Accumulation of transforming growth factor-β2 and nitrated chondroitin sulfate proteoglycans in cerebrospinal fluid correlates with poor neurologic outcome in preterm hydrocephalus

Background: Progressive post-hemorrhagic hydrocephalus in preterm infants strongly predicts abnormal neurologic development, and often accompanies cystic periventricular leukomalacia (cPVL). Transforming growth factor-beta(1) (TGF-beta(1)), associated with hydrocephalus, can upregulate the chondroitin sulfate proteoglycan (CSPG) synthesis. To date, CSPG and their nitrated metabolites (NT-CSPG) have not been evaluated in hydrocephalus. Objectives: We hypothesized that TGF-beta(1), TGF-beta(2), CSPG, and NT-CSPG would accumulate in cerebrospinal fluid (CSF) in preterm hydrocephalus, and their concentrations would correlate with poor long-term outcomes. Methods: TGF-beta(1), TGF-beta(2), CSPG, and NT-CSPG concentrations in CSF were measured prospectively by ELISA in 29 preterm newborns with (n = 22) or without ( n = 34) progressive post-hemorrhagic hydrocephalus, and correlated with progressive neonatal hydrocephalus and neurologic outcome. Only concentrations from each patient's initial CSF sample were used for statistical analysis. Results: Compared to neonates without hydrocephalus, CSF [TGF-beta(1)], [TGF-beta(2)], [CSPG] and [NT-CSPG] were significantly greater by >3-, >35-, >8-, and >3-fold, respectively. Unlike CSF [TGF-beta(2)] and [CSPG], [TGF-beta(1)] correlated with CSF [ total protein]. Only CSF [ NT- CSPG] correlated with cPVL. Unlike [TGF-beta(2)] or [CSPG], [NT-CSPG] correlation with preterm progressive post-hemorrhagic hydrocephalus (PPHH) was explained entirely by the presence of cPVL among these patients. [TGF-beta(2)] was >20-fold greater in preterm survivors who required a ventriculoperitoneal shunt for PPHH ( n = 9), as compared to survivors who did not require a shunt ( n = 2), or those without hydrocephalus ( n = 12). [TGF-beta(2)] and [NT-CSPG] correlated inversely with Bayley Index Scores (15.0 months median adjusted age). Conclusions: This is the first report that [TGF-beta(2)], [CSPG], and [NT-CSPG], measured well before term, accumulate abnormally in preterm progressive post-hemorrhagic hydrocephalus CSF, and correlate with adverse neurologic outcome. Copyright (C) 2005 S. Karger AG, Basel.