstructural damage, indicated by a low mean diffusivity peak height (MD-PH), and multiple immune markers in patients with cerebral small vessel disease (SVD). Methods 200 patients with symptomatic SVD underwent MRI scanning and blood draw. MD-PH was computed from Diffusion Tensor Imaging-derived MD maps within normal appearing white matter. We performed CyTOF on whole blood to obtain the relative abundance of immune populations. Peripheral Blood Mononuclear Cells were stimulated with various inflammatory stimuli for 24 hours to assess cytokine production capacity. Clonal hematopoiesis (CH) driver mutations were identified with targeted sequencing, and Variant Allele Frequency (VAF) was determined. Circulating inflammatory markers were measured in plasma using Olink targeted proteomics. We performed Principal Component Analysis on Olink data to extract PC1. Associations between MD-PH and immune markers, including Olink-PC1, were assessed using partial Spearman correlation, while controlling for sex, age, and recruitment site. Results Mean age of participants was 70.3 years (65.8% male). MD-PH was positively associated with the proportion of CD4+ innate-like T-cells, conventional CD4+ αβ T-cells, nonclassical monocytes, and dendritic cells, and inversely with classical monocytes (Figure1A, Table1). We did not observe an association between MD-PH and cytokine production capacity (Figure1C) or maximum VAF (ρ = -0.065; P = 0.56), nor with Olink-PC1 (ρ = -0.118; P = 0.11) or the separate circulating inflammatory markers (Figure1B). Conclusions White matter microstructural damage in SVD was associated with an immune cell composition characterized by a higher abundance of classical and lower abundance of non-classical monocytes, consistent with a pro-inflammatory immune profile. Conflict of interest None of the authors have anything to disclose. Table 1 - belongs to Results Figure 1 - belongs to Conclusions