The pathobiology of vascular dementia

Abstract

Vascular cognitive impairment defines alterations in cognition, ranging from subtle deficits to full-blown dementia, attributable to cerebrovascular causes. Often coexisting with Alzheimer's disease, mixed vascular and neurodegenerative dementia has emerged as the leading cause of age-related cognitive impairment. Central to the disease mechanism is the crucial role that cerebral blood vessels play in brain health, not only for the delivery of oxygen and nutrients, but also for the trophic signaling that inextricably links the well-being of neurons and glia to that of cerebrovascular cells. This review will examine how vascular damage disrupts these vital homeostatic interactions, focusing on the hemispheric white matter, a region at heightened risk for vascular damage, and on the interplay between vascular factors and Alzheimer's disease. Finally, preventative and therapeutic prospects will be examined, highlighting the importance of midlife vascular risk factor control in the prevention of late-life dementia.

Figure 1

Changing views about dementia through the years. In the early 1900s vascular factors were thought to be the main cause of dementia. Over the next several decades Alzheimer’s disease was felt to be the main cause. Clinical-pathological studies have revealed that mixed dementia, combining feature of vascular dementia and AD, is currently the most common cause of cognitive impairment in the aged.

Figure 2

Evolution of the concept of cognitive impairment on vascular bases. Hardening of the arteries was considered the main cause in the early 1900s. The concept of multi-infarct dementia introduced the possibility of preventing dementia by controlling vascular risk factors. The introduction of brain imaging modalities (computer tomography, then magnetic resonance imaging) led to the realization that white matter disease, termed leukoaraiosis, was a major cause of cognitive impairment. In the 1990s the term VCI was introduced to broaden the spectrum of cognitive deficits caused by vascular factors. At this time, genetic causes of vascular damage causing dementia were also discovered, CADASIL being the first monogenic cause of vascular cognitive impairment, identified by M-G. Bousser and colleagues.

Figure 3

Brain lesions responsible for vascular cognitive impairment. All MRI sequences are diffusion weighted imaging, except for the white matter lesions, which is a fluid attenuated inversion recovery sequence. Images are courtesy of Dr. Hooman Kamel.

Figure 4

Anatomy of the cerebral blood supply. A: Circle of Willis. B: The arterial supply of the deep white matter arises from branches of the ACA and the MCA. The supply of the basal ganglia white matter is provided by arteries arising directly form the circle of Willis and its proximal branches. Abbreviations: ACA: anterior cerebral artery; ICA: internal carotid artery; MCA: middle cerebral artery; PCA: posterior cerebral artery. C: Anatomy of the wall of arteries, arterioles and capillaries.

Figure 5

Vascular lesions leading to VCI and their effects on the brain. See text for details. CAA: cerebral amyloid angiopathy; ATS: atherosclerosis.

Figure 6

Potential mechanisms of the blood vessel damage induced by vascular risk factors. Endothelial dysfunction, impairment of autoregulation and dysfunction of neurovascular coupling, partly mediated by oxidative stress and NO deficit, reduce CBF resulting in hypoperfusion and tissue hypoxia. In addition to hypoperfusion, a critical consequence of endothelial dysfunction is increased BBB permeability, which leads to extravasation of plasma proteins, including fibrinogen, into the brain. Fibrinogen activates CD11b and TLR leading to production of ROS, proinflammatory cytokines and MMPs from activated microglia, reactive astrocytes and OPCs. Inflammation, in turn, aggravates the BBB breakdown and induces expression of adhesion molecules in endothelial cells, contributing to leukocyte and platelet adhesion and microvascular occlusion.

Figure 7

Potential mechanisms of failure to remyelinate the damaged white matter. Inflammation, oxidative stress and hypoxia induced demyelination. OPC proliferate to attempt remyelination. High molecular weight hyaluronic acid (HMW-HA) produced by reactive astrocytes is cleaved by the hyaluronidase PH20 generating digestion products that inhibit OPC maturation through mechanisms involving TLR2 and 4 and GSK3β. The resulting OPC maturation arrest prevents efficient remyelination.