OUP accepted manuscript

Cerebral white matter hyperintensities (WMH) are an important contributor to aging brain pathology. Progression in WMH volume is associated with cognitive decline and gait impairment. Understanding the factors associated with WMH progression provides insight into pathogenesis and may identify novel treatment targets to improve cognitive health. We postulated that the immune system interaction with cerebral vessels and tissue may be associated with disease progression and thus evaluated the relationship of blood leukocyte gene expression to progression of cerebral WMH. A brain MRI was obtained at baseline in 166 patients assessed for a cognitive complaint, and then repeated at regular intervals over a median of 5.9 years (IQR 3.5-8.2 years). WMH volumes were measured by semi-automated segmentation and percent change in WMH per year calculated. A venous blood sample obtained at baseline was used to measure whole-genome expression by RNA sequencing. The relationship between change in WMH volumes over time and baseline leukocyte gene expression was analyzed. The mean age was 77.8 (SD 7.5) years and 60.2% of participants were female. The median WMH volume was 13.4 mL (SD 17.4 mL). The mean change in WMH volume was 12% per year. Patients were divided in quartiles by percent change in WMH volume, which was: -3.5% per year in quartile 1, 7.4% per year in quartile 2, 11.7% in quartile 3, and 33.6% per year in quartile 4. There were 148 genes associated with changing WMH volumes over time (p < 0.05 r>|0.2|). Genes and pathways identified have roles in endothelial dysfunction, extracellular matrix remodeling, altered remyelination, inflammation, and response to ischemia. ADAM8, CFD, EPHB4, FPR2, Wnt-B-catenin, FAK, and SIGLEC1 were among the identified genes. Progression of WMH volumes over time is associated with genes involved in endothelial dysfunction, extracellular matrix remodeling, altered remyelination, inflammation, and response to ischemia. Further studies are needed to evaluate the role of peripheral inflammation in relation to rate of WMH progression and the contribution to cognitive decline.