VASCULAR DEMENTIA

Dementia associated with cerebrovascular disease can be divided into two general
categories: multi-infarct dementia and diffuse white matter disease (also called leukoaraiosis,
subcortical arteriosclerotic leukoencephalopathy, or Binswangers disease). Cerebrovascular
disease appears to be a more common cause of dementia in Asia than in Europe and North
America, perhaps due to the increased prevalence of intracranial atherosclerosis. Individuals
who have had several strokes may develop chronic cognitive deficits, commonly called
multi-infarct dementia. The strokes may be large or small (sometimes lacunar) and usually
involve several different brain regions. The occurrence of dementia depends partly on the
total volume of damaged cortex, but it is also more common in individuals with lefthemisphere lesions, independent of any language disturbance. Patients typically report
previous discrete episodes of sudden neurologic deterioration. Many patients with multiinfarct dementia have a history of hypertension, diabetes, coronary artery disease, or other
manifestations of widespread atherosclerosis. Physical examination usually shows focal
neurologic deficits such as hemiparesis, a unilateral Babinski sign, a visual field defect, or
pseudobulbar palsy.
Recurrent strokes result in a stepwise disease progression. Neuroimaging reveals
multiple areas of infarction. Thus, the history and neuroimaging findings differentiate this
condition from AD; however, both AD and multiple infarctions are common and sometimes
co-occur. With normal aging, there is also an accumulation of amyloid in cerebral blood
vessels, leading to a condition called cerebral amyloid angiopathy (without dementia), which
predisposes older persons to lobar hemorrhage and brain microhemorrhages. AD patients
appear to be at increased risk for amyloid angiopathy, and this may explain some of the
observed association between AD and stroke. Some individuals with dementia are discovered
on MRI to have bilateral abnormalities of subcortical white matter, termed diffuse white
matter disease, often occurring in association with lacunar infarctions. The dementia may be
insidious in onset and progress slowly, features that distinguish it from multi-infarct
dementia, but other patients show a stepwise deterioration more typical of multi-infarct
dementia. Early symptoms are mild confusion, apathy, anxiety, psychosis, and memory,
spatial, or executive deficits. Marked difficulties in judgment and orientation and dependence
on others for daily activities develop later. Euphoria, elation, depression, or aggressive
behaviors are common as the disease progresses. Both pyramidal and cerebellar signs may be
present. A gait disorder is present in at least half of these patients. With advanced disease,

urinary incontinence and dysarthria with or without other pseudobulbar features (e.g.,
dysphagia, emotional lability) are frequent. Seizures and myoclonic jerks appear in a minority
of patients. This disorder appears to result from chronic ischemia due to occlusive disease of
small, penetrating cerebral arteries and arterioles (microangiopathy). Any disease-causing
stenosis of small cerebral vessels may be the critical underlying factor, although hypertension
is the major cause. The term Binswangers disease should be used with caution, because it
does not clearly identify a single entity. Other rare causes of white matter disease also present
with dementia, such as adult metachromatic leukodystrophy (arylsulfatase A deficiency) and
progressive multifocal leukoencephalopathy (JC virus infection).
A dominantly inherited form of diffuse white matter disease is known as cerebral
autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy
(CADASIL). Clinically, there is a progressive dementia developing in the fifth to seventh
decades in multiple family members who may also have a history of migraine and recurrent
lacunar stroke without hypertension. Skin biopsy may show pathognomonic osmophilic
granules in the media of arterioles. The disease is caused by mutations in the Notch 3 gene,
and genetic testing is commercially available. The frequency of this disorder is unknown, and
there are no effective treatments. Mitochondrial disorders can present with stroke-like
episodes and can selectively injure basal ganglia or cortex. Many such patients show other
findings suggestive of a neurologic or systemic disorder such as ophthalmoplegia, retinal
degeneration, deafness, myopathy, neuropathy, or diabetes. Diagnosis is difficult, but serum
or (especially) CSF levels of lactate and pyruvate may be abnormal, and biopsy of affected
tissue, preferably muscle, may be diagnostic.
Treatment of vascular dementia must be focused on preventing new ischemic injury
by stabilizing or removing the underlying causes, such as hypertension, diabetes, smoking, or
lack of exercise. Recovery of lost cognitive function is not likely, although fluctuations with
periods of improvement are common.

PATHOPHYSIOLOGY OF VASCULAR DEMENTIA

Vascular dementia is sometimes further classified as cortical or subcortical dementia.

Vascular disease produces either focal or diffuse effects on the brain and causes cognitive
decline. Focal cerebrovascular disease occurs secondary to thrombotic or embolic vascular
occlusions. Common areas of the brain associated with cognitive decline are the white matter
of the cerebral hemispheres and the deep gray nuclei, especially the striatum and the
thalamus. Hypertension is the major cause of diffuse disease, and in many patients, both focal
and diffuse disease are observed together. The 3 most common mechanisms of vascular
dementia are multiple cortical infarcts, a strategic single infarct, and small vessel disease.
Mild vascular cognitive impairment can occur in elderly persons. It is associated with
cognitive decline that is worse than expected for age and educational level, but the effects do
not meet the criteria for dementia. These people have subjective and objective evidence of
memory problems, but their daily functional living skills are within normal limits.
In multi-infarct dementia, the combined effects of different infarcts produce cognitive
decline by affecting the neural nets.
In single-infarct dementia, different areas in the brain can be affected, which may
result in significant impairment in cognition. This may be observed in cases of anterior
cerebral artery infarct, parietal lobe infarcts, thalamic infarction, and singular gyrus
infarction.
Small vessel disease affects all the small vessels of the brain and produces 2 major
syndromes, Binswanger disease and lacunar state. Small vessel disease results in arterial wall
changes, expansion of the Virchow-Robin spaces, and perivascular parenchymal rarefaction
and gliosis.
Lacunar disease is due to small vessel occlusions and produces small cavitary lesions
within the brain parenchyma secondary to occlusion of small penetrating arterial branches.
These lacunae are found more typically in the internal capsule, deep gray nuclei, and white

matter. Lacunar state is a condition in which numerous lacunae, which indicate widespread
severe small vessel disease, are present.
Binswanger disease (also known as subcortical leukoencephalopathy) is due to diffuse
white matter disease. In Binswanger disease, vascular changes observed are fibrohyalinosis
of the small arteries and fibrinoid necrosis of the larger vessels inside the brain.
In cerebral amyloid angiopathyassociated vasculopathy, aneurysm formation and
stenosis in the leptomeningeal and cortical vessels cause damage to the subcortical white
matter. In hereditary cystatin-C amyloid angiopathy, patients have recurrent cerebral
hemorrhages before age 40 years that can lead to dementia. Prevalence of cerebral amyloid
angiopathy is consistently higher in patients with dementia than in patients without dementia,
which indicates its significant role in the pathogenesis of dementia.[1]
Cerebral

autosomal

dominant

arteriopathy

with

subcortical

infarcts

and

leukoencephalopathy is a rare autosomal dominant condition localized to chromosome arm

19q12 that affects small vessels supplying the deep white matter. Pathologically, multiple
small infarcts are observed in the white matter, thalamus, basal ganglia, and pons.
Other less common syndromes may lead to vascular dementia. Rare arteriopathies
such as inflammatory arteriopathy (eg, polyarteritis nodosa, temporal arteritis) and
noninflammatory arteriopathy (eg, moyamoya disease, fibromuscular dysplasia) can cause
multiple infarcts and can lead to vascular dementia. Hypoperfusion due to large vessel or
cardiac disease can affect the watershed areas of the brain and lead to vascular dementia.
Leukoaraiosis greater than 25% is considered to be pathological. Subcortical vascular
dementia is a diffuse small vessel disease with minimal or absent infarction with homogenous
pathological and clinical features.[2,

3]

White matter ischemic changes affect executive

dysfunction and cause slower processing speed, rather than memory and language
impairment.[4]
Arterial stiffness, which reflects an alteration in arterial mechanics, can be a risk
factor for vascular dementia.[5]
Mixed dementia is diagnosed when patients have evidence of Alzheimer dementiaand
cerebrovascular disease, either clinically or based on neuroimaging evidence of ischemic

lesions. Growing evidence indicates that vascular dementia and Alzheimer dementia often
coexist, especially in older patients with dementia. Autopsy studies have shown an
association between Alzheimer disease and vascular lesions.[6]
Several recent studies also suggest that the risk of developing Alzheimer disease is increased
when a patient is exposed to vascular risk factors such as hypertension, diabetes mellitus,
peripheral arterial disease, and smoking, which usually are associated with cerebrovascular
disease and vascular dementia. Recent evidence suggests that the vascular processes in both
disorders may mutually induce each other. Apolipoprotein E may play a role in Alzheimer
disease and vascular dementia. Apolipoprotein E4 also increases the risk of dementia in
stroke survivors and is a strong risk factor for the development of cerebral amyloid
angiopathy in patients with Alzheimer disease. In elderly individuals, many cases of dementia
may be caused by the cumulative effect of cerebrovascular and Alzheimer pathology.
One-third of patients with vascular dementia are found to have significant Alzheimer disease
pathology with cholinergic deficits in the nucleus basalis of Meynert.[7]
Vascular cognitive disorder (VCD) is a new term used to describe a particular constellation of
cognitive and functional impairment spectrum that ranges from vascular cognitive
impairment (VCI) to subcortical vascular dementia, poststroke dementia, and mixed
dementia.

ETIOLOGY
The etiology of vascular dementia is heterogeneous. Stroke is considered the leading
cause and can be divided into three subtypes: (1) cortical, (2) subcortical, and (3) strategic
infarct. Some level of cognitive impairment develops within 3 months in 35 to 62 percent of
individuals who suffer a stroke. Multiple cortical infarcts, historically termed multi-infarct
dementia, involve multiple small infarcts throughout cortical regions. This is generally a
result of large vessel disease. The location and size of the infarct determines the type and
extent of cognitive impairment. Subcortical infarcts (usually affecting basal ganglia,
thalamus, or deep or periventricular white matter) disrupt strategic cortical-subcortical
circuits, creating disconnection syndromes. These generally reflect small vessel disease. A
single strategically located infarct can also produce dementia.

In addition to infarcts, small vessel ischemic disease causing extensive white matter
changes may disrupt subcortical-cortical pathways. Binswanger's disease, or subcortical
vascular encephalopathy, refers to atherosclerotic changes of small vessels resulting in a
subcortical dementia. Vascular risk factors that contribute to the risk of stroke and small
vessel ischemia include hypertension, diabetes, hyperlipidemia, peripheral artery disease, and
smoking. These factors also play a role in the etiology of Alzheimer's disease, again
suggesting some common pathophysiological mechanisms.
Other cerebrovascular diseases are also associated with vascular dementia.
Hemorrhage, including hemorrhagic stroke, subdural hematoma, epidural hematoma, or
intraparenchymal hemorrhage from aneurysm or trauma, can also produce cognitive
impairment and dementia. In addition, chronic hypoperfusion resulting from hypotension or
other cardiopulmonary etiologies can also cause a dementia syndrome. Cardiovascular
contributing factors to vascular dementia include congestive heart failure and cardiac
arrhythmias such as atrial fibrillation.
Cerebral

autosomal

dominant

arteriopathy

with

subcortical

infarcts

and

leukoencephalopathy is an inherited disorder caused by mutation in the NOTCH3 gene. It

results in osmiophilic deposits in the basal lamina of small intracerebral arteries and
arterioles. Patients develop lacunar infarcts and white matter changes causing a subcortical
dementia.
Brain tissue damage caused by stroke induces a cerebral amyloidogenesis. This leads
to amyloid changes similar to those seen in Alzheimer's disease including soluble amyloid
accumulation, elevated CSF-, and elevated synaptophysin levels indicative of axonal
degeneration.
Cerebral amyloid angiopathy is another cause of cerebrovascular disease and vascular
dementia. Cerebrovascular disease also causes a cholinergic deficit similar to that seen in
Alzheimer's disease. Cholinergic pathways are affected in vascular dementia, and several
studies have shown low levels of acetylcholine in the CSF and reduced levels of
acetylcholinesterase transferase in the cortex, hippocampus, and striatum.

Criteria for the Diagnosis of Vascular Dementia from the NINDS-AIREN

I.

The criteria for the clinical diagnosis of probable vascular dementia include all of the
following:

Dementia defined by cognitive decline from a previously higher level of

functioning and manifested by impairment of memory and of two or more
cognitive domains (orientation, attention, language, visuospatial functions,
executive functions, motor control, and praxis), preferably established by
clinical examination and documented by neuropsychological testing; deficits
should be severe enough to interfere with activities of daily living not due to
physical effects of stroke alone.

Exclusion criteria: Cases with disturbance of consciousness, delirium,

psychosis, severe aphasia, or major sensorimotor impairment precluding
neuropsychological testing. Also excluded are systemic disorders or other
brain diseases (such as Alzheimer's disease) that in and of themselves could
account for deficits in memory and cognition.

Cerebrovascular disease, defined by the presence of focal signs on

neurological examination, such as hemiparesis, lower facial weakness,
Babinski sign, sensory deficit, hemianopia, and dysarthria consistent with
stroke (with or without history of stroke), and evidence of relevant CVD by
brain imaging (CT or MRI) including multiple large-vessel infarcts or a single
strategically placed infarct (angular gyrus, thalamus, basal forebrain, or PCA
or ACA territories), as well as multiple basal ganglia and white matter lacunes,
or extensive periventricular white matter lesions, or combinations thereof.

A relationship between the above two disorders, manifested or inferred by the

presence of one or more of the following: (1) onset of dementia within 3 mos
following a recognized stroke; (2) abrupt deterioration in cognitive functions,
or fluctuating, stepwise progression of cognitive deficits.

II.

Clinical features consistent with the diagnosis of probable vascular dementia include
the following:
o

Early presence of gait disturbance (small-step gait or marche a petits pas, or

magnetic, apraxic-ataxic, or parkinsonian gait)

History of unsteadiness and frequent, unprovoked falls

Early urinary frequency, urgency, and other urinary symptoms not explained
by urological disease

Pseudobulbar palsy

Personality and mood changes, abulia, depression, emotional incontinence, or

other subcortical deficits including psychomotor retardation and abnormal
executive function

b. Features that make the diagnosis of vascular dementia uncertain or unlikely include:
o

Early onset of memory deficit and progressive worsening of memory deficit

and progressive worsening of memory and other cognitive functions such as
language (transcortical sensory aphasia), motor skills (apraxia), and perception
(agnosia), in the absence of corresponding focal lesions on brain imaging

Absence of focal neurological signs, other than cognitive disturbance

Absence of cerebrovascular lesions on brain CT or MRI

c. Clinical diagnosis of possible vascular dementia may be made in the presence of

dementia (section I-1) with focal neurological signs in patients in whom brain
imaging studies to confirm definite CVD are missing; or in the absence of a clear
temporal relationship between dementia and stroke; or in patients with subtle onset
and variable course (plateau or improvement) of cognitive deficits and evidence of
relevant CVD.
d. Criteria for diagnosis of definite vascular dementia are as follows:
o

Clinical criteria for probable vascular dementia

Histopathological evidence of CVD obtained from biopsy or autopsy

Absence of neurofibrillary tangles and neuritic plaques exceeding those

expected for age

o

Absence of other clinical or pathological disorder capable of producing

dementia

e. Classification of vascular dementia for research purposes may be made on the basis of
clinical, radiological, and neuropathological features, for subcategories or defined
conditions such as cortical vascular dementia, subcortical vascular dementia, bipolar
disorder, and thalamic dementia.
The term Alzheimer's disease with CVD should be reserved to classify patients fulfilling the
clinical criteria for possible Alzheimer's disease and who also present clinical or brain
imaging evidence of relevant CVD. Traditionally, these patients have been included with
vascular dementia in epidemiological studies. The term mixed dementia, used hitherto, should
be avoided.

ACA, anterior cerebral artery; CVD, cerebrovascular disease; CT, computed tomography;
MRI, magnetic resonance imaging; NINDS-AIREN, National Institute of Neurological
Communicative Disorders and StrokeAssociation Internationale pour la Recherche' et
l'Enseignement en Neurosciences; PCA, posterior cerebral artery.