Activated Microglia in Cortical White Matter Across Cognitive Aging Trajectories

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.

Receptors for pro‐resolving mediators are increased in Alzheimer's disease brain

“…This early inflammation was also supported by PET-imaging of microglial activation in white matter (60). In a quantitative approach one group investigated microglial density in white matter of cognitively normal young and old individuals (40-100 year of age) showing higher levels of microglial activation in old cases compared to young and the very old (25). In our cohort, we had two white matter regions, BA46 and CG, which showed increased HLA-DR-positive microglia in AD compared to control.…”

Sex-Dependent Pathology in the HPA Axis at a Sub-acute Period After Experimental Traumatic Brain Injury

“…These data indicate a robust neuroinflammatory response to DAI in the DG, where the response in males was larger than females, similar to that previously reported after a focal injury (controlled cortical impact) in mice ( 113 ), but not after mFPI in mice ( 114 ). In our study, we did not follow-up with any behavioral tests to confirm cognitive deficits, but other studies showed that midline FPI-induced age-related microglial activation in the hippocampus was directly related to cognitive decline ( 115 – 117 ).…”

Royal Jelly as an Intelligent Anti-Aging Agent—A Focus on Cognitive Aging and Alzheimer’s Disease: A Review

“…Evidence indicates that aged brains undergo several pathological changes: higher metabolic stress, reduced neurogenesis, increased synaptic aberrations, immune dysregulation (high expression of inflammatory markers), and low expression of neuroprotective factors. Altered brain physiology, along with disturbances in the function and synchronization of the circadian system, significantly increase the prevalence of neurodegeneration, neurobehavioral deficits, and cognitive aging [ 7 , 8 ]. Research documents that normal cognitive aging involves synaptic changes and decreased neuronal plasticity of the cortex and hippocampus, which directly accelerate declines in memory, reasoning, and speed; these alterations may start from early adulthood [ 9 , 10 ].…”

“…A sensitized phenotype of the aged brain is highly vulnerable to secondary insults such as infections and psychological stress. Inflammatory cytokines foster the transcriptional upregulation of β-secretase and APP and increase Aβ aggregation, which contribute to the characteristic neuropathologic substrate of AD—Aβ plaques [ 7 , 11 , 33 ].…”

“…High expression of microglial inflammation markers leads to dystrophic morphology (e.g., deramification, cytoplasmic fragmentation, and shortening of cellular processes). Such manifestation of microglial senescence alters their ability to promote proper neuronal function or protect neurons against the accumulation of NFT and Aβ oligomers [ 7 , 167 ]. Neuroinflammation broadens neuron loss by accelerating oxidative stress.…”