STRAHLE LAB vision
Our goal is to understand germinal matrix hemorrhage-intraventricular hemorrhage (GMH-IVH)-induced brain injury and hydrocephalus in order to develop targeted therapeutics to prevent hydrocephalus, mitigate brain injury, and improve outcomes in infants with GMH-IVH. We study the role of blood and blood breakdown products in the pathogenesis of hydrocephalus and brain injury and examine the role of cilia on the ventricular surface in this pathogenesis. We also focus on the changes in CSF circulation and fluid dynamics after hemorrhage and CSF-neuronal interactions in development. Our multidisciplinary approach spans molecular, cellular, genetic, imaging, and behavioral techniques to answer basic science and clinical questions. We are integrated into the Hope Center for neurologic disorders at Washington University in Saint Louis and are located in BJC-Institute of Health, which provides for a strong interdisciplinary research program.
Biochemical profile of human infant cerebrospinal fluid in intraventricular hemorrhage and post-hemorrhagic hydrocephalus of prematurity
Fluids Barriers CNS. 2021 Dec 24;18(1):62.
Intraventricular hemorrhage (IVH) and post-hemorrhagic hydrocephalus (PHH) have a complex pathophysiology involving inflammatory response, ventricular zone and cell-cell junction disruption, and choroid-plexus (ChP) hypersecretion. CSF osmolality increased in PHH, largely driven by electrolyte changes rather than protein levels. However, serum electrolytes levels were unchanged across groups. CSF osmolality and electrolyte changes were correlated with CSF total nucleated cells which were also increased in PHH, further suggesting PHH is a neuro-inflammatory condition.
Access full-length manuscript here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8710025/
Global cerebrospinal fluid circulation mapping using gold nanoparticle enhanced X-ray microtomography reveals region-specific brain and spinal cord CSF pathways
We developed a novel technique for CSF tracking, gold nanoparticle enhanced X-ray microtomography, to achieve micrometer-scale resolution visualization of CSF pathways during development. Using this method and subsequent histological analysis, we map global CSF pathways and present novel particle size-dependent circulation patterns through the CNS. We identify an intraparenchymal CSF circulation that targets stem cell-rich and cholinergic neuronal populations. CSF solute distribution to these areas is mediated by CSF flow along projections from the basal cisterns which is altered in posthemorrhagic hydrocephalus.
Access full-length manuscript here: https://doi.org/10.1101/2021.12.18.473250
Microstructural Periventricular White Matter Injury in Post-Hemorrhagic Ventricular Dilatation
Neurology. 2021 Nov 19;98(4):e364-e375.
The neurological deficits of neonatal post-hemorrhagic hydrocephalus (PHH) have been linked to periventricular white matter injury. To improve understanding of PHH-related injury, diffusion basis spectrum imaging (DBSI) was applied in neonates, modeling axonal and myelin integrity, fiber density, and extra-fiber pathologies. PHH was associated with diffuse white matter injury, including tract-specific patterns of axonal and myelin injury, fiber loss, cellular infiltration, and inflammation. Larger ventricular size was associated with greater disruption. Postmortem immunohistochemistry confirmed MRI findings. These results demonstrate DBSI provides an innovative approach extending beyond conventional diffusion MRI for investigating neuropathological effects of PHH on neonatal brain development.
Access full-length manuscript here: https://pubmed.ncbi.nlm.nih.gov/34799460/
Does ventricle size contribute to cognitive outcomes in posthemorrhagic hydrocephalus? Role of early definitive intervention
Posthemorrhagic hydrocephalus (PHH) is associated with significant morbidity, smaller hippocampal volumes, and impaired neurodevelopment in preterm infants. The timing of temporary CSF (tCSF) diversion has been studied; however, the optimal time for permanent CSF (pCSF) diversion is unknown. The objective of this study was to determine whether cumulative ventricle size or timing of pCSF diversion is associated with neurodevelopmental outcome and hippocampal size in preterm infants with PHH.
Access full-length article here: https://pubmed.ncbi.nlm.nih.gov/34653990/
Longitudinal CSF Iron Pathway Proteins in Posthemorrhagic Hydrocephalus: Associations with Ventricle Size and Neurodevelopmental Outcomes
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. 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.
Access full-length article here: https://pubmed.ncbi.nlm.nih.gov/34080727/
Use of fast-sequence spine MRI in pediatric patients
The immediate and long-term risk of anesthesia in the pediatric population is controversial. Traditional spine MRI protocols require the patient to remain still during the examination, and in young children this frequently results in the need for sedation administration. The authors' goal was to develop an abbreviated spine MRI protocol to reduce sedation administration in young patients undergoing spine MRI. The authors report the first pediatric series of a fast spine MRI protocol for use in young patients. The protocol does not require sedation and is able to identify and monitor syrinx, spinal dysraphism, and potentially other intraspinal anomalies.
Access full-length article here: https://pubmed.ncbi.nlm.nih.gov/32947256/
Intraventricular Hemorrhage Clearance in Human Neonatal Cerebrospinal Fluid: Associations With Hydrocephalus
Iron has been implicated in ventriculomegaly, hippocampal injury, and poor outcomes following IVH. The purpose of this paper to was to see whether levels of cerebrospinal fluid blood breakdown products and endogenous iron clearance proteins in neonates with IVH differ from those of neonates with IVH who subsequently develop posthemorrhagic hydrocephalus. Neonates with posthemorrhagic hydrocephalus had significantly higher levels of hemoglobin than those with high-grade IVH. Levels of blood breakdown products, hemoglobin, ferritin, and bilirubin correlated with ventricular size. There was no elevation of several iron-scavenging proteins in cerebrospinal fluid in neonates with posthemorrhagic hydrocepehalus, indicative of posthemorrhagic hydrocephalus as a disease state occurring when endogenous iron clearance mechanisms are overwhelmed.
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Impaired hippocampal development and outcomes in very preterm infants with perinatal brain injury
Neuroimage Clin. 2019; 22: 101787.
Preterm infants are at high risk for brain injury during the perinatal period. Intraventricular hemorrhage and periventricular leukomalacia, the two most common patterns of brain injury in prematurely-born children, are associated with poor neurodevelopmental outcomes. The hippocampus is known to be critical for learning and memory; however, it remains unknown how these forms of brain injury affect hippocampal growth and how the resulting alterations in hippocampal development relate to childhood outcomes. To investigate these relationships, hippocampal segmentations were performed on term equivalent MRI scans from 55 full-term infants, 85 very preterm infants (born ≤32 weeks gestation) with no to mild brain injury and 73 very preterm infants with brain injury (e.g., grade III/IV intraventricular hemorrhage, post-hemorrhagic hydrocephalus, cystic periventricular leukomalacia). Consistent with our preclinical findings, these findings demonstrate that perinatal brain injury is associated with hippocampal size in preterm infants, with smaller volumes related to domain-specific neurodevelopmental impairments in this high-risk clinical population.
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Blood Exposure Causes Ventricular Zone Disruption and Glial Activation In Vitro
J Neuropathol Exp Neurol. 2018 Sep 1;77(9):803-813
We reported that application of syngeneic blood to cultured ventricular zone (VZ) cells from newborn (P0-P4) mice resulted in significant decrease in N-cadherin-dependent adherenjunctions, ciliated ependymal cells and increase in glial fibrillary acidic protein. These observations suggest that, in vitro, blood triggers VZ cell loss and glial activation in a pattern that mirrors the cytopathology of human IVH and supports the relevance of this in vitro model to define injury mechanisms.
Access full-length article here: https://www.ncbi.nlm.nih.gov/pubmed/30032242
Predictors of mortality for preterm infants with intraventricular hemorrhage: a population-based study
Childs Nerv Syst. 2018 Jul 9
The goal of this longitudinal, population-level study was to examine factors affecting mortality in preterm infants with intraventricular hemorrhage (IVH). Patients were 36 weeks estimated gestational age (EGA) or less with a diagnosis of IVH. Potential predictors for mortality were investigated with multivariable survival analysis. Results are shown above. This is the first database for population-based investigations of long-term neurosurgical outcomes in preterm infants with IVH.
De Novo Mutation in Genes Regulating Neural Stem Cell Fate in Human Congenital Hydrocephalus
Neuron. 2018 Jul 25;99(2):302-314
CH pathogenesis is poorly understood. Exome sequencing of 125 CH trios and 52 additional probands identified three genes with significant burden of rare damaging de novo or transmitted mutations: TRIM71 (p = 2.15 × 10−7), SMARCC1 (p = 8.15 × 10−10), and PTCH1 (p = 1.06 × 10−6). Additionally, two denovoduplicationswere identified at the SHH locus, encoding the PTCH1 ligand (p = 1.2 × 10−4). Together, these probands account for ∼10% of studied cases. Strikingly, all four genes are required for neural tube development and regulate ventricular zone neural stem cell fate.
Time-to-event analysis of surgically treated posthemorrhagic hydrocephalus in preterm infants: a single-institution retrospective study
Childs Nerv Syst. 2017 Nov;33(11):1917-1926
Grades III-IV IVH did not differ in age at IVH diagnosis, ventriculomegaly, temporizing neurosurgical procedure (TNP) or permanent intervention. Ventricular reservoirs and ventriculosubgalealshunts were used in 68.3% and 28.8%, respectively. 76.9% of the patients ultimately received a VPS. Although most infants who develop IVH and ventriculomegaly will do so within a few days of birth, at-risk infants should be observed for at least four weeks with serial head ultrasounds to monitor for PHH requiring surgery.
Access full-length article here: https://www.ncbi.nlm.nih.gov/pubmed/28884229
Cerebrospinal fluid biomarkers of infantile congenital hydrocephalus
PLoS One. 2017 Feb 17;12(2):e0172353
The objective of this study was to examine the CSF of children with congenital hydrocephalus (CHC) to gain insight into the pathophysiology of hydrocephalus and identify candidate biomarkers of CHC with potential diagnostic and therapeutic value.CSF levels of amyloid precursor protein and derivatives (solubleAPPα, APPβ), Aβ42, tau, phosphorylated tau, cell adhesion markers L1CAM, and NCAM-1 but not aquaporin 4 or total protein were increased in untreated CHC.Predictive ability for CHC was strongest for sAPPα, followedby normalized sAPP, tau, APP, and L1CAM.
Access full-length article here: https://www.ncbi.nlm.nih.gov/pubmed/28212403
Role of hemoglobin and iron in hydrocephalus after neonatal intraventricular hemorrhage
Neurosurgery. 2014 Dec;75(6):696-705
We reported that intraventricular injections of iron or Hemoglobin(Hb) in P7 neonatal rats resulted in ventriculomegaly, neuronal injury and death. Injection with the iron-deficient immediate heme precursor protoporphyrin IX did not result in ventricular enlargement. Furthermore, treatment with an iron-chelator, deferoxamine, post-Hb injection resulted in significant reduction in Hb-induced hippocampal damage and neuronal injury. These results implicate iron and Hb as key neuropathological substrates of GMH-IVH.This has implications for pathogenesis and treatment of hydrocephalus.
Access full-length article here: https://www.ncbi.nlm.nih.gov/pubmed/25121790
Hemoglobin-induced neuronal degeneration in the hippocampus after neonatal intraventricular hemorrhage
Brain Res. 2016 Mar 15;1635:86-94
We evaluated the role of hemoglobin (Hb) in cell death after intraventricular injection in neonatal rats. Hb was injected into the right lateral ventricle of P7 rats. The CA-1 region of the hippocampus was analyzed via immunohistochemistry, hematoxylin and eosin, Fluoro-Jade C staining, Western blots, and double-labeling stains. Compared to controls, intraventricular injection of Hbdecreased hippocampal volume (27% decrease; p<0.05), induced neuronal loss (31% loss; p<0.01), and increased neuronal degeneration (2.7 fold increase; p<0.01), which were all significantly reduced with the iron chelator, deferoxamine.
Access full-length article here: https://www.ncbi.nlm.nih.gov/pubmed/26772987
Role of red blood cell lysis and iron in hydrocephalus after intraventricular hemorrhage
J Cereb Blood Flow Metab. 2014 Jun;34(6):1070-5
In this study investigated the role of red blood cell (RBC) lysis and iron in hydrocephalus after IVH. We found that intraventricular injection of lysed RBCs, but not packed RBCs, resulted in ventricular enlargement and marked increases in brain hemeoxygenase-1 and ferritin at 24 hours. Intraventricular injection of iron also resulted in ventricular enlargement and ventricular wall damage 24 hours later. Coinjection of deferoxamine reduced lysed RBC-induced ventricular enlargement. These results suggest that iron, a degradation product of hemoglobin, has an important role in hydrocephalus development after IVH.
Access full-length article here: https://www.ncbi.nlm.nih.gov/pubmed/24667910
Subarachnoid hemorrhage- induced hydrocephalus in rats
Stroke. 2013 Feb;44(2):547-50.
Hydrocephalus is an important complication of subarachnoid hemorrhage (SAH). SAH was induced by endovascular perforation in adult male Sprague-Dawley rats. Ventricular volume measurements showed a significant increase in surviving SAH rats when compared to sham controls. Ventricular volume correlated with SAH severity as demonstrated by histology, immunohistochemistry, Perls’ staining and Western blot analysis. Periventricular iron deposition was observed and HO-1 and Iba-1 expression were markedly increased in hydrocephalus rats.
Access full-length article here: https://www.ncbi.nlm.nih.gov/pubmed/23212164
SELECTED EXPERIMENTAL TECHNIQUES
We use a diverse approach to study post-hemorrhagic hydrocephalus spanning both the lab and clinic. We utilize neonatal animal models of post-hemorrhagic hydrocephalus, primary cell culture, human CSF analysis, protein and RNA quantification (ELISA, Western blot, rt-PCR), cilia structure and function assays, CSF outflow quantification and behavior studies.
To evaluate ventricle size and brain injury, we use in vivo MRI to quantify ventricular volumetric measurements and assess brain injury.
Cilia Beat Frequency Measurements
As cilia function is implicated in hydrocephalus, we evaluate cilia structure and function in cell culture and after intraventricular hemorrhage in our neonatal rodent model.
In collaboration with the WUCCI, we evaluate CSF pathways through the brain and spinal cord parenchyma using gold nanoparticle-enhanced x-ray nanotomography to obtain high-resolution images of CSF circulation through the brain, neck, and spine.
Meet OUR TEAM
We are a diverse group of committed scientists and medical students driven to making fundamental discoveries in the lab and rapidly translating these insights to the clinic.
Prabagaran Esakky, PhD
Praba got his PhD in Biochemistry with specialization in Male Reproductive Toxicology from (ICMR) University of Mumbai in 2008. He completed his postdoctoral trainings in Developmental Neurobiology at WEHI in Melbourne, Australia (2008-2009), Vascular Physiology at UTHSC, Memphis (2009-2010), followed by training in molecular reproductive toxicology in the Department of OB & GYN at Washington University in St. Louis (2010-2015). Following postdoc trainings, Praba has made significant scientific contributions as a Research Instructor in the department until 2019. His research has primarily focused on unraveling the harmful effects upon paternal exposure to environmental pollutants and germ cell toxicants such as constituents of cigarette smoke and viral pathogens like ZIKA virus on male fertility, male germ cell development, birth defects in embryos and offspring, and developmental and neurobehavioral outcomes in offspring. Praba has joined the Strahle Lab in June 2019 and is currently focusing on the role of proteins in ventricular injury and ependymal ciliary dysfunction and its impact on CSF dynamics in GMH-IVH.
Sruthi Ramagiri, PhD
Sruthi Ramagiri received her Ph.D. in Neuroscience from BITS Pilani in May 2018. She completed her Post-doctoral training in the Department of Pediatrics at Albert Einstein College of Medicine in New York in June 2019. She joined the Dr. Strahle lab in July 2019. Dr. Ramagiri is currently focusing on the role of iron transport at the ependymal surface and its contribution to ciliary dysfunction in IVH-PHH.
Diego Morales, MS
Peter Yang, MD
Peter is a PGY6 neurosurgery resident. He joined the Strahle lab in Summer 2021. Peter studies CSF interactions with the parenchyma in development, transependymal CSF migration, and functional network alterations following GMH/IVH.
Gretchen Koller is a medical student from Kansas City University completing a predoctoral research fellowship with the Strahle Lab and WashU Department of Neurosurgery. She is also earning a Master of Public Health from the University of Nebraska Medical Center. She obtained her Bachelor of Science in biological sciences from the University of Missouri – Columbia, where she conducted research on proinflammatory mediators and their effect on capillary tube regression. While in medical school, she has devoted her time to working with the Medical Student Neurosurgery Training Center and leads their affiliated Neurosurgery Education and Research Virtual Group. Her research interests include congenital malformations within and related to the central nervous system, pediatric neuro-oncology, and clinical outcomes of fetal surgery. In addition to her academic and research pursuits, Gretchen is passionate about increasing involvement and representation of women within the field of neurosurgery and providing equal access to neurosurgical education. She is originally from Ste. Genevieve, Missouri, and enjoys the beautiful wine country, creating charcuterie boards, playing volleyball and racquetball, hosting friends and family, baking, biking, and hiking.
Shelei is an undergraduate in Washington University’s University Scholars Program, where she plans to major in neuroscience and minor in Spanish and medical humanities. She joined the Strahle lab as a high schooler in December 2019. Shelei studies targeted CSF interactions with the parenchyma, CSF pathways in post-hemorrhagic hydrocephalus, and the molecular basis of CSF handling in the developing brain.
Abdul-Haq is an undergraduate at Washington University in the class of 2024. He joined the Strahle lab in 2021. Abdul-Haq studies rostral migratory stream development following IVH-PHH.
Grace Halupnik is an undergraduate at Washington University where she is majoring in the Psychology-Neuroscience-Philosophy program with a minor in biomedical physics. Grace joined the lab in 2022 and studies CSF pathways in post-hemorrhagic hydrocephalus as well as CSF circulation during lymphatic and vascular development.
Bing Xue, MD
Dr. Xue received his M.D. degree from Taishan Medical College in China in July 2002. He received his Ph.D. in Anatomy and Embryology from Ehime University School of Medicine in Japan in July 2007. Dr. Xue completed his Post-doctoral training in Physiology at the University of Kansas Medical Center from 2007 to 2008, followed by training at the University of Missouri-Kansas City School of Medicine from 2008 to 2016. He joined the Strahle Lab in March 2017. Dr. Xue focused on the role of iron transporters and cilia dysfunction and effects on regional and global CSF flow after GMH-IVH.
Sharon Abada, MD
Prior to attending medical school at Washington University in St. Louis, Sharon Abada received her Bachelor's degree in Physiology from UCLA and her Master's in Public Health from the UTHealth School of Public Health. She joined the Strahle Lab in the summer of 2018. In the lab, she worked on studying the role of ependymal iron transporters in post-hemorrhagic hydrocephalus using a neonatal rodent model.
Chandana Buddhala, PhD
Dr. Buddhala received her Ph.D. in Integrative Biology from Florida Atlantic University in May 2012. She completed Post-doctoral training with Dr Paul Kotzbauer in the Department of Neurology at Washington University in Saint Louis in May 2017. She joined the Strahle Lab in July 2017. Dr. Buddhala contributed to findings on Intraventricular Hemorrhage Clearance Markers in Human Neonatal CSF. She focused on CSF iron metabolism predictors of outcome in post hemorrhagic hydrocephalus, iron-mediated ventricular injury and cilia dysfunction in post hemorrhagic hydrocephalus.
Mounica Paturu, MD
Mounica Paturu received her Bachelor of Science from Massachusetts Institute of Technology where she double majored in Bioengineering and International Development. She joined the the Strahle Lab in 2018. Ms. Paturu was involved in clinical research evaluating the relationship of ventricular size to CSF biomarkers of post-hemorrhagic hydrocephalus.
Alex Skidmore, MD
Alex Skidmore completed his Bachelor of Science in Neuroscience from Duke University. He joined the Strahle Lab in the summer of 2018. Alex focused on studying changes in iron transporter expression in hemoglobin and iron-mediated injury in neonatal rat primary cultured ependymal cells.
Jordan Gewirtz is a graduate of Washington University in St. Louis and studied systems engineering and computer science on a pre-medicine track. He joined the Strahle Lab in the summer of 2019. In the lab, he worked on the Park-Reeves Research Consortium focusing on Chiari, syringomyelia, and scoliosis as well as validating a modified spine MRI protocol.
Dhvanii Raval is a 2022 graduate of Saint Louis University. She joined Strahle Lab in February 2020. In the lab, she focused on determining CD163 expression in a rat IVH-PHH model.
Dakota DeFreitas, MA
Dakota received his Masters in Neurobiology at Washington University in St. Louis. He focused on the role of iron transporters in iron-mediated ventricular injury and behavioral deficits after post-hemorrhagic hydrocephalus.
2016 Hydrocephalus Association Innovator Award Recipient
Jennifer M. Strahle
Department of Neurosurgery
Washington University School of Medicine
One Children's Place
Saint Louis, MO 63110