Review Article
Address correspondence to
Dr Eric Smith, University of
Calgary, Room C1261, Foothills
Medical Centre, 1403 29 St NW,
Calgary, AB, Canada,
Eesmith@ucalgary.ca.
Relationship Disclosure:
Dr Smith serves as a board
member of the Quality
Oversight Committee of the
American Heart Association
and as an assistant editor for
Stroke. Dr Smith receives grant
support from the Alzheimer
Society of Canada, the
Canadian Institutes of Health
Research, the Canadian
Partnership Against Cancer,
and the Heart and Stroke
Foundation of Canada and
receives research support
from McMaster University.
Unlabeled Use of
Product/Investigational
Use Disclosure:
Dr Smith discusses the
unlabeled/investigational
use of cholinesterase
inhibitors for the treatment
of vascular dementia.
* 2016 American Academy
of Neurology.

Vascular Cognitive
Impairment
Eric Smith, MD, MPH
ABSTRACT
Purpose of Review: This article provides a diagnostic framework for vascular cognitive impairment, discusses prevalence and relationships to other neurodegenerative
pathologies, and provides advice on diagnostic workup and management.
Recent Findings: Vascular cognitive impairment is the second most common cause
of cognitive impairment and frequently coexists with other neurodegenerative neuropathologies. Three new diagnostic criteria have been published recently; common
diagnostic elements include the need to classify cognitive impairment as mild cognitive impairment or dementia and to link the cognitive impairment to evidence of
clinically significant cerebrovascular disease. Vascular cognitive impairment may be
further subclassified into poststroke vascular cognitive impairment and nonstroke
vascular cognitive impairment, most commonly caused by cerebral small vessel
disease, which may only be recognized on neuroimaging.
Summary: Vascular cognitive impairment is a potentially treatable common cause
of cognitive impairment, progression of which may be slowed or halted by secondary
prevention of vascular disease.
Continuum (Minneap Minn) 2016;22(2):490–509.

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490

INTRODUCTION
Vascular cognitive impairment is the
second most common cause of dementia and may be the most preventable
and treatable cause. Vascular cognitive
impairment is commonly encountered
in two forms. In poststroke vascular cognitive impairment, the cognitive impairment is the immediate and direct
consequence of a symptomatic stroke.
In nonstroke-related vascular cognitive
impairment, the cognitive impairment
is the consequence of clinically hardto-detect cerebrovascular disease, which
may be evident only on neuroimaging
with CT or MRI. Additionally, vascular
cognitive impairment is a frequent
contributor to mixed dementia, accompanied by other neuropathologies such
as Alzheimer pathology. This article
summarizes the classification, diagnosis, and management of vascular cognitive impairment.

CLASSIFICATION OF VASCULAR
COGNITIVE IMPAIRMENT
Classification criteria for vascular cognitive impairment have been published
by the International Classification
of Diseases, Tenth Revision (ICD-10),1
National Institute of Neurological
Disorders and Stroke-Association
Internationale pour la Recherche et
l’Enseignement en Neurosciences
(NINDS-AIREN),2 State of California
Alzheimer’s Disease Diagnostic and
Treatment Centers (ADDTC),3 American
Heart Association/American Stroke Association (AHA/ASA),4 the International
Society of Vascular Behavioural and Cognitive Disorders (Vas-Cog),5 and in the
Diagnostic and Statistical Manual
of Mental Disorders, Fourth Edition
(DSM-IV)6 and Fifth Edition (DSM-5).7
Common elements of recent criteria
are given in Table 6-1. All of these classification schemes require that some

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April 2016

TABLE 6-1 Recent Classification Criteria for Vascular Cognitive Impairment
AHA/ASA4

Vas-Cog Society5

DSM-57

Cognitive criteria Discriminates between vascular
mild cognitive impairment
and vascular dementia

Discriminates between
mild and major vascular
cognitive disorder (dementia)

Discriminates between
mild and major vascular
neurocognitive disorder

There is imaging evidence of
Criteria for
probable vascular cerebrovascular disease
and either:
cognitive
impairment
There is a clear temporal
relationship between a vascular
event (eg, clinical stroke) and
onset of cognitive deficits.

Either:

The criteria are met
for major or mild
neurocognitive disorder.

OR
There is a clear relationship
in the severity and pattern of
cognitive impairment and
the presence of diffuse,
subcortical cerebrovascular
disease pathology.
There should be no history of
gradually progressive
cognitive deficits before or
after stroke that suggest the
presence of a nonvascular
cognitive disorder (eg,
Alzheimer disease).

The onset of cognitive deficits
follows one or more strokes
or there are physical signs
consistent with stroke.

The clinical features are
consistent with a vascular
etiology, as suggested by
either of the following:

OR

If history of stroke or transient
Onset of the cognitive
ischemic attack is absent, then there
deficits is temporally
is evidence of cognitive decline in
related to one or more
speed of information processing,
cerebrovascular events.
complex attention or frontal
executive functions, accompanied OR
by one or more of: gait
Evidence for decline is
disturbances, urinary symptoms,
or personality and mood changes. prominent in complex
attention (including
processing speed) and
There should be neuroimaging
frontal-executive function.
evidence of either large vessel
infarct, strategically placed single There is evidence of
infarct(s) or intracerebral
the presence of
hemorrhages(s), multiple (more cerebrovascular disease
than two) lacunar infarcts outside from history, physical
the brainstem, or extensive and examination, and/or
confluent white matter lesions.
neuroimaging considered
There should not be evidence
of other nonvascular cognitive,
medical, psychiatric, or neurologic
disorders sufficient to explain the
cognitive impairment (including
Alzheimer disease).

sufficient to account for
the neurocognitive deficits.
The symptoms are not
better explained by
another brain disease
or systemic disorder.
Probable vascular
neurocognitive disorder
is diagnosed if one of
the following is present;
otherwise possible
vascular neurocognitive
disorder should
be diagnosed:
Clinical criteria are
supported by
neuroimaging evidence
of significant parenchymal
injury attributed to
cerebrovascular disease
(neuroimaging supported).

Continued on page 492

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491

Vascular Cognitive Impairment

TABLE 6-1 Recent Classification Criteria for Vascular Cognitive Impairment Continued from page 491
AHA/ASA4

Vas-Cog Society5

DSM-57
OR
The neurocognitive
syndrome is temporally
related to one or
more documented
cerebrovascular events.
OR
Both clinical and genetic
(eg, cerebral autosomal
dominant arteriopathy
with subcortical
infarcts and
leukoencephalopathy)
evidence of
cerebrovascular
disease is present.

Criteria for
possible vascular
cognitive
impairment

Meets criteria except that
there is no clear relationship
between the vascular
disease and the cognitive
impairment, there is
insufficient information
(eg, neuroimaging studies
are not available), severe
aphasia precludes accurate
cognitive assessment, or
there is evidence of
other neurodegenerative
conditions (eg, Alzheimer
disease) in addition to
cerebrovascular disease.

Meets criteria except that
neuroimaging is not available.

Clinical criteria are met
but neuroimaging is
not available and the
temporal relationship
of the neurocognitive
syndrome with one or
more cerebrovascular
events is not
established.

Classification
when other
potential causes
are present (ie,
mixed disease)

Possible vascular mild cognitive
impairment or dementia
should be diagnosed when
there is evidence of other
neurodegenerative conditions.

Vascular mild/major cognitive
disorder with concomitant
Alzheimer disease may be
diagnosed when the patient
additionally meets criteria for
probable or possible AD.

Not specifically
addressed.

AHA/ASA = American Heart Association/American Stroke Association; DSM-5 = Diagnostic and Statistical Manual of Mental Disorders,
Fifth Edition; Vas-Cog = International Society of Vascular Behavioural and Cognitive Disorders.

degree of cognitive impairment should
be present along with evidenceV
from some combination of history,
physical examination, cognitive profile, and diagnostic testing, including
neuroimagingVof a vascular contribu-

492

tion to the cognitive impairment. The
term vascular cognitive impairment is
intended to encompass all forms of cognitive impairment, not only dementia,
and to include all cases where vascular disease contributes to impairment,

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April 2016

including in cases where it is not the
sole contributor. More recent classification systemsVthe AHA/ASA, Vas-Cog,
and DSM-5Vdistinguish between vascular mild cognitive impairment (MCI)
(or minor vascular neurocognitive
disorder in the DSM-5) and vascular
dementia (or major vascular neurocognitive disorder in the DSM-5).
AHA/ASA and Vas-Cog criteria further classify vascular cognitive impairment as probable or possible based
on the completeness of the diagnostic workup and the presence or absence
of evidence for competing causes of
dementia, such as Alzheimer disease
(AD). In practice, probable vascular
cognitive impairment may be the minority of cases because comorbid pathologies such as AD are commonly
identified, or at least cannot be ruled
out with certainty.
AHA/ASA, Vas-Cog, and DSM-5 criteria acknowledge that vascular cognitive impairment may come in the
form of poststroke vascular cognitive
impairment or nonstroke forms of vascular cognitive impairment, such as
that caused by subcortical ischemic
disease. This distinction is important
as it makes clear that the absence of a
clinical history of stroke does not exclude vascular cognitive impairment.
Indeed, neuroimaging and neuropathology studies have established that
clinically silent, or ‘‘covert,’’ cerebrovascular disease becomes extremely
common with aging, is associated with
cognitive impairment and the presence
of dementia, and is sufficient to cause
clinically relevant cognitive impairment.
Furthermore, Vas-Cog criteria subclassify vascular cognitive impairment
according to cerebrovascular pathology
(Table 6-2). It is important to recognize that the vascular pathologies underlying vascular cognitive impairment
are extremely diverse (including arteriosclerosis, cerebral amyloid angiopathy,
Continuum (Minneap Minn) 2016;22(2):490–509

atheroembolism, cardiac embolism,
hypoperfusion, and hemorrhage) such
that patient prognosis and management must be highly individualized.
With appropriate case-specific management of the vascular risk factors
relevant to the patient’s vascular pathology, it may be possible to arrest
progression of vascular cognitive impairment by preventing further cerebrovascular injury.
DIAGNOSIS AND DIAGNOSTIC
TESTING
The diagnosis of a patient with possible vascular cognitive impairment may
be considered to consist of three stages.
First, a determination should be made
of whether evidence of cognitive impairment exists, including classification
as MCI or dementia. Second, a workup
for the presence of vascular disease
should be completed, including its
location, severity and underlying
causes, and risk factors. Third, consideration should be given as to whether
the vascular disease is sufficient to
partly or wholly explain the cognitive impairment.
Assessing Cognitive
Impairment in Vascular
Cognitive Impairment
The assessment for cognitive impairment should follow the same principles for assessment of MCI and
dementia as provided in the article
‘‘The Mental Status Examination in
Patients With Suspected Dementia’’ by
Murray Grossman, MD, FAAN, and
David J. Irwin, MD,8 and in the article
‘‘Mild Cognitive Impairment’’ by
Ronald C. Petersen, PhD, MD,9 in this
issue of Continuum. The sensitivity
for detecting vascular cognitive impairment is enhanced by the use of
screening or assessment tools that
interrogate executive function and

KEY POINTS

h Diagnostic criteria for
vascular cognitive
impairment are based
on the presence of
cognitive impairment
and vascular disease
as well as a clinical
judgment that the
vascular disease is
causing the impairment.

h The term vascular
cognitive impairment
encompasses all severity
of cognitive impairment
caused by vascular
disease, including mild
cognitive impairment
and dementia.

h Vascular cognitive
impairment may be
subclassified as
poststroke vascular
cognitive impairment,
which refers to the
direct immediate
consequence of
clinical stroke, or as
nonstroke vascular
cognitive impairment,
which is most commonly
caused by cerebral small
vessel disease.

h Vascular cognitive
impairment has many
vascular causes. The
cause of the vascular
disease should be
identified so that
further progression
or recurrence can
be prevented.

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493

Vascular Cognitive Impairment
KEY POINT

h The clinical assessment
for vascular cognitive
impairment can be
conceived as a
three-stage process
that includes the
following steps:
(1) assess for cognitive
impairment; (2) assess
the presence, severity,
and cause of vascular
disease; and (3) assess
whether the vascular
disease is sufficient to
cause the impairment,
in whole or in part.

a
TABLE 6-2 Vascular Pathology of Vascular Cognitive Impairment

b Parenchymal Lesions of Vascular Etiology
Large vessel atherothromboembolic disease
Multiple infarcts
Single strategically placed infarct
Small vessel disease
Multiple lacunar infarcts
Ischemic white matter damage
Dilated perivascular spaces
Microinfarcts
Microhemorrhages
Hemorrhage
Intracerebral hemorrhage
Multiple microbleeds
Subarachnoid hemorrhage
Hypoperfusion
Hippocampal sclerosis
Laminar cortical necrosis
b Types of Vascular Pathologies
Atherosclerosis
Cardiac, atherosclerotic, and systemic emboli
Arteriolosclerosis
Lipohyalinosis
Cerebral amyloid angiopathy
Vasculitis
Venous collagenosis
Arteriovenous fistulae
Hereditary angiopathies (eg, cerebral autosomal dominant arteriopathy
with subcortical infarcts and leukoencephalopathy [CADASIL])
Berry aneurysms
Miscellaneous vasculopathies (eg, moyamoya disease)
Cerebral venous thrombosis
a

494

Modified with permission from Sachdev P, et al, Alzheimer Dis Assoc Disord.5 journals.lww.com/
alzheimerjournal/Abstract/2014/07000/Diagnostic_Criteria_for_Vascular_Cognitive.2.aspx. B 2014
Lippincott Williams & Wilkins.

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April 2016

processing speed, which are frequently
affected in patients with vascular cognitive impairment. For example, the
Montreal Cognitive Assessment (MoCA)
tool appears to be a more sensitive
tool for vascular cognitive impairment
than the Mini-Mental State Examination
(MMSE), attributed to the relatively
greater degree of executive function
assessment on the MoCA (www.
mocatest.org).10,11 When clinical uncertainty persists despite the use of a
validated bedside cognitive screening
tool, neuropsychological testing is
often helpful. The cognitive profile
of vascular cognitive impairment is
further described later in this article.
Assessing the Presence of
Cerebrovascular Disease in
Patients With Vascular
Cognitive Impairment
The determination of the presence of
cerebrovascular disease may be based
on a combination of history, examination, and diagnostic testing such as
neuroimaging. The clearest evidence
of cerebrovascular disease is when a
clinical history of stroke exists. However, the physician should be sure
that the diagnosis of stroke is well
supported by clinical history, medical
records, physical examination showing
neurologic signs consistent with past
stroke (such as aphasia, dysarthria,
hemianopia, or other focal neurologic
signs) and, if needed or available
from previous stroke workup, neuroimaging evidence of cerebral infarction or hemorrhage consistent with the
signs and symptoms. Patient-reported
history of stroke is generally reliable; however, nonspecific neurologic
symptoms can sometimes be falsely
reported as stroke, introducing diagnostic confusion.
Identifying the presence of cerebrovascular disease is more difficult
Continuum (Minneap Minn) 2016;22(2):490–509

when a history of stroke is absent.
Neuroimaging can identify evidence
of silent strokes and other manifestations of cerebral small vessel disease
that are hard to detect clinically. Clinical history, signs, and symptoms may
be suggestive of nonstroke vascular
cognitive impairment but are not
highly sensitive or specific and should
not be relied on to diagnose vascular
cognitive impairment in the absence
of neuroimaging confirmation. These
signs and symptoms include frontal
gait disorder, urinary incontinence,
a stepwise progression of cognitive
impairment with intervening static periods, prominent executive dysfunction and slowed processing speed on
neuropsychological testing, and minor
asymmetric neurologic signs such as
increased tone, reflex asymmetry, Babinski responses, or frontal release signs.5
The presence of vascular risk factors
such as diabetes mellitus and hypertension should increase suspicion for vascular cognitive impairment but should
not be taken as proof of its presence.
Neuroimaging is recommended by
the AHA/ASA as helpful for the diagnosis of vascular cognitive impairment.4 Neuroimaging is useful not
only for identifying the presence of
cerebrovascular disease, but also the
location and severity of the cerebrovascular lesions, which help determine
the clinical significance of the lesions,
including whether they are sufficient
to account for the cognitive impairment. MRI is superior to CT for identifying small infarcts and hemorrhages
and demonstrates more manifestations of cerebral small vessel disease;
therefore, MRI should be preferred
over CT.12 In patients with a history
of stroke, neuroimaging should generally identify the previous infarct or
hemorrhage unless it is small. In
patients with cerebral small vessel
disease, MRI may identify a range of

KEY POINTS

h Cerebrovascular disease
should be diagnosed by
history, examination,
and diagnostic testing,
including neuroimaging.

h Neuroimaging provides
useful evidence of
the presence, location,
and severity of
cerebrovascular disease.

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495

Vascular Cognitive Impairment
KEY POINT

h Because cerebrovascular
disease is common
and can be incidental,
clinical judgment is
needed in individual
patients to determine
whether cerebrovascular
lesions are sufficient
to cause cognitive
impairment in the
affected individual.

manifestations, including small infarcts, lacunae of presumed vascular
origin, white matter hyperintensities, and others (Figure 6-1). A recent
consensus statement offers recommendations for terms, definitions, and reporting of cerebral
small vessel disease as a contributor
to neurodegeneration.12
Assessing the Relationship
Between Cerebrovascular Disease
and Cognitive Impairment
Determining whether the identified
cerebrovascular disease is sufficient to
account for, in whole or in part, cognitive impairment may be the most
clinically difficult part of the assess-

FIGURE 6-1

ment for vascular cognitive impairment. Although general principles
relating the location and severity of
cerebrovascular disease to the risk for
cognitive impairment have been
established, there are no objectively
derived models or risk scores to predict the presence of cognitive impairment in individual patients based on
their clinical characteristics and burden of cerebrovascular disease. Therefore, clinical judgment is required
to determine whether identified cerebrovascular disease is clinically relevant, or merely an incidental finding.
This judgment is difficult because
cerebrovascular disease is a common

MRI manifestations of cerebral small vessel disease.
DWI = diffusion-weighted imaging; FLAIR = fluid-attenuated inversion recovery; GRE = gradient
recalled echo; SWI = susceptibility-weighted imaging.

Reprinted with permission from Wardlaw JM, et al, Lancet Neurol.
PIIS1474-4422(13)70124-8/abstract. B 2013 Elsevier Ltd.

496

12

www.thelancet.com/journals/laneur/article/

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April 2016

accompaniment of aging that is frequently seen in nonimpaired individuals, as well as in impaired individuals
(where it tends to be more severe
and diffuse). For example, silent
brain infarcts, extensive white matter
hyperintensities, and microbleeds,
are frequently detected on MRI of
older individuals without dementia
(Table 6-3).14Y16
The clearest circumstance where
cerebrovascular disease can be definitively related to cognitive impairment
is in poststroke vascular cognitive impairment, where there is a clinical
history of stroke, preceded by the absence of cognitive symptoms but immediately followed by cognitive
impairment (Case 6-1). In this case,
the diagnosis of vascular cognitive impairment is essentially certain. However, a pitfall to avoid is to overlook a
history of prestroke cognitive decline,
which, if present, could indicate
either a competing neurodegenerative cause of dementia or a mixed
dementia. Formal questionnaires such

as the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE)17
(Supplemental Digital Content 6-1,
http://links.lww.com/CONT/A172) can be
used to assess for prestroke cognitive
decline, or a careful clinical history of
performance on instrumental activities of living (such as driving, shopping, and handling finances) can be
used to screen for prestroke cognitive disabilities.
The number, volume, and location
of infarcts or hemorrhages is related
to the risk for poststroke cognitive impairment. Single, strategic locations
have been identified that are associated
with poststroke cognitive impairment
when affected by stroke. 18 These
locations include left hemisphere
perisylvian language areas, the thalamus, midbrain, medial temporal lobe,
and medial frontal lobe. Single strokes
in these regions can cause cognitive
impairment by affecting brain networks
sustaining language, attention, or
memory. Cognitive impairment may
also result from the combined effect

KEY POINT

h In poststroke vascular
cognitive impairment,
the link between
stroke and subsequent
vascular cognitive
impairment should
be readily apparent.

on Magnetic Resonance Imaging in
TABLE 6-3 Prevalence of Cerebral Small Vessel Disease
the General Population Without Dementiaa
c

Age
Decade Q1 infarct

Q2 infarcts

Microbleeds
Beginning
Confluent or Confluent
Susceptibility-Weighted
T2*-Weighted
White Matter
Imaging (SWI)/
Gradient Recalled High-Sensitivity
Hyperintensities
Echo (GRE)
on MRIb
Sequence

50Y59

5Y8%

1Y2%

1%

3%

12%

60Y69

7Y12%

2Y3%

1Y4%

5Y10%

15Y17%

70Y79

12Y23%

3Y6%

6Y14%

8Y16%

30Y31%

80+

25Y38%

6Y9%

19%

18%

40%

Infarcts

MRI = magnetic resonance imaging.
a
Data are aggregated from multiple population-based studies.
b
As measured using the Fazekas scale.13
c
As can be seen from the table, susceptibility-weighted imaging (SWI) and other newer, high-sensitivity MRI sequences detect about
twice as many microbleeds as older T2*-weighted gradient recalled echo (GRE) sequences.

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497

Vascular Cognitive Impairment

Case 6-1
A 71-year-old woman presented acutely with
confusion, vomiting, left hemianopia, left
hemiparesis, and skew deviation. Head CT was
unremarkable but CT angiography showed that
the basilar artery was occluded due to thrombus
formation on an atherosclerotic plaque. The
patient was treated with IV tissue plasminogen
activator and endovascular thrombectomy. The
patient’s motor and oculomotor findings resolved
after treatment. However, the patient remained
cognitively impaired, with deficits in verbal
learning and recall. Diffusion-weighted MRI showed
acute infarction (bright signal) in the right occipital
and bilateral medial temporal lobes (Figure 6-2).
During follow-up 3 months later, the patient
described symptoms of persistent forgetfulness
that interfered with shopping, finances, and driving.
Poststroke vascular dementia was diagnosed.
Comment. Strategic infarctions in the bilateral
medial temporal lobes caused vascular dementia in
this case. Poststroke dementia has also been
FIGURE 6-2
associated with infarcts in locations such as the left
perisylvian cortex, medial frontal lobe, or thalamus,
or with the presence of multiple cortical infarcts.

KEY POINTS

h Location, as well as size
and severity, must be
taken into account
when considering the
cognitive consequences
of infarcts and other
cerebrovascular lesions.

h The diagnosis of
nonstroke vascular
cognitive impairment
should be supported
by the presence of
diffuse, severe
cerebrovascular disease.

498

of multiple strokes affecting sufficient
brain regions, such as the prefrontal
lobes, involved in cognitive processing. This syndrome has been termed
multi-infarct dementia. By contrast,
the clinician should generally be sceptical of relating cognitive impairment
to single, small to moderately sized
infarcts in brain regions outside the
aforementioned strategic areas for
cognitive processing. No single volume threshold reliably discriminates
patients with poststroke vascular cognitive impairment versus those without because the cognitive effects of
infarcts and hemorrhages depends on
the locations of the lesions as well as
their size.
Consensus criteria recommend that
the diagnosis of nonstroke vascular
cognitive impairment should be

Axial diffusion-weighted MRI of the
patient in Case 6-1 shows acute
infarction (bright signal) in the right
occipital and bilateral medial temporal lobes.

based on a pattern of diffuse, severe
cerebrovascular disease.4,5 In most
cases, nonstroke vascular cognitive
impairment is caused by subcortical
ischemic cerebral small vessel disease, also called Binswanger disease
(Case 6-2). However, our understanding of the relationship between the
location, extent, and severity of the cerebral small vessel disease and the
resulting clinical syndromes is still incomplete; therefore, only general principles can be discussed. Silent brain
infarcts and white matter hyperintensities on MRI predict risk for dementia in population-based studies, and
silent brain infarcts are associated with
presence of dementia in autopsy-based
studies,19Y21 while the relationship of
cerebral microbleeds to cognition is
less clear. Small infarcts in the thalamus

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Case 6-2
A 65-year-old man presented with cognitive slowing, forgetfulness, and decreased gait speed that he
had experienced for approximately 1 year. He was no longer able to manage his own finances or do
his own shopping. He had a history of poorly controlled hypertension. The patient’s Montreal Cognitive
Assessment (MoCA) score was 14 out of 30. Neurologic
examination showed mild hyperreflexia, a few beats
of clonus at each ankle, and a slow, unsteady gait
with a shortened stride length but nearly normal
base width. Brain MRI showed severe white matter
hyperintensities with multiple lacunae of presumed
vascular origin (Figure 6-3). A diagnosis of probable
vascular dementia caused by hypertensive small
vessel disease was given. Despite initiation of aspirin,
improved blood pressure control, and a trial of
cholinesterase inhibition, progressive cognitive
decline ensued.
Comment. This case is consistent with vascular
dementia due to diffuse subcortical cerebrovascular
pathology, also called Binswanger disease. Despite
the absence of symptomatic stroke, the silent brain
infarcts and white matter hyperintensities appear
to be sufficient to cause cognitive decline. The
relatively young age at onset suggests that Alzheimer
pathology is probably absent. However, the presence
of comorbid Alzheimer pathology cannot be
FIGURE 6-3 Axial fluid-attenuated inversion
recovery (FLAIR) MRI of the patient in
completely excluded as amyloid imaging studies in
Case 6-2 shows severe white matter
patients with subcortical ischemic dementia show
hyperintensities (double arrow) with multiple lacunae
of presumed vascular origin (single arrow).
that mixed dementia, with a contribution from
Alzheimer pathology, is relatively common.

may be more likely to affect cognition
than small infarcts in other locations.
Higher numbers of infarcts and
higher volumes of white matter
hyperintensities are associated with
higher risk of cognitive impairment;
however, exact thresholds are not
well defined and likely vary based on
the location of the lesions. To support a
diagnosis of vascular cognitive impairment, the AHA/ASA recommends that
‘‘diffuse, subcortical cerebrovascular
disease pathology’’ should be present,4
while the Vas-Cog Society recommends
that at least three supratentorial
brain infarcts or ‘‘extensive and confluent’’ white matter hyperintensities
should be present. 5 However, these
recommendations, while useful aids to
Continuum (Minneap Minn) 2016;22(2):490–509

clinical judgment, have not been studied for their validity in clinical practice.
Promising new MRI techniques not
yet ready for clinical use may, in the
future, allow better discrimination of
clinically relevant from less clinically
relevant cerebrovascular lesions by
interrogating their impact on brain network function. Subcortical infarction
and ischemic white matter demyelination are presumed to cause cognitive
impairment by disconnecting brain networks subserving cognition. Recent MRI
techniques have demonstrated that
white matter hyperintensities of presumed vascular origin are associated
with reduced structural brain connectivity measured using diffusiontensor imaging,22 and that subcortical
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499

Vascular Cognitive Impairment
KEY POINTS

h Microinfarcts are a
substrate for vascular
cognitive impairment,
but are only visible at
autopsy because they are
too small to see on MRI.

h Although patients
with vascular cognitive
impairment often
exhibit impairments in
executive function and
processing speed, other
cognitive domains may
also be affected.

h Motor signs that may
accompany vascular
cognitive impairment
include frontal gait
disorder, lower body
parkinsonism, apathy,
depression, urinary
incontinence, spasticity,
hyperreflexia, and
frontal release signs.

500

infarction is associated with remote
cortical atrophy in connected areas.23
While neuroimaging remains the
most useful diagnostic test to link
the presence and severity of cerebrovascular disease with the presence of
vascular cognitive impairment, the
clinician must keep in mind that neuroimaging does not have perfect
sensitivity for all clinically relevant
cerebrovascular lesions. Specifically,
neuroimaging is unable to detect microinfarcts, which are infarcts as small
as 0.2 mm in diameter that are visible
at autopsy in approximately onequarter of all deceased elderly but
in up to half of all deceased elderly patients with dementia.24 These infarcts
fall below the limit of spatial resolution
of clinical MRI. About half the time they
occur in the absence of gross infarcts,
such that neuroimaging may falsely suggest the absence of infarction.
When the patient’s neuropsychological profile matches the location
and severity of cerebrovascular disease, the case for clinically relevant cerebrovascular disease is strengthened.
Most commonly, vascular cognitive impairment is associated with relatively
greater impairments in executive function and processing speed than in
episodic memory for a given level of
overall disability.4 By contrast, early AD
is most often associated with episodic
memory impairment.25 However, it is
important to recognize that some degree of memory impairment is very
common in vascular cognitive impairment as well.4 Furthermore, the clinician should be aware that there can be
great variety in the spatial distribution
and severity of cerebrovascular disease,
which determines the neuropsychological profile. Therefore, there is no one
uniform pattern of neuropsychological impairment in all patients with
vascular cognitive impairment. For this
reason, a diagnosis of vascular cognitive

impairment should not be made based
on neuropsychological profile alone,
but should be supported by other
evidence from clinical history, neurologic examination, and neuroimaging
that is consistent with vascular cognitive
impairment. Nonetheless, neuropsychological testing may be very helpful when uncertainty exists regarding
the clinical significance of cerebrovascular disease by identifying whether
the neuropsychological profile is
more or less consistent with the identified cerebrovascular lesions in that
individual patient. Some vascular cognitive impairment diagnostic criteria
require specific supportive clinical features, such as executive dysfunction,
to be present to diagnose nonstroke
vascular cognitive impairment,5,7 while
others do not.1,4
The clinician’s case for clinically
relevant cerebrovascular disease can
be further strengthened if other motor manifestations of cerebral infarction or hemorrhage are identified
based on history and clinical examination. Noncognitive manifestations
of cerebrovascular disease include
frontal gait disorder, lower-body parkinsonism, apathy, depression, urinary
incontinence, spasticity, hyperreflexia,
and frontal release signs.5 Additionally, behavioral disturbances such as
apathy, depression, and emotional incontinence are frequent as well.5 The
presence of these signs, in the absence
of competing nonvascular causes, suggests symptomatic cerebrovascular disease with the implication that the
cerebrovascular disease could also be
affecting cognition.
Nonatherosclerotic and
Nonarteriolosclerotic Causes of
Vascular Cognitive Impairment
The next sections review two important causes of vascular cognitive

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April 2016

impairment unrelated to the conventional vascular factors that cause atherosclerosis and arteriolosclerosis:
cerebral amyloid angiopathy and
monogenic inherited cerebrovascular diseases.
Cerebral amyloid angiopathy. Cerebral amyloid angiopathy is caused
by vascular "-amyloid deposition in
the cerebral cortex and leptomeninges,
leading to fragility of the vessel wall
with rupture and bleeding in some
patients. 26 Cerebral amyloid angiopathy is the second most common
cause of intracerebral hemorrhage
in elderly patients, after hypertensive
vasculopathy. Because vascular amyloid
tends to spare the arteries supplying
the internal part of the brain, cerebral
amyloid angiopathyYrelated hemorrhages predominately occur in the superficial, lobar portions of the cortex and
underlying white matter, or in the
adjacent subarachnoid space, with
sparing of the basal ganglia and the
brainstem. This lobar pattern of hemorrhages and superficial siderosis forms

the basis for clinical diagnosis during
life (Table 6-4).27
The diagnosis of cerebral amyloid
angiopathy is greatly aided by the use
of MRI with hemorrhage-sensitive
sequences such as susceptibilityweighted imaging (SWI), which allows
demonstration of microbleeds caused
by cerebral amyloid angiopathy. Positron emission tomography (PET) amyloid tracers bind to vascular amyloid
as well as senile plaques, and, therefore, cannot be used to distinguish between vascular and parenchymal
amyloid deposits.
Cerebral amyloid angiopathy and
AD exist on a spectrum. Most patients with AD have some amount of
vascular amyloid, although compared
to patients with cerebral amyloid
angiopathyYrelated hemorrhage, the
deposits are more likely to be around
capillaries than within the walls of
arterioles. Patients with AD rarely have
hemorrhagic strokes, although the
frequency of microbleeds is higher
than in non-AD controls. Conversely,

Amyloid
TABLE 6-4 Modified Boston Criteria for Cerebral
Angiopathy–Related Hemorrhagea
Probable Cerebral Amyloid Angiopathy
1. Age Q55
2. Either multiple hemorrhages restricted to lobar, cortical, or
cortico-subcortical regions (cerebellar hemorrhage allowed) OR single
lobar, cortical, or cortico-subcortical hemorrhage and focal or
disseminated superficial siderosis
3. Absence of other cause of hemorrhage or superficial siderosis
Possible Cerebral Amyloid Angiopathy
1. Age Q55
2. Either single lobar, cortical, or cortico-subcortical hemorrhage OR focal
or disseminated superficial siderosis
3. Absence of other cause of hemorrhage or superficial siderosis
a

Modified with permission from Linn J, et al, Neurology.27 www.neurology.org/content/74/17/
1346.short. B 2010 American Academy of Neurology.

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501

Vascular Cognitive Impairment
KEY POINTS

h Cerebral amyloid
angiopathy is an
important cause of
vascular cognitive
impairment, with effects
that are independent
of the degree of
accompanying Alzheimer
disease pathology.

h Cerebral autosomal
dominant arteriopathy
with subcortical
infarcts and
leukoencephalopathy is
the most common
inherited monogenic
cause of vascular
cognitive impairment.

h Vascular cognitive
impairment is the
second most common
cause of cognitive
impairment and
frequently coexists with
other neurodegenerative
pathologies as
mixed dementia.

502

most patients with cerebral amyloid
angiopathy do not have AD dementia.
Community-based autopsy studies
show that cerebral amyloid angiopathy
is associated with cognitive impairment and risk for dementia, even
after accounting for the association
between cerebral amyloid angiopathy
and AD (Case 6-3).28 Controlling for
the degree of coexisting Alzheimer
pathology, cerebral amyloid angiopathy
was associated with worse episodic
memory and perceptual speed.29 These
cognitive impairments could be caused
by cerebral amyloid angiopathyY
related microinfarction, ischemic
white matter demyelination, impaired
vascular reactivity, or the cumulative
effects of hemorrhages.30 There are
no disease-modifying treatments for
cerebral amyloid angiopathy.
Monogenic inherited causes of
vascular cognitive impairment. The
presence of confluent white matter
hyperintensities or multiple lacunae
in excess of that expected by age
and not explained by conventional
vascular risk factors should prompt
consideration of an inherited cause
of vascular cognitive impairment, particularly when a family history is
present.31 The inherited cause of
va scul ar cognitiv e impairment,
which is the most commonly encountered and best studied, may
be cerebral autosomal dominant
arteriopathy with subcortical infarcts
and leukoencephalopathy (CADASIL).
CADASIL is an autosomal dominant
disease caused by mutations in the
NOTCH3 gene. Affected patients develop migraine, lacunar stroke, and
then vascular cognitive impairment
due to the cumulative effects of multiple lacunar infarcts and extensive
white matter hyperintensities. There
are no disease-modifying treatments.
Other inherited diseases that can

cause vascular cognitive impairment
include cerebral autosomal recessive
arteriopathy with subcortical infarcts
and leukoencephalopathy (CARASIL)
(a CADASIL-like disease caused by
mutations in HTRA1) and mutations
in the COL4A1 gene.31
PREVALENCE, NEUROPATHOLOGY,
AND RELATIONSHIP TO OTHER
NEURODEGENERATIVE DISEASES
Both clinical and autopsy data show
that vascular cognitive impairment is
the second most common cause of
later life dementia, after AD. SpecialtyclinicYbased studies show that vascular
cognitive impairment is the diagnosis
in about 10% of patients, while mixed
dementia with a vascular component,
often in combination with AD, is the
diagnosis in a similar or even greater
proportion of cases.32 Epidemiologic
studies are generally consistent with
the clinic-based studies in showing
that vascular dementia is the second
most common cause of dementia.33
However, exact numbers on incidence
and prevalence are difficult to establish because the different vascular dementia criteria appear to vary in their
sensitivity and specificity, inhibiting
cross-cohort comparisons.
Autopsy-based neuropathology
studies of prevalence have a number
of advantages over clinic-based studies. The autopsy allows quantitative
or semiquantitative measurement of
cerebrovascular lesions difficult to
identify on in vivo imaging, such as
microinfarction, and allows quantitative assessment of comorbid pathologies such as neurofibrillary tangles,
amyloid plaques, and Lewy bodies.
Ideally, neuropathology studies would
be nested within community representative samples and have a high
degree of participation in the autopsy arm to avoid the referral and

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April 2016

Case 6-3
A 73-year-old man was seen for forgetfulness and apathy that had been present for approximately
2 years. Activities of daily living were essentially preserved, with the exception of occasional minor
errors such as purchasing incorrect items at the grocery store. The patient’s Montreal Cognitive
Assessment (MoCA) score was 24 out of 30. Scores on the Trail Making B test and a test of verbal
recall were one standard deviation below the mean compared to normative values. Brain MRI
showed six microbleeds on the gradient recalled echo (GRE) sequence, all in lobar locations
(Figure 6-4A), and severe white matter hyperintensities on the fluid-attenuated inversion recovery
(FLAIR) sequence (Figure 6-4B). Fluorodeoxyglucose positron emission tomography (FDG-PET)
scan showed patchy hypometabolism, including in brain regions with microbleeds. However,
metabolism in the posterior cingulate gyrus, a region typically affected by Alzheimer disease,
was preserved, suggesting that Alzheimer disease was probably not the cause of the cognitive
impairment. A diagnosis of probable vascular mild cognitive impairment was given, with cerebral
amyloid angiopathy as the most likely vascular cause. Over the next 2 years, the patient progressed
to mild dementia, with an essentially unchanged FDG-PET scan. Two years after the initial
presentation, the patient had a right parietal intracerebral hemorrhage (Figure 6-4C), typical of
cerebral amyloid angiopathy.

FIGURE 6-4

Axial MRI of the patient in Case 6-3 shows six microbleeds on the gradient recalled echo (GRE) sequence, all
in lobar locations (A), and severe white matter hyperintensities on the fluid-attenuated inversion recovery
(FLAIR) sequence (B). Two years after initial presentation, the patient had a right parietal intracerebral
hemorrhage (C), typical of cerebral amyloid angiopathy.

Comment. Probable cerebral amyloid angiopathy was diagnosed in this case on the basis of
the Boston criteria (Table 6-4), which indicate that cerebral amyloid angiopathy is highly probable
in patients with a lobar intracerebral hemorrhage and MRI evidence of one or more microbleeds
restricted to lobar locations. Patients with multiple lobar-only microbleeds, without hemorrhagic
stroke, are also likely to have cerebral amyloid angiopathy, although the Boston criteria have not
been validated in this setting. Neuropathology studies show that more severe cerebral amyloid
angiopathy is a predictor of cognitive impairment, controlling for the degree of accompanying
Alzheimer pathology.

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503

Vascular Cognitive Impairment
KEY POINTS

h Vascular cognitive
impairment accounts
for up to one-third of
dementia risk.

h Patient and caregiver
support to maintain
quality of life and
prolong community
living are important
aspects of vascular
cognitive impairment
management.

504

selection bias that may affect clinicbased studies.
Cerebrovascular lesions commonly
measured at autopsy include infarcts,
hemorrhages, arteriolosclerosis, and
atherosclerosis. Microinfarcts, which
may be the most clinically relevant
vascular neuropathologic lesion, can
be identified on histology but are
usually not visible grossly or on in
vivo MRI.24 Conversely, it is important to recognize that some lesions
readily visible on MRI, such as microbleeds, may be hard to find at
autopsy and that MRI white matter
hyperintensities, which have such a
dramatic appearance on MRI, are
difficult to visualize at autopsy without special stains and, therefore, can
be overlooked.
Vascular pathology is extremely
common at time of death, both in
persons with and without dementia,
being present in roughly 80% of
brains overall.34 By comprehensively
measuring both vascular as well as
comorbid neurodegenerative pathologies it is possible to estimate, in an
unbiased and objective manner, the
relationship between vascular pathologies and risk for dementia in
community-based studies, while simultaneously controlling for other pathologies. Using this approach, autopsy
studies consistently show that vascular pathology, mostly consisting of manifestations of cerebral small vessel
disease such as small infarcts, independently predicts the risk of dementia
even when accounting for Alzheimer
and Lewy body pathology. These data
suggest that vascular pathology accounts for roughly one-quarter to
one-third of dementia risk.35,36
The frequent co-occurrence of
Alzheimer and vascular pathology with
deleterious effects on cognition has
raised scientific interest in whether
there are deeper, fundamental inter-

actions between these most common
pathologies of dementia. This interest
has been heightened by recent observations that sporadic AD is associated
with a failure of soluble amyloid-" (A")
clearance37 and that soluble A" can
exit the brain through vascular and
perivascular clearance pathways.38 However, autopsy studies generally show
that the burden of cerebrovascular and
Alzheimer pathology are independent
of one another and that effects on
the odds of dementia are additive, not
multiplicative.39 Thus, interactions between cerebrovascular and Alzheimer
pathology seem to be in their combined effects on brain cellular and network function, and not because one
disease directly causes the other; however, note that this observation does
not exclude a role for variance in (nondiseased) vascular clearance of A" in
the pathogenesis of AD.
MANAGEMENT OF VASCULAR
COGNITIVE IMPAIRMENT
Management of vascular cognitive impairment may be categorized as patient and caregiver support, cognitive
rehabilitation for poststroke vascular
cognitive impairment, consideration of
cognitive enhancing medications, and
treatment and secondary prevention
of the causative cerebrovascular process. Recommendations for the mana g e m e n t of va s c ul ar c og ni t i v e
impairment have been published by
the AHA/ASA.4
Personal and caregiver support
should follow general principles of
management for patients with MCI
or dementia and should include
assessments of driving safety, safety
in the home, financial and medical advanced planning, management of
neuropsychiatric complications, and
palliative care, as appropriate for the
individual patient.40

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April 2016

For patients with poststroke vascular
cognitive impairment, cognitive rehabilitation may speed or improve recovery. Many patients with poststroke
vascular cognitive impairment will experience improvements in cognition, or
even resolution of cognitive deficits,
during the stroke recovery process.
Cognitive rehabilitation may include
training for compensatory strategies or
cognitive skills training.41
Randomized controlled trials of cholinesterase inhibitors show that they
have a modest benefit in patients with
vascular dementia, including in mixed
vascular and AD dementia.4 The AHA/
ASA and Canadian Best Practice Recommendations for Stroke Care recommend consideration of cholinesterase
inhibitor therapy with intermediatelevel evidence.4,41 The 2012 Canadian
Consensus Conference on the Diagnosis and Treatment of Dementia
recommends that cholinesterase inhibitor therapy should be considered
in patients with AD with concomitant cerebrovascular disease, with
intermediate-level evidence, but that
there is insufficient evidence to recommend cholinesterase inhibitor
therapy for patients with pure vascular dementia. 4 2 Donepezil and
galantamine are the best-studied cholinesterase inhibitors.4 The benefits of
memantine are not well established.4
This author frequently uses acetylcholinesterase inhibitors in patients with
progressive probable or possible vascular dementia, particularly when a
contribution from comorbid AD cannot be excluded.
Perhaps the most important part of
management of vascular cognitive impairment is the identification of the
causative cerebrovascular processes
and initiation of secondary prevention
strategies to prevent their progression
or recurrence. A list of causes of vascular cognitive impairment is shown in
Continuum (Minneap Minn) 2016;22(2):490–509

Table 6-2. Many vascular diseases can
be prevented or their progression
can be slowed by existing therapies
proven effective by randomized controlled trials. With adequate control
of vascular risk factors, it may be
possible to reduce the rate of progression of vascular cognitive impairment or even arrest any progression,
as long as comorbid neurodegenerative pathologies are not also present
and symptomatic. For patients with
poststroke vascular cognitive impairment, stroke recurrence is a strong
risk factor for cognitive worsening or
onset of new dementia.
For patients with ischemic stroke,
diagnosis of the causes and management of risk factors should be done
according to ischemic stroke secondary prevention guidelines from the
AHA/ASA.43 For patients with intracerebral hemorrhage, diagnosis and management of risk factors should be done
according to intracerebral hemorrhage
guidelines.44 Hypertension is the strongest risk factor for stroke overall and
for each main stroke type individually,
and therefore warrants careful attention to achieve adequate blood pressure control.
The management of patients with
nonstroke vascular cognitive impairment, which is predominantly caused
by cerebral small vessel disease, is less
certain and lacks evidence from randomized trials. The most common
cause of cerebral small vessel disease
is arteriolosclerosis due to aging and
vascular risk factors such as hypertension and diabetes mellitus. However,
cerebral amyloid angiopathy is an important alternative cause in a minority
of patients.45 This author suggests
that patients with arteriosclerotic cerebral small vessel disease should have
measurement of blood pressure, an
ECG to assess for atrial fibrillation,

KEY POINTS

h Acetylcholinesterase
inhibitors have a
modest beneficial
effect in vascular
cognitive impairment.

h The most important
component of vascular
cognitive impairment
management is
identifying and
treating the underlying
cerebrovascular
processes that lead to
brain injury.

h Patients with vascular
cognitive impairment
with stroke should be
treated according to
secondary prevention
guidelines for stroke.

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505

Vascular Cognitive Impairment
KEY POINT

h Careful control of
vascular risk factors
may be an important
component of
dementia prevention.

506

measurement of serum lipid profile,
and measurement of either fasting
blood glucose or glycosylated hemoglobin A1c to assess for diabetes mellitus. More intensive investigations
for proximal sources of embolism,
such as echocardiography, prolonged
cardiac rhythm monitoring for atrial
fibrillation, and noninvasive carotid imaging for carotid-territory infarcts,
should be considered in patients with
infarcts that could be of embolic origin, such as cortical infarcts, but may
not be necessary in patients with only
small subcortical infarcts likely caused
by intrinsic small vessel disease.
There are no proven therapies for
prevention of cognitive decline in patients with cerebral small vessel disease.45 Secondary prevention should
focus on addressing the vascular risk
factors identified in the diagnostic
workup. It is reasonable to start aspirin
in patients with silent brain infarcts,
and this treatment may also be considered in patients with extensive, confluent white matter hyperintensities.
When considering indications for
statin therapy, it is not proven whether
cerebral small vessel disease should be
considered an atherosclerotic disease
equivalent; therefore, the use of statins
may be considered on a case-by-case
basis in individual patients, particularly
when there is hypercholesterolemia.
White matter hyperintensity progression has been evaluated as a secondary
end point in several randomized controlled trials. Progression is probably
slowed by good blood pressure control46 but was not slowed by intensive
glucose management (to glycosylated
hemoglobin A1c level of less than
6.0%),47 with mixed results for two
trials of statin therapy.48 A single trial of
homocysteine-lowering vitamin therapy
showed less MRI white matter hyperintensity progression in the treatment

arm, but only in patients with severe
hyperintensities at baseline.49 A limitation of all of these trials is that the
sample sizes were not large enough to
link slowing of white matter hyperintensity progression with reduction in
clinical end points such as cognitive
decline or stroke.
PREVENTION OF VASCULAR
COGNITIVE IMPAIRMENT
Improved population control of vascular risk factors is one of the most
promising approaches to dementia
prevention. Stroke and cardiovascular
mortality has been declining for several decades, probably partly related
to better control of vascular risk factors as well as better acute management. There is emerging evidence
that the age-standardized incidence
of dementia is declining, but the
degree to which this declining incidence can be attributed to better
vascular risk factor control is unknown.50 The Finnish Geriatric Intervention Study to Prevent Cognitive
Impairment and Disability (FINGER)
study randomly assigned participants
to a vascular risk factor control regimen as part of a multidomain approach to dementia prevention and
found that the multidomain intervention, which also included diet, exercise, and cognitive training, prevented
decline in cognitive test scores.51
CONCLUSION
Vascular cognitive impairment is the second most common cause of dementia
and is a frequent contributor to mixed
dementia. All patients with cognitive
impairment should be assessed for
contributing vascular causes. The diagnostic approach should be based on
identifying cognitive impairment,
identifying vascular disease, including
clinically hard-to-recognize cerebral

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April 2016

small vessel disease on neuroimaging,
and then using clinical judgment to
determine whether the two are related.
Vascular cognitive impairment should
be classified into poststroke and nonstroke forms. The most important
aspect of vascular cognitive impairment
management is to diagnose the causes
and risk factors for the underlying
cerebrovascular diseases and then initiate secondary prevention targeted
against those diseases.
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