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Postgraduate Education Corner: CONTEMPORARY REVIEWS IN SLEEP MEDICINE |

Neurocognitive Impairment in Obstructive Sleep ApneaNeurocognitive Impairment FREE TO VIEW

Chitra Lal, MD, D-ABSM, FCCP; Charlie Strange, MD, FCCP; David Bachman, MD
Author and Funding Information

From the Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine (Drs Lal and Strange), and Division of Neurology, Department of Neurosciences (Dr Bachman), Medical University of South Carolina, Charleston, SC.

Correspondence to: Chitra Lal, MD, D-ABSM, FCCP, Medical University of South Carolina, Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, 96 Jonathan Lucas St, CSB 812, MSC 630, Charleston, SC 29425; e-mail: chitra_lal@hotmail.com


Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


© 2012 American College of Chest Physicians


Chest. 2012;141(6):1601-1610. doi:10.1378/chest.11-2214
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Obstructive sleep apnea syndrome (OSAS) is a common disorder with far-reaching health implications. One of the major consequences of OSAS is an impact on neurocognitive functioning. Several studies have shown that OSAS has an adverse effect on inductive and deductive reasoning, attention, vigilance, learning, and memory. Neurocognitive impairment can be measured objectively with tests such as the Wechsler Adult Intelligence Scale-Revised, the Psychomotor Vigilance Task, the Steer Clear Performance Test, and tests of repetitive finger tapping. In children, OSAS may cause attention-deficit hyperactivity disorder in addition to behavioral problems and learning disabilities. Risk factors for cognitive impairment include increasing age, male sex, apolipoprotein E ε4 allele positivity, current cigarette smoking, obesity, hypertension, diabetes mellitus, metabolic syndrome, Down syndrome, hypothyroidism, significant alcohol consumption, stroke, and the use of psychoactive medications. At a cellular level, OSAS likely causes cognitive impairment through intermittent hypoxia, hormonal imbalance, and/or systemic inflammation, either independently or via the resultant endothelial dysfunction that occurs. Excessive daytime sleepiness should be measured and minimized in all studies of neurocognitive impairment. Recent studies have used functional and structural neuroimaging to delineate the brain areas affected in patients with OSAS with neurocognitive dysfunction. A common finding in several of these studies is decreased hippocampal volume. Other affected brain areas include the frontal and parietal lobes of the brain, which show focal reductions in gray matter. These changes can be reversed at least partially with the use of CPAP, which highlights the importance of early recognition and treatment of OSAS. The currently available data in this field are quite limited, and more research is needed.

Figures in this Article

Obstructive sleep apnea syndrome (OSAS) is a common disorder that is associated with cessation or reduction of airflow during sleep.1-3 It has been known for some time that neurocognitive deficits occur with a high frequency in OSAS.4-7 These deficits can affect any cognitive domain, including learning, memory, and attention. Studies suggest that severe sleep apnea can increase the risk of dementia in the elderly.8

Children with OSAS seem particularly prone to irritability, impaired attention and vigilance, emotional instability, and decreased intelligence.9 This cognitive impairment can cause problematic behavioral manifestations. In fact, neurobehavioral manifestations can also be seen in children with habitual snoring. This would imply that neurocognitive impairment can occur even with milder forms of sleep-disordered breathing (SDB).10

This review catalogs the current extent of our knowledge about the effect of OSAS on the brain. It also seeks to provide a roadmap of critically important research that is needed to understand the pathogenesis of these syndromes and the impact of interventions for OSAS on neurocognitive functioning.

The potential scope of neurocognitive dysfunction due to SDB is high, since OSAS prevalence is estimated to be 2% in women and 4% in men in the 30- to 60-year age group.1 Children are also at risk.

A recent study has shown that compared with children who had never snored, children with primary snoring have more hyperactivity (39% vs 20%) and inattentive behavior (33% vs 11%) as well as poor school performance in mathematics (29% vs 16%), science (23% vs 12%), and spelling (33% vs 20%).11 The strength of these associations reinforces the concept that milder forms of SDB may also have an impact on neurocognitive functioning in children.

The exact prevalence of cognitive dysfunction in adult patients with OSAS is unknown. A prospective observational study of 49 consecutive patients with OSAS showed that one in four patients had some neurocognitive dysfunction. Patients with more severe OSAS had a similar degree of impairment as individuals with multi-infarct dementia, although the pattern of impairment in OSAS was distinctive.12 In adults, OSAS has a profound impact on psychomotor functioning as well as cognitive domains like attention,13 memory,14 and executive functioning,15 although global intelligence is found to be relatively spared. OSAS has been associated with mild cognitive impairment (MCI),16 which is a strong risk factor for development of Alzheimer disease (AD), particularly when significant memory impairment is present. MCI refers to subtle but measurable cognitive impairment greater than what would be expected with normal aging but with preservation of functional activities. Since OSAS can be improved with treatment, it should be considered as a potential causative factor in patients with MCI and treated early.

On the other hand, a recent cross-sectional analysis of a large cohort of adult patients with OSAS who participated in the Apnea Positive Pressure Long Term Efficacy Study (APPLES)17 found no correlation between apnea-hypopnea index and neurocognitive performance after adjustment for education level, ethnicity, and sex. However, the severity of oxygen desaturation was weakly associated with worse performance on some measures of intelligence, attention, and processing speed. This study had several limitations, including lack of a comparison group of adults without OSAS and the high education level of the study cohort, which could have made them relatively resistant to the adverse impact of OSAS. This study highlights the variability in the reported prevalence of cognitive impairment in OSAS.

One of the problems with establishing the epidemiology of neurocognitive dysfunction in OSAS is that some OSAS risk factors are independently associated with abnormalities of brain function and neurocognitive decline (Table 1). A full understanding of cognitive impairment, therefore, requires knowledge of OSAS-associated comorbidities. Preexisting cognitive impairment due to other causes may be exacerbated by OSAS (Fig 1).

Table Graphic Jump Location
Table 1 —Risk Factors for Cognitive Impairment in OSAS

ApoE4 = apolipoprotein E ε4 allele; OSAS = obstructive sleep apnea syndrome.

Figure Jump LinkFigure 1. Proposed model for pathogenesis of neurocognitive impairment in OSAS. ApoE4 = apolipoprotein E ε4 allele; CHF = congestive heart failure; EDS = excessive daytime sleepiness; ETOH = ethanol; HTN = hypertension; MCI = mild cognitive impairment; OSAS = obstructive sleep apnea syndrome.Grahic Jump Location
Demographic Factors

Current studies suggest that age and sex impact cognitive decline18 independent of OSAS. Prevalence of MCI is higher in men.18 The cause of these sex differences is not fully understood. Aging itself also causes cognitive function decline. There are data to suggest that the presence of OSAS in an aging population constitutes a double insult to the brain and may overwhelm the brain’s compensatory mechanisms to respond to cognitive challenges.19 Increased age may also reflect a greater duration of OSAS prior to the diagnosis.12

Genetics

Familial aggregation of OSAS has been seen.20 European ancestry confers a higher risk of developing the OSAS phenotype, whereas West African ancestry is protective.21 The role of environmental and lifestyle factors in the development of OSAS could also contribute to shared familial risks.

Genetic factors influence the development of neurocognitive decline in OSAS. The ε4 isoform of apolipoprotein E (ApoE4) is strongly associated with an increased risk of early-onset AD.22 The mechanism by which the APOE gene influences the risk of AD is not known. A significant association between ApoE4 and the occurrence of SDB has been found in adults.23 Subsequent studies have shown that the association between SDB and neurocognitive decline is stronger in individuals with ApoE4 positivity.24 In children, the ApoE4 allele occurs with a higher frequency in patients with OSAS. Furthermore, this allele has been found to occur with a higher frequency in children with OSAS who have neurocognitive impairment.25

Patients with Down syndrome who present with OSAS also have intrinsic neurocognitive disease. This neurologic impairment is measurable and stays relatively constant over time. Thus, the addition of OSAS in such patients may provide an opportunity to ascertain more subtle degrees of OSAS-associated disease. However, given the significant overlap in the neurobehavioral manifestations of OSAS and Down syndrome, a high index of clinical suspicion would be required in order to make an early diagnosis of OSAS in these patients.26 The concern with any study of more sensitive phenotypes is that generalization to the larger OSAS population may be problematic. Patients with Down syndrome are at high risk of developing AD. One could speculate that this population may be at high risk for cognitive impairment associated with OSAS in view of their combined risk of severe OSAS and AD.

OSAS Medical Comorbidities

Obesity is a risk factor for higher rate of cognitive decline in men independent of other risk factors.27 Therefore, how much of the cognitive impairment seen in patients with OSAS is due to OSAS and how much of it can be attributed to the effect of obesity independent of OSAS is uncertain without further study.

The OSAS population has a large number of comorbidities that can influence neurocognitive function, such as tobacco smoking,28 treatment-resistant hypertension,29 diabetes mellitus,30 congestive heart failure, cerebrovascular accidents,31 hypothyroidism,32 and alcoholism.33 Therefore, large studies with representative populations of these conditions are required to define the relative contributions from each of these toward OSAS-related cognitive decline.

Current cigarette smoking may increase the risk of AD, vascular dementia, and nondementia-associated cognitive decline.34 Given the emerging data linking cigarette smoking to dementia and OSAS, the independent effect of these factors on cognitive decline will need to be delineated.

Hypothyroidism is a risk factor for the development of OSAS, although the reverse is not true.35 Hypothyroidism has also been listed as a cause of “reversible dementia.”32 This view is controversial, as the cognitive response to treatment with thyroid hormone is variable.36 Whether concomitant OSAS in patients who are hypothyroid impacts the variability of response to thyroid hormone supplementation remains unknown.

Hypertension is independently associated with dementia,37,38 although the extent to which associated cerebrovascular disease may have an impact remains unknown. In addition to isolated hypertension, metabolic syndrome has been associated with cognitive decline, particularly due to vascular risk factors.39 When added to the other common risk factors, the independent role of OSAS in the cognitive decline seen in metabolic syndrome will require large studies.

Although light to moderate alcohol consumption may protect against dementia,40 significant alcohol consumption is associated with cognitive impairment manifest as memory loss, personality deterioration, and impaired judgment.33 Alcohol intake close to bedtime impacts sleep architecture. Initially, alcohol acts as a hypnotic, with increased slow wave sleep. However, as it is metabolized from the blood stream, symptoms of alcohol withdrawal appear. These manifest as rebound increase in rapid eye movement sleep, sleep fragmentation,41 and worsening of underlying OSAS. Additionally, alcohol increases upper airway instability, which occurs in a dose-dependent manner.42 Thus, the deleterious effects of significant alcohol consumption on cognition and OSAS make this comorbidity important to study in prospective studies.

Stroke and OSAS

Epidemiologic studies have shown a strong association between ischemic stroke and OSAS. A case-control study of 177 consecutive male subjects aged 16 to 60 years (mean, 49 years) found an increase in the relative risk of stroke in snorers, with an OR of 8.0 (95% CI, 1.07-356.1), after correction for other risk factors such as coronary heart disease, hypertension, obesity, and alcohol consumption.43 More recent studies also have shown an association between mild to moderate OSAS and stroke.44

Silent brain infarction is increased in patients with OSAS.45 Silent brain infarction is associated with increased markers of platelet activation (soluble CD40L and soluble P-selectin) and systemic inflammation (C-reactive protein), which likely precede the development of stroke.45 These biomarkers are reduced by the use of nasal CPAP.45

Stroke, transient ischemic attacks, and silent brain infarction are risk factors for the development of dementia and cognitive decline. Post-stroke dementia has been reported to occur in 20% to 30% of patients affected by stroke.46,47 It would follow that some of the cognitive impairment seen in patients with OSAS is secondary to stroke.

Psychoactive Medications

Polypharmacy is common in the elderly. The use of benzodiazepines, narcotics, barbiturates, and atypical antipsychotics to treat insomnia and “agitation” can worsen underlying OSAS and cause problems with attention and vigilance and increased risk of falls.48,49 The impact of OSAS on cognition might be greater in the elderly than in other OSAS populations because of this confounder.

Despite the difficulty in disentangling the effects of numerous comorbid conditions on the risk of cognitive impairment with OSAS, there is evidence to support the argument that OSAS has a direct effect on cognitive impairment (Fig 1). In the following sections, we present that evidence.

Two broad areas of abnormalities have been studied in patients with OSAS: cognitive function and psychomotor performance. The effects of OSAS on visual and verbal memory have been found to be variable.50 However, OSAS has a significant impact on reasoning, comprehension, and learning, cumulatively termed executive functioning51,52 (Table 2).

Table Graphic Jump Location
Table 2 —Terminology and Definitions

+ = mild impairment; ++ = moderate impairment; +++ = severe impairment; ++++ = very severe impairment. See Table 1 legend for expansion of abbreviation.

Fine motor coordination is impaired in patients with OSAS, although motor speed is unaffected.15,53,54 Vigilance, or “sustained attention,” has been measured by tests such as the Steer Clear Performance Test and the Psychomotor Vigilance Test.55 Vigilance is markedly affected in patients with OSAS.56 Decreased vigilance can increase the risk of motor vehicle accidents in patients with untreated OSAS.57 Some commonly used tests of cognitive impairment in patients with OSAS are described in Table 3.

Table Graphic Jump Location
Table 3 —Tests of Neurocognitive Function Commonly Used in OSAS

See Table 1 legend for expansion of abbreviation.

Studies of OSAS Using Brain Imaging

The presence of structural and functional changes in brain anatomy and function in patients with OSAS provides indirect evidence that OSAS results in damage to brain structures over time. Perhaps these changes serve as the substrate for cognitive impairment. A review article has highlighted the various neuroimaging techniques used in OSAS.58 These techniques include structural MRI, functional MRI, and magnetic resonance spectroscopy. Although some studies have shown no differences in deep white matter and periventricular hyperintensities59 or in gray matter60 in patients with OSAS vs healthy subjects, other studies have suggested a decrease in gray matter in the hippocampus, anterior cingulate, cerebellum, and the frontal, parietal, and temporal lobes in patients with OSAS61-63 (Fig 2).

Figure Jump LinkFigure 2. Significant regional decrease in gray matter of patients with obstructive sleep apnea syndrome rendered onto the brain surface of the mean of 42 registered brain images. Red shaded regions indicate areas of significant difference, with decrease in the red intensity with increasing depth. (Reprinted with permission from Macey et al.62)Grahic Jump Location

A common finding in many studies is decreased hippocampal volume. The hippocampus is located in the medial temporal lobe of the brain and belongs to the limbic system. It plays an important role in memory consolidation. Thus, damage to the hippocampus may result in anterograde and retrograde amnesia. Electrophysiologic studies of a guinea pig model of OSAS revealed that recurrent apnea produced very high levels of glutamate, which promoted excitotoxicity of the hippocampal neurons. This caused apoptosis of the cornu ammonis region 1 hippocampal neurons. The investigators hypothesized that these changes could contribute to the cognitive impairment seen in patients with OSAS.64 This finding is supported by a mouse model study in which investigators reported downregulation of hippocampal brain-derived neurotrophic factor as the molecular mechanism responsible for the neurocognitive deficits seen in OSAS.65

Other studies have found that the frontal and parietal cortices are abnormal in OSAS. Functional MRIs performed in patients with OSAS have shown decreased brain activation in cingulate, frontal, and parietal regions during the performance of sustained attention tasks as compared with control subjects.66 The brain changes seen include focal reductions in gray matter. The anterior cingulate gyrus is a limbic structure associated with pain perception. Dyspnea activates cingulate areas. Thus, focal gray matter loss in this area along with other regions of the brain involved in upper airway sensation and motor control could potentially worsen OSAS by reducing respiratory drive or muscle tone.62

Reversal of gray matter loss on imaging has been seen in one treatment study of OSAS.67 This study used neuropsychologic testing to measure cognitive impairment in patients with OSAS before and after treatment. Voxel-based morphometry (a technique measuring focal differences in brain anatomy using statistical parametric mapping) was used to analyze differences in brain anatomy. Pretreatment, focal reductions in gray matter volume were seen in left hippocampus, left posterior parietal cortex, and right superior frontal gyrus. Posttreatment, significant improvements were seen in various cognitive domains along with increased gray matter volume in hippocampal and frontal areas.61 This would imply that early recognition and aggressive treatment of OSAS could prevent long-term cognitive impairment.

In a pediatric study, proton magnetic resonance spectroscopy was performed on patients with OSAS and on matched control subjects without OSAS. Neuropsychologic test scores and mean neuronal metabolite ratios of target brain areas were compared in the two groups. Children with severe OSAS were found to have significant deficits in executive functioning and decreased mean neuronal metabolite ratio of N-acetyl aspartate to choline in the left hippocampus and right frontal cortex, as compared with control subjects.68 N-acetyl aspartate is required for myelin synthesis, and decreased levels can be seen in several neurologic disorders. Choline is a precursor of acetylcholine, and abnormal levels can indicate degradation of the neuronal cell membrane. A decrease in the N-acetyl aspartate to choline ratio has been used as a marker of neuronal injury. A concern raised by this study is that untreated OSAS could lead to a permanent decrease in a child’s overall cognitive potential.

Thus, emerging data suggest that neurochemical abnormalities in specific brain areas are associated with neurocognitive dysfunction in patients with OSAS. Larger follow-up studies are required to further enhance our understanding in this field. Importantly, these data need to be integrated with clinically available tests to risk stratify patients and optimize treatment of OSAS.

Pathophysiology of OSAS-Associated Neurocognitive Dysfunction
Endothelial Dysfunction and Hypoxemia:

One proposed mechanism for the increased incidence of cognitive impairment in patients with OSAS is the occurrence of hypoxia/reperfusion injury,69 which increases lipid peroxidation.70 Periods of oxidative stress increase production of soluble adhesion molecules71 and other reactive oxygen species potentially harmful to the brain and the heart.

An important intermediary in some vascular events is endothelial dysfunction. The endothelium and its subjacent smooth muscle are a biologically active system, the discussion of which is beyond the scope of this review. However, endothelial dysfunction associated with OSAS72 is used in this paper to describe biochemical and biomechanical dysregulation that results in altered cerebral and myocardial perfusion.

Some of the causes of endothelial dysfunction in OSAS include imbalances between vasoconstrictor (endothelin-1, thromboxane) and vasodilator mediators (nitric oxide, prostacyclin). OSAS decreases the production of nitric oxide.73 A dysregulated endothelium also incites hypercoagulability and predisposes to atherosclerosis.74

The resultant effects of OSAS on cerebral blood flow and cerebral oxygenation could then predispose to the development of brain infarction.75 If this process continues, vascular dementia could result. Thus, ischemic stroke occurring from OSAS may be one of many proximate causes of the neurobehavioral deficits seen in patients with OSAS. The unique patterns of cognitive decline could be related to areas of unique regional hypoxemic sensitivity.

Pediatric data also suggests a shared pathogenetic mechanism between endothelial dysfunction and neurocognitive impairment. Both these disorders are more likely to coexist in children with OSAS. Postocclusive hyperemic vascular response is an indirect method of detecting children with OSAS who have neurocognitive impairment.76 Postocclusive hyperemic response is the reactive hyperemia seen after release of arterial occlusion. In this pediatric study,76 endothelial dysfunction was defined as the time to achieve maximal postocclusive hyperemic response ≥45 s after sphygmomanometer cuff-induced occlusion of the radial and ulnar arteries. Endothelial dysfunction and neurocognitive dysfunction were found to coexist in pediatric patients with OSAS in this study.

Excessive Daytime Sleepiness:

Some of the unique OSAS-associated impairment of neurocognitive functioning may be due to excessive daytime sleepiness (EDS). Studies have shown that the cognitive impairment seen in sleep-deprived patients is similar to the cognitive decline seen in patients with OSAS. This would imply that EDS seen because of sleep fragmentation in patients with OSAS may cause basal slowing of information processing, resulting in impairment in attention, vigilance, and memory.4,5 One wonders whether CPAP compliance might be affected by forgetting to put on the CPAP mask, thus creating a vicious cycle of chronic EDS.

However, the cognitive dysfunction seen with OSAS is only partially reversible with CPAP treatment even after complete resolution of daytime hypersomnolence.77 In this study, patients with average CPAP use >5 h/night, had normalization of their Epworth Sleepiness Scores and performance on tasks of sustained attention but did not show improvement on tasks of executive functioning. This would imply additional mechanisms for the cognitive decline, rather than just persistence of EDS due to nocturnal sleep fragmentation. Nevertheless, trials of medications such as modafinil and armodafinil that improve alertness, wakefulness, and memory when used as adjunctive treatment of patients with OSAS with residual EDS despite being adherent with CPAP therapy78,79 should be explored.

Future Research Questions:

Although a number of studies have addressed the issue of cognitive impairment in OSAS over the years, a number of important issues remain unresolved. Currently available data are limited by small sample sizes, lack of standardized methodology to measure cognitive impairment, failure to measure and account for comorbidities, and absence of long-term follow up.

The problem of dose response of OSAS severity and severity of cognitive impairment remains unanswered. Individuals with MCI constitute a subset of patients distinct from those with cognitive impairment or dementia and need to be categorized and studied separately.

The syndrome needs to be discussed with a common terminology. Should we use the same tools that have been used for neuropsychological testing in other neurodegenerative conditions, or should new tools specific to OSAS be developed? We need definitions and standards that can be used across different patient populations, thus allowing direct comparison between studies. Development and validation of such tools would require international efforts and large studies to verify usefulness and practical application.

Functional neuroimaging can show brain areas affected in OSAS. More work is needed to clearly delineate these affected brain regions, the long-term implications of this involvement, and potential strategies to reverse the abnormalities. Neuroimaging may shed more light on the neurochemical basis for OSAS-associated cognitive decline. An identification of these neuromediators may help to establish therapeutic targets for intervention at a molecular level. In addition, sleep neuroimaging may identify at-risk patients who can develop cognitive impairment from OSAS, so that early intervention can be undertaken for this group of patients.

Last, the impact of treatment on cognitive impairment remains understudied. CPAP improves daytime sleepiness related to OSAS and may slow cognitive decline in patients with comorbid AD and OSAS.80 Since studies of the impact of CPAP on OSAS will likely not involve placebo-controlled studies for ethical reasons, study designs will be more challenging to implement. Well-designed studies will require assessment of the medical, pharmacologic, environmental, and genetic covariates that can affect outcome. The adequacy of therapy will also impact the outcome of the cognitive impairment studies. In summary, the currently available data on neurocognitive decline in patients with OSAS are limited, and much more work needs to be done in this field.

The neurocognitive decline seen in patients with OSAS appears to be a real finding with its own unique pattern of cognitive deficits. However, the association of OSAS with cognitive impairment is complicated by numerous comorbidities, including aging, genetic factors, hypoxemia, EDS, cerebrovascular disease, and endothelial dysfunction. A unique clinical syndrome marked by impairment in attention/working memory, vigilance, and executive functioning has been identified.51,52 Language and global cognitive functioning are relatively spared.81 Much more work needs to be done to better translate these emerging findings to the clinical setting.

Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Other contributions: This work was performed at the Medical University of South Carolina, Charleston, SC.

AD

Alzheimer disease

ApoE4

apolipoprotein E ε4 allele

EDS

excessive daytime sleepiness

MCI

mild cognitive impairment

OSAS

obstructive sleep apnea syndrome

SDB

sleep-disordered breathing

Young T, Palta M, Dempsey J, Skatrud J, Weber S, Badr S. The occurrence of sleep-disordered breathing among middle-aged adults. N Engl J Med. 1993;32817:1230-1235. [CrossRef] [PubMed]
 
Bixler EO, Vgontzas AN, Ten Have T, Tyson K, Kales A. Effects of age on sleep apnea in men: I. Prevalence and severity. Am J Respir Crit Care Med. 1998;1571:144-148. [PubMed]
 
Bixler EO, Vgontzas AN, Lin HM, et al. Prevalence of sleep-disordered breathing in women: effects of gender. Am J Respir Crit Care Med. 2001;1633 pt 1:608-613. [PubMed]
 
Verstraeten E. Neurocognitive effects of obstructive sleep apnea syndrome. Curr Neurol Neurosci Rep. 2007;72:161-166. [CrossRef] [PubMed]
 
Durmer JS, Dinges DF. Neurocognitive consequences of sleep deprivation. Semin Neurol. 2005;251:117-129. [CrossRef] [PubMed]
 
Rhodes SK, Shimoda KC, Waid LR, et al. Neurocognitive deficits in morbidly obese children with obstructive sleep apnea. J Pediatr. 1995;1275:741-744. [CrossRef] [PubMed]
 
Kelly DA, Claypoole KH, Coppel DB. Sleep apnea syndrome: symptomatology, associated features, and neurocognitive correlates. Neuropsychol Rev. 1990;14:323-342. [CrossRef] [PubMed]
 
Kim SJ, Lee JH, Lee DY, et al. Neurocognitive dysfunction associated with sleep quality and sleep apnea in patients with mild cognitive impairment. Am J Geriatr Psychiatry. 2011;194:374-381. [CrossRef] [PubMed]
 
Owens JA. Neurocognitive and behavioral impact of sleep disordered breathing in children. Pediatr Pulmonol. 2009;445:417-422. [CrossRef] [PubMed]
 
Chervin RD, Archbold KH, Dillon JE, et al. Inattention, hyperactivity, and symptoms of sleep-disordered breathing. Pediatrics. 2002;1093:449-456. [CrossRef] [PubMed]
 
Brockmann PE, Urschitz MS, Schlaud M, Poets CF. Primary snoring in school children: prevalence and neurocognitive impairments. Sleep Breath. 2012;161:23-29. [CrossRef] [PubMed]
 
Antonelli Incalzi R, Marra C, Salvigni BL, et al. Does cognitive dysfunction conform to a distinctive pattern in obstructive sleep apnea syndrome? J Sleep Res. 2004;131:79-86. [CrossRef] [PubMed]
 
Mazza S, Pépin JL, Naëgelé B, Plante J, Deschaux C, Lévy P. Most obstructive sleep apnoea patients exhibit vigilance and attention deficits on an extended battery of tests. Eur Respir J. 2005;251:75-80. [CrossRef] [PubMed]
 
Archbold KH, Borghesani PR, Mahurin RK, Kapur VK, Landis CA. Neural activation patterns during working memory tasks and OSA disease severity: preliminary findings. J Clin Sleep Med. 2009;51:21-27. [PubMed]
 
Bédard MA, Montplaisir J, Richer F, Rouleau I, Malo J. Obstructive sleep apnea syndrome: pathogenesis of neuropsychological deficits. J Clin Exp Neuropsychol. 1991;136:950-964. [CrossRef] [PubMed]
 
Caselli RJ. Obstructive sleep apnea, apolipoprotein E e4, and mild cognitive impairment. Sleep Med. 2008;98:816-817. [CrossRef] [PubMed]
 
Quan SF, Chan CS, Dement WC, et al. The association between obstructive sleep apnea and neurocognitive performance—the Apnea Positive Pressure Long-term Efficacy Study (APPLES). Sleep. 2011;343:303-314B. [PubMed]
 
Petersen RC, Roberts RO, Knopman DS, et al. The Mayo Clinic Study of Aging Prevalence of mild cognitive impairment is higher in men. Neurology. 2010;7510:889-897. [CrossRef] [PubMed]
 
Ayalon L, Ancoli-Israel S, Drummond SP. Obstructive sleep apnea and age: a double insult to brain function? Am J Respir Crit Care Med. 2010;1823:413-419. [CrossRef] [PubMed]
 
Ovchinsky A, Rao M, Lotwin I, Goldstein NA. The familial aggregation of pediatric obstructive sleep apnea syndrome. Arch Otolaryngol Head Neck Surg. 2002;1287:815-818. [PubMed]
 
Guindalini C, Colugnati FA, Pellegrino R, Santos-Silva R, Bittencourt LR, Tufik S. Influence of genetic ancestry on the risk of obstructive sleep apnoea syndrome. Eur Respir J. 2010;364:834-841. [CrossRef] [PubMed]
 
Bekris LM, Yu CE, Bird TD, Tsuang DW. Genetics of Alzheimer disease. J Geriatr Psychiatry Neurol. 2010;234:213-227. [CrossRef] [PubMed]
 
Kadotani H, Kadotani T, Young T, et al. Association between apolipoprotein E epsilon4 and sleep-disordered breathing in adults. JAMA. 2001;28522:2888-2890. [CrossRef] [PubMed]
 
Spira AP, Blackwell T, Stone KL, et al. Sleep-disordered breathing and cognition in older women. J Am Geriatr Soc. 2008;561:45-50. [CrossRef] [PubMed]
 
Gozal D, Capdevila OS, Kheirandish-Gozal L, Crabtree VM. APOE epsilon 4 allele, cognitive dysfunction, and obstructive sleep apnea in children. Neurology. 2007;693:243-249. [CrossRef] [PubMed]
 
Trois MS, Capone GT, Lutz JA, et al. Obstructive sleep apnea in adults with Down syndrome. J Clin Sleep Med. 2009;54:317-323. [PubMed]
 
Elias MF, Elias PK, Sullivan LM, Wolf PA, D’Agostino RB. Lower cognitive function in the presence of obesity and hypertension: the Framingham heart study. Int J Obes Relat Metab Disord. 2003;272:260-268. [CrossRef] [PubMed]
 
Wetter DW, Young TB, Bidwell TR, Badr MS, Palta M. Smoking as a risk factor for sleep-disordered breathing. Arch Intern Med. 1994;15419:2219-2224. [CrossRef] [PubMed]
 
Logan AG, Perlikowski SM, Mente A, et al. High prevalence of unrecognized sleep apnoea in drug-resistant hypertension. J Hypertens. 2001;1912:2271-2277. [CrossRef] [PubMed]
 
Elmasry A, Lindberg E, Berne C, et al. Sleep-disordered breathing and glucose metabolism in hypertensive men: a population-based study. J Intern Med. 2001;2492:153-161. [CrossRef] [PubMed]
 
Parra O, Arboix A, Bechich S, et al. Time course of sleep-related breathing disorders in first-ever stroke or transient ischemic attack. Am J Respir Crit Care Med. 2000;1612 pt 1:375-380. [PubMed]
 
Osterweil D, Syndulko K, Cohen SN, et al. Cognitive function in non-demented older adults with hypothyroidism. J Am Geriatr Soc. 1992;404:325-335. [PubMed]
 
Chan KK, Chiu KC, Chu LW. Association between alcohol consumption and cognitive impairment in Southern Chinese older adults. Int J Geriatr Psychiatry. 2010;2512:1272-1279. [CrossRef] [PubMed]
 
Peters R, Poulter R, Warner J, Beckett N, Burch L, Bulpitt C. Smoking, dementia and cognitive decline in the elderly, a systematic review. BMC Geriatr. 2008;8:36. [CrossRef] [PubMed]
 
Lin CC, Tsan KW, Chen PJ. The relationship between sleep apnea syndrome and hypothyroidism. Chest. 1992;1026:1663-1667. [CrossRef] [PubMed]
 
Clarnette RM, Patterson CJ. Hypothyroidism: does treatment cure dementia? J Geriatr Psychiatry Neurol. 1994;71:23-27. [PubMed]
 
Launer LJ, Masaki K, Petrovitch H, Foley D, Havlik RJ. The association between midlife blood pressure levels and late-life cognitive function. The Honolulu-Asia Aging Study. JAMA. 1995;27423:1846-1851. [CrossRef] [PubMed]
 
Launer LJ, Ross GW, Petrovitch H, et al. Midlife blood pressure and dementia: the Honolulu-Asia aging study. Neurobiol Aging. 2000;211:49-55. [CrossRef] [PubMed]
 
Panza F, Frisardi V, Capurso C, et al. Metabolic syndrome and cognitive impairment: current epidemiology and possible underlying mechanisms. J Alzheimers Dis. 2010;213:691-724. [PubMed]
 
Wright CB, Elkind MS, Luo X, Paik MC, Sacco RL. Reported alcohol consumption and cognitive decline: The northern Manhattan study. Neuroepidemiology. 2006;274:201-207. [CrossRef] [PubMed]
 
Feige B, Gann H, Brueck R, et al. Effects of alcohol on polysomnographically recorded sleep in healthy subjects. Alcohol Clin Exp Res. 2006;309:1527-1537. [CrossRef] [PubMed]
 
Issa FG, Sullivan CE. Upper airway closing pressures in snorers. J Appl Physiol. 1984;572:528-535. [PubMed]
 
Palomäki H. Snoring and the risk of ischemic brain infarction. Stroke. 1991;228:1021-1025. [CrossRef] [PubMed]
 
Redline S, Yenokyan G, Gottlieb DJ, et al. Obstructive sleep apnea-hypopnea and incident stroke: the sleep heart health study. Am J Respir Crit Care Med. 2010;1822:269-277. [CrossRef] [PubMed]
 
Minoguchi K, Yokoe T, Tazaki T, et al. Silent brain infarction and platelet activation in obstructive sleep apnea. Am J Respir Crit Care Med. 2007;1756:612-617. [CrossRef] [PubMed]
 
Tatemichi TK, Foulkes MA, Mohr JP, et al. Dementia in stroke survivors in the Stroke Data Bank cohort. Prevalence, incidence, risk factors, and computed tomographic findings. Stroke. 1990;216:858-866. [CrossRef] [PubMed]
 
Desmond DW, Moroney JT, Paik MC, et al. Frequency and clinical determinants of dementia after ischemic stroke. Neurology. 2000;545:1124-1131. [CrossRef] [PubMed]
 
Moore AR, O’Keeffe ST. Drug-induced cognitive impairment in the elderly. Drugs Aging. 1999;151:15-28. [CrossRef] [PubMed]
 
Shirani A, Paradiso S, Dyken ME. The impact of atypical antipsychotic use on obstructive sleep apnea: a pilot study and literature review. Sleep Med. 2011;126:591-597. [CrossRef] [PubMed]
 
Beebe DW, Groesz L, Wells C, Nichols A, McGee K. The neuropsychological effects of obstructive sleep apnea: a meta-analysis of norm-referenced and case-controlled data. Sleep. 2003;263:298-307. [PubMed]
 
Naismith S, Winter V, Gotsopoulos H, Hickie I, Cistulli P. Neurobehavioral functioning in obstructive sleep apnea: differential effects of sleep quality, hypoxemia and subjective sleepiness. J Clin Exp Neuropsychol. 2004;261:43-54. [CrossRef] [PubMed]
 
Wong KK, Grunstein RR, Bartlett DJ, Gordon E. Brain function in obstructive sleep apnea: results from the Brain Resource International Database. J Integr Neurosci. 2006;51:111-121. [CrossRef] [PubMed]
 
Bédard MA, Montplaisir J, Malo J, Richer F, Rouleau I. Persistent neuropsychological deficits and vigilance impairment in sleep apnea syndrome after treatment with continuous positive airways pressure (CPAP). J Clin Exp Neuropsychol. 1993;152:330-341. [CrossRef] [PubMed]
 
Greenberg GD, Watson RK, Deptula D. Neuropsychological dysfunction in sleep apnea. Sleep. 1987;103:254-262. [PubMed]
 
Sforza E, Haba-Rubio J, De Bilbao F, et al. Performance vigilance task and sleepiness in patients with sleep-disordered breathing. Eur Respir J. 2004;242:279-285. [CrossRef] [PubMed]
 
Findley L, Unverzagt M, Guchu R, Fabrizio M, Buckner J, Suratt P. Vigilance and automobile accidents in patients with sleep apnea or narcolepsy. Chest. 1995;1083:619-624. [CrossRef] [PubMed]
 
Findley LJ, Levinson MP, Bonnie RJ. Driving performance and automobile accidents in patients with sleep apnea. Clin Chest Med. 1992;133:427-435. [PubMed]
 
Zimmerman ME, Aloia MS. A review of neuroimaging in obstructive sleep apnea. J Clin Sleep Med. 2006;24:461-471. [PubMed]
 
Davies CW, Crosby JH, Mullins RL, et al. Case control study of cerebrovascular damage defined by magnetic resonance imaging in patients with OSA and normal matched control subjects. Sleep. 2001;246:715-720. [PubMed]
 
O’Donoghue FJ, Briellmann RS, Rochford PD, et al. Cerebral structural changes in severe obstructive sleep apnea. Am J Respir Crit Care Med. 2005;17110:1185-1190. [CrossRef] [PubMed]
 
Gale SD, Hopkins RO. Effects of hypoxia on the brain: neuroimaging and neuropsychological findings following carbon monoxide poisoning and obstructive sleep apnea. J Int Neuropsychol Soc. 2004;101:60-71. [CrossRef] [PubMed]
 
Macey PM, Henderson LA, Macey KE, et al. Brain morphology associated with obstructive sleep apnea. Am J Respir Crit Care Med. 2002;16610:1382-1387. [CrossRef] [PubMed]
 
Morrell MJ, McRobbie DW, Quest RA, Cummin AR, Ghiassi R, Corfield DR. Changes in brain morphology associated with obstructive sleep apnea. Sleep Med. 2003;45:451-454. [CrossRef] [PubMed]
 
Fung SJ, Xi MC, Zhang JH, et al. Apnea promotes glutamate-induced excitotoxicity in hippocampal neurons. Brain Res. 2007;1179:42-50. [CrossRef] [PubMed]
 
Xie H, Leung KL, Chen L, et al. Brain-derived neurotrophic factor rescues and prevents chronic intermittent hypoxia-induced impairment of hippocampal long-term synaptic plasticity. Neurobiol Dis. 2010;401:155-162. [CrossRef] [PubMed]
 
Ayalon L, Ancoli-Israel S, Aka AA, McKenna BS, Drummond SP. Relationship between obstructive sleep apnea severity and brain activation during a sustained attention task. Sleep. 2009;323:373-381. [PubMed]
 
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;18310:1419-1426. [CrossRef] [PubMed]
 
Halbower AC, Degaonkar M, Barker PB, et al. Childhood obstructive sleep apnea associates with neuropsychological deficits and neuronal brain injury. PLoS Med. 2006;38:e301. [CrossRef] [PubMed]
 
Lavie L. Obstructive sleep apnoea syndrome—an oxidative stress disorder. Sleep Med Rev. 2003;71:35-51. [CrossRef] [PubMed]
 
Lavie L, Vishnevsky A, Lavie P. Evidence for lipid peroxidation in obstructive sleep apnea. Sleep. 2004;271:123-128. [PubMed]
 
Dyugovskaya L, Lavie P, Lavie L. Increased adhesion molecules expression and production of reactive oxygen species in leukocytes of sleep apnea patients. Am J Respir Crit Care Med. 2002;1657:934-939. [PubMed]
 
Ip MS, Tse HF, Lam B, Tsang KW, Lam WK. Endothelial function in obstructive sleep apnea and response to treatment. Am J Respir Crit Care Med. 2004;1693:348-353. [CrossRef] [PubMed]
 
Ip MS, Lam B, Chan LY, et al. Circulating nitric oxide is suppressed in obstructive sleep apnea and is reversed by nasal continuous positive airway pressure. Am J Respir Crit Care Med. 2000;1626:2166-2171. [PubMed]
 
Nedeljkovic ZS, Gokce N, Loscalzo J. Mechanisms of oxidative stress and vascular dysfunction. Postgrad Med J. 2003;79930:195-199. [CrossRef] [PubMed]
 
Cohen MV. Free radicals in ischemic and reperfusion myocardial injury: is this the time for clinical trials? Ann Intern Med. 1989;11111:918-931. [PubMed]
 
Gozal D, Kheirandish-Gozal L, Bhattacharjee R, Spruyt K. Neurocognitive and endothelial dysfunction in children with obstructive sleep apnea. Pediatrics. 2010;1265:e1161-e1167. [CrossRef] [PubMed]
 
Ferini-Strambi L, Baietto C, Di Gioia MR, et al. Cognitive dysfunction in patients with obstructive sleep apnea (OSA): partial reversibility after continuous positive airway pressure (CPAP). Brain Res Bull. 2003;611:87-92. [CrossRef] [PubMed]
 
Roth T, Rippon GA, Arora S. Armodafinil improves wakefulness and long-term episodic memory in nCPAP-adherent patients with excessive sleepiness associated with obstructive sleep apnea. Sleep Breath. 2008;121:53-62. [CrossRef] [PubMed]
 
Hirshkowitz M, Black JE, Wesnes K, Niebler G, Arora S, Roth T. Adjunct armodafinil improves wakefulness and memory in obstructive sleep apnea/hypopnea syndrome. Respir Med. 2007;1013:616-627. [CrossRef] [PubMed]
 
Cooke JR, Ayalon L, Palmer BW, et al. Sustained use of CPAP slows deterioration of cognition, sleep, and mood in patients with Alzheimer’s disease and obstructive sleep apnea: a preliminary study. J Clin Sleep Med. 2009;54:305-309. [PubMed]
 
Aloia MS, Arnedt JT, Davis JD, Riggs RL, Byrd D. Neuropsychological sequelae of obstructive sleep apnea-hypopnea syndrome: a critical review. J Int Neuropsychol Soc. 2004;105:772-785. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1. Proposed model for pathogenesis of neurocognitive impairment in OSAS. ApoE4 = apolipoprotein E ε4 allele; CHF = congestive heart failure; EDS = excessive daytime sleepiness; ETOH = ethanol; HTN = hypertension; MCI = mild cognitive impairment; OSAS = obstructive sleep apnea syndrome.Grahic Jump Location
Figure Jump LinkFigure 2. Significant regional decrease in gray matter of patients with obstructive sleep apnea syndrome rendered onto the brain surface of the mean of 42 registered brain images. Red shaded regions indicate areas of significant difference, with decrease in the red intensity with increasing depth. (Reprinted with permission from Macey et al.62)Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1 —Risk Factors for Cognitive Impairment in OSAS

ApoE4 = apolipoprotein E ε4 allele; OSAS = obstructive sleep apnea syndrome.

Table Graphic Jump Location
Table 2 —Terminology and Definitions

+ = mild impairment; ++ = moderate impairment; +++ = severe impairment; ++++ = very severe impairment. See Table 1 legend for expansion of abbreviation.

Table Graphic Jump Location
Table 3 —Tests of Neurocognitive Function Commonly Used in OSAS

See Table 1 legend for expansion of abbreviation.

References

Young T, Palta M, Dempsey J, Skatrud J, Weber S, Badr S. The occurrence of sleep-disordered breathing among middle-aged adults. N Engl J Med. 1993;32817:1230-1235. [CrossRef] [PubMed]
 
Bixler EO, Vgontzas AN, Ten Have T, Tyson K, Kales A. Effects of age on sleep apnea in men: I. Prevalence and severity. Am J Respir Crit Care Med. 1998;1571:144-148. [PubMed]
 
Bixler EO, Vgontzas AN, Lin HM, et al. Prevalence of sleep-disordered breathing in women: effects of gender. Am J Respir Crit Care Med. 2001;1633 pt 1:608-613. [PubMed]
 
Verstraeten E. Neurocognitive effects of obstructive sleep apnea syndrome. Curr Neurol Neurosci Rep. 2007;72:161-166. [CrossRef] [PubMed]
 
Durmer JS, Dinges DF. Neurocognitive consequences of sleep deprivation. Semin Neurol. 2005;251:117-129. [CrossRef] [PubMed]
 
Rhodes SK, Shimoda KC, Waid LR, et al. Neurocognitive deficits in morbidly obese children with obstructive sleep apnea. J Pediatr. 1995;1275:741-744. [CrossRef] [PubMed]
 
Kelly DA, Claypoole KH, Coppel DB. Sleep apnea syndrome: symptomatology, associated features, and neurocognitive correlates. Neuropsychol Rev. 1990;14:323-342. [CrossRef] [PubMed]
 
Kim SJ, Lee JH, Lee DY, et al. Neurocognitive dysfunction associated with sleep quality and sleep apnea in patients with mild cognitive impairment. Am J Geriatr Psychiatry. 2011;194:374-381. [CrossRef] [PubMed]
 
Owens JA. Neurocognitive and behavioral impact of sleep disordered breathing in children. Pediatr Pulmonol. 2009;445:417-422. [CrossRef] [PubMed]
 
Chervin RD, Archbold KH, Dillon JE, et al. Inattention, hyperactivity, and symptoms of sleep-disordered breathing. Pediatrics. 2002;1093:449-456. [CrossRef] [PubMed]
 
Brockmann PE, Urschitz MS, Schlaud M, Poets CF. Primary snoring in school children: prevalence and neurocognitive impairments. Sleep Breath. 2012;161:23-29. [CrossRef] [PubMed]
 
Antonelli Incalzi R, Marra C, Salvigni BL, et al. Does cognitive dysfunction conform to a distinctive pattern in obstructive sleep apnea syndrome? J Sleep Res. 2004;131:79-86. [CrossRef] [PubMed]
 
Mazza S, Pépin JL, Naëgelé B, Plante J, Deschaux C, Lévy P. Most obstructive sleep apnoea patients exhibit vigilance and attention deficits on an extended battery of tests. Eur Respir J. 2005;251:75-80. [CrossRef] [PubMed]
 
Archbold KH, Borghesani PR, Mahurin RK, Kapur VK, Landis CA. Neural activation patterns during working memory tasks and OSA disease severity: preliminary findings. J Clin Sleep Med. 2009;51:21-27. [PubMed]
 
Bédard MA, Montplaisir J, Richer F, Rouleau I, Malo J. Obstructive sleep apnea syndrome: pathogenesis of neuropsychological deficits. J Clin Exp Neuropsychol. 1991;136:950-964. [CrossRef] [PubMed]
 
Caselli RJ. Obstructive sleep apnea, apolipoprotein E e4, and mild cognitive impairment. Sleep Med. 2008;98:816-817. [CrossRef] [PubMed]
 
Quan SF, Chan CS, Dement WC, et al. The association between obstructive sleep apnea and neurocognitive performance—the Apnea Positive Pressure Long-term Efficacy Study (APPLES). Sleep. 2011;343:303-314B. [PubMed]
 
Petersen RC, Roberts RO, Knopman DS, et al. The Mayo Clinic Study of Aging Prevalence of mild cognitive impairment is higher in men. Neurology. 2010;7510:889-897. [CrossRef] [PubMed]
 
Ayalon L, Ancoli-Israel S, Drummond SP. Obstructive sleep apnea and age: a double insult to brain function? Am J Respir Crit Care Med. 2010;1823:413-419. [CrossRef] [PubMed]
 
Ovchinsky A, Rao M, Lotwin I, Goldstein NA. The familial aggregation of pediatric obstructive sleep apnea syndrome. Arch Otolaryngol Head Neck Surg. 2002;1287:815-818. [PubMed]
 
Guindalini C, Colugnati FA, Pellegrino R, Santos-Silva R, Bittencourt LR, Tufik S. Influence of genetic ancestry on the risk of obstructive sleep apnoea syndrome. Eur Respir J. 2010;364:834-841. [CrossRef] [PubMed]
 
Bekris LM, Yu CE, Bird TD, Tsuang DW. Genetics of Alzheimer disease. J Geriatr Psychiatry Neurol. 2010;234:213-227. [CrossRef] [PubMed]
 
Kadotani H, Kadotani T, Young T, et al. Association between apolipoprotein E epsilon4 and sleep-disordered breathing in adults. JAMA. 2001;28522:2888-2890. [CrossRef] [PubMed]
 
Spira AP, Blackwell T, Stone KL, et al. Sleep-disordered breathing and cognition in older women. J Am Geriatr Soc. 2008;561:45-50. [CrossRef] [PubMed]
 
Gozal D, Capdevila OS, Kheirandish-Gozal L, Crabtree VM. APOE epsilon 4 allele, cognitive dysfunction, and obstructive sleep apnea in children. Neurology. 2007;693:243-249. [CrossRef] [PubMed]
 
Trois MS, Capone GT, Lutz JA, et al. Obstructive sleep apnea in adults with Down syndrome. J Clin Sleep Med. 2009;54:317-323. [PubMed]
 
Elias MF, Elias PK, Sullivan LM, Wolf PA, D’Agostino RB. Lower cognitive function in the presence of obesity and hypertension: the Framingham heart study. Int J Obes Relat Metab Disord. 2003;272:260-268. [CrossRef] [PubMed]
 
Wetter DW, Young TB, Bidwell TR, Badr MS, Palta M. Smoking as a risk factor for sleep-disordered breathing. Arch Intern Med. 1994;15419:2219-2224. [CrossRef] [PubMed]
 
Logan AG, Perlikowski SM, Mente A, et al. High prevalence of unrecognized sleep apnoea in drug-resistant hypertension. J Hypertens. 2001;1912:2271-2277. [CrossRef] [PubMed]
 
Elmasry A, Lindberg E, Berne C, et al. Sleep-disordered breathing and glucose metabolism in hypertensive men: a population-based study. J Intern Med. 2001;2492:153-161. [CrossRef] [PubMed]
 
Parra O, Arboix A, Bechich S, et al. Time course of sleep-related breathing disorders in first-ever stroke or transient ischemic attack. Am J Respir Crit Care Med. 2000;1612 pt 1:375-380. [PubMed]
 
Osterweil D, Syndulko K, Cohen SN, et al. Cognitive function in non-demented older adults with hypothyroidism. J Am Geriatr Soc. 1992;404:325-335. [PubMed]
 
Chan KK, Chiu KC, Chu LW. Association between alcohol consumption and cognitive impairment in Southern Chinese older adults. Int J Geriatr Psychiatry. 2010;2512:1272-1279. [CrossRef] [PubMed]
 
Peters R, Poulter R, Warner J, Beckett N, Burch L, Bulpitt C. Smoking, dementia and cognitive decline in the elderly, a systematic review. BMC Geriatr. 2008;8:36. [CrossRef] [PubMed]
 
Lin CC, Tsan KW, Chen PJ. The relationship between sleep apnea syndrome and hypothyroidism. Chest. 1992;1026:1663-1667. [CrossRef] [PubMed]
 
Clarnette RM, Patterson CJ. Hypothyroidism: does treatment cure dementia? J Geriatr Psychiatry Neurol. 1994;71:23-27. [PubMed]
 
Launer LJ, Masaki K, Petrovitch H, Foley D, Havlik RJ. The association between midlife blood pressure levels and late-life cognitive function. The Honolulu-Asia Aging Study. JAMA. 1995;27423:1846-1851. [CrossRef] [PubMed]
 
Launer LJ, Ross GW, Petrovitch H, et al. Midlife blood pressure and dementia: the Honolulu-Asia aging study. Neurobiol Aging. 2000;211:49-55. [CrossRef] [PubMed]
 
Panza F, Frisardi V, Capurso C, et al. Metabolic syndrome and cognitive impairment: current epidemiology and possible underlying mechanisms. J Alzheimers Dis. 2010;213:691-724. [PubMed]
 
Wright CB, Elkind MS, Luo X, Paik MC, Sacco RL. Reported alcohol consumption and cognitive decline: The northern Manhattan study. Neuroepidemiology. 2006;274:201-207. [CrossRef] [PubMed]
 
Feige B, Gann H, Brueck R, et al. Effects of alcohol on polysomnographically recorded sleep in healthy subjects. Alcohol Clin Exp Res. 2006;309:1527-1537. [CrossRef] [PubMed]
 
Issa FG, Sullivan CE. Upper airway closing pressures in snorers. J Appl Physiol. 1984;572:528-535. [PubMed]
 
Palomäki H. Snoring and the risk of ischemic brain infarction. Stroke. 1991;228:1021-1025. [CrossRef] [PubMed]
 
Redline S, Yenokyan G, Gottlieb DJ, et al. Obstructive sleep apnea-hypopnea and incident stroke: the sleep heart health study. Am J Respir Crit Care Med. 2010;1822:269-277. [CrossRef] [PubMed]
 
Minoguchi K, Yokoe T, Tazaki T, et al. Silent brain infarction and platelet activation in obstructive sleep apnea. Am J Respir Crit Care Med. 2007;1756:612-617. [CrossRef] [PubMed]
 
Tatemichi TK, Foulkes MA, Mohr JP, et al. Dementia in stroke survivors in the Stroke Data Bank cohort. Prevalence, incidence, risk factors, and computed tomographic findings. Stroke. 1990;216:858-866. [CrossRef] [PubMed]
 
Desmond DW, Moroney JT, Paik MC, et al. Frequency and clinical determinants of dementia after ischemic stroke. Neurology. 2000;545:1124-1131. [CrossRef] [PubMed]
 
Moore AR, O’Keeffe ST. Drug-induced cognitive impairment in the elderly. Drugs Aging. 1999;151:15-28. [CrossRef] [PubMed]
 
Shirani A, Paradiso S, Dyken ME. The impact of atypical antipsychotic use on obstructive sleep apnea: a pilot study and literature review. Sleep Med. 2011;126:591-597. [CrossRef] [PubMed]
 
Beebe DW, Groesz L, Wells C, Nichols A, McGee K. The neuropsychological effects of obstructive sleep apnea: a meta-analysis of norm-referenced and case-controlled data. Sleep. 2003;263:298-307. [PubMed]
 
Naismith S, Winter V, Gotsopoulos H, Hickie I, Cistulli P. Neurobehavioral functioning in obstructive sleep apnea: differential effects of sleep quality, hypoxemia and subjective sleepiness. J Clin Exp Neuropsychol. 2004;261:43-54. [CrossRef] [PubMed]
 
Wong KK, Grunstein RR, Bartlett DJ, Gordon E. Brain function in obstructive sleep apnea: results from the Brain Resource International Database. J Integr Neurosci. 2006;51:111-121. [CrossRef] [PubMed]
 
Bédard MA, Montplaisir J, Malo J, Richer F, Rouleau I. Persistent neuropsychological deficits and vigilance impairment in sleep apnea syndrome after treatment with continuous positive airways pressure (CPAP). J Clin Exp Neuropsychol. 1993;152:330-341. [CrossRef] [PubMed]
 
Greenberg GD, Watson RK, Deptula D. Neuropsychological dysfunction in sleep apnea. Sleep. 1987;103:254-262. [PubMed]
 
Sforza E, Haba-Rubio J, De Bilbao F, et al. Performance vigilance task and sleepiness in patients with sleep-disordered breathing. Eur Respir J. 2004;242:279-285. [CrossRef] [PubMed]
 
Findley L, Unverzagt M, Guchu R, Fabrizio M, Buckner J, Suratt P. Vigilance and automobile accidents in patients with sleep apnea or narcolepsy. Chest. 1995;1083:619-624. [CrossRef] [PubMed]
 
Findley LJ, Levinson MP, Bonnie RJ. Driving performance and automobile accidents in patients with sleep apnea. Clin Chest Med. 1992;133:427-435. [PubMed]
 
Zimmerman ME, Aloia MS. A review of neuroimaging in obstructive sleep apnea. J Clin Sleep Med. 2006;24:461-471. [PubMed]
 
Davies CW, Crosby JH, Mullins RL, et al. Case control study of cerebrovascular damage defined by magnetic resonance imaging in patients with OSA and normal matched control subjects. Sleep. 2001;246:715-720. [PubMed]
 
O’Donoghue FJ, Briellmann RS, Rochford PD, et al. Cerebral structural changes in severe obstructive sleep apnea. Am J Respir Crit Care Med. 2005;17110:1185-1190. [CrossRef] [PubMed]
 
Gale SD, Hopkins RO. Effects of hypoxia on the brain: neuroimaging and neuropsychological findings following carbon monoxide poisoning and obstructive sleep apnea. J Int Neuropsychol Soc. 2004;101:60-71. [CrossRef] [PubMed]
 
Macey PM, Henderson LA, Macey KE, et al. Brain morphology associated with obstructive sleep apnea. Am J Respir Crit Care Med. 2002;16610:1382-1387. [CrossRef] [PubMed]
 
Morrell MJ, McRobbie DW, Quest RA, Cummin AR, Ghiassi R, Corfield DR. Changes in brain morphology associated with obstructive sleep apnea. Sleep Med. 2003;45:451-454. [CrossRef] [PubMed]
 
Fung SJ, Xi MC, Zhang JH, et al. Apnea promotes glutamate-induced excitotoxicity in hippocampal neurons. Brain Res. 2007;1179:42-50. [CrossRef] [PubMed]
 
Xie H, Leung KL, Chen L, et al. Brain-derived neurotrophic factor rescues and prevents chronic intermittent hypoxia-induced impairment of hippocampal long-term synaptic plasticity. Neurobiol Dis. 2010;401:155-162. [CrossRef] [PubMed]
 
Ayalon L, Ancoli-Israel S, Aka AA, McKenna BS, Drummond SP. Relationship between obstructive sleep apnea severity and brain activation during a sustained attention task. Sleep. 2009;323:373-381. [PubMed]
 
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;18310:1419-1426. [CrossRef] [PubMed]
 
Halbower AC, Degaonkar M, Barker PB, et al. Childhood obstructive sleep apnea associates with neuropsychological deficits and neuronal brain injury. PLoS Med. 2006;38:e301. [CrossRef] [PubMed]
 
Lavie L. Obstructive sleep apnoea syndrome—an oxidative stress disorder. Sleep Med Rev. 2003;71:35-51. [CrossRef] [PubMed]
 
Lavie L, Vishnevsky A, Lavie P. Evidence for lipid peroxidation in obstructive sleep apnea. Sleep. 2004;271:123-128. [PubMed]
 
Dyugovskaya L, Lavie P, Lavie L. Increased adhesion molecules expression and production of reactive oxygen species in leukocytes of sleep apnea patients. Am J Respir Crit Care Med. 2002;1657:934-939. [PubMed]
 
Ip MS, Tse HF, Lam B, Tsang KW, Lam WK. Endothelial function in obstructive sleep apnea and response to treatment. Am J Respir Crit Care Med. 2004;1693:348-353. [CrossRef] [PubMed]
 
Ip MS, Lam B, Chan LY, et al. Circulating nitric oxide is suppressed in obstructive sleep apnea and is reversed by nasal continuous positive airway pressure. Am J Respir Crit Care Med. 2000;1626:2166-2171. [PubMed]
 
Nedeljkovic ZS, Gokce N, Loscalzo J. Mechanisms of oxidative stress and vascular dysfunction. Postgrad Med J. 2003;79930:195-199. [CrossRef] [PubMed]
 
Cohen MV. Free radicals in ischemic and reperfusion myocardial injury: is this the time for clinical trials? Ann Intern Med. 1989;11111:918-931. [PubMed]
 
Gozal D, Kheirandish-Gozal L, Bhattacharjee R, Spruyt K. Neurocognitive and endothelial dysfunction in children with obstructive sleep apnea. Pediatrics. 2010;1265:e1161-e1167. [CrossRef] [PubMed]
 
Ferini-Strambi L, Baietto C, Di Gioia MR, et al. Cognitive dysfunction in patients with obstructive sleep apnea (OSA): partial reversibility after continuous positive airway pressure (CPAP). Brain Res Bull. 2003;611:87-92. [CrossRef] [PubMed]
 
Roth T, Rippon GA, Arora S. Armodafinil improves wakefulness and long-term episodic memory in nCPAP-adherent patients with excessive sleepiness associated with obstructive sleep apnea. Sleep Breath. 2008;121:53-62. [CrossRef] [PubMed]
 
Hirshkowitz M, Black JE, Wesnes K, Niebler G, Arora S, Roth T. Adjunct armodafinil improves wakefulness and memory in obstructive sleep apnea/hypopnea syndrome. Respir Med. 2007;1013:616-627. [CrossRef] [PubMed]
 
Cooke JR, Ayalon L, Palmer BW, et al. Sustained use of CPAP slows deterioration of cognition, sleep, and mood in patients with Alzheimer’s disease and obstructive sleep apnea: a preliminary study. J Clin Sleep Med. 2009;54:305-309. [PubMed]
 
Aloia MS, Arnedt JT, Davis JD, Riggs RL, Byrd D. Neuropsychological sequelae of obstructive sleep apnea-hypopnea syndrome: a critical review. J Int Neuropsychol Soc. 2004;105:772-785. [CrossRef] [PubMed]
 
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    Print ISSN: 0012-3692
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