Deferoxamine Prevents Neonatal Posthemorrhagic Hydrocephalus Through Choroid Plexus-Mediated Iron Clearance.

Posthemorrhagic hydrocephalus occurs in up to 30% of infants with high-grade intraventricular hemorrhage and is associated with the worst neurocognitive outcomes in preterm infants. The mechanisms of posthemorrhagic hydrocephalus after intraventricular hemorrhage are unknown; however, CSF levels of iron metabolic pathway proteins including hemoglobin have been implicated in its pathogenesis. Here, we develop an animal model of intraventricular hemorrhage using intraventricular injection of hemoglobin at post-natal day 4 that results in acute and chronic hydrocephalus, pathologic choroid plexus iron accumulation, and subsequent choroid plexus injury at post-natal days 5, 7, and 15. This model also results in increased expression of aquaporin-1, Na+/K+/Cl- cotransporter 1, and Na+/K+/ATPase on the apical surface of the choroid plexus 24 h post-intraventricular hemorrhage. We use this model to evaluate a clinically relevant treatment strategy for the prevention of neurological sequelae after intraventricular hemorrhage using intraventricular administration of the iron chelator deferoxamine at the time of hemorrhage. Deferoxamine treatment prevented posthemorrhagic hydrocephalus for up to 11 days after intraventricular hemorrhage and prevented the development of sensorimotor gating deficits. In addition, deferoxamine treatment facilitated acute iron clearance through the choroid plexus and subsequently reduced choroid plexus iron levels at 24 h with reversal of hemoglobin-induced aquaporin-1 upregulation on the apical surface of the choroid plexus. Intraventricular administration of deferoxamine at the time of intraventricular hemorrhage may be a clinically relevant treatment strategy for preventing posthemorrhagic hydrocephalus and likely acts through promoting iron clearance through the choroid plexus to prevent hemoglobin-induced injury.

Iron homeostasis and post-hemorrhagic hydrocephalus: a review.

Iron physiology is regulated by a complex interplay of extracellular transport systems, coordinated transcriptional responses, and iron efflux mechanisms. Dysregulation of iron metabolism can result in defects in myelination, neurotransmitter synthesis, and neuronal maturation. In neonates, germinal matrix-intraventricular hemorrhage (GMH-IVH) causes iron overload as a result of blood breakdown in the ventricles and brain parenchyma which can lead to post-hemorrhagic hydrocephalus (PHH). However, the precise mechanisms by which GMH-IVH results in PHH remain elusive. Understanding the molecular determinants of iron homeostasis in the developing brain may lead to improved therapies. This manuscript reviews the various roles iron has in brain development, characterizes our understanding of iron transport in the developing brain, and describes potential mechanisms by which iron overload may cause PHH and brain injury. We also review novel preclinical treatments for IVH that specifically target iron. Understanding iron handling within the brain and central nervous system may provide a basis for preventative, targeted treatments for iron-mediated pathogenesis of GMH-IVH and PHH.

Gold nanoparticle-enhanced X-ray microtomography of the rodent reveals region-specific cerebrospinal fluid circulation in the brain.

Cerebrospinal fluid (CSF) is essential for the development and function of the central nervous system (CNS). However, the brain and its interstitium have largely been thought of as a single entity through which CSF circulates, and it is not known whether specific cell populations within the CNS preferentially interact with the CSF. Here, we develop a technique for CSF tracking, gold nanoparticle-enhanced X-ray microtomography, to achieve micrometer-scale resolution visualization of CSF circulation patterns during development. Using this method and subsequent histological analysis in rodents, we identify previously uncharacterized CSF pathways from the subarachnoid space (particularly the basal cisterns) that mediate CSF-parenchymal interactions involving 24 functional-anatomic cell groupings in the brain and spinal cord. CSF distribution to these areas is largely restricted to early development and is altered in posthemorrhagic hydrocephalus. Our study also presents particle size-dependent CSF circulation patterns through the CNS including interaction between neurons and small CSF tracers, but not large CSF tracers. These findings have implications for understanding the biological basis of normal brain development and the pathogenesis of a broad range of disease states, including hydrocephalus.

Representation of female neurosurgeons as abstract authors at neurological surgery conferences.

OBJECTIVE: Female neurosurgeon representation has increased, but women still represent only 8.4% of neurosurgeons in the US. Women are significantly underrepresented as authors in neurosurgical and spine journals, a key indicator of professional success in academic medicine. In this study, the authors aimed to assess the gender diversity of first and last authors of accepted abstracts at neurosurgical conferences in 2015 and 2019. METHODS: Annual meeting abstracts for 2015 and 2019 of the American Association of Neurological Surgeons (AANS), Congress of Neurological Surgeons (CNS), and pediatrics, spine, stereotactic and functional surgery, and cerebrovascular AANS/CNS subspecialty sections were obtained and analyzed for gender. Partial data were obtained for tumor and pain sections. Composite gender data were obtained from the societies. Percentage differences were calculated using comparison of proportions testing. RESULTS: Overall, female neurosurgeons accounted for only 8.3% of first and 5.8% of last authors, and 7.2% of authors overall. The pediatrics section had the highest proportion of female neurosurgeons as first (13.7%) and last (12.4%) abstract authors, while the spine section had the lowest proportions of female neurosurgeon first (4.6%) and last (2.0%) authors. Qualitatively, a higher proportion of women were first authors, while a higher proportion of men were last authors. Overall, there was no significant change in female neurosurgeon authorship between 2015 and 2019. With regard to society demographics, female neurosurgeons accounted for only 6.3% of AANS membership. The pediatrics section had the highest proportion of female neurosurgeons at 18.1% and the stereotactic and functional surgery section had the lowest of the subspecialty sections (7.6%). While female neurosurgeons represented 12.6% of spine section membership, they represented only 4.7% of first authors (-7.9% difference; p < 0.0001) and 2.4% of last authors (-10.2% difference; p < 0.0001). For the 2019 cerebrovascular section, female neurosurgeons were underrepresented as presenting authors (5.8%) compared with their membership representation (14.8%, -9.0% difference; p = 0.0018). CONCLUSIONS: Despite an increase in the number of female neurosurgeons, there has not been a corresponding increase in the proportion of female neurosurgeons as abstract authors at annual neurosurgery conferences, and female neurosurgeons remain underrepresented as authors compared with their male colleagues.