Neurology -- Correspondence for Levy et al., 59 (11) 1708-1713

Correspondence published:

Reply to Letter to the Editor: Gilberto Levy, Ming-Xin Tang, Elan D. Louis, Lucien J. Cote Brenda Alfaro, Helen Mejia, Yaakov Stern and Karen Marder (26 February 2003)

The association of incident dementia with mortality in PD: Kurt Jellinger (26 February 2003)

Reply to Letter to the Editor 26 February 2003

Gilberto Levy
GH Sergievsky Center New York,
Ming-Xin Tang, Elan D. Louis, Lucien J. Cote Brenda Alfaro, Helen Mejia, Yaakov Stern and Karen Marder
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Re: Reply to Letter to the Editor

levygil{at}sergievsky.cpmc.columbia.edu Gilberto Levy, et al.

We appreciate Dr. Jellinger's report of his clinicopathological study, which adds relevant information to our finding of an association of incident dementia with mortality in PD.[2] However, we would like to comment on two points that need careful consideration when interpreting both studies' findings. First, the relative contribution of subcortical and cortical (cortical Lewy bodies and Alzheimer's changes) pathology to dementia in PD has not been clearly established, and recent studies have shown a greater contribution of cortical Lewy bodies than Alzheimer's pathological changes to cognitive impairment in PD.[3, 4, 5] As suggested in the manuscript,[1] one cannot attribute the effect of dementia on mortality in PD to the presence of concomitant Alzheimer's pathological changes only. Second, the finding of a better outcome of the tremor- dominant type of PD is not necessarily at variance with our study, because of methodological differences in clinical definitions and analytical strategy. Jellinger et al.[1] compared survival of two groups defined by the major initial clinical symptom of PD (tremor vs. akinesia-rigidity). We grouped the items from the Unified Parkinson's Disease Rating Scale (UPDRS) into six motor domains, and assessed the association of higher vs. lower ratings of each domain with mortality in PD (risk ratios represent increase in the mortality risk for 1-point increase in the rating).[2] If the tremor-dominant group had been considered the reference group in Jellinger et al. analysis, the alternative and equivalent conclusion would be that of a worse outcome of the rigid-akinetic type. Postural instability and gait impairment were not taken into account in the analysis and have been shown to be correlated with bradykinesia.[6, 7] In our study, bradykinesia was associated with mortality in univariate analysis, but not when included in the same model with axial (gait and postural) impairment. Finally, we agree with the conclusion that "therapeutic approaches targeting dementia may improve life expectancy in patients with PD". To that end, a better understanding of the structural changes and biological mechanisms underlying dementia in PD will probably be needed.
References:
1. Jellinger KA, Seppi K, Wenning GK, Poewe W. Impact of coexistent Alzheimer pathology on the natural history of Parkinson's disease. J Neural Transm 2002;109:329-339.
2. Levy G, Tang MX, Louis ED, et al. The association of incident dementia with mortality in PD. Neurology 2002;59:1708-1713.
3. Hurtig HI, Trojanowski JQ, Galvin J, et al. Alpha-synuclein cortical Lewy bodies correlate with dementia in Parkinson's disease. Neurology 2000;54:1916-1921.
4. Mattila PM, Rinne JO, Helenius H, et al. Alpha-synuclein- immunoreactive cortical Lewy bodies are associated with cognitive impairment in Parkinson's disease. Acta Neuropathologica 2000;100:285-290.
5. Apaydin H, Ahlskog JE, Parisi JE, et al. Parkinson disease neuropathology. Later-developing dementia and loss of the levodopa response. Archives of Neurology 2002;59:102-112.
6. Zetusky WJ, Jankovic J, Pirozzolo FJ. The heterogeneity of Parkinson's disease: clinical and prognostic implications. Neurology 1985;35:522-526.
7. Stebbins GT, Goetz CG, Lang AE, Cubo E. Factor analysis of the motor section of the Unified Parkinson's Disease Rating Scale during the off-state. Movement Disorders 1999;14:585-589.

The association of incident dementia with mortality in PD 26 February 2003

Kurt Jellinger
Institute of Clinical Neurobiology Vienna Austria
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Re: The association of incident dementia with mortality in PD

kurt.jellinger{at}univie.ac.at Kurt Jellinger

Recently, Levy et al. [1] reported that in a cohort of 180 patients with idiopathic PD, that 22.8% died during a mean follow-up of 3.0�2.2 years, a duration of PD of 7.6�8.8 years, and an age of 75.9�8.7 years. The 48.8 % of deceased patients were demented as compared to 23.9% of those who remained alive with a mean duration of PD of 5.9�6.2 years and a mean age of 69.6�10.3 years. These data indicating that the development of dementia (relation of incident dementia to mortality with a p value of <0.001) independently of the UPDRS motor score is associated with a twofold mortality risk in PD can be confirmed from a personal series of 200 consecutive cases of autopsy-proven idiopathic PD from a specialized Austrian brain bank. In our cohort, the age at death was 58-98 (mean 77.0�9.5) years and the mean duration of PD was 8.4 (95% CI 7.7-9.2) years; Retrospectively assessed major initial clinial symptoms (tremor, akinesia), moderate/severe dementia (MMSE below 20 or CDR 3 plus), and duration of illness were correlated with associated AD pathologies using CERAD, Braak, and NIA-Reagan criteria [2]. Mann-Whitney U-test and Cox regression were used for statistical analysis. While gender had no influence on the clinical motor symptoms and outcome, the tremor-dominant type of PD had a significantly better outcome, i.e. longer survival than akinetic forms even after adjustment with age at onset and associated dementia or AD pathology (p = 0.022), which is at variance to Levy's cohort showing an insignificant relationship between tremor and mortality (p = 0.9). Patients with late onset showed significantly shorter duration of illness irrespective of dementia. Moderate to severe dementia, reported in 33% of the sample, was significantly correlated with AD pathology when assessed by all three criteria, and both dementia and coexistent AD pathology where negatively associated with survival: Mean survival in PD patients with dementia (and co-existent AD pathology) was 4.46 (95%, CI of mean 4.55-5.37) years compared to 10.1 (95% CI of mean 9.3 - 10.89) years in the patients without dementia. These data confirmed previous studies suggesting better outcome of tremor-dominant than rigid-akinetic type of PD [3], significantly worse outcome in PD with late onset and dementia that was significantly correlated with coexistent neuritic AD pathology. Based on these and other studies, it is suggested that therapeutic approaches targeting dementia may improve life expectancy in patients with PD.
References
1. Levy G, Tang MX, Louis ED, et al. The association of incident dementia with mortality in PD. Neurology 2002;59:1708-1713.
2. Jellinger KA, Seppi K, Wenning GK, Poewe W. Impact of coexistent Alzheimer pathology on the natural history of Parkinson's disease. J Neural Transm 2002;109:329-339.
3. Paulus W, Jellinger K. The neuropathologic basis of different clinical subgroups of Parkinson's disease. J Neuropathol Exp Neurol 1991;50:743-755.