title: Extracellular matrix inflammation in vascular cognitive impairment and dementia.
abstract: Vascular cognitive impairment and dementia (VCID) include a wide spectrum of chronic manifestations of vascular disease related to large vessel strokes and small vessel disease (SVD). Lacunar strokes and white matter (WM) injury are consequences of SVD. The main vascular risk factor for SVD is brain hypoperfusion from cerebral blood vessel narrowing due to chronic hypertension. The hypoperfusion leads to activation and degeneration of astrocytes with the resulting fibrosis of the extracellular matrix (ECM). Elasticity is lost in fibrotic cerebral vessels, reducing the response of stiffened blood vessels in times of increased metabolic need. Intermittent hypoxia/ischaemia activates a molecular injury cascade, producing an incomplete infarction that is most damaging to the deep WM, which is a watershed region for cerebral blood flow. Neuroinflammation caused by hypoxia activates microglia/macrophages to release proteases and free radicals that perpetuate the damage over time to molecules in the ECM and the neurovascular unit (NVU). Matrix metalloproteinases (MMPs) secreted in an attempt to remodel the blood vessel wall have the undesired consequences of opening the blood-brain barrier (BBB) and attacking myelinated fibres. This dual effect of the MMPs causes vasogenic oedema in WM and vascular demyelination, which are the hallmarks of the subcortical ischaemic vascular disease (SIVD), which is the SVD form of VCID also called Binswanger's disease (BD). Unravelling the complex pathophysiology of the WM injury-related inflammation in the small vessel form of VCID could lead to novel therapeutic strategies to reduce damage to the ECM, preventing the progressive damage to the WM.
authors.affiliation: Department of Neurology, UNM Memory and Aging Center, University of New Mexico, Albuquerque NM 87131-0001, U.S.A. grosenberg@salud.unm.edu.
authors.forename: Gary A
authors.initials: GA
authors.lastname: Rosenberg
mesh_terms: D000818:Animals; D003072:Cognition Disorders / Q000201:enzymology / Q000209:etiology* / Q000503:physiopathology; D015140:Dementia, Vascular / Q000201:enzymology / Q000209:etiology* / Q000503:physiopathology; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000201:enzymology / Q000473:pathology* / Q000502:physiology; D006801:Humans; D006973:Hypertension / Q000150:complications; D007249:Inflammation / Q000150:complications* / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D061965:Matrix Metalloproteinase Inhibitors / Q000627:therapeutic use; D020782:Matrix Metalloproteinases / Q000378:metabolism
chemical_list: D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases
keywords: Binswanger's disease; demyelination; extracellular matrix; gliosis; matrix metalloproteinases; neuroinflammation; vascular cognitive impairment