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1.  Association of Lifetime Cognitive Engagement and Low β-Amyloid Deposition 
Archives of neurology  2012;69(5):623-629.
Objective
To assess the association between lifestyle practices (cognitive and physical activity) and β-amyloid deposition, measured with positron emission tomography using carbon 11–labeled Pittsburgh Compound B ([11C]PiB), in healthy older individuals.
Design
Cross-sectional clinical study.
Setting
Berkeley, California.
Participants
Volunteer sample of 65 healthy older individuals (mean age, 76.1 years), 10 patients with Alzheimer disease (AD) (mean age, 74.8 years), and 11 young controls (mean age, 24.5 years) were studied from October 31, 2005, to February 22, 2011.
Main Outcome Measures
Cortical [11C]PiB average (frontal, parietal, lateral temporal, and cingulate regions) and retrospective, self-report scales assessing participation in cognitive activities (eg, reading, writing, and playing games) and physical exercise.
Results
Greater participation in cognitively stimulating activities across the lifespan, but particularly in early and middle life, was associated with reduced [11C]PiB uptake (P <.001, accounting for age, sex, and years of education). Older participants in the highest cognitive activity tertile had [11C]PiB uptake comparable to young controls, whereas those in the lowest cognitive activity tertile had [11C]PiB uptake comparable to patients with AD. Although greater cognitive activity was associated with greater physical exercise, exercise was not associated with [11C]PiB uptake.
Conclusions
Individuals with greater early- and middle-life cognitive activity had lower [11C]PiB uptake. The tendency to participate in cognitively stimulating activities is likely related to engagement in a variety of lifestyle practices that have been implicated in other studies showing reduced risk of AD-related pathology. We report a direct association between cognitive activity and [11C]PiB uptake, suggesting that lifestyle factors found in individuals with high cognitive engagement may prevent or slow deposition of β-amyloid, perhaps influencing the onset and progression of AD.
doi:10.1001/archneurol.2011.2748
PMCID: PMC3747737  PMID: 22271235
2.  Cognitive Decline in Prodromal Alzheimer's Disease and Mild Cognitive Impairment 
Archives of neurology  2011;68(3):351-356.
Objective
To characterize the course of cognitive decline during the prodromal phase of Alzheimer's disease.
Design
Longitudinal cohort study with up to 16 years of observation.
Participants
Older persons from two projects underwent annual clinical evaluations that included cognitive function testing and clinical classification of mild cognitive impairment, dementia, and Alzheimer's disease. At baseline, there were 2,071 individuals without dementia and 1,511 without cognitive impairment.
Main Outcome Measures
Change in previously established composite measures of global cognition and specific cognitive domains assessed in mixed-effects models that allow rate of decline to shift at specific points.
Results
During follow-up, 462 persons developed Alzheimer's disease (20 with dementia solely due to another condition were excluded). Five to six years before the diagnosis, rate of global cognitive decline sharply accelerated by more than 15-fold. The acceleration in decline occurred slightly earlier for semantic memory (76 months before diagnosis) and working memory (75 months) than other cognitive functions. Mild cognitive impairment was also preceded by years of cognitive decline which began earlier (80 months before diagnosis) and proceeded more rapidly (annual loss of 0.102 unit) in the amnestic than nonamnestic (62 months, 0.072 unit) subtype.
Conclusion
Dementia due to Alzheimer's disease is preceded by about five to six years of accelerated decline in multiple cognitive functions. By contrast, little decline is evident in persons not developing Alzheimer's disease.
doi:10.1001/archneurol.2011.31
PMCID: PMC3100533  PMID: 21403020
3.  Telephone Assessment of Cognitive Function in the Late Onset Alzheimer’s Disease Family Study 
Archives of neurology  2010;67(7):855-861.
Context
Administration of cognitive test batteries by telephone has been shown to be a valid and cost-effective means of assessing cognition, but it remains relatively uncommon in epidemiological research.
Objective
To develop composite cognitive measures and assess how much of the variability in their scores is associated with mode of test administration (i.e., in person or by telephone).
Design
Cross-sectional cohort study
Setting
Late Onset of Alzheimer’s Disease Family Study conducted at 18 centers across the United States.
Participants
A total of 1,584 persons, 368 with dementia, from 646 families.
Main Outcome Measures
Scores on composite measures of memory and cognitive function derived from a battery of 7 performance tests administered in person (69%) or by telephone (31%) by examiners who underwent a structured performance-based training program with annual recertification.
Results
Based in part on the results of a factor analysis of the 7 tests, we developed summary measures of working memory, declarative memory, episodic memory, semantic memory, and global cognition. In linear regression analyses, mode of test administration accounted for less than 2% of the variance in the measures. In mixed-effects models, variability in cognitive scores due to center was small relative to variability due to differences between individuals and families.
Conclusions
In epidemiologic research on aging and AD, assessment of cognition by telephone has little effect on performance and provides operational flexibility and a means of reducing costs and missing data.
doi:10.1001/archneurol.2010.129
PMCID: PMC2971664  PMID: 20625093
Alzheimer’s disease; dementia; memory; cognition
4.  The Association of Magnetic Resonance Imaging Measures With Cognitive Function in a Biracial Population Sample 
Archives of neurology  2010;67(4):475-482.
Background
White matter hyperintensity volume (WMHV), cerebral infarcts, and total brain volume (TBV) are associated with cognitive function, but few studies have examined these associations in the general population or whether they differ by race.
Objective
To examine the association of WMHV, cerebral infarcts, and TBV with global cognition and cognition in 5 separate domains in a biracial population sample.
Setting
A biracial community population of Chicago, Illinois.
Design
Cross-sectional population study.
Participants
The study population comprised 575 participants from the Chicago Health and Aging Project (CHAP).
Main Outcome Measures
Volumetric magnetic resonance imaging (MRI) measures of WMHV, TBV, and cerebral infarcts and detailed neuropsychological testing assessments of global cognition and 5 cognitive domains.
Results
Overall and among those without dementia, cognition was inversely associated with WMHV and number of infarcts but was positively associated with TBV. When all 3 measures were simultaneously added to the model, the association of global cognition with WMHV and TBV remained significant and unchanged but was no longer significant with infarcts. Among subjects without dementia, all 3 MRI measures were associated with performance in multiple cognitive domains, specifically perceptual speed. However, among subjects with dementia, only TBV was associated with cognition and performance in multiple cognitive systems. Race did not significantly modify any of these associations.
Conclusions
In this biracial general population sample, the associations of MRI measures with cognition differed according to clinical status of subjects (stronger among subjects without dementia) and were not modified by race. These associations did not affect all cognitive domains equally but were more consistent with impairments in perceptual speed.
doi:10.1001/archneurol.2010.42
PMCID: PMC2947487  PMID: 20385915
5.  Association of Muscle Strength with the Risk of Alzheimer’s Disease and the Rate of Cognitive Decline in Community-Dwelling Older Persons 
Archives of neurology  2009;66(11):1339-1344.
Objective
Loss of muscle strength is common and associated with a variety of adverse health outcomes in old age, but few studies have examined the association of muscle strength with the risk of Alzheimer’s disease (AD) or mild cognitive impairment (MCI). We tested the hypothesis that muscle strength is associated with incident AD and MCI.
Design
Prospective, observational cohort study.
Setting
Retirement communities across the Chicago metropolitan area.
Participants
More than 900 community-based older persons without dementia at the baseline evaluation and in whom strength was measured in nine muscle groups in both arms and legs as well as in the axial muscles and summarized into a composite measure of muscle strength.
Main Outcome Measures
Incident AD, MCI and rate of change in global cognitive function.
Results
During a mean follow-up of 3.6 years, 138 persons developed AD. In a proportional hazards model adjusted for age, sex, and education, each 1 unit increase in muscle strength at baseline was associated with about a 43% decrease in the risk of AD (HR, 0.57; 95% CI, 0.41,0.79). The association of muscle strength with AD persisted even after adjustment for several covariates, including body mass index, physical activity, pulmonary function, vascular risk factors, vascular diseases and apolipoprotein E4 status. Further, in a mixed-effects model adjusted for age, sex, education, and baseline level of global cognition, increased muscle strength was associated with a slower rate of decline in global cognitive function (p<0.001). Finally, muscle strength was associated with a decreased risk of MCI, the precursor to AD (HR, 0.67; 95% CI, 0.54, 0.84).
Conclusion
These findings suggest a link between muscle strength, AD and cognitive decline in older persons.
doi:10.1001/archneurol.2009.240
PMCID: PMC2838435  PMID: 19901164
6.  Biracial Population Study of Mortality in Mild Cognitive Impairment and AD 
Archives of neurology  2009;66(6):767-772.
Objective
To assess mortality associated with mild cognitive impairment (MCI) and Alzheimer's disease (AD) in older African Americans and whites from an urban community.
Design
Longitudinal population-based observational study.
Setting
Four adjacent neighborhoods of Chicago, IL.
Participants
1,715 persons deemed free of dementia in a previous wave of data collection and sampled for detailed clinical evaluation: 802 had no cognitive impairment, 597 had MCI, 296 had AD, and 20 had other forms of dementia.
Main Outcome Measure
All-cause mortality.
Results
During up to 10 years of observation (mean = 4.7, SD = 3.0), 634 individuals died (37%). Compared to people without cognitive impairment, risk of death was increased by about 50% in those with MCI (hazard ratio [HR] = 1.48; 95% confidence interval [CI]: 1.22, 1.80) and was nearly threefold greater in those with AD (HR = 2.84; 95% CI:2.29, 3.52). These effects were seen in both African Americans and whites and did not differ by race. In MCI, risk of death increased with increasing severity of cognitive impairment and this effect did not vary by race. A similar effect was seen in AD, but it was slightly stronger for black than white persons. In both MCI and AD, the association of cognitive impairment with survival was stronger for perceptual speed than for other cognitive functions.
Conclusion
The presence and severity of MCI and AD are associated with reduced survival in African Americans and these effects are comparable to those seen in white persons.
doi:10.1001/archneurol.2009.80
PMCID: PMC2743243  PMID: 19506138

Results 1-6 (6)