Abstract WP473: Diabetic Male and Female Rats Are More Susceptible to Infarction and Cognitive Decline in a Microemboli Based Model of Vascular Cognitive Impairment

Abstract

Diabetes increases the risk of VCID but underlying reasons remain unclear. We reported that diabetes-mediated early cerebrovascular dysfunction facilitates the entrapment of microemboli (ME) and results in demyelination/neurodegeneration 6 weeks after ME injection in male diabetic but not control rats. Cognitive decline became apparent by week 8 and further amplified by week 12 in diabetes. The goals of the current study were to determine whether ME injection 1) mediates demyelination and cognitive decline in females, 2) activates microglia and promotes inflammation, 3) causes gait abnormalities and 4) mediates changes in cerebral blood flow (CBF) and brain structure as determined by diffusion MRI. Diabetes was induced by a high fat diet and low dose streptozotocin (35 mg/kg) injection in male and female Wistar rats. After 8 weeks onset of diabetes, control and diabetic rats received cholesterol crystal ME (40-70 μm) injection. In study 1, histology was done at week 6 after injection (3000 crystals) to determine early structural changes and cognition was assessed by novel object recognition (NOR) test. In Study 2, MRI, gait (stand on catwalk) and NOR tests were done at baseline and week 8 after injection (6000 crystals) in male rats and will be further monitored at weeks 12 and 16. Diabetic animals developed inflammation, demyelination, and neurodegeneration associated with cognitive decline that was greater than that observed in males (TABLE). In Study 2, initial analyses show higher infarct score and lower CBF after ME injection with no gait pattern change in diabetic male rats. Longitudinal measurements at weeks 12 & 16 will demonstrate the disease progression. These data suggest that 1) endothelial dysfunction renders diabetic animals more susceptible to infarction and subsequent cognitive decline caused by ME, and 2) intervention strategies can be tried in this clinically relevant model of VCID.