Excerpt from Multi-infarct Dementia

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Background

Dementia is a common neurologic syndrome with significant impact on the mortality and morbidity of elderly persons with the most common forms being Alzheimer disease (AD) and vascular dementia (VaD). VaD is a heterogeneous entity with a large clinicopathological spectrum that has been classically linked to cortical and subcortical ischemic changes resulting from systemic, cardiac, or local large- or small-vessel disease occlusion. Thus, the diagnosis of VaD is usually made on the basis of clinical, neuroimaging, or neuropathological evidence of cerebral ischemia in the presence of progressive cognitive decline. On the other hand, vascular pathology often coexists with AD, and this poses an additional diagnostic challenge. This has led to the existence of the diagnostic term of mixed dementia.

This diagnosis is made in the presence of neuropathologic hallmarks of AD such as accumulation of extracellular amyloid plaques, intracellular neurofibrillary tangles, and cerebral amyloid angiopathy (CAA) as well as evidence of significant ischemic events.

The frequent coexistence of AD and VaD pathologies in postmortem studies has led many to suggest that these two entities are mechanistically related. Further evidence for this comes from the significant overlap in risk factors for AD and vascular disease such as hypertension, diabetes, and apoE4 genotype. Furthermore, cerebral hypoperfusion as detected by positron emission tomography (PET) has been demonstrated in early stages of AD. Also CAA, which is prevalent in AD brains, could further alter cerebral hemodynamics. Despite these observations, the mechanisms of vascular-AD interactions are poorly understood, and the question remains as to whether these two entities interact in a synergistic fashion.

Pathophysiology

Vascular dementia results from brain injury caused by stroke and cerebral ischemia.

Single ischemic or thromboembolic infarcts occurring in strategic areas of the dominant hemisphere (eg, angular gyri, mediodorsal thalamus, anterior thalamus) may cause a dementialike syndrome without the involvement of large volumes of cerebral matter. In general, volume of tissue loss is a poor predictor of the severity of the cognitive impairment.

More commonly, progressive cognitive deficits and dementia can result from multiple temporally staggered small cerebral infarcts. Frontal subcortical regions supplied by small penetrating arterioles may be especially prone to degenerative changes in patients with poorly controlled hypertension, diabetes mellitus, or both.

A less common cause of VaD is global hypoxic-ischemic injury (eg, following cardiac arrest). Irreversible cognitive impairment is frequently observed following coronary bypass surgery.

Whether chronic cerebral ischemia associated with carotid artery stenosis (CAS) may alter cognitive function has not been conclusively demonstrated and remains a controversial concept. Neuropsychometric evaluation of patients undergoing carotid endarterectomy has not conclusively shown cognitive impairment or reductions in the probability of developing dementia in the long term.

An ill-understood form of VaD is Binswanger encephalopathy. Postmortem, myelin loss is observed and is most prominent in the hemispheric deep white matter. Axonal drop out is also observed with little or no signs of inflammation. Neuroimaging shows decreased white matter density on CT scanning and decreased white matter intensity on T1-weighed MRI. Frequently, but not invariably, lacunar strokes are also observed.

Dementia associated with cerebrovascular disease is also observed in a rare genetic condition, ie, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Affected patients often present with migraines with aura. Recurrent strokes start when the patients are aged 30-50 years. Multiple lacunar infarcts, mainly in the frontal white matter and basal ganglia, lead to progressive cognitive decline and finally dementia. However, cognitive decline is thought to begin even before strokes occur, suggesting that chronic cerebral hypoperfusion in the absence of overt stroke might be sufficient to cause significant neuronal circuit disruption.

Lastly, cognitive decline has been reported in association with several other vasculopathies such as temporal arteritis, polyarteritis nodosa, primary cerebral angiopathy, lupus erythematosus, and moyamoya disease.

Frequency

United States

The overall incidence of vascular cognitive impairment or vascular dementia ranges between 10% and 40% with most accepted figures around 20%. This variability is likely to be due to uneven diagnostic criteria used in different studies. Furthermore, the diagnosis requires clinical, neuroimaging, or neuropathological evidence of ischemic events. This may lead to an underestimation of the role of microvascular occlusion and chronic hypoperfusion, which are difficult to detect in routine neuropathological examination. Therefore, the incidence of vascular cognitive impairment may be higher than currently thought.

The incidence of dementia associated with acute stroke may be high, with 10-35% of patients developing dementia within 5 years following a hemispheric stroke. Patients with symptomatic hemispheric strokes have an approximate 4-fold increase in the risk of dementia compared with age-matched controls.

International

Incidence of VaD in Southeast Asia may be greater than in Western countries because of a higher incidence of cerebrovascular disease in that part of the world. For example, in Japan, 50% of cases of dementia are thought to have a vascular etiology. However, geographic differences may reflect diagnostic biases rather than true epidemiologic differences.

Mortality/Morbidity

Median survival depends on whether cognitive decline follows a single large hemispheric stroke or instead is the result of slowly progressive cognitive decline resulting from microvascular pathology. The progression of vascular cognitive impairment is highly variable. In general, when vascular dementia occurs shortly after large hemispheric strokes, the mortality is relatively high (around 4 y).

Race

In the United States, individuals of African descent have a higher incidence of dementia than whites. VaD may be the most common type of dementia affecting blacks.

Sex

Incidence of VaD is higher in males than in females. The converse is true for AD. This difference probably reflects known sex differences in the incidence of cerebrovascular disease.

Age

The incidences of VaD and AD increase similarly with age.

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