Abstract
Neuroimaging has revealed a range of white matter abnormalities that are common in dementia, some that predict cognitive decline. The abnormalities may result from structural diseases of the cerebral vasculature, such as arteriolosclerosis and amyloid angiopathy, but can also be caused by nonstructural vascular abnormalities (eg, of vascular contractility or permeability), neurovascular instability or extracranial cardiac or vascular disease. Conventional histopathological assessment of the white matter has tended to conflate morphological vascular abnormalities with changes that reflect altered interstitial fluid dynamics or white matter ischemic damage, even though the latter may be of extracranial or nonstructural etiology. However, histopathology is being supplemented by biochemical approaches, including the measurement of proteins involved in the molecular responses to brain ischemia, myelin proteins differentially susceptible to ischemic damage, vessel-associated proteins that allow rapid measurement of microvessel density, markers of blood-brain barrier dysfunction and axonal injury, and mediators of white matter damage. By combining neuroimaging with histopathology and biochemical analysis, we can provide reproducible, quantitative data on the severity of white matter damage, and information on its etiology and pathogenesis. Together these have the potential to inform and improve treatment, particularly in forms of dementia to which white matter hypoperfusion makes a significant contribution.