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Catherine Limperopoulos

Breastfeeding boosts metabolites important for brain growth

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.

Sudeepta Basu

GABA concentration in pre-term brain increases with gestational age

Sudeepta Basu

“A more complete understanding of the diagnostic and prognostic importance of GABA and glutamate in the preterm brain will help us to direct treatment strategies for the most vulnerable preterm infants at risk of brain injury,” says Sudeepta K. Basu, M.D.

The major neurotransmitters gamma-aminobutyric acid (GABA) and glutamate are pivotal to fetal and newborn brain development and influence evolution of brain injury and repair following preterm birth. Magnetic resonance spectroscopy (MRS) enables in vivo measurement of brain metabolites. However, GABA and glutamate are found in the developing brain in low concentrations, and their weak signal can be swamped by the stronger signal of more dominant metabolites.

A Children’s research team reports findings from a pilot study utilizing an innovative technique of MRS to reliably measure in vivo GABA in the developing preterm brain. The groundbreaking research done by the team that includes Principal Investigator Sudeepta K. Basu, M.D., neonatology attending at Children’s National Health System, is very unique and original since there are no existing data of in vivo GABA concentrations in the developing cerebellum. Under the mentorship of Catherine Limperopoulos, Ph.D., director of Children’s Developing Brain Research Laboratory, the team of multi-disciplinary specialists is pursuing cutting-edge technologies in advanced MRI neuroimaging to explore brain development and injury in preterm infants.

The research, presented at the Eastern Society for Pediatric Research (ESPR) annual meeting by Dr. Basu, was honored with the “2018 Meritorious Poster Award.” The research titled “Distinct temporal trends of GABA and glutamate in the cerebellum and frontal cortex of preterm infants” reports, for the first time, positive temporal trends in the specific regions of the developing brain intricately involved in cognitive and motor functions. This work lays the foundation for developing novel ways to diagnose, monitor and investigative brain protective therapies for vulnerable prematurely born infants.

The Children’s team performed non-sedated MRS in 44 preterm infants whose mean gestational age at birth was 26.5 weeks, placing voxels at the middle of the cerebellum and the right frontal cortex. GABA and GIx (glutamate combined with glutamine) were positively correlated with post-menstrual age in the frontal cortex, but not the cerebellum.  At the ESPR meeting, the team also presented for the first time that caffeine, a neuroprotective agent in preemies, leads to increased in vivo GABA concentration in the developing frontal cortex.

“Open questions include whether these findings reflect varying paces of maturation and vulnerability to injury among specific regions of the brain. Also, the relationship between clinical factors and medication exposure and changes in the concentration of these neurotransmitters may guide brain protective therapies in future,” Dr. Basu says. “A more complete understanding of the diagnostic and prognostic importance of GABA and glutamate in the preterm brain will help us to direct treatment strategies for the most vulnerable preterm infants at risk of brain injury.”

Children’s senior fellows from Division of Neonatology made four platform presentations during the ESPR conference:

  • “Caffeine increases GABA/Cr ratio in frontal cortex of preterm infants on spectroscopy.” Aditi Gupta; Sudeepta K. Basu, M.D.; Mariam Said, M.D.; Subechhya Pradhan, Linda White; Kushal Kapse; Jonathan Murnick, M.D., Ph.D.; Taeun Chang, M.D.; and Catherine Limperopoulos, Ph.D.
  • “Impact of early nutrition on microstructural brain development in VLBW Infants.” Katherine M. Ottolini, Nickie Andescavage, M.D.; Kushal Kapse; and Catherine Limperopoulos, Ph.D.
  • “Direct measurement of neonatal cardiac output utilizing the CO status monitor.” Simranjeet S. Sran, Mariam Said, M.D.; and Khodayar Rais-Bahrami, M.D.
  • “Cerebro-cerebellar diaschisis in preterm infants following unilateral cerebral parenchymal injury.” Huma Mirza, Yao Wu, Kushal Kapse, Jonathan Murnick, M.D., Ph.D.; Taeun Chang, M.D.; and Catherine Limperopoulos, Ph.D.

Spectral data shine light on placenta

preemie baby

A research project led by Subechhya Pradhan, Ph.D., aims to shed light on metabolism of the placenta, a poorly understood organ, and characterize early biomarkers of fetal congenital heart disease.

The placenta serves as an essential intermediary between a pregnant mother and her developing fetus, transporting in life-sustaining oxygen and nutrients, ferrying out waste and serving as interim lungs, kidneys and liver as those vital organs develop in utero.

While the placenta plays a vital role in supporting normal pregnancies, it remains largely a black box to science. A research project led by Subechhya Pradhan, Ph.D., and partially funded by a Clinical and Translational Science Institute Research Award aims to shed light on placenta metabolism and characterize possible early biomarkers of impaired placental function in fetal congenital heart disease (CHD), the most common type of birth defect.

“There is a huge information void,” says Pradhan, a research faculty member of the Developing Brain Research Laboratory at Children’s National Health System. “Right now, we do not have very much information about placenta metabolism in vivo. This would be one of the first steps to understand what is actually going on in the placenta at a biochemical level as pregnancies progress.”

The project Pradhan leads will look at the placentas of 30 women in the second and third trimesters of healthy, uncomplicated pregnancies and will compare them with placentas of 30 pregnant women whose fetuses have been diagnosed with CHD. As volunteers for a different study, the women are already undergoing magnetic resonance imaging, which takes detailed images of the placenta’s structure and architecture. The magnetic resonance spectroscopy scans that Pradhan will review show the unique chemical fingerprints of key metabolites: Choline, lipids and lactate.

Choline, a nutrient the body needs to preserve cellular structural integrity, is a marker of cell membrane turnover. Fetuses with CHD have higher concentrations of lactate in the brain, a telltale sign of a shortage of oxygen. Pradhan’s working hypothesis is that there may be differing lipid profiles and lactate levels in the placenta in pregnancies complicated by CHD.  The research team will extract those metabolite concentrations from the spectral scans to describe how they evolve in both groups of pregnant women.

“While babies born with CHD can undergo surgery as early as the first few days (or sometimes hours) of life to correct their hearts, unfortunately, we still see a high prevalence of neurodevelopmental impairments in infants with CHD. This suggests that neurological dysfunctional may have its origin in fetal life,” Pradhan says.

Having an earlier idea of which fetuses with CHD are most vulnerable has the potential to pinpoint which pregnancies need more oversight and earlier intervention.

Placenta spectral data traditionally have been difficult to acquire because the pregnant mother moves as does the fetus, she adds. During the three-minute scans, the research team will try to limit excess movement using a technique called respiratory gating, which tells the machine to synchronize image acquisition so it occurs in rhythm with the women’s breathing.