Abstract
Activation of microglia, the primary mediators of inflammation in the brain, is a major component of gliosis and neuronal loss in a number of age-related neurodegenerative disorders, such as Alzheimer’s disease (AD). The role of activated microglia in white matter, and its relationship with cognitive decline during aging are unknown. The current study evaluated microglia densities in the white matter of postmortem specimens from cognitively normal young adults, cognitively normal older adults, and cognitive “SuperAgers,” a unique group of individuals over age 80 whose memory test scores are at a level equal to or better than scores of 50-to-65-year-olds. Whole hemisphere sections from cognitively normal old, young, and “SuperAgers” were used to quantify densities of human leukocyte antigen-D related (HLA-DR)-positive activated microglia underlying five cortical regions. Statistical findings showed a significant main effect of group on differences in microglia density where cognitively normal old showed highest densities. No difference between SuperAgers and young specimens were detected. In two autopsied SuperAgers with MRI FLAIR scans available, prominent hyperintensities in periventricular regions were observed, and interestingly, examination of corresponding postmortem sections showed only sparse microglia densities. In conclusion, activated microglia appear to respond to age-related pathologic changes in cortical white matter, and this phenomenon is largely spared in SuperAgers. Findings offer insights into the relationship between white matter neuroinflammatory changes and cognitive integrity during aging.
Highlights
Microglia are the resident macrophages of the central nervous system (CNS), and dynamically survey their surroundings for foreign antigens, signs of infection, and cell distress (Streit et al, 2014)
Differences in microglia density were analyzed in a two-way ANOVA with post hoc Newman-Keuls multiple comparison tests; brain region (CC, anterior cingulate cortex (ACC), inferior frontal gyrus (IFG), superior temporal gyrus (STG), inferior parietal lobule (IPL), and entorhinal-hippocampus complex (ERC)) and aging trajectory group (Young, Old, and SuperAger) were included
human leukocyte antigen-D related (HLA-DR) staining appeared greater in white matter compared to gray matter, due to larger, denser populations of activated microglia based on examination at high magnification
Summary
Microglia are the resident macrophages of the central nervous system (CNS), and dynamically survey their surroundings for foreign antigens, signs of infection, and cell distress (Streit et al, 2014). Microglia Across Cognitive Aging Trajectories has been suggested to lead to cytotoxic effects (McGeer and McGeer, 2001; Luo et al, 2010). In age-related neurodegenerative diseases, like Alzheimer’s disease (AD), activated microglia appear to be associated with pathological inclusions, such as amyloid-β plaques and neurofibrillary tangles—the characteristic neuropathologic substrates of AD—within cortical gray matter (Serrano-Pozo et al, 2011). Microglia proliferation and activation appear to increase, in response to neurodegenerative pathogens and in brain specimens of cognitively normal elderly who do not show Alzheimer’s pathology (Conde and Streit, 2006). There are no quantitative examinations on regional densities of white matter microglia across cognitive aging trajectories
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