Background
Obstructive sleep apnea (OSA) is a common sleep disorder caused by repetitive episodes of upper airway obstruction due to an obstruction or increased airway resistance [
1], with an incidence rate of 2%-3% in children [
2], 33.9% in men, and 17.4% in women [
3]. The risk factors of OSA include adenoid tonsil hypertrophy (especially in children), obesity, race, craniofacial deformity, and neuromuscular diseases [
4]. In addition, OSA can lead to complications like cognitive dysfunctions, excessive daytime sleepiness, nightly snoring episodes, apneas, choking, increased effort to breathe, hyperextension of the neck, restless sleep, night sweats, nocturnal enuresis, and parasomnias [
5,
6]. These complications in children, especially cognitive dysfunctions have arisen widespread worries and anxieties among parents [
6] and attracted extensive research recently.
Cognitive dysfunctions, including irritability, impaired attention, emotional instability, decreased intelligence, and learning disabilities, is a major complication of OSA in children and can usually be measured with tests such as the Wechsler Adult Intelligence Scale-Revised, the Psychomotor Vigilance Task, and the Steer Clear Performance Test [
7]. Zhao et al. [
8] used the China-Wechsler Younger Children Scale of Intelligence (C-WYCSI) and China-Wechsler Intelligence Scale (C-WISC) for Children and found that mild to moderate OSA was associated with an increased risk of cognitive dysfunctions in children, especially in those < 6 years old. It has been shown that treatment of OSA results in improvements in attention and likely improvements in cognitive abilities [
9‐
11]. Cognitive dysfunctions in children with OSA are attributed to neuronal structural abnormality and dysfunction, such as abnormal neural activities in some brain regions [
12,
13], neuronal injury in the hippocampus and frontal cortex [
14], regional grey matter reduction [
15], brain white matter integrity impairment [
16] and altered regional brain cortical thickness [
17], damage caused by intermittent hypoxia, and hypercapnia in certain brain regions [
10,
18]. In addition, these neuronal changes were always more pronounced in children with moderate-severe OSA. Therefore, early diagnosis and treatment of pediatric OSA are very important. There exists subjective error due to the individual differences in children’s compliance and examiners in these scales. As a result, we need a more objective and convenient measure of neurocognitive function to enable risk and vulnerability stratification during the initial evaluation of snoring and to assess cognitive dysfunction in children with OSA.
As a neuroprotective biomarker, insulin-like growth factors 1 (IGF-1) levels were higher in children with OSA and no neurocognitive deficits. Besides, IGF-1 levels were lower in children with OSA and cognitive deficits [
19]. As for biomarkers of Alzheimer's disease, Amyloid β protein 42 (Aβ42) and pre-senilin 1 (PS1) levels were found to increase in pediatric OSA and declined after treatment of OSA with adenotonsillectomy [
20].
Recently, some biomarkers of brain injury have been detected in adults with OSA. In a study of 119 male Vietnam War veterans, Elias et al. [
21] found that Amyloid β (Aβ) was higher in the OSA group than in the control group quantified by the standardized uptake value ratio of
18F-florbetaben. Aβ40 and Aβ42 levels in cerebrospinal fluid (CSF) were found to be lower in OSA patients than in controls, and the apnea–hypopnea index (AHI) was correlated to the Aβ42/Aβ40 ratio [
22]. Total tau concentrations in plasma were elevated in young participants with moderate-severe OSA than in young participants with mild or no OSA [
23].
Neurofilament light (NfL) is a marker of neuro-axonal damage and can be measured in CSF and serum [
24]. As an important marker of brain injury, NfL has been tested and proposed as a promising biomarker of neuroaxonal injury in various neurodegenerative diseases, such as traumatic brain injury [
25], subarachnoid hemorrhage [
26], sports-related injury [
27], military injury [
28], and ageing-related changes [
24]. Still, the NfL level in children with OSA has not been reported yet.
Therefore, this study aimed to investigate the serum levels of NfL and tau in children with or without OSA and explore their relationship with cognitive dysfunctions potentially caused by OSA. The results of this study could suggest objective blood diagnostic biomarkers of cognitive dysfunctions in children with OSA.
Discussion
OSA in children can potentially cause cognitive dysfunctions [
9‐
11], but the available cognition assessment tools exist subjective measurement error. NfL is a marker of neuro-axonal damage [
24‐
28], but there are no reports of NfL for OSA. This study aimed to investigate the serum levels of NfL and tau in children with or without OSA and explore their relationship with cognitive dysfunctions potentially caused by OSA. Children with OSA had elevated serum levels of NfL compared with children diagnosed with adenotonsillar hypertrophy but without OSA. NfL correlated with PSG (AHI, OAI, OAHI, SaO
2, and RAI) and C-WISC (VIQ, PIQ and FIQ) parameters. Since the eligibility criteria excluded the influence from comorbidities such as the genetic syndromes, history of sedatives and, neurological abnormalities, the most likely etiology of increased concentrations of NfL was OSA. Therefore, the results suggest that serum NfL levels are associated with the severity of cognitive dysfunctions in children diagnosed with adenotonsillar hypertrophy and might be a candidate noninvasive, objective marker to identify cognitive dysfunctions in children with OSA.
Recently, some other approaches were used to assess OSA with cognitive dysfunctions such as imaging and serologic examinations [
4]. Some researchers used magnetic resonance imaging (MRI) to assess brain structural and functional changes in OSA. The cerebral metabolic rate of oxygen was found to be decreased in OSA patients compared with controls in response to apnea [
34]. In addition, OSA patients had significantly altered functional connectivity in multiple brain regions, showing less efficient integration and declined regional topological properties and specialization characteristics [
35]. Based on MRI, cognitive dysfunctions in children with OSA were reported to be associated with neuronal structural abnormality and dysfunction, such as abnormal neural activities in some brain regions [
12,
13], neuronal injury in the hippocampus and frontal cortex [
14], regional grey matter reduction [
15], brain white matter integrity impairment [
16] and altered regional brain cortical thickness [
17]. Serologic examinations also found that Aβ and tau were higher in the OSA group than in the control group in children or adults [
20,
21,
23].
NfL, a novel marker of neuronal and axonal injuries, has attracted widespread attention and has been studied in a wide range of neurologic disorders [
24,
25,
28]. A study showed that serum NfL levels are stable in people below 60 years but significantly increased in people above 60 years [
24]. Moreover, the NfL levels are significantly elevated in traumatic brain injury patients and have a good diagnostic performance for traumatic brain injury, with 92.3% sensitivity and 88.9% specificity [
25]. In subarachnoid hemorrhage, plasma NfL levels are associated with disease severity during early stages and with poor 30-day functional outcome and mortality [
26]. Some studies showed that NfL provides additional information to help discriminate clinical severity in dementia, particularly as the diagnosis progresses from mild cognitive impairment to Alzheimer’s disease (AD), and NfL starts to increase 10 years before AD diagnosis [
36,
37]. Therefore, plasma NfL levels can be regarded as a noninvasive biomarker to identify those at risk for mild cognitive impairment. Serum NfL appears to be an independent determinant of future brain volume loss [
24]. Meanwhile, some researchers also found that grey matter volumes were reduced in pediatric obstructive sleep apnea [
17,
38]. Macey et al. [
17] found significant grey matter volume reduction in OSA throughout the superior frontal and prefrontal areas, superior and lateral parietal cortices, and superior temporal lobe.
In the present study, the serum levels of NfL were measured in children diagnosed with adenotonsillar hypertrophy, and the NfL levels in OSA were increased compared with non-OSA, which strongly suggests that OSA can indeed lead to brain injury. Our results also showed that the NfL levels were correlated with VIQ, PIQ and FIQ, indicating that the NfL levels represented the cognitive status evaluated by the C-WISC. NfL levels might reflect the severity of cognitive dysfunctions in children with OSA. Together with previous reports [
14,
17,
39], these results suggested that OSA can cause brain injuries in children to some extent, which may be the cause of cognitive dysfunctions. NfL might be a novel biomarker of cognitive dysfunctions in children with OSA. Interestingly, the results also showed that the NfL levels were also correlated with the courses of snoring, mouth breathing and choking, A/N ratio, tonsils size, PSG parameters, and C-WISC parameters, which indicated that these symptoms and signs might be hazard factors of brain injuries caused by OSA in children.
Chronic intermittent hypoxia, sleep fragmentation, and inflammatory activation are the main pathophysiological mechanisms of OSA. In multiple regression models, VIQ, PIQ and FIQ were significantly associated with NfL. VIQ and PIQ were also significantly associated with minimum SaO2 and RAI. It is noteworthy that AHI and OAHI, which are used as the objective indicator for the diagnosis of OSA, were not selected as related features in LASSO models. These analyses show that the cognitive deficits associated with pediatric OSA may be more closely related to the drop in blood oxygen levels and sleep fragmentation, rather than sleep apnea/hypopnea.
PSG is the golden diagnostic golden standard of OSA [
31,
32], but the evaluation of cognition in children is complex and arduous. There are some questionnaire tools used for the evaluation of cognitive functions in children, such as Conners’ Parents Rating Scale, Child Behavior Checklist, Differential Ability Scale, Developmental Neuropsychological Assessment to assess neurobehavioral problems [
14], WISC-III, WISC-IV [
39], Hong Kong WISC, Forward Span of the Spatial Span subtest of the Wechsler Memory Scale to assess working memory tasks and visuospatial sketchpad [
8], and the C-WISC [
8,
40], but there is no gold standard among them. Besides, there exist subjective errors and they are not sensitive enough for early cognitive dysfunctions. Therefore, a more objective and time-efficient way to evaluate neurocognitive function is required to enable risk and vulnerability stratification to assess cognitive outcomes in children.
Serologic examinations are relatively cheap, fast, and accessible, and the development of new serologic biomarkers is essential for diagnosing OSA. Here, the results showed that the AUC of NfL was 0.816 (0.736–0.897), indicating that NfL had relatively good sensitivity and specificity as an accessible diagnostic and screening marker of cognitive dysfunction in OSA patients.
A few studies have reported increased serum and cerebrospinal fluid levels of tau in patients with OSA compared to control subjects [
23,
41], which showed that tau might be an indicator of cognitive dysfunctions in patients with OSA. Nevertheless, in the present study, no significant differences in tau levels were identified between the two groups. It might be due to the shorter average duration of OSA in children than in adults.
It is the first study investigating the association between NfL and pediatric OSA. Considering that this study was a retrospective case–control study and the sample size was relatively small, prospective multicenter randomized controlled trials with a larger sample size are needed to confirm the NfL cutoff levels for the diagnosis of OSA and evaluate whether NfL levels are associated with the severity of OSA in children. This study only included patients formally diagnosed with adenotonsillar hypertrophy and who underwent PSG, but whether NfL could be used for OSA-related cognitive dysfunctions screening in the general pediatric population remains to be determined. Future studies will also be necessary to explore the relationships between serum NfL levels and other cognitive evaluation tests in children diagnosed with adenotonsillar hypertrophy and OSA.
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