Abstract: Objective: The authors describe four types of brain structural change in "normal aging:" cortical atrophy, central atrophy, deep white-matter hyperintensities (DWMH), and periventricular hyperintensities (PVH). Cross-sectional investigations have reported that greater volumes of these forms of "subclinical structural brain disease" (SSBD) were found with increasing age. Greater volumes were also associated with poorer cognition, even though subjects performed within the normal range. The natural history of these forms of SSBD and their functional impact are not well established. Methods: Twenty-nine normal subjects, ages 60-89, were examined longitudinally by volumetric magnetic resonance imagery, with two assessments performed at least 2 years apart; 26 also completed neuropsychological testing to evaluate processing speed, executive functions, language, and other cognitive functions. Associations between structure and function were evaluated with regression models. Results: For most subjects, the volumes for signs of all types of SSBD were found to have increased; for many subjects, increases were small, and a few showed no change or small decreases. PVH and DWMH increases were predicted by baseline cerebrovascular risk factors. Cognitive test performance changed little over time for these normal subjects. Conclusions: SSBD volumes increased for most subjects over time, with small average increases for most types. Pretreatment cerebrovascular risk factors were associated with greater increases of PVH and DWMH, suggesting that progression of these types of SSBD may be amenable to intervention.

Abstract: Psychiatric disorders are characterized by diverse clinical manifestations that include deficits in cognition, perception, mood and arousal. These complex processes are not mediated by any specific brain region but require the coordinated activity of several areas that are anatomically connected. Impairments in these neural circuits may therefore be expected to result in an attenuation of the functions regulated by them. The white matter provides the structural and physiological substrate of neural circuits in the central nervous system. We propose that injury to the white matter, from diverse biological sources, may compromise neural connectivity by associated axonal injury or impaired conductivity. Either mechanism could result in clusters of signs and symptoms that are currently recognized as psychiatric disorders. The role of white matter impairment in the pathophysiology of psychiatric illness is under-appreciated in the neurosciences. Focused translational research aimed at identifying the links between white matter compromise and specific behaviors are necessary for a more thorough understanding of the etiology of mental illness to emerge.

Abstract: BACKGROUND: Cortical atrophy, central atrophy, deep white-matter hyperintensities, and periventricular hyperintensities are reported in normal aging. OBJECTIVES: We examined the effects of estrogen replacement therapy (ERT) on these forms of 'subclinical structural brain disease' (SSBD) in normal, postmenopausal women in a pilot, naturalistic, longitudinal study of 15 subjects. METHODS: Two assessments were performed at least two years apart, with volumetric magnetic resonance imaging (MRI) and neuropsychological testing. RESULTS: Women receiving open-label ERT showed significantly less progression of SSBD than those who did not. CONCLUSIONS: The association between reduced SSBD progression and ERT suggests this intervention could help preserve normal brain structure in healthy elderly women.

Abstract: 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.