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-β1 (TGF-β1), 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-β1, TGF-β2, 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-β1, TGF-β2, 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-β1], [TGF-β2], [CSPG] and [NT-CSPG] were significantly greater by >3-, >35-, >8-, and >3-fold, respectively. Unlike CSF [TGF-β2] and [CSPG], [TGF-β1] correlated with CSF [total protein]. Only CSF [NT-CSPG] correlated with cPVL. Unlike [TGF-β2] or [CSPG], [NT-CSPG] correlation with preterm progressive post-hemorrhagic hydrocephalus (PPHH) was explained entirely by the presence of cPVL among these patients. [TGF-β2] 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-β2] and [NT-CSPG] correlated inversely with Bayley Index Scores (15.0 months median adjusted age). Conclusions: This is the first report that [TGF-β2], [CSPG], and [NT-CSPG], measured well before term, accumulate abnormally in preterm progressive post-hemorrhagic hydrocephalus CSF, and correlate with adverse neurologic outcome.