VOL 340: SEPT 12, 1992
Preventable
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645
senility: a call for action against the
vascular dementi as
VLADIMIR HACHINSKI
Introduction
By the age of 65-74 years, 3% of the population have
some cognitive impairment; by 85, nearly half may be
demented.' Vascular dementia is claimed to be the leading
cause of cognitive impairment among elderly people in
Russia and Japan, and second to Alzheimer's disease in the
western world.i-' In Alzheimer's
disease the cortical
microvasculature is abnormal, making it also, in a sense, a
vascular dementia;" whether the vascular changes contribute
to the cognitive impairment remains unclear. The only
major cause of dementia that is preventable is the syndrome
of multi-infarct dementia. Although its precise. incidence
remains to be determined it is common. Yet little research is
being done on the vascular dementias, whch is surprising
and disappointing in view of the growing number of
measures for preventing stroke.V
more can be seen than understood. The most striking
example is the identification of white-matter changes in
elderly people, particularly those with dementia. Such
changes have been uncritically attributed to ischaemia.
Binswanger's disease, which is neither Binswanger's nor a
disease,'? is invoked with unjustified frequency since the
label is seldom supported by pathological data. Such
white-matter changes occur in over 40% of Alzheimer
patients'S and in over 80% of individuals with multi-infarct
dementia," as determined by CT of the brain. The old idea
of chronic ischaemia killing neurons
(gray matter)
resurfaced as ischaernic damage to their myelin-sheathed
extensions (white matter), with no more evidence for this
than for the original idea. However, white-matter changes
are common, vascular risk factors are treatable, strokes are
preventable, so the vascular dementias need to be addressed
because the solutions matter.
Background
Alzheimer gave the first convincing description of the
pathological changes in a vascular dementia." Over the
ensuing seven decades, the view that gradual narrowing of
cerebral blood vessels starved the neurons and caused
dementia has prevailed. This idea became pervasive; it was
invoked by General George Marshall to justify retiring
ineffectual colonels," and by a journalist to explain a Pope's
mental rigidity." The view that mental senility resulted from
slow strangulation of the brain's blood supply proved
logical, compelling, and wrong. Fisher'° pointed out that
when mental impairment due to blood-vessel disease was
responsible, it was the result of strokes, large or small.
Tomlinson and colleagues showed a relation between the
extent of cerebral infarction and the presence of dementia. 11
My colleagues and I crystallised the concept, introduced the
term and proposed a standard method of diagnosing
multi-infarct dementia, to emphasise that the vascular
process is quantal and episodic rather than continuous and
chronic.v-" So far there has been no evidence of chronic
ischaemic states of the brain, either in animals or in man. 14.15
The flagging credibility of a direct association between
atherosclerosis and senility and the increasing recognition
and interest in Alzheimer's disease nurtured the perception
that vascular dementias were rare. 16
A resurgence of interest in vascular dementias arose
from brain-imaging
techniques,
especially computed
tomography (CT) and magnetic resonance imaging (MRI),
which depict changes in the brain so exquisitely that much
Problems
Definition
"Vascular dementia" is easy to define but difficult to
apply. Problems arise from both the term "vascular" and the
word "dementia".
Most individuals would agree that
"vascular" applies to any event leading to stroke, whereas
they will disagree on whether chronic ischaemia exists and
whether the white-matter changes seen on brain scans are
ischaemic or the end-result of multiple processes." No
agreement prevails as to whether "dementia" does or does
not imply global intellectual involvement, progression, and
irreversibility. The DSM-III
criteria for dementia were
developed largely to diagnose Alzheimer's disease, and they
are inappropriate for the vascular dementias, especially
because. of the heavy emphasis on memory impairment,
which is not a universal finding in cognitive impairment due
to vascular causes. Moreover, by the time a patient fulfills
the criteria for dementia, it often is too late to do anything.
"
Incidence and prevalence
Lack of agreement on a definition has resulted in widely
different estimates of incidence and prevalence. "Multiinfarct dementia" has gained status as a specific disorder,
ADDRESS: Department
of Clinical
Neurological
Sciences,
University
of Western
Ontario,
University
Hospital.
339
Windermere Road, London, Ontario, Canada N6A 5A5 (Prof
Vladimir Hachinski,MDl.
646
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even though it is a syndrome resulting from diverse causes
and with multiple manifestations,
depending on the
number, narure, and location of the lesions. Attempts to
develop criteria for vascular dementia have been modeled on
those for Alzheimer's disease." This approach does not
make sense. Alzheimer's disease, whether one disease or
more, has a predictable pattern of progression, whereas
cognitive impairment due to vascular lesions varies greatly
in clinical expression and course.
VOL 340: SEPT 12, 1992
prognosis could be answered in therapeutic and preventive
srudies. The approach should be graded, ranging from
simple prevention srudies to complex longirudinal projects.
The srudies should be modular. Every srudy should
include a minimum core of information that has been agreed
upon; validated scales should be used; and there should be
an emphasis on quantification and standardisation.
Definition
Neuropathologists often do, but should not, have the last
word on the diagnosis of "vascular dementia". When there
is no clear evidence of Alzheimer's disease, a pathologist can
describe the cerebral infarcts and white-matter changes but
is in no better position to determine to what extent the
lesions account for the mental state than is a neurologist
aware of the MRI findings, Nevertheless, only pathological
examination can reveal micro-infarcts,
grade of whitematter change, and nature of the vascular changes, including
the unidentified deposits in the small blood vessels and the
competence of the blood-brain barrier. Some of the leading
clinicopathological
srudiesll,!9.22 were done before the
recognition of the frequency of Lewy body disease, which
can be associated with dementia in the absence of the usual
signs of Alzheimer's disease." Although these srudies!1.19.22
tend to relate multiple infarcts to mental impairment and
draw conclusions regarding bilaterality and multiplicity of
lesions, no systematic attempt has yet been made to correlate
focal lesions with specific brain dysfunctions in multi-infarct
dementia.
"Dementia"
carries so many and contradictory
implications
that a new term has been suggested:
"dysmentia", defined by specified criteria." It is doubtful
that doctors would give up a term so entrenched in usage,
and nothing would prevent use of the new term in the old
way. A more practical solution may be for a definition of
dementia to carry a description --eg, such as "multi-focal
cognitive impairment"-preferably
expressed in terms ofa
standardised set of neuropsychological tests, A range of
increasingly more complex tests could be adopted so that
several tests can be used according to the specific purpose,
All srudies should include at least one or two agreed
measures of cognitive function. In retaining the term
"dementia", it should be understood to be one extreme of a
spectrum encompassing a symptomless "brain-at-risk" and
a warning "pre-dementia"
stage. The brain-at-risk stage
represents individuals in whom symptoms or signs mayor
may not develop. Patients in the pre-dementia stage have
some cognitive impairment that may be focal and may not
add up to a conventional definition of dementia. The
important point is to recognise the impairment and to do
something about it.
Diagnosis
Incidence and prevalence
Difficulties
with
definition
and
misconstrued
pathogenesis unavoidably result in problems with diagnosis.
An ischaemic score':' has been widely used to identify
individuals with multi-infarct dementia. It discriminates
well between Alzheimer's disease and individuals with
multi-infarct dementia and those with mixed dementias as
verified by clinicopathologial srudies;!9.24 Although the score
was originally used to identify two groups of demented
patients for a comparative cerebral blood flow study,':'
definitions of the items used for the score" were published
only after the ischaemic score began to be used by others. A
clinicopathological srudy confirmed the value of some of the
items," but it was too small for validating all the items and
for providing weightings based on their predictive value,
This needs to be done.
These rates will depend on the definition, A srudy should
be designed to identify individuals at all stages of the mental
state. Individuals with an Alzheimer or related process and
co-existent cerebral infarcts will form a "mixed" category.
Pathogenesis and petholoqv
Treatment and prevention
Imprecise diagnosis, uncertainty about pathogenesis, and
the deteriorated state in which most patients come to
medical attention contribute to the scarcity of therapeutic
srudies. Aspirin has been reported to produce improvement
in patients with multi-infarct dementia;" but although
encouraging, the srudy needs to be validated by a larger
series.
Solutions
The first step is to recognise what we know and do not
know. "The
greatest obstacle to discovery is not
ignorance-it
is the illusion of knowledge"." Srudies of the
vascular dementias should preferably be action oriented
since we have the means of treating and preventing strokes.
Many questions about diagnosis, pathophysiology,
and
Diagnosis
The first step is the establishment
of cognitive
impairment. The diagnosis may be purely clinical and based
on the assessment of the individual's behaviour and mental
status as related to some previous time. The family or the
patient'S attendants would have to be relied on for the
history. "Dementia"
is a relative term. A genius with
cognitive impairment may still tower intellecrually over
most other people. At this stage a simple instrument such as
the Mini Mental State can be helpful." The ischaemic
score" distinguishes reliably Alzheimer's disease from
multi-infarct
and
mixed
dementias.">'
After
an
Alzheimer's group has been separated, and treatable causes
of dementia have been ruled out, the doctor ought to indicate
not only whether multi-infarct or mixed dementia exists,
but also its likely cause and the evidence of supporting it.
Since the ischaemic score recognises the effects of focal and
,.cumulative brain damage it identifies a syndrome, and not a
disease.
Imaging of the brain, especially the depiction of whitematter changes, can complicate the diagnosis. In view of the
likely heterogeneity of the white-matter changes.v-" it may
be useful as a working hypothesis to divide individuals with
dementia and white-matter changes into three categories
according to whether white-matter changes are present
without cognitive impairment (as occurs in some normal
elderly individuals."); are associated with hypertension and
VOL 340: SEPT 12, 1992
other evidence of cerebrovascular
with Alzheimer's disease.
THE LANCET
disease; or are associated
Pathogenesis
No animal models of dementia exist but it is possible to
test the effect of specific lesions on animal's learning and
behaviour.P Multiple cerebral embolisms provide a good
human model for studying the effect of individual lesions on
overall brain function. The study of patients after cardiac
arrest or carbon monoxide poisoning can give insights into
the effect of hypotension and hypoxia, respectively, on the
white matter. A study of twins, especially of identical twins
discordant for stroke, could provide clues to the effect of
specific lesions on mental function.
Treatment and prevention
The vascular dementias should be viewed in the broadest
terms, since only a tiny minority of those likely to have
symptoms come to medical attention early. Patients suitable
for prevention or treatment are those in the brain-at-risk
stage (the elderly, hypertensives, smokers, diabetics, in atrial
fibrillation, cardiac patients, subjects with asymptomatic
extracranial arterial disease); those in the pre-dementia stage
(patients with transient ischaemic attack, stroke, subtle
cognitive impairment, silent cerebral infarctions, systemic
lupus erythematosus, or other causes of stroke); and those in
the dementia stage (patients with atherosclerosis of the
extracranial arteries, cardiac embolism, intracranial small
vessel disease, or other causes of stroke). One of the most
promising lines of research is the conduct of trials of
prevention
in individuals with multiple risk factors.
Therapeutic measures for individuals in the brain-at-risk
stage include: smoking cessation, exercise (prevention and
management
of diabetes), diet (control of diabetes,
hyperlipidemias, obesity), K + supplementation
(vascular
protective
effect),
oestrogen
replacement
(for
postmenopausal
women), antihypertensives
(angiotensin
converting enzyme inhibitors and Ca2+ charmel blockers
may be particularly
suitable), lipid-lowering
agents,
anticoagulants (for atrial fibrillation), and aspirin (for
selected patients at high risk). For those in the pre-dementia
stage measures could include: carotid endarterectomy
(patients with symptoms with carotid stenosis of 7(}-99%),
anticoagulants, aspirin, ticlopidine, agents that interfere
with amyloid deposition in vessels, or Ca?" charmel blockers
(pretreatment to attenuate the effect of infarcts). Measures
for the
dementia
stage
include:
antidepressants,
antihypertensives,
cholinergics,
nerve-growth
factors,
aspirin, and ticlopidine.
Implementation
A conference to secure agreement about research
opportunities
in the prevention and treatment of the
vascular dementias
is a desirable prelude
to the
development of a plan of action. The conference should be
attended by epidemiologists,
investigators from major
cardiovascular
and cerebrovascular
trials, leaders of
Alzheimer study centres, sociologists, demographers,
neurologists,
psychiatrists,
representatives
from the
pharmaceutical industry, and the government. Working
groups
on epidemiology,
education,
clinical trials,
longitudinal clinicopathological
studies, and standards
should be set up, as should coordinating and training centres
for exchange
programmes,
regular workshops
and
conferences, and modular research projects. Authors of
.ll.
647
studies on vascular dementia would submit a more detailed
description of their patients than that published in their
papers to a common database. This amplified database
should provide material for computer modelling, metaanalysis, and generation of hypotheses. A close liaison with
existing Alzheimer centres should be developed. In view of
the overlap between Alzheimer's disease and the vascular
dementias, the two processes should be studied together.
Few areas in medicine are as ripe for action as the vascular
dementias.
The author is a career investigator
Ontario.
of the Head and Stroke Foundation
of
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