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Sleep Apnea-Induced Hypoxia Implicates as a Factor in Cognitive Decline

ARTICLE IN BRIEF

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Investigators reported that over 4.7 years of follow-up, 44.8 percent of women with sleep-disordered breathing developed mild cognitive impairment or dementia compared with 31.1 percent of those without sleep-disordered breathing.

Should older patients be tested for obstructive sleep apnea in light of a new report that implicates hypoxia caused by sleep-disordered breathing as a contributor to cognitive impairment? The data, based on a prospective study in the Aug. 10 issue of the Journal of the American Medical Association (JAMA), has generated some debate among experts who say the new findings support such testing and those who say the approach is intriguing but premature and deserves further study.

The lead study author Kristine Yaffe, MD, professor of psychiatry, neurology, and epidemiology at the University of California, San Francisco, and colleagues studied 298 elderly women without dementia who underwent overnight polysomnography, which measured hypoxia, sleep fragmentation, and sleep duration, among other things. The women were enrolled in the Study of Osteoporotic Fractures, a multisite study of community-dwelling women, which was supported by grants from the NIH and the National Institute on Aging.

Slightly over one-third of the women met the criteria for sleep-disordered breathing, defined as 15 or more episodes of apnea and/or hypopnea per hour of sleep. Over 4.7 years of follow-up, 44.8 percent of women with sleep-disordered breathing developed mild cognitive impairment or dementia compared with 31.1 percent of those without sleep-disordered breathing (p=.02). Sleep fragmentation and sleep duration did not correlate with the risk of cognitive impairment.

Although sleep-disordered breathing has long been associated with cognitive impairment, the cause-and-effect relationship has remained ambiguous. Certain neurological conditions including Parkinson disease, amyotrophic lateral sclerosis, and advanced Alzheimer disease (AD) have been known to produce central sleep apnea (CSA), a rare disorder that accounts for less than 1 percent of sleep apnea (although it may play some role in up to 15 percent of cases of obstructive sleep apnea). However, because of the small number of CSA cases likely to be found in a randomly selected group of people with sleep apnea, the probability of neurological problems causing the apnea would be negligible. Also, women with mild cognitive impairment (MCI) or dementia were excluded from the study, Dr. Yaffe pointed out, so the JAMA paper, by showing a marked increase in cognitive impairment among those who experience sleep-disordered breathing, suggests that the breathing problems are the cause, not an effect, of the cognitive decline, Dr. Yaffe said.

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“No observational study can prove causality,” she said, “but our study is the closest and the best one yet.”

That said, Dr. Yaffe and colleagues wrote: “To fully evaluate the impact of treatment for sleep-disordered breathing in elderly populations, additional trials with larger sample sizes, longer treatment periods, and more diverse populations are required.…In addition, future studies should consider the association of sleep-disordered breathing with impairment in specific cognitive domains as well as changes in these variables over time.”

EFFECT OF NASAL CPAP

Assessing the effect of nasal CPAP (continuous positive airway pressure) therapy in patients with sleep-disordered breathing to determine if it reduces their risk of developing cognitive impairment would be the logical next step, said Bradley Boeve, MD, chair of behavioral neurology at Mayo Clinic in Rochester, MN, who was not involved with the JAMA study.

At the 2009 AAN annual meeting in Seattle, Dr. Boeve and colleagues reported data showing that providing CPAP even to patients who already have MCI or Alzheimer disease produces “modest improvement or stabilization of cognition, functional status, mood, daytime sleepiness, and quality of life.

The study involved 14 patients with OSA — seven with MCI and seven with AD — whose functional status, cognition, mood, daytime sleepiness, and quality of life were assessed at baseline and after one, six, and 12 months of CPAP therapy. Although five dropped out because they could not tolerate CPAP, and one due to an unrelated injury, the authors still found tolerability and compliance comparable to neurologically normal patients with OSA. And those who used CPAP recorded improvements in a majority of measures, while their bed-partners also showed improvements in the Geriatric Depression Scale, the Epworth Sleepiness Scale, and quality of life.

“Obstructive sleep apnea must be considered a treatable aspect of cognitive impairment even in the setting of degenerative MCI or dementia, and it should be searched for and treated when present,” Dr. Boeve said. “I screen for obstructive sleep apnea in every patient I see with cognitive issues. This should be standard practice, but unfortunately it is not.”

“We identified severe obstructive sleep apnea in two patients this week who have coexisting Alzheimer's disease, and we hope that CPAP will improve their cognition, while the standard meds have not,” he said. “What needs to be studied now is, does treatment with CPAP lower the risk of future MCI or dementia? This is a very important question, but we don't know the answer yet.”

AN AMBIGUOUS ASSOCIATION

Sleep disorders expert Antonio Culebras, MD, acknowledged that the JAMA study is not powered or even intended to resolve the cause-and-effect question or answer the question regarding sleep apnea and dementia. “I am prepared, however, to accept that the association is probably real, considering all the functional and structural brain lesions — from white matter disease to small-vessel changes, to the presence of circulatory inflammatory factors — that we now know occur in patients with longstanding sleep apnea,” said Dr. Culebras, professor of neurology at Upstate Medical University, Syracuse, NY. Still, he considers it premature to include CPAP in guidelines for reducing the risk of dementia.

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A paper in the May 2011 issue of the American Journal of Respiratory and Critical Care Medicine found that 17 patients who were not treated for sleep apnea displayed impairments in cognition and mood associated with focal reductions of gray-matter volume in the left hippocampus (entorhinal cortex), the left posterior parietal cortex, and right superior frontal gyrus. After CPAP treatment, those volumes increased, and the patients displayed improvements in memory, attention and executive functioning. The authors concluded that the “cognitive and structural deficits in OSA may be secondary to sleep deprivation and repetitive nocturnal intermittent hypoxemia.”

An editorial about the paper in the same issue suggested that the evidence supported more aggressive treatment of sleep-disordered breathing, the third most common respiratory disorder after asthma and chronic obstructive pulmonary disease.

“If intermittent hypoxia is associated with changes in brain morphology and cognitive dysfunction that can be reversed by CPAP treatment, this would argue in favor of early treatment, even in patients who are not subjectively sleepy,” said the authors, Mary J. Morrell, PhD, and Martin Glasser, MBBS, of the National Heart and Lung Institute, Imperial College, London.

In an editorial accompanying the JAMA study, Nicola Canessa, PhD, and Luigi Ferini-Strambi, MD, of San Raffaele University in Italy — coauthors of the May report in the American Journal of Respiratory and Critical Care Medicine — observed how well it supported the conclusion that hypoxia rather than sleep fragmentation or sleep duration promoted cognitive impairment.

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“[T]he hippocampal cortex appears to be involved with both hypoxia and mild cognitive impairment,” the editorial stated. “The study by Yaffe et al nicely links this phenomenon.”

MECHANISMS: HYPOXIA

Recent animal studies have provided evidence suggesting mechanisms by which hypoxia might cause cognitive decline. For example, in an animal study published earlier this year in the International Journal of Experimental Pathology, investigators suggested that the hypoxia inducible factor 1-alpha (HIF-1a), which regulates cellular responses to hypoxia, may contribute to Alzheimer disease. The authors reported that subjecting cultured rat brain endothelial cells to hypoxia for four to six hours induced HIF-1a, elevated levels of angiopoietin-2 (Ang-2), matrix metalloproteinase 2 (MMP2), and caspase 3, and reduced levels of the anti-apoptotic protein Bcl-xL. These changes in protein levels correspond with changes seen in brain-derived microvessels from Tg 2576 mice, an animal model of AD.

“These data suggest the cerebromicrovasculature is an important target for the effects of hypoxia in the AD brain,” the authors concluded.

Also, hypoxia induced increased production of amyloid beta (Abeta) by altering the cleavage of amyloid protein precursor (APP) by beta- and gamma-secretase, and down-regulating neprilysin (NEP), a synaptic enzyme that plays a major role in the clearance of Abeta from the brain, according to an April 2011 article in PLoS One. While over-expression of NEP reduces Abeta in the brains of transgenic AD mice, a decline in NEP due to age and chronic hypoxia slows Abeta clearance, according to the authors. After subjecting mouse primary cortical and hippocampal neurons to hypoxia, they found a significant decrease in NEP expression, apparently due to an increase in histone H3-lysine 9 demethylation (H3K9me2) and a decrease in H3 acetylation (H3-Ace) modulation.

Although these explanations are tentative, Dr. Boeve believes the evidence supports the hypothesis that sleep-disordered breathing contributes to cognitive decline.

“Cognitive impairment does not cause anatomic changes in the oropharynx that could produce obstructive sleep apnea,” said Dr. Boeve. “But obstructive sleep apnea can certainly cause cognitive impairment, and should be treated. The big question remains: Does treatment of obstructive sleep apnea prevent or delay the cascade of events leading to degenerative or vascular dementia? Prospective studies are clearly needed.”

HYPOXIA, NEUROLOGICAL STRESS

Hypoxia, which results from the recurrent cessation of breathing during sleep, has long been recognized as a powerful contributor to neurological stress.

For example, hypoxia may contribute to epilepsy, according to Martina Vendrame, MD, PhD, an assistant professor of neurology at the Boston University School of Medicine. In a paper published in the Aug. 12 online edition of Epilepsia, Dr. Vendrame and colleagues report improved seizure control with treatment of coexisting obstructive sleep apnea. In a study of 41 people with epilepsy, the 28 who were CPAP compliant reduced their seizure frequency from 1.8 per month to 1 per month, while the 13 who were not CPAP compliant showed no difference in seizure frequency.

Dr. Vendrame attributes the improvement among CPAP users to a reduction in their sleep fragmentation, a consequence of obstructive sleep apnea (OSA) known to lower the seizure threshold. However, “OSA-related chronic hypoxia may directly lead to neuronal hyperexcitability, neuronal network disruption and epileptogenesis,” the authors state.

“It could be both, obviously,” Dr. Vendrame told Neurology Today. “It's easier to explain this as probably related to sleep fragmentation. We also know that sleep fragmentation triggers seizures and sleep deprivation promotes the onset of interictal discharges. But you can also think that chronic sleep apnea may produce chronic hypoxia, and treatment of OSA with CPAP may prevent this. We followed our patients for only about six months, and prospective studies with long-term follow up will help us understand further the benefits of CPAP on seizure control.”

—Tom Valeo

REFERENCES:

Yaffe K, Laffan AM, Stone KL, et al. Sleep-disordered breathing, hypoxia, and risk of mild cognitive impairment and dementia in older women. JAMA 2011;306(6):613-619.
    Vendrame M, Auerbach S, Montouris G, et al. Effect of continuous positive airway pressure treatment on seizure control in patients with obstructive sleep apnea and epilepsy. Epilepsia August 12, 2011 epub ahead of print.
      Canessa N, Castronovo V, Cappa SF, et al. Obstructive sleep apnea: brain structural changes and neurocognitive function before and after treatment. Am J Respir Crit Care Med 2011;183(10):1419-1426.
        Morrell M and Glasser M. The Brain in Sleep-Disordered Breathing: A Vote for the Chicken? Am J Respir Crit Care Med 2011;183(10):1292-1294.
          Camessa N and Ferini-Strambi L. Sleep-dsordered breathing and cognitive decline in older adults. JAMA 2011;306(6):654-655.
            Grammas P, Tripathy D, Luo J, et al. Brain microvasculature and hypoxia-related proteins in Alzheimer's disease. Int J Clin Exp Pathol 2011;4(6):616-627.
              Wang Z, Yang D, Le W, et al. Hypoxia-induced down-regulation of neprilysin by histone modification in mouse primary cortical and hippocampal neurons. PLoS One 2011;6(4):e19229.