BOSTON—Although attempts to reduce cognitive deficits by improving sleep have produced mixed results, some data indicate that this strategy may hold promise, according to research reported at the 26th Annual Meeting of the Associated Professional Sleep Societies. Further studies, including trials of sedatives/hypnotics, could clarify the relationship between sleep and cognition, said Donald Bliwise, PhD, Professor of Neurology at Emory University in Atlanta.
Sleep Loss and Protein Aggregation
David Holtzman, MD, Chair of Neurology at Washington University in St. Louis, and colleagues found that sleep deprivation raised levels of amyloid-β in the brains of vulnerable mice. “This is the same protein that tends to aggregate in Alzheimer’s disease,” said Dr. Bliwise. “It certainly is a provocative finding.”
When the researchers restricted animals’ sleep for 20 of 24 hours over 21 days, they found accumulations of amyloid-β throughout the brains. “This is fairly convincing data that sleep might be important here, particularly if an animal or human is deprived of it,” said Dr. Bliwise.
Hypoxia and Cognitive Impairment
Animal studies also have suggested a link between hypoxia, which often results from sleep-disordered breathing, and cognitive impairment. Michael J. Decker, PhD, Associate Professor of Neuroscience at Georgia State University in Atlanta, subjected rat pups to several hours of intermittent hypoxia per day for four days. When he sacrificed the animals 80 days later, he found various changes in their dopamine systems, including an upregulation of their dopamine transporters. The results suggest that hypoxia can impair neurotransmitter systems, said Dr. Bliwise.
David Gozal, MD, Chair of Pediatrics at the University of Chicago School of Medicine, exposed young and old animals to 12 hours of intermittent hypoxia per day for two weeks. The elderly animals experienced much more cell death than younger animals did, which indicates that sleep apnea could hasten degeneration, according to Dr. Bliwise.
Sleep Apnea and Impaired Cognition
Human epidemiologic data are ambiguous about the relationship between sleep-disordered breathing and cognitive impairment. Some large-scale, population-based studies suggest associations between the phenomena, but others do not, said Dr. Bliwise.
A meta-analysis showed that patients with sleep apnea have various forms of cognitive impairment. Researchers at the University of California, Los Angeles, found that the volume of the hippocampus mammillary body tended to be lower in patients with sleep apnea than in controls.
Ruth O’Hara, PhD, Associate Research Professor of Psychiatry and Behavioral Science at Stanford University School of Medicine in California, found a stronger association between sleep apnea and cognitive impairment in subjects who carried the APOE4 gene than in subjects without that gene. The disorder might be a mediating variable in the development of cognitive impairment for individuals with genetic susceptibility, observed Dr. Bliwise.
Similar results were obtained by Adam Spira, PhD, of Johns Hopkins University in Baltimore, who found an association between impaired cognition and sleep apnea among patients with the APOE4 gene. Compared with controls, patients with this gene had a greater risk of a Mini-Mental State Examination (MMSE) score lower than 22.
Treating Sleep Apnea
The only clinical trial of treating sleep apnea to reverse cognitive impairment in dementia patients yielded mixed results. Sonia Ancoli-Israel, PhD, Professor of Psychiatry at the University of California, San Diego, analyzed whether a continuous positive airway pressure (CPAP) device would improve the MMSE score of patients with mild or moderate sleep apnea. For three weeks, one group of patients used a CPAP and another used a sham CPAP. After three weeks, the sham group was given a true CPAP. Patients’ mean MMSE score was 24.
Although three weeks of CPAP treatment improved patients’ mood and sleep architecture, it had little effect on neuropsychologic variables. When Dr. Ancoli-Israel combined the data, however, two of 10 cognitive tests showed an improvement. In addition, five patients who continued to use the CPAP for 13 months in an unblinded treatment protocol showed some improvement in cognitive function.
“I interpret these data as suggesting that we have not hit a home run,” said Dr. Bliwise. The trial might not have resulted in major improvement because of insufficient duration of treatment or an underpowered sample, he added. Patients’ disease may also have been too advanced, or the patients may have been insufficiently hypoxic.
Sleep Loss and Human Cognition
Apart from consideration of sleep apnea as a specific sleep disorder, human research does not strongly support a link between sleep loss and cognitive impairment, according to Dr. Bliwise. Some studies from the past 10 years suggest that the two phenomena are linked, but “the results are certainly not overpowering,” he said. “Moreover, we really don’t have a lot of experimental evidence from sedative/hypnotic trials that improving sleep will reverse [cognitive] deficits.”
One recent study showed that zolpidem, as well as treating insomnia, might improve cognitive function. The trial included patients between ages 18 and 30, but not older patients who may have greater risk for cognitive impairments. Although the data do not show clearly that sedatives/hypnotics can enhance cognition, “the basic science tells us we really need to look at this a little bit more,” said Dr. Bliwise.
Improved Sleep Enhances Mental Performance for Some Patients
Some findings from Dr. Bliwise’s research indicate that better sleep quality could reduce cognitive impairment. One of his patients, a woman, age 79, had sleep apnea and an MMSE score of 22. She had difficulty remembering words and experienced other cognitive problems. After three months of treatment with CPAP, the woman’s MMSE score increased by five points.
In addition, Michael K. Scullin, PhD, a postdoctoral fellow at Emory University School of Medicine in Atlanta, examined data from Dr. Bliwise’s ongoing study of patients with Parkinson’s disease, some of whom had cognitive impairments. He found that patients’ improvements on the Backward Digit-Span test were substantially correlated with the amount of slow-wave sleep that they had had during the previous night. The improvements were not related to the amount of slow-wave sleep that patients had at baseline. “There’s clearly something there,” said Dr. Bliwise. “Maybe there’s more of a story to be told here. We have to learn.”