ABSTRACT NUMBER: ESOC2026A2127 SENESCENCE GENE EXPRESSION IS ASSOCIATED WITH WHITE MATTER HYPERINTENSITY

Abstract Background and aims Cerebral white matter hyperintensities (WMH) are associated with cognitive decline, dementia and stroke risk. Senescent cells have been reported to accumulate in vascular diseases, thus senescence may contribute to WMH. We sought to investigate the relationship of senescence to WMH in patients. Methods In 162 samples of PAXgene blood, gene expression was measured by RNA-sequencing. Senescence was assessed by single-sample Gene Set Enrichment Analysis using the SenMayo gene set. Serial brain MRIs were also obtained over a mean of 5.6 years, and WMH volume was measured by semi-automated segmentation, progression was then calculated (vol/year). Results An increase in senescence gene expression score correlated with an increase in WMH volumes (Fig. 1A, n=162, p=0.019, r=0.184). Patients with no WMH (“none”) had significantly lower senescence from patients with mild (p=0.010), moderate (p=0.012), and severe WMH (Fig. 1B, p=0.024, Bonferroni adjusted). Patients with MCI had higher senescence scores compared with cognitively normal individuals of similar age (60-73 years old) (p=0.047). Conclusions Senescence is associated with severity of cerebral WMH. An increase in senescence may contribute to to WMH, small vessel disease, and associated cognitive decline. Targeting senescence may present a novel strategy to decrease WMH and improve cognition. Conflict of interest All authors: nothing to disclose. GJ receives funding from the Canadian Institutes for Health Research (CIHR), the University Hospital Foundation, Heart and Stroke Foundation, Genome Canada, and the NIH. Figure 1 - belongs to Results