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Research Evaluation and Prospective Diagnosis of Dementia With Lewy Bodies
Oscar L. Lopez, MD;
James T. Becker, PhD;
Daniel I. Kaufer, MD;
Ronald L. Hamilton, MD;
Robert A. Sweet, MD;
William Klunk, MD;
Steven T. DeKosky, MD
Arch Neurol. 2002;59:43-46.
ABSTRACT
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Objective To evaluate the relative merits of recently developed criteria for dementia
with Lewy bodies (DLBs) in a longitudinal study of dementia.
Design The diagnosis of DLBs was used in combination with other clinical diagnosis.
Patients were classified primarily based on the NINCDS-ADRDA (National Institute
of Neurological and Communicative Disorders and Stroke–Alzheimer's Disease
and Related Disorders Association) clinical criteria for probable or possible
Alzheimer disease, or with other disease process that can cause dementia (eg,
Parkinson disease), and secondarily according to the consensus guidelines
for DLBs. This "double" clinical diagnosis was implemented to capture different
pathological entities. The neuropathological diagnosis of Lewy bodies was
made with monoclonal antibodies against  -synuclein.
Setting Multidisciplinary research clinic.
Results Prospective application of the consensus guidelines for DLBs from January
1, 1997, to September 29, 2000, identified 11 patients having the diagnosis
of probable DLBs and 35 having possible DLBs. The diagnosis of probable or
possible DLBs was associated with probable Alzheimer disease in 34 patients,
with possible Alzheimer disease in 5 patients, with Parkinson disease in 2
patients, and with other disease processes in 2 patients. Three patients were
diagnosed as having probable DLBs alone. An autopsy was performed in 26 of
the cases who were clinically examined during the study period. Cortical Lewy
bodies were identified in 13 cases; 4 had had premortem diagnosis of DLBs
(sensitivity, 30.7%; specificity, 100%).
Conclusions The prospective validation of the clinical criteria for DLBs showed
poor accuracy in this series. We believe that current criteria for DLBs are
useful when DLBs occur in isolation, but have low sensitivity when Lewy bodies
coexist with the pathological abnormalities of Alzheimer disease.
INTRODUCTION
THE RECENT proposal of clinical criteria for the diagnosis of dementia
with Lewy bodies (DLBs) presents new opportunities and challenges for clinicians
and researchers alike.1-3
Both Alzheimer disease (AD) and DLBs can have similar symptoms, and some studies
have shown that the criteria for diagnosis of DLBs have low sensitivity with
high specificity.4-7
However, most studies of the accuracy of these clinical criteria for DLBs
were retrospective, in most cases using patients whose clinical data were
gathered before the publication of current diagnostic criteria.1
This can mean that important aspects of the syndrome were either not recorded
or not carefully reviewed. Thus, it was thought that the accuracy for DLBs
would improve in prospective studies, and indeed, McKeith et al8
have reported a sensitivity of 83% and a specificity of 95% from their cohort.
The present report describes the merits of these new criteria when they were
applied in the context of an Alzheimer's Disease Research Center, University
of Pittsburgh, Pittsburgh, Pa. We used the DLB criteria in tandem with validated
criteria to diagnose other dementia syndromes of elderly persons (eg, NINCDS-ADRDA
[National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer's
Disease and Related Disorders Association],9
NINDS-AIREN [National Institute of Neurological Disorders and Stroke–Association
Internationale pour la Recherche et L'Enseigment en Neurosciences]10) and describe how this affected the accuracy of the
clinical DLBs classification.
SUBJECTS, MATERIALS, AND METHODS
DATA COLLECTION
We examined the clinical diagnosis and neuropsychiatric characteristics
of 46 subjects who presented to the Alzheimer's Disease Research Center, University
of Pittsburgh, Pittsburgh, Pa, and who were ultimately diagnosed as having
DLBs between January 1, 1997, and September 29, 2000. Each participant received
an extensive neuropsychiatric evaluation, including medical history and physical
examination, neurologic history and examination, semistructured psychiatric
interview, and neuropsychological assessment.11-12
At the conclusion of these studies, each individual's results were reviewed
by the study team (ie, neurologists, neuropsychologists, and psychiatrists)
at a consensus diagnostic conference. The diagnosis of dementia (a necessary
precondition for any consensus classification) was made when there was objective
evidence of progressive alterations in social or work abilities secondary
to cognitive loss, and when neuropsychological testing revealed impairments
in 2 or more cognitive domains (which did not necessarily include memory)
in the absence of reversible causes of cognitive impairment.
Once a patient was diagnosed as having dementia, we next applied the
NINCDS-ADRDA criteria for AD.9 After we had
determined whether an AD-related diagnosis was mandated, we then considered
other causes of dementia (eg, Parkinson disease, progressive supranuclear
palsy, or Creuztfeldt-Jacob disease). Once we had determined whether any of
these causes of dementia were present, or had specifically excluded them based
on existing clinical criteria, we secondarily applied the criteria for DLBs.
Thus, the diagnosis of DLBs was considered in all patients, but with other
causes of dementia being considered first. If patients with dementia met the
criteria for Parkinson disease13 based only
on motor symptoms, and had normal cognition (by history) for at least 3 years
after the Parkinson disease diagnosis, and prior to their dementia, they were
classified as having Parkinson disease with DLBs.
The diagnosis of DLBs was based on the consensus guidelines for the
clinical and pathological diagnosis of DLBs.1
Patients were classified as having probable DLBs when they had dementia and
2 of the 3 core features (ie, fluctuating cognition with pronounced variations
in attention and alertness, recurrent visual hallucinations, or spontaneous
motor features of parkinsonism), and possible DLBs when dementia and only
1 core feature was present.
NEUROPATHOLOGICAL DIAGNOSIS
The areas of the brain examined for pathological diagnosis were the
frontal cortex, anterior cingulate gyrus, insular cortex, amygdala, hippocampus,
enthorinal and transenthorinal cortices, parietal cortex, superior and middle
temporal cortices, thalamus, caudate nucleus, putamen, globus pallidus, substantia
nigra, and locus coeruleus. The neuropathological diagnosis of AD was based
on the Consortium to Establish a Registry for Alzheimer's Disease neuropathological
criteria14 and the National Institute on Aging
and Reagan Institute Working Group on Diagnostic Criteria for the Neuropathological
Assessment of Alzheimer's Disease.15
Lewy bodies (LBs) were identified using monoclonal antibodies against -synuclein,
which is increasingly recognized as a highly specific and sensitive marker
for LBs.16-18
Briefly, the deparaffinized sections of the appropriate regions were digested
for 1 minute with 100-mg type XXIV protease (Sigma-Tau Pharmaceuticals Inc,
Gaithersburg, Md) in 350 mL of distilled water to 37°C, followed by primary
antibody diluted in common antibody diluent (1:1600 for Chemicon and 1:1200
for LB509) (Biogenex, San Ramon, Calif). The staining was visualized using
a commercially available kit (LSAB-2 Kit; Dako, Carpenteria, Calif) containing
diaminobenzidine, and counterstained with Mayer hematoxylin. All round, -synuclein–positive
structures were considered as LBs, including intracytoplasmatic, intraneuritic,
and extracellular LBs. Lewy bodies were considered cortical if they were found
in any cortical region, including the neocortex and allocortex.
RESULTS
CLINICAL DIAGNOSIS
Of the 46 patients with DLBs, 35 had a clinical diagnosis of possible
DLBs, and 11 of probable DLBs; only 3 patients were clinically diagnosed as
having DLBs alone (ie, no AD or other dementia syndrome). The clinical diagnosis
of probable or possible DLBs was used associated with probable AD in 34 patients,
with possible AD in 5 patients, with Parkinson disease in 2 patients, and
with other disease process in 2 patients (Table 1).
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Table 1. Relationship Between the Clinical Diagnosis of Dementia With
Lewy Bodies (DLBs) and Other Disease Processes
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The demographic and clinical characteristics of the patients with DLBs
were compared and contrasted with those of 287 patients with probable AD who
were enrolled in the study registry during the same period (Table 2). Patients with possible DLBs were older than those with
probable AD and probable DLBs. Although the proportion of men was not statistically
different among the 3 groups, there were more men with DLBs (possible DLBs
+ probable DLBs) than with probable AD ( 21 = 3.65, P = .05). Patients with possible DLBs had lower Mini-Mental
State Examination19 and Mattis Dementia Rating
Scale20 scores than those with probable AD
and probable DLBs. By contrast, patients with possible DLBs had higher Clinical
Dementia Rating Scale,21 Blessed Dementia Rating
Scale for activities of daily living,22 and
Hamilton Depression Rating Scale23 scores than
those with probable DLBs and probable AD. Patients with probable and possible
DLBs had higher New York Univesity Parkinson Disease Scale24
scores than patients with probable AD. The patients with probable AD and possible
DLBs had more hypertension than those with probable DLBs.
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Table 2. Prospective Diagnosis of Dementia With Lewy Bodies (DLBs)
From January 1, 1997, to September 29, 2000*
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NEUROPATHOLOGICAL CLASSIFICATION
Twenty-six of the 333 patients with dementia examined between January
1, 1997, and September 29, 2000, had autopsies performed, and 13 had cortical
LBs. Three cases had brainstem and cortical LBs without AD pathological features
("pure" DLBs), and 10 cases had both AD and LBs. Only 4 of the 13 cases pathologically
identified with LBs had been diagnosed clinically as having probable DLBs
or possible DLBs (Table 3). When
the clinical diagnosis of these 26 cases was compared with the neuropathological
diagnosis, the sensitivity for the clinical diagnosis for DLBs (with or without
comorbid AD) was 30.7% and the specificity was 100%.
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Table 3. Pathological Diagnoses in 26 Autopsied Cases Examined Clinically
Between January 1, 1997, and September 29, 2000
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COMMENT
This prospective analysis of the clinical criteria for DLBs reveals
low sensitivity and high specificity of the diagnostic criteria, consistent
with several retrospective clinicopathological studies.4-7
There are a variety of reasons that this might be the case, but 2 important
factors to consider are (1) there is great overlap between the clinical symptoms
of DLBs and AD. Both diseases can have the "core" signs and symptoms of DLBs
depending on the stage of clinical dementia based on the development of extrapyramidal
signs and psychotic symptoms. At various points in the natural history, AD
may be clinically indistinguishable from DLBs. (2) Neuropathological studies
have found that 20% to 30% of the elderly patients with degenerative dementia
have LBs in the neocortex and brainstem, using antiubiquitin inmunostaining,25-26 and as many as 60% using -synuclein–based
methods.18 Thus, the pathological overlap between
the diseases may further cloud the clinical presentation. Dementia secondary
to "only" cortical LBs is infrequent (only 11.5% in this series).
Given the wealth of accumulating evidence regarding the presentation
and progression of DLBs, it may be appropriate to consider modifications to
the existing clinical criteria, as has been done for the neuropathological
criteria. Although the consensus guidelines for the neuropathological diagnosis
of DLBs stated that LBs must be identified with antiubiquitin inmunohistochemistry,1 the report of the Second DLBs International Workshop
recognized that the use of -synuclein–based methods constituted
a significant advance in the neuropathological diagnosis of DLBs, and recommended
their use for research.27 We would further
suggest that the neuropathological criteria be expanded, so the amygdala be
included in the brain regions that should be surveyed, since the consensus
guidelines for the neuropathological diagnosis of DLBs do not recommend this
region. We based this suggestion on the observation that abundant LBs can
be found in the amygdala, especially when LBs coexist with AD pathological
features.18, 28
Thus, it is timely to consider updating the clinical criteria, as well.
For example, recent studies have found that depression27, 29
and diurnal hypersomnia29 are strongly associated
with cortical LBs, and perhaps, depression should be a supportive symptom
for the diagnosis of DLBs.27 Clarification
and standardization of the assessment of some of the most difficult signs
and symptoms may be important (eg, fluctuating consciousness), especially
if they appear to differ qualitatively between dementia disorders.
Although the sample size in this study is small compared with other
similar evaluations that we have conducted,4, 29
we can reach 2 important conclusions: first, the specificity of the diagnosis
of DLBs is appropriately high, especially when the disorder occurs in isolation.
However, the clinical sensitivity to DLBs is unacceptably low. Second, because
LBs overlap with AD pathological features in 10 (50%) of the 20 cases studied,
DLBs is virtually undetectable when it occurs in the context of clinical AD.
We conclude, therefore, that these criteria for DLBs—whether in a research
or clinical setting—should only be used in conjunction with the NINCDS-ADRDA
criteria for AD and other clinical criteria for determining dementia in elderly
persons. This double diagnosis allows us to preserve the information necessary
to effectively evaluate the merits of the classification rules and to understand
the interaction between these various clinical entities.
AUTHOR INFORMATION
Accepted for publication July 11, 2001.
Author Contributions: Study concept and
design (Drs Lopez, Becker, and DeKosky); acquisition of data (Drs Lopez, Kaufer, Hamilton, Sweet, Klunk, and DeKosky); analysis
and interpretation of data (Drs Lopez, Becker, Sweet and DeKosky); drafting of the manuscript (Drs Lopez, Becker, and DeKosky); critical revision of the manuscript for important intellectual content
(Drs Lopez, Becker, Kaufer, Hamilton, Sweet, Klunk, and Dekosky); statistical
expertise (Drs Lopez and Becker); obtained funding (Drs
Becker and Dekosky); administrative, technical, and material support (Drs Lopez, Becker, Kaufer, Hamilton, Sweet, and Dekosky); and study supervision (Drs Klunk and Dekosky).
This study was supported by grant AG05133 from the National Institute
on Aging, Bethesda, Md. Dr Becker is the recipient of Research Scientist Development
Award (Level II) KO2-MH01077 from the National Institute of Mental Health.
Corresponding author: Oscar L. Lopez, MD, 3501 Forbes Ave, Suite
830, Oxford Bldg, Pittsburgh, PA 15213.
From the Alzheimer's Disease Research Center, University of Pittsburgh
(Drs Lopez, Becker, Kaufer, Hamilton, Sweet, Klunk, and DeKosky), and the
Departments of Psychiatry, (Drs Lopez, Becker, Kaufer, Sweet, Klunk, and DeKosky),
Neurology (Drs Lopez, Becker, Kaufer, and DeKosky), and Pathology (Neuropathology)
(Dr Hamilton), University of Pittsburgh School of Medicine, Pittsburgh, Pa.
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