Introduction

Obstructive sleep apnea syndrome (OSAS) is characterized by recurrent episodes of partial or complete airflow restraint during sleep [1]. OSAS with excessive daytime sleepiness occurred in 6% (range, 3–18%) of men and in 4% (range, 1–17%) of women. The prevalence increased with time and OSAS was reported in 37% of men and in 50% of women [2]. The pathophysiology of OSAS involves both anatomical factors and functional factors, such as upper airway narrowing, defective activation of upper airway dilator muscles [3]. In the diagnosis of OSAS, the number of apneas per hour of sleep (apnea index), excluding time awake, should exceed five [4]. The apnea/hypoapnea index (AHI) is acquired by an overnight polysomnography (PSG) that also consent to obtain several sleep variables, including the number of awakenings during the total sleep time and the time as well as time in each sleep stage as a percentage of total sleep time [3]. In patients with severe OSAS, the AHI may be greater than 50. A frequent symptom is the excessive daytime sleepiness, evaluating by Epworth Sleepiness Scale, a simple, self-administered questionnaire which is shown to provide a measurement of the subject’s genera1 level of daytime sleepiness [5].

Continuous positive airway pressure (CPAP) [6] is typically the first-line treatment recommended for OSAS [7]. It consists of a nasal mask attached to a pneumatic pump that is able to improve oxygen saturation and reduce sleep fragmentation [8]. OSAS is associated with an increased risk of serious medical conditions, such as vascular disease (hypertension, heart disease, and stroke), but also psychiatric disorders (depression and anxiety) [9]. Indeed, OSAS patients present clinical features including snoring, sleep disruption, nocturnal hypoxemia, cardiovascular complications, irritability, and vigilance impairment that may extend from the simple inability to perform everyday tasks to a real daytime sleepiness [10]. Moreover, OSAS is associated with cognitive impairment (CI) such as deficit in attention, executive functions, and memory [11]. The onset of neuropsychological impairments remains unclear and controversial, maybe due to the lack of correlation between measures of a given deficit and the progressive pathogenic factors [12].

This descriptive review focused on literature studies that investigated relationship between OSAS and cognitive impairment deepening potential anathomical mechanism of this association.

Materials and methods

Search strategy

This research was conducted on the presence of cognitive impairment in OSAS patients. Studies were identified by searching on PubMed database (1991, year of the first-related published article-February 2020). The search combined the following terms: (“obstructive sleep apnea”[All Fields] OR “sleep apnea, obstructive”[MeSH Terms] OR (“sleep”[All Fields] AND “apnea”[All Fields] AND “obstructive”[All Fields]) OR “obstructive sleep apnea”[All Fields] OR (“obstructive”[All Fields] AND “sleep”[All Fields] AND “apnea”[All Fields])) AND (“cognitive dysfunction”[MeSH Terms] OR (“cognitive”[All Fields] AND “dysfunction”[All Fields]) OR “cognitive dysfunction”[All Fields] OR (“cognitive”[All Fields] AND “impairment”[All Fields]) OR “cognitive impairment”[All Fields]) AND (“adult”[MeSH Terms] OR “adult”[All Fields]). The search terms were identified as title and abstract. All articles were evaluated based on title, abstract, and text. Studies that examined the relationship between OSAS and cognitive impairment were included, after they fulfilled the following criteria:

  • Published peer-reviewed research;

  • The sample population included OSAS patients;

  • Studies specifically assessed the relationship between OSAS and cognitive impairments;

We imposed the following additional exclusion criteria:

case studies and meta-analysis;

  • studies that used only screening test (Mini Mental State Examination-MMSE or Montreal Cognitive Assessment—MoCA) for the neuropsychological evaluation

  • studies including children and/or adolescents defined as participants less than 18 years of age.

Results

Of 190 studies identified only 17 met the inclusion criteria (Fig. 1). All studies conducted research on 603 OSAS patients and 396 Health Controls (HCs) (Table 1). All OSAS patients were non-demented and free of other neurological and psychiatric diseases. They fulfilled diagnostic criteria for OSAS according to the Association of Sleep Disorder Centers. HCs were volunteers with no history of neurological diseases and they were matched for age, education, and sex. OSAS patients and HCs were within a range of age between 18 and 65 years and had at least 5 years of education.

Fig. 1
figure 1

Search and selection of eligible articles

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Table 1 Studies assessing cognitive impairment in OSAS patients
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The neuropsychological functions were evaluated by 34 different standardized tests (Table 2). Five tests evaluated global functioning; memory domain was assessed by seven tests; attentional domain was investigated by seven tests; 13 tests were used to estimate the executive functions; visuo-constructive abilities were evaluated by four different tests.

Table 2 Tests used for neuropsychological assessment
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Seven studies used neuro-imaging instrument to explore structural and functional brain changes in OSAS patients.

Neuropsychological functions

The majority of studies investigated found neuropsychological deficits in memory, attention, executive functions, and visuo-constructive abilities. In contrast, language abilities and global cognitive functioning were spared. The cognitive profile of these patients changed due to the severity of the syndrome: severe OSAS patients with AHI > 30 showed worse performance in neuropsychological tests than moderate OSAS patients (AHI: 10–30) and both patients groups exhibited poorer performance than HCs. These findings demonstrate a consistent relationship between OSAS severity and cognitive impairment. In particular, attention/vigilance and global cognitive functioning seem to be more related to measure of severity [13].

We have divided studies according to the different neuropsychological functions investigated.

Memory

Some studies have reported in OSAS patients deficits in verbal memory [14,15,16,17], visual episodic memory [14, 18], and semantic memory [3, 14, 17,18,19,20], suggesting deficit in learning new information.

Twigg et al. [21] investigated memory and attention in a large group of 60 OSAS patients and 60 HCs using an overnight PSG and to an extent memory battery. The results showed in OSAS patients deficit in immediate and delayed recall, but normal recognition memory and retention of information over time in the logical memory test. Working memory and attention appeared to be unaffected in OSAS patients.

Edwards et al. [22] investigated the relationship between the level of night plasma cortisol and neuropsychological deficit in 55 OSAS patients. A neuropsychological battery, assessed 7 cognitive domains, was administered to each patient. Results showed that the OSAS performance at neurocognitive tests was poorer than HCs performance. In addition, higher levels of cortisol during the nighttime were associated with neurocognitive impairment, especially regarding learning abilities, memory, and working memory. Exposure to high levels of glucocorticoids in the setting of healthy aging was associated with deficits in memory and structural changes to the hippocampus [23, 24].

In Delhikar et al. [25], a particular kind of memory was assessed in OSAS patients. Authors have hypothesized the presence of autobiographical memory deficit in population who suffered of obstructive apnea syndrome. Findings demonstrated that in OSAS patients, autobiographical memory impairments were prevalent, in comparison to healthy controls. Specifically, OSAS participants had significantly poorer semantic recall of early adult life. These cognitive impairment is related to higher depression levels.

Attention

Patients with OSAS seemed affected in a wide range of attentional processes including sustained and divided attention. Kotterba et al. [26] studied vigilance, alertness, selective attention, divided attention, and permanent attention in 31 male OSAS patients using the Wiener Testsystem (WT, to evaluate alertness, selective attention, and permanent attention) and the Zimmermann Testbatterie (ZT, to evaluate vigilance and divided attention). In addition, visual evoked-related potentials were recorded while the patients have to conduct a computer tasks and P300 component was evaluated. The results showed that vigilance parameters of OSAS patients were not significantly different from HCs; however, patient had worse scores in all attention parameters, especially regarding alertness and continuous attention. In addition, P300 component of the event-related potentials was prolonged.

In the study by Shpirer et al. [1], 40 OSAS patients were tested attention domains, working memory, and shifting with Conner’s Continuous Performance Test (CPT) [27], Trail Making Test, versions A&B (TMT-A, TMT-B) [28], and Digit Span subtest from WAIS-III [29]. To estimate executive functioning were used The Tower of London Test (ToL), the Wisconsin Card Sorting Test (WCST) [30], and Phonological and Semantic fluency test. Results showed that patients’ performance was significantly worse on measures of attention and executive functions compared to the HCs. Attention deficits significantly correlated with OSAS severity as determined by the AHI, the average SpO2 and the percent time spent with SpO2 < 90%.

Devita et al. [31] investigated cognitive and motor reactions time in 33 OSAS patients and 30 HCs. They used four computerized tasks to evaluate information processing speed in several difficulties and to test participant’s reaction time to a moving stimulus with a congruent or incongruent motor response. Patients underwent to MoCA test to estimate global cognitive functioning. In this study, the cognitive component of RTs would correspond to the decision time and to the premotor time, while the motor component of RTs would correspond to the selection and the implementation of an appropriate motor response. OSAS patients performed worse than controls at the MoCA test, showing that this syndrome globally impairs cognitive functioning and slower reaction time only for the motor component.

In OSAS patients, motor slowdown could had a substantial impact on daily living by worsening cognitive functions.

Executive functions

OSAS patients show impairments in executive functions. Chou et al. [32] used the computerized versions of the Flanker task [33] in 25 OSAS patients and 12 HCs to evaluated executive functions. Compared with HCs, the patients with OSAS presented a significantly lower correct response rate in congruent and incongruent trials. The post-error correction rate was significantly lower in the patients with OSAS than in the controls. Action monitoring function was impaired in the patients with OSAS and that sleep fragmentation was a major determinant of impaired action monitoring in these patients.

Tulek et al. [34] also investigated executive functions in 24 OSAS patients and 14 HCs using Flanker task, Simon task [35], and Stroop task [36]. For each task, the average error rate (ER) and reaction time (RT) of correct responses were measured. Results indicated that attentional control was partially dysfunctional in OSAS patients due to frontal lobe dysfunction.

Zhang et al. [37] investigated Working Memory (WM) in 20 HCs and 24 OSAS patients, divided into two groups according to severity degree of the syndrome (12 mild OSAS and 12 sever OSAS). Subjects underwent a modified Sternberg Paradigm, a visual S1–S2 matching paradigm when the information in the second stimulus (S2) conflicts with that of the first stimulus (S1). During this task, ERP component N270 was recorded. N270 is elicited when the probe item conflicted with the preceding memorized item, and it is encoded in WM. Results showed that for OSAS patients, the negative component N270 elicited in low- and high-conflict conditions was significantly reduced than HCs, suggesting that WM was impaired.

Neuro-imaging studies

Only three of the 17 studies have used neuro-imaging investigations, finding brain tissue damage that could explain cognitive performance in OSAS patients.

Yaouhi et al. [11] assessed functional and morphological brain’s differences between 16 OSAS patients and 14 HCs using the optimized voxel-based morphometry procedure for the MRI data, resting-state 18F-fluoro-2-deoxy-D-glucose positron emission tomography (18FDG-PET) with correction for partial volume effects (PVEs) and voxel-based analyses. Cerebral data revealed gray matter loss in the frontal and temporo–parieto–occipital cortices, the thalamus, hippocampal region, some basal ganglia, and cerebellar regions, mainly in the right hemisphere. Moreover, authors found a decrease in brain metabolism of the precuneus, the middle and posterior cingulate gyrus, and the parieto–occipital cortex and prefrontal cortex. These results could explain the impairment in memory and in motor domains that was found in these sample of OSAS patients which recorded objective daytime somnolence.

Torelli et al. [38] evaluated brain morphological changes in 16 OSAS patients compared to 14 HCs. All the participants underwent to 3.0 T brain magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) [39] to investigate white matter and voxel-based morphometry (VBM) [11, 39,40,41] to analyze gray matter. Brain investigations revealed that cortical gray matter, right and left hippocampus, right and left caudate, and lateral temporal regions of OSAS patients had a significant smaller volume than HCs. All subjects were also undergoing to neuropsychological tests to assess memory (Rey Auditory Verbal Learning Test, Digit span backward and forward, Visual Memory Test, Rey-Osterreith Figure recall), executive functions (Stroop color/word test, phonological fluency), attention (Stroop color/word test), language (semantic fluency), praxia (copy drawing, Rey-Osterreith Figure copy), and non-verbal learning. Results showed that patients had a significant worse performance than HCs in memory and executive functions tests. Data confirmed that CI in patients with moderate-severe OSAS were associated with brain tissue damage. Moreover, a metabolic impairment in the deep white matter seems to selectively affected in OSAS [42]; other studies demonstrated a reduction in absolute concentrations of in N-acetylaspartate (NAA) and choline (Cho) in the FWM of OSAS patients when compared to HCs that indicates axonal loss and/or dysfunction [43, 44]. Zhang et al. [45] used fMRI to estimate resting-state activity and functional disconnection of the right anterior insula in 24 OSAS patients and 21 HCs. The right anterior insula (AIns) is a critical node of the salience network (SN) that serves to switch between the central executive network (CEN) and the default mode network (DMN) through their anatomical connections, which is important for cognitive performance. Results demonstrate a functional disconnection between the right AIns and the DMN in OSAS; also, the decreased rsFCs between the right AIns and the critical nodes of the DMN were associated with OSAS severity and impaired working memory performance.

Discussion

OSAS is a respiratory disorder identified by partial or total obstruction of the airway during sleep [46]. It causes arousals, intermittent hypoxemia and hypercapnia, and excessive daytime sleepiness [47]. OSAS is also associated with poorer cognitive performances [48].

The neuropsychological profile of OSAS patients is defined by cognitive deficits [49] associated with functional and morphological brain changes, involving gray and white matter, especially in frontal regions [41]. Studies [50,51,52,53] showed altered functional connections (FC) in the whole-brain areas in OSAS subjects. The most affected FC were related to cerebellar regions, but the declines were not site specific, and appeared across whole brain regions. These authors found many brain networks with reduced connectivity such as bilateral anterior cingulate cortex (ACC), left insula, left supplementary motor area (SMA), right para-hippocampal gyrus, and right superior temporal pole. In contrast, increased FC in OSAS emerged in temporal–parietal networks. Finally, reduced FC or increased FC also appeared in temporal–occipital networks in OSAS. Lesser FC (the right inferior parietal lobule, right supramarginal gyrus, right calcarine, and left fusiform gyrus) and higher FC (the bilateral calcimine, bilateral fusiform gyrus, bilateral paracentral lobule, and left pre- and post-central gyrus) were also found in parietal–occipital areas of OSAS subjects. These findings indicated that OSAS subjects had abnormal resting-state FC in various brain regions largely related to autonomic, affective, executive, sensorimotor, and cognitive regulatory functions, areas that appeared with structural injury in previous studies of OSAS subjects, as well as areas that appeared abnormal resting-state FC. In comparison to HCs, OSAS patients showed gray matter atrophy and para-hippocampal and frontotemporal cortex seems to be the brain region most affected [54].

Pathological basis for underlying neuropsychological comorbidities in OSAS is poorly understood.

Some authors suggested that CI are induced by nocturnal hypoxemia and oxygen deprivation in several brain areas during sleep [1, 55]; other studies associated CI to daytime vigilance impairment due to excessive sleepiness [31, 56, 57]. In this case, CI seems to be improved through the use of continuous positive airway pressure (CPAP) that is defined as the gold standard treatment for OSAS. CPAP may slow cognitive decline in patients with comorbid neurodegenerative disorders and OSAS [58]. Indeed, CPAP treatment is associated with improvements in attention and memory domains, but not in executive functions [54]. Only two of the 16 studies have compared performance before and after CPAP treatment, finding not only improvement in alertness, vigilance, and memory, but also increase of gray matter volume in hippocampal and frontal structures [26, 56].

The contribution of nocturnal hypoxemia and vigilance impairment on the CI differed between moderate and severe OSAS. In fact, progressively increasing deficits from moderate to severe include attentional tasks, immediate and delayed recall of verbal and visual materials, planning and sequential thinking. Deficits appeared only in severe OSAS were dampening of general intellectual functioning and executive functions (especially shifting and constructive abilities). These results suggested that both nocturnal hypoxemia and vigilance impairment contribute to CI in OSAS patients, but a different level. Attentional and memory deficits seem primarily related to a decrease of daytime vigilance, while dampening of general intellectual performances and executive functions deficits were related to the nocturnal hypoxemia [3].

This review focused on cognitive impairment in OSAS patients. Neuropsychological deficits include attention, memory, and executive functions.

The studies in this review involve only a limited number of participants, considering the incidence of the syndrome and the sample heterogeneity. Plus, the different tests used did not always permit a comparison between studies. Moreover, only few studies used neuro-imaging investigation; for this reason, there is still lack of correlation between neuropsychological deficits and brain changes. Future research should be conducted on the mechanisms underlying CI in OSAS in order to find preventive measure and rehabilitation for these patients. In addition, further investigations needed to clarify the relation between hypoxemia and vigilance alterations on cognitive impairment in OSAS patients.