Neurology -- Correspondence for Boyle et al., 67 (3) 441-445

Correspondence published:

Reply from the Authors: Patricia A Boyle, David A. Bennett (4 October 2006)

Mild cognitive impairment: Risk of Alzheimer disease and rate of cognitive decline: Francesco Panza, Cristiano Capurso, Alessia D’Introno, Anna M. Colacicco, Antonio Capurso, and Vincenzo Solfrizzi (4 October 2006)

Reply from the Authors 4 October 2006

Patricia A Boyle,
Rush Alzheimer's Disease Center
600 S Paulina, Suite 1020B Chicago IL 60612,
David A. Bennett
Send Correspondence to journal:
Re: Reply from the Authors

Patricia_Boyle{at}rush.edu Patricia A Boyle, et al.

We appreciate Panza and et al's comments regarding our recent findings showing that MCI is associated with a substantially increased risk of developing AD and a more rapid rate of decline in cognitive function among community-based older persons [1]. They raised several points regarding the study of MCI, including that referral bias is an important source of variability in studies examining rates of conversion from MCI to dementia and that the classification of MCI is unstable in population-based studies.
Citing data from the Italian Longitudinal Study on Aging [2,4], they described MCI as a heterogeneous condition and suggested that subtypes based on cognitive features or likely etiology may be useful for determining who will progress to AD and other dementias. We agree that referral bias is an important source of variability, particularly in studies involving clinic-based persons. Thus, a unique feature or our study is that it involved community-based persons rather than persons who came to the attention of the healthcare system. While we found that those with MCI were almost seven times more likely to develop AD than comparable persons without cognitive impairment, we also found some instability in the classification of MCI, as reported by Panza et al. [2,4] and others [6]; about 14% of persons with MCI at baseline had no cognitive impairment at follow-up.
Another potential source of variability and a factor that may predict stability in MCI classification is age. Participants in the Rush Memory and Aging Project were more than 80 years old at entry. In a separate study of older Catholic clergy (the Religious Orders Study) that used a nearly identical design, the relative risk of incident AD was about three times higher among those with MCI. [7] Participants in that study were only about 75 at entry. In addition, they were followed for an average of 4.5 years compared to 2.5 years in the current study. The risk of developing AD also may have been higher in our study due to the shorter duration of follow-up.
We agree that MCI is a heterogeneous condition and that subtypes may be differentially related to risk of AD. Unfortunately, we did not have sufficient power to examine this issue. However, in a previous work with another cohort, persons with impaired episodic memory were more than twice as likely to develop AD as those with impairment in other cognitive domains. [8] Interestingly, the statistical models violated the assumptions of proportional hazards (we used accelerated failure models) because the risk of AD was highest during the early years of follow-up. Additional follow-up is needed in the Memory and Aging Project before we can attempt to replicate that finding, and more studies are needed to examine the outcomes associated with various MCI subtypes.
The recent interest in MCI stems largely from the desire to identify persons with AD at the earliest stage of disease. Available data suggest that MCI often represents an early manifestation of the pathology of AD. [9,10] However, MCI may not necessarily represent the earliest manifestation of AD; a recent study in Neurology reported that AD pathology is commonly found in persons without dementia or MCI and that its presence is related to episodic memory performance. [11] Thus, identifying the earliest clinical signs of AD will require studies of older persons before they develop MCI.
References
6. Ritchie K, Artero S, Touchon J, et al. Classification criteria for mild cognitive impairment: a population-based validation study. Neurology. 2001;56:37-42.
7. Bennett DA, Wilson RS, Schneider JS, et al. Natural history of mild cognitive impairment in older persons. Neurology 2002; 59(2):198-205.
8. Aggarwal NT, Wilson RS, Beck T, et al. Mild cognitive impairment in different functional domains and incident Alzheimer's disease. J Neurol Neurosurg Psychiatry 2005;76:1479-84.
9. Markesbery WR, Schmitt FA, Kryscio RJ, et al. Neuropathologic substrate of mild cognitive impairment. Arch Neurol 2006;63:38-46.
10. Petersen RC, Parisi JE, Dickson DW, et al. Neuropathologic features of amnestic mild cognitive impairment. Arch Neurol 2006;63:665-672.
11. Bennett DA, Schneider JA, Arvanitakis Z, et al. Neuropathology of older persons without cognitive impairment from two community-based studies.Neurology 2006;66:1837-1844.
Disclosure: The authors report no conflicts of interest.

Mild cognitive impairment: Risk of Alzheimer disease and rate of cognitive decline 4 October 2006

Francesco Panza,
Department of Geriatrics, Center for Aging Brain, Memory Unit, University of Bari
Policlinico, Piazza Giulio Cesare, 11, 70124 Bari - Italy,
Cristiano Capurso, Alessia D’Introno, Anna M. Colacicco, Antonio Capurso, and Vincenzo Solfrizzi
Send Correspondence to journal:
Re: Mild cognitive impairment: Risk of Alzheimer disease and rate of cognitive decline

geriat.dot{at}geriatria.uniba.it Francesco Panza, et al.

We read with great interest the study by Boyle et al reporting findings from the Rush Memory and Aging Project, in which over an average of 2.5 years of follow-up, 57 persons with mild cognitive impairment (MCI) (25.8% of 221) and 23 persons without cognitive impairment developed Alzheimer’s disease (AD) (4.1% of 565); 32 persons with MCI (14.4% of 221) showed no subsequent evidence of cognitive impairment on follow-up. [1]
Furthermore, Boyle et al found that persons with MCI were almost seven times more likely to develop AD than comparable persons without cognitive impairment. In addition, persons with MCI declined considerably more rapidly each year on a measure of global cognitive function than those without cognitive impairment. [1]
The Authors reported in the Introduction and Discussion sections some clinical features of the progression to dementia of MCI and other predementia syndromes, citing the findings of the Italian Longitudinal Study on Aging (ILSA) [2] and other population-based or clinical-based studies. [3,4] In the ILSA, a population-based study with a 3.5-year follow-up, involving a total of 2,963 individuals from age 65 to 84, we found a progression rate to dementia of 3.8/100 person-years (2.3/100 person-years to AD), and among those who progressed to dementia, 60% progressed to AD and 33% to vascular dementia (VaD). [2]
Boyle et al reported that although several previous studies have examined the progression from MCI to AD, rates of conversion vary widely across studies, both population-based or clinical-based, with estimates ranging from about 4% to 40% per year. [1-5] The Authors suggested some methodological limitations as cause of the inconsistencies across studies but we suggest the referral patterns of various studies as another important source of variability in MCI progression to dementia.
Previous data suggest that, in contrast to clinical-based studies where progression is more uniform, in population-based studies the MCI classification is unstable. In population-based samples, from 11% to 56% of subjects MCI or other predementia syndromes remained cognitively stable or improved in follow-ups from 2 to 3.5 years. [2-4] Thus, the apparent homogeneity of MCI and its progression to AD in clinical-based samples may reflect referral patterns and selection criteria, suggesting that MCI is a heterogeneous descriptor and that the outcome at follow-up depends on which population is studied and how MCI is defined. [5]
The recent subclassification of MCI according to its cognitive features [dysexecutive MCI and amnestic MCI (aMCI) or aMCI and non-amnestic MCI (naMCI): single domain aMCI and multiple domain aMCI or single domain naMCI, and multiple domain naMCI], clinical presentation (MCI with parkinsonism or cerebrovascular disease), or likely etiology (MCI-AD, vascular MCI, or MCI-Lewy Body Disease) represents an attempt to control this heterogeneity. [3-5]
References
1. 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.
2. Solfrizzi V, Panza F, Colacicco AM, et al for The Italian Longitudinal Study on Aging Working Group. Vascular risk factors, incidence of MCI, and rates of progression to dementia. Neurology 2004;63:1882–1891.
3. Panza F, D'Introno A, Colacicco AM, et al. Current epidemiology of mild cognitive impairment and other predementia syndromes. Am J Geriatr Psychiatry 2005;13:633-644.
4. Panza F, D'Introno A, Colacicco AM, et al. Cognitive frailty: Predementia syndrome and vascular risk factors. Neurobiol Aging. 2006;27:933-940.
5. Gauthier S, Reisberg B, Zaudig M, et al; International Psychogeriatric Association Expert Conference on mild cognitive impairment. Mild cognitive impairment. Lancet 2006;367:1262-1270.
Disclosures: The authors report no conflicts of interest.