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ARTICLES: Julie A. Schneider, Zoe Arvanitakis, Woojeong Bang, and David A. Bennett Mixed brain pathologies account for most dementia cases in community-dwelling older persons Neurology 2007; 69: 2197-2204 [Abstract] [Full text] [PDF]

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Mixed brain pathologies account for most dementia cases in community-dwelling older persons

R. N. Kaveer Nandigam, MD   (19 September 2007)

Reply from the authors

Julie A. Schneider, Zoe Arvanitakis, Woojeong Bang, and David A. Bennett   (19 September 2007)

Mixed brain pathologies account for most dementia cases in community-dwelling older persons 19 September 2007
R. N. Kaveer Nandigam, MD, Research Fellow, Neurology, Massachusetts General Hospital MGH Stroke Center, 175 Cambridge St, Suite 300, Boston, MA 02114 Send Correspondence to journal: Re: Mixed brain pathologies account for most dementia cases in community-dwelling older persons rnandigam{at}partners.org R. N. Kaveer Nandigam, MD	I read the article by Schneider et al describing the chronic brain pathologies in dementia with interest . [1] The authors reported a high prevalence of mixed brain pathologies at autopsy among the elderly and that the presence of more than one pathology triples the risk of dementia. Over 70% of those without clinical dementia were also found to have significant chronic brain pathology. In this study, clinical diagnosis assigned at death was based on the last follow-up annual clinical evaluation which could range from 1 day to 12 months prior to autopsy for any given patient. This variation in time period from last clinical exam to autopsy was not reported. Moreover, the analysis of the clinical evaluation included only a binary categorization of cognitive impairment as 'presence or absence' of dementia. Since there was no separate category for subjects with mild cognitive impairment (MCI) at last follow-up exam, these subjects were probably classified as ‘without dementia’. Bennett et al reported that among subjects with MCI, 33% had one or more cerebral infarctions, 8% met criteria for Lewy body disease and most had intermediate levels of AD pathology. [2] It is possible that in the present study, most autopsied subjects ‘without dementia’ had MCI as over two-thirds of them have significant chronic brain pathology. This also raises the question of selection bias since persons with MCI were about 1.7 times more likely to die over the follow-up period compared with those without cognitive impairment. [3] Rates of conversion to dementia among persons with MCI was about 26% over an average of 2.5 years follow-up, [4] and due to variable and lengthy time period from last clinical exam to autopsy, it is possible that a few subjects classified as ‘without dementia’ actually converted to dementia at the time of death. The multivariate logistic regression analysis to estimate the risk of multiple brain pathologies to develop dementia would give inaccurate estimates since the number of subjects assigned to each category of the dependant variable, i.e. dementia, is not accurate. Authors reported that infarctions were present in cortico-subcortical regions in 49/52 subjects. Cerebral amyloid angiopathy (CAA) commonly affects the small vessels in cortico-subcortical region and is also responsible for AD pathology. Most of these cases with cortico-subcortical infarctions and AD pathology may have CAA and it must be considered as a single cerebral pathology causing dementia rather than two separate pathologies in these cases. As the authors noted, systematic investigation and neuroimaging for CAA would have answered this question. References 1.Schneider JA, Arvanitakis Z, Bang W, Bennett DA. Mixed brain pathologies account for most dementia cases in community- Neurology 2007; 0: 01.wnl.0000271090.28148.24v1 2.Bennett DA, Schneider JA, Bienias JL, Evans DA, Wilson RS. Mild cognitive impairment is related to alzheimer disease pathology and cerebral infarctions. Neurology 2005;64:834-841. 3.Gussekloo J, Westendorp RG, Remarque EJ, Lagaay AM, Heeren TJ, Knook DL. Impact of mild cognitive impairment on survival in very elderly people: Cohort study. BMJ 1997;315:1053-1054. 4.Boyle PA, Wilson RS, Aggarwal NT, Tang Y, Bennett DA. Mild cognitive impairment: Risk of alzheimer disease and rate of cognitive decline. Neurology 2006;67:441-445. Disclosure: The author reports no conflicts of interest.
Reply from the authors 19 September 2007
Julie A. Schneider, Rush University Medical Center 600 S. Paulina St. AAC Suite 1022F, Zoe Arvanitakis, Woojeong Bang, and David A. Bennett Send Correspondence to journal: Re: Reply from the authors julie_a_schneider{at}rush.edu Julie A. Schneider, et al.	We thank Dr. Nandigam for his interest in our article. [1] He raises a number of important issues. First, Dr. Nandigam questions diagnostic accuracy given the interval between the last clinical examination and death. We agree that this is an important issue. The current study uses subjects from the Rush Memory and Aging Project which conducts annual evaluations. The average interval between the last exam and death is 6.1 months. This is relatively short compared to most other community-based clinical-pathologic studies. Because dementia progresses slowly, it is unlikely that many diagnoses would have changed over this interval. It is possible to shorten the interval and increase diagnostic precision with more frequent evaluations. However, this would increase participant burden and, scientifically, the resources are probably better spent on increasing the sample size and autopsy number. Second, Dr. Nandigam notes that deceased subjects are a nonrandom subset of the cohort and may introduce selection bias. This is also notable because older subjects who are impaired and have pathology are at greater risk of death, death represents informative censoring. The Rush Memory and Aging Project has both high rates of follow-up and autopsy, and our study included all consecutive autopsies. Although these factors increase the internal validity of study findings, one should be cautious when extrapolating results, especially estimates of disease occurrence, to the general population. Dr. Nandigam also raises concerns regarding the number of subjects with mild cognitive impairment (MCI) in the no dementia group. The no dementia group included 43 persons with MCI and 48 without cognitive impairment. We agree that persons with MCI are at high risk for dementia and may differ in important ways from those without cognitive impairment. Consequently, it will be important in future studies to investigate mixed pathologies in MCI. Finally, Dr. Nandigam notes a role for amyloid angiopathy and a potential etiologic link between AD and cerebral infarcts. This is a potentially important observation. We previously showed, using data from the Religious Orders Study, that the apolipoprotein E ĺ4 allele increases the odds of AD pathology and cerebral infarcts. [5] However, we also showed that AD pathology and cerebral infarcts were not strongly related to each other and that the cognitive effects of AD pathology and cerebral infarcts appeared to be additive.[6] We agree, however, that the relationship between amyloid angiopathy, cerebral infarcts, AD pathology and cognitive function deserves further study. References 5. Schneider JA, Bienias JL, Wilson RS, Berry-Kravis E, Evans DA, Bennett DA. Apolipoprotein E ĺ4 increases the odds of chronic cerebral infarctions detected at autopsy. Stroke 2005;36:954-959. 6. Schneider JA, Wilson RS, Bienias JL, Evans DA, and Bennett DA. Cerebral infarctions and the likelihood of dementia from Alzheimer's disease pathology. Neurology 2004;62:1148-1156. Disclosure: The authors report no conflicts of interest.