Cognitive deficits in adults with obstructive sleep apnea compared to children and adolescents

Overviews of the identified studies investigating cognitive deficits due to OSA in the adult population are presented in Tables 1 and 2. Unfortunately, the exact prevalence of the cognitive dysfunctions in adults with OSA is still unknown and varies widely depending on study design. For example, in one study (Saunamäki et al. 2009), most OSA patients performed at a normal level; only few patients had mild (2.5–12.5 %) or moderate-to-severe (5–15 %) cognitive dysfunction. In contrast, a prospective observational study reported that one in four newly diagnosed OSA patients had a severe and distinctive neuropsychological dysfunction (Antonelli Incalzi et al. 2004). Finally, Pierobon et al. (2008) reported that at least 59.2 % of obese OSA patients had at least one cognitive impairment. Therefore a large, multi-center study on the cognitive deficits in OSA patients, with and without obesity, is still required to accurately determine its prevalence.

According to a recent meta-analysis (Bucks et al. 2013), most published studies have identified executive functions, attention, and memory as the most affected cognitive domains in OSA. Moreover, a systematic review published by Saunamäki and Jehkonen (2007) stated that executive functioning is the most impaired cognitive domain in OSA in the adult population (Fig. 1).

Neuroimaging assessment in conjunction with neuropsychological studies can help us to confirm the cognitive deficits in OSA. The studies that have used such neuroimaging techniques are summarized in Table 2.

Zhang et al. (2011) assessed severe OSA patients with both neuropsychological and neuroimaging tests (i.e., functional magnetic resonance imaging, fMRI, during a brief visual delayed matching-to-sample task), and showed a reduced mismatch-related activation in frontal regions. This impairment correlated with the arousal index and hypoxia in these patients, suggesting that hypoxia may cause this cognitive deficit. In a similar study (Thomas et al. 2005), fMRI was used to map cerebral activation during a 2-back verbal working memory task. Working memory speed in OSA patients was significantly slower than in the control group and was associated with the absence of dorsolateral prefrontal cortex activation. Therefore, by combining these neuropsychological and neuroimaging tests, it was confirmed that working memory is affected in adults with OSA.

As the hippocampus and frontal cortex are closely associated with memory processes and executive functions, and are particularly susceptible to sleep fragmentation, hypoxemia and hypercapnia (Beebe and Gozal 2002), most studies show altered brain metabolism and neuronal loss in these areas in OSA patients. For example, Alchanatis et al. (2004) examined OSA patients using proton magnetic resonance spectroscopy (MRS) and found that the N-acetylaspartate-to-creatine ratio (indicative of axonal loss and/or dysfunction) and the choline-to-creatine ratio (indicative of myelin lipid loss and or/phospholipid metabolism dysfunction) were significantly lower in the frontal white matter of OSA patients compared controls. In regards to the frontal lobe, white matter lesions are known to be associated with a cognitive executive dysfunction, which may explain the irreversibility of some cognitive deficits related to OSA. Moreover, a study performed on hippocampal area metabolites (Bartlett et al. 2004) reported that in the left hippocampal area, the N-acetyl-containing:creatine-containing compound ratio was significantly increased in OSA subjects. As there was no significant difference in the hippocampal N-acetyl-containing compounds levels, the observed alterations were most likely due to a decrease in creatine-containing compounds. These lower levels of hippocampal creatine-containing compounds were correlated with a worse OSA severity and neurocognitive performance. Finally, using voxel-based morphometry, Morrell et al. (2003) reported a significantly lower gray matter concentration within the left hippocampus in right-handed OSA patients compared to controls. The results of these studies indicate the brain morphology changes in the hippocampus are associated with OSA.

Similarly, Yaouhi et al. (2009) reported that significant cerebral changes, as assessed by MRI, precede the onset of neuropsychological impairment in patients with OSA. Indeed, indications of axonal injury in axons linking major structures within the limbic system, pons, frontal, temporal, and parietal cortices and projections to and from the cerebellum have been reported in OSA patients (Macey et al. 2008). Torelli et al. (2011) also evaluated brain morphological changes and their relationship to neuropsychological test results in moderate to severe OSA patients. The volumes of cortical gray matter, as well as the size of the right hippocampus, right and left caudate, were smaller in OSA patients compared to the control group and correlated with poorer performance in several neuropsychological tests. In addition, when brain activation during a response inhibition test (i.e., a Go/No-go task) was examined using fMRI, OSA patients showed lower ability to withhold a response, and this was associated with decreased brain activation in the left postcentral gyrus, cingulate gyrus, and inferior parietal lobe, right insula and putamen (Ayalon et al. 2009). Therefore, different areas in the brain can be morphologically affected in OSA patients, and these changes correspond to differing cognitive deficits.

By combining neuropsychological assessment and neuroimaging studies, we can precisely identify the areas in the brain responsible for cognitive impairments in OSA patients. There should be more focus on identifying the particular areas in the brain that are responsible during assessment of OSA patients with cognitive deficits. Such combined studies would help us to determine whether these changes are due to hypoxemic episodes of OSA or other causes.

While there are only limited studies on cognitive deficits in children and adolescents, the accessible findings show that the type and intensity of symptoms presented in young patients vary according to age. Unfortunately, while there is substantial evidence confirming the presence of a cognitive deficit in school-aged children, the number of studies examining pre-school children is much lower (Jackman et al. 2012). A summary of the available studies on the cognitive deficits in children and adolescents with OSA is shown in Table 3.

In one of their studies, Jackman et al. (2012) focused on children (aged 3–5 years) with primary snoring and mild/moderate/severe OSA syndrome compared to non-snoring children. Overnight polysomnography and cognitive battery were applied, along with behavioral analyses. The authors reported that sleep-disordered breathing (SDB) of any severity was associated with poorer behavior, but not decreased cognitive performance. The authors also drew attention to the possible study limitations, such as the fact that during cognitive assessments of young children, it is often more difficult to keep them engaged in assessment procedures as they are also more easily distracted than older children. Also, children of this age may often refuse to complete subtests or are not sufficiently cooperative.

Jackman et al. (2012) also suggested that early treatment of OSA may prevent cognitive deficits arising later in childhood. Unfortunately, there is evidence that cognitive impairment is already found in children as young as 5 years. For example, Gottlieb et al. (2004) found that SDB symptoms are associated with poorer executive function and memory skills and lower general intelligence in children aged 5 years (using a parent-completed questionnaire, polysomnography, and standardized neurocognitive tests). Moreover, when school-aged children with SDB were treated with adenotonsillectomy, improvements in SDB after 4 years were concomitant with improvements in some areas of neurocognition, but not in academic ability or behavior (Biggs et al., 2014). Therefore, an earlier diagnosis (before age 5) and treatment may have prevented some of these cognitive deficits from occurring.

As mentioned above, there have been more studies on school-aged children. Bourke et al. (2011) found that neurocognitive deficits are common in children with SDB (aged 7–12 years) regardless of the disease severity. Archbold et al. (2004) examined 12 children with mild SBD (aged 8.0–11.9 years) and found they showed significant impairment in sustained attention and vigilance on a computerized continuous performance test. While a number of studies present cognitive domains that are similarly affected in both adults and children, such as executive functioning or attention, specific impaired domains for the pediatric population, such as phonological processing, have also been reported. For example, O’Brien et al. (2004) showed that children with SDB scored significantly lower than controls on the attention/executive function domain, and specifically on the visual attention and executive function. In addition, children with SDB scored significantly lower than controls on phonological processing, the skill that is critical for learning how to read. In a study performed a few years later by Hamasaki Uema et al. (2007), it was observed that children aged 6–12 years with OSA show worse Rey test scores, which could indicate deficits in a number of cognitive domains, such as visuo-spatial memory, attention, and working memory. In addition, Lau et al. (2015) found that verbal working memory impairment related to OSA in children may have a further negative impact on learning potential and neurocognitive development. However, it is important to note that Biggs et al. (2011) examined 127 children aged 7–12 years with SDB to find out whether the deficits in memory were due to parental overestimation, and found that parents of children with less severe SDB tend to overestimate their symptoms. This suggests that observation of deficits in working memory may be largely dependent on the assessment method, and that children with SDB may not be as impaired as previously thought.

Some unique cognitive deficits in school-aged children with OSA have been described compared with the adult population. For example, Kheirandish-Gozal et al. (2014) showed that cognitive and empathetic processing (as measured by a fMRI during a color-word Stroop task and an empathy task) was deteriorated in 10 children (aged 7–11 years) with polysomnographically diagnosed OSA. However, a much larger sample size is required to confirm this finding.

Another study in school-aged children found that children with OSA have a higher arousal index than controls (Miano et al. 2011). Therefore, they hypothesized that arousal is a defensive mechanism that may preserve cognitive function by counteracting the respiratory events at the expense of sleep maintenance. Moreover, they reported that children with OSA had a higher ADHD rating, which negatively correlated with the level of oxygen saturation during the night. This suggests a correlation between attention deficits and OSA in children, most likely due to hypoxia.

Similar to the findings in adults, neuroimaging or neuroelectrophysiological studies can confirm the cognitive deficits in children with OSA. For example, Quan et al. (2013) examined children with SDB by neurocognitive battery and electroencephalographic monitoring, and showed that long-term changes in executive function were undetectable by neuropscyhological testing, but were visible during neuroelectrophysiological monitoring. Moreover, in a study by Barnes et al. (2012), children with OSA underwent overnight sleep studies and neuropscyhological testing, as well as the oddball attention task, while event-related potentials (ERPs) were recorded. They concluded that specific ERPs during a single attention task can reliably identify the presence of OSA-associated cognitive dysfunction. According to authors, electrophysiological approaches during specific cognitive tasks may serve as simple, complementary, and reliable reporters of cognitive dysfunction associated with OSA in children.

The effects of obesity on cognitive deficits in children with OSA have also been investigated. In a study by Tan et al. (2014), 31 adolescents (aged 10–18 years) with OSA and obesity (mean BMI of 32.3 ± 4.9) were assessed according to intelligence, memory, learning, academic achievement, behavior, and executive functioning. The authors concluded that children with OSA and obesity may have an increased risk for some poorer educational and behavioral outcomes. In addition, Hannon et al. (2012) postulated that sleep fragmentation and poorer sleep quality have implications for neurocognitive functioning in obese adolescents. Similar conclusions were drawn by the research group from the Children’s Hospital of Philadelphia, who found that obese adolescents with OSA presented impaired executive and behavioral functions compared to controls, and were more likely to score in the clinically abnormal range on measures of neurobehavioral functioning (Xanthopoulos et al. 2014). Similarly, in the study performed by Vitelli et al. (2015), it was observed that in the group of children with OSA, the worst cognitive performance was found in the subgroup with comorbid obesity. According to the authors, these findings were very important, as this period of life is crucial for the development of proper frontal lobe functioning.

There are also other comorbidities described in the literature associated with OSA in children, such as Down syndrome (Lal et al. 2015). Among children with this condition, mean verbal IQ score was found to be lower in patients with comorbid OSA than in those without OSA, and performance on measures of cognitive flexibility was poorer (Breslin et al. 2014).

In summary, the cognitive dysfunctions in children focus on slightly different areas of cognition than in adults, such as behavioral and educational aspects, visual attention, and phonological processing, which are necessary for the proper intellectual development of a child. Based on the early changes in neuroimaging and neuropsychological presentation, these children should be treated early to prevent persistent, irreversible cognitive changes in the future. There should be more direct focus on assessing the cognitive functions in the youngest patients with OSA, however, due to their inability to verbally express their thoughts, there is limited ability for neuropsychological assessment.