Clinical Neuroscience Research 3 (2004) 437–448

www.elsevier.com/locate/clires

Vascular dementia
David W. Desmond*
Departments of Neurology and Pathology, SUNY Downstate Medical Center, 450 Clarkson Avenue, Box 25, Brooklyn, NY 11203, USA

Abstract
Advances in medical practice have significantly increased the longevity of our population during the last 100 years. As the number of
persons with dementia has grown, the significance of the contribution of cerebrovascular disease has become apparent, and it is now
recognized to be the second most frequent cause of dementia in Western countries and perhaps the most frequent cause of dementia in Asian
countries. Factors that increase the risk of vascular dementia include stroke, particularly more severe strokes involving the left hemisphere;
vascular risk factors, such as diabetes mellitus; and host characteristics, such as older age and fewer years of education. Genetic factors are
causative in familial disorders such as CADASIL, and the apolipoprotein E 14 allele may also make a contribution. Certain patients with
vascular dementia may exhibit the stereotypic clinical features of executive dysfunction and a stepwise course of cognitive decline,
particularly when subcortical disease is predominant, but the clinical distinctions between cerebrovascular disease and Alzheimer’s disease
may be subtle, in part because those two diseases frequently coexist. Two approaches to the treatment of patients with vascular dementia
should be considered. First, treatment for stroke prophylaxis, including the careful management of vascular risk factors, could be worthwhile.
Second, a variety of agents that have been investigated for the treatment of Alzheimer’s disease might also prove to be beneficial for patients
with vascular dementia, including cholinesterase inhibitors, neuroprotective agents, statins, calcium-channel blockers, anti-inflammatory
medications, and antioxidants.
q 2004 Elsevier B.V. All rights reserved.
Keywords: Dementia; Vascular dementia; Stroke; Cerebrovascular disease; Alzheimer’s disease

1. Introduction cognitive profile of vascular dementia, (4) the clinical

course of vascular dementia, and (5) treatment of patients
Advances in medical practice have significantly with vascular dementia.
increased the longevity of our population during the last
100 years. As a result, the number of persons with
dementia is growing dramatically. In the year 2000, there 2. Frequency of vascular dementia
were four million cases of Alzheimer’s disease, and
statistical models predict a three-fold rise in the number Community-based epidemiologic studies of dementia
of cases by the year 2050 [1]. As more attention has from Western countries have generally reported consistent
become focused on dementia, the significance of the prevalence ratios, with Alzheimer’s disease being more
contribution of cerebrovascular disease has become common than vascular dementia [7]. In Japan and other
apparent, and it is now recognized to be the second Asian countries, cerebrovascular disease appears to be more
most frequent cause of dementia in Western countries common than Alzheimer’s disease as a basis for dementia
and perhaps the most frequent cause of dementia in Asian [8,9], but it has been suggested that the relative frequencies
countries. Vascular dementia in turn increases the risk of of those two dementia subtypes are becoming less disparate
dependent living [2], recurrent stroke [3], and early [10]. In a study from Hisayama, Japan, for example,
death [4 – 6]. prevalence surveys of individuals $ 65 years old were
This review will provide a comprehensive overview of performed in 1985 and 1992 and the ratio of patients with
cerebrovascular disease as a risk factor for dementia. Taken vascular dementia to those with Alzheimer’s disease shifted
in order, it will discuss (1) the frequency of vascular from 1.8:1 to 1.1:1 during those years [10]. The prevalence
dementia, (2) risk factors for vascular dementia, (3) the of vascular dementia decreased among males more than
females, matching a decline in stroke incidence among
* Tel.: þ1-718-270-1291; fax: þ 1-718-270-3313. males that was associated with targeted efforts towards
E-mail address: [email protected] (D.W. Desmond). stroke prevention. These findings support the obvious yet
1566-2772/$ - see front matter q 2004 Elsevier B.V. All rights reserved.
doi:10.1016/j.cnr.2004.04.009
438 D.W. Desmond / Clinical Neuroscience Research 3 (2004) 437–448

important idea that targeted efforts to reduce the incidence and Alzheimer’s disease, the diagnosis of which was
of stroke may have a significant impact on the frequency of suggested by a pre-stroke history of functional impairment;
vascular dementia. While methodologic variation may and 4.2% had dementia for other reasons, such as alcohol
contribute to the discrepancies between the results of abuse. In another large epidemiologic study that was
studies performed in different parts of the world, these performed in Finland using similar methods, Pohjasvaara
results further suggest that the preponderance of vascular et al. [14] reported that 107 of 337 patients (31.8%) met
dementia relative to Alzheimer’s disease in Asian countries dementia criteria 3 months after ischemic stroke. Finally, in
is likely to be due, at least in part, to the greater incidence of a study performed in Spain, Barba et al. [15] reported that 75
stroke in those regions. of 251 patients (29.9%) met dementia criteria 3 months after
As suggested by the findings of Kiyohara et al. [10], ischemic stroke. In both of those latter studies, most cases of
patients who have experienced one or more ischemic strokes dementia were felt to be primarily due to stroke.
would appear to be at greatest risk of vascular dementia. Although estimates of the frequency of dementia, and
Thus, the findings of the few formal epidemiologic studies thus the determinants of dementia that will be identified,
that have focused on that subgroup of patients would will vary depending on the diagnostic paradigm that is used
provide particularly useful information. First, in work [14,16,17], the results of these three studies are consistent in
performed at Columbia-Presbyterian Medical Center in having found that one-fourth to one-third of elderly patients
New York, 453 patients age 60 and older who were meet operationalized criteria for dementia 3 months after
consecutively hospitalized with acute ischemic stroke were stroke, suggesting that dementia after stroke is exceedingly
recruited in two phases. Three months after stroke, they common. The estimates of the frequency of dementia after
were examined with neuropsychological tests tapping stroke reported by these three studies are quite similar, but it
multiple cognitive domains as well as a measure of is important to note that the same factors that increase the
functional ability. The diagnosis of dementia was based risk of dementia also increase the risk of morbidity and
on criteria modified from DSM-III-R [11]. The method for mortality, thus reducing the availability of patients with
diagnosing vascular dementia was consistent with the dementia for enumeration, suggesting that the frequency of
NINDS-AIREN guidelines later developed by Román et al. dementia after stroke may actually be higher than
[12] that are shown in Table 1. In addition to the presence of previously reported [18].
cognitive and functional impairment indicative of dementia,
it was required that significant cerebrovascular disease be 2.1. Vascular Cognitive Impairment
evident based on brain imaging, clinical history, and
neurologic examination, and that there be a meaningful Certain recent studies have focused on patients with
relationship between those two disorders. cerebrovascular disease who are less severely affected and
One-hundred and nineteen patients, or 26.3% of the do not meet operationalized criteria for dementia, such as
cohort, were demented 3 months after stroke [13]. Within those with mild Vascular Cognitive Impairment (VCI) [19],
the sample of 119 demented patients, 57.1% had dementia based on the belief that they may be more responsive to
that was directly attributable to stroke, or vascular dementia; pharmacologic treatment. Similar to the concept of Mild
38.7% had dementia due to the combined effects of stroke Cognitive Impairment that was derived from studies of
Alzheimer’s disease [20], VCI is a broad concept which
Table 1
encompasses patients across the entire continuum of
NINDS-AIREN criteria for the diagnosis of vascular dementia (adapted
from Ref. [12]) cognitive impairment resulting from cerebrovascular dis-
ease, ranging from high-risk patients with no frank
Required elements: cognitive deficit (the ‘brain-at-risk’ stage) through severe
(1) Dementia involving deficits in memory and two or more other cognitive
dementia. In proposing that concept, Hachinski [19] argued
domains, with concomitant impairment of functional capabilities.
(2) Cerebrovascular disease, with evidence provided by patient history, that there is little agreement regarding the methods for the
examination findings, and/or the results of brain imaging. diagnosis and the features of cognitive impairment resulting
(3) A causal relationship between elements (1) and (2), as determined based from cerebrovascular disease. He suggested that the term
on a temporal relationship between stroke and dementia, abrupt or ‘vascular’ is too generic and fails to communicate specific
stepwise decline in cognitive function or a fluctuating course, and/or
etiologies that might be amenable to treatment. Similarly, he
brain imaging findings documenting damage to brain structures relevant
to cognitive function. felt that the term ‘dementia’ identifies patients who are too
severely affected to be helped. Hachinski suggested that
Supportive information:
cognitive impairment should be described in the language of
(1) History of risk factors for cerebrovascular disease (e.g., hypertension,
diabetes). standardized neuropsychological measures and related to
(2) Presence of a gait disturbance or a history of falls. the specific vascular cause among more mildly affected
(3) Early appearance of urinary incontinence not explained by urologic patients so that treatment can be initiated.
disease. Among those studies that have thus far explicitly focused
(4) Frontal lobe or extrapyramidal features.
on patients with VCI, Rockwood et al. [21] examined
(5) Pseudobulbar features.
412 consecutive patients presenting to a memory clinic.
 D.W. Desmond / Clinical Neuroscience Research 3 (2004) 437–448 439

They found that 80 of those patients (19.4%) had VCI. requiring that patients be between the ages of 40 and 79
Those 80 cases could be further broken down into three and have no history of prior stroke or preexisting dementia.
subgroups: VCI but no dementia ðn ¼ 19Þ; vascular They found that 15 of 110 patients (13.6%) met criteria for
dementia ðn ¼ 48Þ; and vascular dementia with concomitant dementia 3 months after stroke. They could not perform a
Alzheimer’s disease ðn ¼ 13Þ: In the Canadian Study of formal multivariate analysis due to a lack of statistical
Health and Aging, a longitudinal population-based study, a power, but univariate analyses suggested that dementia was
high rate of conversion to dementia was noted among associated with clinical features that included left hemi-
patients initially diagnosed with VCI without dementia [22], sphere infarction, total anterior circulation infarcts, stroke
and the rates of cognitive decline, institutionalization, and severity, aphasia, diabetes mellitus, and atrial fibrillation.
mortality were significantly higher for subjects with VCI Although the frequency of dementia that Censori et al.
than subjects without VCI [22,23]. reported was notably lower than those that were recognized
in the studies of Desmond et al. [13] and Pohjasvaara et al.
[14], most likely due to their recruitment of a younger
3. Risk factors for vascular dementia sample that was free of prior stroke and preexisting
dementia, their univariate findings were otherwise
3.1. Stroke, vascular risk factors, and host characteristics compatible.

Community-based epidemiologic studies of cerebrovas- 3.2. Genetic factors

cular disease and dementia tend to be limited in the
information that they can provide regarding risk factors Although it is understood that certain host character-
because brain imaging is typically not performed. Although istics, such as older age and fewer years of education, may
ischemic stroke represents cerebrovascular disease in its increase the risk of dementia among patients with
most potent form and stroke patients may not be fully cerebrovascular disease, studies focusing on the role of
representative of all patients with vascular dementia, those genetic factors were sporadic until the 1990s, consisting
patients usually undergo comprehensive assessments, primarily of reports by Van Bogaert [25] and Sourander
suggesting that stroke studies can be quite informative with and Wålinder [26] of a hereditary form of multi-infarct
regard to risk factors. In the study performed at Columbia- dementia. At that time, renewed interest led to a better
Presbyterian Medical Center described above [13], for understanding of the phenotypic manifestations and genetic
example, dementia was found to be associated with a variety basis for that disorder, which has been termed ‘cerebral
of clinical determinants, including stroke characteristics, autosomal dominant arteriopathy with subcortical infarcts
such as the severity and location of the presenting stroke, and leukoencephalopathy’ (CADASIL) [27]. Initial symp-
with more severe left hemisphere infarcts in the anterior and toms typically include migraine or an ischemic event
posterior cerebral artery territories of greatest importance; occurring in young or middle adulthood, respectively
vascular risk factors, including diabetes mellitus and prior [28 –31], and certain studies have suggested that some
stroke; and host characteristics, including older age, fewer affected individuals may become symptomatic early in
years of education, and nonwhite race/ethnicity. childhood with migraine or a learning disorder [32].
In the cohort of Pohjasvaara et al. [14], the clinical Regarding clinical course, affected patients typically
determinants of dementia included a major dominant experience multiple recurrent subcortical ischemic events,
hemispheral syndrome, a history of prior cerebrovascular leading to a stepwise decline and a dementia syndrome
disease (e.g., ischemic stroke, intracerebral hemorrhage, with frontal lobe features [28 – 31]. Depression is also
subarachnoid hemorrhage), aphasia, and # 6 years of common, and survival is reduced. Brain imaging findings
education. That model was essentially unchanged when include ischemic changes in the periventricular and
patients with ‘mixed’ dementia were excluded. Although subcortical white matter and lacunar infarctions in the
more severe left hemisphere stroke syndromes were thalami, basal ganglia, and brainstem, with normal-
associated with dementia status in the Columbia study appearing cortex and cerebellum [33]. The anterior
[13], aphasia was not related. This discrepancy with regard temporal poles may be differentially involved [34].
to the importance of aphasia may have resulted from Pathologic study reveals a small vessel arteriopathy with
differences between the studies in the methods that were media thickened by osmiophilic, granular, electron-dense
used for the assessment and diagnosis of dementia. material of unknown origin; the absence of atherosclerosis
Pohjasvaara et al. did not require evidence of nonverbal and amyloid angiopathy; and, in most cases, normal cortex
memory impairment for the diagnosis of dementia in [35]. CADASIL is the result of mutations of the Notch3
aphasic patients, for example, which may have contributed gene located on chromosome 19 [36].
to the increased frequency of dementia that they found The apolipoprotein E (APOE) 14 allele has been
among those patients in their study. implicated as a risk factor or risk marker for Alzheimer’s
Censori et al. [24] performed a similar study on a more disease [37] and cerebrovascular disease [38], and
highly selected sample of ischemic stroke patients, additional recent efforts have focused on the role of
440 D.W. Desmond / Clinical Neuroscience Research 3 (2004) 437–448

APOE in the determination of dementia among patients with infarcts. In contrast, among 41 participants who did not
cerebrovascular disease. In one population-based case- meet neuropathologic criteria for Alzheimer’s disease, brain
control study of APOE in Rotterdam and New York, infarcts were only weakly associated with poor cognitive
Slooter et al. [39] examined 187 patients with dementia and function and dementia.
stroke and 507 controls who were comparable with regard to Even among relatively pure cases of vascular dementia
age and racial/ethnic group. Overall, patients with dementia and Alzheimer’s disease, the clinical manifestations of those
and stroke had a higher frequency of the APOE 14 allele two dementia subtypes may not be fully distinct. In one
than controls. Compared with APOE 13 homozygotes, study [55], investigators from six sites in the United States
APOE 14 homozygotes had a seven-fold increased risk of and Europe participated in a meta-analysis of the Hachinski
dementia in a setting of stroke, while APOE 14 hetero- Ischemic Score (HIS) by contributing original clinical data
zygotes had a nearly two-fold increase in risk. Consistent and pathologic diagnoses on a large sample of patients with
with the findings of many [40 –44] but not all [45 – 48] dementia. As part of that study, they examined the
recent investigations, the results of this study suggest that frequencies with which clinical features conventionally
that the APOE 14 allele may be a genetic risk factor for accepted to be typical of ‘multi-infarct dementia’ (MID) and
dementia among patients with stroke, but further work is Alzheimer’s disease were actually present among patients
needed. with those pathologically confirmed dementia subtypes.
They found that 10.7% of patients with pathologically
3.3. The coexistence of cerebrovascular disease confirmed MID were misdiagnosed with Alzheimer’s
and Alzheimer’s disease disease due to the absence of symptomatic cerebrovascular
disease while 11.0% of patients with pathologically
Neuropathologic studies of patients with dementia have confirmed Alzheimer’s disease were misdiagnosed with
found that cerebrovascular disease and Alzheimer’s disease MID due to positive responses to HIS items referring to
frequently coexist [49 – 51], suggesting that ‘pure’ vascular vascular disease. The cases of pathologically confirmed
dementia may be relatively rare and that ‘mixed’ dementia MID who were misdiagnosed with Alzheimer’s disease had
may be more common than previously recognized. In a little of the clinical symptomatology usually associated with
relevant clinical study, Hénon et al. [52] investigated the MID (e.g., abrupt onset, stepwise deterioration, fluctuating
frequency of preexisting dementia in 202 stroke patients course), and, interestingly, none had a history of clinically
using an informant-based questionnaire and found that evident stroke. If we assume that those patients had
16.3% of those patients were demented prior to stroke onset, sufficient cerebral infarctions on pathologic study to be
providing support for the idea that preexisting Alzheimer’s diagnosed with MID, this finding raises questions about the
disease may be an important contributor to post-stroke role of ‘silent’ brain infarction in vascular dementia. As
dementia. suggested by Meyer et al. [56], clinically ‘silent’ recurrent
It has also been shown that concomitant cerebrovascular stroke may serve as a basis for gradually progressive
disease helps to determine the severity of dementia among cognitive decline, thus mimicking the stereotypic course of
patients with Alzheimer’s disease. Heyman et al. [53] a primary degenerative dementia such as Alzheimer’s
studied 74 patients with neuropathologic findings of disease, and it is possible that such decline may be
Alzheimer’s disease and 32 patients with Alzheimer’s prevented by the initiation of treatment to prevent stroke
disease and concomitant cerebral infarctions. They found recurrence.
that the severity of dementia was greater in patients with
Alzheimer’s disease and cerebrovascular lesions than in
patients with Alzheimer’s disease alone and that those 4. The cognitive profile of vascular dementia
patients performed significantly worse on measures of
confrontation naming and verbal fluency. In the Nun Study, 4.1. Vascular dementia versus Alzheimer’s disease
Snowdon et al. [54] assessed cognitive function and the
prevalence of dementia among 102 college-educated The ability to recognize a distinctive pattern of cognitive
women aged 76 to 100 years who later died. Among deficits attributable to cerebrovascular disease, or a
61 participants who met neuropathologic criteria for ‘cognitive syndrome,’ is of importance not only because it
Alzheimer’s disease, those with cerebral infarcts had poorer provides information regarding the clinical impact of varied
cognitive function and a higher frequency of dementia than brain lesions but also because it facilitates the determination
those without infarcts. Participants with lacunar infarcts in of the dementia subtype (e.g., vascular dementia versus
the basal ganglia, thalamus, or deep white matter had a Alzheimer’s disease), which can be helpful in patient
particularly high frequency of dementia compared with management [57]. Prior studies that have administered
those who did not have infarcts. Fewer neuropathologic comprehensive neuropsychological test batteries to patients
lesions of Alzheimer’s disease appeared to result in with dementia and identified differences in performance
dementia in those with lacunar infarcts in the basal ganglia, between patients with different dementia subtypes have
thalamus, or deep white matter than in those without such suggested that patients with vascular dementia exhibit
 D.W. Desmond / Clinical Neuroscience Research 3 (2004) 437–448 441

greater impairment of executive functions but superior evident in patients with cerebrovascular disease when
performance in memory testing relative to patients with concomitant Alzheimer’s disease is present, memory
Alzheimer’s disease [58], even early in the course of both impairment may also occur as a primary consequence of
disorders [59]. It has also been reported that vascular cerebrovascular disease, such as following a posterior
dementia is characterized by ‘patchy’ deficits [60], or cerebral artery territory infarction involving the medial
inconsistent patterns of relative strengths and weaknesses temporal lobe, or as a secondary consequence of a cognitive
between patients, and that patients with vascular dementia syndrome involving inattention due to primary executive
more frequently exhibit fluctuations in cognitive function dysfunction. Relevant to the latter point, Reed et al. [87]
than patients with Alzheimer’s disease [61]. performed neuropsychological testing and positron emis-
In patients with vascular dementia, the executive, or sion tomography to compare cognitively impaired patients
frontal lobe, functions that tend to be disproportionately with subcortical ischemic stroke with patients with
impaired include planning and sequencing [62 – 64], speed Alzheimer’s disease. They found that performance in
of mental processing [65,66], performance on unstructured memory testing was correlated with prefrontal metabolism
tasks [67], and attention [62,68]. Although it has been in stroke patients and left hippocampal and left temporal
reported that patients with vascular dementia exhibit greater lobe metabolism in patients with Alzheimer’s disease,
deficits on measures of verbal fluency than patients with suggesting that defects in working memory and executive
Alzheimer’s disease [64,68 – 72], most likely due to the function underlie episodic memory impairment in stroke
frontal lobe demands of those tasks, and that the motor patients while failure of storage mechanisms underlies
aspects of language production may be impaired in patients episodic memory impairment in patients with Alzheimer’s
with vascular dementia [73], primary language functions disease.
otherwise tend to be preserved. As noted by Censori et al.
[24], however, a number of vascular dementia studies have 4.2. Patterns of cognitive deficits by vascular
excluded patients with significant aphasia, thus reducing dementia subtype
their ability to characterize language functions accurately in
patients with that dementia subtype. Patients with vascular The pattern of cognitive deficits that is exhibited may
dementia also exhibit significantly more perseverations than vary dramatically in association with characteristics such as
patients with Alzheimer’s disease, particularly during tasks infarct location, number, and size. In part for that reason, it
that assess frontal lobe functions [71,74,75]. has been suggested that studies of cognitive impairment
Patients with Alzheimer’s disease have been reported resulting from cerebrovascular disease focus on more
to exhibit greater deficits than patients with vascular homogeneous subgroups of patients, particularly patients
dementia in functions mediated by posterior cortical with a subcortical, small-vessel basis for their deficits [88,
structures, such as the temporal and parietal lobes, including 89]. Although the leading edge of the cognitive syndrome of
memory [62,67 – 72,75 –80], with a faster rate of infor- subcortical vascular dementia typically involves executive
mation decay [79,81], a reduced ability to benefit from cues function due to lacunar infarctions affecting the structures
to facilitate retrieval [78,82,83], and a higher frequency of (e.g., thalamus, caudate) and connecting pathways of
intrusion errors [70,71,76– 78,84], as well as certain aspects frontal-subcortical circuits [90] and may resemble the
of language function, such as naming [62,73,77], which may syndrome seen in other subcortical diseases [91], it later
exacerbate their deficits on verbal memory tasks [80]. It has broadens to encompass other aspects of cognitive function
also been suggested that Alzheimer’s disease tends to affect in association with multiple recurrent subcortical strokes.
lexicon while vascular dementia tends to affect syntax [85]. Separate from these cognitive deficits, patients with
When patients with Alzheimer’s disease exhibit persevera- subcortical vascular dementia may exhibit disinhibited or
tions, they tend to be elicited by tests of semantic knowledge unusual behavior consistent with frontal lobe dysfunction as
[74]. Despite the findings of the above studies, however, it is well as other neuropsychiatric symptoms, such as apathy or
important to note that a number of prior studies have failed abulia, emphasizing the need for the rigorous and objective
to identify significant differences in patterns of cognitive assessment of behavior and mood in patients with
impairment between groups of patients with vascular cerebrovascular disease [92].
dementia and Alzheimer’s disease [86]. Single subcortical gray matter infarctions involving the
The role of memory impairment in the cognitive thalamus and caudate have been shown to serve as a basis
syndrome of vascular dementia has been controversial for cognitive impairment in case series [93 – 95], but it has
[57]. As reviewed above, memory impairment is recognized also been reported that certain patients who experience
to be a hallmark of Alzheimer’s disease, but its frequency in single small, deep white matter infarctions may exhibit
patients with vascular dementia is less clear. In part, that significant cognitive impairment. Specifically, the syn-
may be due to the emphasis that has been placed on the drome of ‘strategic infarct dementia’ was proposed as a
frequency of executive dysfunction resulting from either result of the observation of a series of six patients with
frontal lesions or disruption of frontal-subcortical pathways single small, deep white matter infarctions involving the
in such patients. Although memory impairment is typically inferior capsular genu that resulted in an abrupt change in
442 D.W. Desmond / Clinical Neuroscience Research 3 (2004) 437–448

behavior [96,97]. The acute cognitive syndrome featured described by Luria [102], while the latter lesion can produce
fluctuating alertness, inattention, memory loss, apathy, a syndrome that is often mistakenly termed an anomic
abulia, and psychomotor retardation, suggesting frontal aphasia but which actually involves a primary disorder of
lobe dysfunction. Neuropsychological testing in five memory. For that reason, despite the current controversy
patients with left-sided infarcts revealed severe verbal reviewed above, memory impairment separate from execu-
memory loss, while a right-sided infarct caused transient tive dysfunction can be a predominant feature in patients
impairment in visuospatial memory. Additional cognitive with cerebrovascular disease for reasons unrelated to
deficits consistent with dementia occurred in four patients. Alzheimer’s disease due to the vascular involvement of
Functional brain imaging in three patients showed a focal the same structures that Alzheimer’s disease tends to affect.
reduction in hemispheric perfusion, most prominent in the Regarding other subtypes of vascular dementia, hypo-
ipsilateral inferior and medial frontal cortex. It is likely that perfusion dementia can result from the coexistence of a
the capsular genu infarcts in these patients interrupted the variety of medical illnesses, such as congestive heart failure,
inferior and anterior thalamic peduncles, causing functional systemic hypotension, or pneumonia [103 – 105], which can
deactivation of the ipsilateral frontal cortex, supporting the cause the insidious onset and gradual progression of
idea that lacunar infarction can cause cognitive decline generalized cognitive deficits, thus mimicking the stereo-
through disconnection of thalamocortical white matter typic course of Alzheimer’s disease. In addition, although
tracts. dementia from bilateral internal carotid artery (ICA)
Other subtypes of vascular dementia have also been occlusions is a recognized syndrome [106,107], generally
recognized and they are worthy of note with regard to both thought to result from multifocal infarction in the
their similarities to and differences from the subcortical borderzone territory, consistent with the concept of MID
forms of vascular dementia that may result from one and associated with executive dysfunction when those
strategically located lesion or the cumulative effects of infarctions involve the anterior borderzone territory, a less
multiple subcortical lesions. For many years, MID [98] was commonly recognized mechanism for intellectual decline
the predominant subtype of vascular dementia in research from ICA occlusion is chronic ischemia due to hemo-
studies. As originally conceived, multiple completed dynamic insufficiency. Certain examples in the literature
thrombo-embolic infarctions were thought to cause a [108 –112] support the causal role of perfusion insufficiency
stereotypically stepwise course of cognitive decline and from bilateral ICA occlusions by demonstrating reversal of
dementia. Although some authors have suggested that MID intellectual deficits and improved cerebral perfusion
is associated with multiple lacunar infarctions [99], most following surgical intervention.
authors consider MID to be the result of cortical damage Finally, although cerebral hemorrhage is a less common
[100,101]. Paradoxically, a single large cortical infarction cause of dementia than ischemic cerebrovascular disease,
can result in less significant clinical consequences than a hemorrhagic dementia warrants consideration. When
single strategically located subcortical infarction because its hemorrhagic dementia results from multiple lobar hemor-
effects are restricted to the region of infarction, while a rhages in a setting of hypertension or amyloid angiopathy
strategically located subcortical infarction can have clinical [113], the clinical course and consequences associated
effects remote from and disproportionate to its location and with the lesions may be similar to those seen in MID.
size due to the metabolic abnormalities that may result from Amyloid angiopathy frequently exists in combination with
pathway disruption. Thus, while some patients with Alzheimer’s disease [114,115], however, which would have
multiple infarcts may meet criteria for MID, other patients a significant impact on the cognitive presentation of the
with multiple infarcts may exhibit features of multiple focal patient. Similarly, as reviewed above, studies suggest that
stroke syndromes, such as aphasia and spatial neglect, while it is quite common for cerebrovascular disease and
failing to fully meet operationalized criteria for dementia. In Alzheimer’s disease to coexist, such as when a patient
addition, unless an MID patient has a frontal lobe lesion, with incipient or frank Alzheimer’s disease experiences a
executive dysfunction should not predominate in the clinical stroke. In most of those cases, the clinical picture is
picture. When patients with multiple infarcts do meet primarily determined by Alzheimer’s disease, not cerebro-
dementia criteria, it is typically due to the combined effects vascular disease.
of a number of focal stroke syndromes that compromise
functional competence. 4.3. Cognition and white matter lesions
It should be noted that certain single cortical infarcts can
have dramatic clinical consequences, however, such as Most prior studies of white matter lesions and cognitive
those in the anterior cerebral artery territory affecting the function have focused on the risk associated with varying
medial frontal lobe and those in the posterior cerebral artery severities of white matter lesions, while fewer studies have
territory affecting the medial temporal lobe, particularly investigated the importance of the location of the lesions.
when they are located in the left hemisphere [13]. The Typically, studies that have administered neuropsychologi-
former lesion can also produce executive dysfunction, and, cal test batteries have recognized deficits in executive
in more severe cases, the ‘oneroid state’ that has been function in association with more severe white matter
 D.W. Desmond / Clinical Neuroscience Research 3 (2004) 437–448 443

lesions [116 –119]. In one influential study, Boone and co- 5. Clinical course of vascular dementia
workers [120] examined a sample of 100 subjects between
the ages of 45 and 83 who were free of neurologic disease. Longitudinal epidemiologic studies have investigated the
On MRI, 46% of those subjects had no white matter lesions, frequency of delayed dementia as well as the role of
48% had minimal or moderate white matter lesions, and 6% dementia as a predictor of other adverse outcomes. Those
had severe white matter lesions. Those three groups studies have found that delayed dementia is common among
received virtually identical mean Mini-Mental State Exam- patients with cerebrovascular disease [44,105,124 – 129],
ination total scores, all of which fell above 29 out of a particularly in a setting of comorbid illnesses that might
possible score of 30, and they did not differ significantly result in cerebral hypoxia or ischemia [103 –105,130], and
with regard to their scores on neuropsychological measures that stroke-related dementia is a significant predictor of
of general intelligence, verbal and nonverbal memory, adverse outcomes such as recurrent stroke [3] and death
visuospatial function, or language. Significant deficits on [4 –6]. The findings of these and other investigations permit
measures of attention and other executive functions were the complex natural history of dementia after stroke to be
detected in the group of subjects with severe white matter characterized in perhaps its most stereotypic form. First,
lesions, however, suggesting that a threshold for the total following a period of indeterminate length in which
area of the white matter lesions must be surpassed before cerebrovascular disease and any associated cognitive
cognitive deficits occur. When the extent of the white matter deficits are absent, patients may develop mild cognitive
lesions is large, multiple brain regions tend to be affected, deficits in association with certain vascular risk factors, such
which may be of differing importance to cognitive function. as diabetes mellitus. Next, those vascular risk factors may
Thus, it is likely that if a threshold exists, it varies in result in a clinically evident or ‘silent’ first cerebral
association with the specific locations of the white matter infarction, exacerbating those baseline cognitive deficits.
lesions, with a smaller total area of white matter lesion being Following that first cerebral infarction, one or more
required to produce cognitive deficits when certain critical clinically evident or ‘silent’ recurrent strokes, as well as
locations are involved. certain comorbid medical conditions, such as those that
might result in cerebral hypoxia or ischemia, may then
Lesion location has been examined by de Groot and
cause further cognitive decline and dementia. Finally,
co-workers [121] who performed MRI on 1,077 subjects
dementia may then serve as a risk factor for additional
between the ages of 60 and 90 randomly selected from the
recurrent strokes, further cognitive decline, and death. It is
general population and also administered multiple measures
important to note that certain of the components of this
of psychomotor speed and memory. They found that both
dynamic process may serve as both a risk factor and an
periventricular and subcortical white matter lesions were
adverse outcome, with dementia, for example, serving as
associated with poorer performance on all cognitive
both a consequence of and a risk factor for recurrent stroke.
measures, particularly those related to psychomotor speed.
In certain cases, the nature of the course of cognitive
They further noted that this association was maintained for
decline can be informative with regard to the determination
periventricular white matter lesions while adjusting for the of the dementia subtype. Specifically, issues such as
presence of subcortical white matter lesions, while the whether the onset of cognitive decline is abrupt or gradual,
association was not maintained for subcortical white matter whether it persists, and whether its course is stepwise or
lesions while adjusting for the presence of periventricular gradually progressive are relevant. Many studies have
white matter lesions. Among the few studies that have also demonstrated that the typical course of decline in patients
investigated the relative importance of periventricular and with Alzheimer’s disease is gradual and progressive, but it is
subcortical white matter lesions locations, Ylikoski and probably not truly linear and may vary in rate between and
co-workers [122] and Fukui and co-workers [123] have within patients in association with the onset of certain
reported a similar association between periventricular white clinical features, such as extrapyramidal signs [131,132]. In
matter lesions and processing speed, which may be due to contrast, little effort has been made to document the
the high density of pathways running through periventri- presumed stepwise or fluctuating course of decline in
cular regions and interconnecting distant cortical structures. vascular dementia. Consistent with the concept of MID [98]
Although prior studies have suggested that cognitive and the results of certain prior prospective studies of risk
deficits are associated with increasing severities of white factors for incident vascular dementia [133], that stepwise
matter lesions, it is also likely that the number of subcortical or fluctuating course has been thought to result from
infarctions will increase and tend to be masked by more multiple recurrent strokes, each of which may cause an
extensive white matter lesions and serve as a direct cause of acute change in the patient’s level of cognitive function
those cognitive deficits. In addition, it is important to note followed by a period of stability or partial recovery.
that certain concomitant neurologic disorders, such as Fischer et al. [134] studied the course of cognitive
Alzheimer’s disease, are also associated with white matter decline in a sample of patients with either MID or
lesions and can significantly influence the clinical presen- Alzheimer’s disease. As expected, they found that 94% of
tation of the patient. patients with Alzheimer’s disease experienced an insidious
444 D.W. Desmond / Clinical Neuroscience Research 3 (2004) 437–448

onset of their dementia syndrome and that 81% of patients the assumption that many of them may have a ‘mixed’
with that dementia subtype exhibited a gradually progress- dementia. Given that Alzheimer’s disease results in the
ive course of decline, with 81% of patients with Alzheimer’s widespread cholinergic deficits, it was hypothesized that
disease exhibiting both of those stereotypic characteristics. pharmacologic enhancement of acetylcholine levels might
Surprisingly, 54% of patients with MID experienced the prove to be an effective treatment. There are now four
insidious onset of their symptoms and 50% of patients with cholinesterase inhibitor drugs approved by the Food and
that dementia subtype experienced a gradually progressive Drug Administration for use in patients with Alzheimer’s
course of decline. Only 34% of patients with MID exhibited disease, including tacrine hydrochloride, donepezil hydro-
both of the stereotypic characteristics of an abrupt onset of chloride, rivastigmine tartrate, and galantamine hydrobro-
dementia followed by a stepwise course of decline. mide. Clinical trials are now underway to study the effects
It has been reported that certain stroke patients exhibit a of some of these agents, including donepezil [144],
gradually progressive course of cognitive decline due to rivastigmine [145], and galantamine [146], in patients
clinically ‘silent’ recurrent stroke [56] or exposure to with vascular dementia.
disorders that might result in cerebral hypoxia or ischemia Other classes of agents could also be beneficial in
[105]. In addition, one-third [135] to one-half [125] of vascular dementia. Neuroprotective strategies might be best
patients with pathologic evidence of vascular dementia lack for the early, ‘brain-at-risk’ stage, and limited trials using
a history of stroke. Gradually progressive decline in patients the NMDA-receptor antagonist memantine have been
with stroke may also be indicative of concomitant promising [147,148]. Clinical trials have also investigated
Alzheimer’s disease. Comparative studies of patients with the use of statins, which are conventionally prescribed to
those two dementia subtypes are warranted in order to treat hypercholesterolemia, in the treatment of Alzheimer’s
determine whether features of the course of cognitive disease [149,150]. Statins might prove to be particularly
decline can reliably facilitate differential diagnosis. valuable in the treatment of vascular dementia because of
the increased frequency of hyperlipidemia among those
patients. Nimodipine, a calcium-channel blocker, is fre-
6. Treatment of patients with vascular dementia quently prescribed in Europe for cognitive impairment and
may be beneficial in the treatment of patients with certain
Given the financial costs associated with cognitive dementia subtypes [151], although patients with subcortical
impairment resulting from cerebrovascular disease [136, vascular dementia may derive more benefit than vascular
137], which are likely to be significantly higher than the dementia patients in general [152,153]. Nonsteroidal anti-
costs associated with Alzheimer’s disease or the costs of inflammatory drugs, such as Cox-2 inhibitors and ibuprofen,
medical care for the nondemented elderly [136], and have been proposed as possible protective agents for
recognizing the societal burden associated with dementia Alzheimer’s disease [154,155], but their utility in the
of any etiology, the development of an effective treatment treatment of vascular dementia is unclear [155]. Finally,
for vascular dementia would be of great importance. Two certain studies have suggested that treatment with antiox-
complementary approaches to the treatment of patients with idants is safe, and might have some benefit in slowing
vascular dementia are worthy of consideration. functional decline in patients with Alzheimer’s disease
First, since patients with vascular dementia may be at an [156,157].
elevated risk of stroke [3,138], which could exacerbate their
baseline cognitive deficits, treatment for the prevention of
stroke [139] should be considered. That treatment could Acknowledgements
include agents such as aspirin or warfarin, which tend to be
underutilized in patients with dementia [140], unless This work was supported by Grants R01-NS26179 and
contraindicated for specific patients due to characteristics K07-AG00959 from the National Institutes of Health.
such as bleeding disorders, a tendency to fall, or severe
dementia leading to erratic compliance. In addition, a
variety of vascular risk factors have been implicated in both
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