Biogenic amines including dopamine, epinephrine, norepinephrine, and serotonin are involved in the regulation of various neuronal functions, while changes in the monoamine levels of the CSF have been detected in multiple disorders [74,75]. They reported that the 3-methoxy-4-hydroxyphenylglycol level of the CSF was significantly higher in pediatric patients with astrocytoma than in those with medulloblastoma [74]. A prospective clinical observational study demonstrated that children with newly diagnosed brain tumors exhibit markedly elevated CSF cleaved tau levels, which were suggestive of axonal damage [76].
Prostaglandin D2 synthase (PGD2S) levels were six-fold lower in the pediatric tumor samples versus control samples in study by Rajagopal et al. [77]. The authors speculated that the reduction is a host response to the presence of the tumor [77]. PGD2S is a glycoprotein that is abundant in the CSF and is synthesized and secreted by both glial cells and the choroid plexus [78]. De Bont et al. [79] showed that apolipoprotein A-II (APO A-II) was highly overexpressed in the CSF of pediatric brain tumor patients, which is most likely is associated with a disrupted blood-brain barrier. APO A-II is the second most abundant human high-density lipoprotein apolipoprotein and synthesized predominantly in the liver [80]. APO A-II is known to influence the metabolism of high-density lipoprotein and glucose and was recently linked to malignancies [81]. The CSF level of basic fibroblast growth factor (bFGF) was also increased in pediatric patients with brain tumors. 82) Moreover, bFGF is a widely distributed angiogenic molecule, and most cells produce it or have receptors for it [83].
4. Hypoxic-ischemic encephalopathy
Hypoxic-ischemic encephalopathy (HIE) contributes to worldwide major perinatal mortality and long-term disability in neonates [84]. In neonates with HIE, CSF levels of neuron-specific enolase (NSE) have been shown to play an important role as a marker of brain damage extent and enabled the prediction of the outcomes of infants with HIE in the prehypothermia era (Table 4) [85-89]. NSE is a glycolytic enzyme, and structural damage to neuronal cells causes leakage of NSE into the extracellular compartment [90]. Interlukin-6, neurofilament protein, GFAP, and protein S-100 are known to be associated with neonatal HIE [85,88]. Therapeutic hypothermia appears to lower CSF NSE levels in infants with HIE; however, the predictive value of CSF NSE for neurodevelopmental impairment at 12 months of age is not affected by cooling [91]. One study showed that CSF levels of NSE predicted brain damage severity in newborns with hypothermiatreated HIE [92]. Increased CSF levels of activin A were detected in term neonates with perinatal asphyxia, and the highest concentrations were found among neonates with the most severe HIE [93]. Activin A is a member of the transforming growth factor-beta family, and it enhanced expression is known to represent a common response to acute neuronal damage of various origins [94].
5. Traumatic brain injury
In one study, the levels of platelet selectin (P-selectin), an adhesion molecule associated with ischemia and reperfusion, were elevated in pediatric patients’ CSF with TBI versus those with meningitis or controls (Table 5) [95]. Increased blood-brain barrier permeability may contribute to the increased CSF P-selectin levels of pediatric patients with TBI [95]. Platelets are a major source of P-selectin; therefore, hemorrhage might cause the elevated P-selectin level in the CSF of TBI patients [95]. Shore et al. [96] reported that, compared to continuous CSF drainage, intermittent drainage of the CSF was associated with 2-fold greater CSF concentrations of NSE, s100B, interleukin (IL)-6, and vascular endothelial growth factor (VEGF) [96]. CSF VEGF levels were increased after TBI versus control in another study [97]. VEGF is known to be neuroprotective in several experimental brain injury models, and its levels are increased in the brain after TBI in humans and experimental animals [97]. CSF levels of cytokines such as IL-1β, IL-8, IL-10, IL-12P70, and macrophage inflammatory protein-1 alpha were also increased after TBI compared to controls in another study [98]. Early nerve growth factor and doublecortin concentrations also seemed to be correlated with TBI severity [99].
An miRNA study of the CSF and saliva after childhood TBI described 6 parallel changes in miRNA (miR-182-5p, miR-221-3p, miR-26b-5p, miR-320c, miR-29c-3p, and miR-30e-5p) in both [100].
6. Intraventricular hemorrhage
Intraventricular hemorrhage (IVH) has a high risk of neonatal mortality and later neurodevelopmental impairment in preterm infants [101]. One study analyzed proinflammatory cell-free miRNA levels in the CSF of 47 preterm infants with grade III or IV IVH versus controls and reported that the levels of miR-223, miR-155, miR-181b, miR-126, and IL-8 were elevated in the CSF after the onset of IVH versus controls (Table 6) [101]. The authors claimed that hemorrhage-induced CSF miRNA levels reflected inflammatory conditions as potential biomarkers in cases of preterm IVH [101].
7. Congenital hydrocephalus
The variety of etiologies of pediatric hydrocephalus creates additional complexities in biomarker analyses [9]. A recent study of the CSF of infants with untreated congenital hydrocephalus showed a significant increase in CSF amyloid precursor protein (APP) (Table 6) [102]. In this study, CSF levels of APP and its derivative isoforms sAPPα, sAPPβ, Aβ42, tau, phosphorylated tau, L1 neural cell adhesion molecule, and neural cell adhesion molecule but not aquaporin 4 or total protein were increased in untreated congenital hydrocephalus, particularly in children ≤1 year of age, and CSF sAPPα levels showed the strongest relationship with congenital hydrocephalus [102]. AAP is released in the setting of axonal injury, and hydrocephalus-related ventriculomegaly causes axonal pathology [103]. In addition, APP and its derivative isoforms are trophic factors with important roles in synaptogenesis and other aspects of neurodevelopment [104].
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Seh Hyun Kim, MD, PhD1; Soo Ahn Chae, MD, PhD1
1Department of Pediatrics, Chung-Ang University Hospital, Seoul, Korea
2College of Medicine, Chung-Ang University, Seoul, Korea
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