title: Gliovascular disruption and cognitive deficits in a mouse model with features of small vessel disease.
abstract: Cerebral small vessel disease (SVD) is a major cause of age-related cognitive impairment and dementia. The pathophysiology of SVD is not well understood and is hampered by a limited range of relevant animal models. Here, we describe gliovascular alterations and cognitive deficits in a mouse model of sustained cerebral hypoperfusion with features of SVD (microinfarcts, hemorrhage, white matter disruption) induced by bilateral common carotid stenosis. Multiple features of SVD were determined on T2-weighted and diffusion-tensor magnetic resonance imaging scans and confirmed by pathologic assessment. These features, which were absent in sham controls, included multiple T2-hyperintense infarcts and T2-hypointense hemosiderin-like regions in subcortical nuclei plus increased cerebral atrophy compared with controls. Fractional anisotropy was also significantly reduced in several white matter structures including the corpus callosum. Investigation of gliovascular changes revealed a marked increase in microvessel diameter, vascular wall disruption, fibrinoid necrosis, hemorrhage, and blood-brain barrier alterations. Widespread reactive gliosis, including displacement of the astrocytic water channel, aquaporin 4, was observed. Hypoperfused mice also demonstrated deficits in spatial working and reference memory tasks. Overall, gliovascular disruption is a prominent feature of this mouse, which could provide a useful model for early-phase testing of potential SVD treatment strategies.
authors: Centre for Neuroregeneration, Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
authors: Philip R
authors: PR
authors: Holland
authors: Centre for Neuroregeneration, University of Edinburgh, Edinburgh, UK.
authors: James L
authors: JL
authors: Searcy
authors: Centre for Neuroregeneration, University of Edinburgh, Edinburgh, UK.
authors: Natalia
authors: N
authors: Salvadores
authors: Centre for Neuroregeneration, University of Edinburgh, Edinburgh, UK.
authors: Gillian
authors: G
authors: Scullion
authors: Centre for Neuroregeneration, University of Edinburgh, Edinburgh, UK.
authors: Guiquan
authors: G
authors: Chen
authors: Centre for Neuroregeneration, University of Edinburgh, Edinburgh, UK.
authors: Greig
authors: G
authors: Lawson
authors: Centre for Neuroregeneration, University of Edinburgh, Edinburgh, UK.
authors: Fiona
authors: F
authors: Scott
authors: Centre for Cognitive Ageing and Cognitive Epidemiology, Scottish Imaging Network, A Platform for Scientific Collaboration (SINAPSE), Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.
authors: Mark E
authors: ME
authors: Bastin
authors: Department of Stroke and Cerebrovascular Diseases, National Cerebral and Cardiovascular Center Hospital, Osaka, Japan.
authors: Masafumi
authors: M
authors: Ihara
authors: Institute of Neuroscience, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, UK.
authors: Rajesh
authors: R
authors: Kalaria
authors: Centre for Cognitive and Neural Systems and Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
authors: Emma R
authors: ER
authors: Wood
authors: Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.
authors: Colin
authors: C
authors: Smith
authors: Centre for Cognitive Ageing and Cognitive Epidemiology, Scottish Imaging Network, A Platform for Scientific Collaboration (SINAPSE), Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.
authors: Joanna M
authors: JM
authors: Wardlaw
authors: Centre for Neuroregeneration, Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
authors: Karen
authors: K
authors: Horsburgh
mesh_terms: D000818:Animals; D001284:Atrophy / Q000473:pathology; D001812:Blood-Brain Barrier / Q000473:pathology; D001921:Brain / Q000473:pathology*; D059345:Cerebral Small Vessel Diseases / Q000150:complications / Q000473:pathology*; D003071:Cognition; D056324:Diffusion Tensor Imaging; D004195:Disease Models, Animal; D008279:Magnetic Resonance Imaging; D008297:Male; D008810:Mice, Inbred C57BL; D055806:Microvessels / Q000473:pathology*; D009457:Neuroglia / Q000473:pathology; D066127:White Matter / Q000473:pathology