A Novel Mouse Model of Subcortical Infarcts with Dementia

Abstract

Subcortical white matter (WM) is a frequent target of ischemic injury and extensive WM lesions are important substrates of vascular cognitive impairment (VCI) in humans. However, ischemic stroke rodent models have been shown to mainly induce cerebral infarcts in the gray matter, while cerebral hypoperfusion models show only WM rarefaction without infarcts. The lack of animal models consistently replicating WM infarct damage may partially explain why many neuroprotective drugs for ischemic stroke or VCI have failed clinically, despite earlier success in preclinical experiments. Here, we report a novel animal model of WM infarct damage with cognitive impairment can be generated by surgical implantation of different devices to the right and left common carotid artery (CCA) in C57BL/6J mice. Implantation of an ameroid constrictor to the right CCA resulted in gradual occlusion of the vessel over 28 d, whereas placement of a microcoil to the left CCA induced ϳ50% arterial stenosis. Arterial spin labeling showed a gradual reduction of cerebral blood flow over 28 d post operation. Such reductions were more marked in the right, compared with the left, hemisphere and in subcortical, rather than the cortical, areas. Histopathological analysis showed multiple infarct damage in right subcortical regions, including the corpus callosum, internal capsule, hippocampal fimbria, and caudoputamen, in 81% of mice. Mice displaying such damage performed significantly poorer in locomotor and cognitive tests. The current mouse model replicates the phenotypes of human subcortical VCI, including multiple WM infarcts with motor and cognitive impairment.

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

“…We have recently established a model of WM infarct damage called the ACAS (asymmetric CCA surgery) model by placing an AC with an ID of 0.5 mm on the right CCA and a microcoil with an ID of 0.18 mm on the left CCA 18. The ACAS model exhibits gradual but more profound CBF reduction than the GCAS model.…”

Animal Models of Vascular Cognitive Impairment and Dementia (VCID)

“…Placement of the AC on the right CAA produced gradual narrowing of the inner lumen until finally occluding (approximately 28 days postsurgery), with blood pressure unaffected. Cerebral blood flow on the microcoil side decreased until plateau around 7 days post-operation (Hattori et al 2015). The AC side decreased in CBF with slight recovery at day 7 until plateau at BCAS level around day 28 post-operation.…”

Emerging Evidence for Pathogenesis of Sporadic Cerebral Small Vessel Disease

“…For instance, another hypoperfusion model in mice (asymmetric common carotid artery surgery model) has offered promise in reproducing WM infarct damage following gradual but not acute cerebral blood flow reduction over 1 month. 78 Still, limitations exist in the asymmetric common carotid artery surgery model, including relatively low survival rate (~80%) and limited area of mouse WM available for the pathological evaluation of infarct damage. The lack of rodent models that consistently replicate WM infarct damage may partly explain why many neuroprotective drugs for ischemic stroke or VCI have failed to translate to clinical efficacy, despite earlier success in preclinical experiments using gray matter ischemia models.…”

“…Модели, в которых воспроизводят особенности субкортикальной ишемии при СКН, а также посте-пенное снижение церебрального кровотока, могут в значительной степени способствовать развитию научно-исследовательской деятельности при БМЦС. Например, другая модель гипоперфузии у мышей (модель асимме-тричного стеноза общей сонной артерии) является пер-спективной в отношении воспроизведения повреждения БВГМ с постепенным, но не острым снижением цере-брального кровотока -в течение 1 месяца [78]. До сих пор существуют ограничения в использовании модели асимметричного стеноза общей сонной артерии, в т.ч.…”