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In the Clinic-Sleep Apnea
Obstructive Sleep Apnea Affects Female and Male Brains Differently, Which May Account for Clinical Differences



REGIONS SHOWING CORTICAL THINNING in OSA compared to controls, accounting for sex. Hemisphere views include lateral, medial, frontal, and posterior. Pial and inflated views depicted, with light gray indicating gyri and dark gray sulci. (i) left hemisphere cluster extending into postcentral gyrus from lips and face to fingers sensory areas, precentral gyrus from neck to hand motor areas, supramarginal gyrus, Wernickes area, and superior temporal lobe; (ii) left hemisphere cluster extending into mid and posterior insula, temporal pole; (iii) right hemisphere cluster extending along the postcentral gyrus from upper airway to hand sensory areas, precentral gyrus in pharynx/tongue to lip motor areas.

Researchers found more cortical thinning in women with obstructive sleep apnea, in several areas, including the left and right superior frontal lobes, left and right rostral middle frontal lobes, and the right paracentral lobe, which they believe may account for differences in clinical symptoms.

Multiple regions of the cortex are thinner in people with obstructive sleep apnea (OSA), and a distinct regional pattern of thinning in women with OSA may explain the more significant cognitive and psychological symptoms seen in female OSA patients, according to a March 6 study in PLOS One.

“Sleep apnea has typically been seen as a male disease,” said Charlene Gamaldo, MD, FAAN, associate professor of neurology and medical director of the Johns Hopkins University Center for Sleep at Howard County General Hospital in Baltimore, who was not involved in the study. “What this study suggests is that while women may not suffer from sleep apnea as much, the repercussions in those who do may actually be disproportionately higher than in men.”

“Throughout the 1990s we began to recognize that people with sleep apnea had more problems than just not sleeping properly,” said the lead author of the new study, Paul M. Macey, PhD, associate professor of nursing and a member of the Brain Research Institute at the University of California, Los Angeles. “There are problems with memory, depression, decision-making, and autonomic output.”

There has also been a growing recognition that OSA can cause physical changes in the brain. In a series of studies in the 2000s, Dr. Macey and others showed there was gray matter damage in OSA patients, and more recently, that white matter was also affected in patients as a group, but male-female differences in gray matter had not been explored. When another group showed that brains of female rats were relatively protected from intermittent hypoxia — a partial model of OSA — Dr. Macey wondered whether the same might be true in female OSA patients. As it turned out, the opposite was the case.


To investigate sex differences in OSA, Dr. Macey recruited 48 patients, 12 female and 24 male, with mild to severe symptoms, along with 22 female and 40 male non-affected controls. OSA patients were newly diagnosed and not yet receiving treatment. Compared to controls, patients had a greater body mass index, had more anxiety and depression, and were sleepier. Both control and OSA patients underwent magnetic resonance imaging (MRI) to measure cortical thickness.

When compared to controls, OSA patients as a group showed cortical thinning in multiple areas, including the left and right precentral and postcentral gyruses, left superior temporal gyrus, left superior parietal lobe, left insula, and others. Thinning in most, though not all, of these areas had been seen in previous studies.

Comparing OSA patients by sex, Dr. Macey found more thinning in women in several areas, including the left and right superior frontal lobes, left and right rostral middle frontal lobes, and the right paracentral lobe.

While the number of patients in the study was small, Dr. Macey said, “our results suggest there are significant differences between males and females” in the effects of OSA on the brain. The thinning in these regions “could contribute to mood disturbances, such as depression,” along with impairments in executive function and working memory, he added.


Dr. Gamaldo of Johns Hopkins noted that the clinical presentation of OSA in women often differs from that in men. Loud snoring and overt apnea — the dramatic signs that will spur the bed partner to urge the patient to get evaluated — are less common in women. “Instead, women are more likely to demonstrate more subtle signs of sleep apnea, including mood changes, depression and fatigue, that, without a formal evaluation, may remain undiagnosed for a much longer time.”

The discovery that women with OSA have more cortical thinning in areas connected to these symptoms “is a very powerful finding, which gives a nice physiological link to the clinical differences in presentation,” she said.

“This is a very interesting study, which adds to the broad stream of thinking of what sleep apnea does to the brain,” commented Antonio Culebras, MD, FAAN, FAHA, professor of neurology and medical director of the Upstate Sleep Center at SUNY Upstate Medical University in Syracuse, NY. “The important message is that sleep apnea is very common,” affecting between 10 percent and 15 percent of the population, “and it is a serious disorder that can cause structural problems lesions in the brain.”

The mechanism of that damage is not well known, and may not be a direct consequence of hypoxia, Dr. Culebras said. Patients with advanced sleep apnea, especially those with diabetes, hypertension, or a history of smoking, will often have periventricular small vessel disease. “These lesions partially disconnect the core of the brain with the cortex, and this may be the real cause” of the cortical thinning observed in the study.

Dr. Macey noted that multiple mechanisms may be at work, including hypoxia and impaired perfusion. Why specific regions of women's brains should be more susceptible to these processes than the same regions in men remains unclear, he added. “I don't yet have a theory I believe.”

While the study was small and needs to be replicated in larger numbers of patients, Dr. Culebras said it highlights the potential gravity of OSA and the need to recognize and treat it early. “Stroke neurologists should always consider sleep apnea as a possible risk factor in their patients. I have been very critical of the new American Heart Association guidelines, which don't recommend routine sleep apnea testing in patients with acute ischemic stroke. This is not what we see in the stroke unit: 75 percent of the patients coming to our stroke unit have sleep apnea, and unless that is addressed, the patient is not well taken care of.”

But one factor that stands in the way of early treatment, and one highlighted by this study, Dr. Gamaldo pointed out, is under-recognition of OSA in women. The criteria for determining disease severity and disease burden may differ for women and men, she said, and may contribute to both under-diagnosis and under-treatment (and reimbursement) for women. The apnea-hypopnea index, a standard measure of OSA, “may need to be reevaluated in the context of sex differences,” she said. The differential pathophysiology revealed in this study points out that “we haven't really done enough research on sex differences in this area as a whole, and reinforces the importance of research that can help close the potential health disparity gap that could be lurking behind such findings.”

“Don't just think of sleep apnea as a male disease,” Dr. Macey said. “When a woman in your clinic reports multiple nonspecific symptoms, which may include disordered sleep, insomnia, depression, anxiety, and cognitive concerns, consider sleep apnea.”