Research Evaluation and Prospective Diagnosis of Dementia With Lewy Bodies FREE

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.

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.

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 α-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, α-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.

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).

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 (χ²₁ = 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.

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%.

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 α-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 α-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 depression^{27 ,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.

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.