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zika virus

The importance of following the Zika population long-term

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zika virus

Invited commentary by Sarah Mulkey, M.D., Ph.D., prenatal-neonatal neurologist in the Division of Prenatal Pediatrics at Children’s National Hospital, emphasizes importance of studying the Zika population long term.

A simple measuring tape could be the key to identifying which children could develop neurological and developmental abnormalities from Zika virus exposure during gestation. This is according to an invited commentary published July 7, 2020 in JAMA Network Open and written by Sarah Mulkey, M.D., Ph.D., prenatal-neonatal neurologist in the Division of Prenatal Pediatrics at Children’s National Hospital.

Zika virus (ZIKV), first isolated in 1947 in the Zika Forest in Uganda, made headlines in 2015-2016 for causing a widespread epidemic that spread through parts of North and South America, several islands in the Pacific and parts of Southeast Asia. Although previously linked with no or mild symptoms, researchers discovered during this epidemic that Zika can cross from a pregnant woman to her gestating fetus, leading to a syndrome marked by microcephaly (decreased brain growth), abnormal neurologic tone, vision and hearing abnormalities and joint contractures.

“For the 90% to 95% of ZIKV-exposed infants who fortunately were not born with severe abnormalities at birth and were normocephalic, our hope was that these children would have normal neurodevelopmental outcomes,” Dr. Mulkey writes in the commentary. “Unfortunately, this has not been the case.”

Her commentary expands on a study in the same issue entitled “Association between exposure to antenatal Zika virus and anatomic and neurodevelopmental abnormalities in children” by Cranston et al. In this study, the researchers find that head circumference — a simple measure taken regularly at postnatal appointments in the U.S. — can provide insight into which children were most likely to develop neurologic abnormalities. Their findings show that 68% of those whose head circumference was in the “normal” range at birth developed neurologic problems. Those whose head circumference was at the upper end of this range were significantly less likely to have abnormalities than those at the lower end.

Just this single measurement offers considerable insight into the risk of developing neurologic problems after Zika exposure. However, notes Dr. Mulkey, head circumference growth trajectory is also key. Of the 162 infants whose heads were initially in the normocephalic range at birth, about 10.5% went on to develop microcephaly in the months after birth.

“Because early head growth trajectory is associated with cognitive outcomes in early childhood,” Dr. Mulkey writes, “following the head circumference percentile over time can enable recognition of a child with increased risk for poor outcome who could benefit from early intervention therapies.”

This simple assessment could be significantly augmented with neuroimaging, she adds. The study by Cranston et al., as well as others in the field, have shown that brain imaging often reveals problems in ZIKV-exposed children, such as calcifications and cerebral atrophy, even in those with normal head circumferences. This imaging doesn’t necessarily need to take place at birth, Dr. Mulkey says. Postnatal development of microcephaly, failure to thrive or developmental delay can all be triggers for imaging later on.

Together, Dr. Mulkey says, the study by Cranston et al. and others that focus on ZIKV-exposed children support the need for following these patients long term. Children exposed to ZIKV in the epidemic nearly five years ago are now approaching school age, a time fraught with more complicated cognitive and social demands. Through her own research at Children’s National’s Congenital Zika Virus Program and collaboration with colleagues in Colombia, Dr. Mulkey is following multiple cohorts of ZIKV exposed children as they grow. She recently published a study on neurological abnormalities in one of these cohorts in JAMA Pediatrics in January 2020.

“It’s really important to follow these children as long as possible so we’ll really know the outcomes of this virus,” Dr. Mulkey says.

Newborn baby laying in crib

Can cells collected from bone marrow stimulate generation of new neurons in babies with CHD?

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Newborn baby laying in crib

The goal of the study will be to optimize brain development in babies with congenital heart disease (CHD) who sometimes demonstrate delay in the development of cognitive and motor skills.

An upcoming clinical trial at Children’s National Hospital will harness cardiopulmonary bypass as a delivery mechanism for a novel intervention designed to stimulate brain growth and repair in children who undergo cardiac surgery for congenital heart disease (CHD).

The NIH has awarded Children’s National $2.5 million to test the hypothesis that mesenchymal stromal cells (MSCs), which have been shown to possess regenerative properties and the ability to modulate immune responses in a variety of diseases, collected from allogeneic bone marrow, may promote regeneration of damaged neuronal and glial cells in the early postnatal brain. If successful, the trial will determine the safety of the proposed treatment in humans and set the stage for a Phase 2 efficacy trial of what could potentially be the first treatment for delays in brain development that happen before birth as a consequence of congenital heart disease. The study is a single-center collaboration between three Children’s National physician-researchers: Richard Jonas, M.D., Catherine Bollard, M.B.Ch.B., M.D. and Nobuyuki Ishibashi, M.D.

Dr. Jonas, chief of cardiac surgery at Children’s National, will outline the trial and its aims on Monday, November 18, 2019, at the American Heart Association’s Scientific Sessions 2019. Dr. Jonas was recently recognized by the Cardiac Neurodevelopmental Outcome Collaborative for his lifelong research of how cardiac surgery impacts brain growth and development in children with CHD.

Read more about the study: Researchers receive $2.5M grant to optimize brain development in babies with CHD.

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Regenerative Cell Therapy in Congenital Heart Disease – Protecting the Immature Brain
Presented by Richard Jonas, M.D.
AHA Scientific Sessions
Session CH.CVS.608 Congenital Heart Disease and Pediatric Cardiology Seminar: A Personalized Approach to Heart Disease in Children
9:50 a.m. to 10:05 a.m.
November 18, 2019

Antonio R. Porras

Antonio R. Porras, Ph.D., awarded prestigious NIH grant for craniosynostosis modeling, career advancement

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Antonio R. Porras

Antonio R. Porras, Ph.D., is a staff scientist in the Sheikh Zayed Institute for Pediatric Surgical Innovation at Children’s National Health System.

Antonio R. Porras, Ph.D., a staff scientist in the Sheikh Zayed Institute for Pediatric Surgical Innovation at Children’s National Health System, has received the prestigious Pathway to Independence Award from the National Institutes of Health (NIH). This award funds Dr. Porras’ research for the next five years, enabling him to develop two bone growth models that will better inform clinicians treating patients with craniosynostosis and help to optimize outcomes. Also referred to as the K99/R00 grant, this NIH award is for researchers who are either in the postdoctoral/residency period or who are early career investigators. It is designed to transition them from mentored positions to independent, tenure-track or equivalent faculty positions so that they can launch competitive research careers.

Marius George Linguraru, D.Phil., M.A., M.Sc., a principal investigator in the Sheikh Zayed Institute for Pediatric Surgical Innovation, is Dr. Porras’ primary mentor on this research project along with co-mentors Robert Keating, M.D., division chief of neurosurgery at Children’s National, and Maximilian Muenke, M.D., chief in the Medical Genetics Branch at the National Human Genome Research Institute.

Dr. Porras has taken a research interest in craniosynostosis, the early fusion of one or more cranial sutures that may lead to craniofacial malformations and brain growth constraints during childhood. With this NIH K99/R00 award, Dr. Porras will employ his expertise in computer science, biomedical engineering, quantitative imaging and statistical modeling to create a personalized computational predictive model of cranial bone growth for subjects without cranial pathology and for patients with craniosynostosis. Dr. Porras will also quantify the coupled growth patterns of the cranial bones and the brain using an existing brain growth model.

Affecting one in 2,100 to 2,500 live births, craniosynostosis complications can result in elevated intra-cranial pressure and subsequent impaired brain growth. While treatable, optimal outcomes are stymied by subjectivity in the evaluation of cranial malformations and prediction of cranial bone development. There are currently no personalized clinical tools available to predict healthy or pathological cranial growth and no objective techniques to optimize the long-term outcome of treatment for patients with craniosynostosis.

Catherine Limperopoulos

Breastfeeding boosts metabolites important for brain growth

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Catherine Limperopoulos

“Proton magnetic resonance spectroscopy, a non-invasive imaging technique that describes the chemical composition of specific brain structures, enables us to measure metabolites that may play a critical role for growth and explain what makes breastfeeding beneficial for newborns’ developing brains,” says Catherine Limperopoulos, Ph.D.

Micro-preemies who primarily consume breast milk have significantly higher levels of metabolites important for brain growth and development, according to sophisticated imaging conducted by an interdisciplinary research team at Children’s National.

“Our previous research established that vulnerable preterm infants who are fed breast milk early in life have improved brain growth and neurodevelopmental outcomes. It was unclear what makes breastfeeding so beneficial for newborns’ developing brains,” says Catherine Limperopoulos, Ph.D., director of MRI Research of the Developing Brain at Children’s National. “Proton magnetic resonance spectroscopy, a non-invasive imaging technique that describes the chemical composition of specific brain structures, enables us to measure metabolites essential for growth and answer that lingering question.”

According to the Centers for Disease Control and Prevention, about 1 in 10 U.S. infants is born preterm. The Children’s research team presented their findings during the Pediatric Academic Societies 2019 Annual Meeting.

The research-clinicians enrolled babies who were very low birthweight (less than 1,500 grams) and 32 weeks gestational age or younger at birth when they were admitted to Children’s neonatal intensive care unit in the first week of life. The team gathered data from the right frontal white matter and the cerebellum – a brain region that enables people to maintain balance and proper muscle coordination and that supports high-order cognitive functions.

Each chemical has its own a unique spectral fingerprint. The team generated light signatures for key metabolites and calculated the quantity of each metabolite. Of note:

  • Cerebral white matter spectra showed significantly greater levels of inositol (a molecule similar to glucose) for babies fed breast milk, compared with babies fed formula.
  • Cerebellar spectra had significantly greater creatine levels for breastfed babies compared with infants fed formula.
  • And the percentage of days infants were fed breast milk was associated with significantly greater levels of both creatine and choline, a water soluble nutrient.

“Key metabolite levels ramp up during the times babies’ brains experience exponential growth,” says Katherine M. Ottolini, the study’s lead author. “Creatine facilitates recycling of ATP, the cell’s energy currency. Seeing greater quantities of this metabolite denotes more rapid changes and higher cellular maturation. Choline is a marker of cell membrane turnover; when new cells are generated, we see choline levels rise.”

Already, Children’s National leverages an array of imaging options that describe normal brain growth, which makes it easier to spot when fetal or neonatal brain development goes awry, enabling earlier intervention and more effective treatment. “Proton magnetic resonance spectroscopy may serve as an important additional tool to advance our understanding of how breastfeeding boosts neurodevelopment for preterm infants,” Limperopoulos adds.

Pediatric Academic Societies 2019 Annual Meeting presentation

  • “Improved cerebral and cerebellar metabolism in breast milk-fed VLBW infants.”
    • Monday, April 29, 2019, 3:30–3:45 p.m. (EST)

Katherine M. Ottolini, lead author; Nickie Andescavage, M.D., Attending, Neonatal-Perinatal Medicine and co-author; Kushal Kapse, research and development staff engineer and co-author; Sudeepta Basu, M.D., neonatologist and co-author; and Catherine Limperopoulos, Ph.D., director of MRI Research of the Developing Brain and senior author, all of Children’s National.

Preemie Baby

Brain food for preemies

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Preemie Baby

Babies born prematurely – before 37 weeks of pregnancy – often have a lot of catching up to do. Not just in size. Preterm infants typically lag behind their term peers in a variety of areas as they grow up, including motor development, behavior and school performance.

New research suggests one way to combat this problem. The study, led by Children’s researchers and presented during the Pediatric Academic Societies 2018 annual meeting, suggests that the volume of carbohydrates, proteins, lipids and calories consumed by very vulnerable premature infants significantly contributes to increased brain volume and white matter development, even though additional research is needed to determine specific nutritional approaches that best support these infants’ developing brains.

During the final weeks of pregnancy, the fetal brain undergoes an unprecedented growth spurt, dramatically increasing in volume as well as structural complexity as the fetus approaches full term.

One in 10 infants born in the U.S. in 2016 was born before 37 weeks of gestation, according to the Centers for Disease Control and Prevention. Within this group, very low birthweight preemies are at significant risk for growth failure and neurocognitive impairment. Nutritional support in the neonatal intensive care unit (NICU) helps to encourage optimal brain development among preterm infants. However, their brain growth rates still lag behind those seen in full-term newborns.

“Few studies have investigated the impact of early macronutrient and caloric intake on microstructural brain development in vulnerable preterm infants,” says Katherine Ottolini, lead author of the Children’s-led study. “Advanced quantitative magnetic resonance imaging (MRI) techniques may help to fill that data gap in order to better direct targeted interventions to newborns who are most in need.”

The research team at Children’s National Health System enrolled 69 infants who were born younger than 32 gestational weeks and weighed less than 1,500 grams. The infants’ mean birth weight was 970 grams and their mean gestational age at birth was 27.6 weeks.

The newborns underwent MRI at their term-equivalent age, 40 weeks gestation. Parametric maps were generated for fractional anisotropy in regions of the cerebrum and cerebellum for diffusion tensor imaging analyses, which measures brain connectivity and white matter tract integrity. The research team also tracked nutritional data: Grams per kilogram of carbohydrates, proteins, lipids and overall caloric intake.

“We found a significantly negative association between fractional anisotropy and cumulative macronutrient/caloric intake,” says Catherine Limperopoulos, Ph.D., director of Children’s Developing Brain Research Laboratory and senior author of the research. “Curiously, we also find significantly negative association between macronutrient/caloric intake and regional brain volume in the cortical and deep gray matter, cerebellum and brainstem.”

Because the nutritional support does contribute to cerebral volumes and white matter microstructural development in very vulnerable newborns, Limperopoulos says the significant negative associations seen in this study may reflect the longer period of time these infants relied on nutritional support in the NICU.

In addition to Ottolini and Limperopoulos, study co-authors include Nickie Andescavage, M.D., Attending, Children’s Neonatal-Perinatal Medicine; and Kushal Kapse.