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ARTICLES: D. Weisman, M. Cho, C. Taylor, A. Adame, L. J. Thal, and L. A. Hansen In dementia with Lewy bodies, Braak stage determines phenotype, not Lewy body distribution Neurology 2007; 69: 356-359 [Abstract] [Full text] [PDF]

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In dementia with Lewy bodies, Braak stage determines phenotype, not Lewy body distribution

Dennis W. Dickson, Hiroshige Fujishiro   (4 December 2007)

Reply from the authors

David C. Weisman, MD, M. Cho, C. Taylor, PhD, A. Adame, L. J. Thal, MD and L. A. Hansen, MD   (4 December 2007)

In dementia with Lewy bodies, Braak stage determines phenotype, not Lewy body distribution

Kurt A. Jellinger   (2 October 2007)

In dementia with Lewy bodies, Braak stage determines phenotype, not Lewy body distribution 4 December 2007
Dennis W. Dickson, Mayo Clinic 4500 San Pablo Road, Jacksonville, FL 32224, Hiroshige Fujishiro Send Correspondence to journal: Re: In dementia with Lewy bodies, Braak stage determines phenotype, not Lewy body distribution dickson.dennis{at}mayo.edu Dennis W. Dickson, et al.	Weisman et al [1] reported the validation of revised neuropathologic criteria for dementia with Lewy bodies (DLB) proposed by the Consortium for Dementia with Lewy Bodies. [2] In their analysis, they incorrectly assess the application of the new neuropathologic criteria. The new recommendations for neuropathologic diagnosis of DLB propose that the neuropathologic assessment should generate a probability statement about the likelihood that the pathology would be associated with the DLB clinical syndrome. The probability is positively related to the extent of Lewy body pathology (increasing from brainstem to limbic to diffuse Lewy body types) and negatively related to the severity of Alzheimer type pathology (decreasing from high to intermediate to low likelihood Alzheimer’s disease). Evidence available at the time of the formulation of the criteria suggested that many cases in both the intermediate and high probability groups would have the DLB syndrome. In the Weisman report, they classified cases of diffuse Lewy body disease and high likelihood AD (Braak stages V-VI) as “low probability DLB”, but the classification should be “intermediate probability DLB”. [2] The frequency of the DLB clinical syndrome in this group was 33%, which was the same as in the other intermediate probability group (limbic Lewy bodies with intermediate likelihood AD, Braak stage III -IV; 33%), lower in frequency than the three bins considered to have a high probability of the DLB syndrome (40-63%), and greater than the four groups considered to have a low probability of the DLB syndrome (0-13%). It would appear that the proposed criteria are better than Weisman et al. contend and that the likelihood of the DLB syndrome in their series is indeed a function of both Lewy bodies and Alzheimer pathology. They reported that the distinction between diffuse and limbic Lewy body disease did not help to predict the DLB clinical syndrome, but this would not be the case if the criteria were accurately applied. For cases with advanced Alzheimer type pathology (high likelihood AD, Braak stages V-VI), the frequency of the DLB clinical syndrome was greater in diffuse Lewy body disease—33% (i.e. intermediate probability of the DLB syndrome)—than in limbic Lewy body disease 13% (i.e. low probability of the DLB syndrome). This fits with the proposed criteria and not with the notion that NFT alone determines the accuracy of diagnosis of the DLB clinical syndrome. A caveat of their study is that some cases were diagnosed before and some diagnosed after the Consortium criteria were initially proposed in 1996. [3] Thus, this is not really a prospective validation of the new DLB criteria. In the revised clinical criteria, rapid eye movement sleep behavior disorder, severe neuroleptic sensitivity and reduced striatal dopamine transporter activity on functional neuroimaging are given greater diagnostic weight as clinical features suggestive of DLB. Given that some of these features were not recognized in their retrospective cases, the validity of the revised criteria awaits a series of prospectively diagnosed DLB cases at autopsy. References 1. Weisman D, Cho M, Taylor C, Adame A, Thal LJ, Hansen LA. In dementia with Lewy bodies, Braak stage determines phenotype, not Lewy body distribution. Neurology 2007;69:356-359. 2. McKeith IG, Dickson DW, Lowe J, et al. Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology 2005;65:1863-1872. 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.
Reply from the authors 4 December 2007
David C. Weisman, MD, Unviersity of California, San Diego 8950 Villa La Jolla Drive, Suite C227, La Jolla, CA 92037-1712, M. Cho, C. Taylor, PhD, A. Adame, L. J. Thal, MD and L. A. Hansen, MD Send Correspondence to journal: Re: Reply from the authors davew{at}graffiti.net David C. Weisman, MD, et al.	We thank Drs. Dickson and Fujishiro for catching this error. Assigning ‘intermediate’ probability of a DLB phenotype to high Braak stage and diffuse Lewy Bodies changes the probability of a DLB diagnosis in this likelihood category from 33 to 25 percent. It also decreases the DLB diagnosis in categories with a low probability from 15 to 9 percent. [1,2] If diagnostic probabilities are a function of both Lewy body pathology and Braak stage, or a function primarily determined by Braak stage alone remains unclear. The primary data shows that Lewy body distribution is not a primary predictor. It appears that Braak staging plays a greater role than Lewy body distribution, particularly at lower Braak stages. Among the highest Braak stages, there were only six cases diagnosed as DLB divided evenly as limbic and diffuse. By percentage, these small numbers suggest DLB distribution determines DLB phenotype (13% in limbic and 33% in diffuse). Dickson and Fujishiro are correct in identifying this trend, but a chi-square test was neither significant within this Braak group nor within combined Braak stages III to VI. Furthermore, the trend was only seen at high Braak stages. At low Braak stages, these differences not only seem to fade, but were dwarfed by an increasing DLB diagnostic likelihood into the 63rd%. Although this data is also not significant within each DLB classification, the trend between DLB distributions is smaller than the trend between Braak stages. A greater ‘n’ might flush out these trends and it would be interesting to look at other centers’ retrospective data. As we mentioned in the paper: “One limitation of our study is the slightly different criteria used to diagnose DLB in our center over the years. Shifting clinical emphasis on early parkinsonism to visual hallucinations and certain cognitive profiles may account for false negatives.” Disclosure: The authors report no conflicts of interest.
In dementia with Lewy bodies, Braak stage determines phenotype, not Lewy body distribution 2 October 2007
Kurt A. Jellinger, Institute of Clinical Neurobiology Kenyongasse 18, A-1070 Vienna, Austria Send Correspondence to journal: Re: In dementia with Lewy bodies, Braak stage determines phenotype, not Lewy body distribution kurt.jellinger{at}univie.ac.at Kurt A. Jellinger	In a recent clinicopathologic study of 88 cases of autopsy-proven dementia with Lewy bodies (DLB) only 36% were diagnosed intra vitam correctly, the others as probable/possible Alzheimer disease (AD). [1] The sensitivity of diagnostic accuracy was 52% in subjects with low AD Braak stage and neocortical LBs, but only 15% in those with high Braak stages suggesting that AD pathology has more influence on both phenotype and diagnostic accuracy than cortical LB distribution. These data are confirmed by the results of a consecutive series of 103 cases of autopsy-proven DLB. Average age at onset (parkinsonism 61%, dementia 39%) was 68 (SD 12.7) years; mean survival from symptom onset 6.7(range <1 to 16; median 5.0) years. [2] Patients with initial parkinsonism were younger than those with initial dementia (mean 63, SD 14.6, vs 70, SD 10.6 years (p = 0.002). Sixty-four cases (62%) showed low AD Braak stages (mean 3.5, range 1.5-4.0), mean age at death 75.0 (range 44-90) years - 68% limbic/transitional (LB PD stages 5), 22% diffuse cortical DLB (LB PD stage 6) [3]; 39 (38%) with high AD Braak stages (mean 4.5, range 4 -6), mean age at death of 78.7 (range 66-96) years, included 67% diffuse cortical and 33% limbic DLB. Presenting clinical symptoms in DLB with low AD Braak stages were parkinsonism (56%); psychiatric features (visual hallucinations, fluctuating cognition, depression) were less frequent. By contrast, the majority of DLB patients with high AD Braak stages presented with initial dementia, fluctuating cognition, and later development of parkinsonism. [2] Initial dementia, fluctuating cognition, and hallucinations strongly predicted shorter survival than initial extrapyramidal symptoms and longer delay of dementia development (mean 5.6 vs 3.3 years, p < 0.001). Sensitivity, specificity, and positive predictive value (PPV) of the McKeith criteria for probable DLB [4] were retrospectively assessed from hospital charts at last visit (66, SD 55 months after onset). Sensitivity for the whole cohort was 0.60, specificity 0.85 and PPV 0.60. Clinical accuracy for DLB cases with low AD Braak stages, similar to the findings by others [1, 5] was higher (70%) than for patients with high Braak stages (22%). These studies suggest a higher influence of concomitant neuritic AD pathology on phenotype and clinical diagnostic accuracy of DLB than cortical LB distribution. The pathogenic relationship between both pathologies and their impact on clinical features and natural history of DLB is still unclear. References 1. Weisman D, Cho M, Taylor C, Adame A, Thal LJ, Hansen LA. In dementia with Lewy bodies, Braak stage determines phenotype, not Lewy body distribution. Neurology 2007;69:356-359. 2. Jellinger KA, Wenning GK, Seppi K. Predictors of survival in dementia with Lewy bodies and Parkinson dementia. Neurodeg Dis 2007;(in press). 3. Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN, Braak E. Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging 2003;24:197-211. 4. McKeith IG, Dickson DW, Lowe J, et al. Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology 2005;65:1863-1872. 5. 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. The authors of the article were offered the opportunity to respond but declined. Disclosure: The author reports no conflicts of interest.