REVIEW ARTICLE
Neuropathology Lessons in Vascular Dementia
Helena Chui, MD
(Alzheimer Dis Assoc Disord 2005;19:45–52)
U nlike Alzheimer disease (AD), no consensus has been
reached regarding the pathologic diagnosis of vascular
dementia (VaD). Conceptually, VaD may be regarded as severe
cognitive impairment resulting from cerebrovascular-related
brain injury (CVBI), which in turn is attributed to cerebro- or
cardio-vascular disease (CVD) (Fig. 1). Unfortunately, this
concept has defied simple translation into practice.
While there is good correlation between the severity of
cognitive impairment and the density of neurofibrillary tangles
or neuritic plaques in AD, no simple metric has been
discovered for VaD. Large infarct volume (eg, .50 mL) is
associated with dementia, but a small strategically placed 1-cm
lacune may do the same. The level of heterogeneity in the size,
location, and number of CVBI and the variability in behavioral
manifestations are not well suited to simple phenotypic or
categorical classification. Nonetheless, this is the state of art
that is reviewed here.
As the database grows, new continuous and quantitative
brain-behavior models will evolve. Meanwhile, we may
consider the lessons that neuropathology has to offer here
and now. First, neuropathology is the best method to ascertain
the severity and type of underlying CVD. Second, neuropa-
thology is still needed to validate the use of MRI as a surrogate
marker for CVBI. Finally, neuropathology is still the best way
to assess the presence and severity of Alzheimer pathology and
to address the relative contributions of AD and CVBI to
cognitive impairment.
This review is organized as follows:
Common types of cerebrovascular disease (CVD)
Common types of cerebrovascular brain injury (CVBI)
Detection of CVBI by MRI
Categorical diagnosis of VaD
Contributions of CVBI to cognitive impairment along
a continuum
Received for publication August 23, 2004; accepted September 6, 2004.
From the Department of Neurology, University of Southern California, Los
Angeles, California.
Supported by the National Institute on Aging: P01 AG12435.
Reprints: Helena Chui, Department of Neurology, University of Southern
California, 1510 San Pablo Street, Room 643, Los Angeles, CA 90033
(e-mail: chui@usc.edu).
Copyright Ó 2005 by Lippincott Williams & Wilkins
Alzheimer Dis Assoc Disord  Volume 19, Number 1, January–March 2005
COMMON TYPES OF
CEREBROVASCULAR DISEASE
Atherosclerosis affects the intimal and subintimal lining
of blood vessels. Cholesterol deposits and associated in-
flammatory changes are noted in large arteries. These pathol-
ogies are associated with artery-to-artery thromboembolism
and large cortical-subcortical infarcts. Smaller vessels may also
be involved. Subintimal accumulations of foam cells may be
observed in the proximal portions of small perforating arteries
(200–800 mm in diameter). These are associated with small,
deep infarcts in basal ganglia, thalamus, and pons. Risk factors
include hyperlipidemia, diabetes mellitus, smoking, hyper-
homocysteinemia, and elevated C-reactive protein. Thickness
of the carotid artery intima, brachial-foot ratio, and pulsatility
index provide clinical measures of atherosclerosis.
Arteriolosclerosis affects the media of small arterioles.
One observes onion-skin concentric proliferation of smooth
muscle cells, degeneration of the tunica media and internal
elastic lamina, and replacement of smooth muscle cell
replacement by fibroblasts, collagen, and laminin. The vessel
becomes an elongated, tortuous, narrow, and paucicellular
hyaline tube.1 Arteriolosclerosis is associated with lacunar
infarcts in deep white and gray matter structures. Fibrinoid
necrosis refers to focal segmental necrosis of small arterioles
(40–300 mm diameter). The media is replaced with collage-
nous sclerosis and mural foam cells (lipohyalinosis).1 Fibri-
noid necrosis is associated with hemorrhages and lacunar
infarcts in the basal ganglia, thalamus, pons, and cerebellum.
Major risk factors include hypertension and diabetes mellitus.
Assessment of the retinal arterioles on funduscopic examina-
tion offers a clinical measure of arteriolosclerosis.
Cerebral amyloid angiopathies (CAA) comprise a group
of disorders characterized by the deposition of amyloidogenic
proteins in the walls of cerebral blood vessels. The proteins
deposited may differ widely in amino acid sequence, but share
the common propensity to form beta-pleated sheets. The 40 to
42 amino acid a-beta protein is deposited in the CAA asso-
ciated with Alzheimer disease2 and the Dutch form of heredi-
tary cerebral hemorrhage with amyloid (HCHWA-Dutch). At
least 8 hereditary forms of CAA have been identified, includ-
ing Familial AD, HCHWA-Dutch, HCHWA-Icelandic, famil-
ial amyloid polyneuropathy/meningo-vascular amyloidoses,
familial amyloidoses Finnish type, familial prion disease,
familial British dementia, and Familial Danish dementia.3
CAA is associated with lobar hemorrhages, microinfarcts, and
leukoencephalopathy. Genetic forms may be diagnosed by
DNA sequencing. The sporadic forms often go unsuspected
until there is a clinical event and often unconfirmed until
neuropathological examination.
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Chui Alzheimer Dis Assoc Disord  Volume 19, Number 1, January–March 2005
FIGURE 1. Conceptualization of the pathogenesis of VaD.
A genetic disorder affecting the Notch3 gene, known as
cerebral autosomal dominant arteriopathy with subcortical
infarcts and leukoencephalopathy (CADASIL) affects the
small-arteries of the brain.4,5 CADASIL is associated with
progressive degeneration of vascular smooth muscle cell and
the accumulation of granular osmiophilic deposits in the
vascular basal lamina. CADASIL is associated with sub-
cortical infarcts and leukoencephalopathy beginning in early
adulthood. CADASIL mutations can be confirmed by com-
mercially available DNA sequencing.
Neuropathological examination sheds light on other
types of cardio- or cerebro-vascular disease. These include
cardio-embolism, vasculitis, fibromuscular dysplasia, Moya
Moya disease, vascular malformations, telangiectasias, aneur-
ysms, and venous thrombosis. As discussed above, neuropa-
thology may provide the first indication and diagnosis of CAA.
COMMON TYPES OF CEREBROVASCULAR
BRAIN INJURY
We introduce the generic term cerebrovascular brain
injury (CVBI) to encompass hemorrhage, infarction (both
complete and incomplete), and other types of changes in brain
parenchyma resulting from alterations in substrate delivery,
metabolic clearance, or disruptions of the blood brain barrier.
Hemorrhage refers to the rupture of the blood vessel wall and
extravasation of blood into the surrounding tissue. Complete
infarction refers to necrosis of all tissue elements due to is-
chemic brain injury, while incomplete infarction refers to
selective loss of neurons, myelin, and oligodendrocytes, without
cystic necrosis. Incomplete infarction was initially used to
describe the peripheral, less involved, portion of major artery
distribution infarcts (eg, penumbra).6 But the concept has also
been applied to demyelination and astrocytosis with variable
axonal loss found in the periventricular and deep white matter.7
Infarcts usually result from occlusion of a single vessel,
with size largely determined by the dimensions of the
compromised vessel(s). Occlusion of the major cerebral arter-
ies or their branches results in large wedge-shaped infarcts
involving cortex and underlying white matter. Occlusions of
small and medium arterioles feeding the white matter, basal
ganglia, thalamus, and pons results in lacunar infarcts, which
appear as round lesions ,2 cm in diameter. Occlusion of small
cortical arteries and capillaries results in microinfarcts, which
46
by definition fall below the threshold for detection by the
unaided human eye. Microinfarcts appear as round, stellate, or
barrel-shaped areas of cystic- or non-cystic necrosis sur-
rounded by reactive astrocytes (Fig. 2).
Infarction may also arise from hypoperfusion simulta-
neously affecting multiple blood vessels, due to widespread
stenosis or systemic hypotension. In these scenarios, the
terminal feeding zones of end-arterioles are most vulnerable.
Frontal and parietal border zones fall at the distal reaches of
the anterior, middle, or posterior cerebral arteries. The
periventricular white matter represents a small artery border
zone, which depends upon long-penetrating medullary end-
arterioles. Parallel-arranged cortical columns represent border
zones between radially penetrating cortical arterioles.
It is worthy of note that not all tissue cavitations (so-
called lacunes) seen in the deep white or gray matter represent
lacunar infarcts. Lammie1 has subdivided lacunes into 3 major
types (see Table 1, Fig. 3). Dilated perivascular spaces (PVS)
are CSF-filled spaces surrounding arteries and veins. PVS are
postulated to arise from increased arterial permeability, peri-
vascular inflammatory factors, and increased mechanical
pulsatility. PVS may be particularly prominent in the infra-
putaminal region and just above the above the lateral portion of
the anterior commissure.8
The hippocampus is the key enabler of episodic mem-
ory. Hippocampal sclerosis (HS) refers to selective neuronal
loss in the absence of cystic cavitation or neurofibrillary
degeneration. HS is most prominent in the CA-1 sector of the
hippocampus, extending into the subiculum. It has been
reported to be a common neuropathologic finding in persons
with dementia who are very old (80+ yrs),9 among 12% of
elderly persons with dementia10 or with cardiac disease.11 The
pathogenesis of HS is still disputed, but systemic hypoxia-
ischemia12 and ischemia due to intrinsic cerebrovascular
disease are hypothesized, as CA-1 neurons have a relatively
high metabolic rate but relatively poor vascular supply (Fig. 4).
DETECTION OF CEREBROVASCULAR BRAIN
INJURY BY MAGNETIC RESONANCE IMAGING
In most cases, neuropathological data only becomes
available after death. Neuroimaging has the potential to pro-
vide an in vivo surrogate. Amyloid markers are under develop-
ment for AD. Structural MRI is accepted as an excellent
FIGURE 2. Cortical incomplete infarction: microinfarcts.
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Alzheimer Dis Assoc Disord  Volume 19, Number 1, January–March 2005
TABLE 1. Subtypes of Lacunes
Type I—An irregular cavity 1 to 20 mm in diameter, most commonly found
in putamen, caudate, thalamus, pons, internal capsule, and hemispheric
white matter (complete small infarct)
Type Ib—Mirror Type I lacune in size, shape, and distribution, but shows
only selective loss of vulnerable cellular elements, falling short of pan-
necrosis (incomplete small infarcts)
Type II—Cavity with numerous hemosiderin-laden macrophages, assumed
to represent an old, small hemorrhage or old hemorrhagic microinfarct
Type III—Dilated perivascular space
marker for stroke and often discloses ‘‘silent’’ infarcts (hyper-
intensities presumably related to CVBI, but without recog-
nized clinical event). Gradient-echo T2*-weighted MRI allows
detection of micro-bleeds associated with hypertensive micro-
angiopathy, CAA,13 and CADASIL.14 There are few system-
atic imaging-pathologic studies addressing the question: How
good is MRI as a surrogate marker for CVBI?
Ischemic Vascular Dementia Program Project
Clinical-pathologic and quantitative MRI correlations
were analyzed for the first 20 and 46 autopsies in a prospective
study of SIVD, AD, and normal aging (Table 2).15 The
apolipoprotein e4 allele was rarely found in autopsy cases of
pure CVD (9%), in contrast to AD (46%) or Mixed AD/CVD
(44%) (P = 0.03). Conversely, hippocampal sclerosis was
found more frequently in CVD (50%) or Mixed AD/CVD
(28%) cases, than AD (7%). Similarly, a large amount of white
matter signal hyperintensity was found more frequently in
Mixed AD/CVD (86%) or CVD (75%) than AD (36%) (P =
0.08). High WML was associated with either arteriolosclerosis
or CAA. On the other hand, hippocampal and cortical gray
matter atrophy were found in 88% and 80% of the dementia
cases, irrespective of dementia subtype.
FIGURE 3. Subtypes of Lacunes.
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Neuropathology Lessons in Vascular Dementia
These findings suggest that hippocampal and cortical
gray matter atrophy may represent the sine qua non of the
dementia syndrome. Other factors, however, may help to
differentiate specific etiologic process. The apolipoprotein e4
allele increases the risk of AD or Mixed AD/CVD, while high
WML increases the likelihood of CVD or Mixed AD/CVD.
The pathologies that contribute to hippocampal atrophy in
SIVD include neurofibrillary degeneration and hippocampal
sclerosis, while those contributing to cortical gray matter
atrophy in SIVD are still unknown. Candidate mechanisms
include a-beta toxicity, micro- or incomplete cortical infarcts,
and secondary deafferentation of the cortex resulting from
underlying subcortical pathology.
CATEGORICAL DIAGNOSIS OF
VASCULAR DEMENTIA
As VaD is currently conceptualized, its pathologic
diagnosis is problematic: not because it is difficult to make
a pathologic diagnosis of cerebrovascular injury, but because it
is difficult to determine postmortem whether a vascular lesion
was causal, contributory, or coincidental to the dementia. No
consensus has been reached about how to make a pathologic
diagnosis of VaD. Typically, there is a requirement for vascular
lesions, often of a certain size or volume, in the absence of
degenerative lesions.16–18 Joachim et al19 considered strokes to
have contributed to the clinical dementia if sufficiently remote
or larger in size than lacune, or if the vascular lesions involved
the hippocampus, amygdala, thalamus, or basal forebrain. In
another schema, softening in the hippocampus and serum pro-
teins in the perivascular parenchyma were additional require-
ments for a diagnosis of vascular dementia.17 Gold et al20,21
defined vascular dementia as cortical-subcortical infarcts in
parietal, temporal, or frontal lobes—subcortical infarcts by
themselves were not considered sufficient for a pathologic
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Chui Alzheimer Dis Assoc Disord  Volume 19, Number 1, January–March 2005
FIGURE 4. CA1 Hippocampal Sclerosis.
diagnosis of VaD. A pathologic diagnosis of Binswanger’s
subcortical arteriosclerotic encephalopathy can be made in the
presence of severe white matter changes with demyelination
and axonal loss plus severe and widespread changes of
arteriolosclerosis.19 Knopman et al22 defined VaD by the
presence of multiple, bilateral gray matter lesions rostral to the
thalamus. The need to develop standardized pathologic
methods and descriptors for CVBI was highlighted in a recent
review.23
In evidence-based medicine, the positive likelihood ratio
(LR+) provides a measure of the power of a diagnostic test. In
the following section, we consider various clinical criteria for
VaD as ‘‘diagnostic tests’’ and use the pathologic diagnosis of
VaD as the reference standard for VaD. In this context, the LR+
is defined as the likelihood that the criteria for a clinical
diagnosis of VaD will be met among persons with VaD divided
by the likelihood that the clinical criteria will be met by
persons without VaD. The LR+ is calculated by dividing
sensitivity by 1 minus the specificity. A LR+ .10 is desirable,
as it will generate large and often conclusive changes in the
pre- to post-test probability of having VaD.24
Hachinski Ischemia Score
A meta-analysis of the Hachinski Ischemia Score (HIS)
was reported by Moroney et al.25 In this multicenter study,
clinical and pathologic data were retrospectively analyzed for
312 cases (165 AD, 109 MID, 38 MIX). MID was defined by
HIS $ 7, MIX by a score of 5 to 6, and AD by HIS $ 4. The
LR+ was 4.6 for a clinical diagnosis of MID (84% sensitive,
82% specific). LR+ was 3.5 for a diagnosis of MIX (sensitivity
83%, specificity 76%). Several subsets of items were found
either more commonly in MID than AD, or explained a
significant portion of the variance in a logistic regression.
48
Slightly larger LR+ of 6.2 to 10.1 was reported by Gold et al,20
with similar specificity (88–97%), but far lower sensitivity
(30–43%). It is difficult to understand the source of these
differences, because the pathologic definitions of VaD in the
two studies were not comparable.
DSM Criteria
In a larger retrospective study of 677 autopsied cases, an
LR+ of 7.3 to 12.0 was reported for a DSM-III diagnosis of
MID.26 These cases were compiled from three different
hospitals. But aside from citing DSM-III criteria, little detail is
provided about the reliability of the clinical diagnosis. Similar
LR+ values (4.0 to 11.5) were reported in a much smaller
study of 27 MID, 5 AD, and 5 other dementias.27 In this study,
the same neurologist made all of the clinical diagnoses, but the
number of non-MID cases was small. Based on this limited
data, the LR+ associated with DSM-III criteria for MID would
generate moderate shifts in pre- to post-test probability. In
a recent study by Gold et al,21 the DSM-IV criteria for VaD had
a sensitivity of 50% and a specificity of 84% (LR+ = 3.1).
NINDS-AIREN Criteria
The NINDS-AIREN criteria are used most frequently in
clinical pharmacological trials. The accuracy of the NINDS-
AIREN criteria for VaD was partially addressed in an earlier
study by Gold et al.20 In this study where only 20% of cases
had neuroimaging studies, the NINDS-AIREN and ADDTC
criteria performed virtually identically: LR = 1.7 to 4.8; low
sensitivity (43–58%), and higher specificity (79–91%). In an
independent sample of autopsied patients from a geriatric and
psychiatric hospital, all 89 cases had neuroimaging.21 A
clinical diagnosis of probable VaD had a sensitivity of 20%
and specificity of 93% (LR+ = 2.8) A clinical diagnosis of
possible VaD had a sensitivity of 55% and a specificity of 84%
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TABLE 2. Clinical-Pathological Correlation in VaD (Class I and II Evidence)

Pathological Criteria for
Study N Clin Dx MID VaD VaD PPV NPV SS SP LR+
Erkinjuntti 37 hospital DSM-III Presence of multiple MID 0.89 0.56 0.68 0.83 4.0
(1988) 5 AD, 27 MID, 5 ischemic lesions in MID + MIX 0.96 0.85 0.92 0.92 11.5
Class I B Other dementia cortical or
subcortical areas
(or both), without
AD-type changes
Jellinger 675 convenience DSM-III-R 1. One or more large MID 0.57 0.96 0.80 0.89 7.3
(1990) hospital cerebral infarcts or MID + MIX, PD 0.79 0.95 0.84 0.93 12.0
Class II B Autopsy extensive cortical
diagnoses: 400 granular atrophy
AD, 146 MID, 21 2. Diffuse or
MIX, 108 multiple focal
PD+other white matter
damage with small
disseminated
infarcts or lacunes
3. Multiple small
lesions or lacunes
in basal ganglia or
mixed cortical and
subcortical
vascular lesions
Moroney 312 from 6 centers HIS: MID $ 7 Multiple ischemic MID 0.61 0.94 0.84 0.82 4.6
(1997) Autopsy diagnoses: lesions in cortex or MID + MIX
Class II B 165 AD, 109 HIS MIX = 5–6 subcortical regions MID+MIX 0.69 0.88 0.83 0.76 3.5
MID 38 MIX without marked
AD changes
Gold 113 hospital HIS $ 7 Multiple MID 0.68 0.71 0.43 0.88 6.2
(1997) macroscopic and MID + MIX 0.96 0.34 0.30 0.97 10.1
Class II B NINDS-AIREN microscopic MID 0.61 0.77 0.58 0.79 2.7
Possible VaD cortical infarct
or lacunar MID + MIX 0.92 0.39 0.43 0.91 4.8
ADDTC Possible IVD state, which MID 0.49 0.76 0.63 0.64 1.7
involved the MID + MI 0.92 0.45 0.58 0.88 4.8
hippocampus and
3 or more
neocortical areas
except primary
and secondary
visual cortex*
Gold 89 hospital (CT or DSM-IV Multiple MID 0.48 0.85 0.50 0.84 3.1
(2002) MRI) ICD-10 macroscopic and MID 0.5 0.80 0.20 0.94 3.3
Class IIB NINDS ps VaD microscopic MID 0.50 0.87 0.55 0.84 3.4
cortical infarcts,
NINDS PrVaD which involved 3 MID 0.44 0.80 0.20 0.91 2.2
ADDTC ps IVD or more MID 0.48 0.90 0.70 0.78 3.2
ADDTC pr IVD neocortical areas, MID 0.45 0.81 0.25 0.91 2.8
exclusive of
primary and
secondary visual
cortex*
Knopman 89 autopsied NINDS including Multiple and Pure VaD 0.25 0.96 6.4
(2003) dementia cases WML bilateral VaD+ 0.22 0.98 11.0
from 482 incident DSM-IV infarctions in gray VaD 0.75 0.64 2.1
cases of dementia matter structures
(18% met Mayo Pure VaD: Braak VaD+ 0.74 0.70 2.5
criteria and 4% ICD-10 # II and sparse VaD 0.75 0.74 2.9
NINDS-AIREN neuritic plaques VaD+ 0.70 0.80 3.5
criteria or VaD ADDTC (not blinded to VaD 0.67 0.79 3.2
clinical
VaD+ 0.57 0.83 3.3
information)
Mayo Clinic VaD 0.75 0.73 2.8
VaD+ 0.70 0.79 3.3
*Vascular lesions confined to the subcortical structures were not considered for the diagnosis of vascular dementia.

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Chui Alzheimer Dis Assoc Disord  Volume 19, Number 1, January–March 2005
(LR+ = 3.4). Similar results were reported by Knopman et al22
in a community-based, incident-dementia autopsy series.
ADDTC Criteria
In a recent study,21 a clinical diagnosis of probable IVD
had a sensitivity of 25% and a specificity of 91% (LR+ = 2.9);
a diagnosis of possible IVD had a sensitivity of 70% and
a specificity of 78% (LR+ = 3.2). In a community-based,
incident-dementia autopsy series, similar positive likelihood
ratios were found.22
It is difficult to compare the accuracy of different criteria
for clinical diagnosis of VaD, given the multiplicity of
pathologic reference standards. In 2 studies, the LR+ for the
DSM-III criteria fell in the 5 to 10 range, which is associated
with moderate changes in pre-and post-test probability. In
general, however, the LR+ associated with the Hachinski
Ischemic Score, as well as the NINDS-AIREN and ADDTC
criteria, fall in the 2 to 5 range—where small, but sometimes
important, changes can be expected between pre- and post-test
probability. These values are similar as those found for the
NINCDS-ADRDA and DSM-III diagnoses of AD.28 Clearly,
better diagnostic methods are still needed for VaD, as well as AD.
In general, the NINDS-AIREN and ADDTC criteria for
probable VaD/IVD show a very high specificity (91–93%), but
very low sensitivity (20–25%). The corresponding criteria for
possible VaD/IVD achieve gains in sensitivity (55–70%),
without too much loss of specificity (78–84%). The newer
clinical criteria for VaD miss a substantial number of cases that
have pathologically defined CVD. On the other hand,
a diagnosis of VaD by these criteria usually means that CVBI
will indeed be found at autopsy.
CONTRIBUTIONS OF CEREBROVASCULAR
BRAIN INJURY TO COGNITIVE IMPAIRMENT
ALONG A CONTINUUM
Cerebrovascular brain injury, Alzheimer-changes (ie,
NFT and NP; tauopathy and beta-amyloidosis) and Parkinson-
changes (Lewy bodies, alpha-synucleinopathy) often co-exist,
particularly in an aging population. In a large unselected,
community-based neuropathology study (70–103 years old),
cerebrovascular (78%) and Alzheimer-type pathology (70%)
were common.29 The following question may be posed. How
do these pathologies interact to impact behavior and cogni-
tion? Relevant data are emerging from several longitudinal
autopsy series.
The Nun Study
The Nun Study is a prospective longitudinal study of
aging and AD.30 Participants are highly educated and have
history of homogenous environment and lifestyle. The autopsy
rate of 88% is high (146 of 161 deaths). Cases with hippo-
campal sclerosis, and other non-AD, non-CVD dementias/le-
sions were excluded.
The final autopsy sample comprised 102 college-
educated women aged 76 to 100 years. Of these 44% (n =
45) had dementia. (Dementia defined as scores , 5th percentile
on CERAD neuropsychological battery); 39 had infarcts
(based on gross examination of 1.5-cm thick coronal brain
sections; lacunes were defined as small infarcts , 1.5 cm).
50
Sixty-one cases met pathologic criteria for AD (defined as
abundant cortical senile plaques .= 16/mm2 and NFT in at
least 1 lobe); 41 cases did not. Of the 61 AD cases, 24 (39%)
had at least 1 infarct (12 at least 1 large infarct; 15 had at least 1
lacunar infarct); 37 cases had no infarcts. Among the 45
dementia cases, 47% (n = 21) had both AD and at least 1
infarct, so Mixed AD/CVD was a common occurrence. The
study did not conduct an examination for microinfarcts.
Among non-AD cases, the presence of infarction was
associated lower scores on constructional praxis, but not for
MMSE or 5 other cognitive tests. Among the AD cases, the
prevalence of dementia was 57% for those without infarcts,
75% for those with a large infarct (OR 6.7 [95% CI = 0.9 to
48.3]), and 93% for those with at least 1 lacunar infarct (OR
20.7 [95% CI = 1.5 to 288.0]). AD cases with lacunar infarcts
had significantly lower MMSE and CERAD test scores
compared with those with large infarcts. These findings
suggest that CVD may result in mild cognitive impairment. For
cases with AD pathology, the presence of small infarcts (more
so than large infarcts) was associated with greater cognitive
impairment. It is unclear whether the additional burden on
cognitive function is imposed by the lacune itself, or whether
the lacune serves as a marker for more widespread pathologic
changes associated with small-vessel disease.
Honolulu Asia Aging Study
The Honolulu-Asia Aging Study (HAAS) is a supple-
mentary study to the Honolulu Heart Program (HHP). The
HHP sample comprised Japanese-American men born 1900 to
1919 who were living on the island of Oahu in 1965 (n =
8006). Beginning in 1991 and every 3 years thereafter, the
surviving participants (n = 3734 men in 1991) were admin-
istered the Cognitive Abilities Screening Instrument (CASI).31
Petrovitch et al,32 reported 220 consecutive autopsies
from the HAAS. Among 79 cases with dementia, 34 cases
were diagnosed pathologically as pure CVD. In a later study,
285 autopsies were classified using an algorithm among 4
primary pathologic processes (IVD, AD, Lewy bodies, and
HS).33 Substantial overlap was found among the 4 pathologic
processes and mixed pathologies appeared to be associated
with a higher prevalence of dementia. Among 118 decedents
identified as demented or cognitively impaired, 36% were
attributed to AD and 30% were attributed at least in part to
microinfarcts. This study suggests that microinfarcts may play
an important role in dementia.
Oxford Project to Investigate Memory and
Ageing (OPTIMA) Study
Serial mental status examinations were performed among
a population-based sample of elderly persons living in
Cambridge, England (n = 2616). Among the first 101 con-
secutive autopsy cases,34,35 over 80% were older than 85 years
at the time of death, and approximately half were considered to
be at least minimally demented. Considerable overlap was
observed in the types of pathology found in the demented and
non-demented cases, with dementia cases showing signifi-
cantly greater numbers of tangles and plaques as expected. A
weaker but non-statistically significant association was found
between dementia and the presence of Lewy bodies.
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FIGURE 5. Probability of dementia diagnosis.
Cerebral amyloid angiopathies were found in 38% of
cases. CVBI was found in 24 cases: 7 with large vessel in-
farcts, 3 with subcortical lacunes or microinfarcts, and the
remainder with subcortical small-vessel disease with widened
perivascular spaces, accompanied by patchy pallor of white
matter myelin. The relation between CVBI and cognitive
status was complex. The presence of CVBI in cases with
entorhinal-stage AD was associated with greater decline in the
CAMDEX cognitive score. In limbic and cortical stage AD,
however, the presence of CVD was not associated with
cognitive decline.34 As in the HAAS, the pathologic correlates
of dementia are complex and multidimensional. This study
suggests that CVBI contributes to cognitive impairment in
early-stage AD, but not once AD pathology becomes more
advanced.
The Religious Orders Study
The Religious Orders Study (ROS) is a longitudinal,
clinical-pathologic study of older nuns, priests, and brothers
from 40 sites in the United States. Between 1994 and 2004,
950 subjects had enrolled and annual follow-up rates for
neuropsychological testing were high (95%). Among 164
consecutive autopsies, both AD and macroscopic infarcts were
independently associated with dementia.36,37 The probability
of dementia increased as a function of the severity of AD
pathology, and was greater in the presence of cerebral infarc-
tions (OR 2.1, 95% CI 1.06–4.25). Large infarctions (.33
mL) increased the likelihood four-fold (OR 4.35, 95% CI
0.95–11.8). There was no statistically significant interaction
between AD and infarcts, supporting and additive rather than
synergistic contribution to dementia (Fig. 5).
CONCLUSION
Neuropathology plays an important role in understand-
ing the contribution of cerebrovascular disease to cognitive
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Neuropathology Lessons in Vascular Dementia
impairment. An emerging database suggests that CVBI contri-
butes significantly to mild cognitive impairment and can
precipitate the appearance of dementia in early stages of AD
pathology. However, the effects of CVBI may become
submerged once AD-pathology arrives at the isocortical
stages. The traditional categorical approach, which seeks a
unifying definition for VaD to place subjects into finite boxes,
may be over simplistic and futile. Standardized methods of
describing the severity and distribution of CVD and CVBI are
essential to enable the development of new quantitative and
continuous brain-behavior models. Pathologic validation of
in vivo digital neuroimaging markers may greatly accelerate
this endeavor.
REFERENCES
1. Lammie A. Hypertensive cerebral small vessel disease and stroke. Brain
Pathol. 2002;12:358–370.
2. Vinters HV, Vonsattel JP. Neuropathologic features and grading of
Alzheimer-related and sporadic CAA. In: Verbeek MM, De Wall RMW,
Vinters HVD, eds. Cerebral Amyloid Angiopathy in Alzheimer’s Disease
and Related Disorders. Dordrecht: Kluwer Academic Publishers; 2000:
137–155.
3. Revesz T, Holton JL, Lashley TM, et al. Sporadic and familial cerebral
amyloid angiopathies. Brain Pathol. 2002;12:343–357.
4. Tournier-Lasserve E, Iba-Zizen MT, Romero N, et al. Autosomal
dominant syndrome with stroke like-episodes and leukoencephalopathy.
Stroke. 1991;22:1297–1302.
5. Kalimo H, Ruchoux M-M, Viitanen M, et al. CADASIL: a common form
of hereditary arteriopathy causing brain infarcts and dementia. Brain
Pathol. 2002;12:371–384.
6. Garcia JH, Lassen N, Weiller C, et al. Ischemic stroke and incomplete
infarction. Stroke. 1996;27:761–765.
7. Brun A, Englund E. A white matter disorder in dementia of the Alzheimer
type: a pathoanatomic study. Ann Neurol. 1986;19:253–262.
8. Pullicino PM, Miller LL, Alexandrov A, et al. Infra putaminal Ôlacunes.Õ
Clinical and pathological correlations. Stroke. 1995;26:1598–1602.
9. Dickson DW, Davies P, Bevona C, et al. Hippocampal sclerosis: a common
pathological feature of dementia in very old (greater than 80 years of age)
humans. Acta Neuropathol (Berl). 1994;88:212–221.
10. Leverenz JB, Agustin CM, Tsuang D, et al. Clinical and neuropathological
characteristics of hippocampal sclerosis. Arch Neurol. 2002;59:1099–1106.
11. Corey-Bloom J, Sabbagh MN, Bondi MW, et al. Hippocampal sclerosis
contributes to dementia in the elderly. Neurology. 1997;48:154–160.
12. Crystal HA, Dickson DW, Sliwinski MJ, et al. Pathological markers
associated with normal aging and dementia in the elderly. Ann Neurol.
1993;34:566–573.
13. Jeong S-W, Jung K-H, Chu K, et al. Clinical and radiologic differences
between primary intracerebral hemorrhage with and without microbleeds on
gradient-echo magnetic resonance imaging. Arch Neurol. 2004;61:905–909.
14. Oberstein SAJ, vad den Boom R, van Buchem MA, et al. for the Dutch
CADASIL Research Group. Cerebral microbleeds in CADASIL.
Neurology. 2001;57:1066–1070.
15. Vinters H, Ellis W, Zarow C, et al. Neuropathologic substrates of ischemic
vascular dementia. J Neuropathol Exp Neurol. 2000;59:911–945.
16. Tomlinson BE, Blessed G, Roth M. Observations on the brains of
demented old people. J Neurol Sci. 1970;11:205–424.
17. Alafuzoff I, Iqbal K, Friden H, et al. Histopathological criteria for
progressive dementia disorders: clinical-pathological correlation and
classification by multivariate data analysis. Acta Neuropathol (Berl).
1987;74:209–225.
18. Tierney M, Fisher RH, Lewis AJ, et al. The NINCDS-ADRDA work
group criteria for the clinical diagnosis of probable Alzheimer’s disease:
a clinicopathologic study of 57 cases. Neurology. 1988;38:359–364.
19. Joachim CL, Morris JH, Selkoe DJ. Clinically diagnosed Alzheimer’s
disease: autospy results in 150 cases. Ann Neurol. 1988;24:50–56.
20. Gold G, Giannakopoulos P, Montes-Paixao JC, et al. Sensitivity and
specificity of newly proposed clinical criteria for possible vascular
dementia. Neurology. 1997;49:690–694.
51
Chui Alzheimer Dis Assoc Disord  Volume 19, Number 1, January–March 2005
21. Gold G, Bouras C, Canuto A, et al. Clinicopathological validation study of
four sets of clinical criteria for vascular dementia. Am J Psychiatry. 2002;
159:82–87.
22. Knopman DS, Parisi JE, Boeve BF, et al. Vascular dementia in
a population-based autopsy study. Arch Neurol. 2003;60:569–575.
23. Pantoni L, Palumbo V, Sarti C. Pathological lesions in vascular dementia.
Ann N Y Acad Sci. 2002;977:279–291.
24. Jaeschke R, Guyatt GH, Sackett D, for the Evidence-Based Medicine
Working Group. User’s guide to the medical literature. III. How to use an
article about a diagnostic test. B. What are the results and will they help
me in caring for my patients? JAMA. 1994;271:703–707.
25. Moroney JT, Bagiella E, Desmond DW, et al. Meta-analysis of the
Hachinski Ischemia Score in pathologically-verified dementias. Neurol-
ogy. 1997;49:1096–1105.
26. Jellinger K, Danielczyk W, Fischer P, et al. Clinicopathological analysis of
dementia disorders in the elderly. J Neurol Sci. 1990;95:239–258.
27. Erkinjunutti T, Haltia M, Palo J, et al. Accuracy of the clinical diagnosis
of vascular dementia: a prospective clinical and post-mortem neuro-
pathological study. J Neurol Neurosurg Psychiatry. 1988;51:1037–
1044.
28. Chui H, Zarow C, Ellis W, et al. Diagnosis of ischemic vascular dementia
(IVD): clinical-pathological correlations. In: Korczyn A, ed. First Inter-
national Congress on Vascular Dementia. Bologna: Monduzzi Editore;
1999:27–32.
29. Neuropathology Group. Medical Research Council Cognitive Function
and Aging Study. Pathological correlates of late-onset dementia in
52
a multicentre, community-based population in England and Wales. Lancet.
2001;357:169–175.
30. Snowdon DA, Greiner LH, Mortimer JA, et al. Brain infarction and the
clinical expression of Alzheimer disease: The Nun Study. JAMA. 1997;
277:813–817.
31. White L, Petrovitch H, Ross GW, et al. Prevalence of dementia in older
Japanese-American men in Hawaii. The Honolulu Asia Aging Study.
JAMA. 1996;276:955–960.
32. Petrovitch H, White LR, Ross GW, et al. Accuracy of clinical criteria for
AD in the Honolulu Asia Aging Study, a population-based study.
Neurology. 2001;57:226–234.
33. White L, Petrovitch H, Hardman J, et al. Cerebrovascular pathology and
dementia in autopsied Honolulu-Asia Aging Study participants. Ann N Y
Acad Sci. 2002;977:9–23.
34. Esiri MM, Nagy Z, Smith MZ, et al. Cerebrovascular disease and
threshold for dementia in the early stages of Alzheimer disease. Lancet.
1999;354:919–920.
35. Xuereb JH, Brayne C, Dufouil C, et al. Neuropathological findings in the
very old: results from the first 101 brains of a population-based longitudinal
study of dementing disorders. Ann N Y Acad Sci. 2000;903:490–496.
36. Schneider JA, Wilson RS, Cochran EJ, et al. Relation of cerebral
infarctions to dementia and cognitive function in older persons.
Neurology. 2003;60:1082–1088.
37. Schneider JA, Wilson RS, Bienias JL, et al. Cerebral infarctions and the
likelihood of dementia from Alzheimer disease pathology. Neurology.
2004;62:1148–1155.
q 2005 Lippincott Williams & Wilkins