Aging and the cerebral microvasculature: Clinical implications and potential therapeutic interventions

This chapter reviews age-related changes in the cerebral microvasculature, their clinical consequences, and potential preventive and therapeutic approaches that are under investigation. The consequences of large vessel atherosclerosis, such as coronary artery disease, stroke, and renal failure, have received the greatest attention over the past 50 years, it is now becoming clear that alterations in the microvasculature, particularly small vessels of the brain, can have equally important clinical consequences. Advanced imaging techniques are now identifying abnormalities in the brain that were initially thought to be "covert" strokes (not associated with acute stroke symptoms) or "incidental" hyperintensities, "consistent with age," and of no major significance. However, these findings are rapidly gaining importance as significant clinical entities, with profound effects on cognition, mobility, affect, and continence. Aging and the accumulation of vascular risk factors are associated with cerebral endothelial dysfunction that may impair the ability of cerebral microvessels to meet the metabolic demands of various neuronal networks in the brain. The mismatch between blood supply and metabolic demand may lead to the accumulation of ischemic damage in the watershed regions of the brain. Watershed regions are areas of the brain that receive a dual blood supply from the most distal branches of two large cerebral arteries and are particularly vulnerable to ischemia during hypoperfusion. If pathogenic mechanism of cerebral microvascular disease is verified in longitudinal studies, future efforts to reduce cardiovascular risk factors and improve cerebral perfusion may help reduce the burden of falls and dementia in the elderly population. Promising approaches to improving cerebral perfusion include HIF-1 activation, flavonoids, and inhibitors of the renin-angiotensin system.