Cognitive Consequences of Thalamic, Basal Ganglia, and
Deep White Matter Lacunes in Brain Aging and Dementia
Gabriel Gold, MD; Enikö Kövari, MD; François R. Herrmann, MD, MPH; Alessandra Canuto, MD;
Patrick R. Hof, MD; Jean-Pierre Michel, MD; Constantin Bouras, MD; Panteleimon Giannakopoulos, MD
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Background and Purpose—Most previous studies addressed the cognitive impact of lacunar infarcts using radiologic
correlations that are known to correlate poorly with neuropathological data. Moreover, absence of systematic bilateral
assessment of vascular lesions and masking effects of Alzheimer disease pathology and macrovascular lesions may
explain discrepancies among previous reports. To define the relative contribution of silent lacunes to cognitive decline,
we performed a detailed analysis of lacunar and microvascular pathology in both cortical and subcortical areas of 72
elderly individuals without significant neurofibrillary tangle pathology or macrovascular lesions.
Methods—Cognitive status was assessed prospectively using the Clinical Dementia Rating (CDR) scale; neuropathological
evaluation included A␤-protein deposition staging and bilateral assessment of microvascular ischemic pathology and
lacunes; statistical analysis included multivariate models controlling for age, amyloid deposits, and microvascular
pathology.
Results—Thalamic and basal ganglia lacunes were negatively associated with CDR scores; cortical microinfarcts,
periventricular and diffuse white matter demyelination also significantly affected cognition. In a multivariate model,
cortical microinfarcts and thalamic and basal ganglia lacunes explained 22% of CDR variability; amyloid deposits and
microvascular pathology explained 12%, and the assessment of thalamic and basal ganglia lacunes added an extra 17%.
Deep white matter lacunes were not related to cognitive status in univariate and multivariate models.
Conclusions—In agreement with the recently proposed concept of subcortical ischemic vascular dementia, our autopsy
series provides important evidence that gray matter lacunes are independent predictors of cognitive decline in elderly
individuals without concomitant dementing processes such as Alzheimer disease. (Stroke. 2005;36:1184-1188.)
Key Words: aging 䡲 brain injuries 䡲 cognition 䡲 dementia 䡲 lacunar infarction 䡲 vascular diseases
M
orphological substrates of cognitive decline associated
with cerebrovascular disease are still strongly debated.
The traditional view of a close relationship between a volume
of cerebral infarcts ⬎100 mL and dementia proposed by
Tomlinson1 has been challenged by neuropathological studies
that indicated that small macroinfarcts and even microscopic
ischemic lesions can lead to dementia.2– 6 More recently,
focus has shifted to the identification of more homogeneous
subtypes of vascular dementia such as subcortical ischemic
vascular dementia, characterized clinically by a dysexecutive
syndrome and memory deficits and neuropathologically by
lacunes and deep white matter changes.7–10 Although the
contribution of deep white matter changes to cognitive
decline is now well-documented,4,11,12 the clinical significance of lacunes has been difficult to establish.13,14 In the
Cardiovascular Health Study, 23% of individuals older than
age 65 had MRI evidence of lacunes; however, 89% were
essentially clinically silent from a cognitive point of view. In
other studies, the prevalence of silent lacunes ranged from
11% to 24%.7 In a large neuropathological series, lacunes
were present in approximately one-quarter of elderly cases
without psychiatric or neurological disease.14 In contrast, the
Nun study demonstrated that cognitive function was markedly influenced by thalamic, basal ganglia, and deep white
matter lacunes in individuals with Alzheimer disease (AD)
neuropathology.15 Moreover, a recent study reported intriguing results regarding the cognitive consequences of silent
brain infarcts. At baseline, no relationship was found between
the presence of silent brain infarcts and impaired cognition,
yet cases with new silent brain infarcts during follow-up did
have cognitive decline.13
Several methodological issues may explain difficulties
encountered when attempting to define the role of lacunar
Received November 30, 2004; final revision received February 15, 2005; accepted February 25, 2005.
From the Departments of Psychiatry (A.C., E.K., C.B., P.G.) and Geriatrics (G.G., F.R.H., J.P.M.), HUG Belle-Idée, University of Geneva School of
Medicine, Geneva, Switzerland; Service of Old Age Psychiatry (P.G.), University of Lausanne School of Medicine, Lausanne; Fishberg Research Center
for Neurobiology and Kastor Neurobiology of Aging Laboratories (P.R.H., C.B.), and the Departments of Geriatrics and Adult Development and
Ophthalmology (P.R.H.), Mount Sinai School of Medicine, New York, NY.
G.G. and E.K. contributed equally to this work.
Correspondence to Dr Gabriel Gold, Department of Geriatrics, University of Geneva Hospitals, 1226 Thônex-Geneva, Switzerland. E-mail
[email protected]
© 2005 American Heart Association, Inc.
Stroke is available at http://www.strokeaha.org
DOI: 10.1161/01.STR.0000166052.89772.b5
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pathology in brain aging. Because lacunes occur diffusely
within the brain, a valid evaluation of their repercussion on
cognition presupposes their systematic bilateral assessment in
regions known to be highly involved in dementia and prone to
development of lacunes such as the thalamus, basal ganglia,
and deep white matter. Moreover, the concomitant presence
of other age-related dementing pathology may mask the
cognitive consequences of lacunes. This includes AD pathology such as amyloid deposits and, most importantly, neurofibrillary tangles (NFT), which represent the strongest correlate of neuronal loss and cognition in AD,16,17 and also
microvascular lesions such as cortical microinfarcts and
periventricular and diffuse white matter demyelination, which
have been shown to negatively influence cognitive performance in brain aging.4
To address these issues, we report clinicopathological
correlations in a series of prospectively investigated elderly
individuals with various degrees of cognitive impairment but
without significant NFT pathology or macrovascular lesions.
To define the cognitive consequences of lacunar pathology,
we compared the semi-quantitative assessment of cognitive
findings to the semi-quantitative assessment of lacunes in the
deep white matter, basal ganglia, and thalamus. The present
analysis is based on multivariate models that control for the
interaction with age, amyloid deposits, and significant microvascular pathology.
Materials and Methods
We surveyed a 5-year autopsy population of 629 cases from the
Geriatric and Psychiatric Hospitals, Geneva University School of
Medicine. All patients were from the Geneva area and older than 65
years; there were 270 men (81.0⫾7.1 years) and 359 women
(82.8⫾7.3 years). In these institutions, all patients older than 65
undergo cognitive screening using the Mini-Mental State Examination18 and clock drawing test.19 If, as a result, dementia is suspected,
neuropsychological evaluation is performed using tests appropriate
to each situation. All cases are also rated according to the clinical
dementia rating scale (CDR), a validated scale that is widely used for
the clinical staging of dementia.20 It assigns cognitive function to
five levels defined as no dementia (CDR 0), questionable dementia
(CDR 0.5), mild dementia (CDR 1), moderate dementia (CDR 2),
and severe dementia (CDR 3). Cases with stroke history or other
central nervous system disorders (ie, tumors, inflammation, Parkinson disease, Lewy body disease) were excluded. Such ascertainment
was based on review of written and computerized medical records.
Brains were fixed in 15% formaldehyde for a minimum of 4 weeks
and cut into 1-cm coronal slices. Cases were classified according to
Braak21 and Thal22 using highly specific, fully characterized antibodies to microtubule-associated ␶ protein and to core-amyloid
A␤-protein as described elsewhere.4 Antibodies were a monoclonal
anti-␶ antibody (AT8, 1/1000; Immunogenetics) and a monoclonal
anti-A␤ antibody (4G8, 1/1000; Signet Laboratories). Tissues were
incubated overnight at 4°C and sections were then processed by the
PAP method using 3,3⬘-diaminobenzidine as a chromogen.6 For
NFT, cases were classified as either transentorhinal (I and II), limbic
(III and IV), or neocortical Braak stages (V and VI). A␤-protein
deposition staging was performed according to the 4-phase nomenclature proposed by Thal.22 In phase 1, diffuse A␤ deposits are found
in the basal temporal neocortex. In phase 2, diffuse A␤ deposits
occur within external entorhinal layers, whereas punctate amyloid
deposits (“fleecy amyloid”) are seen in internal entorhinal layers and
the CA1 field of the hippocampus. The third phase is characterized
by increased A␤ deposition in the molecular layer of the dentate
gyrus, entorhinal cortex, and temporal neocortex, and in the parvopyramidal layer of the presubiculum. In phase 4, diffuse A␤ deposits
Cognitive Impact of Lacunes in the Elderly
1185
Demographic Data
Mean Age in Years
(SD)
No. of Cases
(Women/Men)
0
77.9 (9.2)
17 (10/7)
0.5
84.2 (9.3)
20 (11/9)
1
88.3 (4.2)
4 (1/3)
2
86.0 (7.2)
17 (8/9)
3
84.2 (5.6)
14 (7/7)
All cases combined
83.4 (8.4)
72 (37/35)
CDR
CDR indicates Clinical Dementia Rating; SD, standard deviation.
and core-only senile plaques (SP) are observed in the CA3– 4
hippocampal fields. This sequence of A␤ deposition is also followed
by neuritic plaques, which progressively invade the medial temporal
lobe in sites receiving afferent input from NFT-containing neurons.
To avoid the masking effect of substantial NFT-related pathology,
only cases with very early Braak NFT stages I and II were considered
in the present study (223 cases excluded with NFT stage ⬎II). For
the same reasons, cases with significant macrovascular pathology
other than lacunes were excluded. The final sample included 72
patients aged 63 to 100 years who did not meet any of the
aforementioned exclusion criteria and for whom presence and
severity of dementia was assessed in all cases using the CDR during
the 3 months before death (Table). All procedures involving use of
postmortem human brain were conducted after written consent of the
patients or their family and were approved by the Ethics Committee.
Lacunes were defined as small definitive ischemic necrosis, 1 mm
to 1.5 cm, located in white matter, basal ganglia, or thalamus. On
histological examination, lacunes consist of cavitations of cerebral
tissue with scattered fat-laden macrophages and surrounding gliosis.
Younger lesions show mild to severe rarefaction of neurons with
reduced number of oligodendrocytes and early signs of cavitation.
To visualize lacunes and significant microvascular pathology (ie,
cortical microinfacts, periventricular and diffuse white matter demyelination), tissue blocks from the anterior hippocampus, inferior
temporal cortex (area 20), frontal cortex (area 9), and parietal cortex
(area 40) bilaterally and basal ganglia and thalamus were cut into
20-␮m-thick sections and stained with the Globus silver impregnation technique4 (Figure 1). To assess diffuse white matter and
periventricular demyelination, coronal slices at the level of the
anterior border of the corpus callosum were embedded in paraffin,
cut into 20-␮m-thick sections, and stained with Luxol-van Gieson.
Lacunes and microvascular pathology assessed semiquantitatively in 10 sections per area were scored as follows: 0
(absence of such lesions), 1 (⬍3 lesions per slide), 2 (3 to 5 lesions
per slide), and 3 (⬎5 lesions per slide). A total score was obtained by
adding the scores of each area. Severity of diffuse white matter and
periventricular demyelination in each hemisphere was estimated in
Luxol-van Gieson–stained sections using a semi-quantitative scale:
0⫽absent, 1⫽mild, 2⫽moderate, and 3⫽severe. Scores for each
hemisphere were added to obtain a total score. Thus, 6 scores were
determined in each case and used for statistical analysis: a microinfarct score (all microinfarcts regardless of location), 2 demyelination
scores (diffuse white matter and periventricular white matter), and 3
lacunar scores according to region of interest (deep white matter,
basal ganglia, and thalamus). All neuropathological analyses were
performed by 2 independent investigators (E.K. and C.B.), blind to
the clinical findings, with a high inter-rater reliability (␬⫽0.90 to
0.95).
Maximal likelihood ordered logistic regression with proportional
odds was used to evaluate the association between CDR scores (the
dependent variable) and neuropathological parameters (A␤-protein
deposition staging, lacune and microvascular pathology scores as the
independent variables) in a univariate model. Subsequently, the same
method was applied in a multivariate model to take into account the
effect of age and the interaction between neuropathological variables. A␤-protein deposition staging, an ordinal scale with 4 levels,
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Figure 1. Cortical areas studied (a, b)
and representative examples of diffuse
white matter demyelination (c) with preservation of U-fibers, basal ganglia lacune
(d), and cortical microinfarcts (arrows) (e).
Scale bar indicates: c, 8 mm; d and e,
400 ␮m.
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was entered in the models as 3 dummy variables. Maximum
likelihood ordered logistic regression could be used to measure the
relationship between an ordinal outcome variable (CDR) and several
independent variables. It can also evaluate the amount of variability
of the outcome variable (ie, the CDR score) that can be explained by
the independent variables (ie, age, A␤-protein phase, lacune scores,
microinfarcts, and demyelination) and thus provide an estimate of
the strength of the relationship. Statistical analyses were performed
with Stata software package, release 8.2 (College Station, Tex).
Results
The study sample included 17 cases with no dementia (CDR
0), 20 cases with questionable dementia (CDR 0.5), and 35
cases with varying severity of dementia (CDR 1 to 3) (Table).
Lacunes were present in 21 cases in the basal ganglia, in 18
cases in deep white matter, and in 9 cases in the thalamus.
Cortical microinfarcts were found in 29 cases, periventricular
demyelination in 43 cases, and diffuse white matter demyelination in 62 cases. Mild A␤-protein deposition was present in
most cases (45.8% were stage A, 27.8% stage B), but 26%
displayed substantial A␤-protein deposition within the medial
temporal lobe (22.2% stage C, 4.2% stage D).
There were 16 cases with lacunes and without cortical
microinfarcts: 3 cases with no dementia (CDR⫽0), 3 cases
with questionable dementia, 6 cases with moderate dementia
(CDR⫽2), and 4 cases with severe dementia (CDR⫽3). The
3 cases with no dementia had small amounts of lacunes (score
of ⱕ1) in both deep white matter and basal ganglia. All but
one of these cases also had white matter lesions.
In a univariate model, A␤-protein deposition staging explained 7% (P⫽0.002; R2⫽0.07) and age only 3% (P⫽0.02;
R2⫽0.03) of the variability in CDR scores. Among the
different types of microvascular pathology, cortical microinfarcts (P⬍0.001), diffuse white matter (P⫽0.03), and
periventricular demyelination (P⫽0.01) were all significant
correlates of cognitive function and explained, respectively,
11% (R2⫽0.11), 6% (R2⫽0.06), and 6% (R2⫽0.06) of the
variability in cognitive function as measured by the CDR.
Lacunes in the thalamic and basal ganglia significantly
predicted cognitive status (P⫽0.02) and explained 5%
(R2⫽0.05) and 6% (R2⫽0.06) of CDR variability, respectively. However, there was no significant relationship between deep white matter lacunes and CDR score (P⫽0.19).
We performed a multivariate model including the following variables: age, A␤-protein deposition staging, thalamic
and basal ganglia lacune scores, microinfarct scores, and
periventricular and diffuse demyelination scores. It explained
29% of the clinical variability. In this analysis, only A␤protein deposition staging, cortical microinfarcts, and basal
ganglia and thalamic lacunes scores were significantly related
to CDR. The latter 3 vascular variables were used to develop
a combined vascular score ([thalamic score ⫹ basal ganglia
score ⫹ microinfarct score] ⫼ 4; the microinfarct score was
divided by 4 to ensure that each of the 3 subscores had the
same weight). This combined score explained 22% of the
CDR variability (Figure 2). Importantly, in a forward stepwise regression model, the best predictors of cognitive status
were in order of decreasing strength cortical microinfarcts,
basal ganglia lacunes, thalamic lacunes, and A␤-protein
deposition staging. In this model, lacunes explained 17% of
the clinical variability.
Discussion
To our knowledge, this is the first study addressing the
cognitive impact of silent lacunar infarcts and microvascular
changes in an autopsy series of prospectively assessed elderly
individuals. Its strengths include the detailed analysis of
lacunes and different types of microvascular lesions in
cortical areas bilaterally and control for the most important
confounding variables (substantial NFT pathology corresponding to limbic and neocortical Braak stages and macroinfarcts) and use of multivariate models for statistical analysis, which can estimate the predictive value of each
neuropathological measure taking into account the strength of
their interaction. As usual, limitations related to the size of
Gold et al
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Figure 2. Relationship between clinical severity and the combined vascular score (see text for details).
the study population and neuropathological sampling methods must also be taken into account. However, in view of the
relative scarcity of cases with pathological changes confined
to lacunes, demyelination, and microinfarcts, our series represents an unusually large autopsy cohort. Moreover, although we cannot exclude that additional pathology may have
been present mainly in neocortical areas, we have minimized
this bias by examining ten sections per area.
Consistent with our previous observations in an autopsy
sample including elderly individuals with isolated microvascular pathology,4 cortical microinfarcts and periventricular
and diffuse white matter demyelination were all significant
determinants of cognitive decline in this series. Not surprisingly, this association was substantially weaker in the present
cohort of cases with mixed vascular pathology compared with
our previous results.4 Most importantly, the relationship
between CDR scores and both diffuse white matter and
periventricular demyelination was no longer significant after
controlling for lacunes using multivariate models. This is not
surprising because lacunes and demyelination often co-exist
(95% of our cases with lacunes also had white matter
demyelination); thus, once one variable is taken into account,
in a multivariate model, the other adds little information.
More importantly, our neuropathological data suggest that
lacunes were the stronger correlate of cognitive status and
that additional white matter demyelination had little added
effect on intellectual function. This contrasts with results of
several structural imaging studies that reported that white
matter signal hyperintensities but not lacunes were related to
cognitive measures in brain aging.23–25 One possible explanation for this discrepancy resides in poor radiologic–pathologic correlation. Two recent contributions comparing MRI to
postmortem data demonstrated poor association between the
presence of whiter matter hyperintensities and demyelination.26,27 White matter lesions depicted on MR images corre-
Cognitive Impact of Lacunes in the Elderly
1187
spond to variable combinations of myelin and axonal loss and
scattered microinfarcts, astrogliosis, and dilatation of
periventricular spaces.27 Moreover, the radiologic concept of
lacune covers a wide spectrum of histological changes such
as complete infarcts, areas of focal gliosis, and perivascular
space.24,28 In agreement with the recently developed concept
of subcortical ischemic vascular dementia, our series provides
important autopsy evidence that thalamic and basal ganglia
lacunes are independent predictors of cognitive decline in the
elderly.14,29,30
The present data also support the strategic importance of
location in defining the cognitive impact of lacunes.31,32 In
univariate and multivariate models, thalamic and basal ganglia but not deep white matter lacunes significantly predicted
CDR scores. It has long been considered that cognitive
deterioration in patients with lacunes may result from disruption of subcortical–frontal circuits.33,34 The present findings
are partly consistent with this hypothesis because they indicate that damage in subcortical gray matter may decisively
influence cognitive performances. However, they clearly
demonstrate that the frequent development of lacunes within
deep white matter in brain aging is not sufficient to induce
dementia.5
It is noteworthy that assessment of vascular pathology in
the present series can predict at best 22% of CDR variability.
This value is comparable to that previously reported for NFT
Braak staging in a large autopsy series,16 indicating that
assessment of microvascular changes and lacunes may represent a valid predictor of cognitive decline, in the absence of
substantial NFT pathology, as strong as NFT staging in
elderly individuals without vascular pathology. The relative
weakness of the relationship between vascular pathology and
cognitive status may reflect methodological issues related to
semi-quantitative assessment of microvascular changes and
lacunes. This possibility is further supported by recent findings showing that rigorous stereological assessment of NFT
in vascular pathology-free cases leads to ⬎85% prediction of
clinical variability.17 Alternatively, other neuropathological
variables such as neuronal or synaptic loss may decisively
contribute to cognitive impairment in this context. The
analysis of large autopsy series including various cognitive
parameters and stereological assessment of microvascular
changes, lacunes, as well as neuronal and synaptic loss is
warranted to define precisely the structural background of
dementia in cases with predominant vascular pathology.
These new data may be also relevant with respect to current
efforts at neuropathological standardization in the dementia
field. The current debate regarding the definition of these
conditions mostly reflects the difficulty in evaluating the
relative clinical impact of the various types of vascular
lesions in pure vascular cases and defining the synergistic
effect of vascular and AD-type changes in mixed conditions.
Our previous work in cases with isolated microscopic ischemic pathology led to the conclusion that cortical microinfarcts are a strong predictor of cognitive changes in brain
aging.4 The present observations complete this first study by
providing an estimate of the cognitive consequences of gray
matter lacunes in cases without AD neuronal pathology.
These findings may be of particular importance for the
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June 2005
definition of neuropathological criteria for vascular and
mixed dementia and should serve as a basis for future
clinicopathological studies exploring the combined effect of
clinically relevant macroscopic and microscopic ischemic
vascular and degenerative changes in mixed conditions.
Acknowlegments
Supported by grants AG02219 and AG05138 from the National
Institutes of Health, Bethesda, Md (P.R.H.) and by an unrestricted
grant from the Jérôme Tissières Foundation (P.G.)
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Cognitive Consequences of Thalamic, Basal Ganglia, and Deep White Matter Lacunes in
Brain Aging and Dementia
Gabriel Gold, Enikö Kövari, François R. Herrmann, Alessandra Canuto, Patrick R. Hof,
Jean-Pierre Michel, Constantin Bouras and Panteleimon Giannakopoulos
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Stroke. published online May 12, 2005;
Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
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