Abstract Body: Carotid artery stenosis (CS) is a leading cause of stroke in the elderly and can be a risk factor for dementia. In this study, we used a translationally relevant mouse model of chronic progressive CS, and applied multi-parametric neuroimaging, including arterial spin labeling (ASL) MRI, T₂^*, Magnetization Transfer Contrast (MTC) and Diffusion Tensor Imaging (DTI) to define the neuropathological underpinnings of cognitive impairment in both symptomatic and asymptomatic CS.
Adult C57BL/6J mice were implanted with ameroid constrictors around both common carotid arteries (CS). Mice without constrictors served as sham (SH). Cerebral blood flow (CBF) was measured using ASL MRI before constrictor placement or sham surgeries and subsequently at 2, 4, 6 and 12 weeks after surgery. At 3 months, mice underwent neurocognitive testing using the Morris water maze (MWM), followed by T₂^*, MTC and DTI.
The 12-week survival rate was 69.56% in CS (n = 16) and 100% in SH (n = 14) mice. CBF gradually decreased from 100% before surgery to 83.04% by 2 weeks, 84.22% by 4 weeks, 52.08% by 6 weeks, and to 51.08% by 12 weeks in CS, while remaining at or above baseline in SH mice. Cerebrovascular reactivity to hypercapnia decreased from 25.9% at 6 weeks to 2.14% at 12 weeks in CS, but not in SH mice (p<0.05, n = 6-7/group). Performance in the MWM was significantly impaired at 12 weeks in CS vs. SH. MRI showed no evidence of brain pathologies in 12.5% of CS mice; 25% had ventricular enlargement; and 62.5% had multiple brain pathologies including lacunar infarcts, microbleeds, focal and diffuse white matter (WM) changes, with significantly reorganized WM tracts, ventricular enlargement and cortical atrophy.
Progressive bilateral carotid artery occlusion induces a state of chronic cerebral hypoperfusion, which leads to cognitive impairment and pathological changes in brain that highly resemble changes observed in human brain with dementia due to vascular causes, including white matter lesions, microinfarctions and microbleeds.