Abstract TMP111: Gradual Carotid Artery Stenosis in Mice Closely Replicates Hypoperfusive Vascular Dementia in Humans

Abstract

Rationale: Existing rodent models of vascular cognitive impairment (VCI) show abrupt change in cerebral blood flow (CBF) and do not completely mirror clinical pathogenesis of VCI. Objective: To establish a mouse model of VCI where CBF gradually decreases with subsequent motor and cognitive impairment. Methods and Results: Adult C57BL/6J male mice were subjected to gradual common carotid artery stenosis (GCAS) surgery using an ameroid constrictor (AC) vessel-constricting device with inner diameter of 0.75 mm. The common carotid arteries narrowed gradually after gradual constriction of ACs over 28 days after GCAS, with subsequent 79.3% area stenosis due to smooth muscle cell proliferation and macrophage infiltration in the tunica intima. The 28-day survival rate was 100%. Arterial spin labeling demonstrated gradual and continuous reduction of cortical and subcortical CBF (ratio to the preoperative value) to 54.6% and 51.5%, respectively, over 28 days. However, magnetic resonance angiography showed increment of collateral flow signals in the leptomeningeal artery. Rarefaction and proliferation of astrocytes and microglia with loss of oligodendrocytes was found in the white matter at 32 days. Hippocampal neuronal loss was observed in only 25% of GCAS mice, consistent with lack of abnormalities in the Morris water maze test. The rotarod test showed motor impairment whereas the Y-maze test showed that working memory was impaired. Conclusions: The GCAS model successfully generated gradual and continuous CBF reduction over 28 days, with replication of key histological, radiological, and behavioral features associated with cerebral hypoperfusion leading to VCI.