title: Cerebrospinal fluid biomarkers of infantile congenital hydrocephalus.
abstract: BACKGROUND
  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.
authors.affiliation: Department of Neurological Surgery, Washington University in St. Louis, School of Medicine, Saint Louis, MO, United States of America.|Department of Pediatrics, Washington University in St. Louis, School of Medicine, Saint Louis, MO, United States of America.
authors.forename: David D
authors.initials: DD
authors.lastname: Limbrick
authors.affiliation: Department of Neurological Surgery, Washington University in St. Louis, School of Medicine, Saint Louis, MO, United States of America.
authors.forename: Brandon
authors.initials: B
authors.lastname: Baksh
authors.affiliation: Barrow Neurological Institute, Phoenix, AZ, United States of America.
authors.forename: Clinton D
authors.initials: CD
authors.lastname: Morgan
authors.affiliation: Department of Neurological Surgery, Washington University in St. Louis, School of Medicine, Saint Louis, MO, United States of America.
authors.forename: Gakwaya
authors.initials: G
authors.lastname: Habiyaremye
authors.affiliation: Department of Neurological Surgery, Washington University in St. Louis, School of Medicine, Saint Louis, MO, United States of America.
authors.forename: James P
authors.initials: JP
authors.lastname: McAllister
authors.affiliation: Department of Pediatric, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States of America.
authors.forename: Terrie E
authors.initials: TE
authors.lastname: Inder
authors.affiliation: Department of Neurological Surgery, Washington University in St. Louis, School of Medicine, Saint Louis, MO, United States of America.
authors.forename: Deanna
authors.initials: D
authors.lastname: Mercer
authors.affiliation: Department of Neurology, Washington University in St. Louis, School of Medicine, Saint Louis, MO, United States of America.
authors.forename: David M
authors.initials: DM
authors.lastname: Holtzman
authors.affiliation: Department of Neurological Surgery, Washington University in St. Louis, School of Medicine, Saint Louis, MO, United States of America.|Department of Pediatrics, Washington University in St. Louis, School of Medicine, Saint Louis, MO, United States of America.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Strahle
authors.affiliation: Department of Biostatistics, Washington University in Saint Louis, School of Medicine, Saint Louis, MO, United States of America.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Wallendorf
authors.affiliation: Department of Neurological Surgery, Washington University in St. Louis, School of Medicine, Saint Louis, MO, United States of America.
authors.forename: Diego M
authors.initials: DM
authors.lastname: Morales
mesh_terms: D000375:Aging / Q000134:cerebrospinal fluid; D016564:Amyloid beta-Protein Precursor / Q000134:cerebrospinal fluid; D015415:Biomarkers / Q000134:cerebrospinal fluid; D002648:Child; D005260:Female; D006801:Humans; D006849:Hydrocephalus / Q000134:cerebrospinal fluid* / Q000151:congenital*; D007223:Infant; D007231:Infant, Newborn; D008297:Male
chemical_list: D016564:Amyloid beta-Protein Precursor; D015415:Biomarkers