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Vittorio Gallo

Perinatal brain injury headlines American Society for Neurochemistry

Vittorio Gallo

Dr. Gallo’s research could have major implications for overcoming the common behavioral and developmental challenges associated with premature birth.

Children’s National Chief Research Officer Vittorio Gallo, Ph.D., recently had the honor of presenting a presidential lecture at the 48th Annual Meeting of the American Society for Neurochemistry (ASN). The lecture focused on his lifelong investigations of the cellular and molecular mechanisms of white matter development and injury, including myelin and glial cells – which are involved in the brain’s response to injury.

Specifically, he outlined the underlying diffuse white matter injury observed in his lab’s pre-clinical model of perinatal hypoxia, and presented new, non-invasive interventions that promote functional recovery and attenuate developmental delay after perinatal injury in the model. Diffuse white matter injuries are the most frequently observed pattern of brain injury in contemporary cohorts of premature infants. Illuminating methods that might stimulate growth and repair of such injuries shows promise for potential noninvasive strategies that might mitigate the long-term behavioral abnormalities and developmental delay associated with premature birth.

Dr. Gallo’s work in developmental neuroscience has been seminal in deepening understanding of cerebral palsy and multiple sclerosis. During his tenure as center director, he transformed the Center for Neuroscience Research into one of the nation’s premier programs.

ASN gathers nearly 400 delegates from the neurochemistry sector each year, including bench and clinical scientists, principal investigators, graduate students and postdoctoral fellows all actively involved in research from North America and around the world.

Joseph Scafidi

Developing brains are impacted, but can recover, from molecularly targeted cancer drugs

Joseph Scafidi

“The plasticity of the developing brain does make it susceptible to treatments that alter its pathways,” says Joseph Scafidi, D. O., M.S. “Thankfully, that same plasticity means we have an opportunity to mitigate the damage from necessary and lifesaving treatments by providing the right support after the treatment is over.”

One of the latest developments in oncology treatments is the advancement of molecularly targeted therapeutic agents. These drugs can be used to specifically target and impact the signaling pathways that encourage tumor growth, and are also becoming a common go to for ophthalmologists to treat retinopathy of prematurity in neonates.

But in the developing brain of a child or adolescent, these pathways are also crucial to the growth and development of the brain and central nervous system.

“These drugs have been tested in vitro, or in tumor cells, or even in adult studies for efficacy, but there was no data on what happens when these pathways are inhibited during periods when their activation is also playing a key role in the development of cognitive and behavioral skills, as is the case in a growing child,” says Joseph Scafidi, D. O., M.S., a neuroscientist and pediatric neurologist who specializes in neonatology at Children’s National Health System.

As it turns out, when the drugs successfully inhibit tumor growth by suppressing receptors, they can also significantly impact the function of immature brains, specifically changing cognitive and behavioral functions that are associated with white matter and hippocampal development.

The results appeared in Cancer Research, and are the first to demonstrate the vulnerability of the developing brain when this class of drugs is administered. The pre-clinical study looked at the unique impacts of drugs including gefitinib (Iressa), sunitib malate (Sutent) and rapamycin (Sirolimus) that target specific pathways responsible for the rapid growth and development that occurs throughout childhood.

The agents alter signaling pathways in the developing brain, including decreasing the number of oligodendrocytes, which alters white matter growth. Additionally, the agents also impact the function of specific cells within the hippocampus related to learning and memory. When younger preclinical subjects were treated, impacts of exposure were more significant. Tests on the youngest pre-clinical subjects showed significantly diminished capacity to complete cognitive and behavioral tasks and somewhat older, e.g. adolescent, subjects showed somewhat fewer deficits. Adult subjects saw little or no deficit.

“The impacts on cognitive and behavioral function for the developing brain, though significant, are still less detrimental than the widespread impacts of chemotherapy on that young brain,” Dr. Scafidi notes. “Pediatric oncologists, neuro-oncologists and ophthalmologists should be aware of the potential impacts of using these molecularly targeted drugs in children, but should still consider them as a treatment option when necessary.”

The effects are reversible

Researchers also found measurable improvements in these impaired cognitive and behavioral functions when rehabilitation strategies such as environmental stimulation, cognitive therapy and physical activity were applied after drug exposure.

“The plasticity of the developing brain does make it susceptible to treatments that alter its pathways,” says Dr. Scafidi. “Thankfully, that same plasticity means we have an opportunity to mitigate the damage from necessary and lifesaving treatments by providing the right support after the treatment is over.”

Many major pediatric oncology centers, including the Center for Cancer and Blood Disorders at Children’s National, already incorporate rehabilitation strategies such as cognitive therapy and increased physical activity to help pediatric patients return to normal life following treatment. The results from this study suggest that these activities after treatment for pediatric brain tumors may play a vital role in improving recovery of brain cognitive and behavioral function in the pediatric population.

This research was funded by grants to Dr. Scafidi from the National Brain Tumor Society, Childhood Brain Tumor Foundation and the National Institutes of Health.

Carlos Ferreira Lopez

Researchers discover new gene variant for inherited amino acid-elevating disease

Carlos Ferreira Lopez

What’s known

Hypermethioninemia is a rare condition that causes elevated levels of methionine, an essential amino acid in humans. This condition stems from genetic variations inherited from one or both parents. Some forms of hypermethioninemia are recessive, meaning that two copies of defective genes are necessary to cause this disease. Other forms are dominant, meaning that only one copy can cause hypermethioninemia. Recessive forms of the disease tend to have more serious consequences, causing elevated methionine levels throughout life and leading to changes in the brain’s white matter visible on magnetic resonance imaging that can cause neurological problems. The dominant forms are generally thought to be largely benign and require minimal follow-up.

What’s new

A research team led by Carlos R. Ferreira, M.D., a medical geneticist at Children’s National Health System, discovered a new gene variant that had not been associated with hypermethioinemia previously when an infant who had tested positive for elevated methionine on newborn blood-spot screening came in for a follow-up evaluation. While the majority of dominant hypermethioninemia are caused by a genetic mutation known as MAT1A p.Arg264His, the child didn’t have this or any of the common recessive hypermethioninemia mutations. Genetic testing showed that she carried a different mutation to the MAT1A gene known as p.Ala259Val, of which she carried only a single copy. The child fit the typical profile of having the dominant form of the disease, with methionine levels gradually declining over time. Testing of her mother showed that she carried the same gene variant, with few consequences other than a hepatitis-like illness as a child. Because liver disease can accompany dominant hypermethioninemia, the infant’s doctors will continue periodic follow-up to ensure she remains healthy.

Questions for future research

Q: Besides the potential for harmful liver effects, does dominant hypermethioninemia have other negative consequences?

Q: How common is this gene variant, and are certain people at more risk for carrying it?

Source: Confirmation that MAT1A p.Ala259Val mutation causes autosomal dominant hypermethioninemia. Muriello, M.J., S. Viall, T. Bottiglieri, K. Cusmano-Ozog and C. R. Ferreira. Published by Molecular Genetics and Metabolism Reports December 2017.

effects of cardiopulmonary bypass surgery on the white matter of piglets.

The effects of cardiopulmonary bypass on white matter development

 cardiopulmonary bypass

Nobuyuki Ishibashi, M.D., and a team of researchers looked the effects of cardiopulmonary bypass surgery on the white matter of an animal model.

Mortality rates for infants born with congenital heart disease (CHD) have dramatically decreased over the past two decades, with more and more children reaching adulthood. However, many survivors are at risk for neurodevelopmental abnormalities  associated with cardiopulmonary bypass surgery (CPB), including long-term injuries to the brain’s white matter and neural connectivity impairments that can lead to neurological dysfunction.

“Clinical studies have found a connection between abnormal neurological outcomes and surgery, but we don’t know what’s happening at the cellular level,” explains Nobuyuki Ishibashi, M.D., Director of the Cardiac Surgery Research Laboratory at Children’s National. To help shed light on this matter, Ishibashi and a team of researchers looked at the effects of CPB on the white matter of an animal model.

The research team randomly assigned models to receive one of three CPB-induced insults: a sham surgery (control group); full-flow bypass for 60 minutes; and 25°C circulatory arrest for 60 minutes. The team then used fractional anisotropy — a technique that measures the directionality of axon mylenation — to determine white matter organization in the models’ brains. They also used immunohistology techniques to assess the integrity of white matter oligodendrocytes, astrocytes and microglia.

The results, published in the Journal of the American Heart Association, show that white matter experiences region-specific vulnerability to insults associated with CPB, with fibers within the frontal cortex appearing the most susceptible. The team also found that fractional anisotropy changes after CPB were insult dependent and that regions most resilient to CPB-induced fractional anisotropy reduction were those that maintained mature oligodendrocytes.

From these findings, Ishibashi and his co-authors conclude that reducing alterations of oligodendrocyte development in the frontal cortex can be both a metric and a goal to improve neurodevelopmental impairment in the congenital heart disease population. “Because we are seeing cellular damage in these regions, we can target them for future therapies,” explains Ishibashi.

The study also demonstrates the dynamic relationship between fractional anisotropy and cellular events after pediatric cardiac surgery, and indicates that the technique is a clinically relevant biomarker in white matter injury after cardiac surgery.

Vittorio Gallo

How the environment helps to shape the brain

Vittorio Gallo

“The strength, duration and timing of environmental experience influences plasticity in brain circuitry, which is made up of communication cables called axons that link neurons throughout the brain and are coated by myelin, a fatty substance that helps nerve impulses speed from place to place,” says Vittorio Gallo, Ph.D., Chief Research Officer at Children’s National and senior study author.

Researchers have long known that babies of all kinds need to be exposed to rich, complex environments for optimal brain health and potential. Exposure to new sights, sounds and other sensory experiences appears to be critical for strengthening infants’ developing brains and encouraging smoothly running neural networks. Until recently, little was known about the biological mechanisms behind this phenomenon.

In a review article published online Aug. 22, 2017 in Trends in Neurosciences, Children’s National Health System researchers discuss the role of environmental stimuli on the development of myelin—the fatty insulation that surrounds the extensions that connect cells throughout the nervous system and make up a large part of the brain’s white matter. Positive influences, such as exposure to a large vocabulary and novel objects, can boost the growth of myelin. Conversely, negative influences, such as neglect and social isolation, can harm it, potentially altering the course of brain development.

“The strength, duration and timing of environmental experience influences plasticity in brain circuitry, which is made up of communication cables called axons that link neurons throughout the brain and are coated by myelin, a fatty substance that helps nerve impulses speed from place to place,” says Vittorio Gallo, Ph.D., Chief Research Officer at Children’s National and senior study author. “As it responds to environmental stimuli, the brain continually shores up myelin’s integrity. Just as important, damaged myelin can leave gaps in the neural network which can lead to cognitive, motor and behavioral deficits.”

According to Gallo and study lead author Thomas A. Forbes, a pool of oligodendrocyte progenitor cells (OPCs) specialize in making myelin and do so from childhood into adulthood. The resulting oligodendrocyte cells (OLs) form an important working partnership with axons. From approximately 23 to 37 weeks’ gestation, OLs develop in the fetal brain and they continue to be generated after birth until adolescence.

“This dynamic feedback loop between myelin plasticity and neuronal excitability is crucial,” Forbes says. “It helps to strengthen motor and cognitive function and permits children and adults to learn new skills and to record new memories.”

In utero, genetics plays an outsized role in the initial structure of white matter, which is located in the subcortical region of the brain and takes its white color from myelin, the lipid and protein sheath that electrically insulates nerve cells. Defects in the microstructural organization of white matter are associated with many neurodevelopmental disorders. Once infants are born, environmental experiences also can begin to exert a meaningful role.

“The environment can be viewed as a noninvasive therapeutic approach that can be employed to bolster white matter health, either on its own or working in tandem with pharmacologic therapies,” Gallo adds. “The question is how to design the best environment for infants and children to grow and to achieve the highest cognitive function. An enriched environment not only involves the opportunity to move and participate in physical exercise and physical therapy; it is also an environment where there is novelty, new experiences and continuously active learning. It is equally important to minimize social stressors. It’s all about the balance.”

Among the potential interventions to boost brain power, independent of socioeconomic status:

  • Exposing children to new and different objects with an opportunity for physical activity and interaction with a number of playmates. This type of setting challenges the child to continuously adapt to his or her surroundings in a social, physical and experiential manner. In experimental models, enriched environments supported brain health by increasing the volume and length of myelinated fibers, the volume of myelin sheaths and by boosting total brain volume.
  • Exposure to music helps with cognition, hearing and motor skills for those who play an instrument, tapping multiple areas of the brain to work together collaboratively. Diffusion tensor imaging (DTI) reveals that professional pianists who began playing as children have improved white matter integrity and plasticity, Gallo and Forbes
  • At its heart, active learning requires interacting with and adapting to the environment. Generating new OLs influences learning new motor skills in the very young as well as the very old. And cognitive training and stimulation shapes and preserves white matter integrity in the aging.
  • DTI studies indicate that four weeks of integrative mind-body training alters myelination and improves white matter efficiency with especially pronounced changes in the area of the brain responsible for self-regulation, impulse control and emotion.
  • Voluntary exercise in experimental models is associated with OPCs differentiating into mature OLs. Imaging studies show a positive relationship between physical fitness, white matter health and the brain networks involved in memory.

Conversely, such negative influences as premature birth, poor nutrition, disease, neglect and social isolation can degrade myelin integrity, compromising the person’s ability to carry out basic motor skills and cognitive function. Usually, the pool of OPCs expands as the fetus is about to be born. But brain injury, lack of oxygen and restricted blood supply can delay maturation of certain brain cells and can cause abnormalities in white matter that diminish the brain’s capacity to synthesize myelin. Additional white matter insults can be caused by use of anesthesia and stress, among other variables.

The environmental influence has the potential to be “the Archimedes’ Lever to appropriating WM development among a limited range of only partially efficacious treatment options,” the authors conclude.

Breastfeeding Mom

Breast milk helps white matter in preemies

Breastfeeding Mom

Critical white matter structures in the brains of babies born prematurely at low birth weight develop more robustly when their mothers breast-feed them, compared with preemies fed formula.

Breast-feeding offers a slew of benefits to infants, including protection against common childhood infections and potentially reducing the risk of chronic health conditions such as asthma, obesity and type 2 diabetes. These benefits are especially important for infants born prematurely, or before 37 weeks gestation – a condition that affects 1 in 10 babies born in the United States, according to the Centers for Disease Control and Prevention. Prematurely born infants are particularly vulnerable to infections and other health problems.

Along with the challenges premature infants face, there is a heightened risk for neurodevelopmental disabilities that often do not fully emerge until the children enter school. A new study by Children’s National Health System researchers shows that breast-feeding might help with this problem. The findings, presented at the 2017 annual meeting of the Pediatric Academic Societies, show that critical white matter structures in the brains of babies born so early that they weigh less than 1,500 grams develop more robustly when their mothers breast-feed them, compared with preemie peers who are fed formula.

The Children’s National research team used sophisticated imaging tools to examine brain development in very low birth weight preemies, who weighed about 3 pounds at birth.

They enrolled 37 babies who were no more than 32 weeks gestational age at birth and were admitted to Children’s neonatal intensive care unit within the first 48 hours of life. Twenty-two of the preemies received formula specifically designed to meet the nutritional needs of infants born preterm, while 15 infants were fed breast milk. The researchers leveraged diffusion tensor imaging – which measures organization of the developing white matter of the brain – and 3-D volumetric magnetic resonance imaging (MRI) to calculate brain volume by region, structure and tissue type, such as cortical gray matter, white matter, deep gray matter and cerebellum.

“We did not find significant differences in the global and regional brain volumes when we conducted MRIs at 40 weeks gestation in both groups of prematurely born infants,” says Catherine Limperopoulos, Ph.D., director of the Developing Brain Research Laboratory and senior author of the paper. “There are striking differences in white matter microstructural organization, however, with greater fractional anisotropy in the left posterior limb of internal capsule and middle cerebellar peduncle, and lower mean diffusivity in the superior cerebellar peduncle.”

White matter lies under the gray matter cortex, makes up about half of the brain’s volume, and is a critical player in human development as well as in neurological disorders. The increased white matter microstructural organization in the cerebral and cerebellar white matter suggests more robust fiber tracts and microarchitecture of the developing white matter which may predict better neurologic outcomes in preterm infants. These critical structures that begin to form in the womb are used for the rest of the person’s life when, for instance, they attempt to master a new skill.

“Previous research has linked early breast milk feeding with increased volumetric brain growth and improved cognitive and behavioral outcomes,” she says. “These very vulnerable preemies already experience a high incidence rate of neurocognitive dysfunction – even if they do not have detectable structural brain injury. Providing them with breast milk early in life holds the potential to lessen those risks.”

The American Academy of Pediatrics endorses breast-feeding because it lowers infants’ chances of suffering from ear infections and diarrhea in the near term and decreases their risks of being obese as children. Limperopoulos says additional studies are needed in a larger group of patients as well as longer-term follow up as growing infants babble, scamper and color to gauge whether there are differences in motor skills, cognition and writing ability between the two groups.

A sirtuin might help repair a common neonatal brain injury

Sirtuin could repair common neonatal brain injury

A sirtuin might help repair a common neonatal brain injury

A team of researchers  investigated the molecular mechanisms behind oligodendrocyte progenitor cell proliferation in neonatal hypoxia.

What’s known

Hypoxia, or a lack of oxygen, is a major cause of diffuse white matter injury (DWMI). This condition leads to permanent developmental disabilities in prematurely born infants. The long-term abnormalities of the brain’s white matter that characterize DWMI are caused by the loss of a specific type of cells known as oligodendrocytes, which support nerve cells and produce myelin, a lipid and protein sheath that electrically insulates nerve cells. Oligodendrocytes are produced by a population of immature cells known as oligodendrocyte progenitor cells (OPCs). Previous research has shown that hypoxia can trigger OPCs to proliferate and presumably produce new oligodendrocytes. The molecular pathways that hypoxia triggers to make new OPCs remain unclear.

What’s new

A team of researchers led by Vittorio Gallo, Ph.D., director of the Center for Neuroscience Research and the Intellectual and Developmental Disabilities Research Center at Children’s National Health System, investigated the molecular mechanisms behind what prompts OPCs to proliferate in a preclinical model of neonatal hypoxia. The researchers found that a molecule known as Sirt1 acts as a major regulator of OPC proliferation and regeneration. Sirt1 is a sirtuin, a class of molecules that has attracted interest over the past several years for its role in stem cells, aging and inflammation. Hypoxia appears to induce Sirt1 formation. When the researchers prevented brain tissues in petri dishes from making Sirt1 or removed this molecule in preclinical models, these actions prevented OPC proliferation. What’s more, preventing Sirt1 production also inhibited OPCs from making oligodendrocytes. These findings suggest that Sirt1 is essential for replacing oligodendrocytes to repair DWMI after hypoxia. Additionally, finding ways to enhance Sirt1 activity eventually could provide a novel way to help infants recover after hypoxia and prevent DWMI.

Questions for future research

Q: How can Sirt1 activity be enhanced in preclinical models and humans?
Q: Can deficits triggered by diffuse white matter injury be prevented or reversed with Sirt1?
Q: Which other treatments might be useful for diffuse white matter injury?

Source: Sirt1 regulates glial progenitor proliferation and regeneration in white matter after neonatal brain injury.” Jablonska, M., M. Gierdalski, L. Chew, T. Hawley, M. Catron, A. Lichauco, J. Cabrera-Luque, T. Yuen, D. Rowitch and V. Gallo. Published by Nature Communications on Dec. 19, 2016.

Congenital heart disease and cortical growth

The cover of  Science Translational Medicine features a new study of the cellular-level changes in the brain induced by congenital heart disease. Reprinted with permission from AAAS. Not for download

Disruptions in cerebral oxygen supply caused by congenital heart disease have significant impact on cortical growth, according to a research led by Children’s National Health System. The findings of the research team, which include co-authors from the National Institutes of Health, Boston Children’s Hospital and Johns Hopkins School of Medicine, appear on the cover of Science Translational Medicine. The subventricular zone (SVZ) in normal newborns’ brains is home to the largest stockpile of neural stem/progenitor cells, with newly generated neurons migrating from this zone to specific regions of the frontal cortex and differentiating into interneurons. When newborns experience disruptions in cerebral oxygen supply due to congenital heart disease, essential cellular processes go awry and this contributes to reduced cortical growth.

The preliminary findings point to the importance of restoring these cells’ neurogenic potential, possibly through therapeutics, to lessen children’s long-­term neurological deficits.

“We know that congenital heart disease (CHD) reduces cerebral oxygen at a time when the developing fetal brain most needs oxygen. Now, we are beginning to understand the mechanisms of CHD-­induced brain injuries at a cellular level, and we have identified a robust supply of cells that have the ability to travel directly to the site of injury and potentially provide help by replacing lost or damaged neurons,” says Nobuyuki Ishibashi, M.D., Director of the Cardiac Surgery Research Laboratory at Children’s National, and co­-senior study author.

The third trimester of pregnancy is a time of dramatic growth for the fetal brain, which expands in volume and develops complex structures and network connections that growing children rely on throughout adulthood. According to the National Heart, Lung, and Blood Institute, congenital heart defects are the most common major birth defect, affecting 8 in 1,000 newborns. Infants born with CHD can experience myriad neurological deficits, including behavioral, cognitive, social, motor and attention disorders, the research team adds.

Cardiologists have tapped non­invasive imaging to monitor fetal hearts during gestation in high-­risk pregnancies and can then perform corrective surgery in the first weeks of life to fix damaged hearts. Long­ term neurological deficits due to immature cortical development also have emerged as major challenges in pregnancies complicated by CHD.

“I think this is an enormously important paper for surgeons and for children and families who are affected by CHD. Surgeons have been worried for years that the things we do during corrective heart surgery have the potential to affect the development of the brain. And we’ve learned to improve how we do heart surgery so that the procedure causes minimal damage to the brain. But we still see some kids who have behavioral problems and learning delays,” says Richard A. Jonas, M.D., Chief of the Division of Cardiac Surgery at Children’s National, and co-­senior study author. “We’re beginning to understand that there are things about CHD that affect the development of the brain before a baby is even born. What this paper shows is that the low oxygen level that sometimes results from a congenital heart problem might contribute to that and can slow down the growth of the brain. The good news is that it should be possible to reverse that problem using the cells that continue to develop in the neonate’s brain after birth.”

Among preclinical models, the spatiotemporal progression of brain growth in this particular model most closely parallels that of humans. Likewise, the SVZ cytoarchitecture of the neonatal preclinical model exposed to hypoxia mimics that of humans in utero and shortly after birth. The research team leveraged CellTracker Green to follow the path traveled by SVZ­ derived cells and to illuminate their fate, with postnatal SVZ supplying the developing cortex with newly generated neurons. SVZ­ derived cells were primarily neuroblasts. Superparamagnetic iron oxide nanoparticles supplied answers about long­ term SVZ migration, with SVZ ­derived cells making their way to the prefrontal cortex and the somatosensory cortex of the brain.

“We demonstrated that in the postnatal period, newly generated neurons migrate from the SVZ to specific cortices, with the majority migrating to the prefrontal cortex,” says Vittorio Gallo, Ph.D., Director of the Center for Neuroscience Research at Children’s National, and co­-senior study author. “Of note, we revealed that the anterior SVZ is a critical source of newborn neurons destined to populate the upper layers of the cortex. We challenged this process through chronic hypoxia exposure, which severely impaired neurogenesis within the SVZ, depleting this critical source of interneurons.”

In the preclinical model of hypoxia as well as in humans, brains were smaller, weighed significantly less and had a significant reduction in cortical gray matter volume. In the prefrontal cortex, there was a significant reduction in white matter neuroblasts. Taken as a whole, according to the study authors, the findings suggest that impaired neurogenesis within the SVZ represents a cellular mechanism underlying hypoxia ­induced, region ­specific reduction in immature neurons in the cortex. The prefrontal cortex, the region of the brain that enables such functions as judgment, decision­ making and problem solving, is most impacted. Impairments in higher ­order cognitive functions involving the prefrontal cortex are common in patients with CHD.

This is the consequential malfunction of the brain during congenital heart defects.

Congenital heart disease and white matter injury

This is the consequential malfunction of the brain during congenital heart defects.

Although recent advances have greatly improved the survival of children with congenital heart disease, up to 55 percent will be left with injury to their brain’s white matter – an area that is critical for aiding connection and communication between various regions in the brain.

What’s known

Eight of every 1,000 children born each year have congenital heart disease (CHD). Although recent advances have greatly improved the survival of these children, up to 55 percent will be left with injury to their brain’s white matter – an area that is critical for aiding connection and communication between various regions in the brain. The resulting spectrum of neurological deficits can have significant costs for the individual, their family and society. Although studies have demonstrated that white matter injuries due to CHD have many contributing factors, including abnormal blood flow to the fetal brain, many questions remain about the mechanisms that cause these injuries and the best interventions.

What’s new

A Children’s National Health System research team combed existing literature, reviewing studies from Children’s as well as other research groups, to develop an article detailing the current state of knowledge on CHD and white matter injury. The scientists write that advances in neuroimaging – including magnetic resonance imaging, magnetic resonance spectroscopy, Doppler ultrasound and diffusion tensor imaging – have provided a wealth of knowledge about brain development in patients who have CHD. Unfortunately, these techniques alone are unable to provide pivotal insights into how CHD affects cells and molecules in the brain. However, by integrating animal models with findings in human subjects and in postmortem human tissue, the scientists believe that it will be possible to find novel therapeutic targets and new standards of care to prevent developmental delay associated with cardiac abnormalities.

For example, using a porcine model, the Children’s team was able to define a strategy for white matter protection in congenital heart surgery through cellular and developmental analysis of different white matter regions. Another study from Children’s combined rodent hypoxia with a brain slice model to replicate the unique brain conditions in neonates with severe and complex congenital heart disease. This innovative animal model provided novel insights into the possible additive effect of preoperative hypoxia on brain insults due to cardiopulmonary bypass and deep hypothermic circulatory arrest.

The Children’s research team also recently published an additional review article describing the key windows of development during which the immature brain is most vulnerable to CHD-related injury.

Questions for future research

Q: Can we create an animal model that recapitulates the morphogenic and developmental aspects of CHD without directly affecting other organs or developmental processes?
Q: What are the prenatal and neonatal cellular responses to CHD in the developing brain?
Q: What are the molecular mechanisms underlying white matter immaturity and vulnerability to CHD, and how can we intervene?
Q: How can we accurately assess the dynamic neurological outcomes of CHD and/or corrective surgery in animal models?
Q: Prenatal or postnatal insults to the developing brain: which is most devastating in regards to developmental and behavioral disabilities?
Q: How can we best extrapolate from, and integrate, neuroimaging findings/correlations in human patients with cellular/molecular approaches in animal models?

Source: Reprinted from Trends in Neurosciences, Vol. 38/Ed. 6, Paul D. Morton, Nobuyuki Ishibashi, Richard A. Jonas and Vittorio Gallo, “Congenital cardiac anomalies and white matter injury,” pp. 353-363, Copyright 2015, with permission from Elsevier.

Harnessing progenitor cells in neonatal white matter repair

The sirtuin protein Sirt1 plays a crucial role in the proliferation and regeneration of glial cells from an existing pool of progenitor cells — a process that rebuilds vital white matter following neonatal hypoxic brain injury. Although scientists do not fully understand Sirt1’s role in controlling cellular proliferation, this pre-clinical model of neonatal brain injury outlines for the first time how Sirt1 contributes to development of additional progenitor cells and maturation of fully functional oligodendrocytes.

The findings, published December 19 in Nature Communications, suggest that modulation of this protein could enhance progenitor cell regeneration, spurring additional white matter growth and repair following neonatal brain injury.

“It is not a cure. But, in order to regenerate the white matter that is lost or damaged, the first steps are to identify endogenous cells capable of regenerating lost cells and then to expand their pool. The glial progenitor cells represent 4 to 5 percent of total brain cells,” says Vittorio Gallo, Ph.D., Director of the Center for Neuroscience Research at Children’s National, and senior author of the study. “It’s a sizable pool, considering that the brain is made up of billions of cells. The advantage is that these progenitor cells are already there, with no requirement to slip them through the blood-brain barrier. Eventually they will differentiate into oligodendrocyte cells in white matter, mature glia, and that’s exactly what we want them to do.”

The study team identified Sirt1 as a novel, major regulator of basal oligodendrocyte progenitor cell (OPC) proliferation and regeneration in response to hypoxia in neonatal white matter, Gallo and co-authors write. “We demonstrate that Sirt1 deacetylates and activates Cdk2, a kinase which controls OPC expansion. We also elucidate the mechanism by which Sirt1 targets other individual members of the Cdk2 signaling pathway, by regulating their deacetylation, complex formation and E2F1 release, molecular events which drive Cdk2-mediated OPC proliferation,” says Li-Jin Chew, Ph.D., research associate professor at Children’s Center for Neuroscience Research and a study co-author.

Hypoxia-induced brain injury in neonates initiates spontaneous amplification of progenitor cells but also causes a deficiency of mature oligodendrocytes. Inhibiting Sirt1 expression in vitro and in vivo showed that loss of its deacetylase activity prevents OPC proliferation in hypoxia while promoting oligodendrocyte maturation – which underscores the importance of Sirt1 activity in maintaining the delicate balance between these two processes.

The tantalizing findings – the result of four years of research work in mouse models of neonatal hypoxia – hint at the prospect of lessening the severity of developmental delays experienced by the majority of preemies, Gallo adds. About 1 in 10 infants born in the United States are delivered preterm, prior to the 37th gestational week of pregnancy, according to the Centers for Disease Control and Prevention.  Brain injury associated with preterm birth – including white matter injury – can have long-term cognitive and behavioral consequences, with more than 50 percent of infants who survive prematurity needing special education, behavioral intervention and pharmacological treatment, Gallo says.

Time is of the essence, since Sirt1 plays a beneficial role at a certain place (white matter) and at a specific time (while the immature brain continues to develop). “We see maximal Sirt1 expression and activity within the first week after neonatal brain injury. There is a very narrow window in which to harness the stimulus that amplifies the progenitor cell population and target this particular molecule for repair,” he says.

Sirt1, a nicotinamide adenine dinucleotide-dependent class III histone deacetylase, is known to be involved in normal cell development, aging, inflammatory responses, energy metabolism and calorie restriction, the study team reports. Its activity can be modulated by sirtinol, an off-the-shelf drug that inhibits sirtuin proteins. The finding points to the potential for therapeutic interventions for diffuse white matter injury in neonates.

Next, the research team aims to study these processes in a large animal model whose brains are structurally, anatomically and metabolically similar to the human brain.

“Ideally, we want to be able to promote the timely regeneration of cells that are lost by designing strategies for interventions that synchronize these cellular events to a common and successful end,” Gallo says.