Longitudinal CSF Iron Pathway Proteins in Posthemorrhagic Hydrocephalus: Associations with Ventricle Size and Neurodevelopmental Outcomes

Abstract

Iron has been implicated in the pathogenesis of brain injury and hydrocephalus after preterm germinal matrix hemorrhage-intraventricular hemorrhage, however, it is unknown how external or endogenous intraventricular clearance of iron pathway proteins affect the outcome in this group. Methods: This prospective multicenter cohort included patients with posthemorrhagic hydrocephalus (PHH) who underwent (1) temporary and permanent cerebrospinal fluid (CSF) diversion and (2) Bayley Scales of Infant Development-III testing around 2 years of age. CSF proteins in the iron handling pathway were analyzed longitudinally and compared to ventricle size and neurodevelopmental outcomes. Results: Thirty-seven patients met inclusion criteria with a median estimated gestational age at birth of 25 weeks; 65% were boys. Ventricular CSF levels of hemoglobin, iron, total bilirubin, and ferritin decreased between temporary and permanent CSF diversion with no change in CSF levels of ceruloplasmin, transferrin, haptoglobin, and hepcidin. There was an increase in CSF hemopexin during this interval. Larger ventricle size at permanent CSF diversion was associated with elevated CSF ferritin (p = 0.015) and decreased CSF hemopexin (p = 0.007). CSF levels of proteins at temporary CSF diversion were not associated with outcome, however, higher CSF transferrin at permanent CSF diversion was associated with improved cognitive outcome (p = 0.015). Importantly, longitudinal change in CSF iron pathway proteins, ferritin (decrease), and transferrin (increase) were associated with improved cognitive (p = 0.04) and motor (p = 0.03) scores and improved cognitive (p = 0.04), language (p = 0.035), and motor (p = 0.008) scores, respectively. Interpretation: Longitudinal changes in CSF transferrin (increase) and ferritin (decrease) are associated with improved neurodevelopmental outcomes in neonatal PHH, with implications for understanding the pathogenesis of poor outcomes in PHH.

Biochemical profile of human infant cerebrospinal fluid in intraventricular hemorrhage and post-hemorrhagic hydrocephalus of prematurity

“…The change in sodium concentration contributes over 50% of the change in osmolality (Table 4 ). However, protein concentration is believed to contribute only minimally to osmolality [ 29 , 37 ] and similarly, our results show that change in protein concentration only contributes about 8% to osmolality change (Table 4 ). In addition, compared to control, total protein concentrations are increased in both HGIVH and PHH but osmolality, sodium, and chloride concentrations are increased in PHH only.…”

“…However, the increased total protein may be related to blood and its metabolites. Other studies [ 6 , 29 ] have also shown increased total protein in PHH as well as increased hemoglobin, other blood metabolites, and hemoglobin associated proteins in PHH. Further emphasizing the possible involvement of inflammation in CSF biochemical profile changes is decreased glucose in PHH compared to control, LGIVH, and HGIVH.…”

“…PHH is a complex condition that involves neuro-inflammation [ 8 ], alterations in ventricular zone (VZ) junctional biology [ 10 – 14 ], and choroid plexus (ChP) hypersecretion [ 15 ], among other processes. CSF studies of human infants with PHH [ 2 , 4 , 16 , 17 ] have shown elevated inflammatory markers (chemokines and cytokines) [ 18 – 24 ]; mediators of neurodevelopment [ 25 ], extracellular matrix proteins [ 2 , 7 , 25 , 26 ]; blood-associated proteins and metabolites (hemoglobin, ferritin)[ 6 , 27 – 29 ]; proteins involved in coagulation (fibrin and fibrin degradation products)[ 30 , 31 ]; and cell junction proteins [ 2 , 7 ]. However, only a limited number of studies have examined the biochemical profile of CSF in other forms of hydrocephalus [ 32 , 33 ], and no studies have reported these in PHH in human preterm infants to date.…”

Risk Factor of Posthemorrhagic Hydrocephalus: Cerebrospinal Fluid Total Protein

“…The contents of I C-terminal propeptide (PICP), N-terminal procollagen III, propeptide (PIIINP), hyaluronic acid (HA), and laminin (LN) in the cerebrospinal fluid of patients with chronic hydrocephalus after craniocerebral trauma were significantly higher than those in the control group ( 34 , 35 ), suggesting that the subarachnoid space and arachnoid granulations of the patients had obvious fibrosis formation, which may be the pathological basis of chronic hydrocephalus after TBI ( 34 ). In a PHH study on children, longitudinal changes in CSF transferring (increased) and ferritin (decreased) levels were associated with ventricular changes and improved neurodevelopmental outcomes ( 36 ). In addition, interleukin-10 (IL-10), interleukin-6 (IL-6), interleukin-8 (IL-8), matrix metalloprotein-7 (MMP-7), and matrix metalloprotein-9 (MMP-9) levels were significantly elevated in the CSF protein analysis of PHH ( 37 ).…”

Mechanisms of neuroinflammation in hydrocephalus after intraventricular hemorrhage: a review

“…Of those neonates who develop high grade IVH, about 25-30% develop post-hemorrhagic hydrocephalus (PHH) [1,2]. Left untreated, hydrocephalus can contribute to white matter injury, seizures, cognitive impairment and even death [3].…”