Abstract
OBJECTIVES:
The aim of this study was to investigate neuropsychological performance and biomarkers of oxidative stress in patients with obstructive sleep apnea and the relationships between these factors.
METHODS:
This was an observational, cross-sectional study of 14 patients (36.0±6.5 years old) with obstructive sleep apnea and 13 controls (37.3±6.9 years old). All of the participants were clinically evaluated and underwent full-night polysomnography as well as neuropsychological tests. Blood samples were used to assay superoxide dismutase, catalase, glutathione and homocysteine, as well as vitamins E, C, B11 and B12.
RESULTS:
The patients performed poorly relative to the controls on several neuropsychological tests, such as the attention test and tests of long-term memory and working memory/executive function. They also had lower levels of vitamin E (p<0.006), superoxide dismutase (p<0.001) and vitamin B11 (p<0.001), as well as higher concentrations of homocysteine (p<0.02). Serum concentrations of vitamin C, catalase, glutathione and vitamin B12 were unaltered. Vitamin E levels were related to performance in the backward digit span task (F = 15.9; p = 0.002) and this correlation remained after controlling for age and body mass index (F = 6.3, p = 0.01). A relationship between superoxide dismutase concentrations and executive non-perseveration errors in the Wisconsin Card Sorting Test (F = 7.9; p = 0.01) was also observed.
CONCLUSIONS:
Decreased levels of antioxidants and lower performance on the neuropsychological tasks were observed in patients with obstructive sleep apnea. This study suggests that an imbalance between antioxidants and pro-oxidants may contribute to neuropsychological alterations in this patient population.
Sleep Apnea; Neuropsychological Tests; Oxidative Stress; Vitamin E; Superoxide Dismutase
INTRODUCTION
Obstructive sleep apnea (OSA) is characterized by recurrent episodes of either total or partial
obstruction of the upper airway during sleep, which leads to intermittent hypoxemia, transitory
hypercapnia and frequent arousals (11. Sleep-related breathing disorders in adults: recommendations for syndrome
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cardiovascular morbidity, OSA is associated with a wide spectrum of cognitive symptoms, from mild
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long-term episodic memory and working memory/executive function (88. Naegele B, Launois SH, Mazza S, Feuerstein C, Pepin JL, Levy P. Which memory
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intermittent hypoxemia and frequent arousals, either individually or in combination, are involved in
these cognitive alterations, the pathophysiology of the neuropsychological deficits has not yet been
completely determined (1414. Canessa N, Castronovo V, Cappa SF, Aloia MS, Marelli S, Falini A, et al.
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The relationship between cognitive dysfunction and oxidative stress has not been extensively
investigated, although higher levels of oxidative stress biomarkers have been linked to increased
cardiovascular morbidity in OSA individuals (1616. Feng J, Zhang D, Chen B. Endothelial mechanisms of endothelial dysfunction in
patients with obstructive sleep apnea. Sleep Breath. 2012;16(2):283-94,
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). However,
controversy remains regarding the best marker of oxidative stress. High levels of certain
biomarkers, including lipid peroxidation products (1717. Franco CM, Lima AM, Ataide L, Jr., Lins OG, Castro CM, Bezerra AA, et al.
Obstructive Sleep Apnea Severity Correlates with Cellular and Plasma Oxidative Stress Parameters and
Affective Symptoms. 2012;47(2):300-10.),
homocysteine (1818. Monneret D, Tamisier R, Ducros V, Garrel C, Levy P, Baguet JP, et al. The impact
of obstructive sleep apnea on homocysteine and carotid remodeling in metabolic syndrome. Respir
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), 8-hydroxy-2'-deoxyguanosine in urine
(1919. Yamauchi M, Nakano H, Maekawa J, Okamoto Y, Ohnishi Y, Suzuki T, et al.
Oxidative stress in obstructive sleep apnea. Chest. 2005;127(5):1674-9,
http://dx.doi.org/10.1378/chest.127.5.1674.
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) and interleukin 10 or TNF-alpha in exhaled air (2020. Li Y, Chongsuvivatwong V, Geater A, Liu A. Exhaled breath condensate cytokine
level as a diagnostic tool for obstructive sleep apnea syndrome. Sleep Med. 2009;10(1):95-103,
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), have been reported. Higher-than-normal levels of plasma
homocysteine, which is an indirect marker of oxidative stress, have been detected in OSA patients
(2121. Jordan W, Berger C, Cohrs S, Rodenbeck A, Mayer G, Niedmann PD, et al.
CPAP-therapy effectively lowers serum homocysteine in obstructive sleep apnea syndrome.
J Neural Transm. 2004;111(6):683-9.). Christou et al. provided further evidence showing that
patients with severe OSA have a reduced antioxidant capacity (2222. Christou K, Markoulis N, Moulas AN, Pastaka C, Gourgoulianis KI. Reactive oxygen
metabolites (ROMs) as an index of oxidative stress in obstructive sleep apnea patients. Sleep
Breath. 2003;7(3):105-10, http://dx.doi.org/10.1007/s11325-003-0105-9.
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). Other studies have indicated that continuous positive airway pressure (CPAP) therapy
diminishes plasma oxidative stress (2323. Oyama J, Yamamoto H, Maeda T, Ito A, Node K, Makino N. Continuous positive
airway pressure therapy improves vascular dysfunction and decreases oxidative stress in patients
with the metabolic syndrome and obstructive sleep apnea syndrome. Clin Cardiol. 2012;35(4):231-6,
http://dx.doi.org/10.1002/clc.21010.
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and carbonyl stress in patients with obstructive sleep apnea treated with continuous positive airway
pressure. Sleep Breath. 2012;16(2):393-8,
http://dx.doi.org/10.1007/s11325-011-0510-4.
http://dx.doi.org/10.1007/s11325-011-051...
). However, few studies have examined a wider array of antioxidant biomarkers as
surrogate measures of oxidative stress in OSA patients.
Preliminary evidence indicates that folic acid and vitamin B12 have anti-apoptotic efficacy and
the ability to preserve mitochondrial function (2525. Majumdar S, Maiti A, Karmakar S, Sekhar Das A, Mukherjee S, Das D, et al.
Antiapoptotic efficacy of folic acid and vitamin B(12) against arsenic-induced toxicity. Environ
Toxicol. 2012;27(6):351-63, http://dx.doi.org/10.1002/tox.20648.
http://dx.doi.org/10.1002/tox.20648...
).
Furthermore, vitamin B11 deficiency has been associated with elevated concentrations of homocysteine
in the plasma of elderly non-demented patients (2626. de Lau LM, Refsum H, Smith AD, Johnston C, Breteler MM. Plasma folate
concentration and cognitive performance: Rotterdam Scan Study. Am J Clin Nutr.
2007;86(3):728-34.,2727. Pfeiffer CM, Caudill SP, Gunter EW, Osterloh J, Sampson EJ. Biochemical
indicators of B vitamin status in the US population after folic acid fortification: results from the
National Health and Nutrition Examination Survey 1999-2000. Am J Clin Nutr.
2005;82(2):442-50.). High vitamin B11 (plasma folate) concentrations have been
associated with improved global cognitive function (2626. de Lau LM, Refsum H, Smith AD, Johnston C, Breteler MM. Plasma folate
concentration and cognitive performance: Rotterdam Scan Study. Am J Clin Nutr.
2007;86(3):728-34.).
However, the association between homocysteinemia and decreased cognition was only observed in
participants with low folate levels (2828. Vidal JS, Dufouil C, Ducros V, Tzourio C. Homocysteine, folate and cognition in
a large community-based sample of elderly people--the 3C Dijon Study. Neuroepidemiology.
2008;30(4):207-14, http://dx.doi.org/10.1159/000126914.
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), which suggests
potential interplay between these factors. Recently, Singh et al. (2009) determined that both CPAP
treatment and antioxidant treatment (oral vitamin E and C) reduced oxidative stress in OSA patients
(2929. Singh TD, Patial K, Vijayan VK, Ravi K. Oxidative stress and obstructive sleep
apnoea syndrome. Indian J Chest Dis Allied Sci. 2009 Oct-Dec;
51(4):217-24.). Despite these findings, a relationship between
antioxidant biomarkers and cognitive impairment has not been established in OSA patients.
The aim of this study was to investigate neuropsychological performance and oxidative stress biomarkers in OSA patients and to evaluate the relationship between these factors.
MATERIAL AND METHODS
Study Design and Subjects
All of the subjects were clinically evaluated, underwent neuropsychological tests and polysomnography and had blood samples taken in the morning. The study was approved by the Ethics Committee for Research of the Hospital São Paulo-UNIFESP (# CEP 1266/03), and all of the participants provided written informed consent.
The male patients were consecutively recruited at the Sleep Institute of São Paulo. The inclusion
criteria included an age between 25 to 65 years, a body mass index (BMI) <40 and a minimum of 11
years of formal education. All of the cases had confirmed clinical and polysomnographic diagnoses of
OSA: apnea-hypopnea index (AHI) above 10 events/h (rather than 5) and at least one symptom or AHI
above 15. The exclusion criteria included previous CPAP therapy, the presence of shift work, severe
depression, endocrinopathies, (including dyslipidemia, diabetes, obesity or metabolic syndrome),
arterial hypertension, anemia, AIDS, current acute myocardial failure or arrhythmia, history of
neoplasia, and neurologic or psychiatric disease (including substance/alcohol abuse), as well as the
use of hypnotics, neuroleptics, beta-blockers, anti-epileptics, anti-rheumatic medication, steroids
and non-steroid anti-inflammatory drugs (NSAIDs), lipid reducers and vitamins. The control group was
recruited from the relatives of patients and the employees of the Sleep Institute. The control
subjects were matched according to age, sex, weight, scores on the Beck Depression Inventory (3030. Beck AT, Steer RA. Internal consistencies of the original and revised Beck
Depression Inventory. J Clin Psychol. 1984;40(6):1365-7,
http://dx.doi.org/10.1002/1097-4679(198411)40:6<1365::AID-JCLP2270400615>3.0.CO;2-D.
http://dx.doi.org/10.1002/1097-4679(1984...
) and years of education, and they were subject to the same
inclusion and exclusion criteria as patients, except that they had no sleep disorders (confirmed by
polysomnography).
Clinical Assessment
Examination included measurement of weight, height and blood pressure; ectoscopy; neurological
examination; ear, nose and throat exam; electrocardiography (ECG) and polysomnography. Sleep
complaints were evaluated using a questionnaire that had been adapted for local use, daytime
sleepiness was evaluated using the Epworth Sleepiness Scale (ESS) (3636. Lazzeroni V. [Experimental research on the application of the Toulouse-Pieron
test to the study of distributed attention]. Atti Accad Fisiocrit Siena Med Fis.
1954;1:116-31.) and depressive symptoms were evaluated using the Beck Depression Inventory (3030. Beck AT, Steer RA. Internal consistencies of the original and revised Beck
Depression Inventory. J Clin Psychol. 1984;40(6):1365-7,
http://dx.doi.org/10.1002/1097-4679(198411)40:6<1365::AID-JCLP2270400615>3.0.CO;2-D.
http://dx.doi.org/10.1002/1097-4679(1984...
,3131. Gorenstein C, Pompeia S, Andrade L. Scores of Brazilian University students on
the Beck Depression and the State Trait Anxiety Inventories. Psychol Rep. 1995;77(2):635-41,
http://dx.doi.org/10.2466/pr0.1995.77.2.635.
http://dx.doi.org/10.2466/pr0.1995.77.2....
). The
neuropsychological test battery included measures of various different cognitive functions. Blood
samples were collected to assay oxidative stress biomarkers.
Polysomnography
The recorded parameters included the following: electroencephalogram, electrooculogram, electromyogram (submentonian region and tibialis anterior muscle), electrocardiogram, air flow (recorded by a nasal pressure cannula and a buccal thermistor), respiratory effort by abdominal and thoracic movement (inductance plethysmography), body position, oximetry and snoring (Sonolab Meditron¯). The sleep stage scoring (3232. Rechtschaffen A, Kales A. A Manual of Standardized Terminology, Techniques and Scoring System for Sleep Stages of Human Subjects. US Department of Health, Education and Welfare Public Health Service. Health NIo, editor. Bethesda 1968.), respiratory patterns (11. Sleep-related breathing disorders in adults: recommendations for syndrome definition and measurement techniques in clinical research. The Report of an American Academy of Sleep Medicine Task Force. Sleep. 1999;22(5):667-89.), arousals (3333. EEG arousals: scoring rules and examples: a preliminary report from the Sleep Disorders Atlas Task Force of the American Sleep Disorders Association. Sleep. 1992;15(2):173-84.) and periodic leg movements were analyzed according to international criteria (3434. Recording and scoring leg movements. The Atlas Task Force. Sleep. 1993;16(8):748-59.).
Neuropsychological Tests
Classical psychometric tests adapted for local use were selected to assess attention, various
subcomponents of working memory (including executive functions) and episodic memory. Testing was
carried out at approximately 10:00 AM during two sessions that lasted approximately 45 minutes each.
The neuropsychological measures were investigated using the Toulouse-Piéron Attention Test (3535. Montiel J, Figueiredo E, Lustosa D, Dias N. Evidência de validade para o Teste
de Atenção Concentrada Toulouse-Piéron no contexto de trânsito. Psicologia: Pesquisa & Trânsito.
2006;2:19-27.,3636. Lazzeroni V. [Experimental research on the application of the Toulouse-Pieron
test to the study of distributed attention]. Atti Accad Fisiocrit Siena Med Fis.
1954;1:116-31.), the Wisconsin Card
Sorting Test (WCST) for executive functions (3737. Salorio CF, White DA, Piccirillo J, Duntley SP, Uhles ML. Learning, memory, and
executive control in individuals with obstructive sleep apnea syndrome. J Clin Exp
Neuropsychol. 2002;24(1):93-100, http://dx.doi.org/10.1076/jcen.24.1.93.973.
http://dx.doi.org/10.1076/jcen.24.1.93.9...
,3838. Ingram F, Greve KW, Ingram PT, Soukup VM. Temporal stability of the Wisconsin
Card Sorting Test in an untreated patient sample. Br J Clin Psychol. 1999;38 (Pt
2):209-11.), the Digit Symbol Substitution Test (3939. Wechsler D. WAlS-R: manual. San Antonio: The Psychological Corporation,
1981.) for the processing of visual figures, the forward Digit Span measuring the
functioning of phonological storage within working memory and the backward Digit Span evaluating
executive functions. Other tests included the Similarities Test to evaluate abstract verbal
reasoning, the Logical Memory and Verbal Paired Association Tests to evaluate episodic memory
(immediate recall short-term verbal memory) and long-term memory (delayed recall long-term verbal
memory) (1313. Baddeley AD, Andrade J. Working memory and the vividness of imagery. J Exp
Psychol Gen. 2000;129(1):126-45, http://dx.doi.org/10.1037/0096-3445.129.1.126.
http://dx.doi.org/10.1037/0096-3445.129....
), and the immediate and delayed recall of the
Rey-Osterrieth Complex Figure Test (4040. Poulton RG, Moffitt TE. The Rey-Osterreith Complex Figure Test: norms for young
adolescents and an examination of validity. Arch Clin Neuropsychol.
1995;10(1):47-56.,4141. Beebe DW, Wells CT, Jeffries J, Chini B, Kalra M, Amin R. Neuropsychological
effects of pediatric obstructive sleep apnea. J Int Neuropsychol Soc.
2004;10(7):962-75.) to evaluate short- and long-term visual non-verbal memory, respectively, as
well as planning and perceptual organization.
Biomarkers of Oxidative Stress
For the biochemical analyses, venous blood was collected in the morning, at approximately 8:00 AM
after 12 hours of fasting. The red blood cells were washed and hemolyzed to assay the antioxidant
enzymes and glutathione, whereas the plasma was used for the vitamin and amino acid assays. Two
enzymatic antioxidants were assayed, i.e., superoxide dismutase (SOD) (4242. McCord JM, Fridovich I. The utility of superoxide dismutase in studying free
radical reactions. I. Radicals generated by the interaction of sulfite, dimethyl sulfoxide, and
oxygen. J Biol Chem. 1969 25;244(22):6056-63.) and catalase (4343. Adamo AM, Llesuy SF, Pasquini JM, Boveris A. Brain chemiluminescence and
oxidative stress in hyperthyroid rats. Biochem J. 1989;263(1):273-7.), in addition to three
other non-enzymatic antioxidants, i.e., glutathione (4444. Tietze F. Enzymic method for quantitative determination of nanogram amounts of
total and oxidized glutathione: applications to mammalian blood and other tissues. Anal Biochem.
1969;27(3):502-22, http://dx.doi.org/10.1016/0003-2697(69)90064-5.
http://dx.doi.org/10.1016/0003-2697(69)9...
) and
vitamins B11 and B12 (4545. Sharma SK, Dakshinamurti K. Determination of vitamin B6 vitamers and pyridoxic
acid in biological samples. J Chromatogr. 1992;578(1):45-51,
http://dx.doi.org/10.1016/0378-4347(92)80223-D.
http://dx.doi.org/10.1016/0378-4347(92)8...
).
Statistical Analysis
Descriptive statistics are presented as the mean±standard deviation, range and frequency (% values). Fisher exact tests for categorical variables, the Mann-Whitney U test for continuous variables and Student's t test for normally distributed data with equal variances were performed to compare the cases and controls. Linear regression analysis was used to examine the relationship between scores of neuropsychological tests (dependent variables) and the levels of biomarkers for oxidative stress. Posterior adjustments for age and BMI were performed. The level of significance was set at p<0.05. Analyses were conducted using the Statistical Package for Social Sciences V16.0 [SPSS Inc., Chicago, IL, USA].
RESULTS
In total, 32 out of 63 consecutively evaluated OSA patients from an outpatient sleep disorder clinic met the inclusion requirements. Of these 32 patients, 18 were initially recruited; the remaining 14 cases were excluded because the presence of shift work (N = 4), the use of medication (NSAIDs and vitamins, N = 1), the presence of arterial hypertension (N = 1), high scores on the Beck Depression Inventory (N = 5), refusal of neuropsychological testing (N = 3) or refusal to participate without a specific reason (N = 4). Fourteen patients who met the eligibility requirements and 13 controls were studied. Thirteen controls were included. The cases and controls were similar with regard to years of schooling (>11 years), age (p = 0.62) and BMI (p = 0.12). As expected, the OSA patients presented more sleep complaints (UNIFESP sleep questionnaire) than the controls (p<0.001) and more daytime sleepiness (ESS, p<0.001). Excessive daytime sleepiness (ESS>10) was more frequent in the OSA patients than in the controls (78.6% vs 15.4%; p = 0.001). Depressive symptoms (according to the BDI) were similar between the cases and controls (p = 0.08).
By definition, the cases presented higher values of AHI than the controls (p<0.001), as well as lower minimum oxygen saturation levels (SpO2 minimum) (p = 0.003) and an increased micro arousal index (p = 0.006) (Table 1).
Neuropsychological Tests
The patients performed worse in the classical attention test (Toulouse-Piéron), with significantly more errors (p<0.02). Working memory was also significantly impaired in the patients with regard to retention of the episodic buffer (Logical Memory A+B immediate recollection, p<0.04; Rey Immediate Recall, p<0.001) and executive measures (backward digit span, p = 0.006; similarities, p<0.005; perseveration errors in the WCST, p<0.04).
The patients also showed worse verbal memory performance according to the Logical Memory Delayed Recollection (A+B, p<0.05) and the verbal paired associates delayed recollection (easy plus difficult, p<0.02). Furthermore, reduced values were observed on the Rey Figure Delayed Recall, which is a long-term non-verbal memory test (p<0.001) (Table 2).
Antioxidant and Pro-Oxidative Stress Markers in Patients and Controls
The patients presented lower levels of vitamin E (p<0.006), SOD (p<0.001) and vitamin B11 (p<0.001), as well as higher levels of homocysteine (p<0.02). Serum concentrations of vitamin C, catalase, glutathione and vitamin B12 were equivalent and within the normal range (Table 3).
Correlations between Oxidative Stress Markers and Neuropsychological Test Scores
Comparisons between levels of oxidative stress markers and neuropsychological results revealed a correlation between serum concentrations of vitamin E and the results of the backward digit span task (r = 0.76; p = 0.002) in the OSA patients (Figure 1); a similar correlation was not observed in the controls (r = 0.23; p = 0.43). A correlation was observed between the SOD concentration and the executive non-perseveration errors on the WCST in the OSA patients (r = 0.63; p = 0.01) (Figure 2); a similar correlation was not observed in the controls (r = -0.44; p = 0.10). The correlation between vitamin E levels and the backward digit span task remained after controlling for age and BMI (r = 0.69; p = 0.009), as did the correlation between SOD levels and WCST scores (r = 0.63, p = 0.02). No correlations were found among the other oxidative stress parameters, the neuropsychological results and the polysomnographic variables in the OSA patients and in the controls.
Serum concentrations of vitamin E are positively correlated with backward digit span task results in obstructive sleep apnea patients (r = 0.75, p = 0.002).
Superoxide dismutase concentrations are positively correlated with nonperseverative errors in the Wisconsin Card Sorting Test in obstructive sleep apnea patients (r = 0.63, p = 0.01).
DISCUSSION
The present study, which evaluated a wide range of oxidative stress biomarkers, confirms that
oxidative stress is critically elevated in OSA patients. The present study also substantiates an
important role for vitamin E and SOD, as it demonstrates a relationship between these antioxidants
and neuropsychological performance. It should be noted that the association between OSA and
cognitive impairment is complicated by numerous comorbidities, including aging, obesity, genetic
factors, hypoxemia, daytime somnolence, cerebrovascular disease and endothelial dysfunction (77. Lal C, Strange C, Bachman D. Neurocognitive impairment in obstructive sleep
apnea. Chest. 2012;141(6):1601-10, http://dx.doi.org/10.1378/chest.11-2214.
http://dx.doi.org/10.1378/chest.11-2214...
). To address this issue, this study considered matched groups of
patients and controls, so that the only difference across the groups was a high or low apnea index.
It should also be noted that the present study did not find a correlation between neuropsychological
results and polysomnographic measures, including oxygen desaturation and/or sleep fragmentation.
To date, various cognitive deficits have been identified in OSA patients. Deficits in attention,
vigilance, memory and executive function have all been described. Attempts to explain these
alterations have been made using both animal models and patients with OSA. Gozal et al. studied
young adult rats and examined the effects of fluctuating ambient oxygenation on learning and
neuronal health (4646. Gozal D, Daniel JM, Dohanich GP. Behavioral and anatomical correlates of chronic
episodic hypoxia during sleep in the rat. J Neurosci. 2001;21(7):2442-50.). Based on their results, a model was
proposed for a conceptual framework. In this model, sleep fragmentation and/or intermittent
hypoxemia and hypercarbia disrupt the restorative features of sleep and consequently disrupt
cellular or chemical homeostasis (4747. Beebe DW, Gozal D. Obstructive sleep apnea and the prefrontal cortex: towards a
comprehensive model linking nocturnal upper airway obstruction to daytime cognitive and behavioral
deficits. J Sleep Res. 2002;11(1):1-16,
http://dx.doi.org/10.1046/j.1365-2869.2002.00289.x.
http://dx.doi.org/10.1046/j.1365-2869.20...
). All of these
disturbances induce cellular and biochemical stress. Oxidative stress (4848. Nair D, Dayyat EA, Zhang SX, Wang Y, Gozal D. Intermittent hypoxia-induced
cognitive deficits are mediated by NADPH oxidase activity in a murine model of sleep apnea. PLoS
One. 2011;6(5):e19847, http://dx.doi.org/10.1371/journal.pone.0019847.
http://dx.doi.org/10.1371/journal.pone.0...
), apoptosis-related neural injury, reduced expression of brain-derived
neurotrophic factor (BDNF) (4949. Xie H, Yung WH. Chronic intermittent hypoxia-induced deficits in synaptic
plasticity and neurocognitive functions: a role for brain-derived neurotrophic factor. Acta
Pharmacol Sin. 2012;33(1):5-10, http://dx.doi.org/10.1038/aps.2011.184.
http://dx.doi.org/10.1038/aps.2011.184...
) and molecular alterations
(5050. Row BW. Intermittent hypoxia and cognitive function: implications from chronic
animal models. Adv Exp Med Biol. 2007;618:51-67,
http://dx.doi.org/10.1007/978-0-387-75434-5_5.
http://dx.doi.org/10.1007/978-0-387-7543...
) have been described in association with neural injury in
OSA (5151. Dempsey JA, Veasey SC, Morgan BJ, O'Donnell CP. Pathophysiology of sleep apnea.
Physiol Rev. 2010;90(1):47-112, http://dx.doi.org/10.1152/physrev.00043.2008.
http://dx.doi.org/10.1152/physrev.00043....
). Consequently, alterations of the cerebral cortex,
particularly the pre-frontal cortex, and cognitive dysfunction occur. Neuroimaging studies have
confirmed the involvement of the pre-frontal cortex in OSA (5252. Zhang X, Ma L, Li S, Wang Y, Wang L. A functional MRI evaluation of frontal
dysfunction in patients with severe obstructive sleep apnea. Sleep Med. 2011;12(4):335-40,
http://dx.doi.org/10.1016/j.sleep.2010.08.015.
http://dx.doi.org/10.1016/j.sleep.2010.0...
). These alterations have been shown to improve with treatment (5353. Canessa N, Castronovo V, Cappa SF, Aloia MS, Marelli S, Falini A, et al.
Obstructive sleep apnea: brain structural changes and neurocognitive function before and after
treatment. Am J Respir Crit Care Med. 2011;183(10):1419-26,
http://dx.doi.org/10.1164/rccm.201005-0693OC.
http://dx.doi.org/10.1164/rccm.201005-06...
). In addition, recent studies showed that young children with sleep apnea may
also undergo neuronal loss and cognitive impairments (5454. Halbower AC, Degaonkar M, Barker PB, Earley CJ, Marcus CL, Smith PL, et al.
Childhood obstructive sleep apnea associates with neuropsychological deficits and neuronal brain
injury. PLoS Med. 2006;3(8):e301, http://dx.doi.org/10.1371/journal.pmed.0030301.
http://dx.doi.org/10.1371/journal.pmed.0...
).
Controversy remains regarding the role of hypoxia in cerebral changes related to OSA. For
example, most animal models have used fluctuating ambient oxygen patterns to reproduce the chronic
intermittent hypoxia associated with OSA. Therefore, the observed brain alterations could merely be
secondary to cerebral hypoxia. In contrast to this explanation, sleep fragmentation was recently
shown to have an impact on both brain-specific alterations and general metabolism (5555. Baud MO, Magistretti PJ, Petit JM. Sustained sleep fragmentation affects brain
temperature, food intake and glucose tolerance in mice. J Sleep Res. 2012 26.). Furthermore, Thomas et al. examined OSA patients using
functional magnetic resonance imaging and demonstrated a lower level of activation of the prefrontal
cortex while performing a working memory task that was similar in hypoxic and nonhypoxic subjects,
which indicates that hypoxia does not influence the cortical dysfunction observed in sleep apnea
(5656. Thomas RJ, Rosen BR, Stern CE, Weiss JW, Kwong KK. Functional imaging of working
memory in obstructive sleep-disordered breathing. J Appl Physiol. 2005;98(6):2226-34,
http://dx.doi.org/10.1152/japplphysiol.01225.2004.
http://dx.doi.org/10.1152/japplphysiol.0...
).
Previous studies of the effects of vitamin E on cognition and the role of inflammation and
oxidative stress in OSA are controversial. Recently, an uncontrolled study of 20 patients receiving
CPAP therapy found that antioxidant intake improved the quality of sleep (2929. Singh TD, Patial K, Vijayan VK, Ravi K. Oxidative stress and obstructive sleep
apnoea syndrome. Indian J Chest Dis Allied Sci. 2009 Oct-Dec;
51(4):217-24.). In addition, CPAP has been reported to improve airway inflammation and
oxidative stress (5757. Petrosyan M, Perraki E, Simoes D, Koutsourelakis I, Vagiakis E, Roussos C, et
al. Exhaled breath markers in patients with obstructive sleep apnoea. Sleep Breath.
2008;12(3):207-15, http://dx.doi.org/10.1007/s11325-007-0160-8.
http://dx.doi.org/10.1007/s11325-007-016...
). Dietary intake of ω-3 PUFA has been
associated with lower plasma levels of Aβ42, and this pattern has also been linked with a reduced
risk of incident Alzheimer's disease and slower cognitive decline (5858. Gu Y, Schupf N, Cosentino SA, Luchsinger JA, Scarmeas N. Nutrient intake and
plasma beta-amyloid. Neurology. 2012;78(23):1832-40,
http://dx.doi.org/10.1212/WNL.0b013e318258f7c2
http://dx.doi.org/10.1212/WNL.0b013e3182...
). In contradiction to these findings, a metanalysis has shown a lack of evidence for the
efficacy of vitamin E in the prevention or treatment of dementia (5959. Isaac MG, Quinn R, Tabet N. Vitamin E for Alzheimer's disease and mild cognitive
impairment. Cochrane Database Syst Rev. 2008(3):CD002854.). Similar to our findings, increased oxidative stress in the hippocampus and cognitive
impairment were previously associated with sleep deprivation and the Western diet (6060. Alzoubi KH, Khabour OF, Salah HA, Abu Rashid BE. The Combined Effect of Sleep
Deprivation and Western Diet on Spatial Learning and Memory: Role of BDNF and Oxidative Stress.
J Mol Neurosci. 2012 10.1007/s12031-012-9881-7 [Epub ahead of print].), which indicates that oxidative stress may present an
additional risk factor for the complex cognitive impairment in OSA.
It should be noted that despite the obvious relationship between neuropsychological testing and cognitive function, neuropsychological evaluations describe performance that is not necessarily related to reduced cognition or dementia. In other words, neuropsychological tests should be considered to reflect a cerebral functional state rather than an established brain alteration. As an example of intermittent alterations, studies of seals have recently demonstrated increased levels of endogenous antioxidants to counteract noxious intermittent hypoxemia and chronic cycles of ischemia/reperfusion (6161. Vazquez-Medina JP, Zenteno-Savin T, Elsner R, Ortiz RM. Coping with physiological oxidative stress: a review of antioxidant strategies in seals. J Comp Physiol B. 2012;182(6):741-50.). OSA patients are continuously exposed to intermittent hypoxemia and chronic cycles of ischemia/reperfusion. Thus, it is possible that the adaptive mechanisms observed in seals are species-specific. Other studies may help to corroborate these findings.
This study confirms previous data showing compromised performance in specific neuropsychological
tests, particularly in tests measuring attention and memory. Most of previous studies did not
examine a wide range of neuropsychological tests. It has recently been noted that relatively little
research has specifically examined the influence of OSA on intellectual function (33. Kielb SA, Ancoli-Israel S, Rebok GW, Spira AP. Cognition in Obstructive Sleep
Apnea-Hypopnea Syndrome (OSAS): Current Clinical Knowledge and the Impact of Treatment.
Neuromolecular Med. 2012;14(3):180-93, http://dx.doi.org/10.1007/s12017-012-8182-1.
http://dx.doi.org/10.1007/s12017-012-818...
). Furthermore, in the present study, subjective somnolence was
observed in 85% of patients, which agrees with previous studies estimating that 80% of OSA patients
present excessive daytime somnolence or some other cognitive alteration (6262. Weaver TE, Maislin G, Dinges DF, Bloxham T, George CF, Greenberg H, et al.
Relationship between hours of CPAP use and achieving normal levels of sleepiness and daily
functioning. Sleep. 2007;30(6):711-9.). Regarding simple attention, a higher number of errors was observed in the
Toulouse-Piéron test, which supports a previous report of a significant reduction in attention on
various tests (6363. Ferini-Strambi L, Baietto C, Di Gioia MR, Castaldi P, Castronovo C, Zucconi M,
et al. Cognitive dysfunction in patients with obstructive sleep apnea (OSA): partial reversibility
after continuous positive airway pressure (CPAP). Brain Res Bull. 2003;61(1):87-92,
http://dx.doi.org/10.1016/S0361-9230(03)00068-6.
http://dx.doi.org/10.1016/S0361-9230(03)...
). Detrimental effects were also
observed in episodic and working memory, which corroborates previous findings that these cognitive
domains are impaired in OSA patients (6464. Naegele B, Pepin JL, Levy P, Bonnet C, Pellat J, Feuerstein C. Cognitive
executive dysfunction in patients with obstructive sleep apnea syndrome (OSAS) after CPAP treatment.
Sleep. 1998;21(4):392-7.).
With regard to oxidative stress markers, a reduction in the blood concentration of vitamin E was
observed, which agrees with the findings in a previous report (6565. Barcelo A, Barbe F, de la Pena M, Vila M, Perez G, Pierola J, et al. Antioxidant
status in patients with sleep apnoea and impact of continuous positive airway pressure treatment.
Eur Respir J. 2006;27(4):756-60,
http://dx.doi.org/10.1183/09031936.06.00067605.
http://dx.doi.org/10.1183/09031936.06.00...
). With regard to enzymatic antioxidants, the OSA patients exhibited a decrease in SOD,
which is the first enzyme of the antioxidizing pathway and may represent an oxidant signal. A
previous study showed that fMLP-stimulated superoxide release was markedly increased in OSA patients
when compared to a control group (6666. Schulz R, Mahmoudi S, Hattar K, Sibelius U, Olschewski H, Mayer K, et al.
Enhanced release of superoxide from polymorphonuclear neutrophils in obstructive sleep apnea. Impact
of continuous positive airway pressure therapy. Am J Respir Crit Care Med. 2000;162(2 Pt
1):566-70.). However, another study
found that SOD concentrations were within normal levels in these patients (6767. Alzoghaibi MA, Bahammam AS. Lipid peroxides, superoxide dismutase and
circulating IL-8 and GCP-2 in patients with severe obstructive sleep apnea: a pilot study. Sleep
Breath. 2005;9(3):119-26, http://dx.doi.org/10.1007/s11325-005-0022-1.
http://dx.doi.org/10.1007/s11325-005-002...
). These discrepancies in SOD findings may be the result of methodological
differences. Although the current study measured SOD values in erythrocytes, Schulz et al. (2000)
analyzed neutrophils (6666. Schulz R, Mahmoudi S, Hattar K, Sibelius U, Olschewski H, Mayer K, et al.
Enhanced release of superoxide from polymorphonuclear neutrophils in obstructive sleep apnea. Impact
of continuous positive airway pressure therapy. Am J Respir Crit Care Med. 2000;162(2 Pt
1):566-70.). Furthermore, other factors (such
as age) are known to influence antioxidant measurements. In this study, we observed an increase in
homocysteine and a reduction of vitamin B11 but not B12, both of which play fundamental roles in
homocysteine metabolism. The vitamin B11 reduction was accompanied by augmented plasma
concentrations of homocysteine, as expected (2828. Vidal JS, Dufouil C, Ducros V, Tzourio C. Homocysteine, folate and cognition in
a large community-based sample of elderly people--the 3C Dijon Study. Neuroepidemiology.
2008;30(4):207-14, http://dx.doi.org/10.1159/000126914.
http://dx.doi.org/10.1159/000126914...
). Our data
are in agreement with another study showing increased homocysteine levels in OSA patients (6868. Steiropoulos P, Tsara V, Nena E, Fitili C, Kataropoulou M, Froudarakis M, et al.
Effect of continuous positive airway pressure treatment on serum cardiovascular risk factors in
patients with obstructive sleep apnea-hypopnea syndrome. Chest. 2007;132(3):843-51,
http://dx.doi.org/10.1378/chest.07-0074.
http://dx.doi.org/10.1378/chest.07-0074...
). In the present study, blood was obtained from individuals in
the morning, at a time when homocysteine concentrations are usually low, and yet concentrations of
homocysteine were elevated beyond the normal range.
Some limitations to this study must be acknowledged. This study was an observational cross-sectional evaluation, and a cause/effect relationship among neuropsychological dysfunction, vitamin E and SOD cannot be established. The present evidence is important because it has potential implications for future therapies; however, these data only provide initial evidence, and more experiments to assess the relationship between antioxidants and neuropsychological tests in OSA patients are warranted. In this study, a wide sample of neuropsychological tests and several antioxidant biomarkers was examined. It should be noted that all of the study subjects were male, and the results may not be generalized to women. These results are unique and have not been previously shown. The evidence described here could be corroborated by prospectively studying the effects of administering vitamin E and other antioxidants on neuropsychological test scores in OSA patients.
In conclusion, decreased levels of antioxidants were observed in OSA patients. This study raises the possibility that an imbalance between antioxidants and pro-oxidants may contribute to the neuropsychological alterations observed in OSA patients. To the best of our knowledge, this is the first clinical investigation to relate neuropsychological alterations to oxidative stress biomarkers in OSA.
This work was supported in part by the AFIP, FAPESP/CEPID and MCT/CNPq.
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No potential conflict of interest was reported.
Publication Dates
-
Publication in this collection
Apr 2013
History
-
Received
11 Aug 2012 -
Reviewed
7 Sept 2012 -
Accepted
4 Dec 2012