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An Investigation of Clinical Correlates of Lewy Bodies in Autopsy-Proven Alzheimer Disease
Yaakov Stern, PhD;
Diane Jacobs, PhD;
James Goldman, MD;
Estrella Gomez-Tortosa, PhD;
Bradley T. Hyman, MD, PhD;
Yan Liu, MD;
Juan Troncoso, PhD;
Karen Marder, MD, MPH;
Ming X. Tang, PhD;
Jason Brandt, PhD;
Marilyn Albert, PhD
Arch Neurol. 2001;58:460-465.
ABSTRACT
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Background Studies of patients meeting clinical and pathologic criteria for Alzheimer
disease (AD) have not consistently found associations between the presence
of Lewy bodies (LBs) at postmortem examination and a higher frequency during
life of the clinical features of dementia with LBs.
Objective To evaluate the clinical correlates of LBs in patients with AD.
Design and Methods Fifty-one patients were diagnosed as having probable AD during life
and met pathologic criteria for AD. Semiquantitative ratings for LBs were
obtained in 4 brain regions: substantia nigra, cingulate, insular cortex,
and hippocampus. The patients had been followed up semiannually for up to
9.9 years before death, and clinical features associated with dementia with
LBs, including extrapyramidal signs and visual hallucinations, were assessed
at each study visit. Logistic regression analyses determined whether patients
who had LBs were more likely than those without LBs to express specific clinical
signs during follow-up. Cox analyses determined whether patients with LBs
developed clinical signs or died earlier. Generalized estimating equations
were used to compare rates of cognitive or functional change.
Results Nineteen of the 51 patients had at least 1 LB in one of the studied
regions. In no case was a significant relation noted between LBs and the presence
of a measured clinical sign. No LB measure was associated with an increased
risk of developing any of the evaluated clinical signs earlier in the disease.
There was no association between the presence of LBs and more rapid mortality
or more rapid disease progression.
Conclusions In patients diagnosed as having AD during life, we did not observe a
relation of LBs noted during postmortem examination with the presence of any
clinical feature that we assessed or with the rapidity of disease progression.
The relation between LBs and specific clinical manifestations may be tenuous
in these patients.
INTRODUCTION
AS MANY AS one third to half of patients diagnosed as having Alzheimer
disease (AD) have concomitant Lewy bodies (LBs) when examined at autopsy.
Several studies have asked whether, in patients who meet clinical and pathologic
criteria for AD, there are unique or additional clinical features associated
with the presence of LBs.1, 2, 3, 4, 5, 6, 7, 8, 9
The clinical features of interest are those that have been associated with
dementia with Lewy bodies (DLB), including extrapyramidal signs (EPS) and
psychiatric features (especially visual hallucinations).10
The findings to date have been inconsistent. The present study was designed
to address this issue, using patients from the Predictors Study.11
The Predictors Study was designed to study the natural history of patients
who meet clinical criteria for probable AD. These patients were followed up
prospectively with semiannual visits for up to 9.9 years before their death,
and clinical features were recorded at each visit. None of the patients in
the Predictors Study could be clinically diagnosed as having DLB to the exclusion
of AD. However, many had some of the clinical manifestations associated with
DLB, including visual hallucinations and EPS. At autopsy, semiquantitative
ratings for LBs were obtained in 4 brain regions. The present analyses determined
whether those who had LBs were more likely than those without to exhibit some
of the clinical features that have been associated with DLB.
SUBJECTS AND METHODS
SUBJECTS
The Predictors Study cohort consists of 236 patients with probable AD
recruited at 3 sites: Columbia University College of Physicians and Surgeons,
New York, NY, The Johns Hopkins University School of Medicine, Baltimore,
Md, and Massachusetts General Hospital, Boston. Inclusion and exclusion criteria,
recruitment methods, and the full evaluation methods have been described previously.11 All patients met National Institute of Neurological
Disorders and Stroke–Alzheimer's Disease and Related Disorders Association
criteria for probable AD,12 except that clinically
silent, small subcortical lesions were allowed. To ensure that severity of
dementia was mild at study entry, all patients were required to have a modified
Mini-Mental State Examination (mMMSE)13 score
of 30 or above (corresponding to approximately 16 on the standard MMSE). To
ensure accurate initial assessment of psychotic symptoms, all patients were
required to have not been taking neuroleptic medications for at least 1 month
before their initial evaluation.
We attempted to follow up all subjects semiannually until they died.
At the time of these analyses, 130 patients had died; autopsies were obtained
for 61 of them. Final neuropathologic diagnoses are available from 57 autopsies.
In 52 (91%) of these 57 cases, the diagnosis of AD was confirmed at autopsy.
Two additional cases had senile changes consistent with AD that were not sufficient
for the diagnosis of AD (eg, focal tangles). Of the remaining 3 patients,
2 had hippocampal sclerosis and 1 had Creutzfeldt-Jacob disease. Of the 52
patients diagnosed as having AD at postmortem examination, material for this
pathologic evaluation study was available for 51.
Thus, 51 patients were included in the present study. These patients
were members of the Predictors Study cohort who underwent autopsy, who were
diagnosed as having AD at postmortem examination, and for whom sufficient
postmortem material was available for these pathologic studies.
CLINICAL FEATURES
The following clinical features were assessed at each 6-month visit
from the initial study visit until death.
Extrapyramidal Signs
Selected items from the Unified Parkinson's Disease Rating Scale14 were used to rate extrapyramidal motor signs. Hypophonia,
masked facies, resting tremor, rigidity (neck and each limb), bradykinesia
or hypokinesia, and posture and gait abnormalities were rated as absent, slight,
mild-moderate, marked, or severe (see Richards et al15
for complete form). In addition to evaluating individual motor signs, the
presence or absence of EPS in general was considered. Patients who had at
least 1 sign rated mild-moderate or worse were considered to have EPS, since
ratings of this severity are relatively more reliable and are likely to be
noted by the average clinician.15 Our analyses
focused on both drug- and non–drug-induced EPS. If, at the visit when
they were first detected, the patient was currently taking or had ever taken
medications that could induce EPS, then the signs were considered to be drug
induced. Otherwise, they were considered non–drug induced, even if at
subsequent visits the patient received medications that could induce EPS.
Myoclonus
The presence of myoclonus was also assessed as part of the neurological
evaluation and through a structured clinical history.
Psychosis
A semistructured interview, the Columbia University Scale for Psychopathology
in Alzheimer's Disease,16 was used to elicit
information about delusions, hallucinations, and other specific behavioral
signs and mental states that occurred the month before assessment. Specific
delusions queried included paranoid delusions, delusions of abandonment, somatic
delusions, and misidentifications. For the purpose of the present analyses,
a delusion was considered present regardless of its frequency of expression
or the patient's acceptance of dissuasion. Visual, auditory, olfactory, and
tactile hallucinations and illusions were specifically queried.
Cognition
Cognitive function was examined using the mMMSE,13, 17
which includes the standard MMSE,18 the Wechsler
Adult Intelligence Scale digit span subtest,19
and additional attention and calculation, general knowledge, language, and
construction items. The maximum score on this test is 57.
Other measures were also obtained at each study visit, including the
Blessed Dementia Rating Scale (part 1)20 (BDRS)
to assess functional capacity and the Clinical Dementia Rating (CDR) scale21 to rate the overall severity of the dementia.
The apolipoprotein E (APOE)  genotypes were available for 32 of
the patients. The APOE genotype was determined after isolating DNA from white
blood cells and digesting the DNA with HhaI. The
method for APOE genotyping by Hixson and Vernier22
was modified slightly.23
NEUROPATHOLOGIC EVALUATION
All cases considered herein met neuropathologic criteria for AD using
the Consortium to Establish a Registry for Alzheimer's Disease criteria.24 In addition, the presence of LBs was evaluated.
Lewy bodies in the substantia nigra were rated as present or absent.
We performed semiquantitative ratings of LBs in 3 other brain regions. Paraffin
sections of cingulate, insular cortex, and hippocampus (parahippocampal cortex
at the level of the lateral geniculate nucleus) were cut 7-µm thick
and stained with an antibody to ubiquitin, using an avidin-biotin peroxidase
technique and microwaving (10 minutes at high, 10 minutes at defrost in citrate
buffer, pH 6.0, for antigen retrieval). Three randomly selected x10
microscopic fields from each section were rated for the presence of ubiquitin-reactive
inclusions, using the following scale: absent, 1 to 5 per field, 6 to 10 per
field, or more than 10 per field. The mean of the 3 ratings was used as a
quantitative measure of LB pathologic findings. For some analyses, LBs were
also rated as present or absent in each brain region.
STATISTICAL ANALYSES
The intent of the analyses was to determine whether there were differences
in the clinical presentation of patients with and without LBs. Both summary
variables (such as EPS or psychosis) and specific components of these summary
variables (such as rigidity or hallucinations) were included in separate analyses.
The following clinical outcomes were evaluated: the presence of non–drug-induced,
drug-induced, or both non–drug-induced and drug-induced EPS and specific
motor signs, including tremor, rigidity, bradykinesia, gait disorder, or hypophonia;
myoclonus; the presence of psychotic features and specific features, including
hallucination (and, specifically, visual hallucinations), delusions, and illusions;
and mortality. The initial approach used cross-tabulation and the  2 statistic to compare the frequency of specific clinical signs at any
point during follow-up in patients with and without LBs. Comparisons were
conducted for each region using both the semiquantitative ratings and the
present vs absent classification. In addition, patients with and without any
LBs in any region were compared. Follow-up logistic regression analyses were
used to control for disparities in sex and duration of illness.
Cox analyses were used to determine whether the presence of LBs at postmortem
examination was associated with clinical signs emerging earlier in the disease.
Cox analyses were also used to evaluate potential differences in survival
among patients with and without LBs.
To determine whether the rate of decline differed in patients with and
without LBs, analysis of prospective change in the mMMSE and BDRS scores was
performed by applying generalized estimating equations to regression analyses
with repeated measures.25
RESULTS
CLINICAL SEVERITY AT ENTRY AND FREQUENCY OF LBs
Most patients had mild disease severity at the intake visit; CDR was
rated as mild in 84.3% (Table 1)
and the mMMSE score averaged 36.9 of 57. Table 2 summarizes the frequency of observed LBs in the studied
regions of interest. Nineteen of the 51 patients had at least one LB in one
of the studied regions. Demographic and clinical features of the patients
at the intake visit were compared in patients who did and did not have LBs.
At the initial visit, there was no significant difference between the groups
in age, mMMSE score, BDRS score, education, or frequency of patients with
an APOE 4 allele. Patients with LBs were more
likely to be male (2 = 8.1, P<.01).
There was a trend for the patients with LBs to have a longer duration of illness
at the initial study visit than those without LBs (t
= 1.8, P<.09) and for them to have a CDR of mild
vs moderate dementia severity (2 = 2.5, P<.12).
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Table 1. Demographic and Clinical Variables at the Intake Visit in
Patients With and Without Lewy Bodies (LBs)*
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Table 2. Number of Lewy Bodies Noted at Postmortem Examination in 51
Patients*
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RELATION OF LBs TO CLINICAL MANIFESTATIONS
Table 3 summarizes the frequency of the occurrence of specific clinical features
in patients with and without LBs. The relation between the presence of LBs
and specific clinical features of the disease was explored using cross-tabulation,
the 2 statistic, and logistic regression analyses. Clinical
features were considered to have been present if they were expressed at any
point during patient follow-up. The presence or absence of any LBs, the presence
or absence of LBs in each sampled area, and the semiquantitative ratings for
LBs in each sampled area were all considered in separate analyses. In each
case, separate analyses explored the potential relation between LBs and each
of the clinical signs listed in Table 1. Follow-up logistic regression analyses controlled for sex or duration
of illness. In no case was a significant relation between LBs and the presence
of a clinical sign noted.
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Table 3. Frequency of the Occurrence of Clinical Signs at Any Time
During Follow-up in Patients Without and With Lewy Bodies (LBs) at Postmortem
Examination
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RELATION OF LBs TO RISK OF EXPRESSION OF CLINICAL SIGNS AND MORTALITY
Cox proportional hazard analyses were conducted to determine if the
presence of LBs at postmortem examination was associated with an increased
risk of expressing a clinical sign during the disease or an increased risk
of expressing the sign earlier. No LB measure was associated with an increased
risk of any of the evaluated clinical signs. Follow-up analyses included duration
of illness as a covariate. Again, no LB measure was associated with an increased
risk of any of the evaluated clinical signs.
Using Cox analyses, there was no association between the presence of
LBs and more rapid mortality.
RAPIDITY OF PROGRESSION
Generalized estimating equation analyses were applied to the prospectively
collected mMMSE scores. Separate generalized estimating equation analyses
were conducted to assess the effect of the presence or absence of LBs in each
brain region. The analyses demonstrated a significant decline in mMMSE scores
over time of approximately 3.6 points per 6-month follow-up interval. Across
all analyses, there were no differences between patients with and without
LBs in mMMSE scores at the initial evaluation (ie, no significant group effect)
or in the rate of change of mMMSE scores over time (ie, no significant interaction
effect). Similar analysis of the prospectively collected BDRS scores showed
no difference between the groups at the initial visit and no group differences
in the rate of change over time. Thus, the rate of cognitive and functional
progression of the disease did not differ across the 2 groups.
COMMENT
We attempted to determine if there was an association between the presence
of LBs in 4 selected brain regions post mortem and clinical features noted
in extensive follow-up of the patients during life. We found that the presence
of LBs was not related to increased frequency of EPS in general or of any
specific extrapyramidal motor sign, psychosis or any specific psychotic feature,
or myoclonus. Similarly, we found no relation between LBs and increased risk
of developing any of these disease features. Finally, we found no relation
between LBs and more rapid disease progression or mortality.
A major contribution of the present analyses lies in the careful clinical
follow-up that patients received. The patients were studied prospectively,
with semiannual examinations, for a mean ± SD of 4.6 ± 2.0 years.
Clinical signs of interest were ascertained and coded in a standardized fashion
at each study visit. This eliminates the potential biases inherent in deriving
clinical information from retrospective chart reviews. Long-term follow-up
of the patients also minimized the possibility that clinical signs were not
detected at a single clinical evaluation or developed after the clinical evaluation.
We also recognize several weaknesses to the analyses presented herein.
With regard to the pathologic studies, the semiquantitative analyses of LBs
were limited to a small number of brain regions and did not include any regions
of association cortex, and some brain samples were unavailable for some of
the patients. However, we analyzed the nigra and the paralimbic regions of
the brain that are among the most severely affected brain regions in DLB.
We also recognize that ubiquitin may not be as sensitive or specific as  -synuclein
immunostaining for detecting LBs, and in principle neurofibrillary tangles
might be misidentified as LBs. However, quantitative analyses in our laboratories
have shown that the number of ubiquitin-positive LBs is virtually identical
to the number of -synuclein–positive LBs,26
and experienced investigators can differentiate LBs from neurofibrillary tangles.
Some clinical features that have been associated with DLB (eg, falls,
syncope, or fluctuations in cognitive functioning) were not formally assessed.
It is possible that these might have shown a stronger relation to the presence
of LBs.
It is important to stress that the present sample did not include patients
encompassing the full clinical spectrum of DLB. Rather, all of the patients
in the present study were diagnosed clinically as having AD, had to be mildly
impaired clinically, and had to not be taking neuroleptics for 1 month before
the initial evaluation. All patients were evaluated initially for cognitive
as opposed to motor complaints. These data are most relevant to the issue
of whether variability in the clinical spectrum in patients diagnosed clinically
as having probable AD is a function of LBs. The data herein do not provide
information about clinicopathologic relations in DLB.
Table 4 summarizes other
studies that have compared clinical features of patients with AD with and
without LBs. For many of the clinical features addressed in these studies,
the results are inconsistent. Compared with those without LBs, patients with
AD with LBs have been reported to have more essential tremor and masked facies1; more severe rigidity,3
increased bradykinesia, masked facies, shuffling gait, and rigidity4; and increased frequency of 1 or more of a group of
EPS.5, 6 Two studies2, 7
besides our own found no differences in the frequency of EPS, although the
latter found more frequent extrapyramidal side effects of neuroleptics.
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Table 4. Summary of Articles Comparing Patients With Alzheimer Disease
(AD) With and Without Lewy Bodies (LBs)*
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It is notable that EPS were present in 32 subjects who lacked LBs at
autopsy. Another study evaluated EPS in patients with AD who had no LBs and
found that they were associated with the number of neurofibrillary tangles
and neuropil threads in the substantia nigra.27
This suggests that there can be multiple causes of EPS in AD, and their presence
does not necessarily indicate the presence of LBs. A recent study of diagnostic
accuracy of dementia with LBs in 10 patients also found that of the 5 misdiagnosed
patients 4 had AD with EPS.28
With regard to psychiatric symptoms, 2 studies2, 7
reported increased frequency of hallucinations, delusions, and depression,
and another4 reported increased visual hallucinations
only in AD with LBs. Two other studies1, 3
besides our own reported no differences in psychiatric features.
Four studies3, 6, 7, 8
besides our own noted no difference in dementia severity in patients with
AD with and without LBs. Another found that patients with AD with LBs performed
worse on delayed recall on a list learning task but not on other memory measures
or cognitive tests.5 One reported increased
dementia severity.2 Three studies found different
patterns of cognitive changes in the face of equivalent overall dementia severity.
One reported that patients with AD with LBs had greater deficits in attention,
fluency, and visuospatial processing.1 A second
found that patients with AD plus LBs performed more poorly on tests of arithmetic,
verbal fluency, visuospatial processing, and psychomotor speed.4
The third found that patients with AD without LBs performed more poorly on
the memory subscale on the Dementia Rating Scale, whereas the AD plus LB group
performed more poorly on the initiation and perseveration scale.9
Six studies1, 3, 4, 5, 7, 8
besides our own noted no differences in rate of disease progression or survival
between patients with AD with and without LBs. One study2
reported decreased survival time, and another6
reported both an increased rate of cognitive decline and decreased survival
time.
Several considerations affect the interpretation of studies in this
area and may account for some of the variability in findings. Since LBs are
just one of many pathologic variables that may contribute to the clinical
picture, it may be important to evaluate clinical correlates of LBs in the
context of other pathologic indices, particularly measures of amyloid burden
and cell loss; to date, this has not been done systematically. In addition,
many studies, including the present one, examined brain tissue from a limited
number of areas. Often, only the presence or absence of LBs was coded. Finally,
the quality of the clinical information about patients during their lifetime
and the extent of clinical follow-up are variable.
In patients with AD, we did not observe any relation between the presence
or absence of LBs and any clinical feature that we assessed. Despite the quality
of our clinical information, one possibility is that more extensive neuropathologic
analyses will be required to observe these clinicopathologic relations. The
contribution of the LB to the clinical phenotype may not be sufficiently strong
enough to be revealed in the presence of concomitant AD. Alternately, the
relation between LBs and specific clinical manifestations may be tenuous among
patients with pathologically confirmed AD.
AUTHOR INFORMATION
Accepted for publication September 26, 2000.
This study was supported by federal grants AG07370, AG07232, and RR00645
and the Charles S. Robertson Gift for Alzheimer's Disease from the Banbury
Fund.
From the Departments of Neurology (Drs Stern, Jacobs, and Marder),
Psychiatry (Drs Stern and Marder), Pathology (Drs Goldman and Liu), and Biostatistics
(Dr Tang) and the Gertrude H. Sergievsky Center (Drs Stern, Jacobs, Marder,
and Tang) and Taub Alzheimer's Disease Research Center (Drs Stern, Goldman,
and Marder), Columbia University College of Physicians and Surgeons, New York,
NY; Departments of Pathology (Dr Troncoso) and Psychiatry and Behavioral Sciences
(Dr Brandt) and Alzheimer's Disease Research Center (Drs Troncoso and Brandt),
The Johns Hopkins University School of Medicine, Baltimore, Md; and Departments
of Neurology (Drs Gomez-Tortosa and Hyman) and Psychiatry (Dr Albert), Massachusetts
General Hospital, Harvard Medical School, Boston.
Corresponding author and reprints: Yaakov Stern, PhD, Sergievsky
Center, 630 W 168th St, New York, NY 10032 (e-mail: ys11{at}columbia.edu).
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