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Effect of Extrapyramidal Signs and Lewy Bodies on Survival in Patients With Alzheimer Disease
Mary N. Haan, MPH, DrPH;
William J. Jagust, MD;
Douglas Galasko, MD;
Jeffrey Kaye, MD
Arch Neurol. 2002;59:588-593.
ABSTRACT
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Background Patients with Alzheimer disease (AD) who have psychiatric and parkinsonian
symptoms experience faster cognitive deterioration and shorter survival vs
those without such disease features. Extrapyramidal signs (EPSs) in particular
have been associated with the presence of Lewy bodies (LBs) on autopsy and
with poorer survival in patients with AD. Lewy bodies found at autopsy are
not always correlated with EPSs during late life.
Objective To determine whether the association between LBs and age at death is
modified by the presence of EPSs, hallucinations, or delusions.
Design An autopsy series of patients with clinically diagnosed AD.
Settings Three AD clinics (San Diego and Sacramento, Calif, and Portland, Ore).
Patients Data on 379 patients with a clinical diagnosis of AD who were initially
assessed between May 1, 1984, and August 1, 1996, and who were autopsied between
January 1, 1990, and April 1, 1998, were pooled from 3 AD centers.
Main Outcome Measures Presence of LBs on autopsy and differences in age at death in those
with EPSs, LBs, or both.
Results Individuals with EPSs at initial assessment were more than 3 times as
likely to have LBs at autopsy than were those without EPSs. Age at death was
younger in those with LBs and EPSs than in those with LBs only and those without
EPSs or LBs.
Conclusions The presence of EPSs in patients with AD indicates worse prognosis and
may be related to underlying LBs. The presence of EPSs is a strong predictor
of LBs.
INTRODUCTION
IT IS WELL RECOGNIZED that disease progression and survival in patients
with Alzheimer disease (AD) vary considerably from patient to patient. Although
a host of clinical and demographic factors have been associated with prognosis,
some of the most widely reported and replicated factors include the presence
of extrapyramidal signs (EPSs) and symptoms of delusions and hallucinations.1-2 Patients with AD who have such symptoms
experience faster cognitive deterioration and shorter survival compared with
patients without these disease features.3 Such
patients may progress more rapidly for several reasons: they may be treated
more often with neuroleptic agents, they may have more advanced disease, or
they may have a distinct and more fulminant type of AD. A prime candidate
for a different form of AD that may progress more rapidly may be dementia
with Lewy bodies (DLB) because its diagnostic hallmarks include EPSs and psychotic
symptoms,4 which are associated with more rapid
progression. We sought to investigate the relationship between EPSs and symptoms
of delusions or hallucinations and (1) the presence of Lewy bodies (LBs) and
(2) survival in a cohort of 379 autopsied individuals enrolled and followed
at 3 AD centers.
PATIENTS AND METHODS
STUDY POPULATION
Study patients were evaluated, diagnosed, and followed clinically and
autopsied as part of 3 ongoing series at dementia research programs at the
National Institute on Aging Alzheimer Disease Centers at the University of
California, Davis; the University of California, San Diego; and Oregon Health
Sciences University. Patients provided written informed consent, and the study
was approved by the institutional review boards at the respective institutions.
Patients were initially evaluated at 1 of the 3 AD centers between May 1,
1984, and August 1, 1996. Only patients with a clinical diagnosis of AD who
were autopsied between January 1, 1990, and April 1, 1998, were included (N
= 379). Although these AD centers did not originally collaborate on data collection
or attempt to coordinate protocols for this study, each followed comparable
and standardized research protocols for clinical and pathological evaluation
and made clinical and pathological diagnoses using the same guidelines. Individuals
with DLB were excluded because they do not meet CERAD (Consortium to Establish
a Registry for Alzheimer's Disease) criteria for AD. Each contributing site
had few such patients, and there was not sufficient power to analyze DLB as
a subgroup. Patients with a clinical diagnosis of LBs or DLB also met criteria
for possible AD. Because DLB criteria were not published until 1996, they
were not available for most patients in this study.
Patients at each AD center underwent a comprehensive initial evaluation
that included neurological, psychiatric, and medical histories; a structured
neurological examination; psychometric testing; laboratory testing to exclude
treatable or reversible causes of dementia; and review of neuroimaging studies.
At the initial assessment, patients were asked for autopsy consent. For this
analysis, each center provided demographic information, initial Mini-Mental
State Examination (MMSE) scores, and information on symptoms of delusions
or hallucinations and EPSs from each patient's initial evaluation. A structured
examination of parkinsonian features (EPSs) was carried out by a neurologist
(W.J.J., D.G., and J.K.) for each patient included in this analysis. All 3
AD centers have used the Unified Parkinson's Disease Rating Scale5 since the early 1990s, and the sample was restricted
to patients autopsied from 1990 onward. Before use of the Unified Parkinson's
Disease Rating Scale, a structured neurological examination rating most aspects
of parkinsonism that are assessed in the Columbia Rating Scale was used. Extrapyramidal
signs were defined as present if at least 2 of the following signs were noted:
bradykinesia, rigidity, rest tremor, parkinsonian gait, and masked facies.
Information about the presence or absence of delusions and hallucinations
was also collected from informants of patients using semistructured interviews.
From 1985 onward, the Diagnostic Inventory Schedule was used as a structured
inquiry about psychiatric symptoms and alcohol use. Cases with AD and LBs
are equivalent to the LB variant of AD. Patients were selected for inclusion
in this analysis based on neuropathological diagnoses. All patients who met
CERAD criteria6 for definite, probable, or
possible AD were included. These patients were then categorized as to the
presence or absence of LBs in the brain in at least 1 of the following areas:
substantia nigra, nucleus basalis of Meynert, temporal lobe, frontal lobe,
parietal, cingulate cortex, and hippocampal structures. Counts of the total
number of LBs in each brain by region were not available; therefore, LBs were
simply categorized as present or absent. Sixty-two percent of patients who
died were autopsied during the study (January 1, 1990, to April 1, 1998).
AUTOPSY EVALUATION
All 3 AD centers used a similar set of procedures to examine brains
at autopsy. The brain was removed, usually within 24 hours of death, and sagittally
divided. Coronal slices were cut and examined for infarcts and other gross
pathological features. Half of each brain was frozen for neurochemical examination,
and the other half was fixed in formalin, stained, and examined microscopically.
Sections from standardized brain regions were examined for AD pathological
features and other lesions, as specified by the CERAD recommendations for
autopsy evaluation.7 At each AD center, paraffin
blocks were obtained from at least the following regions: the neocortex of
the frontal, parietal, superotemporal, and occipital lobes; hippocampus; entorhinal
cortex; amygdala; substantia innominata; substantia nigra; basal ganglia;
pons; and cerebellar vermis. Sections from all blocks were stained with hematoxylin-eosin,
and additional staining methods were used to detect plaques and tangles (thioflavin-S
at the San Diego center and Bielschowsky silver impregnation at the Davis
and Oregon centers). Plaques and tangles were visually counted on 10-µm
sections of each neocortical and hippocampal area. After surveying each section
to find areas with the most lesions, senile plaques were counted in 3 microscopic
fields (original magnification x125), and neurofibrillary tangles were
counted in 3 fields (original magnification x500). Lewy bodies were
initially detected by examining hematoxylin-eosin–stained sections of
substantia nigra and other subcortical and neocortical areas and were confirmed
by immunostaining with antibodies against ubiquitin. The neuropathological
diagnosis of AD was based on semiquantitative assessment of the frequency
of neuritic plaques, adjusted for age according to CERAD guidelines.
STATISTICAL METHODS
Extrapyramidal signs, psychiatric symptoms, LBs, and AD diagnosis were
coded as binomial variables. Univariate and bivariate descriptive analyses
of categorical variables were performed using percentage and frequency distributions.
Mean differences by LBs for age at initial assessment and at death, years
of education, and MMSE score at initial assessment were compared using analysis
of variance (SAS PROC GLM; SAS Institute Inc, Cary, NC). The percentages of
EPSs, delusions, and hallucinations were examined overall and were compared
with respect to the presence or absence of LBs. Differences at AD centers
with respect to the occurrence of LBs, psychiatric symptoms, and EPSs were
also compared using a logistic regression model. Center was included as a
covariate in all regression models. We first examined differences in survival
using a life-table approach (PROC LIFETEST; SAS Institute Inc), with age at
death as the time variable. Log-rank tests were used to test survival differences
across strata categorized by the presence or absence of LBs and EPSs. We further
examined survival differences by the presence or absence of EPSs and LBs,
with age at death as the dependent variable in a regression model. The statistical
model used was a life-table regression procedure (PROC LIFEREG; SAS Institute
Inc), with a Weibull distribution assumption for failure time included. The
LIFEREG procedure fits parametric models to failure time data that can be
right, left, or interval censored. The models for the response variable consist
of a linear effect composed of the covariates and a random disturbance term.
The random disturbance term in this study was a Weibull distribution. The
PROC LIFEREG estimates the SEs of the variable estimates from the inverse
of the observed information matrix. The accelerated failure time model assumes
that the effect of independent variables on an event time distribution is
multiplicative on the event time. This model included age at death as the
dependent variable and EPSs, LBs, or combined EPSs and LBs along with a variable
accounting for AD center. Other potentially important confounders (age at
initial assessment, sex, educational level, and MMSE score) were examined.
These did not affect the statistical significance or the magnitude of the
association between EPSs, LBs, or EPSs and LBs and were not included in the
final model.
RESULTS
Table 1 gives mean values
for age at initial assessment, age at death, education, MMSE score, and survival
from initial assessment overall and by pathological diagnosis status. Nearly
24% of men and 14% of women had LBs (P = .01). Age
at clinical diagnosis, education, and MMSE score did not differ significantly
across diagnostic categories. There were significant differences by diagnostic
category for age at death and for time from initial assessment to death. Age
at death was lower for those with EPSs and LBs compared with those with no
disease (P = .008) but did not differ significantly
from those with EPSs only (P = .24) or LBs only (P = .09). Follow-up was significantly shorter in those
with EPSs and LBs compared with those with neither (P<.001)
and those with LBs only (P = .04). Table 2 give the mean (SD) values for age at initial assessment,
age at death, education, MMSE score, and follow-up by AD center. There were
significant AD center differences in age at initial assessment, education,
MMSE score, and follow-up. Compared with patients at the Sacramento and Oregon
centers, those at the San Diego clinic were younger at initial assessment,
had higher MMSE scores, and had longer follow-up. Patients at the San Diego
center were more educated than those at the Sacramento center but not those
at the Oregon AD center. The Sacramento and Oregon centers did not differ
on any of these measures.
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Table 1. Characteristics of 379 Autopsied Patients With Alzheimer Disease
by Neuropathological Diagnosis of Lewy Bodies*
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Table 2. Characteristics of 379 Autopsied Patients With Alzheimer Disease
by Alzheimer Disease Center From an ANOVA Regression Model*
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Table 3 gives percentages
and odds ratios with 95% confidence intervals from a logistic regression model
for the association between EPSs, hallucinations, or delusions and the presence
or absence of LBs. Patients with EPSs had a 3.5-fold increased risk of LBs,
and those with hallucinations had a 3.6-fold increased risk of LBs on autopsy.
Delusions were not associated with an increased risk of LBs. Most patients
with LBs did not have EPSs, hallucinations, or delusions (57%). However, the
ability of EPSs to predict the presence of LBs was relatively low. The sensitivity
and specificity of EPSs in detecting LBs were 36% and 87%, respectively. The
positive predictive value was 39%, and the negative predictive value was 85.3%.
The overall prevalence of LBs in patients with EPSs was 39% (26/67). The absence
of EPSs was a strong predictor of a lack of LBs found on autopsy.
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Table 3. Association Between Extrapyramidal Signs and Psychiatric Symptoms
and LBs From a Logistic Regression Model*
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Life-table analyses were used to examine unadjusted differences in age
at death for patients with LBs, EPSs, and LBs and EPSs combined compared with
those with neither diagnosis (Figure 1). All 3 groups with pathological symptoms from LBs or EPSs differed significantly
from those with no pathological symptoms (log-rank test for model, 13.8; P = .003). Among patients with at least 1 pathological
symptom, those with EPSs only had the longest survival (oldest age at death),
followed by patients with LBs only.
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Survival differences by the presence of extrapyramidal signs (EPSs)
and Lewy bodies (LBs) from a life-table analysis.
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Survival differences by LBs, EPSs, and LBs and EPSs combined were further
examined using a regression model with a Weibull distribution that included
adjustment for AD center and had age at death as the dependent variable (Table 4). The estimates shown are exponentiated
regression coefficients. For a 5-year difference in age at death, survival
among patients with EPSs and LBs combined was significantly worse compared
with those with no pathological diagnosis and those with either pathological
diagnosis. Survival rates in those with LBs or EPSs only were worse compared
with those with no pathological disease, but the 95% confidence interval included
1.0. Inclusion of AD center also did not affect the significance or magnitude
of the association between pathological diagnosis and age at death.
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Table 4. Association Between Age at Death (1-Year Difference) in Autopsied
Patients With a Clinical Diagnosis of AD With LBs, EPSs, or Both From a Regression
Model (Weibull Distribution) Including AD Center*
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COMMENT
We found that patients with AD who have LBs die at a significantly earlier
age than those who do not have LBs. Among those with EPSs only, the overall
survival rate is substantially worse compared with those with no pathological
disease. The survival rate is significantly worse in those with both LBs and
EPSs, suggesting a synergistic effect and that EPSs may be associated with
more advanced disease. These findings agree with those of many previous studies1-3 that the presence of
clinical signs of EPSs may be a prognostic indicator for survival in patients
with AD. However, our results extend those of these studies by linking the
clinical signs to the presence of LBs and by linking the presence of LBs to
survival. Although EPSs are not sensitive as indicators of the presence of
LBs, the absence of EPSs is a fairly strong indicator that LBs are not present
(specificity). The positive and negative predictive values of EPSs for LBs
are fairly high as well. However, most patients with EPSs do not have LBs,
and there is not a perfect correlation between this symptom and underlying
LBs.
Lewy bodies are detected in 15% to 25% of autopsies of individuals who
had primary progressive dementia. Our finding of 19% in autopsied cases is
in the mid-range. There are indications in some other studies that patients
with AD and LBs may progress more rapidly and may have worse survival rates
than those with AD alone. However, other researchers8
have not found any survival difference. Lopez et al9
reported recently that in a sample of 185 patients with AD, patients with
LBs are more likely to be institutionalized and to develop EPSs than those
without LBs but that they do not differ from patients without LBs with respect
to survival rate and cognitive and functional decline. Patients with LBs in
the study by Lopez and colleagues also did not differ from patients without
LBs with respect to delusions and hallucinations. To our knowledge, ours is
the largest study to date that pools patients from several AD centers to examine
this question and that adjusts for other covariates. Three hallmark clinical
features of DLB have been defined recently: fluctuation, parkinsonism, and
visual hallucinations, along with a group of supporting features.4 Although some of the reported variability in the prevalence
of these symptoms may be due to differences in clinical assessment methods
or in dementia severity, another possibility is that LBs may not always produce
a distinct clinical phenotype in patients with dementia. For example, in several
studies, LBs were thought to be incidental (or preclinical) lesions in elderly
patients.10-11 Factors such as
LB burden or distribution, or the presence and severity of associated AD lesions,
may modulate whether LBs manifest clinically. Conversely, the presence of
EPSs may mean different things in different patients. Bradykinesia and rigidity
are seen with a variety of motor disorders and do not imply specificity for
parkinsonian or nigrostriatal disorders. Our findings that EPSs in association
with LBs confer an even poorer prognosis than either finding alone may reflect
the fact that EPSs may have multiple different pathogenic mechanisms and that
LBs may be incidental or clinically unimportant in some patients.
There are other potential explanations for the effects of LBs combined
with EPSs or hallucinations on survival rates. First, DLB accompanied by symptoms
such as parkinsonism or hallucinations may indicate a heavier burden of pathological
disease or neurochemical changes related to the presence or development of
LBs. Second, symptoms such as EPSs or hallucinations might lead to more treatment
with medications that can adversely affect patients' survival or cognitive
status, such as neuroleptics. Patients with DLB show neuroleptic sensitivity.12 We could not precisely ascertain data on neuroleptic
exposure before or after initial evaluation systematically, and we did not
analyze the contribution of such agents to survival. Finally, LBs may differ
from one another in a significant way, such as brain location or burden, so
that their presence in some locations is more likely to produce symptoms.
However, results of recent work by Gomez-Tortosa et al13
suggest that LBs do not correlate well with clinical symptoms and that brain
location does not affect this kind of pattern.
Although the 3 AD centers had not previously agreed on clinical or pathological
assessment methods, there were many broad similarities between the findings
within each center. This large autopsy sample spanned about 7 years of consistently
applied clinical and pathological protocols. We restricted our sample to those
who died during or after 1990 to control for changes in pathological diagnostic
procedures. The CERAD procedures used at the 3 AD centers have previously
been found to be robust and reliable when applied across different centers
for the assessment of AD pathological conditions.14
At each AD center, LBs were identified using broadly similar approaches. Because
we did not exchange tissue, we cannot comment specifically about interrater
reliability among the neuropathologists at each site. We therefore did not
try to evaluate LB density or burden as a variable but used the simplest possible
categorization of LBs being present or absent in any location in the brain.
This approach would tend to bias our results toward the null hypothesis because
presumably patients with more LBs would have a worse prognosis, and we have
combined them with those with only 1 LB.
The method of detecting LBs, using hematoxylin-eosin and anti-ubiquitin
staining, may be less sensitive for appreciating the full extent of LB pathological
effects than immunostaining for  -synuclein. However, the techniques
used and the areas of brain tissue examined were consistent with standard
pathological practice at the time and were based on examination of representative
sections from a broad set of brain regions.
Despite the reasonable similarity of procedures across AD centers, several
factors may limit the interpretation of our results. There were center differences
in a variety of demographic and clinical variables. We adjusted for AD center
in all multivariate analyses to minimize this variability. Because we measured
dementia severity (MMSE), EPSs, and psychiatric symptoms at the initial evaluation
only, we have no way of knowing whether or when patients may have developed
these symptoms during follow-up. This constitutes a form of misclassification
that would be likely to attenuate the association found between these symptoms
and survival. Differences by AD center in the prevalence of EPSs, hallucinations,
and delusions may reflect differences in specific ratings or their interpretation
or differences in referral patterns among centers. We also excluded patients
in whom Parkinson disease may have preceded dementia, which has not always
been done in autopsy series of AD with LBs.
Extrapyramidal signs at initial assessment are associated with the presence
of LBs, and EPSs and LBs are independently associated with shorter survival.
Furthermore, the presence of EPSs and LBs in the same individual is associated
with a still poorer survival rate than either finding alone. These results
have consequences for our understanding of the pathogenesis of DLB. They confirm
the association between LBs and specific symptom complexes such as EPSs and
specific psychiatric symptoms (delusions and hallucinations). However, they
suggest that the relationship among EPSs, LBs, and survival rate is not straightforward
because EPSs and LBs contribute independently to survival. Finally, these
results suggest that the presence or absence of EPSs adds to the prediction
of LBs and thus provides additional pathological prognostic information.
AUTHOR INFORMATION
Accepted for publication November 29, 2001.
Author contributions: Study concept and design (Drs Haan, Jagust, and Galasko); acquisition of data (Drs Haan, Jagust, Galasko, and Kaye); analysis and interpretation
of data (Drs Haan, Jagust, Galasko, and Kaye); drafting
of the manuscript (Drs Haan and Jagust); critical
revision of the manuscript for important intellectual content (Drs Haan, Jagust, Galasko, and Kaye); statistical expertise (Dr Haan); obtained funding (Drs Jagust
and Kaye); administrative, technical, and material support (Drs Haan, Jagust, Galasko, and Kaye); study supervision (Dr Jagust).
This study was supported by grant NIA AG05131, National Institute on
Aging, Bethesda, Md.
Corresponding author and reprints: Mary N. Haan, MPH, DrPH, Department
of Epidemiology, University of Michigan, School of Public Health, 109 S Observatory
St, Ann Arbor, MI 48109-2029 (e-mail: mnhaan{at}umich.edu).
From the Department of Epidemiology, University of Michigan, School
of Public Health, Ann Arbor (Dr Haan); the Department of Neurology, University
of California, School of Medicine, Davis (Dr Jagust) and San Diego (Dr Galasko);
and the Department of Neurology, Oregon Health Sciences University, and Portland
Veterans Affairs Medical Center, Portland (Dr Kaye).
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