Cognitive and physiologic correlates of subclinical structural brain disease in elderly healthy control subjects

Context: Healthy elderly persons commonly show 4 types of change in brain structure-cortical atrophy, central atrophy, deep white-matter hyperintensities, and periventricular hyperintensities-as forms of subclinical structural brain disease (SSBD). Objectives: To characterize the volumes of SSBD present with aging and to determine the associations of SSBD, physiology, and cognitive function. Design: Cross-sectional study. Setting: University of California, Los Angeles, Neuropsychiatric Institute. Subjects: Forty-three community-dwelling healthy control subjects, aged 60 through 93 years. Main Outcome Measures: Volumetric magnetic resonance imaging, neuropsychological testing, and quantitative electroencephalographic coherence (functional connectivity) between brain regions. Results: Regression models demonstrated significant relationships between SSBD volumes, age, cognitive performance, and connectivity. Cortical and central atrophy and periventricular hyperintensities had significant associations with age while deep white-matter hyperintensities did not. Posterior atrophy showed stronger associations with age than did anterior atrophy. Only a subset of subjects at older ages showed large SSBD volumes; older subjects primarily showed increasing variance of SSBD. Although all subjects scored within the normal range on cognitive testing, SSBD volume was inversely related to performance, most notably on the Trail-Making Test part B and the Shipley-Hartford Abstract Reasoning test. Coherence had significant associations with SSBD. Path analysis supported mediation of the effects of deep white-matter hyperintensities and periventricular hyperintensities on cognition by altered connectivity. For several measures, cognitive performance was best explained by coherence, and only secondarily by SSBD. Conclusions: Modest volumes of SSBD were associated with decrements in cognitive performance within the normal range in healthy subjects. Lower coherence was associated with greater volumes of SSBD and increasing age. Path analysis models suggest that brain functional connectivity mediates some effects of SSBD on cognition.