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.
Our data suggest that cerebral endothelial activation in deep penetrating arteries is not associated with SVD. Endothelial thrombomodulin increased with SVD severity, and CADASIL data suggest that this may be a cerebral response to SVD. Elevated thrombomodulin may be a protective agent in SVD. Our data confirm endothelial involvement in SVD.
Vascular myocytes are central to brain aging. Small vessel disease (SVD; arteriolosclerosis) is a widespread cause of lacunar stroke and vascular dementia, and is characterised by fibrosis and depletion of vascular myocytes in small penetrating arteries. Vascular endothelial growth factor (VEGF) is associated with brain aging, and VEGFR2 is a potent determinant of cell fate. Here, we tested whether VEGFR2 in vascular myocytes is associated with older age and SVD in human brain.VEGFR2 immunolabelling in deep grey matter was assessed in older people with or without moderate-severe SVD, or in younger people without brain pathology or with a monogenic form of SVD (CADASIL). All cases were without Alzheimer's disease pathology. Myocyte VEGFR2 was associated with increasing age (p=0.0026) but not with SVD pathology or with sclerotic index or blood vessel density. We conclude that VEGFR2 is consistently expressed in small artery myocytes of older people, and may mediate effects of VEGF on brain vascular aging.[word count: 156; <170]
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.