Ecology of the aging human brain

Abstract

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.

Figure 1

Brain autopsy results from cognitively normal (CN) individuals expressed as Summary Neuropathology Score (range 0 to 9) ranked from lowest to highest. Each stacked bar shows an individual’s burden of AD (blue), LBD (green), and μVBI (red). (A) 116 Adult Changes in Thought (ACT) study participants, (B) 106 Nun Study (NS) participants, (C) 59 Honolulu Asian Aging Study (HAAS) participants, and (D) 55 Oregon Health & Science (OBAS) study participants.

Figure 2

Cumulative relative frequency of Summary Neuropathology Score for those autopsied individuals with complete neuropathologic examination from the four studies who were CN as defined in Table 1 (n=336), those with lower cognitive function (LCF) defined as those individuals last evaluated within two years of death at which time they were diagnosed as not dementia but scored in the lowest quintile on the cognitive screening test (n=189), and those who were diagnosed with dementia (n=522). Non-parametric analysis of variance comparing the Summary Neuroapthology Score among the three groups had P < 0.0001 and Dunn’s corrected multiple paired comparisons had P < 0.0001 for CN vs. LCF, LCF vs. Dementia, and CN vs. Dementia.