Publications

The processes involved with beta-amyloid (Abeta) degradation and clearance in human brain are not well understood. We hypothesized that the distribution of oxidatively modified Abeta, as determined by an affinity-purified antibody in the entorhinal and frontal cortices of Alzheimer's disease (AD), Down syndrome (DS), nondemented elderly control cases, and canine brain, would provide insight into the mechanisms of Abeta accumulation. Based upon plaque counts, oxidized Abeta was present within 46-48% of diffuse and primitive plaques and 98% of cored plaques. Dense punctate deposits of oxidized Abeta were distributed throughout the neuropil in AD and DS brains but were also present within controls with mild neuropathology and isolated cognitive impairments. Confocal studies indicate that punctate oxidized Abeta deposits were within activated microglia. Oxidatively modified Abeta may reflect the efforts of microglial cells to take up and degrade Abeta. Oxidative modification of Abeta may be an early event in Abeta pathogenesis and may be important for plaque biogenesis.

Progressive declines in memory function accompany normal aging, mild cognitive impairment (MCI), and Alzheimer's disease (AD). Neuropathological studies suggest that damage to neurons providing connections between cortical areas may contribute to memory impairments in AD. Because AD develops slowly, similar neuropathological changes, to a lesser degree, may be present in MCI and some asymptomatic elderly subjects. In this study we tested the hypothesis that corticocortical interactions between sensory regions are impaired in aging, MCI, and AD, as compared with young subjects. When sensory cortical evoked potentials are elicited by pairs of stimuli the amplitudes of potentials to the second stimulus are attenuated. Corticocortical interactions were assessed by presenting stimulus pairs in different modalities (auditory/visual). There were significant group differences in the degree that a visual stimulus attenuated subsequent auditory potentials (young > healthy elderly > MCI > AD). Control experiments indicated equivalent amplitude reductions for all groups to the second stimulus for stimulus pairs having the same modality. These findings are compatible with progressive declines in corticocortical processing in aging, MCI, and AD.