Experimental models of vascular dementia and vascular cognitive impairment: a systematic review

Abstract

J. Neurochem. (2010) 115, 814–828. Abstract Vascular cognitive impairment (VCI) encompasses vascular dementia and is the second most common cause of dementing illness after Alzheimer’s disease. The main causes of VCI are: cerebral small vessel disease; multi‐infarct dementia; strategic infarct (i.e. located in a functionally‐critical brain area); haemorrhage/microbleed; angiopathy (including cerebral amyloid angiopathy); severe hypoperfusion (e.g. cardiac arrhythmia); and hereditary vasculopathy (e.g. cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, CADASIL). In this systematic analysis, we aimed to relate cognitive and neuropathological features of experimental models to clinical VCI. We extracted data from 107 studies covering 16 models. These included: brief global ischaemic insults (in rats, mice or gerbils); chronic global hypoperfusion (rats, mice, gerbils); chronic hypertension (in primates or stroke‐prone, spontaneously‐hypertensive rats); multiple ischaemic lesions because of intra‐vascular emboli (in rodents, rabbits or primates); strategic ischaemic lesions (in rats or mini‐pigs); generalised vasculopathies, because of mutant Notch3, hyperhomocysteinaemia, experimental diabetes mellitus or lack of cerebral vasodilator M5 receptors (rats or mice). Most cognitive testing showed deficits in working and reference memory. The lesions observed were microinfarcts, diffuse white matter lesions, hippocampal neuronal death, focal ischaemic lesions and micro‐haemorrhages. The most‐used model was bilateral carotid artery occlusion in rats, leading to chronic hypoperfusion and white matter injury.

Cerebral hemodynamics and cognitive impairment

“…17,18 Both sets of patients may have microinfarcts and other ischemic lesions, which are associated with cognitive decline. [18][19][20][21] Several case series have shown cognitive dysfunction in patients with carotid artery stenosis or occlusion [22][23][24] and even showed reversibility of cognitive impairment with revascularization, [2][3][4] but an independent association with hypoperfusion has been difficult to establish.…”

Consensus statement for diagnosis of subcortical small vessel disease

“…Most animal studies are based on either hypoxic hypoperfusion secondary to bilateral carotid artery occlusion in normotensive rats or SVD secondary to hypertension in the spontaneously hypertensive/stroke prone rat (SHR/SP). 69,116 Bilateral Carotid Artery Occlusion Bilateral carotid artery occlusion (BCAO) produces hypoxic hypoperfusion, which primarily affects the deep white matter. 117 The tissue is assumed to be hypoxic although direct measurements of tissue oxygen levels have not been made.…”

Gradual cerebral hypoperfusion in spontaneously hypertensive rats induces slowly evolving white matter abnormalities and impairs working memory

“…Loss of vasomotor reactivity in the small vessels due to vascular risk factors such as hypertension 2 and resultant chronic cerebral hypoperfusion with blood-brain barrier (BBB) disruption and glial activation may underlie the white matter changes. 3,4 To mimic the expected pathological changes and explore the underlying mechanisms, bilateral common carotid artery (CCA) or 2-vessel occlusion (2VO) model in rats has been frequently used 5 and may become important once genetically-modified rats are widely available. The 2VO model exhibits characteristic features of SIVD, such as white matter damage, 6,7 and cognitive impairment.…”