Etiology, clinical manifestations, and diagnosis of vascular dementia
Clinton B Wright, MD, MS
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INTRODUCTION — Vascular dementia (VaD) has a long history; however, our
current understanding of this entity is in a considerable state of flux.
VaD was first described in the late 19th century by Binswanger and Alzheimer who
also recognized and described a variety of underlying pathologic mechanisms
including the role of multiple infarctions and chronic ischemia. For nearly 50 years
this was held to be the predominant form of dementia. Subsequently, pathologic
studies demonstrated that the amyloid plaques and neurofibrillary tangles of
Alzheimer's disease (AD) were much more common in the brains of the demented
elderly than previously thought [1]; chronic ischemic injury was thought to be quite
rare, and VaD was understood as the sequelae of recurrent strokes or "multi-infarct
dementia" (MID) [2]. With the advent of sophisticated neuroimaging techniques,
computed tomography (CT) and magnetic resonance imaging (MRI), in the latter
part of the twentieth century, the extent of chronic ischemic injury in the brain was
reappreciated, and interest in the role of vascular disease, including the role of
progressive ischemic injury, on cognitive decline reemerged.
Despite this surge of interest, certain issues impede progress. There are no
pathologic criteria for the diagnosis of VaD, as there are for AD. A number of clinical
diagnostic criteria exist but are poorly validated and inconsistently applied.
Even basic terminology requires clarification. As an example, the traditional definition
of dementia was originally developed in the context of AD in which memory loss
occurs prominently and early on in the disease. However, in patients with cognitive
deficits ultimately attributable to VaD, memory impairment appears somewhat later,
and these patients may have significant cognitive disability long before they meet
criteria for dementia.
This has led to the proposed concept of "vascular cognitive impairment" or VCI [3,4].
This term was originally conceived as an umbrella term for all cognitive disorders
attributable to vascular disease. However, others propose and use VCI to identify
only those patients with cognitive disorders attributable to vascular disease who do
not meet the definition of dementia. This is somewhat analogous to the more
accepted term "mild cognitive impairment" or MCI [5]. Others use the term
"cognitive impairment, no dementia" or CIND. Criteria as to what deficits qualify as
cognitive impairment are somewhat loose [5]. Some authors still use the term
Binswanger's disease to apply to VaD or a subset of VaD.
At the foundation of some of these problems is the fact that cerebrovascular disease
is itself a heterogeneous disorder, with a variety of pathophysiologic mechanisms
and clinical manifestations. At present, the entity of VaD is best understood as a
heterogeneous syndrome rather than a distinct disorder, in which the underlying
cause is cerebrovascular disease in some form and its ultimate manifestation is
dementia.
This topic will review the etiology, pathogenesis, clinical manifestations, and
diagnosis of vascular dementia. The prevention, treatment, and prognosis are
discussed separately. (See "Treatment and prevention of vascular dementia").
EPIDEMIOLOGY — Using traditional definitions, vascular dementia (VaD) is the
second most common form of dementia after Alzheimer's disease (AD) in most
series, and it makes up 10 to 20 percent of cases in North America and Europe [6,7].
The relative preponderance of the two disorders may be reversed in other countries,
such as Japan and China [8].
Differences in screening methods and diagnostic criteria lead to variability in
reported prevalence and incidence, but some trends seem consistent. Estimated
prevalences of VaD vary from 1.2 to 4.2 percent of individuals over 65 years [9]. In
the European collaborative study of population-based cohorts, the pooled estimate of
VaD prevalence was 1.6 percent in those over the age of 65 [6]. The prevalence
increased successively with increasing age deciles to about 3.6 to 5.8 percent in men
and women, respectively, over the age of 90 years. In Canada, similar age trends
were seen for VaD as well as the entire group of vascular cognitive impairment
(VCI); the latter increased from 2.0 percent in those 65 to 74 years to 13.7 percent
in those over 85 years [10].
Age-adjusted incident rates (IRs) are overall estimated at 6 to 12 cases per 1000
person years over the age of 70 years [9]. In Canada, the incidence increased from
0.9 per 1000 person years in those aged 65 to 69 years to 6.74 in those greater than
90 years [11]. Similar trends were seen in Europe [7] and the United States [12]. A
meta-analysis of 23 studies from around the world, despite much variability between
studies, showed an overall trend for an exponential increase of incident VaD with age
[13].
Some prevalence and incidence data suggest an overall higher preponderance of the
disease in men [7], while others note this only in the younger age groups [6,13],
and still others note no gender differences [10-12,14,15]. One study found no
significant difference in IRs in blacks versus whites [12]; another found a higher
incidence in blacks [14].
While it is expected that VaD would share risk factors with cerebrovascular disease,
the evidence is not compelling. Variable degrees of association and, in some studies,
no associations have been found for hypertension, diabetes and insulin resistance,
dyslipidemia, and heart disease with VaD in population-based cohorts [11,14,16-21].
These differences might be partly explained by differences in control groups; some
studies specifically excluded patients with cerebrovascular disease and/or other
forms of dementia, while others did not.
Dementia after stroke — A number of studies have demonstrated a high incidence
of dementia after stroke with rates reported around the world ranging from 6 to 32
percent in patients followed from three months to 20 years [22-29]. In one study
that used a control group, stroke was associated with a 3.83 relative risk (RR) for
dementia compared with nonstroke hospitalized controls [23]. In contrast, a
prospective community-based sample of 99 patients with mild to moderate
nonaphasic first ever stroke found an increase in the risk of cognitive impairment no
dementia (CIND) (37.5 versus 17.6 percent) but no significant difference in the risk
of dementia compared with controls at one year [30].
Age is nearly uniformly found to increase the risk of dementia after stroke. Other risk
factors commonly, but not uniformly, identified in this setting include increased
severity of the index stroke, atrial fibrillation, the presence of white matter disease
and cortical atrophy on imaging, multiple clinical events or lesions on neuroimaging,
hypertension, and diabetes mellitus [24-29,31]. Some studies indicate that stroke in
the left hemisphere, particularly those with associated aphasia, is a risk factor.
Evidence of premorbid cognitive impairment was also a risk factor. Most studies did
not identify gender as a risk factor, but two identified a higher incidence in females
[23,27] and one in males [29].
While some studies indicate that most of these cases accrue early after stroke
[14,32], others have demonstrated fairly steady accrual of cases over years of
annual screening evaluations [22,24,29]. Most studies did not identify cases as AD or
VaD; in those studies that did, VaD rather than AD was the diagnosis in most cases
(51 to 66.7 percent) [22,24,32].
Silent brain infarction — Silent brain infarction is also a risk factor for
subsequent cognitive decline. In one study, nondemented patients without stroke
history but with evidence of cerebral infarction on magnetic resonance imaging (MRI)
had double the risk of dementia over five years of follow-up compared with controls
with normal MRIs [33]. The presence of multiple silent infarctions was more strongly
associated with subsequent cognitive decline than single lesions, and the decline in
cognitive function was restricted to those with accrual of silent infarcts on follow-up
imaging. The presence of white matter changes and subcortical atrophy also was
associated with risk of dementia. A clinicopathologic study of 72 individuals without
Alzheimer pathology found a significant correlation between clinically silent thalamic
and basal ganglia lacunes and clinical dementia rating scores [34].
ETIOLOGY AND PATHOPHYSIOLOGY — Three common pathological entities
contribute substantively to vascular dementia (VaD):

Large artery infarctions, usually cortical, sometimes also or exclusively
subcortical in location.

Small artery infarctions or lacunes, exclusively subcortical, in the distribution
of small penetrating arteries, affecting the basal ganglia, caudate, thalamus,
and internal capsule as well as the cerebellum and brainstem. (See "Lacunar
infarcts").

Chronic subcortical ischemia occurring in the distribution of small arteries in
the periventricular white matter and leading to selective loss of tissue
elements in order of their selective vulnerability - neuron, oligodendrocyte,
myelinated axon, astrocyte, and endothelial cell [35].
The small artery disease underlying both lacunar infarctions and subcortical ischemia
is most commonly attributed to lipohyalinosis or microatheroma affecting the small
penetrating arteries. These are particularly prevalent in the elderly and those with
hypertension and/or diabetes. Sharing a primary vascular pathology, it is not
surprising that lacunar infarctions and chronic ischemic changes in the white matter
more often occur together than apart. Some subcategorize this entity as subcortical
VaD, and the term Binswanger's disease generally refers to this subset of VaD
patients.
Each of the above findings is common. They are not mutually exclusive and in fact
share underlying risk factors. Any one or more may be present in a patient with VaD
and also may be found in patients with Alzheimer's disease (AD) and in
nondemented individuals.
While intracerebral hemorrhage is potentially a contributor to VaD, it is not generally
described, perhaps because these are less likely to be recurrent events.
Subarachnoid hemorrhage, cognitive impairment after cardiac bypass surgery,
hypoxic ischemic encephalopathy, and watershed infarction in the setting of profound
hypotension are vascular events that may cause permanent, devastating cognitive
impairment. However, these are more appropriately considered under the rubric of a
"static encephalopathy" rather than dementia because of the lack of expected
progression.
While the volume of damaged tissue is clearly important in producing VaD [36], the
distribution of injury is a critical component. Certain sites in the brain are "strategic"
for producing deficits that cause, simulate, or add to a dementia syndrome. These
may be cortical (hippocampus, angular gyrus, gyrus cinguli, frontal lobe) or
subcortical (thalamus, fornix, basal forebrain , caudate, globus pallidus and the genu
or anterior limb of the internal capsule) [37,38]. Because of the prominent and
disabling cognitive effects of a single stroke in these areas, these patients are often
labeled as having "strategic infarct dementia," although in such cases the course
may be static rather than progressive [39].
The potential causes of cerebral infarcts, both large and small, are numerous [5].
(See "Overview of the evaluation of stroke"). Two entities, cerebral amyloid
angiopathy and CADASIL, require specific discussion in this context.
Cerebral amyloid angiopathy — Cerebral amyloid angiopathy (CAA) is a disorder
caused by accumulation of amyloid in cerebral vessels, and it leads to multiple lobar
hemorrhages, microbleeds, or infarctions. CAA is prevalent in those with AD, and
dementia in these individuals has been traditionally ascribed to AD. However,
extensive CAA can also cause ischemic white matter damage, a complication that is
presumably related to diffuse narrowing of penetrating cortical vessels by amyloid
deposits [40,41]. These patients can present with VaD. Population-based autopsy
series suggest that CAA is associated with cognitive impairment even after
controlling for age and AD pathology [42-44]. (See "Cerebral amyloid angiopathy").
Cadasil — Linked to the notch 3 gene on chromosome 19, cerebral autosomal
dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)
produces a subcortical VaD syndrome developing in the fifth to seventh decades.
Pathology reveals extensive lacunar infarctions and white matter ischemia from
occlusion of vessels by disease-specific granular material. The simultaneous
prevalence of migraine and the absence of traditional atherosclerotic risk factors in
multiple affected family members suggest this diagnosis [5].
Mixed dementia — Mixed dementia, or AD with cerebrovascular disease, refers to
the concurrence of AD and VaD and is increasingly recognized as a condition
requiring independent consideration. It is often difficult to distinguish AD and VaD let
alone determine which is etiologically most important when both are present.
The high prevalence of both AD and VaD are such that their concurrence is also
common. In autopsy series, vascular pathology was found in 34 to 50 percent of
those with pathologic AD [45-47]. About one-third of patients diagnosed with VaD
will have AD pathology at autopsy [47]. Using the relatively loose definitions of
pathologic criteria for AD and VaD, patients with clinical dementia are in fact more
likely to have combined pathology rather than either AD or VaD in isolation [36].
In addition to their frequent coincidence, there is increasing evidence that AD and
VaD may share etiologic or pathogenic features and/or influence each other's course.
In some studies, AD and VaD appear to share vascular risk factors including
hypertension and hyperlipidemia [48,49] and possibly diabetes and smoking as well
[50]. A population-based cohort of 599 85-year-old individuals found that the
baseline burden of generalized atherosclerosis was associated with cognitive decline
over a five-year follow-up period [51]. The apolipoprotein E genotype has been
associated with cardiovascular disease as well as AD [45], and, more specifically,
with subcortical microvascular changes in a neuropathologic study in patients with
AD [52].
A number of studies have also associated certain cerebrovascular manifestations with
AD. A small autopsy series of 10 AD patients and 10 nondemented controls of similar
age and gender mix found that patients with AD had a significantly higher burden of
atherosclerosis in both the circle of Willis and leptomeningeal arteries [53]. The
presence of large vessel atherosclerosis (but not cerebral infarction) was associated
with an increased frequency of neuritic plaque but not neurofibrillary tangles in a
study of 1054 autopsies from the US National Alzheimer's Coordinating Center [54].
These findings suggest that atherosclerosis might lead to neuritic plaque formation
by some pathway other than infarction, perhaps by directly influencing amyloid
deposition. Asymptomatic cervical carotid disease has also been associated with
cognitive impairment independent of other vascular risk factors [55]. From these and
other studies, some conclude that a vascular mechanism may be a primary etiologic
factor in AD [56].
Some speculate that in the setting of cerebrovascular disease, a smaller degree of
AD pathology is required to produce dementia. In the Nun study, among the 61
patients meeting neuropathologic criteria for AD, clinical dementia was more likely in
patients with compared to those without infarctions (OR 20.7) [57]. Fewer
neuropathologic lesions of AD appeared to result in dementia if infarction was
present. In the 41 patients without any AD pathology, infarction was less strongly
associated with cognitive impairment or dementia. Similarly, from a communitybased registry of incident dementia, autopsy results in 124 individuals revealed 30
with "pure" AD and 18 with AD pathology and significant vascular lesions [58]. After
adjusting for education and Mini-Mental State Examination (MMSE) scores, pure AD
cases had significantly more severe AD pathology than AD plus vascular cases.
While these findings suggest an interaction between infarction and AD pathology, the
Religious Orders Study [59] found otherwise. Clinical neuropathologic correlation in
153 deceased clergy with and without dementia followed prospectively in life found
that cerebral infarctions and AD pathology contributed independently in an additive
fashion to the likelihood of dementia.
CLINICAL FEATURES — Given the diverse pathologies, it is not surprising that the
clinical manifestations of vascular dementia (VaD) are diverse. Clinicians and
investigators have long recognized two clinical patterns - one in which the
predominant pathology and clinical features are cortical and one in which they are
subcortical. While in themselves heterogeneous, these two patterns nonetheless
have distinct features.
In primarily cortical VaD, cognitive features are specific to the areas affected:

Medial frontal: executive dysfunction, abulia, or apathy. Bilateral medial
frontal lobe infarction may cause akinetic mutism.

Left parietal: aphasia, apraxia, or agnosia.

Right parietal: hemineglect (anosognosia, asomatagnosia), confusion,
agitation, visuospatial and constructional difficulty.

Medial temporal: anterograde amnesia.
Cortical branch occlusions are often caused by embolism from the heart or large
arteries and may present with clinical stroke. However, when the superior division of
the middle cerebral artery is not involved, hemiparesis may not be an obvious signal
to its sudden appearance. Onset may appear more insidious as a result, and it is not
uncommon for the patient to improve again before the next event. The course is thus
often, but not necessarily, perceived as fluctuating or stepwise. As few as one-third
of patients with multi-infarct dementia (MID) experience both an abrupt onset and
stepwise deterioration [60].
In subcortical pathology, both lacunar infarctions and chronic ischemia affect the
deep cerebral nuclei and white matter pathways. These often disrupt frontal lobe and
other cortico-cortico circuits, producing deficits attributable to remote brain areas
[39,61]. Characteristic features include:







Focal motor signs
Early presence of gait disturbance (marche a petit pas or magnetic, apraxic
gait or Parkinsonian gait)
History of unsteadiness and frequent, unprovoked falls
Early urinary frequency, urgency, and other urinary symptoms not explained
by urologic disease
Pseudobulbar palsy
Personality and mood changes, abulia, apathy, depression, emotional
incontinence
Cognitive disorder characterized by relatively mild memory deficit,
psychomotor retardation, and abnormal executive function
The course of subcortical VaD may be gradual or stepwise and either slow or fast in
decline.
DIAGNOSIS — The initial approach to a patient with evidence of cognitive decline is
presented elsewhere. (See "Evaluation of cognitive impairment and dementia"). The
specific approach in patients with suspected vascular dementia (VaD) is presented
here.
Neuroimaging — While not essential in the evaluation of all patients with dementia,
neuroimaging should be performed in patients with suspected VaD by virtue of
stroke history, vascular risk factors, abnormal neurologic examination, or a course or
symptom complex atypical for AD. MRI is significantly more sensitive than CT;
however, if sufficient evidence of vascular pathology is seen on CT, an MRI may not
be necessary. MRI will show the fundamental hallmarks of VaD including cortical and
subcortical infarctions as well as the presence of subcortical ischemic changes or
leukoaraiosis. However, radiographic criteria alone have been shown to be
inadequate at differentiating between poststroke patients with and without dementia
[62].
White matter lesions — Cerebral white matter lesions (WML) or leukoaraiosis on
brain MRI is understood to be a nonspecific radiologic finding. These changes are
somewhat ubiquitous in the normal as well as the demented elderly population.
Radiologic WML do not define a single neuropathology and are associated with
nonvascular pathology including infections, demyelination, neoplasia, and metabolic
disorders. In VaD, WML are believed to be related to cerebral hypoperfusion or
ischemia [63]. WML are significantly associated with age and hypertension [63-68]
as well as with elevated homocysteine levels [69]. They are more common in
patients with ischemic stroke and are associated with the incidence of silent
infarctions [64,70].
Studies have not consistently shown a relationship between the extent of WML and
the presence of dementia. Reasons for this include the fact that the traditional
definitions of dementia may be an insensitive measure of cognitive change in this
setting. WML do appear to more consistently affect subsets of cognition, in particular
tests of executive control [71]. The fact that WML are more reliably associated with
increased risk of cognitive decline and dementia rather than prevalent dementia is
consistent with this [33,61,72-74].
Methods quantifying WML severity are inconsistent and often subjective.
Nonetheless, volumetric changes do indicate that the greater brain volume affected
by such changes, the greater the risk of concurrent or future cognitive decline [75].
In addition, increased white matter lesion burden on serial MRI scans has been
associated with accelerated cognitive decline [76]. Evidence from several studies
indicates that cognitive impairment is better associated with periventricular rather
than subcortical WML [61,70,74,77]. This observation suggests that disruption of
periventricular long association fibers connecting distant cortical regions causes
greater cognitive impairment than disruption of subcortical association arcuate fibers
[74,78].
Diagnostic criteria — A number of clinical criteria have been published for the
diagnosis of VaD. The earliest of these, the Hachinski Ischemic Score (HIS; show
table 1) is still used today and was established to distinguish multi-infarct dementia
(MID) from AD rather than as independent diagnostic criteria for VaD. The HIS items
highlight clinical features specific to VaD, such as stepwise deterioration, fluctuating
course, hypertension, history of stroke, and focal neurologic symptoms [79]. Data
from pathologically verified cases show that an HIS of seven or more has a
sensitivity and specificity of about 90 percent for VaD and good inter-rater reliability
[79]. However, differentiating VaD from mixed dementia is a difficult problem with
all the available criteria. This is no less true of the HIS, in which the specificity in
separating either VaD or AD from mixed dementia has been found to be 17.2 and
29.4 percent, respectively [79].
There are four widely used independent diagnostic criteria for VaD:




Diagnostic and Statistical Manual of Mental Disorders (DSM-IV)
State of California Alzheimer's Disease Diagnostic and Treatment Centers
(ADDTC)
National Institute for Neurological Disorders and Stroke-Association
Internationale pour la Recherche et l'Enseignement en Neurosciences
(NINDS-AIREN)
International Classification of Diseases, tenth edition (ICD-10)
The criteria vary by:






How dementia is defined
What types of CVD are included
What other disorders must be specifically excluded
Whether focal examination findings are required
Whether the presence of vascular disease must be corroborated by
neuroimaging
Whether a temporal relationship between stroke event and cognitive decline
is required
The NINDS-AIREN criteria are the most detailed and most widely used (show table
2). In all but the ADDTC criteria, a memory disorder is a requirement in addition to
the involvement of other cognitive domains [80]. Both NINDS/AIREN and ADDTC rely
on neuroimaging confirmation of cerebrovascular lesions and require a temporal
association but not an anatomic association between cognitive/functional decline and
stroke event. A number of studies have shown that the different criteria do not
identify the same patients, leading to variations in published prevalence and
incidence estimates as well as treatment effects [79,81-86]. As an example, in the
assessment of 167 patients with probable dementia, the number of cases diagnosed
with VaD were: DSM-IV = 45, ADDTC = 23, NINDS-AIREN = 12, and ICD-10 = 21
[81]. Only five cases met criteria for VaD using all four diagnostic tools.
Overall, the HIS and DSM-IV criteria appear the most liberal in the identification of
VaD and the NINDS-AIREN the most conservative. In addition, data suggest interrater reliability (kappa = 0.44 to 0.61) is only moderate for these criteria [82].
Because of its more distinctive and perhaps more uniform clinical profile, for which
the above criteria may be insensitive, separate criteria for subcortical VaD have been
proposed. This requires neuroimaging evidence of subcortical vascular pathology and
a typical neuropsychiatric profile [87].
While necessary for research studies, clinical criteria that distinguish VaD from AD or
mixed dementia seem less clinically imperative. In the evaluation of patients with
dementia, it may be more important to identify a potential contribution from vascular
pathology rather than to specifically diagnose VaD. The HIS is well suited for this
purpose.
Neuropsychological testing — Formal neuropsychological testing quantitates the
degree of cognitive impairment and the domains involved in order to provide a
baseline measurement to follow the course of disease and response to treatment.
Testing can also help detect cognitive patterns suggestive of certain disorders such
as VaD, Alzheimer's disease (AD), Lewy Body disease, and frontotemporal dementia.
One review found that patients with VaD have similar deficits compared with AD
patients (on tests of language, construction, and memory registration) but are
significantly less impaired on tests of recognition memory and more impaired on
measures of executive functioning [88]. Executive functioning is the ability to
conceptualize all facets of an activity and translate that into appropriate and effective
behavior; tests of this domain might include trail making and the digit symbol test
[89]. Deficits in this area are common to all dementias but are distinctive in VaD, in
that measurable deficits often occur prior to the diagnosis of dementia, correlate best
with neuroimaging findings, and cause most of the early impairments prior to the
development of severe memory loss [90]. These tenets have not been well validated
with clinical neuropathologic studies.
When attempting to distinguish static cognitive deficits after a stroke from dementia,
serial neuropsychological testing, usually annually, is often invaluable. Deficits
detected on neuropsychological tests can frequently be helpful clinically and guide
decisions regarding independent living, safety restrictions, and the like.
Testing for underlying vascular pathology — When cerebral infarction occurs or
is identified on neuroimaging, evaluation to define a specific stroke subtype or
etiology should be initiated. (See "Overview of the evaluation of stroke"). At a
minimum, in the typical elderly individual with VaD, patients should have carotid
Doppler ultrasound or other carotid imaging if strokes in that territory have occurred.
Work-up for cardiogenic emboli usually includes an echocardiogram and often a
holter monitor. Patients should be screened for usual risk factors including
hypertension, diabetes, and hyperlipidemia. These are recommended on the basis
that such testing leads to effective preventative strategies for recurrent stroke, but
this approach has not been shown to improve prognosis in patients with or at risk for
VaD per se.
Specific testing for the more unusual causes of stroke and VaD should be guided by
specific circumstances that make these disorders suspect (an unusual situation). For
patients with a history suggestive of CADASIL, a commercially available genetic test
is available.
SUMMARY AND RECOMMENDATIONS — While considerable uncertainty continues
to surround vascular dementia (VaD), the following summarizes current
understanding and offers some pragmatic suggestions for evaluation.

The presentation of cognitive impairment in VaD may be quite distinct from
Alzheimer's disease (AD), especially early in the disease course, with
prominent deficits in executive dysfunction causing significant disability, even
while memory impairment is quite mild and before the patient reaches criteria
for dementia. (See "Clinical features" above).

Neuropsychological testing can be helpful to better profile the nature and
severity of the cognitive deficits and chart disease course in VaD. (See
"Neuropsychological testing" above).

There is considerable overlap between AD and VaD with regard to comorbidity
as well as shared risk factors and even pathogenesis. The combination of
pathologies may be more common than either in isolation. (See "Mixed
dementia" above).

There are no uniform diagnostic criteria for VaD. Evidence of prominent
executive dysfunction, a stroke history, vascular risk factors, and a high
Hachinski Ischemic Score (show table 1) should suggest either the diagnosis
of VaD or AD with cerebrovascular disease and prompt a neuroimaging study.
(See "Diagnosis" above).
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