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Original Contributions |

Ecology of the Aging Human Brain

Joshua A. Sonnen, MD; Karen Santa Cruz, MD; Laura S. Hemmy, PhD; Randall Woltjer, MD, PhD; James B. Leverenz, MD; Kathleen S. Montine, PhD; Clifford R. Jack, MD; Jeffrey Kaye, MD; Kelvin Lim, MD; Eric B. Larson, MD, MPH; Lon White, MD, MPH; Thomas J. Montine, MD, PhD
Arch Neurol. 2011;68(8):1049-1056. doi:10.1001/archneurol.2011.157.
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Background Alzheimer disease, cerebral vascular brain injury, and isocortical Lewy body disease (LBD) are the major contributors to dementia in community- and population-based studies.

Objective To estimate the prevalence of clinically silent forms of these diseases in cognitively normal (CN) adults.

Design Autopsy study.

Setting Community- and population based.

Participants A total of 1672 brain autopsies from the Adult Changes in Thought study, Honolulu-Asia Aging Study, Nun Study, and Oregon Brain Aging Study, of which 424 met the criteria for CN.

Main Outcome Measures Of these, 336 cases had a comprehensive neuropathologic examination of neuritic plaque density, Braak stage for neurofibrillary tangles, LB distribution, and number of cerebral microinfarcts.

Results Forty-seven percent of CN cases had moderate or frequent neuritic plaque density; of these, 6% also had Braak stage V or VI for neurofibrillary tangles. Fifteen percent of CN cases had medullary LBD; 8% also had nigral and 4% isocortical LBD. The presence of any cerebral microinfarcts was identified in 33% and of high-level cerebral microinfarcts in 10% of CN individuals. Overall, the burden of lesions in each individual and their comorbidity varied widely within each study but were similar across studies.

Conclusions These data show an individually varying complex convergence of subclinical diseases in the brain of older CN adults. Appreciating this ecology should help guide future biomarker and neuroimaging studies and clinical trials that focus on community- and population-based cohorts.

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Figures

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Figure 1. Brain autopsy results from 336 cognitively normal individuals expressed as summary neuropathology scores (range, 0-9) ranked from lowest to highest. Each stacked bar shows an individual's burden of Alzheimer disease (AD) (blue), Lewy body disease (LBD) (green), and microvascular brain injury (μVBI) (red). A, One hundred sixteen Adult Changes in Thought study (ACT) participants. B, One hundred six Nun Study (NS) participants. C, Fifty-nine Honolulu-Asia Aging Study (HAAS) participants. D, Fifty-five Oregon Brain Aging Study (OBAS) participants.

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Figure 2. Cumulative relative frequency of the summary neuropathology score for autopsied individuals with complete neuropathologic examination from the 4 studies who were cognitively normal (CN) as defined in Table 1 (n = 336); those with lower cognitive function (LCF), defined as individuals last evaluated within 2 years of death at which time they were diagnosed as not having dementia but scored in the lowest quintile on the cognitive screening test (n = 189); and those who were diagnosed as having dementia (n = 522). Nonparametric analysis of variance comparing summary neuropathology scores among the 3 groups had P < .001 and the Dunn corrected multiple paired comparisons had P < .001 for CN vs LCF, LCF vs dementia, and CN vs dementia.

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