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May 27, 2003; 60 (10) Articles

Influence of Alzheimer pathology on clinical diagnostic accuracy in dementia with Lewy bodies

A. R. Merdes, L. A. Hansen, D. V. Jeste, D. Galasko, C. R. Hofstetter, G. J. Ho, L. J. Thal, J. Corey-Bloom
First published May 27, 2003, DOI: https://doi.org/10.1212/01.WNL.0000065889.42856.F2
A. R. Merdes
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L. A. Hansen
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D. V. Jeste
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D. Galasko
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C. R. Hofstetter
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G. J. Ho
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L. J. Thal
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J. Corey-Bloom
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Influence of Alzheimer pathology on clinical diagnostic accuracy in dementia with Lewy bodies
A. R. Merdes, L. A. Hansen, D. V. Jeste, D. Galasko, C. R. Hofstetter, G. J. Ho, L. J. Thal, J. Corey-Bloom
Neurology May 2003, 60 (10) 1586-1590; DOI: 10.1212/01.WNL.0000065889.42856.F2

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Abstract

Objective: To determine whether AD neurofibrillary pathology influences clinical diagnostic accuracy in dementia with Lewy bodies (DLB).

Background: Pathologic diagnosis of DLB mandates Lewy bodies but also allows for AD pathology in the form of plaques and tangles. Because clinical diagnostic accuracy of DLB remains low, the authors questioned whether the severity of AD pathology in the form of tangles might affect the clinician’s ability to correctly diagnose DLB in life. Design/Methods: Ninety-eight subjects with autopsy-proven DLB who had been evaluated annually at the University of California San Diego AD Research Center were identified. The clinical diagnosis used was the last diagnosis before death. Pathologic diagnosis of DLB was made according to Consensus guidelines, and Braak staging was used to assess the degree of neurofibrillary AD pathology. The clinical characteristics of subjects with DLB with low vs high Braak stages were compared and the clinical diagnostic accuracy for subjects stratified according to Braak stage was determined.

Results: Only 27% of the subjects with DLB demonstrated both visual hallucinations and spontaneous extrapyramidal signs (EPS). The low Braak stage (0 to 2, n = 24) subjects had a higher frequency of visual hallucinations (65%) than did subjects with DLB with higher (3 to 6, n = 66) Braak stages (33%, p = 0.008), and showed a slightly greater but not significant degree of EPS. Although clinical diagnostic accuracy for DLB was relatively low (49%), it was higher for subjects with low (75%) compared to high (39%) Braak stages (p = 0.0039).

Conclusions: The degree of concomitant AD tangle pathology has an important influence on the clinical characteristics and, therefore, the clinical diagnostic accuracy of DLB.

Dementia with Lewy bodies (DLB) is the second most common form of dementia in the elderly after AD.1 In addition to dementia, the Consortium on Dementia With Lewy Bodies described three core clinical features of DLB: recurrent visual hallucinations, fluctuating cognition, and spontaneous motor features of parkinsonism.1 Accurate clinical differentiation of this entity is important because DLB may have a distinct clinical course,2 more rapid rate of progression,3 and dissimilar response to treatment4 than other dementing illnesses. Pathologic diagnosis of DLB mandates Lewy bodies1 but also allows for Lewy-related neurites, neuronal loss, spongiform change, synapse loss, and Alzheimer pathology in the form of plaques and tangles.

Because such diverse pathologic features are allowed in the pathologic diagnosis of DLB, and the clinical diagnostic accuracy of DLB remains low,5-10⇓⇓⇓⇓⇓ we hypothesized that the extent of concurrent AD pathology might confound the clinical characteristics of DLB and, as a result, influence the clinician’s ability to correctly diagnose DLB in life. Whereas increasing neurofibrillary tangle burdens correlate well with worsening dementia in AD, plaque counts do not,11 and a significant percentage of nondemented elderly controls have enough plaques to meet some criteria for AD.12 We therefore decided to focus this investigation on the possible confounding effects of tangle pathology in DLB as measured by Braak stage.13

Methods.

Subjects.

The patients included in this study were followed clinically at the University of California San Diego (UCSD) AD Research Center (ADRC) and represent those patients who came to autopsy between 1985 and 2001 with a pathologic diagnosis of DLB (n = 106). Two patients were excluded owing to concomitant hippocampal sclerosis and six were excluded owing to lack of sufficient clinical data. Thus, 98 patients with autopsy-proven DLB were included in the current analysis: 89 who had concomitant neocortical senile plaque pathology sufficient to meet National Institute on Aging (NIA)14 and Consortium to Establish a Registry for AD criteria15 for definite or probable AD (i.e., Lewy body variant of AD [LBV]16) and 9 who were without significant concomitant AD senile plaque pathology and were diagnosed pathologically with diffuse Lewy body disease (DLBD).

Subjects had been evaluated annually at the UCSD ADRC with medical, neurologic, neuropsychological, and laboratory examinations. All subjects met the Diagnostic and Statistical Manual of Mental Disorders (DSM-III-R) criteria for a clinical diagnosis of dementia.17 Clinical signs and symptoms (e.g., hallucinations and extrapyramidal signs [EPS]) were rated as present or absent based on their appearance at any point during the course of the patient’s illness. Ratings of hallucinations were based on the National Institute of Mental Health Diagnostic Interview Schedule18 for DSM-III and confirmed by a board-certified research psychiatrist (D.V.J.). Spontaneous EPS were regarded as present when bradykinesia, masked facies, rigidity, parkinsonian tremor, parkinsonian speech, or parkinsonian gait was rated in the motor examination subsection of the Unified PD Rating Scale19 (UPDRS) as ≥2, in the absence of neuroleptic treatment. In the years before implementing the UPDRS at our center, parkinsonian signs were rated as part of a structured neurologic examination. Clinical diagnoses were established prospectively on the basis of a standardized diagnostic worksheet (DWS). For this study, diagnosis represents the last clinical diagnosis before death. Because the diagnosis of DLB has only been part of the DWS at our center since 1991, records of clinical history and neurologic examination for those subjects whose final clinical diagnosis was made before 1991 (n = 34) were re-examined by two independent examiners (J.C.-B., D.G.), blinded to clinical diagnoses.

For the initial analysis of overall clinical diagnostic accuracy, the last clinical diagnoses before death for the 98 subjects with pathologically confirmed DLB were examined. For subsequent analyses, those subjects with DLB with a clinical diagnosis other than DLB or AD (n = 8) were excluded. Thus, 90 subjects with autopsy-confirmed DLB were stratified into two groups: subjects with low (0 to 2) Braak stage (n = 24) and subjects with high (3 to 6) Braak stage (n = 66). We chose this division because the 1997 NIA/Reagan Working Group consensus recommendations20 for the postmortem diagnosis of AD confer a “low likelihood” that dementia could be attributed to AD pathology when neurofibrillary tangles are restricted in distribution to Braak stages 0, 1, or 2. The low Braak stage group included 17 LBV and 7 DLBD patients; the high Braak stage group included 66 LBV patients. All subjects with DLBD were part of the low Braak stage group. The clinical characteristics of subjects with DLB with low vs high Braak stages were compared, and the clinical diagnostic accuracy for subjects stratified according to Braak stage was determined.

Neuropathologic examination.

Pathologic assessment was made by one observer (L.A.H.). Autopsy was performed within 24 hours of death using a protocol described by Terry et al.21 The left hemibrain was fixed by immersion in 10% formalin for 5 to 7 days. The paraffin-embedded blocks from midfrontal, rostral superior temporal, and inferior parietal areas of neocortex, hippocampus, entorhinal cortex, basal ganglia/substantia innominata, mesencephalon, and pons were cut at 7 μm thickness for hematoxylin and eosin (H-E) and thioflavin-S staining. Neuritic plaques were assessed on thioflavin-S or Bielschowsky silver stains of cerebral neocortex. Total plaque, neuritic plaque, and neurofibrillary tangle counts were determined by the same examiner with the same criteria used consistently. Lewy bodies were detected using H-E or antiubiquitin immunostaining as recommended by the Consortium on DLB criteria for a pathologic diagnosis of DLB.1 Cases were neuropathologically diagnosed with DLB only if Lewy bodies were found in the locus coeruleus, substantia nigra, or nucleus basalis of Mynert, as well as in the neocortex. We did not include as DLB brains with Lewy bodies recognized only after immunohistochemical staining for alpha-synuclein, or with Lewy bodies confined to the amygdala as described by Hamilton.22 Each brain was staged for the degree of neurofibrillary pathology by a modification23 of the method of Braak and Braak.13

Statistical analysis.

Comparisons of demographic data were carried out using Student t-tests; categorical data were compared using χ2 analysis or Fisher exact tests. Multiple logistic regression was used to examine the association between significant factors detected in the χ2 analyses.

Results.

Results for the initial analysis of overall clinical diagnostic accuracy for the cohort of 98 autopsy-confirmed DLB subjects are as follows: 44.9% were correctly diagnosed by the clinician with DLB, 46.9% were diagnosed with AD, 6.1% with mixed dementia (AD with additional vascular component), 1% with progressive supranuclear palsy, and 1% as normal.

Results for the subsequent analyses are confined to the 90 autopsy-proven DLB subjects with a clinical diagnosis of either AD or DLB. Demographic data for the low vs high Braak stage groups are summarized in table 1. They did not differ significantly with regard to sex, education, age at onset, or age at death. There were also no significant differences with regard to Mini-Mental State Examination24 (MMSE) score at presentation or interval from last MMSE to death. However, disease duration did differ between the two cohorts (p = 0.04), with a longer mean duration of illness in the high Braak stage group. In addition, mean MMSE score at last examination before death was lower in the high Braak stage subjects (p = 0.03).

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Table 1. Demographics of DLB cohort with clinical diagnoses of DLB or AD and Braak staging (n = 90)*

Clinical characteristics of the cohorts are presented in table 2. Overall, visual hallucinations—one of the core clinical features of the Consortium criteria1—were present in fewer than half of the patients with DLB (42%). Spontaneous EPS—another core clinical feature—were present in only 55% of the patients with DLB. Only 27% of the autopsy-confirmed patients with DLB demonstrated both visual hallucinations and spontaneous EPS at any point in the course of their illness. Almost a third (30%) of the patients with DLB never had visual hallucinations or spontaneous EPS.

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Table 2. Braak stage cohorts and clinical features

After stratifying the DLB subjects into low and high Braak stage, we found that visual hallucinations were more common in those patients with low (65%) vs high (33%, p = 0.008) Braak stage. The prevalence of spontaneous EPS, on the other hand, was similar in both groups (low Braak 61% vs high Braak 53%, p = 0.51). Only 21% of the patients in the high Braak stage group had both visual hallucinations and EPS. A surprising 35% of the patients in the high Braak stage group did not show EPS or visual hallucinations at any point in the course of their disease (see table 2). Other clinical signs, such as rigidity, parkinsonian tremor, and bradykinesia, did not differ significantly in prevalence between the two Braak stage groups.

To control for the influence of sex, education, age at death, duration, rigidity, parkinsonian tremor, bradykinesia, and depression on the significant difference between the low and high Braak stage groups with regard to visual hallucinations, we entered these variables into a logistic regression analysis. In this analysis, an association between visual hallucinations and subjects in the low Braak stage group remained (OR 8.56, p < 0.01).

Overall, only 49% of the DLB study subjects were correctly diagnosed with DLB by the clinicians (table 3). When the patients with DLB were stratified by Braak stage, clinical diagnostic accuracy was higher in subjects with low (75%) compared to high (39%) Braak stages (p = 0.0039). An examination of clinical diagnostic accuracy by individual Braak stage revealed that the lower the Braak stage, the more likely the subject was to have been diagnosed with DLB; the higher the Braak stage, the more likely the patient was to have been diagnosed with AD (table 4).

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Table 3. Braak stage and clinical diagnostic accuracy*

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Table 4. Individual Braak stage and clinical diagnostic accuracy*

Discussion.

We examined the accuracy of the clinical diagnosis of DLB and the hypothesis that superimposed AD neurofibrillary pathology affects the clinical characteristics, and thus the clinical diagnostic accuracy, of DLB. Assessment of clinical diagnostic accuracy in relation to Braak stage has not, to our knowledge, been described previously. We found that the clinical diagnostic accuracy of DLB remains low—less than 50%. In addition, we found that only 27% of our pathologically confirmed DLB cohort developed both visual hallucinations and spontaneous EPS, two of the core clinical features for the diagnosis of DLB. Clinical diagnostic accuracy was strongly influenced by Braak stage: patients with lower Braak stages were significantly more likely to have been diagnosed with DLB by the clinician.

Several studies have found relatively low clinical diagnostic accuracy for DLB5-10⇓⇓⇓⇓⇓ with sensitivity ranging from 34% to 65%.5-8,10⇓⇓⇓⇓⇓ Only one prospective study25 to date has reported high diagnostic accuracy of 83% for DLB. Differences in referral practices and patient populations may have been responsible for this discrepancy.

The prevalence of core clinical features of DLB in our cohort was low: only 42% showed visual hallucinations and only 55% demonstrated spontaneous EPS during the course of their illness. In fact, only 27% of the subjects in our sample demonstrated both visual hallucinations and EPS, two of the three core clinical features of DLB. This low prevalence of core clinical features is supported by a study, in which hallucinations could be identified in only 42% of 56 patients with DLB and concomitant AD pathology.9 It is further supported by a recent study6 of subjects with DLB in which only 50% showed visual hallucinations and only 66% developed EPS. This is in contrast, however, to one study25 in which high prevalence rates (85% visual hallucinations and 87% EPS) for these features were observed.

We did not consider fluctuating cognition—the third core clinical feature of DLB—in our analyses, because this feature has been the most difficult to define and report reliably,8,10,26,27⇓⇓⇓ but this did not preclude the clinician from using fluctuating cognition—or any of the additional supporting features of DLB (e.g., repeated falls, syncope, neuroleptic sensitivity)—in the clinical assessment. However, recognizing that clinicians often cannot assess the presence of fluctuating cognition with any consistency, and that interrater reliability studies6,8⇓ suggest that identifying fluctuations remains problematic, we believed that we were not able to reliably ascertain the prevalence of this feature in our cohort and therefore chose not to include it in our analyses. On the other hand, as assessed by the kappa statistic, hallucinations and EPS appear to be some of the most reliable symptoms in interrater reliability studies in DLB. For example, kappa scores of 0.9 for EPS and 0.87 for visual hallucinations but only 0.57 for fluctuations have been reported6 in subjects with DLB. Because the purpose of the current study was to examine the hypothesis that superimposed AD neurofibrillary pathology affects the clinical characteristics, and thus the clinical diagnostic accuracy, of DLB, we thought it imperative to analyze those clinical characteristics that have been reliably operationalized. Although the Newcastle group25,28⇓ has reported prevalence rates for fluctuating cognition of up to 85%, which may have enhanced their ability to diagnose DLB in life, others6 suggest that less than a third of patients with DLB develop all three core clinical features. In light of the low prevalence of core clinical features in patients with DLB, it is not surprising that clinical diagnostic accuracy for this entity is low. In our study, clinical diagnostic accuracy of DLB improved when core features were present.

Consistent with previous studies,6,28⇓ we found that the subjects with pure DLB showed a higher prevalence of core symptoms than those subjects with admixed AD pathology. In our sample, only 33% of patients with DLB and AD pathology developed visual hallucinations, as opposed to 65% of patients with predominantly DLB pathology. This was in keeping with a report8 that found that 42% of patients with admixed AD pathology, as opposed to 70% of patients with pure DLBD, had hallucinations.

There are several possible explanations for these findings. First, it may be that patients with DLB with high Braak stages, and thus more extensive AD neurofibrillary pathology, show a pattern of clinical and behavioral change so typical of AD that the core clinical features of DLB are essentially masked, despite the added presence of Lewy bodies. Second, it is possible that the extent of Lewy bodies or α-synuclein pathology varies and is less extensive in patients with DLB with high Braak stages. Novel antibodies29 that recognize pathologic but not normal α-synuclein may allow appropriate quantification of the burden of Lewy bodies and neuritic pathology to address this question. Third, it may be that differential cholinergic and other transmitter deficits contribute to the occurrence of EPS and visual hallucinations in these patients. A comparison of levels of midfrontal choline acetyltransferase activity between the two cohorts in our study, however, failed to reveal any differences (p = 0.69, data not presented).

Several potential limitations and issues related to this study should be addressed. First, the subjects who comprised this study were followed prospectively and assessed on an annual basis. However, it was not until 1991 that the diagnosis of DLB existed formally on our DWS, necessitating that the records of a subset of the subjects (approximately one third) be reassessed in a blinded fashion. We do not feel, however, that this altered the outcome of these results in any way, because there were no significant differences with regard to diagnostic accuracy in our prospectively (46%) vs retrospectively (53%) diagnosed patients with DLB.

Second, we recognize that H-E and ubiquitin staining to detect Lewy bodies is less sensitive than α-synuclein staining. Whereas the latter method may have identified more Lewy bodies, it would not have changed any of the classifications in our study, because all subjects already met criteria for DLB,1 and the purpose of this investigation was to assess the influence of concomitant tangles on clinical characteristics and clinical diagnostic accuracy.

Finally, in our study, the duration of illness of the high Braak stage patients was significantly longer than that of the low Braak stage subjects, suggesting several interesting possibilities. It may be that because the subjects in the high Braak stage group live longer, there is a greater opportunity to develop additional pathologic features. Alternatively, it may be that patients in the low Braak stage group demonstrate more hallucinations and spontaneous EPS—symptoms that, in themselves, have been reported to be negative predictors for survival in patients with dementia.30

This study examined the hypothesis that concomitant AD tangle pathology confounds the clinical characteristics—and thus the clinical diagnostic accuracy—of DLB. We found that subjects with DLB with high tangle load in the limbic and neocortical cortex are less likely to express the clinical features of DLB, making the recognition of DLB, and differentiation from AD, more difficult. The current study emphasizes the need for better diagnostic tools for DLB, including options such as neuroimaging or biomarkers, to ensure improved recognition and potential intervention for patients with DLB.

Acknowledgments

Supported by NIA AG-05131.

Footnotes

  • See also page 1571

  • Received October 8, 2002.
  • Accepted February 17, 2003.

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Disputes & Debates: Rapid online correspondence

  • Influence of Alzheimer pathology on clinical diagnostic accuracy in dementia with Lewy bodies
    • Kurt A Jellinger, Institute of Clinical Neurobiology, Kenyongasse 18 Vienna Austria A-1070kurt.jellinger@univie.ac.at
    Submitted July 16, 2003
  • Reply to Letter to the Editor
    • Jody Corey-Bloom, UCSD/VA Neurology (MC9127), 3350 La Jolla Village Drive San Diego CA 92161jcoreybl@vapop.ucsd.edu
    • Annette R Merdes and Lawrence A Hansen
    Submitted July 16, 2003
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    • Results.
    • Discussion.
    • Acknowledgments
    • Footnotes
    • References
  • Figures & Data
  • Info & Disclosures
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