Multi-Infarct Dementia: Pathophysiology and Clinical Features
Jiong Shi, MD, PhD
Patricio F. Reyes, MD
Division of Neurology, Barrow Neurological Institute, St. Joseph’s Hospital and Medical Center, Phoenix, Arizona
Multi-infarct dementia is one of the most common causes of dementia in the elderly. The dementia of MID results from ischemic or hemorrhagic cerebrovascular disease and from cardiac and circulatory disorders. It usually has a fluctuating clinical course and is often associated with focal deficits of a stroke. Cerebrovascular abnormalities appear with normal aging. Beta-amyloid also may interact with the cerebrovascular pathology. There are several risk factors for MID. The best management strategy is to prevent stroke. Both N-methyl-d-aspartate antagonists and cholinesterase inhibitors have been shown to attenuate the symptoms of MID.
Key Words: aging, Alzheimer’s disease, apolipoprotein, beta-amyloid, cerebrovascular disease, dementia, multi-infarct dementia
Abbreviations used: AD, Alzheimer’s disease; ApoE, apolipoprotein E; BBB, blood-brain barrier; MID, multi-infarct dementia
As discussed by Roman,20 Thomas Willis first described postapoplectic dementia in 1672 by stating that “in many, stupidity has accompanied the palsie or has gone before apoplexy.” In 1894 Alois Alzheimer, whose name is well recognized in association with AD, and Otto Binswanger distinguished MID from neurosyphilis, the most frequent cause of dementia at that time.20 In the United States and other Western countries, MID is second only to AD as the cause of dementia and accounts for 20% of all cases of dementia.14 However, in Asia and many developing countries, MID is the most common cause of dementia. Two major epidemiological studies on MID, one conducted in Helsinki and the other in New York City, found that about 25% of patients developed MID 3 months after an ischemic stroke.18,27 In the United States, there are probably one million cases of post-stroke MID. Each year there are about 125,000 new cases of MID, which is a third of the incidence of AD.27
In MID, dementia results from ischemic or hemorrhagic cerebrovascular disease and from cardiac and circulatory disorders. Symptoms of MID, which often develop in a stepwise manner, include problems with recent memory, confusion, wandering, getting lost in familiar places, incontinence, labile emotion, and difficulty solving problems.
The causes of MID can be divided into two major categories: large-vessel disease and small-vessel disease.7 In large-vessel disease, a large stroke involves strategic locations such as the frontal lobe, hippocampus, and basal forebrain. The ensuing deficits may or may not fulfill the diagnostic criteria for dementia. In small-vessel disease, the damage is usually so slight that the change is noticeable only as a series of small steps. Over time, however, as more small vessels are blocked, there is a gradual decline in mentation. MID, which typically begins between the ages of 60 and 75 years, affects men more often than women.
Cerebrovascular functions decline with normal aging. The dominant changes in aging include loss of endothelial mitochondria, a decrease in cerebral blood flow, an apparent thickening of the vascular basement membrane, and an increase in degenerative pericytes. Bostrom and Hassler2 observed a number of structural alterations including looping, twining, and braiding of vessels in individuals older than 70 years old. Mancardi et al.16 and Bell and Ball1 reported significant aberrations in the capillary walls of individuals with dementia, including decreased capillary diameter and increased capillary densities. Donahue et al.8 showed that agrin was deposited in capillaries in dementia, highlighting the thinning and fragmentation of the basal lamina in dementia.
Thinning of the capillary basement membrane and breakdown of the BBB may play a central role in dementia. Cases of AD have shown atrophy of smooth muscle cells in cerebral vessels17 and attenuation of capillary endothelium. Beta-amyloid has been shown to damage endothelial cells.31 These vascular changes are predominantly restricted to neocortical regions abundant in beta-amyloid deposits and are less frequent in regions of neurofibrillary tangles.12 This finding suggests that beta-amyloid is closely associated with vascular abnormalities in these patients. There is no evidence that aging is associated with functional impairment of the permeability of the BBB or with a transient alteration in its the integrity.11 However, Wisniewski et al.34 observed resistance to endogenous albumin transvasation by microvascular systems adjacent to beta-amyloid deposits. Hachinski and Munoz10 proposed that the BBB was involved in AD based on the association of the serum amyloid P component (a protein not synthesized in the brain) with senile plaques and neurofibrillary tangles. The interaction between AD pathology and aberrations in cerebral microvessels suggests that the changes in vasculature are closely related to the development of dementia.
Identification of the ApoE genotype as a risk factor in developing sporadic and late-onset AD represents a breakthrough in the understanding of AD.29 Rather than the rare mutations found in hereditary early onset familial AD, ApoE4 plays a role in about 50% of all cases of AD.27 Therefore, as a risk factor, its importance is secondary only to aging.
ApoE binds to lipids and then transports them in the blood. It is found in neurons in certain regions of the brains of humans and nonhuman primates.4,24,33 The ApoE genotype is associated with atherosclerosis, which also increases the risk of AD. In a study using positron emission tomography, subjects with ApoE4/E4 alleles showed a significant decrease in the metabolism of cerebral glucose almost two decades before signs and symptoms of dementia were detected clinically.23 In general, individuals with ApoE4 alleles are vulnerable to insults to the brain. They tend to recover from head injuries more slowly than others, and they have a higher tendency to develop cognitive impairment after a cardiopulmonary bypass procedure.30 Besides AD, individuals with the ApoE4 allele have an increased risk for coronary artery disease and hypertension.28 These findings furnish a strong link between cognitive impairment and vascular compromise. They may indicate a common genetic mechanism underlying vascular disease and neurodegenerative disease or, alternatively, an interaction between these two disease entities.