Abstract TP564: Diabetic but Not Control Rats Develop White Matter Injury and Cognitive Deficits in a Microemboli Injection Model of VCID

Diabetes doubles the risk of vascular cognitive impairment and dementia (VCID), a disease is associated with small vessel disease (SVD) of the brain. Given that diabetes mediates early cerebrovascular dysfunction, and microemboli are common in the cerebral circulation and can penetrate into the brain parenchymal arterioles without causing an infarction, we tested the hypothesis that entrapment of microemboli in dysfunctional vessel walls accelerates the development of SVD ultimately resulting in VCID in diabetes. Diabetes was induced by a high fat diet and low dose streptozotocin (35 mg/kg, IP) injection in male Wistar rats. Cholesterol crystal microemboli [40-70 μm, 3000 (Group A) or 6000 (Group B) per 200 μl saline] were injected 8 weeks later through internal carotid artery. Cognitive function was monitored by the novel object recognition (NOR) test. White matter injury was assessed by Luxol fast blue (LFB) and hematoxylin/eosin (HE) staining in Group A. Cerebral blood flow (CBF), white matter hyperintensities (T2 map), microbleeds (T2 asterisk), and microinfarcts (T2 W) were assessed by MRI in Group B. In Group A, there was increased white matter degeneration in diabetic animals compared to controls. This degeneration was aggravated by microembolic injection. We found that cognitive function was exacerbated in Group B diabetes animals. MRI results showed these animals also had decreased CBF but no change on microinfarcts or microbleed. These results suggest that white matter degeneration starts in the early stages of diabetes, and that microemboli exacerbate these pathological changes even before the appearance of any neurobehavioral deficits. Additional studies are needed to examine the precise time course for development of cerebral neurovascular changes relative to appearance of behavioral deficits and explore potential therapeutic targets for VCI in diabetes.