Accumulation of transforming growth factor-beta2 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-beta1 (TGF-beta1), 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.


OBJECTIVE
We hypothesized that TGF-beta1, TGF-beta2, 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-beta1, TGF-beta2, 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-beta1], [TGF-beta2], [CSPG] and [NT-CSPG] were significantly greater by >3-, >35-, >8-, and >3-fold, respectively. Unlike CSF [TGF-beta2] and [CSPG], [TGF-beta1] correlated with CSF [total protein]. Only CSF [NT-CSPG] correlated with cPVL. Unlike [TGF-beta2] or [CSPG], [NT-CSPG] correlation with preterm progressive post-hemorrhagic hydrocephalus (PPHH) was explained entirely by the presence of cPVL among these patients. [TGF-beta2] 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-beta2] and [NT-CSPG] correlated inversely with Bayley Index Scores (15.0 months median adjusted age).


CONCLUSIONS
This is the first report that [TGF-beta2], [CSPG], and [NT-CSPG], measured well before term, accumulate abnormally in preterm progressive post-hemorrhagic hydrocephalus CSF, and correlate with adverse neurologic outcome.
Chow
Lily C
LC
Division of Neonatology, Department of Pediatrics, Cedars-Sinai Medical Center, The David Geffen School of Medicine at UCLA, Los Angeles, Calif. 90048, USA.
Soliman
Antoine
A
Zandian
Mandana
M
Danielpour
Moise
M
Krueger
Richard C
RC
D015153:Blotting, Western; D011508:Chondroitin Sulfate Proteoglycans / Q000134:cerebrospinal fluid*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D006849:Hydrocephalus / Q000134:cerebrospinal fluid*; D007231:Infant, Newborn; D007234:Infant, Premature; D007235:Infant, Premature, Diseases / Q000134:cerebrospinal fluid*; D008297:Male; D010865:Pilot Projects; D011446:Prospective Studies; D018709:Statistics, Nonparametric; D016212:Transforming Growth Factor beta / Q000134:cerebrospinal fluid*; D053773:Transforming Growth Factor beta1; D053781:Transforming Growth Factor beta2
D011508:Chondroitin Sulfate Proteoglycans; C508960:TGFB1 protein, human; C509041:TGFB2 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D053781:Transforming Growth Factor beta2