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ARTICLES: A. R. Merdes, L. A. Hansen, D. V. Jeste, D. Galasko, C. R. Hofstetter, G. J. Ho, L. J. Thal, and J. Corey-Bloom Influence of Alzheimer pathology on clinical diagnostic accuracy in dementia with Lewy bodies Neurology 2003; 60: 1586-1590 [Abstract] [Full text] [PDF]

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

Kurt A Jellinger   (16 July 2003)

Reply to Letter to the Editor

Jody Corey-Bloom, Annette R Merdes and Lawrence A Hansen   (16 July 2003)

Influence of Alzheimer pathology on clinical diagnostic accuracy in dementia with Lewy bodies 16 July 2003
Kurt A Jellinger, Institute of Clinical Neurobiology Kenyongasse 18 Vienna Austria A-1070 Send Correspondence to journal: Re: Influence of Alzheimer pathology on clinical diagnostic accuracy in dementia with Lewy bodies kurt.jellinger{at}univie.ac.at Kurt A Jellinger	In a recent comparative clinico-pathologic study of 98 autopsy-proven cases of dementia with Lewy bodies (DLB), Merdes et al. [1] observed that DLB patients with low Braak stages (0-2) had a higher frequency of visual hallucinations and extrapyramidal signs (EPS) but a non-significantly higher degree of EPS than those with high neuritic Braak stages (3-6). The clinical diagnostic accuracy for DLB was relatively low (48%), but higher for subjects with lower (75%) than those with higher (38%) Braak stages, suggesting that the degree of concomitant AD tangle pathology has an important influence on both clinical features and clinical diagnostic accuracy of DLB. These data can, at least in part, be confirmed by the results of a personal consecutive series of 96 cases of autopsy-proven DLB. Average age at onset was 67 (SD 12.7) years, and median survival from symptom onset was 5.0, 95% CL of median 4.6-5.4, mean 6.7 years [2]. The cohort included 60 cases with low Braak stages - mean 3.5 (range 1.5 - 4) - 24 men, 36 women, with a mean age of 76.9 (range 44-90) years; 72% limbic or transitional, and 28% cortical forms - and 36 cases with high Braak stages (mean 3.9; range 4-5) - 15 men and 21 women, mean age 78.7 (range 66-91) years. Sensitivity, specificity, and positive predictive value (PPV) of the McKeith criteria for probable DLB [3] were assessed retrospectively for the total cohort at first neurologic visit (19, SD 19, months) and the last visit (66, SD 55, months after symptom onset).At first visit, sensitivity was 0.22, specificity was 0.97, and PPF was 0.71, but at last visit, sensitivity (0.60) increased, while both specificity (0.85) and PPV (0.60) decreased [4]. The presenting clinical symptoms of both limbic and neocortical types of DLB with low Braak stages were EPS alone (36%); psychiatric features, such as visual hallucinations, delusions, and depression were less frequent at symptom onset. Patients with intial EPS were younger than those without (mean 63, SD 14.6 vs 69, SD 10.6) years. In contrast, increased age at symptom onset was observed in patients presenting with fluctuating cognition (mean age 75 SD 6.5 vs 66 SD 12.9 years; p = 0.001). By contrast, the majority of DLB patients with high Braak stages clinically presented with initial dementia often associated with fluctuating cognition, with or without later development of EPS. Dementia, fluctuating cognition, and hallucinations at symptom onset and shorter latencies to dementia onset strongly predicted shorter survival than initial EPS and longer delay of development of dementia (mean 5.6 vs 3.3 years - p < 0.001) (5). For all visits, the McKeith criteria distinguished better DLB from PD (possible DLB at first visit 0.72; at last visit 0.86; probable DLB at first visit 1.00, last visit 0.94) than from AD (possible DLB first visit 0.67; last visit 0.45; probable DLB first visit 0.71, last visit 0.68) (4). The clinical accuracy for DLB cases with low Braak stages, using the McKeith criteria for probable DLB, similar to the findings by Merdes et al. [1] was higher (70%) than for patients with severe neuritic AD pathology (high Braak stages) that detected fewer DLB patients (22%) but also included a significant number of subjects with false positive diagnosis (29%) [4]. Both studies, although using somewhat different degrees of Braak staging for the assessment of concomitant neuritic AD pathology and showing differences in the predominant presenting clinical symptoms between DLB cases with mild and severe AD lesions, emphasize the important influence of concomitant neuritic AD pathology on the clinical features, natural history, and the clinical diagnostic accuracy of DLB. However, the pathogenic relationship between Lewy body and Alzheimer pathologies and their relative impact on the clinical course of DLB cases with different degrees of concomitant Alzheimer pathology remain to be elucidated. References: 1.Merdes AR, Hansen LA, Jeste DV, et al. Influence of Alzheimer pathology on clinical diagnostic accuracy in dementia with Lewy bodies. Neurology 2003;60:1586-1590. 2.Jellinger KA. Prevalence of vascular lesions in Dementia with Lewy Bodies. A postmortem study. J Neural Transm 2003; DOI.10.1007; s00702-000- 0824-x, published online. 3.McKeith IG, Galasko D, Kosaka K, et al. Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB international workshop. Neurology 1996;47:1113-1124. 4.Seppi K, Jellinger K, Litvan I, et al. Impact of disease progression upon accuracy of the McKeith criteria for dementia with Lewy bodies: A clinicopathological study. Neurology 2001;56 (Suppl.3):A127. 5.Luginger E, Seppi K, Litvan I, et al. Associated Alzheimer pathology modifies the natural history of demenita with Lewy bodies (DLB): A clinicopathological study. Mov Disord 200;15:226
Reply to Letter to the Editor 16 July 2003
Jody Corey-Bloom, UCSD/VA Neurology (MC9127) 3350 La Jolla Village Drive San Diego CA 92161, Annette R Merdes and Lawrence A Hansen Send Correspondence to journal: Re: Reply to Letter to the Editor jcoreybl{at}vapop.ucsd.edu Jody Corey-Bloom, et al.	We thank Dr. Jellinger for his interest in our article. [1] His results provide support for our conclusion that the degree of concomitant neuritic Alzheimer’s disease (AD) pathology in dementia with Lewy bodies (DLB) has an important influence on the clinical characteristics and, therefore, the clinical diagnostic accuracy of DLB. As in our study, Dr. Jellinger finds relatively low overall clinical diagnostic accuracy for DLB. He also reports very similar accuracies for patients with low (70% his vs 75% ours) compared to high (22% his vs 38% ours) Braak stages and low prevalences for at least some of the core clinical features of DLB in his samples. This is particularly interesting in light of the fact that our cohorts differ somewhat pathologically with regard to Braak stage stratification. However, the greatest difference in our cohorts is likely clinical since, as a dementia referral center, the initial presenting symptom in all of our subjects was dementia. Despite this, and consistent with previous studies, [2, 3] it appears that the prevalence of core clinical features in DLB is low and that, not surprisingly, clinical diagnostic accuracy remains poor. In our study, clinical diagnostic accuracy of DLB improved when core clinical features were present. We found that DLB subjects with high Braak stages were less likely to express the clinical features of DLB, making its recognition, and differentiation from AD, more difficult. We believe that our results and those of Dr. Jellinger emphasize the need for better diagnostic tools for DLB to ensure improved identification of these individuals in life. References: 1.Merdes AR, Hansen LA, Jeste DV, et al. Influence of Alzheimer pathology on clinical diagnostic accuracy in dementia with Lewy bodies. Neurology 2003;60:586-1590. 2.Verghese J, Crystal HA, Dickson DW, Lipton RB. Validity of clinical criteria for the diagnosis of dementia with Lewy bodies. Neurology 1999;53:974-1982. 3.Hohl U, Tiraboschi P, Hansen LA, Thal LJ, Corey-Bloom J. Diagnostic accuracy of dementia with Lewy bodies. Arch Neurol 2000;57:347-351.