Hypercapnia impaired cognitive and memory functions in obese patients with obstructive sleep apnoea

Obstructive sleep apnoea (OSA) is a sleep disorder involving repeated nocturnal desaturation and sleep fragmentation. OSA can result in decreased daytime alertness and neurocognitive dysfunction. Hypercapnia status is also related to neurocognitive dysfunction in patients with pulmonary diseases. We evaluated the effects of hypercapnia on cognitive performance and memory function in a prospective case-controlled study. We enrolled thirty-nine obese patients with OSA and collected their arterial blood samples. All the participants provided arterial blood samples, and completed two questionnaires (the Pittsburgh Sleep Quality Index and the Epworth Sleepiness Scale) and six cognitive tasks (the psychomotor vigilance task [PVT], the Stroop task, the Eriksen flanker task, processing speed [DSST], and verbal and visual memory [LM&FM]), which were used to evaluate daytime sleepiness, cognitive function, and memory function within one week of a polysomnographic study. When compared to the OSA without diurnal hypoventilation, the patients with stable hypercapnia (OHS) had increased reaction times in the PVT, Stroop task, and flanker task. Hypercapnic obese patients with OSA also had comparatively significantly lower scores in the processing speed and logical memory tests. OHS had increased reaction times in the attention and cognitive function assessments, and deficits in the logical memory, when compared to those with OSA without diurnal hypoventilation.

as the factors underlying neurocognitive dysfunction 13 . However, the influence of hypercapnic status on cognition still needs to be determined. We aimed to compare the impact of chronic stable hypercapnic status (arterial blood gas pH > 7.35 and partial pressure of CO 2 [PaCO 2 ] > 45 mmHg) on the neurocognitive function (attention, executive function, and memory function) in the patients with OSA. We hypothesized that the hypercapnic would impaired neurocognitive function in OSA patients.

Methods
In this prospective study, we enrolled consecutive 39 obese patients (body mass index [BMI] ≥ 30) with moderate-to-severe OSA (AHI score ≥ 15, derived using standard polysomnography) from 150 clinical patients at the Sleep Center at the Hualien Tzu-Chi General Hospital during 2016 and 2017. All the enrolled subjects underwent an arterial blood test within 1 week of the neurocognitive test and completed the neurocognitive tests prior to any treatment of their OSA. All the enrolled subjects completed the Epworth Sleepiness Scale (ESS), the Pittsburgh Sleep Quality Index (PSQI), the psychomotor vigilance task, the Eriksen flanker task, the Stroop task, and a memory test. All the enrolled subjects were >20 years in age. Those with BMI (body mass index) ≧30 can met our obesity criteria. The following patients were excluded from the study: those who had previously been diagnosed or treated for any neurological or psychological diseases that would interfered with the neurocognitive tests, those with chronic lung (standard pulmonary function shows obstructive or restrictive lung disease) or neuromuscular diseases that would have interfered with the neurocognitive task, and those who could not cooperate with the tasks. Patients with unstable vital signs (unstable blood pressure, tachypnoea [respiratory rate > 28 bpm], or acidaemia [pH < 7.35]) were also excluded from our study. The hospital's Institutional Review Board approved this study (IRB105-20-A), and all the participants provided informed consent. All the research methods were performed in accordance with the relevant guidelines and regulations. The study was funded by Buddhist Tzu Chi General Hospital, Hualien, Taiwan (TCRD 106-19).
Polysomnography. All the patients underwent one night of standard type-1 attended polysomnography (Embla A10, Embla; Broomfield, CO) at our Sleep Center. Sleep and arousal periods were scored according to the standard criteria 2 . AHI and 4% Oxygen Desaturation Index (ODI) were calculated as the markers of disease severity.
Arterial blood test. All enrolled subjects provided arterial blood samples for testing within 1 week of the neurocognitive test during the daytime. According to the result of arterial blood test, the subjects were divided into PaCO2 ≧ 45 mmHg and PaCO2 < 45 mmHg 2 groups.

Measures.
Questionnaires. The ESS is an 8-item questionnaire asking respondents to answer each question using a number between 0 to 3, with a total score ranging from 0 (minimum) to 24 (maximum) 14 . All enrolled subjects also completed the PSQI including 19 sleep item 15 .

Studied tasks.
The enrolled patients were asked to complete attention (psychomotor vigilance task), cognitive (Flanker and Stroop tasks) and memory task. All the cognitive tasks for these tests were generated using E-prime 2.0 16 . Attention and processing speed tasks. Psychomotor vigilance task. The patients were instructed to press a button as quickly as possible when a red 500-ms counter appeared on a small screen. We assessed and collected the following outcome measures of (1) omission rate (OR); (2) lape rate (LR); (3) hit rate (HR); (4) fast rate (FR); (5) reciprocal reaction time (RT); (6) measure of speed (1/RT); (7) false RT; (8) the fastest 10% of the RT and the slowest 10% of RT 16,17 .

Digit Symbol Substitution Test (DSST). The DSST is a component of the Wechsler Adult Intelligence Scale-Third
Edition (WAIS-III). The test requires the subjects to transcribe a unique geometric symbol with its corresponding Arabic number. The outcome measures of correct items completed within 120 seconds 16 . Executive tasks. Flanker task. In this study, we used the computerized arrow version of the Flanker task.
Colour-word Stroop task. Subjects were presented with coloured-words (red, blue, yellow, and green) printed either in ink matching the colour denoted by the word or in a colour not matching that denoted by the word in a computer. Congruent and incongruent trials were presented with equal probabilities. Subjects were instructed to respond to the ink colour of the words by pressing one of four response keys with maximal speed and accuracy. We collected the measurements of: (1) omission rate (OR), (2) error rate (ER), (3) accuracy rate (AR); (4) correct RT 16,19,20 .

Results
Demographic data. Of the 39 enrolled obese patients with OSA, 15 were hypercapnic (arterial blood PaCO 2 ≧ 45 mmHg and pH ≧ 7.35), which consistent to diagnosis of obesity hypoventilation syndrome (OHS).
Our study thus included 24 education-matched normocapnic subjects (OSA without diurnal hypoventilation). There was no difference between the two groups in age, BMI, or polysomnographic data, including AHI, ODI, and arousal index. There were only significant differences in PaCO 2 (mean PaCO2, hypercapnic: 52.75 ± 8.40, normocapnic: 39.65 ± 3.58) between the two groups (Table 1).
ESS and PSQI questionnaires. The mean ESS score was 11.86 ± 3.92 in the hypercapnic group and 12.71 ± 5.71 in the normocapnic group. The mean PSQI score was 11.07 ± 3.71 in hypercapnic patients and 11.04 ± 4.94 in normocapnic patients. There were no significant differences between the groups in ESS or PSQI scores (Table 1).
Attention and Processing speed tasks. PVT. There was a significant increase in both, lapse rate and RT; and a decreased fast rate in the PVT in the hypercapnic group when compared to the normocapnic group (Table 2).
Processing speed (DSST). Processing speed and all measures of logical memory were significantly worse in the hypercapnic patients with OSA than in the normocapnic patients with OSA (Table 2).
Executive tasks. Stroop task: No significant differences in the omission rate, error rate, or accuracy rate were observed in the congruent and incongruent Stroop tests. However, the correct RT was longer in the hypercapnic group (mean ± standard deviation [SD]: 905.27 ± 18.6 ms) than in normocapnic patients with OSA (mean ± SD: 733.2 ± 157.19 ms). The longer RTs were observed in both the congruent and incongruent tests in the Stroop task ( Table 2).
Flanker task. In the flanker task, a significantly increased correct RT was observed in the hypercapnic patients (mean ± SD: 451.89 ± 79.57 ms) when compared to the normocapnic patients (mean ± SD: 395.04 ± 69.6 ms). The increased correct RTs were found in both, the congruent and the incongruent trials, in the flanker task. However, no differences in omission rate, error rate, or accuracy rate in the flanker test were found between the two groups ( Table 2).

Memory tests.
We assessed two memory parameters in our study: logical memory (immediate logical memory, logical memory learning, delayed logical memory, logical memory percentage, and logical memory recognition), and visual memory (immediate face memory, delayed face memory, and face memory percentage). There were no significant differences in the verbal memory between the two groups (Table 3). Table 4 shows linear regression of each significant neurocognitive tasks and memory test with clinical and polysomnographic characteristics. LR, FR and RT was correlated to ODI, AHI and daytime PaCO2 levels. RT of Stroop task but not flanker task was correlated with daytime PaCO2 levels. In the other hands, most of the

Discussion
In the present study, obese patients with OSA and stable hypercapnia (OHS) had deficits in logical memory and attention, as well as increased correct RT in executive tasks when compared to those with OSA without diurnal hypoventilation. However, although the hypercapnic obese patients with OSA required longer to perform the executive and attention tasks, there were no differences in accuracy or error rate in the cognitive tasks. No differences in working memory or visual memory were found between hypercapnic and normocapnic patients with OSA. With the multiple regression, prolonged reaction time was correlated with intermittent nocturnal hypoxemia and daytime hypercapnia, as well as impaired momory was related with age and daytime hypercapnia. Many studies have reported deficits in memory and cognitive ability in patients with OSA compared to individuals without OSA 5,9,21 . Most of these studies conclude that the memory or cognitive impairments were due to the pathophysiology of intermittent hypoxemia.
A few studies have addressed the importance of monitoring hypercapnia in the daytime or during sleep. Wang et al. 22 have shown that hypercapnia may slow brain neural activity and lead to neurobehavioral impairments. In another brain imaging study, breathing 5% CO 2 significantly suppressed all magnetic resonance imaging indices of functional connectivity 23 . In addition, animal studies have shown that hypercapnia leads to slower    28 . In addition, cognitive impairments have been noted in patients with COPD, although the relationship among cognitive impairment, hypoxemia and hypercapnia is still debated 29 . In the present study, daytime hypercapnia was associated with increased RT in attention (PVT) and executive function (Stroop task and flanker task) tasks in patients with OSA.
In addition to attention and executive impairments, memory impairments have also been reported in the patients with OSA and COPD 21,29 . A majority of studies have reported impairments in the short-term verbal 5 and visual memory, as well as the long-term semantic memory 30 and procedural memory 31 in the patients with OSA. Memory impairments have also been noted in COPD with underlying chronic hypoxia-hypercapnia pathology in animals 11 , although the effects of hypercapnia in human beings are not well-understood. In the present study, we demonstrated that hypercapnia impaired processing speed and logical memory, but not visual or working memory in obese patients with OSA.
On the other hand, ODI was not different between the groups, but hypercapnia was. Moreover, some studies reported an increase in the blood pressure during apnoea-hypopnea. This may be due to the exacerbation of nocturnal hypoxemia and hypercapnia as a result of apnoea-hypopnea. The severity of hemodynamic changes due to apnoea-hypopnea may be related to the duration of apnoea-hypopnea episodes, which can vary from 10 seconds to 1 minute, but may not be reflected in the AHI and ODI scores. Further, prolonged apnoea events may even lead to a decrease in the AHI and ODI index 32 . The mechanism and relationship between PSGdeoxygenation index and hypercapnia should be investigated in the future research.
Our study had some limitations. First, the hypercapnic obese OSA group had a small sample size. Second, we used a daytime blood test to define hypercapnia rather than nocturnal non-invasive blood carbon dioxide monitoring. Furthermore, the blood carbon dioxide levels were not determined during the neurocognitive tests. In addition, research including larger samples of patients with OSA should be considered for future studies.
In conclusion, not all the measured parameters in the neurocognitive tests were worse in OHS than OSA without diurnal hypoventilation. However, daytime stable hypercapnia prolonged the RT in the cognitive and attention function tests and led to deficits in logical memory function in obese patients with OSA without diurnal hypoventilation.