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Comparison of Cognitive Functions Between Obstructive Sleep Apnea Syndrome and Simple Snoring Patients: OSAS May Be a Modifiable Risk Factor for Cognitive Decline a
a
a
a
a
Berna Arli , Sule Bilen , Ayse Pinar Titiz , Ersin Kasim Ulusoy , Semra Mungan , Erdem a
a
b
a
Gurkas , Zeynep Nese Oztekin , Muge Ozcan & Fikri Ak a
Neurology, Ankara Numune Education and Research Hospital, Ankara, Turkey
b
Otolaryngology, Ankara Numune Education and Research Hospital, Ankara, Turkey Published online: 12 Dec 2014.
To cite this article: Berna Arli, Sule Bilen, Ayse Pinar Titiz, Ersin Kasim Ulusoy, Semra Mungan, Erdem Gurkas, Zeynep Nese Oztekin, Muge Ozcan & Fikri Ak (2014): Comparison of Cognitive Functions Between Obstructive Sleep Apnea Syndrome and Simple Snoring Patients: OSAS May Be a Modifiable Risk Factor for Cognitive Decline, Applied Neuropsychology: Adult, DOI: 10.1080/23279095.2014.925901 To link to this article: http://dx.doi.org/10.1080/23279095.2014.925901
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APPLIED NEUROPSYCHOLOGY: ADULT, 0: 1–5, 2015 Copyright # Taylor & Francis Group, LLC ISSN: 2327-9095 print/2327-9109 online DOI: 10.1080/23279095.2014.925901
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Comparison of Cognitive Functions Between Obstructive Sleep Apnea Syndrome and Simple Snoring Patients: OSAS May Be a Modifiable Risk Factor for Cognitive Decline Berna Arli, Sule Bilen, Ayse Pinar Titiz, Ersin Kasim Ulusoy, Semra Mungan, Erdem Gurkas, and Zeynep Nese Oztekin Neurology, Ankara Numune Education and Research Hospital, Ankara, Turkey
Muge Ozcan Otolaryngology, Ankara Numune Education and Research Hospital, Ankara, Turkey
Fikri Ak Neurology, Ankara Numune Education and Research Hospital, Ankara, Turkey
By comparing neurocognitive test results from patients with obstructive sleep apnea syndrome (OSAS) and those from patients with simple snoring, we aimed to establish whether OSAS negatively influences cognition. Patients with mild-to-severe OSAS (n ¼ 29) and nonhypoxic simple-snoring patients (n ¼ 30) were admitted to the study. All participants in both groups were evaluated with polysomnography and neurocognitive tests, including the Stroop Test, Rey Auditory Verbal Learning Test, Judgment of Line Orientation, Trail-Making Test, and Symbol Digit Modalities Test (SDMT). Significant differences were identified between the groups for test scores on the Rey 1, SDMT, and Stroop tests. We propose that accurate OSAS diagnosis and treatment might help to prevent cognitive decline.
Key words: cognitive decline, neurocognitive tests, obstructive sleep apnea syndrome, simple snoring INTRODUCTION The obstructive sleep apnea syndrome (OSAS) is characterized by a recurrent obstruction (collapse) of the upper airway. Obstruction of the upper airway (pharynx), which leads to hypoxemia, hypercapnia, changes in the autonomic nervous system, and interruptions during sleep, is implicated in the pathophysiology of OSAS (Lal, Strange, & Bachman, 2012). Frequently reported symptoms in OSAS are loud snoring, daytime sleepiness, waking in the night with shortness of breath and a sense of choking, waking in the Address correspondence to Sule Bilen, Neurology, Ankara Numune Education and Research Hospital, Ankara Numune Egitim ve Arastirma Hastanesi, Ankara, 06100 Turkey. E-mail: [email protected]
morning feeling unrested, restless sleep, and morning headache. Behavioral changes may be seen in individuals due to sleeplessness, such as having a quick temper and maladjustment. These nonspecific symptoms may lead to delay in diagnosis of OSAS. The basic symptoms are snoring, daytime sleepiness, and difficulty concentrating, of which the patients are generally not aware as they have difficulties in perceiving or abstain from reporting these symptoms. Patients may attribute the sleepiness-related complaints to fatigue or may hide their sleepiness due to social reasons (El-Ad & Lavie, 2005). OSAS may cause cognitive decline as a result of influencing learning ability, attention, and memory. The foremost criteria of OSAS include endothelial dysfunction and hypoxemia in the pathophysiology of patients, leading
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to cognitive dysfunction. Lipid peroxidation increases in patients with OSAS as a result of hypoxia and reperfusion damage. The resultant increase in oxidative stress may cause an increase in the amount of dissolvable adhesion molecules and other reactive oxygen molecules, potentially leading to tissue damage, particularly in the brain and heart (Canessa et al., 2011; Lavie, 2003; Redline et al., 2010). Hypoxemia, which is related to apnea, has been shown to have impairing influences on cognitive functions (Amato et al., 2006; Karakas, Eski, & Oktem-Tanor, 2004). OSAS has been shown to result in a range of negative effects, particularly on judgment, comprehension and learning, and motor coordination, whereas motor speed generally remains unaffected (Farnik & Pierzchaa, 2007). OSASrelated neurocognitive impairment may be associated with excessive daytime sleepiness, and it has been demonstrated that cognitive impairment in sleep-deprived patients is similar to that observed in patients with OSAS. Excessive daytime sleepiness caused by sleep interruptions influences attention, memory, and vigilance by inducing slowing in information processing (Saunamäki & Jehkonen, 2007). Although many studies have addressed cognitive impairment, some significant problems have not yet been solved. The small size of sample groups, the lack of standardized measurement methods for measuring cognitive loss, and the inability to obtain long-term follow-up outcomes are the most important problems encountered (Jones & Harrison, 2001; Lojander, Kajaste, Maasilta, & Partinen, 1999). It should also be kept in mind that many comorbidities may be present in cognitive loss seen in OSAS, such as age, genetic factors, hypoxemia, excessive daytime sleepiness, cerebrovascular diseases, and endothelial dysfunction (Kiratli, Demir, Volkan-Salanci, Demir, & Sahin, 2010). An imbalance between the vasoconstrictor mediators (endothelin 1 and tromboxane) and vasodilator mediators (nitric oxide and prostacyclin) observed in OSAS contributes to endothelial dysfunction. OSAS brings about a reduction in the production of nitric oxide. Endothelial dysregulation induces hypercoagulability and thus creates a predisposition to atherosclerosis. A prolongation of this process with an impairment in cerebral oxygenation and blood flow may cause susceptibility to cerebral infarctions, thus leading to the possible occurrence of vascular dementia (Canessa et al., 2011). Here, by assessing the cognitive functions in those patients diagnosed with OSAS, we aimed to compare present findings to those of a simple-snoring group, thus establishing whether OSAS negatively influences cognition. METHOD Participants Twenty-nine patients with mild-to-severe OSAS who were hospitalized at the Ankara Numune Education and Research
Hospital and diagnosed according to the criteria of the American Academy of Sleep Medicine (AASM; Iber, Ancoli-Israel, Chesson, & Quan, 2007) and 30 nonhypoxic simple-snoring patients (control group) with an apnea hypopnea index (AHI) equal to or lower than 5 were enrolled in the study. The patient and control groups were composed of 7 women and 22 men and 9 women and 21 men, respectively. Those who were pregnant; who had cardiovascular, pulmonary, psychiatric, or brain diseases; whose Mini Mental State Examination score was 25 or lower; who had significant cognitive loss; or who were receiving antipsychotics, sedatives, or stimulant medications were excluded from the study. Written informed consent from the patients and ethical approval from our institution were received. Polysomnography The patients included in the study had a whole-night polysomnography in the sleep laboratory. A four-channel electroencephalogram was recorded with Alice 5 (Philips Respironics) equipment. To determine leg movements, patients’ electromyographies (EMGs) were recorded bilaterally from the anterior tibial muscles. Chin EMG was also recorded and a nasal cannula was used to record airflow. Lying position, oxygen saturation, abdominal thoracal movements, and electrocardiograms were also recorded. The records obtained during the sleep study were scored manually according to AASM 2007 criteria (Iber et al., 2007). Neuropsychological Evaluation The neuropsychological tests performed on the groups were as follows. The Rey Auditory Verbal Learning Test. The Rey Auditory Verbal Learning Test (AVLT) is related to memory and can also provide a quantitative assessment of parameters that are determined by experimental psychological studies. The AVLT is easily administered, is simply scored, and allows the study of many aspects of memory. The AVLT is considered an adequate and efficient test for the diagnosis and assessment of verbal learning and short-term memory (Grammaldo et al., 2006; Karakas et al. 2004). The Judgment of Line Orientation Test. The Judgment of Line Orientation Test (JLO) evaluates spatial orientation and is generally considered to measure the visuospatial perception. Visuospatial perception is composed of orientation and visualization elements. Various studies in which the JLO was employed have shown that this test provides an effective measurement of visuospatial perception and accordingly relates to the activities of the right hemisphere, particularly of the right parietal area (Karakas et al., 2004).
OSAS MAY BE A RISK FACTOR FOR COGNITIVE DECLINE
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Trail-Making Test. The Trail-Making Test evaluates attention, information-processing speed, motor speed, visual scanning, mental flexibility, perseverance, response inhibition, and susceptibility to interference. This test, specifically the Trail-Making Test, is accepted as an indicator of executive functions (Mahurin et al., 2006). Stroop Test. The Stroop Test measures the ability to shift one’s perceptual set according to changing demands under interference, the ability to suppress a habitual behavioral pattern, the ability to focus attention, and speed of information processing. This test is considered appropriate for assessing the inhibition of inappropriate impulses and is particularly sensitive to the left frontal lobe, particularly damage to the orbitofrontal cortex. The Stroop Test is composed of five sections (Stroop 1–5; Amato et al., 2006). Verbal Fluency Test. The Verbal Fluency Test (FAS) is used to assess the ability of word-list generation, fluency, and mental retrieval. A successful performance on this test implies normal perseverance and scanning of internal data storage. Patients who cannot sustain behavioral output may show generalized mental slowing and delayed response time, symptoms that may be observed in patients with frontal-lobe lesions (Archbold, Borghesani, Mahurin, Kapur, & Landis, 2009). Symbol Digit Modalities Test. The Symbol Digit Modalities Test (SDMT) is designed to isolate alertness and vigilance while placing minimal demands on two other components of attention: selectivity and capacity. Because the participants tested can give written or spoken responses, the test can be used with almost anyone, including those with motor disabilities or speech disorders. Furthermore, because it involves only geometric figures and numbers, the SDMT is generally not culture-specific and can be administered to people who do not speak English (Williams, O’Rourke, Hutchinson, & Tubridy, 2006). Statistical Analysis The Statistical Package for the Social Sciences Version 17.0 was used for data analysis. The student’s t test was used for the descriptive analysis. Chi-square analysis was performed to analyze the significance level of these distributions and p < .005 was accepted as showing statistical significance. RESULTS Female participants accounted for 24.2% and 30.0% of the patient and control groups, respectively. The mean age of participants in the patient group and control group was 49.55 ± 8.29 years and 51.17 ± 10.32 years, respectively.
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The mean education level of the patients and control group was 10.45 years and 9.23 years, respectively. No significant differences were found between the groups in terms of gender (X2 ¼ 0.256, p ¼ .613) and education (X2 ¼ 7.206, p ¼ .302). Significant differences were found between the groups in terms of the test scores of the utilized measures, including the Rey 1, SDMT, and Stroop 4 tests for time and correction, whereas no significant differences were found with respect to the scores of other measures (Table 1). Our data indicate that the control group obtained higher test scores than the patient group, suggesting that the short-term memory functions of the control group are better than those of the patient group. The control group also scored better than the patient group on the SDMT. The Stroop 4 test includes the scores of attention under interference. While performing the Stroop 4 test, the patients were asked to say the color of neutral words printed on colored cards. In our study, three items of the Stroop 4 test were assessed: the time for completing the test, the number of errors, and the number of corrections. The patient group completed this task in a longer period of time compared with the control group. Similarly, we found that the patient group made more errors than the control group and that the patient group was more inclined to correct their errors than the control group. Taken together, these results demonstrate that the ability of patients to focus their attention was more impaired than that of the control group. No significant differences were found in terms of the scores of other test measures TABLE 1 Comparison of the Scores of Tests Between the Groups Tests
Groups
N
Mean
SD
t
p
Rey 1
Patient Control Patient Control Patient Control Patient Control Patient Control Patient Control Patient Control Patient Control Patient Control Patient Control Patient Control
29 30 29 30 29 30 29 30 29 30 29 30 29 30 29 30 29 30 29 30 29 30
5.04 8.07 9.97 10.67 12.45 12.7 95.14 74.1 3.41 1.8 1.83 0.87 31.79 40.5 20.28 22.33 52.69 45.7 1.04 91.07 30.21 34.33
1.78 2.1 1.9 1.83 2.08 1.44 24.09 12.6 2.38 1.56 1.93 1.25 11.81 9.81 4.6 3.14 17.74 12.27 35.37 24.04 9.45 9.2
5.987
.000
1.574
.121
0.538
.593
4.183
.000
3.065
.004
2.262
.028
3.075
.003
1.998
.051
1.754
.086
1.689
.097
1.698
.095
Rey 5 Rey Recognition correct answers Stroop 4 time Stroop 4 wrong answers Stroop 4 correction SDMT JLO Trail-Making Number Trail-Making Letter FAS
SDMT ¼ Symbol Digit Modalities Test; JLO ¼ Judgment of Line Orientation Test.
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administered to the participants, including Rey 5 recognition in right and wrong responses, JLO, the Trail-Making Test (number and letter), and FAS. Results for these parameters show that no significant difference was present between the groups in terms of long-term memory functions, visuospatial perception abilities, executive functions, and verbal fluency abilities.
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DISCUSSION In our study, we compared patients with severe OSAS to nonhypoxic simple-snoring patients with an AHI less than 5. This comparison of patients with severe OSAS to simple-snoring patients revealed no significant differences in terms of awakening and movement arousal. Hypoxemiarelated cognitive loss has been suggested to occur in patients with mild-to-severe OSAS and OSAS-related cognitive impairment has been previously demonstrated. However, the OSAS groups in those studies were typically compared to normal control groups. In the case of our study, a group of snoring patients was selected as the control group, who had sleep interruptions but were free of hypoxemia (Kim, Lee, Lee, Jhoo, & Woo, 2011; Naismith, Winter, Gotsopoulos, Hickie, and Cistulli, 2004). The use of such a control group allows us to determine if sleep fragmentation also has a role in cognitive decline. When we compared patients with OSAS to the snoring group, it was observed that patients with OSAS obtained significantly worse scores on the Rey 1, SDMT, and Stroop Test. These tests assess memory, attention, and information-processing speed. A prominent impairment was seen in the OSAS group in terms of attention and memory abilities, compared with the simple-snoring group. Frequent nocturnal sleep interruptions seen in both groups were not considered to impact significantly on attention and memory. The p value in the JLO was close to .05, and it is expected that an enlargement of the sample group would yield a significant difference between the OSAS and simple-snoring groups. This, in turn, may indicate impairment in spatial perception and orientation abilities of the OSAS group as compared with the snoring group. It was shown in 76 patients with hypoxic OSAS that hypoxemia leads to cognitive loss. However, the relation of sleep irregularity and sleep fragmentation to cognition has not been examined. Patients with OSAS and hypoxemia were compared to patients with OSAS who were free of hypoxemia, and a pronounced impairment was reported in the hypoxic group in terms of attention, concentration, ability to solve complex problems, etc., as compared with patients without hypoxemia. In line with our study, it was shown that sleep fragmentation and daytime sleepiness had no pronounced influence on cognition (Csábi, Janacsek, Várszegi, & Németh, 2011; Lal et al., 2012).
Similar to Adams, Strauss, Schluchter, and Redline (2001), it was shown in our study that hypoxia in patients with OSAS (but not sleep interruption and sleep index) caused cognitive impairment. In Laganier et al. (2012), hypoxia was stated to be the primary factor leading to cognitive dysfunction in patients with OSAS, similar to our results. However, the lack of a control group limited that study. Our study design was advantageous compared with others in that we were able to compare both the hypoxemia group and the sleep fragmentation group, as well as daytime sleepiness between the two groups. The tests we administered to our patients were those used to assess cognitive loss in neurodegenerative diseases. Such testing requires standards that may be used among different patient groups, and the development, validation, and practicing of such tools require international efforts and large studies (Aloia, Arnedt, Davis, Riggs, & Byrd, 2004). In conclusion, according to the results of our study, OSAS may be included among the factors contributing to decline of cognitive functions, whereas simple snoring does not lead to such decline (despite sleep fragmentations). Therefore, it would be beneficial to accurately assess those patients with acquired cognitive impairment symptoms for OSAS to implement appropriate treatment at the earliest time possible. REFERENCES Adams, N., Strauss, M., Schluchter, M., & Redline, S. (2001). Relation of measures of sleep-disordered breathing to neuropsychological functioning. American Journal of Respiratory and Critical Care Medicine, 163, 1626–1631. Amato, M. P., Portaccio, E., Goretti, B., Zipoli, V., Ricchiuti, L., De Caro, M. F., . . . Trojano, M. (2006). The Rao’s Brief Repeatable Battery and Stroop Test: Normative values with age, education and gender corrections in an Italian population. Multiple Sclerosis, 12, 786–793. Aloia, M. S., Arnedt, J. T., Davis, J. D., Riggs, R. L., & Byrd, D. (2004). Neuropsychological sequelae of obstructive sleep apnea-hypopnea syndrome: A critical review. Journal of the International Neuropsychological Society, 10, 772–785. Archbold, K. H., Borghesani, P. R., Mahurin, R. K., Kapur, V. K., & Landis, C. A. (2009). Neural activation patterns during working memory tasks and OSA disease severity: Preliminary findings. Journal of Clinical Sleep Medicine, 5, 21–27. Canessa, N., Castronovo, V., Cappa, S. F., Aloia, M. S., Marelli, S., Falini, A., . . . Ferini-Strambi, L. (2011). Obstructive sleep apnea: Brain structural changes and neurocognitive function before and after treatment. American Journal of Respiratory and Critical Care Medicine, 183, 1419–1426. Csábi, E., Janacsek, K., Várszegi, M., & Németh, D. (2011). Different effect of sleep on working memory and skill learning: Cognitive function in obstructive sleep apnea. Psychiatrica Hungarica, 26, 78–86. El-Ad, B., & Lavie, P. (2005). Effect of sleep apnea on cognition and mood. International Review of Psychiatry, 17, 277–282. Farnik, M., & Pierzchała, W. (2007). Emotions, cognitive functions and quality of life in OSAS patients. Pneumonologia I Alergologia Polska, 75(Suppl. 1), 77–79. Grammaldo, L. G., Giampa, T., Quarato, P. P., Picardi, A., Mascia, A., Sparano, A., . . . Di Gennaro, G. (2006). Lateralizing value of memory
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OSAS MAY BE A RISK FACTOR FOR COGNITIVE DECLINE tests in drug resistant temporal lobe epilepsy. European Journal of Neurology, 13, 371–376. Iber, C., Ancoli-Israel, S., Chesson, A., & Quan, S. (2007). The AASM manual for the scoring of sleep and associated events: Rules, terminology and technical specifications. Westchester, IL: American Academy of Sleep Medicine. Jones, K., & Harrison, Y. (2001). Frontal lobe function, sleep loss and fragmented sleep. Sleep Medicine Reviews, 5, 463–475. Karakas, S., Eski, R., & Oktem-Tanor, O. (2004). Sayi dizisi ögrenme testi, cizgi yonunu belirleme testi, isaretleme testi, Raven standart progresif matrisler testi uygulama ve puanlama yonergesi [Line Orientation Test, Cancellation Test and Raven Standard Progressive Matrices]. In S. Karakas (Ed.), Bilnot bataryasi el kitabi: Noropsikolojik testler icin arastirma ve gelistirme calismalari [BILNOT battery: research and development of neuropsychological tests] (pp. 257–302). Ankara, Turkey: Dizayn Ofset. Kim, S. J., Lee, J. H., Lee, D. Y., Jhoo, J. H., & Woo, J. I. (2011). Neurocognitive dysfunction associated with sleep quality and sleep apnea in patients with mild cognitive impairment. American Journal of Geriatric Psychiatry, 19, 374–381. Kiratli, P. O., Demir, A. U., Volkan-Salanci, B., Demir, B., & Sahin, A. (2010). Cerebral blood flow and cognitive function in obstructive sleep apnea syndrome. Hellenic Journal of Nuclear Medicine, 13, 138–143. Laganier, J., Monti, A., Pariel-Madjlessi, S., Mitha, N., Gouronnec, A., & Pautas, E. (2012). Sleep apnea syndrome and cognitive impairment. Soins Gérontologie, 97, 31–35.
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Lal, C., Strange, C., & Bachman, D. (2012). Neurocognitive impairment in obstructive sleep apnea. Chest, 141, 1601–1610. Lavie, L. (2003). Obstructive sleep apnea syndrome—an oxidative stress disorder. Sleep Medicine Reviews, 7, 35–51. Lojander, J., Kajaste, S., Maasilta, P., & Partinen, M. (1999). Cognitive function and treatment of obstructive sleep apnea syndrome. Journal of Sleep Research, 8, 71–76. Mahurin, R. K., Velligan, D. I., Hazleton, B., Mark Davis, J., Eckert, S., & Miller, A. L. (2006). Trail Making Test errors and executive function in schizophrenia and depression. The Clinical Neuropsychologist, 20, 271–288. Naismith, S., Winter, V., Gotsopoulos, H., Hickie, I., & Cistulli, P. (2004). Neurobehavioral functioning in obstructive sleep apnea: Differential effects of sleep quality, hypoxemia and subjective sleepiness. Journal of Clinical and Experimental Neuropsychology, 26, 43–54. Redline, S., Yenokyan, G., Gottlieb, D. J., Shahar, E., O’Connor, G. T., Resnick, H. E., . . . Punjabi, N. M. (2010). Obstructive sleep apneahypopnea and incident stroke: The Sleep Heart Health Study. American Journal of Respiratory and Critical Care Medicine, 182, 269–277. Saunamäki, T., & Jehkonen, M. (2007). A review of executive functions in obstructive sleep apnea syndrome. Acta Neurologica Scandinavica, 115, 1–11. Williams, J., O’Rourke, K., Hutchinson, M., & Tubridy, N. (2006). The Face-Symbol Test and The Symbol-Digit Test are not reliable surrogates for the Paced Auditory Serial Addition Test in multiple sclerosis. Multiple Sclerosis, 12, 599–604.
Applied Neuropsychology: Adult Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/hapn21
Click for updates
Comparison of Cognitive Functions Between Obstructive Sleep Apnea Syndrome and Simple Snoring Patients: OSAS May Be a Modifiable Risk Factor for Cognitive Decline a
a
a
a
a
Berna Arli , Sule Bilen , Ayse Pinar Titiz , Ersin Kasim Ulusoy , Semra Mungan , Erdem a
a
b
a
Gurkas , Zeynep Nese Oztekin , Muge Ozcan & Fikri Ak a
Neurology, Ankara Numune Education and Research Hospital, Ankara, Turkey
b
Otolaryngology, Ankara Numune Education and Research Hospital, Ankara, Turkey Published online: 12 Dec 2014.
To cite this article: Berna Arli, Sule Bilen, Ayse Pinar Titiz, Ersin Kasim Ulusoy, Semra Mungan, Erdem Gurkas, Zeynep Nese Oztekin, Muge Ozcan & Fikri Ak (2014): Comparison of Cognitive Functions Between Obstructive Sleep Apnea Syndrome and Simple Snoring Patients: OSAS May Be a Modifiable Risk Factor for Cognitive Decline, Applied Neuropsychology: Adult, DOI: 10.1080/23279095.2014.925901 To link to this article: http://dx.doi.org/10.1080/23279095.2014.925901
PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content. This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http:// www.tandfonline.com/page/terms-and-conditions
APPLIED NEUROPSYCHOLOGY: ADULT, 0: 1–5, 2015 Copyright # Taylor & Francis Group, LLC ISSN: 2327-9095 print/2327-9109 online DOI: 10.1080/23279095.2014.925901
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Comparison of Cognitive Functions Between Obstructive Sleep Apnea Syndrome and Simple Snoring Patients: OSAS May Be a Modifiable Risk Factor for Cognitive Decline Berna Arli, Sule Bilen, Ayse Pinar Titiz, Ersin Kasim Ulusoy, Semra Mungan, Erdem Gurkas, and Zeynep Nese Oztekin Neurology, Ankara Numune Education and Research Hospital, Ankara, Turkey
Muge Ozcan Otolaryngology, Ankara Numune Education and Research Hospital, Ankara, Turkey
Fikri Ak Neurology, Ankara Numune Education and Research Hospital, Ankara, Turkey
By comparing neurocognitive test results from patients with obstructive sleep apnea syndrome (OSAS) and those from patients with simple snoring, we aimed to establish whether OSAS negatively influences cognition. Patients with mild-to-severe OSAS (n ¼ 29) and nonhypoxic simple-snoring patients (n ¼ 30) were admitted to the study. All participants in both groups were evaluated with polysomnography and neurocognitive tests, including the Stroop Test, Rey Auditory Verbal Learning Test, Judgment of Line Orientation, Trail-Making Test, and Symbol Digit Modalities Test (SDMT). Significant differences were identified between the groups for test scores on the Rey 1, SDMT, and Stroop tests. We propose that accurate OSAS diagnosis and treatment might help to prevent cognitive decline.
Key words: cognitive decline, neurocognitive tests, obstructive sleep apnea syndrome, simple snoring INTRODUCTION The obstructive sleep apnea syndrome (OSAS) is characterized by a recurrent obstruction (collapse) of the upper airway. Obstruction of the upper airway (pharynx), which leads to hypoxemia, hypercapnia, changes in the autonomic nervous system, and interruptions during sleep, is implicated in the pathophysiology of OSAS (Lal, Strange, & Bachman, 2012). Frequently reported symptoms in OSAS are loud snoring, daytime sleepiness, waking in the night with shortness of breath and a sense of choking, waking in the Address correspondence to Sule Bilen, Neurology, Ankara Numune Education and Research Hospital, Ankara Numune Egitim ve Arastirma Hastanesi, Ankara, 06100 Turkey. E-mail: [email protected]
morning feeling unrested, restless sleep, and morning headache. Behavioral changes may be seen in individuals due to sleeplessness, such as having a quick temper and maladjustment. These nonspecific symptoms may lead to delay in diagnosis of OSAS. The basic symptoms are snoring, daytime sleepiness, and difficulty concentrating, of which the patients are generally not aware as they have difficulties in perceiving or abstain from reporting these symptoms. Patients may attribute the sleepiness-related complaints to fatigue or may hide their sleepiness due to social reasons (El-Ad & Lavie, 2005). OSAS may cause cognitive decline as a result of influencing learning ability, attention, and memory. The foremost criteria of OSAS include endothelial dysfunction and hypoxemia in the pathophysiology of patients, leading
Downloaded by [University of Saskatchewan Library] at 07:55 30 December 2014
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ARLI ET AL.
to cognitive dysfunction. Lipid peroxidation increases in patients with OSAS as a result of hypoxia and reperfusion damage. The resultant increase in oxidative stress may cause an increase in the amount of dissolvable adhesion molecules and other reactive oxygen molecules, potentially leading to tissue damage, particularly in the brain and heart (Canessa et al., 2011; Lavie, 2003; Redline et al., 2010). Hypoxemia, which is related to apnea, has been shown to have impairing influences on cognitive functions (Amato et al., 2006; Karakas, Eski, & Oktem-Tanor, 2004). OSAS has been shown to result in a range of negative effects, particularly on judgment, comprehension and learning, and motor coordination, whereas motor speed generally remains unaffected (Farnik & Pierzchaa, 2007). OSASrelated neurocognitive impairment may be associated with excessive daytime sleepiness, and it has been demonstrated that cognitive impairment in sleep-deprived patients is similar to that observed in patients with OSAS. Excessive daytime sleepiness caused by sleep interruptions influences attention, memory, and vigilance by inducing slowing in information processing (Saunamäki & Jehkonen, 2007). Although many studies have addressed cognitive impairment, some significant problems have not yet been solved. The small size of sample groups, the lack of standardized measurement methods for measuring cognitive loss, and the inability to obtain long-term follow-up outcomes are the most important problems encountered (Jones & Harrison, 2001; Lojander, Kajaste, Maasilta, & Partinen, 1999). It should also be kept in mind that many comorbidities may be present in cognitive loss seen in OSAS, such as age, genetic factors, hypoxemia, excessive daytime sleepiness, cerebrovascular diseases, and endothelial dysfunction (Kiratli, Demir, Volkan-Salanci, Demir, & Sahin, 2010). An imbalance between the vasoconstrictor mediators (endothelin 1 and tromboxane) and vasodilator mediators (nitric oxide and prostacyclin) observed in OSAS contributes to endothelial dysfunction. OSAS brings about a reduction in the production of nitric oxide. Endothelial dysregulation induces hypercoagulability and thus creates a predisposition to atherosclerosis. A prolongation of this process with an impairment in cerebral oxygenation and blood flow may cause susceptibility to cerebral infarctions, thus leading to the possible occurrence of vascular dementia (Canessa et al., 2011). Here, by assessing the cognitive functions in those patients diagnosed with OSAS, we aimed to compare present findings to those of a simple-snoring group, thus establishing whether OSAS negatively influences cognition. METHOD Participants Twenty-nine patients with mild-to-severe OSAS who were hospitalized at the Ankara Numune Education and Research
Hospital and diagnosed according to the criteria of the American Academy of Sleep Medicine (AASM; Iber, Ancoli-Israel, Chesson, & Quan, 2007) and 30 nonhypoxic simple-snoring patients (control group) with an apnea hypopnea index (AHI) equal to or lower than 5 were enrolled in the study. The patient and control groups were composed of 7 women and 22 men and 9 women and 21 men, respectively. Those who were pregnant; who had cardiovascular, pulmonary, psychiatric, or brain diseases; whose Mini Mental State Examination score was 25 or lower; who had significant cognitive loss; or who were receiving antipsychotics, sedatives, or stimulant medications were excluded from the study. Written informed consent from the patients and ethical approval from our institution were received. Polysomnography The patients included in the study had a whole-night polysomnography in the sleep laboratory. A four-channel electroencephalogram was recorded with Alice 5 (Philips Respironics) equipment. To determine leg movements, patients’ electromyographies (EMGs) were recorded bilaterally from the anterior tibial muscles. Chin EMG was also recorded and a nasal cannula was used to record airflow. Lying position, oxygen saturation, abdominal thoracal movements, and electrocardiograms were also recorded. The records obtained during the sleep study were scored manually according to AASM 2007 criteria (Iber et al., 2007). Neuropsychological Evaluation The neuropsychological tests performed on the groups were as follows. The Rey Auditory Verbal Learning Test. The Rey Auditory Verbal Learning Test (AVLT) is related to memory and can also provide a quantitative assessment of parameters that are determined by experimental psychological studies. The AVLT is easily administered, is simply scored, and allows the study of many aspects of memory. The AVLT is considered an adequate and efficient test for the diagnosis and assessment of verbal learning and short-term memory (Grammaldo et al., 2006; Karakas et al. 2004). The Judgment of Line Orientation Test. The Judgment of Line Orientation Test (JLO) evaluates spatial orientation and is generally considered to measure the visuospatial perception. Visuospatial perception is composed of orientation and visualization elements. Various studies in which the JLO was employed have shown that this test provides an effective measurement of visuospatial perception and accordingly relates to the activities of the right hemisphere, particularly of the right parietal area (Karakas et al., 2004).
OSAS MAY BE A RISK FACTOR FOR COGNITIVE DECLINE
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Trail-Making Test. The Trail-Making Test evaluates attention, information-processing speed, motor speed, visual scanning, mental flexibility, perseverance, response inhibition, and susceptibility to interference. This test, specifically the Trail-Making Test, is accepted as an indicator of executive functions (Mahurin et al., 2006). Stroop Test. The Stroop Test measures the ability to shift one’s perceptual set according to changing demands under interference, the ability to suppress a habitual behavioral pattern, the ability to focus attention, and speed of information processing. This test is considered appropriate for assessing the inhibition of inappropriate impulses and is particularly sensitive to the left frontal lobe, particularly damage to the orbitofrontal cortex. The Stroop Test is composed of five sections (Stroop 1–5; Amato et al., 2006). Verbal Fluency Test. The Verbal Fluency Test (FAS) is used to assess the ability of word-list generation, fluency, and mental retrieval. A successful performance on this test implies normal perseverance and scanning of internal data storage. Patients who cannot sustain behavioral output may show generalized mental slowing and delayed response time, symptoms that may be observed in patients with frontal-lobe lesions (Archbold, Borghesani, Mahurin, Kapur, & Landis, 2009). Symbol Digit Modalities Test. The Symbol Digit Modalities Test (SDMT) is designed to isolate alertness and vigilance while placing minimal demands on two other components of attention: selectivity and capacity. Because the participants tested can give written or spoken responses, the test can be used with almost anyone, including those with motor disabilities or speech disorders. Furthermore, because it involves only geometric figures and numbers, the SDMT is generally not culture-specific and can be administered to people who do not speak English (Williams, O’Rourke, Hutchinson, & Tubridy, 2006). Statistical Analysis The Statistical Package for the Social Sciences Version 17.0 was used for data analysis. The student’s t test was used for the descriptive analysis. Chi-square analysis was performed to analyze the significance level of these distributions and p < .005 was accepted as showing statistical significance. RESULTS Female participants accounted for 24.2% and 30.0% of the patient and control groups, respectively. The mean age of participants in the patient group and control group was 49.55 ± 8.29 years and 51.17 ± 10.32 years, respectively.
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The mean education level of the patients and control group was 10.45 years and 9.23 years, respectively. No significant differences were found between the groups in terms of gender (X2 ¼ 0.256, p ¼ .613) and education (X2 ¼ 7.206, p ¼ .302). Significant differences were found between the groups in terms of the test scores of the utilized measures, including the Rey 1, SDMT, and Stroop 4 tests for time and correction, whereas no significant differences were found with respect to the scores of other measures (Table 1). Our data indicate that the control group obtained higher test scores than the patient group, suggesting that the short-term memory functions of the control group are better than those of the patient group. The control group also scored better than the patient group on the SDMT. The Stroop 4 test includes the scores of attention under interference. While performing the Stroop 4 test, the patients were asked to say the color of neutral words printed on colored cards. In our study, three items of the Stroop 4 test were assessed: the time for completing the test, the number of errors, and the number of corrections. The patient group completed this task in a longer period of time compared with the control group. Similarly, we found that the patient group made more errors than the control group and that the patient group was more inclined to correct their errors than the control group. Taken together, these results demonstrate that the ability of patients to focus their attention was more impaired than that of the control group. No significant differences were found in terms of the scores of other test measures TABLE 1 Comparison of the Scores of Tests Between the Groups Tests
Groups
N
Mean
SD
t
p
Rey 1
Patient Control Patient Control Patient Control Patient Control Patient Control Patient Control Patient Control Patient Control Patient Control Patient Control Patient Control
29 30 29 30 29 30 29 30 29 30 29 30 29 30 29 30 29 30 29 30 29 30
5.04 8.07 9.97 10.67 12.45 12.7 95.14 74.1 3.41 1.8 1.83 0.87 31.79 40.5 20.28 22.33 52.69 45.7 1.04 91.07 30.21 34.33
1.78 2.1 1.9 1.83 2.08 1.44 24.09 12.6 2.38 1.56 1.93 1.25 11.81 9.81 4.6 3.14 17.74 12.27 35.37 24.04 9.45 9.2
5.987
.000
1.574
.121
0.538
.593
4.183
.000
3.065
.004
2.262
.028
3.075
.003
1.998
.051
1.754
.086
1.689
.097
1.698
.095
Rey 5 Rey Recognition correct answers Stroop 4 time Stroop 4 wrong answers Stroop 4 correction SDMT JLO Trail-Making Number Trail-Making Letter FAS
SDMT ¼ Symbol Digit Modalities Test; JLO ¼ Judgment of Line Orientation Test.
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administered to the participants, including Rey 5 recognition in right and wrong responses, JLO, the Trail-Making Test (number and letter), and FAS. Results for these parameters show that no significant difference was present between the groups in terms of long-term memory functions, visuospatial perception abilities, executive functions, and verbal fluency abilities.
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DISCUSSION In our study, we compared patients with severe OSAS to nonhypoxic simple-snoring patients with an AHI less than 5. This comparison of patients with severe OSAS to simple-snoring patients revealed no significant differences in terms of awakening and movement arousal. Hypoxemiarelated cognitive loss has been suggested to occur in patients with mild-to-severe OSAS and OSAS-related cognitive impairment has been previously demonstrated. However, the OSAS groups in those studies were typically compared to normal control groups. In the case of our study, a group of snoring patients was selected as the control group, who had sleep interruptions but were free of hypoxemia (Kim, Lee, Lee, Jhoo, & Woo, 2011; Naismith, Winter, Gotsopoulos, Hickie, and Cistulli, 2004). The use of such a control group allows us to determine if sleep fragmentation also has a role in cognitive decline. When we compared patients with OSAS to the snoring group, it was observed that patients with OSAS obtained significantly worse scores on the Rey 1, SDMT, and Stroop Test. These tests assess memory, attention, and information-processing speed. A prominent impairment was seen in the OSAS group in terms of attention and memory abilities, compared with the simple-snoring group. Frequent nocturnal sleep interruptions seen in both groups were not considered to impact significantly on attention and memory. The p value in the JLO was close to .05, and it is expected that an enlargement of the sample group would yield a significant difference between the OSAS and simple-snoring groups. This, in turn, may indicate impairment in spatial perception and orientation abilities of the OSAS group as compared with the snoring group. It was shown in 76 patients with hypoxic OSAS that hypoxemia leads to cognitive loss. However, the relation of sleep irregularity and sleep fragmentation to cognition has not been examined. Patients with OSAS and hypoxemia were compared to patients with OSAS who were free of hypoxemia, and a pronounced impairment was reported in the hypoxic group in terms of attention, concentration, ability to solve complex problems, etc., as compared with patients without hypoxemia. In line with our study, it was shown that sleep fragmentation and daytime sleepiness had no pronounced influence on cognition (Csábi, Janacsek, Várszegi, & Németh, 2011; Lal et al., 2012).
Similar to Adams, Strauss, Schluchter, and Redline (2001), it was shown in our study that hypoxia in patients with OSAS (but not sleep interruption and sleep index) caused cognitive impairment. In Laganier et al. (2012), hypoxia was stated to be the primary factor leading to cognitive dysfunction in patients with OSAS, similar to our results. However, the lack of a control group limited that study. Our study design was advantageous compared with others in that we were able to compare both the hypoxemia group and the sleep fragmentation group, as well as daytime sleepiness between the two groups. The tests we administered to our patients were those used to assess cognitive loss in neurodegenerative diseases. Such testing requires standards that may be used among different patient groups, and the development, validation, and practicing of such tools require international efforts and large studies (Aloia, Arnedt, Davis, Riggs, & Byrd, 2004). In conclusion, according to the results of our study, OSAS may be included among the factors contributing to decline of cognitive functions, whereas simple snoring does not lead to such decline (despite sleep fragmentations). Therefore, it would be beneficial to accurately assess those patients with acquired cognitive impairment symptoms for OSAS to implement appropriate treatment at the earliest time possible. REFERENCES Adams, N., Strauss, M., Schluchter, M., & Redline, S. (2001). Relation of measures of sleep-disordered breathing to neuropsychological functioning. American Journal of Respiratory and Critical Care Medicine, 163, 1626–1631. Amato, M. P., Portaccio, E., Goretti, B., Zipoli, V., Ricchiuti, L., De Caro, M. F., . . . Trojano, M. (2006). The Rao’s Brief Repeatable Battery and Stroop Test: Normative values with age, education and gender corrections in an Italian population. Multiple Sclerosis, 12, 786–793. Aloia, M. S., Arnedt, J. T., Davis, J. D., Riggs, R. L., & Byrd, D. (2004). Neuropsychological sequelae of obstructive sleep apnea-hypopnea syndrome: A critical review. Journal of the International Neuropsychological Society, 10, 772–785. Archbold, K. H., Borghesani, P. R., Mahurin, R. K., Kapur, V. K., & Landis, C. A. (2009). Neural activation patterns during working memory tasks and OSA disease severity: Preliminary findings. Journal of Clinical Sleep Medicine, 5, 21–27. Canessa, N., Castronovo, V., Cappa, S. F., Aloia, M. S., Marelli, S., Falini, A., . . . Ferini-Strambi, L. (2011). Obstructive sleep apnea: Brain structural changes and neurocognitive function before and after treatment. American Journal of Respiratory and Critical Care Medicine, 183, 1419–1426. Csábi, E., Janacsek, K., Várszegi, M., & Németh, D. (2011). Different effect of sleep on working memory and skill learning: Cognitive function in obstructive sleep apnea. Psychiatrica Hungarica, 26, 78–86. El-Ad, B., & Lavie, P. (2005). Effect of sleep apnea on cognition and mood. International Review of Psychiatry, 17, 277–282. Farnik, M., & Pierzchała, W. (2007). Emotions, cognitive functions and quality of life in OSAS patients. Pneumonologia I Alergologia Polska, 75(Suppl. 1), 77–79. Grammaldo, L. G., Giampa, T., Quarato, P. P., Picardi, A., Mascia, A., Sparano, A., . . . Di Gennaro, G. (2006). Lateralizing value of memory
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Lal, C., Strange, C., & Bachman, D. (2012). Neurocognitive impairment in obstructive sleep apnea. Chest, 141, 1601–1610. Lavie, L. (2003). Obstructive sleep apnea syndrome—an oxidative stress disorder. Sleep Medicine Reviews, 7, 35–51. Lojander, J., Kajaste, S., Maasilta, P., & Partinen, M. (1999). Cognitive function and treatment of obstructive sleep apnea syndrome. Journal of Sleep Research, 8, 71–76. Mahurin, R. K., Velligan, D. I., Hazleton, B., Mark Davis, J., Eckert, S., & Miller, A. L. (2006). Trail Making Test errors and executive function in schizophrenia and depression. The Clinical Neuropsychologist, 20, 271–288. Naismith, S., Winter, V., Gotsopoulos, H., Hickie, I., & Cistulli, P. (2004). Neurobehavioral functioning in obstructive sleep apnea: Differential effects of sleep quality, hypoxemia and subjective sleepiness. Journal of Clinical and Experimental Neuropsychology, 26, 43–54. Redline, S., Yenokyan, G., Gottlieb, D. J., Shahar, E., O’Connor, G. T., Resnick, H. E., . . . Punjabi, N. M. (2010). Obstructive sleep apneahypopnea and incident stroke: The Sleep Heart Health Study. American Journal of Respiratory and Critical Care Medicine, 182, 269–277. Saunamäki, T., & Jehkonen, M. (2007). A review of executive functions in obstructive sleep apnea syndrome. Acta Neurologica Scandinavica, 115, 1–11. Williams, J., O’Rourke, K., Hutchinson, M., & Tubridy, N. (2006). The Face-Symbol Test and The Symbol-Digit Test are not reliable surrogates for the Paced Auditory Serial Addition Test in multiple sclerosis. Multiple Sclerosis, 12, 599–604.
