Abstract TMP119: Evaluation of Cognitive Function and Plasma Biomarkers in a Microemboli-Based VCID Model in Rats: Applying Clinical Recommendations From MarkVCID and the Lacunar Intervention Trial-2 (LACI-2) to a Preclinical Model

Abstract

Diabetes doubles the risk of VCID. The underlying reasons are not understood, and preventive therapeutic strategies are lacking. We showed that diabetic but not control rats develop a progressive cognitive decline in a microemboli (ME) model of VCID. Given that cerebrovascular dysfunction is a common pathology between diabetes and VCID, we hypothesized that improvement of endothelial function in diabetes prevents ME-mediated cognitive impairment. Our treatment paradigm was based on the recently reported LACI-2 Trial which assessed the efficacy of isosorbide mononitrate (ISMN) and cilostazol (CZL) in the prevention of small vessel disease (SVD) progression. At 7-8 weeks after diabetes onset, control and diabetic rats were treated with ISMN/CZL for 4 weeks, then injected with cholesterol crystal ME and behavioral outcomes were monitored longitudinally for 16 weeks. Plasma biomarkers recommended by MarkVCID and D eterminants of I ncident S troke C ognitive O utcomes and V ascular E ffects on R ecover Y (DISCOVERY) Consortiums were measured using the angiogenesis (Flt-1, VEGF and FGF), neurology (GFAP, phosphoTau and Neurofilament Light NfL) and amyloid beta 42/40 panels from the Meso Scale Discovery. Behavioral deficits observed in the untreated diabetic rats were not noted in the treated group. Some of the biomarkers were unchanged (Table). This suggests that drug treatment with ISMN/CZL before ME injection prevented the possible deleterious effects of the latter in the diabetic rats by improving the endothelial integrity and it is a viable preventive and possibly therapeutic strategy for VCID.