Monument Valley in Arizona

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.

Clinical Diagnosis

The National Institute of Neurological Disorders and Stroke, with the support of the Association Internationale pour la Recherche et l’Enseignement en Neurosciences devised the diagnostic criteria for MID:22 demonstration that a patient is demented, evidence of cerebrovascular disease, and a relationship between dementia and cerebrovascular disease. Memory, however, is not always impaired in patients with MID, especially in those with the slowly progressive form. Diagnosing MID requires dysfunction in at least two domains, and the overall dementia must be severe enough to impair the patient’s activities of daily living, independent of motor deficits produced by the stroke. Evidence of cerebrovascular disease must be proven by findings on computed tomography or magnetic resonance imaging. Finally, a relationship between dementia and cerebrovascular disease must be established. In patients with a slowly progressive course, the length of time that it takes for dementia to develop after symptomatic stroke is an important factor. In patients with small-vessel disease, disruption of specific frontal-subcortical circuits results in frontal lobe dysfunction: apathy, attentional deficits, and changes in personality. In contrast, a significant memory deficit is the first and foremost symptom of AD.

Risk Factors

Seven major risk factors separate typical stroke patients who recover and have normal cognitive function from patients who develop MID as the result of a stroke. Older age is the primary risk. To have a lacunar or a large cortico-subcortical stroke at the age of 85 years is not the same as having the same type of stroke at the age of 45 years. An age-associated vulnerability of cerebral vessels makes elderly stroke victims more susceptible to dementia than younger stroke patients.

A low level of education also places patients at risk. Patients who are illiterate or who have only a few years of school do much more poorly than more highly educated patients. This relationship is true for AD and for dementia in general.5 Hypotension is the third risk factor. In an animal model of permanent bilateral occlusion of the carotid arteries, the behavioral profile of rats (Morris maze) shifted toward that of aged rats.6 Chronic hypoperfusion may induce episodes of hypoxia-ischemia in the brain, triggering free radical-oxidative cascades. Patients with low blood pressure or orthostatic hypotension do poorly, probably because of impaired cerebral perfusion.21 The lower the blood pressure is, the more frequent are episodes of orthostatic hypotension and the higher is the likelihood of symptomatic dementia. This relationship seems to be true of the dementia that follows congestive heart failure. Low systolic blood pressure and a low left ventricular ejection fraction correlate with deficits on cognitive examination.3

A 15-year prospective study found an association between hypertension and dementia.26 Long-standing or untreated hypertension may cause lipohyalinosis and thickening of the vessel walls. In turn, the lumen of small perforating arterioles in the brain narrows. The rigidity of cerebral vessels in response to a decrease in cerebral perfusion pressure may reduce cerebral blood flow.6 Hypertension is also known to break down the integrity of the BBB. Leakage of the BBB may cause cerebral edema and introduce systemic elements into the brain.25

In a large retrospective cohort study, Leibson et al.15 found that adult onset diabetes mellitus was a major risk factor for both AD and nonAD dementia. Diabetes mellitus contributes to vascular disease and hypertension. Therefore, cognitive impairment in persons with long-standing diabetes mellitus is not surprising.

Left hemisphere strokes tend to increase the risk of MID five-fold when speech is not involved. When speech is involved, the chances of having sequelae of dementia are much higher. Finally, smokers also have a higher risk of MID than nonsmokers.

Prevention and Treatment

The ideal treatment of acute stroke and the prevention of stroke recurrence are the best strategies to decrease the incidence of MID. Controlling risk factors is essential to prevent stroke. Cardiac abnormalities, in particular, atrial fibrillation, arterial hypertension, lipid abnormalities, and diabetes mellitus, are risk factors that need to be controlled. A European study (Syst-Eur) recruited more than 3000 subjects older than 60 years with a sitting systolic blood pressure of 160 to 219 mm Hg and diastolic pressure of less than 95 mm Hg.9 The treatment group received nitrendipine and dihydropyridine. The Committee for Safety terminated the trial early after finding a significant difference in the incidence of stroke between the placebo and active treatment groups. At that time they noted a 50% reduction in the incidence of dementia in the active treatment group. This study demonstrated the importance of controlling hypertension as a risk factor in stroke prevention.

The treatment of MID has evolved as our understanding of its underlying mechanisms improves. Vasodilators, a common treatment for MID several decades ago, were not supported as beneficial in controlled trials. Calcium-channel blockers, especially nimodipine, have demonstrated some effectiveness in treating small-vessel disease. Neuroprotective agents have been studied extensively. Memantine appears to be a good candidate. A European study found that memantine improves the symptoms of MID and slows its progression.13 Since the level of acetylcholine is reduced in the brains of patients with MID, cholinesterase inhibitors help blunt the progression of MID.32 Donepezil, galantamine, and rivastigmine all have beneficial effects in treating MID.19


MID is the second most common cause of dementia. It results from large-vessel or small-vessel disease. The latter usually has an insidious course. The best strategy in preventing MID is to control risk factors. Several lines of medication are now available to help slow the progression of MID.


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