Neurological Manifestations of Vascular Dementia

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 and vascular dementia. Vascular dementia 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 vascular dementia 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 Alzheimer disease[1, 2] , 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 Alzheimer disease such as accumulation of extracellular amyloid plaques, intracellular neurofibrillary tangles, and cerebral amyloid angiopathy as well as evidence of significant ischemic events. Significant associations between both, deep white matter and periventricular hyperintensities, and focal atrophy of medial temporal lobe structures have been described. These findings might indicate that not only vascular factors alone but also degenerative factors favor the occurrence of white matter hyperintensities after the age of 75 years.[10]

The frequent coexistence of Alzheimer disease and vascular dementia pathologies in postmortem studies has led many to suggest that these 2 entities are mechanistically related. Further evidence for this comes from the significant overlap in risk factors for Alzheimer disease and vascular disease such as hypertension, diabetes, and apoE4 genotype. In one study, Alzheimer's disease with cerebrovascular disease was found to be under-recognized in Asia. Authors have proposed the need for future research to establish the true prevalence of this treatable and potentially preventable disease.[11] Furthermore, cerebral hypoperfusion as detected by positron emission tomography (PET) has been demonstrated in early stages of Alzheimer disease. Also cerebral amyloid angiopathy, which is prevalent in Alzheimer disease brains, could further alter cerebral hemodynamics. Despite these observations, the mechanisms of vascular-Alzheimer disease interactions are poorly understood, and the question remains as to whether these two entities interact in a synergistic fashion.

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 dementia-like 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 vascular dementia is global hypoxic-ischemic injury (eg, following cardiac arrest). Irreversible cognitive impairment is frequently observed following coronary bypass surgery.[12]

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 vascular dementia 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).[13] 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.

Qian et al looked into early biomarkers for poststroke cognitive impairment. They revealed that only ß-secretase enzyme and soluble receptor levels for advanced glycation end products, not neprilysin or APOE genotypes, may be biomarkers diagnosing poststroke cognitive impairment.[14] . Chronic high blood pressure via its changes to the cerebral vasculature including cerebral arterial stiffening and microvascular dysfunction, leads to increasing impairment of Aβ clearance. This, in essence, can cause Aβ deposition in the brain.[15]

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 vascular dementia 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).[16]

Race

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

Sex

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

Age

The incidences of vascular dementia and Alzheimer disease increase similarly with age.

Criteria for the diagnosis of dementia require impairment in memory and at least 1 other cognitive domain (eg, orientation, language, praxis, executive functions, visuospatial abilities). These should be serious enough to affect activities of daily living and be consistently present to distinguish dementia from episodic impairments of consciousness such as delirium.

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

• Vascular risk factors such as hypertension, coronary disease, and diabetes mellitus[17]

• Specific evidence of cerebrovascular disease, eg, strokes and transient ischemic attacks: The cerebrovascular insult should precede (by no more than 3 months) 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 vascular dementia.

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

Differences between the cognitive disturbances in vascular dementia and Alzheimer disease are of limited value in discriminating vascular dementia from Alzheimer disease in a clinical setting.

• Vascular dementia is thought to be associated with less significant memory dysfunction than Alzheimer disease.[3]

• Frontal dysfunction due to widespread involvement of subcortical structures in vascular dementia 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 Alzheimer disease. Patients with dementia and vascular disease frequently have mixed pathology (ie, both Alzheimer disease and vascular dementia).

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.[5]

• 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.

Vascular dementia 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 vascular dementia is clearly indicated.

• Evidence for tobacco consumption as a risk factor for vascular dementia is conflicting. However, a multiethnic, population-based study published in 2010 suggested that the brain is not immune to long-term consequences of heavy smoking. In fact, 21,123 heavy midlife smokers were followed for a mean of 23 years and were found more than 2 decades later to have a greater than 100% increased risk of dementia, Alzheimer disease, and vascular dementia.[18]

• Limited alcohol consumption may be protective.[19]

All patients with dementia should have laboratory testing to rule out reversible causes of dementia.

CBC, electrolytes, thyroid-stimulating hormone (TSH), folate, and vitamin B-12 levels should be obtained. The American Academy of Neurology no longer recommends syphilis screening in the routine evaluation of dementia if patients come from geographic regions with a very low base rate of syphilis. In specific cases, screening for syphilis is indicated.

If the clinician has reason to suspect an angiitis affecting cerebral vessels, then an erythrocyte sedimentation rate (ESR) and specific panels may be ordered.

Patients with newly diagnosed dementia undergo neuroimaging studies to rule out treatable causes of dementia and to aid the differential diagnosis.

Either CT scanning or MRI of the head should be performed.

In patients with vascular dementia, multiple cortical, and more commonly subcortical, infarcts or single strokes affecting the thalamus, angular gyrus, and the territory supplied by the anterior cerebral arteries are observed.

Decreased white matter density (on CT scanning) or decreased T1 or increased T2 signal intensities (on MRI) are associated with dementia. Multiple pathologies, including small vessel disease and decreased integrity of the blood-brain barrier, have been associated with these findings.

Measurement of cerebral blood flow using single photon emission computerized tomography (SPECT) or positron emission tomography (PET) scanning is not recommended for diagnostic purposes.

The treatment of vascular dementia is symptomatic. Behavioral and psychiatric disturbances such as agitation, depression, and psychosis are common. Cerebrovascular disease should be treated by an internist and/or a neurologist familiar with the management of cerebrovascular disease.

• Established protocols for the evaluation and treatment of stroke are available. The individual approach combines a vascular risk factor modification and various treatments addressing the specific subtypes of stroke, such as antiplatelet drugs for the prevention of cerebral infarction in large and small artery diseases of the brain, carotid endarterectomy or stenting for tight carotid artery stenosis, and oral anticoagulants for the prevention of cardiac emboli.[8]

• The presence of a rapidly progressive dementia and multiple strokes in a young patient may indicate uncommon causes of stroke such as CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) or angiitis. If suspected on clinical grounds, these conditions should be excluded with the appropriate testing procedures (ie, skin biopsy, cerebral angiography). The decision to use anticoagulation in patients with vascular disease and dementia is particularly challenging because of the increased risk of falls and potential noncompliance in this group.

• Patients with vascular dementia are prominently affected by depression and emotional incontinence. Both conditions respond well to treatment with serotonin reuptake inhibitors.

• Patients with agitation may respond to environmental modification. Pharmacologic treatment can be useful in controlling agitation through sedation.

• In a prospective study done by Ancelin et al (2012), no evidence was found that lipid-lowering agents given in late life reduced the risk of cognitive decline and dementia. However, it did raise the possibility that women with treatment-resistant high low-density lipoprotein (LDL) cholesterol may be at increased risk of decline in visual memory.[9] . Vascular cognitive impairment seems to be a treatable common cause of memory impairment and its progression can be slowed by secondary prevention of vascular disease.[20]

Researchers at Johns Hopkins University have developed a new 6-step nonpharmacologic approach for identifying and managing behavioral problems in patients with dementia, as follows[6, 7] :

1. Screen annually with validated behavioral assessment tools (eg, Neuropsychiatric Inventory) and implement preventive measures (eg, caregiver counseling regarding patient self-care, adequate stimulation, nutrition, sleep, and detection of early symptoms)

2. Describe presenting behaviors by interviewing the patient and caregiver

3. Identify potential underlying causes (eg, medical illness, pain, medications; caregiver behaviors; home environment)

4. Devise a treatment plan that targets behaviors (eg, exercise, structured routines, meaningful activities) and eliminates modifiable triggers (eg, caffeinated beverages, afternoon napping, stimulating distractions such as nighttime TV)

5. Determine the effectiveness of the nonpharmacologic strategies (eg, Has there been any behavioral improvement? Have there been any changes in the patient’s behavioral characteristics, environment, or health status that might have affected or been affected by the treatments?)

6. Perform ongoing monitoring to determine whether new behavioral symptoms are emerging and whether nonpharmacologic therapies need to be adjusted or changed

No approved pharmacologic treatment exists for vascular dementia.

Risk factors for cerebrovascular disease should be treated when present.

Retrospective data indicate that normotensive patients with vascular dementia may have greater cognitive decline than hypertensive patients. This finding, as well as the known loss of cerebral blood flow autoregulation in chronic hypertension and cerebrovascular disease, should temper overenthusiastic attempts to normalize the blood pressure in patients with vascular dementia.

Treatment with antiplatelet agents may be initiated as indicated by the nature of the patient's underlying vascular pathology.

Cholinesterase inhibitors, which include donepezil, rivastigmine, and galantamine, have proven symptomatic efficacy in Alzheimer disease and may also have a role in the treatment of vascular dementia according to the findings of limited studies. Presently, their use may have some justification given the prevalence of dementia with mixed pathology.

The rate of progression of cognitive impairment in vascular dementia is variable; some patients progress at a slower rate than patients with Alzheimer disease. The mortality rate, however, is higher in patients with vascular dementia than in patients with Alzheimer disease, with 50% of patients with vascular dementia not living longer than 4 years.

While waiting for effective drug therapies and first-level evidence data, healthcare professionals should be encouraged to improve early diagnosis of cognitive impairment and activate control strategies against vascular disease and unhealthy lifestyle habits.

Once the diagnosis of dementia is established, patients and patients' families should be educated about the nature of the condition with great sensitivity. The clinician should balance his or her explanation to avoid provoking negative reactions from the patient or the family.

Potentially dangerous activities (eg, driving) should be discussed; provide advice regarding possible interventions (eg, driving evaluation).

The patient should be advised about electing a power of attorney in case the patient becomes incapacitated.

Caregivers require support as well. Provide contact information to caregivers for the local chapter of the Alzheimer's Association, which organizes support groups for caregivers of individuals with dementia.

For excellent patient education resources, visit eMedicineHealth's Brain and Nervous System Center. Also, see eMedicineHealth's patient education articles Dementia Overview, Dementia Medication Overview, Alzheimer Disease, Stroke, and Stroke-Related Dementia.