INTRODUCTION	Section 2 of 10
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

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:

• In the US: 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.

• Internationally: 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.

	CLINICAL	Section 3 of 10
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

History: Criteria for the diagnosis of dementia require impairment in memory and 2 other cognitive domains (eg, orientation, language, praxis, executive functions, visuospatial abilities) at least. These should be serious enough to affect activities of daily living and be consistently present in order to distinguish dementia from episodic impairments of consciousness such as delirium.

• Currently, several sets of diagnostic criteria for VaD exist. This list summarizes the main common criteria.

• Vascular risk factors such as hypertension, coronary disease, and diabetes mellitus

• Specific evidence of cerebrovascular disease, eg, strokes and transient ischemic attacks: The cerebrovascular insult should precede (by no more than 3 mo) or coincide with the onset or worsening of cognitive abnormalities.

• Neuroimaging evidence of strokes

• Lateralizing neurologic signs

• Psychiatric disturbances (eg, emotional lability, depression, apathy)

• Depression is a common comorbidity in patients with cerebrovascular disease and VaD.

• Medications should be reviewed because of the potential of drugs to interfere with alertness and cognition.

• Differences between the cognitive disturbances in VaD and AD are under investigation and have little value in discriminating VaD from AD in a clinical setting.

• VaD is thought to be associated with less significant memory dysfunction than AD.

• Frontal dysfunction due to widespread involvement of subcortical structures in VaD is thought to lead to a dysexecutive syndrome with abulia and apathy.

• A cognitively impaired patient with vascular risks factors but no history of cerebrovascular disease is most likely to have AD. Patients with dementia and vascular disease frequently have mixed pathology (ie, both AD and VaD).

Physical: The physical examination should be focused on the cardiovascular system and neurologic localizing signs.

• The temporal arteries may show decreased pulsatility, local tenderness, and thickening associated with giant cell arteritis.

• Funduscopic examination provides important information regarding end-organ effects of hypertension and diabetes mellitus.

• Cardiac auscultation may detect rhythmic and valvular abnormalities.

• Low scores on a standardized instrument (eg, Mini Mental Status Examination, Short Blessed questionnaire) can provide corroborating evidence of a cognitive disturbance.

• Spasticity, hemiparesis, visual field defects, pseudobulbar palsy, and extrapyramidal signs confirm focal pathology.

Causes: Obviously, VaD and cerebrovascular disease share risk factors, including age, male sex, diabetes mellitus, hypertension, cardiomyopathy, and possibly homocysteine levels.

• So far, no relationship between cholesterol, serum lipoproteins, and the risk of VaD is clearly indicated.

• Evidence for tobacco consumption as a risk factor for VaD is conflicting.

• Alcohol consumption may be protective.