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December 01, 1999; 53 (9) Articles

Clinicopathologic correlates in temporal cortex in dementia with Lewy bodies

T. Gómez-Isla, W.B. Growdon, M. McNamara, K. Newell, E. Gómez-Tortosa, E.T. Hedley-Whyte, B.T. Hyman
First published December 1, 1999, DOI: https://doi.org/10.1212/WNL.53.9.2003
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Abstract

Objective: To address the relationship between dementia and neuropathologic findings in dementia with Lewy bodies (DLB) in comparison with AD.

Methods: We evaluated the clinical presentation of autopsy-confirmed DLB in comparison with AD according to new Consortium on DLB criteria and compared the two conditions using quantitative neuropathologic techniques. This clinicopathologic series included 81 individuals with AD, 20 with DLB (7 “pure” DLB and 13 “DLB/AD”), and 33 controls. We counted number of LB, neurons, senile plaques (SP), and neurofibrillary tangles (NFT) in a high order association cortex, the superior temporal sulcus (STS), using stereologic counting techniques.

Results: The sensitivity and specificity of Consortium on DLB clinical criteria in this series for dementia, hallucinations, and parkinsonism are 53% and 83%, respectively, at the patient’s initial visit and 90% and 68%, respectively, if data from all clinic visits are considered. In pathologically confirmed DLB brains, LB formation in an association cortical area does not significantly correlate with duration of illness, neuronal loss, or concomitant AD-type pathology. Unlike AD, there is no significant neuronal loss in the STS of DLB brains unless there is concomitant AD pathology (neuritic SP and NFT).

Conclusions: The evaluation of new Consortium on DLB criteria in this series highlights their utility and applicability in clinicopathologic studies but suggests that sensitivity and specificity, especially at the time of the first clinical evaluation, are modest. The lack of a relationship of LB formation to the amount of Alzheimer-type changes in this series suggests that DLB is a distinct pathology rather than a variant of AD.

Recent data suggest that dementia with Lewy bodies (DLB) represents the second most frequent cause of degenerative dementia in the elderly after AD.1-6 However, the relationship between DLB and AD continues to be confusing. The pathologic hallmarks of these conditions—senile plaques (SP) and neurofibrillary tangles (NFT) in AD, and LB in DLB—often coexist in the brain.3,7,8 Furthermore, differing diagnostic criteria variably segregate dementia brains into AD plus DLB or pure DLB categories.9 Many series thus include a mixture of patients with different degrees and overlap of both types of pathologic changes, complicating the task of comparing observations reported by different groups.

The underlying cause of dementia in DLB, which resembles the dementia of AD in many respects, remains unknown. Neurochemical assessments have found a profound deficiency of cortical acetylcholine activity in DLB even exceeding that seen in AD brains, suggesting a common pathologic involvement of the basal forebrain in these two conditions.10-12 The significance of abnormal intraneuronal inclusions in DLB brains, the so-called LB, remains uncertain. Furthermore, the relative contribution of LB and of concomitant AD changes in many of these brains to dementia is poorly understood. Despite the frequent coexistence of LB and AD-related changes, the topographic distribution of LB in DLB does not match the distribution of Alzheimer-type pathologic changes. Cortical LB are preferentially present in the deeper layers of the frontal, cingulate, insular, and temporal cortices, whereas NFT develop most frequently in layers II, III, and V of high order association cortices13-15 as well as the entorhinal cortex, hippocampal formation, and amygdala. Whether these differences reflect unique and recognizable patterns of neuronal vulnerability in DLB remains unresolved. Furthermore, although it is well established that loss of neurons and synapses closely correlates with the progression of cognitive deficits in AD brains,16 less is known about the clinicopathologic correlations of these changes in DLB brains.17-19

Overall, increasing evidence suggests that DLB and AD may be successfully discriminated from both clinical and pathologic perspectives. Recently the Consortium on DLB International Workshop proposed consensus guidelines to help clinical and neuropathologic efforts to further understand this type of dementia.20 The unifying term “dementia with Lewy bodies” has been suggested.20 Recurrent visual hallucinations, spontaneous motor features of parkinsonism, and fluctuating cognition have been proposed as cardinal clinical features that predict DLB with high likelihood.20 The Consortium on DLB recommended describing and staging the presence of LB to establish the pathologic diagnosis based on a brain sampling scheme and a semiquantitative scale consistent with the Consortium to Establish a Registry for AD (CERAD) and noting any coexisting pathologic lesions such as AD-related pathology. These consensus criteria now need to be tested with further clinicopathologic studies.

The present study aimed 1) to evaluate the new Consortium on DLB criteria in a clinicopathologic series, 2) to address whether or not LB accumulate with time in association cortices in DLB, and 3) to assess whether other neuropathologic changes, such as loss of cortical neurons and concomitant AD pathology, correlate with LB formation or significantly contribute to dementia in DLB.

Methods.

Patient selection.

We studied 134 individuals—81 with AD, 20 with DLB, and 33 controls. The 81 cases of AD had been examined and followed in the clinical units of the Massachusetts General Hospital Alzheimer’s Disease Research Center and had a subsequent neuropathologic diagnosis of definite AD21,22 without evidence of strokes, LB, or other lesions. In 50 cases, tissue was available for detailed quantitative neuropathologic assessments. Published data on 34 of these cases23 are presented here for comparison. The 20 cases of DLB came from the clinical units of the Massachusetts General Hospital where they had undergone neurologic examinations. In all, the neuropathologic assessment had shown the presence of numerous cortical LB with or without concomitant AD changes. Following the Consortium on DLB guidelines, hematoxylin-eosin sections containing the entorhinal (BA28), cingulate (BA24), temporal (BA21), frontal (BA8/9), and parietal (BA40) regions were scored for the number of LB according to a scale where 0 indicates no LB, 1 indicates less than or equal to five LB, and 2 indicates more than five LB.20 All 20 cases met criteria for neocortical DLB. In addition, 13 met criteria for definite AD (DLB/AD), whereas in the remaining 7 neither a significant number of neuritic plaques22 nor neocortical NFT24 were noted. These seven cases are referred to here as DLB.

All AD, DLB/AD, and DLB cases had clinical histories of dementia with well-documented duration of disease. Most patients had been diagnosed by the clinicians as having probable or possible AD. Two of the pathologically confirmed AD/DLB cases had been clinically diagnosed as having PD with dementia on initial presentation. Most of the patients had undergone biannual serial evaluations that included standardized general medical and neurologic examinations as well as neuropsychological assessments over an average of 34.5 ± 19.3 months for the AD group, 17.2 ± 12.1 months for the DLB/AD group, and 26.4 ± 22.4 months for the DLB group. We charted measures of global cognitive and functional impairment derived from the information, memory, and concentration subtest of the Blessed Dementia Scale (IMC-BDS)25 and the Activities of Daily Living (ADL) scale.26 The rate of global cognitive deterioration was calculated as the total change in scores between the first and last test divided by the time elapsed between them.27

The sex distribution, age at death, age at onset, and duration of illness for each subgroup are shown in table 1. No significant differences were observed in age at onset or duration of clinical symptoms among the three dementia groups—AD, DLB/AD, and DLB.

View this table:
Table 1.

Demographics of individuals studied

The control tissue for the quantitative histologic assessment came from 33 individuals with normal brains by neuropathologic examination. Data on 14 have been previously reported and are presented here for comparison.23 None of the 33 control cases met neuropathologic criteria for AD or DLB.21 Chart review of these individuals did not reveal evidence for neurologic illness.

Tissue processing.

All brains (50 AD, 13 DLB/AD, 7 DLB, and 33 controls) were fixed in 10% buffered formalin or 4% paraformaldehyde within 36 hours after death. With a freezing sledge microtome, 50-μm–thick sections were obtained from blocks containing the superior temporal sulcus (STS) region. Adjacent sections were stained using the Nissl method for neuronal counts and immunohistochemistry with antibodies against ubiquitin (Chemicon, Temecula, CA) to visualize LB, paired helical filaments (PHF-1, courtesy of Dr. Peter Davies, Bronx, NY) for NFT, and β-amyloid (10D5, courtesy of Drs. Peter Seubert and Dale Schenk, Athena Neurosciences, South San Francisco, CA) for SP.

Quantitation of neurons, LB, NFT, and SP.

Neuronal, LB, and NFT counts were performed following the stereologic optical disector procedure as previously described.23 In brief, the region counted was located in the inferior bank of the STS, approximately 1 cm medial to the crown of the gyrus. Volume density was assessed in an area measuring 700 μm along the pial surface by the full width of the gray matter. Data were recorded by the Bioquant Image Analysis System (Nashville, TN). The total number of STS neurons, LB, and NFT per section was estimated for each case by multiplying the volume density obtained from the optical disector counts by the volume of the STS measured on each cross-section. An estimate of neuronal loss in AD, DLB/AD, and DLB brains was calculated by subtracting the number of neurons in each individual case from the average number obtained in the control group. LB and NFT counts were obtained from adjacent sections using anti-ubiquitin and PHF-1 antibodies, respectively. In two cases where numerous LB coexisted with abundant NFT in the STS, a double fluorescent labeling was performed in the same section to ensure the accuracy of LB counts and to distinguish between small, globose, ubiquitin-positive NFT and LB.

The percentage of cortical area covered by SP (amyloid burden) was assessed in the same brain region using an anti-Aβ monoclonal antibody (10D5). The video images were captured, and an optical density threshold able to discriminate the immunostaining was obtained. In each field manual editing eliminated artifacts and the staining associated with blood vessels.23,28

Statistical analysis.

The comparison of BDS and ADL scale rates between AD and DLB and DLB/AD groups was done by a multivariate analysis that included initial BDS and ADL scale scores and the total length of follow-up as possible predictors of global clinical decline. A linear regression analysis was used to compare neuron number in STS among AD, DLB/AD, and DLB groups and to correlate neuron number with duration of illness, LB, NFT, and SP. The comparison of total number of neurons between AD, DLB/AD, and DLB versus control group; the amyloid burden between AD, DLB/AD, and DLB groups; and the number of NFT between AD and DLB/AD groups was performed by analysis of variance, with statistical significance at the p < 0.05 level. The comparison of the adjusted means of number of neurons between AD and DLB/AD groups was done by analysis of covariance (ANCOVA) with statistical significance at the p < 0.05 level.

Results.

Goal 1: Clinicopathologic correlation studies of DLB.

We compared the rate of clinical decline in these neuropathologically defined diagnostic groups. Serial scores in the IMC-BDS were charted to assess cognitive change, and serial scores in the ADL scale were used to assess functional decline. No significant differences among AD, DLB/AD, and DLB groups were observed in the IMC-BDS and ADL scale scores at entry (table 2). Thus, the groups were well matched for level of cognitive impairment at entry. No significant differences were detected in the annual rate of change in IMC-BDS score among the three groups. However, DLB/AD and DLB cases had higher rates of annual decline in the ADL scale (43.2 ± 39.5, p < 0.01, and 28.5 ± 14.2, p = 0.05, respectively) when compared with the AD group (9.1 ± 10). A multivariate analysis looking at BDS/ADL scale rates, covarying first BDS/ADL scale score and time interval between first and last BDS/ADL scale score, confirmed that there was no significant difference in the annual BDS score rates of decline between AD and DLB/AD and DLB groups. However, we still found a marginal difference for annual ADL scale score rates of decline (p = 0.08), with higher rates in DLB/AD and DLB than in AD patients, probably reflecting the increased behavioral and motor deficits in the DLB groups.

View this table:
Table 2.

Rates of cognitive and functional decline

We evaluated standardized clinical records using the new Consortium on DLB clinicopathologic criteria in this series. The Consortium on DLB has proposed the following as cardinal clinical features that predict DLB with high likelihood: the presence of recurrent visual hallucinations (well formed and detailed), spontaneous motor features of parkinsonism, and fluctuating cognition20 (table 3). Reliable data were available from the charts on the presence of recurrent visual hallucinations and spontaneous parkinsonism because these data are explicitly recorded in the standardized clinical examination forms that are completed at every visit to the Memory Disorder Unit of the Massachusetts Alzheimer’s Disease Research Center. Data on fluctuating cognition were not collected in a uniform way, and therefore they are not considered further in our analysis. Based on the information available, at the time of the first clinical evaluation a diagnosis of possible or probable DLB could have been made only in 53% of the neuropathologically confirmed DLB/AD and DLB cases. However, this increased to 90% at later points of the clinical course (see table 3). In addition, 17% of the neuropathologically confirmed pure AD cases met Consortium on DLB criteria for possible DLB and 0% for probable DLB at entry. This increased to 30% for possible DLB and 2% for probable DLB during the clinical course despite the absence of LB at autopsy.

View this table:
Table 3.

Clinical features and number (%) of autopsy-confirmed DLB patients meeting consensus criteria for possible or probable DLB at clinical examination

Goal 2: Relation between LB number and duration of illness.

All DLB/AD and DLB cases presented in this series met pathologic Consortium on DLB criteria for the neocortical DLB category. For the purpose of detailed neuroquantitative assessments, the STS region was selected for several reasons: 1) It contains one of the brain areas designated by the Consortium on DLB for evaluation of LB distribution and frequency (BA21). 2) It represents a high order association area that receives multiple inputs from association and limbic cortical regions. 3) It is consistently affected by LB in the neocortical category of DLB, and by SP and NFT in AD. 4) Previously studied control and AD cases are available for comparison.

Data from the quantitative neuropathologic assessments are summarized in table 4. We found no correlation between number of LB in the STS and duration of clinical dementia symptoms in either the DLB or DLB/AD groups (R2 = 0.16, p = 0.16, not significant [NS]). Whether the number of LB might correlate with other clinical measurements of dementia severity could not be reliably addressed in this study due to the lack of enough cases with a BDS score within a year from death.

View this table:
Table 4.

Quantitative neuropathologic studies

Goal 3: Correlation between LB and other cortical pathologic changes.

We evaluated the possibility that neuropathologic changes other than neocortical LB accumulation, such as neuronal loss or AD-related pathology (NFT and SP), may significantly contribute to the clinical progression of dementia in DLB and DLB/AD. We have previously reported a dramatic neuronal loss in the STS of pure AD brains that parallels the chronologic evolution of dementia.23 In the current series, the average number of STS neurons per 50-μm–thick section in the control group was 92,900 ± 9,100 (see table 4). No significant gender differences were detected in the number of STS neurons in control brains. The total number of STS neurons was reduced by 49% in pure AD (p < 0.001) and by 40% in DLB/AD brains (p < 0.001) compared with the average number of neurons estimated in the control group. Of note, a smaller amount of neuronal loss was detected in the DLB group where an average of only 11% of STS neurons were lost compared with control brains (p = 0.21, NS) (figure 1). This finding points to a remarkably better preservation of neuronal number in the STS association cortex in DLB brains compared with pure AD or DLB/AD brains. We tested whether AD and DLB/AD groups differed significantly in the number of neurons in the STS after covarying for duration of illness. There was a within-group relation between the number of neurons and the logarithm of duration of illness (p < 0.05). After an ANCOVA adjustment was made for this curvilinear relationship, the DLB/AD group had a higher adjusted mean number of neurons in the STS than the AD group (p < 0.02). Thus, the amount of neuronal loss in the STS was greater in AD than in DLB/AD brains after taking into account duration of illness (figure 2). In addition, the number of LB did not correlate with STS neuronal loss in either DLB/AD or DLB brains.

Figure

Figure 1. The average total number of neurons in the superior temporal sulcus (STS) volume assessed was reduced by 49% in the AD group (n = 50) (p < 0.001), by 40% in the dementia with Lewy bodies (DLB)/AD group (n = 11) (p < 0.001), and by 11% in the DLB group (n = 6) (p = 0.21, not significant) when compared with the control group (n = 33). Data were not available on two DLB/AD cases and one DLB case. y Axis = number of STS neurons per 50-μm–thick section.

Figure

Figure 2. There was a within-group relation between the number of neurons and the logarithm of duration of illness (p < 0.05). After an analysis of covariance adjustment was made for this curvilinear relationship, the dementia with Lewy bodies (DLB)/AD group had a higher adjusted mean number of neurons in the superior temporal sulcus (STS) than the AD group (p < 0.02). y Axis = number of STS neurons per 50-μm–thick section.

Finally, we evaluated the possible contribution of concomitant AD-type pathologic changes in the association cortices of DLB brains. Of note, assessment of SP showed abundant and comparable amounts of Aβ deposits in the STS of all AD, DLB/AD, and DLB groups with the exception of one brain from the latter group (see table 4). However, none of the DLB cases (by definition) had enough neuritic plaques, (despite abundant Aβ diffuse deposits) to make the diagnosis of concomitant AD according to CERAD criteria.22 The percentage of STS covered by Aβ (amyloid burden) did not correlate with duration of illness or amount of neuronal loss in any of the groups. The number of NFT in DLB/AD brains was lower than it was in pure AD brains (p < 0.05) despite similar duration and degree of cognitive impairment, and did not correlate with any of the above variables. Furthermore, the presence of LB did not correlate positively with the amount of Aβ in either the DLB/AD or DLB groups (R2 = 0.04, NS) or the number of NFT in the DLB/AD group (R2 = 0.11, NS).

Discussion.

This study suggests the following: 1) The new Consortium on DLB criteria are useful in clinicopathologic studies on DLB, but their sensitivity and specificity at the time of the first clinical evaluation are moderate. 2) In pathologically confirmed DLB and DLB/AD brains, LB formation in association cortices does not significantly increase with time or the progression of other neuropathologic changes, e.g., neuronal loss and concomitant AD-type pathology. 3) Unlike pure AD or DLB/AD, there is minimal neuronal loss in the STS of DLB brains without concomitant neuritic SP or NFT.

Our study focuses on two aspects of DLB—the clinical presentation of autopsy-confirmed cases and a quantitative neuropathologic study of the disease in comparison with AD. With regard to the clinical presentation, we applied the Consortium on DLB guidelines to further assess the clinicopathologic correlations of DLB with and without concomitant AD neuritic pathology.20 In this study patients were divided into three pathologic groups based on the presence or absence of LB, neuritic plaques, and NFT—pure AD, DLB/AD, and DLB. None of the pure AD cases met pathologic Consortium criteria for DLB. All DLB/AD and DLB cases met Consortium criteria for DLB, falling into the category of neocortical DLB. The sensitivity and specificity of the Consortium clinical criteria in this series for dementia, hallucinations, and parkinsonism are 53% and 83%, respectively, at the patient’s initial visit and 90% and 68%, respectively, if data from all clinic visits are considered.

The three dementia groups studied here had similar mean age at dementia onset and length of survival from the onset of dementia symptoms. Furthermore, AD, DLB/AD, and DLB patients had similar degrees of global cognitive decline and functional impairment at entry as measured by the IMC-BDS and the ADL scale. Even though the annual rates of cognitive decline, as measured by IMC-BDS serial scores, were comparable among the three groups, we noticed a faster decline in ADL performance in DLB/AD and DLB patients than in AD patients. We believe this observation might reflect the additional burden that recurrent visual hallucinations and extrapyramidal symptoms adds in DLB cases to the successful performance of routine daily activities evaluated by this scale.

We also applied quantitative neuropathologic techniques to DLB brains because the neuropathologic substrate of dementia in DLB is uncertain. Whether LB are true markers of neuronal injury, represent a protective cell response, or are simply a nonspecific epiphenomenon is unknown. Furthermore, the mechanism by which cortical LB formation may lead to a clinical dementia syndrome, the amount required to produce a clinically detectable cognitive impairment, and their correlation with the progression of symptoms and with AD concurrent pathologic changes are controversial.19,29-31 Some neuropathologic studies have suggested that the cortical LB burden is a meaningful measure that correlates with the severity of cognitive impairment before death.19,29,31 No significant correlation was observed between the number of LB in the STS and the duration of the clinical symptoms of dementia in either DLB/AD or DLB brains in this series, although we were unable to compare directly the number of LB with neuropsychological testing because, among the DLB cases, few had been tested within 1 year of death.

Based on these results, we suggest that other pathologic changes including loss of neurons or synapses or AD-related pathology might be more directly related to dementia in DLB than LB formation. When compared with nondemented controls, almost one-half the neuronal population normally present in the STS region is lost in an average AD brain.23 The data from this study indicate a similar behavior in DLB/AD brains with 40% of STS neuronal loss as an average, even though the amount of neuronal loss in AD brains is significantly greater than it is in DLB/AD after adjusting for duration of illness. However, the preservation of overall STS neuron number in pure DLB brains without concomitant AD pathology suggests that dementia in DLB is not due to a generalized neuronal depletion in areas affected by LB.

Thus, if not neuronal loss, what underlies dementia in DLB? Several alternatives can be suggested. LB might affect and destroy a relatively small but critical subpopulation of cortical or subcortical neurons leading to widespread functional impairments. Alternatively, LB might lead to functional or anatomic synaptic disruption. Some studies have suggested that in DLB the amount of synapse loss might be comparable with that seen in pure AD brains,17 whereas others have failed to show any significant correlation between anti-synaptophysin reactivity and degree of cognitive impairment in DLB.19 Nevertheless, the possibility of an underlying synaptic alteration in DLB has very recently gained increased attention due to the finding of mutations in the gene that codifies for the presynaptic protein α-synuclein in families with autosomal dominant PD.32,33

Finally, we have evaluated the relationship between DLB and AD. All the DLB/AD and DLB brains examined in this study but one had amounts of Aβ deposits in the STS comparable with those seen in pure AD. These results are in agreement with previous reports.34,35 No correlation was found, however, between the amount of amyloid deposited in the STS and LB counts. Could it be assumed that amyloid deposition is directly related to dementia in DLB? Several observations argue against this possibility. It is known that some elderly individuals have abundant diffuse amyloid deposits in the cortex without apparent cognitive deficits.36-38 Furthermore, clinicopathologic studies have demonstrated that diffuse plaques have little or no correlation with clinical measures of cognition39,40 and are not accompanied by synaptic loss.41

Even though DLB/AD brains had abundant NFT in the STS coexisting with LB and amyloid deposits, their number was significantly lower than it was in AD despite similar duration and severity of dementia. This finding is in agreement with studies reported by others.3,42,43 Furthermore, NFT number did not correlate with the number of LB. Taken altogether, the lack of an obvious positive relationship of LB formation to the amount of Alzheimer-type changes (neuritic SP, NFT, neuronal loss) observed in this series favors a model where DLB and AD likely represent two distinct pathologic processes, even though their frequent co-occurrence raises the possibility of a common underlying risk factor.

Acknowledgments

Supported by NIH grants AG08031, AG06786, AG05134, and AG08487.

Acknowledgment

The authors thank Joseph Locascio for his help with the statistical analysis.

  • Received September 18, 1998.
  • Accepted July 10, 1999.

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