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The Role that Fragmented Sleep Plays in Cognition

Article In Brief

A new study suggests that disrupted sleep throughout older age is accompanied by microglial cells that age faster and become overly active, potentially contributing to cognitive impairment.

Older adults who had experienced greater fragmented sleep showed higher levels of a gene signature suggestive of aged microglia, and they performed worse on annual cognitive tests.

The findings—which were based on data from two prospective, observational, community-based studies of older persons who had donated their brains and medical records for research purposes—underscore the role that poor sleep can play in late life and cognition.

“These findings add more evidence that fragmented sleep is bad for the brain,” said Andrew S.P. Lim, MD, associate professor of neurology at University of Toronto and senior investigator of the study, published December 11 in Science Advances. “It means that sleep problems in older people need to be taken seriously.”

More research is needed to test whether modifying sleep can reverse these changes, and to figure out how much sleep fragmentation is enough to trigger activated microglia or other changes in the brain's innate immune cells that regulate inflammation and other immune system functions, Dr. Lim said.

There is growing evidence that microglia play a role in Alzheimer's disease (AD) and in sleep. “Understanding microglia biology could ultimately allow us to target pathways in the brain that can reverse these problems,” said Dr. Lim, a sleep neurologist.

Study Design, Findings

Dr. Lim and his colleagues drew data from the Rush Memory and Aging Project and the Religious Orders Study. At the time of this assessment, 685 adults, 65-years-old or older—265 with AD and 420 without—were enrolled in the study. A subset of study participants agreed to an annual test to measure movement during sleep. Results from this wristwatch-like accelerometer were paired with their yearly cognitive test scores. In subsets of participants, the autopsied tissue was also tested in two ways: first, neocortical microglial gene expression was quantified by RNA sequencing and then, neocortical microglial density and morphologic activation was assessed by immunohistochemistry.

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“The results from the current study are clinically significant because they highlight the importance of sleep and circadian health for successful brain aging, but also point to the potential of sleep and circadian–based approaches as a component for disease modification therapies in age-related cognitive decline and dementia.”—DR. PHYLLIS C. ZEE

The researchers reported that people who had more sleep fragmentation had higher expression of marker genes characteristic of aged microglia, an increased level of activated microglia, and worse cognition before they died. The problems with sleep fragmentation and its relationship to expression of genes related to aging microglia, and worsening scores on cognitive tests were present in patients with AD, as well as people who were not diagnosed with AD, said Dr. Lim.

“The transcriptional changes were independent of chronological age, density of microglia, and dementia-related brain pathologies and were not completely accounted for by the increased density of morphologically activated microglia,” the study authors wrote. “...These findings raise the possibility that microglial aging and activation may be a consequence of sleep fragmentation and may link sleep fragmentation to poor cognition in older adults.”

The researchers are still not sure whether microglial aging or activated microglia leads to sleep fragmentation or whether waking up throughout the night triggers microglial aging and activation, and how this contributes to dementia pathologies.

It is possible that both processes play a role in what Dr. Lim and his colleagues called “a two-hit model.”

They wrote that it is also possible that “greater sleep fragmentation is associated with higher expression of genes characteristic of aged microglia, irrespective of the presence or absence of AD pathology, but the subsequent impact of microglial transcriptional aging on cognition is greatest in those who also have AD pathology, in whom microglial transcriptional aging amplifies the cognitive impact of AD pathology.”

The scientists said that they need to study sleep fragmentation in middle-aged people to understand how long the problem exists before it leads to changes in gene expression and activated microglia.

Expert Commentary

“This is an exciting and interesting paper linking sleep fragmentation to microglial function that could open the door to new insights into how sleep protects the brain,” said Erik S. Musiek, MD, PhD, associate professor of neurology at Washington University School of Medicine in St. Louis.

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“In general, microglia gene expression patterns suggest aging and microglial activation, indicative of inflammation, in people with sleep fragmentation. Sleep fragmentation and microglial changes were also correlated with poor memory performance. This suggests that sleep fragmentation may contribute to brain inflammation via microglial activation in aging.”—DR. ERIK S. MUSIEK

“There are a number of studies suggesting that sleep disruption can increase inflammation in the periphery, and some animal studies show a relationship between sleep loss and inflammation in the brain. This study supports those previous findings and adds a new wrinkle—sleep fragmentation. This method to measure sleep fragmentation is quite powerful and has previously been used to correlate sleep fragmentation and risk of incident dementia. The participants in the study had their sleep measured on average about 1.5 years before they died, and there are correlations between sleep fragmentation and microglial gene expression.

“In general,” Dr. Musiek added, “microglia gene expression patterns suggest aging and microglial activation, indicative of inflammation, in people with sleep fragmentation. Sleep fragmentation and microglial changes were also correlated with poor memory performance. This suggests that sleep fragmentation may contribute to brain inflammation via microglial activation in aging.”

He added that “some caveats include the fact that all of the findings are correlational, and further experiments would be needed to show true causality. Also, the use of post-mortem tissue can be a problem, as death and postmortem interval may alter microglial gene expression. Confirmation of these finding using CSF biomarkers in living people would be an important next step. Finally, sleep fragmentation may result from disruption of the circadian clock, which has also been implicated in regulation of neuroinflammation.”

“This is another study that supports the importance of sleep for cognition,” added Rachel Marie E. Salas, MD, FAAN, associate professor of neurology at Johns Hopkins Medicine and assistant medical director for the Johns Hopkins Center for Sleep.

“Fragmented sleep is so common with older adults for many reasons. It is very important to address and optimize your sleep environment or it can have negative consequences. Sleep is a basic human need and we tell our patients that only they can make it a priority. Not only do we need enough sleep but it has to be quality sleep.”

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“Fragmented sleep is so common with older adults for many reasons. It is very important to address and optimize your sleep environment or it can have negative consequences. Sleep is a basic human need and we tell our patients that only they can make it a priority. Not only do we need enough sleep but it has to be quality sleep.”—DR. RACHEL MARIE E. SALAS

“Although the pathways linking sleep and circadian rhythms with neurologic health are likely multifactorial—including alterations in interstitial and CSF flow dynamics, neuronal metabolism, and oxidative stress—recent evidence in animals indicate that alterations in microglial function, together with microglial activation and neuro-inflammation are potential common pathways,” added Phyllis C. Zee, MD, PhD, professor of neurology and director of the Center for Circadian and Sleep Medicine at Northwestern University Feinberg School of Medicine.

“Although the causal role of sleep fragmentation and alterations in microglial aging was not directly addressable in the study, we now have further insight into accelerated microglial aging as a potential mechanism linking sleep disturbance and neurodegeneration in humans.”

Dr. Zee added: “The results from the current study are clinically significant because they highlight the importance of sleep and circadian health for successful brain aging, but also point to the potential of sleep and circadian–based approaches as a component for disease modification therapies in age-related cognitive decline and dementia.”

Disclosures

Drs. Lim, Musiek, Salas, and Zee had no competing interests.

Link Up for More Information

• Kaneshwaran K, Olah M, Tasaki S, et al. Sleep fragmentation, microglial aging, and cognitive impairment in adults with and without Alzheimer's dementia https://advances.sciencemag.org/content/5/12/eaax7331?utm_campaign=toc_advances_2019-12-13&et_rid=329694843&et_cid=3122845. Science Advances 2019; 5:eaax7331.