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Frequent flu-like infections could be contributing to age-related cognitive decline. Anna Malgina/Stocksy
  • Studies in humans have shown that greater exposure to microbial infections during one’s lifetime is associated with a greater decline in cognitive function with aging.
  • A new animal study assessed the impact of inflammation caused by repeated microbial infections on cognitive function by intermittently administering the inflammation-inducing bacterial toxin, lipopolysaccharide, to mice.
  • The study found that mild-to-moderate inflammation induced by repeat lipopolysaccharide administration resulted in deficits in memory and learning in early middle-aged mice.
  • These findings in agings mice suggest that mild-to-moderate sickness caused due to microbial infections may need more aggressive treatment than the current standard of care, especially in populations vulnerable to cognitive impairment, such as elderly individuals.

Medical advice for individuals with mild-to-moderate infections generally involves getting adequate rest and increasing fluid intake. Interestingly, a recent study published in the journal Brain, Behavior, and Immunity suggests that repeated inflammation caused by the administration of a bacterial toxin to middle-aged mice led to cognitive deficits. These cognitive deficits were also accompanied by changes in the plasticity of neurons in the hippocampus, a region that plays a central role in learning and memory.

Elderly individuals are more susceptible to microbial infections, and such infections could worsen the decline in cognitive function in these individuals, leading to mild cognitive impairment or dementia.

The findings of the present study suggest that more aggressive treatments could be necessary for older adults to prevent the lasting effects of these infections on cognitive function. However, it is important to note that this study was conducted in a mouse model, and the generalizability of these results to humans is not yet known.

A decline in certain cognitive abilities is observed over the course of normal aging and is a consequence of the biological processes associated with brain aging. Similarly, pathological brain aging is linked to cognitive impairment observed in neurodegenerative conditions such as Alzheimer’s disease.

Studies suggest that inflammation caused due to microbial infections could contribute, among a multitude of factors, to brain aging. For instance, greater exposure to infectious agents during an individual’s lifetime is associated with lower cognitive function and a greater decline in cognitive function in the elderly.

Furthermore, studies in animal models have shown that inflammation due to microbial exposure can influence cognitive function. One of the models for examining the impact of inflammation caused by microbial infections involves injecting animals with the toxin lipopolysaccharide (LPS) that is present in the outer membrane of gram-negative bacteria.

These animal studies have shown that LPS administration can increase the levels of cytokines, a class of inflammatory proteins, in the brain and cause deficits in cognitive function. In addition, these adverse effects of LPS become more pronounced with advancing age.

Most of these studies have examined the impact of either a single dose or continuous administration of LPS on the brain and cognitive function. These studies have shown that even a single dose of LPS-induced inflammation can cause lasting changes in the brain.

However, researchers have not extensively studied the impact of repeated exposure during the lifetime to microbial infections on changes in the brain and cognitive function. Limited evidence from animal studies shows that repeated administration of LPS can increase the risk of cognitive dysfunction in genetically engineered rodent models of Alzheimer’s disease.

To further understand the impact of lifetime exposure to microbial infections on cognitive function, the study’s authors assessed the impact of recurring inflammation caused by intermittent LPS injections on the cognitive function of healthy middle-aged mice.

In the present study, the researchers administered increasing doses of LPS to the mice every 15 days for 2.5 months. Previous studies have shown that repeated administration of the same dose of LPS results in the development of tolerance, involving the absence of an inflammatory response.

To circumvent this issue, the researchers used a progressively higher dose of LPS over the course of the five injections. Each injection of LPS resulted in moderate sickness, from which the mice recovered during the 15-day period.

The researchers then conducted behavioral tests to assess the cognitive function of the animals two weeks after the final lipopolysaccharide dose. The researchers also sacrificed the animals to examine the impact of lipopolysaccharide-induced inflammation on the brain at 5-6 weeks after the final injection.

The control group consisted of mice treated with saline. The mice were 10 months at the time of the onset of the study, which is around the time between the transition from late adulthood to middle age.

The researchers found that mice receiving the LPS injections showed cognitive deficits in learning and retention of memory of information learned during the previous day.

After examining brain tissue, researchers saw that mice intermittently injected with LPS also showed changes in the hippocampus. The hippocampus plays a key role in memory and learning and is one of the regions that shows the earliest signs of degeneration in Alzheimer’s disease.

These changes included an increase in the expression of the gene for the cytokine interleukin-6 (IL-6) in the hippocampus of LPS-treated mice. This is consistent with previous studies showing elevated IL-6 levels in brain regions involved in cognition after LPS administration.

The researchers also found that administering LPS also modulated the plasticity between neurons but not baseline signal transmission. Specifically, the mice researchers administered LPS to showed decreased long-term potentiation between neurons in the hippocampus.

Long-term potentiation (LTP) describes the strengthening of synapses between neurons after the frequent activation of one neuron by the other. This strengthening of connections between neurons allows easier activation of the neuron by the connected neuron. The decrease in LTP in the hippocampus neurons of LPS-treated mice is especially significant given that LTP is considered to be the mechanism underlying the formation of memories and learning.

These results suggest that repeated LPS-induced inflammation in middle-aged mice can lead to cognitive deficits accompanied by changes in the hippocampus.

The study’s co-author Dr. Elizabeth Engler-Chiurazzi, a behavioral neuroscientist at Tulane University, said the findings have important implications for brain health and disease in humans.

“Currently, the standard of care for the common cold or the flu bug is to stay home, get plenty of rest, drink soup, and let your body do its job to clear the infection. This guidance is applied broadly to the population and, to my knowledge, is given regardless of risk for subsequent dementia development (e.g. patients carrying genes that are associated with early-onset Alzheimer’s disease),” she told Medical News Today.

“[O]ur findings may be the first step in a series of studies that could indicate that treatment for the common cold or other sources of intermittent infection among patients at high risk for cognitive decline/dementia may need to be more aggressive than the standard recommendations of rest and fluids.”
— Dr. Elizabeth Engler-Chiurazzi

“These data may also indicate that a greater history of ‘flu-like’ infections could serve as a predictor for cognitive dysfunction later in life. Some studies done in humans have begun to explore this association with evidence in alignment with our observations in mice,” added Dr. Engler-Chiurazzi.

Dr. Engler-Chiurazzi cautioned that these results may or may not be generalizable to humans.

“The composition of the immune system between mice and humans is similar though important species differences in how these systems respond are known, and the extent to which these findings replicate in human populations needs to be further investigated,” she said.

The authors also intend to examine the mechanisms that contributed to the cognitive deficits after repeated LPS administration.

Dr. Engler-Chiurazzi said, “An immediate next step for our group is to repeat these studies and determine the extent to which common brain consequences seen in dementia, such as a leaky blood-brain barrier or activation of brain immune cells (microglia), are observed after repeated intermittent exposure to sickness-like inflammation in the body.”

Dr. Engler-Chiurazzi also noted that they did not investigate the impact of viral infections on cognitive function and are currently examining its impact in an animal model.