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Cerebrospinal fluid biomarkers of infantile congenital hydrocephalus
David D Limbrick1,2, Brandon Baksh1, Clinton D Morgan3
1Department of Neurological Surgery, Washington University in St. Louis, School of Medicine, Saint Louis, MO, United States of America.
Insights
Biomarkers in cerebrospinal fluid (CSF) show promise for diagnosing congenital hydrocephalus (CHC) in infants. Elevated levels of soluble amyloid precursor protein alpha (sAPPα) are particularly effective predictors in children under 12 months.
Area of Science:
- Neurology
- Biochemistry
- Pediatrics
Background:
- Hydrocephalus significantly impacts the central nervous system, especially in developing children.
- Cerebrospinal fluid (CSF) biochemical profiles are altered in hydrocephalus, necessitating biomarker identification.
Purpose of the Study:
- To investigate CSF protein levels in children with congenital hydrocephalus (CHC).
- To identify potential diagnostic and therapeutic biomarkers for CHC.
- To gain insights into CHC pathophysiology during neurodevelopment.
Main Methods:
- Measured CSF levels of amyloid precursor protein (APP) and its isoforms, tau, phosphorylated tau (pTau), L1CAM, NCAM-1, aquaporin 4 (AQP4), and total protein (TP) using ELISA in 20 CHC patients.
- Compared CHC patients with age-matched controls and children with other neurological diseases.
- Utilized logistic regression and receiver operating characteristic (ROC) curves to assess protein associations with CHC.
Main Results:
- Elevated CSF levels of APP, sAPPα, sAPPβ, Aβ42, tau, pTau, L1CAM, and NCAM-1 were observed in untreated CHC.
- Soluble amyloid precursor protein alpha (sAPPα) demonstrated the strongest predictive ability for CHC, especially in infants ≤12 months (AUC = 0.99).
- A normalized CSF sAPPα cut-point of 0.41 accurately predicted CHC in infants ≤12 months, indicating a significantly higher likelihood of the condition.
Conclusions:
- CSF proteins, particularly sAPPα, show significant potential as biomarkers for CHC in infants and young children.
- These findings offer valuable insights into the pathophysiology of CHC during critical neurodevelopmental stages.
- Further research into these biomarkers could lead to improved diagnostic and therapeutic strategies for CHC.
Introduction:
Hydrocephalus is a complex neurological disorder with a pervasive impact on the central nervous system. Previous work has demonstrated derangements in the biochemical profile of cerebrospinal fluid (CSF) in hydrocephalus, particularly in infants and children, in whom neurodevelopment is progressing in parallel with concomitant neurological injury. The objective of this study was to examine the CSF of children with congenital hydrocephalus (CHC) to gain insight into the pathophysiology of hydrocephalus and identify candidate biomarkers of CHC with potential diagnostic and therapeutic value.
Methods:
CSF levels of amyloid precursor protein (APP) and derivative isoforms (sAPPα, sAPPβ, Aβ42), tau, phosphorylated tau (pTau), L1CAM, NCAM-1, aquaporin 4 (AQP4), and total protein (TP) were measured by ELISA in 20 children with CHC. Two comparative groups were included: age-matched controls and children with other neurological diseases. Demographic parameters, ventricular frontal-occipital horn ratio, associated brain malformations, genetic alterations, and surgical treatments were recorded. Logistic regression analysis and receiver operating characteristic curves were used to examine the association of each CSF protein with CHC.
Results:
CSF levels of APP, sAPPα, sAPPβ, Aβ42, tau, pTau, L1CAM, and NCAM-1 but not AQP4 or TP were increased in untreated CHC. CSF TP and normalized L1CAM levels were associated with FOR in CHC subjects, while normalized CSF tau levels were associated with FOR in control subjects. Predictive ability for CHC was strongest for sAPPα, especially in subjects ≤12 months of age (p<0.0001 and AUC = 0.99), followed by normalized sAPPβ (p = 0.0001, AUC = 0.95), tau, APP, and L1CAM. Among subjects ≤12 months, a normalized CSF sAPPα cut-point of 0.41 provided the best prediction of CHC (odds ratio = 528, sensitivity = 0.94, specificity = 0.97); these infants were 32 times more likely to have CHC.
Conclusions:
CSF proteins such as sAPPα and related proteins hold promise as biomarkers of CHC in infants and young children, and provide insight into the pathophysiology of CHC during this critical period in neurodevelopment.
