Cognitive Effects of Treating Obstructive Sleep Apnea: A Meta-Analysis of Randomized Controlled Trials

Abstract

Background:

Obstructive sleep apnea (OSA) is associated with cognitive impairment and increased risks of dementia. However, the effect of continuous positive airway pressure (CPAP) on cognitive function in patients with OSA is still controversial.

Objective:

To evaluate the cognitive effects of CPAP treatment on OSA.

Methods:

We systematically searched PubMed, EMBASE, and Cochrane Library for randomized controlled trials (RCT) in the corresponding fields.

Results:

Totally 14 studies and 1,926 participants were included in our meta-analysis. Standardized mean difference (SMD) or weighted mean difference (WMD) were calculated for subjective sleepiness and cognitive domains including attention and speed of information processing, executive function, and memory. Individual cognitive scale and subgroup analyses according to OSA severity, length of trial, and RCT design type were further conducted. Significant treatment effect on attention and speed of information processing was only observed in severe OSA patients (SMD, 0.17; 95% CI, 0.02 to 0.31; p = 0.025; I² = 0%).

Conclusions:

Therefore, our meta-analysis indicates that CPAP treatment can partially improve cognitive impairment in the population of severe OSA.

Keywords

Cognition continuous positive airway pressure meta-analysis obstructive sleep apnea

INTRODUCTION

Obstructive sleep apnea (OSA) is one of the most common types of sleep disorders characterized by repeated obstruction of upper airway during sleep [1 –3], which leads to intermittent hypoxemia, sleep fragment, and daytime sleepiness [4, 5]. Mounting evidences have demonstrated that cognitive impairment is one of the core consequences of OSA [6], with a series of mechanisms proposed. Intermittent hypoxia may destroy the integrity of white matter as the result of systemic inflammation and altered permeability of blood–brain barrier, which leads to changes of synaptic plasticity and consequently cognitive impairment [7, 8]. At the same time, disturbed sleep in OAS may directly contribute to Alzheimer’s disease (AD) by increasing generation and deposition of amyloid-β (Aβ), promoting tau hyperphosphorylation, as well as decreasing Aβ clearance [9].

Continuous positive airway pressure (CPAP) is considered as an effective way to treat OSA via steady airflow supplement with devices worn during sleep [10, 11]. However, the cognitive effect of CPAP treatment on patients with OSA is still controversial. Some studies demonstrated that CPAP treatment could partly reverse the cognitive impairment attributed to OSA [12, 13], whereas others did not find sufficient improvement after CPAP treatment [14, 15]. Although two meta-analyses had been performed previously [16, 17], they included only a limited population or were performed a few years ago. Hence, we aim to comprehensively evaluate the effects of CPAP on cognition so as to provide an evidence-based clinical guidance for future treatment of OSA patients.

METHODS

Inclusion/exclusion criteria

Articles were included if they: 1) defined OSA by apnea-hypopnea index (AHI), oxygen desaturation index (ODI), or respiratory disturbance index (RDI); 2) were randomized controlled trials (RCTs) of CPAP compared with sham CPAP (or standard care) conducted in adults (aged≥18 years) with OSA; 3) were with outcomes of cognitive function assessed by effective neuropsychological tests. In addition, only articles with valid data or data that could be transformed into valuable information or obtained from authors were included.

Abstracts, comments, case reports, reviews, and meta-analyses were excluded from the research. We also excluded duplicate reports and those conducted in children. Language of publication was restricted to English, and the date of publication was updated to October 24, 2019.

Search strategy

Two investigators independently searched for the relevant articles through electronic databases, including PubMed, EMBASE, and Cochrane Library. We applied the same search terms associated with three major themes into the online databases, which were sleep-related breathing disorders, cognition, and treatment. The specific search terms were as follows: ((sleep disorder breathing) or (sleep apnea) or (upper airway resistance)) and (cognition or cognitive or dementia or memory or Alzheimer or neuropsychological or neuropsychology) and ((effect or treatment or improvement or therapy or management or (positive airway pressure)). Moreover, reference lists of the relevant articles and reviews were scanned by hand for additional articles.

Data extraction and quality assessment

Preliminarily included articles were independently identified by two investigators according to title and abstract. If the reviewer was uncertain about the eligibility, the article was read in full. Disagreements were discussed by two investigators in order to reach consensus. Major disagreements included the eligibility of a crossover trial with three different treatments and cognitive outcomes of some cognitive scales. Any disagreement was resolved by consensus discussion and consultation with a third investigator. Data were extracted independently by investigators with the following information: author, year of publication, sample size, definition of OSA, way of intervention, cognitive outcomes, etc. Insufficient data were solved by asking the author through E-mail or by transforming the data through statistical methods.

Quality of the included RCTs was performed by two investigators independently according to the Jadad scale, which assesses randomization procedure, blinding and description of dropout [18].

Statistical analysis

Data-analysis was performed with STATA. Means and standard deviation of cognitive change, as well as number of participants were used to calculate the effect size. Results were presented as standardized mean difference (SMD) when different scales were used to assess one cognitive domain, or weighted mean difference (WMD) when the cognitive domain derived from the same scales. Value of p < 0.05 was considered statistically significant. I² statistics were used in conjunction with chi-square test to describe the percentage of variability and quantify the degree of heterogeneity. Random-effect model was used in our analysis considering the heterogeneity of the samples. Begg’s and Egger’s tests were conducted to evaluate the publication bias. Epworth sleepiness scale (ESS) was used to assess subjective sleepiness. Three cognitive domains, attention and speed of information processing, executive function, and memory were evaluated in the study. Subgroup analyses were further conducted according to OSA severity (mild to moderate or severe), length of trial (4 weeks or more than 4 weeks) and RCT design type (parallel or crossover).

RESULTS

Study identification and characteristics

Totally 1,149 articles were identified from the electronic databases. After applying the inclusion and exclusion criteria, inappropriate articles were excluded according to title and abstract. Thirty-eight articles were carefully read in full to verify the eligibility, and 15 articles were removed afterwards. We further excluded 9 articles for insufficient data, which cannot be transformed through statistical methods or acquired from authors. Eventually, 14 articles were included in this meta-analysis [12–15 , 19–28]. The process was displayed in Fig. 1.

Fig.1

Flow diagram of systematic search and study selection.

All articles identified were published between 1998 and 2016, including 1,926 participants (mean age of 57.0 years) from 6 different countries. The sample size ranged from 23 to 843 participants, with 995 in the experimental groups and 931 in the control groups. Of the 14 RCTs, 11 were parallel trials and 3 were crossover trials; one was performed in the population of Parkinson’s disease, and one was performed in the population of stroke. The definition of OSA was based on AHI > 5 events/h, except for one article using oxygen desaturation index (ODI) > 7.5 events/h and one using respiratory disturbance index (RDI) > 15. Treatment adherence and duration ranged from 2.5 to 6.4 h per night and 1 to 24 weeks respectively. Study characteristics were listed in Tables 1 and 2.

Table 1

Clinical characteristics of studies included in the meta-analysis

Study	Participants, N(E/C)	Mean Age	BMI, kg/m²	Mean AHI (Range) Events/h	Criteria for Scoring Hypopneas
Aaronson et al. 2016 [13]	36 (20/16)	59.1	27.1	34.2 (15–83)	a reduction of airflow of≥50% for≥10 s followed by an oxygen desaturation≥3%
Barbe et al. 2001 [14]	54 (29/25)	53.1	29	55.4 (≥30)	a significant reduction in respiratory flow followed by an arousal or an episode of arterial oxygen desaturation greater than 4%
Bardwell et al. 2001 [15]	36 (20/16)	47.4	31.4	RDI: 50.9 (–)	–
Barnes et al. 2004 [19]	179 (89/90)	46.4	31.0	21.0 (5–30)	–
Dalmases et al. 2015 [20]	31 (16/15)	71.3	31.39	55.49 (37.86–73.12)	–
Engleman et al. 1998 [21]	23 (10/13)	47	30	43 (≥15)	–
Engleman et al. 1999 [22]	34 (17/17)	44	30	10 (5–15)	abdominal or thoracic respiratory movement amplitude was reduced to 50% or less of the preceding stable baseline value for 10 s or longer, during sleep
Gast et al. 2006 [23]	29 (17/12)	52.3	37.1	43.1 (12–85)	≥10-s reduction of nasal-oral airflow of≥50%
Harmell et al. 2016 [24]	34 (17/17)	67.2	27.5	22.3 (≥10)	there was a 50–90% decrease in amplitude lasting≥10 s
Joyeux-Faure et al. 2016 [25]	36 (18/18)	55	29.5	37.1 (20.8–53.4)	–
Kushida et al. 2012 [12]	843 (442/401)	51.5	32.3	40.1 (≥10)	–
Martínez-García et al. 2015 [26]	224 (115/109)	75.5	32.9	50.4 (35.5–65.3)	a 30–90% reduction in the oronasal airflow for≥10 s associated with a desaturation of≥3% (and/or an arousal in the case of a PSG study)
McMillan et al. 2014 [27]	242 (119/123)	71.1	33.8	ODI:28.7 (–)	–
Monasterio et al. 2001 [28]	125 (66/59)	54	29	20 (10–30)	–

N, number of patients (E, experimental group; C, control group); BMI, body mass index; AHI, apnea-hypopnea index; CPAP, continuous positive airway pressure.

Table 2

Comparison between groups, duration, design, country, and Jadad rating score of studies included in the meta-analysis

Study	CPAP	CPAP, h/night	Control	Sham CPAP, h/night	Follow-up, Week	RCT Design	Country	Jadad
Aaronson et al. 2016 [13]	CPAP	2.5	usual	3.2	4	parallel	Netherlands	2
Barbe et al. 2001 [14]	CPAP	5.0	sham CPAP	4.0	6	parallel	Spain	5
Bardwell et al. 2001 [15]	CPAP	5.5	placebo CPAP	4.9	1	parallel	USA	1
Barnes et al. 2004 [19]	CPAP	3.6	placebo tablets	–	12	crossover	Australia	5
Dalmases et al. 2015 [20]	CPAP+ conservative	6.0	conservative	–	12	parallel	Spain	2
Engleman et al. 1998 [21]	CPAP	2.8	oral placebo	–	4	crossover	UK	2
Engleman et al. 1999 [22]	CPAP	2.8	oral placebo	–	4	crossover	UK	2
Gast et al. 2006 [23]	CPAP	_	no treatment	–	1	parallel	USA	2
Harmell et al. 2016 [24]	CPAP	4.9	placebo CPAP	6.0	3	parallel	USA	4
Joyeux-Faure et al. 2016 [25]	CPAP	4.5	sham CPAP	4.4	6	parallel	France	3
Kushida et al. 2012 [12]	Active CPAP	4.2	sham CPAP	3.4	24	parallel	USA	3
Martínez-García et al. 2015 [26]	CPAP	4.9	no therapy	–	12	parallel	Spain	1
McMillan et al. 2014 [27]	CPAP+ supportive	6.4	supportive care	–	12	parallel	London	3
Monasterio et al. 2001 [28]	CPAP+ conservative	4.8	conservative treatment	–	24	Parallel	Spain	3

RCT, randomized controlled trial; CPAP, continuous positive airway pressure; Jadad, rating score for the quality of a randomized controlled trial-controlled trial.

Main results

No improvement of subjective sleepiness was observed in CPAP treatment group compared with controls (WMD, –2.36; 95% CI, –4.93 to 0.21; p = 0.07; I² = 95.8%) (Fig. 2). Similarly, CPAP could not improve attention and speed of information processing (SMD, 0.05; 95% CI, –0.02 to 0.12; p = 0.15; I² = 0%), executive function (SMD, 0.01; 95% CI, –0.11 to 0.11; p = 0.93; I² = 0%), and memory (SMD, –0.02; 95% CI, –0.46 to 0.43; p = 0.95; I² = 25.7%) (Fig. 3). However, subgroup analysis found that CPAP treatment could significantly improve attention and speed of information processing in patients with severe OSA (SMD, 0.17; 95% CI, 0.02 to 0.31; p = 0.025; I² = 0%) (Fig. 4). No significant improvements were observed when patients were assessed with individual cognitive scale (Figs. 5 and 6), including Trail Making A (WMD, –2.58; 95% CI, –5.56 to 0.40; p = 0.09; I² = 0%), Trail Making B (WMD, 0.09; 95% CI, –5.91 to 6.09; p = 0.98; I² = 0%), Digit Symbol (WMD, 0.80; 95% CI, –0.25 to 1.86; p = 0.13; I² = 20.5%), Digit Symbol Substitution (WMD, 0.52; 95% CI, –0.61 to 1.65; p = 0.37; I² = 0%), Verbal Fluency (WMD, –0.67; 95% CI, –4.93 to 3.60; p = 0.76; I² = 0%), Digit Span (WMD, 0.17; 95% CI, –0.21 to 0.54; p = 0.38;I² = 0%), Digit Span Forward (WMD, 0.02; 95% CI, –1.54 to 1.58; p = 0.98;I² = 55%), and Digit Span Backward (WMD, –0.16; 95% CI, –0.46 to 0.14; p = 0.30; I² = 0%).

Fig.2

Forest plot of studies on association between CPAP and subjective sleepiness: Epworth Sleepiness Scale.

Fig.3

Forest plot of studies on association between CPAP and cognition: attention and speed of information processing, executive function, and memory.

Fig.4

Forest plot of studies on association between CPAP and cognition: attention and speed of information processing (subgroup 1: severe OSA, subgroup 2: mild to moderate OSA).

Fig.5

Forest plot of Studies on association between CPAP and cognition: Trail making A, Trail making B, Digit symbol, and digit symbol substitution.

Fig.6

Forest plot of studies on association between CPAP and cognition: Verbal fluency, Digit Span, Digit Span Forward, and Digit Span Backward.

As there was significant heterogeneity in Epworth Sleepiness Scale (I² = 95.8%) and Digit Span Forward (I² = 55.0%), sensitivity analysis was performed to explore the sources of heterogeneity as well as the stability of the results. The heterogeneity of Epworth Sleepiness Scale was not improved when each study was removed sequentially, whereas that of Digit Span Forward decreased from 55.0% to 0% after removing Gast et al. [23]. No significant publication bias was found in our meta-analysis with Begg’s and Egger’s test. Funnel plot for attention and speed of information processing was displayed in Fig. 7.

Fig.7

Funnel plot for attention and speed of information processing.

DISCUSSION

In this meta-analysis, CPAP treatment could significantly improve attention and speed of information processing in patients with severe OSA. However, the improvement was not observed in other cognitive domains. The results were in line with the previous meta-analyses conducted in all participants, which showed that CPAP could partially improve cognitive function, with a small but significant effect on attention and vigilance [16, 17].

It is known that the speed of information processing is essential to the downstream processes of attention and executive functions [29], all of which are associated with the function of frontal lobe [30, 31]. A previous meta-analysis revealed that frontal cortex is one of the lobes that are most likely to display atrophy in OSA patients [32], which could partially be reversed by CPAP treatment [33]. Although significant effect size of executive function in severe OSA patients was observed, only two clinical trials were included in the analysis, so we fail to make an exact conclusion. Hence, more observations are needed to verify the authenticity of the conclusions.

Interestingly, only patients with severe OSA benefit from CPAP treatments in the analysis. It was found that patients with mild OSA were less likely to be successfully treated than those with severe OSA syndrome [34]. It is recognized that the effectiveness of CPAP therapy is time-dependent [35] and associated with the compliance of CPAP [36]. Compared with those with mild and moderate OSA, patients with severe OSA were reported to have a better compliance to CPAP treatment [37, 38], and therefore, a longer treatment duration and better therapeutic effectiveness.

In the current meta-analysis, most cognitive domains did not achieve significant improvements, which might be due to the following factors. First, the treatment duration is not sufficiently long for the biological and structural recovery of the brain. Previous study has showed that continuous CPAP treatment for 3 months could significantly increase the connectivity of right middle frontal gyrus [20]. If the treatment lasted for 6 months, the change of Cho/Cr in the hippocampus could be reversed, whereas no change was observed in the frontal lobe [39]. Similarly, another study revealed that the change of white matter was very limited after 3 months’ treatment, whereas both the change of white matter and cognitive function could be completely reversed if the treatment lasted for 12 months [35], which indicates a time-dependent effect of CPAP treatment. Although mounting evidence have indicated that CPAP treatment could decrease Aβ₄₂, normalized CSF Aβ₄₂ and t-tau/Aβ₄₂ ratio [40], there is still a long distance from pathological change to clinical improvement. In the current meta-analysis, the treatment duration in most of the studies were no more than 6 weeks; hence, treatment with longer duration is needed in the future to achieve obvious cognitive improvement. Second, the poor compliance of CPAP might dilute the effectiveness of treatment. Previous studies found that the effectiveness of CPAP treatment is closely related to the hours of treatment in routine clinical practice [41, 42]. The whole-night effective AHI < 5 could only be achieved when CPAP treatment lasted for more than 6 h per night, otherwise the effectiveness occurred only in non-supine position [43]. In fact, a great number of patients cannot tolerate the side effects of CPAP in spite of its effectiveness [44]. The average usage of CPAP in this meta-analysis was only 3.8 h per night, which indicates poor compliance and acceptance as well as limited improvement of cognition. Third, the clinical phenotypes and endotypes of OSA may affect the outcomes of CPAP treatment. It was found that if the patient had a lack of subjective daytime sleepiness, CPAP treatment could not improve their cognitive function in spite of the severity of OSA [14]. In addition, compared to patients with subjective daytime sleepiness, those without the symptom had mild hypoxemia, less sleep fragment, and poor CPAP compliance [45]. Therefore, treatment based on clinical phenotype is of great importance to the therapeutic effect and prognosis of OSA patients [46]. It is known that different pathogenetic mechanisms (endotypes) might lead to similar phenotype. Therefore, further exploration according to the endotypes of OSA might facilitate the precise treatment.

There are some limitations in our meta-analysis. First, we were unable to access all the outcome data from the studies even though we have transformed the data via statistical method or have asked the authors. We have contacted 8 authors for insufficient data; however, only 2 of them replied, which undermined the strength of the finding. Second, we tried to obtain information about relevant grey literature that has been completed but never been published through the following ways: 1) The International Clinical Trials Registry Platform Search Portal; 2) formal letters of request to colleagues for information about the unpublished studies. Unfortunately, we did not find the relevant grey literature that could minimize the bias of the meta-analysis. Third, the majority of the studies enrolled around 50 participants, whereas one study enrolled nearly 1,000 participants; thereby, the main effect may be partially driven by the results from the study. Finally, the cognitive function in the current meta-analysis was divided into several domains, each of which is evaluated by multiple scales and some of which may lack certain sensitivity and representativeness.

In summary, our meta-analysis found that CPAP treatment could only improve attention and speed of information processing in patients with severe OSA. Future studies need to pay more attention to the following aspects: 1) the effects of long-term CPAP treatment on cognitive function; 2) methods to increase the compliance and adherence of CPAP; and 3) precise therapy based on clinical phenotypes and endotypes.

Footnotes

ACKNOWLEDGMENTS

We thank all participants for their assistance and support. This study was supported by grants from the Qingdao Municipal Science and Technology Bureau (Grant No. 18-6-1-78-nsh) and the Afflicted Hospital of Qingdao University.

Authors’ disclosures available online ().

References

Semelka

, Wilson

, Floyd

(2016) Diagnosis and treatment of obstructive sleep apnea in adults. Am Fam Physician 94, 355–360.

Bucks

, Olaithe

, Rosenzweig

, Morrell

(2017) Reviewing the relationship between OSA and cognition: Where do we go from here? Respirology 22, 1253–1261.

Lim

, Pack

(2017) Obstructive sleep apnea: Update and future. Annu Rev Med 68, 99–112.

Jordan

, McSharry

, Malhotra

(2014) Adult obstructive sleep apnoea. Lancet 383, 736–747.

Barnes

, Houston

, Worsnop

, Neill

, Mykytyn

, Kay

, Trinder

, Saunders

, Douglas McEvoy

, Pierce

(2002) A randomized controlled trial of continuous positive airway pressure in mild obstructive sleep apnea. Am J Respir Crit Care Med 165, 773–780.

Kerner

, Roose

(2016) Obstructive sleep apnea is linked to depression and cognitive impairment: Evidence and potential mechanisms. Am J Geriatr Psychiatry 24, 496–508.

Lim

, Pack

(2014) Obstructive sleep apnea and cognitive impairment: Addressing the blood-brain barrier. Sleep Med Rev 18, 35–48.

Chen

, Lu

, Lin

, Chen

, Chou

, Lin

, Tsai

, Su

, Friedman

, Lin

(2015) White matter damage and systemic inflammation in obstructive sleep apnea. Sleep 38, 361–370.

Baril

, Carrier

, Lafreniere

, Warby

, Poirier

, Osorio

, Ayas

, Dube

, Petit

, Gosselin

(2018) Biomarkers of dementia in obstructive sleep apnea. Sleep Med Rev 42, 139–148.

10.

Eisele

, Markart

, Schulz

(2015) Obstructive sleep apnea, oxidative stress, and cardiovascular disease: Evidence from human studies. Oxid Med Cell Longev 2015, 608438.

11.

Sharma

, Varga

, Bubu

, Pirraglia

, Kam

, Parekh

, Wohlleber

, Miller

, Andrade

, Lewis

, Tweardy

, Buj

, Yau

, Sadda

, Mosconi

, Li

, Butler

, Glodzik

, Fieremans

, Babb

, Blennow

, Zetterberg

, Lu

, Badia

, Romero

, Rosenzweig

, Gosselin

, Jean-Louis

, Rapoport

, de Leon

, Ayappa

, Osorio

(2018) Obstructive sleep apnea severity affects amyloid burden in cognitively normal elderly. A longitudinal study. Am J Respir Crit Care Med 197, 933–943.

12.

Kushida

, Nichols

, Holmes

, Quan

, Walsh

, Gottlieb

, Simon

Jr , Guilleminault

, White

, Goodwin

, Schweitzer

, Leary

, Hyde

, Hirshkowitz

, Green

, McEvoy

, Chan

, Gevins

, Kay

, Bloch

, Crabtree

, Dement

(2012) Effects of continuous positive airway pressure on neurocognitive function in obstructive sleep apnea patients: The Apnea Positive Pressure Long-term Efficacy Study (APPLES). Sleep 35, 1593–1602.

13.

Aaronson

, Hofman

, van Bennekom

, van Bezeij

, van den Aardweg

, Groet

, Kylstra

, Schmand

(2016) Effects of continuous positive airway pressure on cognitive and functional outcome of stroke patients with obstructive sleep apnea: A randomized controlled trial. J Clin Sleep Med 12, 533–541.

14.

Barbe

, Mayoralas

, Duran

, Masa

, Maimo

, Montserrat

, Monasterio

, Bosch

, Ladaria

, Rubio

, Medinas

, Hernandez

, Vidal

, Douglas

, Agusti

(2001) Treatment with continuous positive airway pressure is not effective in patients with sleep apnea but no daytime sleepiness. a randomized, controlled trial. Ann Intern Med 134, 1015–1023.

15.

Bardwell

, Ancoli-Israel

, Berry

, Dimsdale

(2001) Neuropsychological effects of one-week continuous positive airway pressure treatment in patients with obstructive sleep apnea: A placebo-controlled study. Psychosom Med 63, 579–584.

16.

Pan

, Deng

, Xu

, Liu

(2015) Effects of continuous positive airway pressure on cognitive deficits in middle-aged patients with obstructive sleep apnea syndrome: A meta-analysis of randomized controlled trials. Chin Med J (Engl) 128, 2365–2373.

17.

Kylstra

, Aaronson

, Hofman

, Schmand

(2013) Neuropsychological functioning after CPAP treatment in obstructive sleep apnea: A meta-analysis. Sleep Med Rev 17, 341–347.

18.

Jadad

, Moore

, Carroll

, Jenkinson

, Reynolds

, Gavaghan

, McQuay

(1996) Assessing the quality of reports of randomized clinical trials: Is blinding necessary? Control Clin Trials 17, 1–12.

19.

Barnes

, McEvoy

, Banks

, Tarquinio

, Murray

, Vowles

, Pierce

(2004) Efficacy of positive airway pressure and oral appliance in mild to moderate obstructive sleep apnea. Am J Respir Crit Care Med 170, 656–664.

20.

Dalmases

, Sole-Padulles

, Torres

, Embid

, Nunez

, Martinez-Garcia

, Farre

, Bargallo

, Bartres-Faz

, Montserrat

(2015) Effect of CPAP on cognition, brain function, and structure among elderly patients with OSA: A randomized pilot study. Chest 148, 1214–1223.

21.

Engleman

, Martin

, Kingshott

, Mackay

, Deary

, Douglas

(1998) Randomised placebo controlled trial of daytime function after continuous positive airway pressure (CPAP) therapy for the sleep apnoea/hypopnoea syndrome. Thorax 53, 341–345.

22.

Engleman

, Kingshott

, Wraith

, Mackay

, Deary

, Douglas

(1999) Randomized placebo-controlled crossover trial of continuous positive airway pressure for mild sleep Apnea/Hypopnea syndrome. Am J Respir Crit Care Med 159, 461–467.

23.

Gast

, Schwalen

, Ringendahl

, Jörg

, Hirshkowitz

(2006) Sleep-related breathing disorders and continuous positive airway pressure–related changes in cognition. Sleep Med Clin 1, 499–511.

24.

Harmell

, Neikrug

, Palmer

, Avanzino

, Liu

, Maglione

, Natarajan

, Corey-Bloom

, Loredo

, Ancoli-Israel

(2016) Obstructive sleep apnea and cognition in Parkinson’s disease. Sleep Med 21, 28–34.

25.

Joyeux-Faure

, Naegele

, Pepin

, Tamisier

, Levy

, Launois

(2016) Continuous positive airway pressure treatment impact on memory processes in obstructive sleep apnea patients: A randomized sham-controlled trial. Sleep Med 24, 44–50.

26.

Martinez-Garcia

, Chiner

, Hernandez

, Cortes

, Catalan

, Ponce

, Diaz

, Pastor

, Vigil

, Carmona

, Montserrat

, Aizpuru

, Lloberes

, Mayos

, Selma

, Cifuentes

, Munoz

, Spanish Sleep Network (2015) Obstructive sleep apnoea in the elderly: Role of continuous positive airway pressure treatment. Eur Respir J 46, 142–151.

27.

McMillan

, Bratton

, Faria

, Laskawiec-Szkonter

, Griffin

, Davies

, Nunn

, Stradling

, Riha

, Morrell

(2014) Continuous positive airway pressure in older people with obstructive sleep apnoea syndrome (PREDICT): A 12-month, multicentre, randomised trial. Lancet Respir Med 2, 804–812.

28.

Monasterio

, Vidal

, Duran

, Ferrer

, Carmona

, Barbe

, Mayos

, Gonzalez-Mangado

, Juncadella

, Navarro

, Barreira

, Capote

, Mayoralas

, Peces-Barba

, Alonso

, Montserrat

(2001) Effectiveness of continuous positive airway pressure in mild sleep apnea-hypopnea syndrome. Am J Respir Crit Care Med 164, 939–943.

29.

Poggel

, Strasburger

(2004) Visual perception in space and time–mapping the visual field of temporal resolution. Acta Neurobiol Exp (Wars) 64, 427–437.

30.

Usui

, Haji

, Maruyama

, Katsuyama

, Uchida

, Hozawa

, Omori

, Tsuji

, Kawashima

, Taira

(2009) Cortical areas related to performance of WAIS Digit Symbol Test: A functional imaging study. Neurosci Lett 463, 1–5.

31.

Lau

, Eskes

, Morrison

, Rajda

, Spurr

(2010) Executive function in patients with obstructive sleep apnea treated with continuous positive airway pressure. J Int Neuropsychol Soc 16, 1077–1088.

32.

Weng

, Tsai

, Chen

, Lin

, Yang

, Tsai

, Yang

(2014) Mapping gray matter reductions in obstructive sleep apnea: An activation likelihood estimation meta-analysis. Sleep 37, 167–175.

33.

Kim

, Joo

, Suh

, Kim

, Hong

(2016) Effects of long-term treatment on brain volume in patients with obstructive sleep apnea syndrome. Hum Brain Mapp 37, 395–409.

34.

Gagnadoux

, Le Vaillant

, Paris

, Pigeanne

, Leclair-Visonneau

, Bizieux-Thaminy

, Alizon

, Humeau

, Nguyen

, Rouault

, Trzepizur

, Meslier

, Institut de Recherche en Sante Respiratoire des Pays de la Loire Sleep Cohort Group (2016) Relationship between OSA clinical phenotypes and CPAP treatment outcomes. Chest 149, 288–290.

35.

Castronovo

, Scifo

, Castellano

, Aloia

, Iadanza

, Marelli

, Cappa

, Strambi

, Falini

(2014) White matter integrity in obstructive sleep apnea before and after treatment. Sleep 37, 1465–1475.

36.

Deering

, Liu

, Zamora

, Hamilton

, Stepnowsky

(2017) CPAP adherence is associated with attentional improvements in a group of primarily male patients with moderate to severe OSA. J Clin Sleep Med 13, 1423–1428.

37.

Baratta

, Pastori

, Bucci

, Fabiani

, Brunori

, Loffredo

, Lillo

, Pannitteri

, Angelico

, Del Ben

(2018) Long-term prediction of adherence to continuous positive air pressure therapy for the treatment of moderate/severe obstructive sleep apnea syndrome. Sleep Med 43, 66–70.

38.

Berkani

, Dimet

(2015) [Acceptability and compliance to long-term continuous positive pressure treatment]. Rev Mal Respir 32, 249–255.

39.

O’Donoghue

, Wellard

, Rochford

, Dawson

, Barnes

, Ruehland

, Jackson

, Howard

, Pierce

, Jackson

(2012) Magnetic resonance spectroscopy and neurocognitive dysfunction in obstructive sleep apnea before and after CPAP treatment. Sleep 35, 41–48.

40.

Liguori

, Chiaravalloti

, Izzi

, Nuccetelli

, Bernardini

, Schillaci

, Mercuri

, Placidi

(2017) Sleep apnoeas may represent a reversible risk factor for amyloid-beta pathology. Brain 140, e75.

41.

Weaver

, Maislin

, Dinges

, Bloxham

, George

, Greenberg

, Kader

, Mahowald

, Younger

, Pack

(2007) Relationship between hours of CPAP use and achieving normal levels of sleepiness and daily functioning. Sleep 30, 711–719.

42.

Gulati

, Ali

, Davies

, Quinnell

, Smith

(2017) A prospective observational study to evaluate the effect of social and personality factors on continuous positive airway pressure (CPAP) compliance in obstructive sleep apnoea syndrome. BMC Pulm Med 17, 56.

43.

Boyd

, Upender

, Walters

, Goodpaster

, Stanley

, Wang

, Chandrasekhar

(2016) Effective Apnea-Hypopnea Index (“Effective AHI”): A new measure of effectiveness for positive airway pressure therapy. Sleep 39, 1961–1972.

44.

Engleman

, Wild

(2003) Improving CPAP use by patients with the sleep apnoea/hypopnoea syndrome (SAHS). Sleep Med Rev 7, 81–99.

45.

Garbarino

, Scoditti

, Lanteri

, Conte

, Magnavita

, Toraldo

(2018) Obstructive sleep apnea with or without excessive daytime sleepiness: Clinical and experimental data-driven phenotyping. Front Neurol 9, 505.

46.

Zinchuk

, Gentry

, Concato

, Yaggi

(2017) Phenotypes in obstructive sleep apnea: A definition, examples and evolution of approaches. Sleep Med Rev 35, 113–123.