Urinary Neurotransmitters Are Selectively Altered in Children With Obstructive Sleep Apnea and Predict Cognitive Morbidity

Abstract

Snoring is a very frequent complaint affecting 10% to 12% of all children 1 and is the primary symptom of obstructive sleep apnea (OSA). OSA is the occurrence of repeated events of partial or complete upper airway obstruction during sleep, leading to disruption of normal ventilation, and to hypoxemia and sleep fragmentation. The pathophysiology of pediatric OSA is multifactorial, but adenotonsillar hypertrophy with or without concurrent obesity constitutes the major pathophysiologic mechanism underlying OSA in children. 2 Pediatric OSA has been extensively associated with an increased risk for behavioral and mood disturbances, as well as with cognitive defi cits. Furthermore, cardiovascular and metabolic morbidities, such as pulmonary hypertension, systemic hypertension, endothelial dysfunction, insulin resistance, and serum lipid alterations, are also frequently observed. 3 However, identifi cation of those children who have developed any such OSAassociated morbidities is diffi cult, and is usually complicated by the need for laborious and onerous test batteries that are not routinely available in most clinical settings. Therefore, such assessments are usually not pursued.Background: Pediatric obstructive sleep apnea (OSA) is associated with cognitive dysfunction, suggesting altered neurotransmitter function. We explored overnight changes in neurotransmitters in the urine of children with and without OSA. Methods: Urine samples were collected from children with OSA and from control subjects before and after sleep studies. A neurocognitive battery assessing general cognitive ability (GCA) was administered to a subset of children with OSA. Samples were subjected to multiple enzyme-linked immunosorbent assays for 12 neurotransmitters, and adjusted for creatinine concentrations. Results: The study comprised 50 children with OSA and 20 control subjects. Of the children with OSA, 20 had normal GCA score (mean Ϯ SD) (101.2 Ϯ 14.5) and 16 had a reduced GCA score (87.3 Ϯ 13.9; P , .001). Overnight increases in epinephrine, norepinephrine, and g -aminobutyric acid (GABA) levels emerged in children with OSA; taurine levels decreased. Using combinatorial approaches and cutoff values for overnight changes of these four neurotransmitters enabled prediction of OSA (area under the curve [AUC]: 0.923; P , .0001). Furthermore, GABA and taurine alterations, as well as overnight reductions in phenylethylamine, were more prominent in children with OSA and low GCA than in children with OSA and normal GCA ( P , .001), and they reliably discriminated GCA status (AUC: 0.977; P , .0001). Conclusions: Pediatric OSA is associated with overnight increases in urinary concentrations of catecholamines indicative of heightened sympathetic outfl ow. Increases in GABA levels and decreases in taurine levels could underlie mechanisms of neuronal excitotoxicity and dysfunction. Combinatorial approaches using defi ned cutoffs in overnight changes in concentrations of selected neurotransmitters in urine may not only predict OSA but also the presence ...

Evaluation and Validation of a Method for Determining Platelet Catecholamine in Patients with Obstructive Sleep Apnea and Arterial Hypertension

“…In children with OSA an overnight increase in urinary concentrations of catecholamine was found [42]. There are many problems inherent in the evaluation of plasma catecholamine levels, in particular as a SNS activation index, because these concentrations show large intra-variability that is exacerbated by factors such as venipuncture, stress, and physical exertion.…”

Pediatric OSA Syndrome Morbidity Biomarkers

“…13,14,[85][86][87] These early indicators of individual susceptibility are further buttressed by findings showing alterations in the urinary concentrations of a number of neurotransmitters among children with OSAS who were also manifesting evidence of cognitive deficits. 38 However, even though the long-term implications of cognitive losses are obviously of great concern, relatively fewer studies have attempted to identify markers of cognitive susceptibility, [88][89][90] most likely because of the labor-intensive nature of psychometric testing and the relatively large number of children required for such endeavors. 2,4 Taken together, it appears that the presence of morbidities that have been thus far associated with pediatric OSAS illustrates the complex interactions between biologic pathways activated by the presence of the disease (eg, inflammation, oxidative stress), environmental factors (eg, diet, physical activity, pollution), and genetic determinants (ie, singlenucleotide polymorphisms in relevant genes involved in the pathophysiology of end-organ dysfunction).…”

“…20 Over the last decade, a constellation of morbidity-related biomarkers has been proposed for pediatric OSAS, and a scoping review was previously published and investigated potential associations and predictive abilities of such published candidate biomarkers in OSAS-induced morbidities in both adults and children. 21 In this article, we focus on the more promising of such biomarkers, and particularly on those potentially contributing to detection and monitoring of cardiometabolic morbidity (see Table 1 [22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38] residual OSAS following T&A. 23 On the basis of the interindividual variability of the responses to T&A we previously found in a large panel of inflammatory markers among a large group of obese children with OSAS, 24 it is likely that use of CRP alone, rather than as a component of a multiarray panel, may not provide sufficiently accurate prediction of CVD risk or its resolution with treatment.…”

Home sleep testing for the diagnosis of pediatric obstructive sleep apnea

“…To this effect, identification of children who are less susceptible to cognitive morbidity, for example, is likely possible using single-nucleotide polymorphisms among selected genes that underlie the adverse consequences of SDB [54]. Conversely, identification of those patients who are more likely to exhibit neurocognitive dysfunction associated with SDB can be pursued using urinary markers [55]. A comprehensive and critical assessment of this specific topic was recently published [56 & ].…”