Neurology and Neurosurgery

T2-Weighted Magnetic Resonance (MR) Imaging Brain Segmentation

Maternal mental health alters structure and biochemistry of developing fetal brain

Even when pregnant women have uncomplicated pregnancies and high socioeconomic status, when they experience elevated anxiety, stress or depression these prenatal stressors can alter the structure of the developing fetal brain and disrupt its biochemistry, according to Children’s National Hospital research published online Jan. 29, 2020, in JAMA Network Open.

The Children’s National research findings “have enormous scientific, clinical and public health implications,” Charles A. Nelson III, Ph.D.,  Boston Children’s Hospital, writes in a companion editorial.

“Previously we found that 65% of pregnant women who received a diagnosis of fetal congenital heart disease had elevated levels of stress. It’s concerning but not surprising that pregnant women who wonder if their baby will need open heart surgery would feel stress,” says Catherine Limperopoulos, Ph.D., director of the Center for the Developing Brain at Children’s National and the study’s senior author. “In this latest study, we ran the same panel of questionnaires and were surprised to find a high proportion of otherwise healthy pregnant women whose unborn babies are doing well also report high levels of stress.”

Anxiety and depression are the most common mental health problems during pregnancy. To learn more about the implications for the developing fetal brain, the Children’s National research team recruited 119 healthy volunteers with low-risk pregnancies from obstetric clinics in Washington, D.C., from Jan. 1, 2016, to April 17, 2019. The women’s mean age was 34.4 years old. All were high school graduates, 83% were college graduates, and 84% reported professional employment.

T2-Weighted Magnetic Resonance (MR) Imaging Brain Segmentation.

T2-Weighted Magnetic Resonance (MR) Imaging Brain Segmentation. Segmentation results of total brain (orange), cortical gray matter (green), white matter (blue), deep gray matter (brown), brainstem (yellow), cerebellum (light blue), left hippocampus (purple) and right hippocampus (red) on a 3-Dimensional reconstructed T2-weighted MR image of a fetus at 26.4 gestational weeks. The hippocampus plays a central role in memory and behavioral inhibition and contains high concentrations of corticosteroid receptors and, thus, this brain region is sensitive to stress. Credit: JAMA Network Open.

The team performed 193 fetal brain magnetic resonance imaging (MRI) sessions between 24-40 weeks gestation and measured the volume of the total fetal brain as well as the cortical gray matter, white matter, deep gray matter, cerebellum, brainstem and hippocampus volumes. On the same day as their MRI visit, the pregnant women completed validated questionnaires to measure maternal stress, anxiety and depression, answering questions such as “how do you feel right now,” “how do you generally feel” as well as the degree of stressful feelings they experienced the month prior.

Of the pregnant women in the study:

  • 27% tested positive for stress
  • 26% tested positive for anxiety
  • 11% tested positive for depression
  • Maternal anxiety and stress were associated with increased fetal cortical gyrification
  • Elevated maternal depression was associated with decreased creatine and choline levels in the fetal brain
  • Maternal stress scores decreased with increasing gestational age, while anxiety and depression did not

“We report for the first time that maternal psychological distress may be associated with increased fetal local gyrification index in the frontal and temporal lobes,” says Yao Wu, Ph.D., a research associate working with Limperopoulos at Children’s National and the study’s lead author. “We also found an association with left fetal hippocampal volume, with maternal psychological distress selectively stunting the left hippocampal volumetric growth more than the right. And elevated maternal depression was associated with decreased creatine and choline levels in the fetal brain,” Wu adds.

Late in pregnancy – at the time these women were recruited into the cohort study – the fetal brain grows exponentially and key metabolite levels also rise. Creatine facilitates recycling of adenosine triphosphate, the cell’s energy currency. Typically, levels of this metabolite rise, denoting rapid changes and higher cellular maturation; creatine also is known to support cognitive function. Choline levels also typically rise, marking cell membrane turnover as new cells are generated and support memory, mental focus and concentration.

“These women were healthy, and of high socioeconomic status and educational level, leading us to conclude that the prevalence of prenatal maternal psychological distress may be underestimated,” Limperopoulos adds. “While stress is an everyday reality for most of us, this is different because elevated stress during pregnancy can alter fetal brain programming. Our findings underscore the critical need to universally screen all pregnant women for prenatal psychological distress, even young mothers whose pregnancies wouldn’t otherwise raise red flags.”

In addition to Limperopoulos and Wu, Children’s National study co-authors include Yuan-Chiao Lu, Ph.D., research associate; Marni Jacobs, Ph.D., biostatistician; Subechhya Pradhan, Ph.D., research faculty; Kushal Kapse, MS, staff engineer; Li Zhao, Ph.D., research faculty; Nickie Niforatos-Andescavage, M.D., neonatologist; Gilbert Vezina, M.D., director of the neuroradiology program; and Adré  J. du Plessis, M.B.Ch.B., director, Fetal Medicine Institute. Research coordinators Catherine Lopez, MS, Kathryn Lee Bannantine, BSN, and Jessica Lynn Quistorff, MPH, assisted with subject recruitment.

Financial support for the research described in this post was provided by the National Institutes of Health under grant No. RO1 HL116585-01 and the Thrasher Research Fund under Early Career award No. 14764.

Journal Reference:
Yao Wu, Yuan-Chiao Lu, Marni Jacobs, Subechhya Pradhan, Kushal Kapse, Li Zhao, Nickie Niforatos-Andescavage, Gilbert Vezina, Adré J. du Plessis, Catherine Limperopoulos. “Association of prenatal maternal psychological distress with fetal brain growth, metabolism and cortical maturation,” JAMA Network Open, 3(1): e1919940, 2020

Gilbert Vezina

Gilbert Vezina, M.D., recognized with American Society of Pediatric Neuroradiology Gold Medal Award

Gilbert Vezina

Gilbert Vezina, M.D., Director of Neuroradiology in the Division of Diagnostic Imaging and Radiology at Children’s National Hospital, is being recognized at the 2020 American Society of Pediatric Neuroradiology 2nd Annual Meeting with the society’s most distinguished honor, the Gold Medal Award.

The American Society of Pediatric Neuroradiology (ASPNR) Gold Medal is awarded for both professional and personal excellence, honoring individuals who are superb pediatric neuroradiologists, scientists, and/or physicians, and mentors and who also are truly outstanding people. Recipients have consistently extended themselves beyond self-interest to make contributions to the field of pediatric neuroradiology and as such, have elevated the subspecialty. This medal recognizes the exceptional service and achievements of these individuals.

Dr. Vezina completed his undergraduate degree at the Collège Jean-de-Brébeuf, Montréal, Canada and medical school at McGill Medical School, Montréal, Canada. He completed a mixed internship at Montreal General Hospital, Montreal, Canada; residency in Diagnostic Radiology, Massachusetts General Hospital, Boston, Massachusetts followed by a fellowship in Neuroradiology, Boston, Massachusetts.

He began his career at Children’s National Hospital in 1990. He is currently the Director of the Neuroradiology Program at Children’s National Hospital and Professor of Radiology and Pediatrics at George Washington University School of Medicine and Health Sciences, Washington DC. He created the Neuroradiology Fellowship Program in 1993 where he impacted medical students, residents and fellows from around the world. He served as president of ASPNR from 2001-2002 and past President from 2002-2005. He also served as the Interim Chief, Diagnostic Imaging and Radiology at Children’s National for a brief period in 2017.

Congratulations, Dr. Vezina!

William Gaillard

William D. Gaillard, M.D., elected president of the American Epilepsy Society

William Gaillard

“The AES, is one of the oldest neurological professional organizations in the country dedicated to the scientific investigation, exchange of clinical information and eradication of epilepsy and associated disorders, and I’m honored to serve as the new president,” Dr. Gaillard said.

In early December 2019, William D. Gaillard, M.D., chief of the Divisions of Child Neurology, Epilepsy and Neurophysiology at Children’s National Hospital, began his term as president of the American Epilepsy Society (AES) at the annual meeting in Baltimore. The AES is a medical and scientific society with over 4,000 members consisting of clinicians, scientists investigating basic and clinical aspects of epilepsy, and other professionals interested in seizure disorders.

“The AES, is one of the oldest neurological professional organizations in the country dedicated to the scientific investigation, exchange of clinical information and eradication of epilepsy and associated disorders, and I’m honored to serve as the new president,” Dr. Gaillard said.

Dr. Gaillard’s clinical research focuses on the use of advanced imaging to investigate the effect of childhood epilepsy on brain structure and function with an emphasis on cognitive systems. His group also develops and implements imaging strategies to improve epilepsy outcomes.

In addition, Dr. Gaillard, an active participant in AES activities, has served as treasurer and as chair of the Clinical Investigator Workshop and Pediatric Content Committees. He also serves as an associate editor for the journal Epilepsy Research, and as a regular reviewer on AES and Epilepsy Foundation study sections.

As division chief of Child Neurology, Epilepsy and Neurophysiology, Dr. Gaillard directs a team of pediatric specialists who see thousands of patients each year. Dr. Gaillard has worked throughout his career to care for children and young adults with epilepsy from the onset of seizures through novel therapeutic interventions, medication trials and, when appropriate, surgery. Treatment options at Children’s National addresses the full range of the condition, including problems of difficult-to-control epilepsy. Additionally, treatment includes the concurrent social, education and emotional issues faced by children with the condition and their families.

His academic appointments include Professor of Pediatrics and Neurology at George Washington University, Professor of Neurology at Georgetown University, and Professor (adjunct), Hearing and Speech, University of Maryland, College Park.

Lataisia C. Jones on Mission Unstoppable

Getting to know the unstoppable Lataisia C. Jones, Ph.D.

Lataisia C. Jones on Mission Unstoppable

Children’s National Hospital neuroscientist Lataisia C. Jones, Ph.D., appears in the Jan. 18, 2020, edition of Mission Unstoppable, a Saturday morning show aired by CBS that spotlights cutting-edge women leaders in science, technology, engineering and math.

Budding neuroscientist Lataisia C. Jones, Ph.D., is unstoppable. For instance, using everyday items that families can pluck from their own kitchen cabinets, she walks kids through the steps of creating homemade lava lamps. In the process, the youngsters learn a bit of science, like the fact that oil and water do not mix provides the hypnotic magic behind their new lamps.

Jones’ infectious enthusiasm for science that Children’s National Hospital patients and families experience in person during weekly Young Scientist sessions she hosts will be shared nationwide as Jones appears in the Jan. 18, 2020, edition of “Mission Unstoppable.” The half-hour show aired by CBS on Saturday mornings is co-produced by the Geena Davis Institute on Gender in Media and spotlights cutting-edge women leaders in science, technology, engineering and math (STEM).

“I’m excited,” Jones says of the filming experience. “It’s going to be an amazing opportunity to show kids that there is a fun way of learning. This show is opening a lot of doors and a lot of eyes to the fact that science can be fun.”

Jones’ scientific inquiry focuses on the corpus callosum, a network of fibers centrally located in the middle of the brain that is responsible for transferring information from one lobe to another. Her current research leverages experimental models to better understand brain abnormalities associated with autism spectrum disorder. Or, as she tells CBS viewers, studying the brain helps the field better understand how information is processed in order for people to move, learn and think effortlessly.

Lataisia C. Jones on Mission Unstoppable

“I’m excited,” Jones says of the filming experience. “It’s going to be an amazing opportunity to show kids that there is a fun way of learning. This show is opening a lot of doors and a lot of eyes to the fact that science can be fun.”

In September 2019, Jones was selected to serve as an IF/THEN Ambassador by the American Association for the Advancement of Science, the world’s largest general scientific society, to inspire the next generation of women pursuing STEM careers. A postdoctoral fellow in the Center for Neuroscience Research lab run by Masaaki Torii, Ph.D., Jones now also serves as a role model for future scientists, connecting with middle school students in person, virtually and via the CBS network television show.

“A lot of my inspiration comes from individuals who I mentor, which also shows that I am learning as well. If I am able to teach science, translate it in different ways to different audiences, I am helping to fulfill my lifelong dream,” she adds. “I always say we all have an inner scientist.”

As the first African American to earn a Ph.D. from Florida State University’s College of Medicine, Department of Neuroscience, Jones has continued to acquire “first” experiences throughout her academic and professional career. But she’s also motivated to diversify the ranks of science to ensure she’s not the last.

“I am not the normal face you see in science,” she says. “Another reason for me to be stronger and to work harder and get more things done in science is so people who look like me know they can do the same things and know that they’re just as good.”

WATCH: Lataisia C. Jones, Ph.D., explains her research

Epilepsy infographic

At a glance: Comprehensive Pediatric Epilepsy Program

Epilepsy is one of the most common neurological conditions that lasts a lifetime, and, in extreme cases, can lead to death. It affects one out of every 26 people across their lifetime, and 8% of children will have a seizure before leaving childhood. One in 10 children with epilepsy is a candidate for surgery.

Children’s National has one of the largest and most experienced multidisciplinary epilepsy programs in the country with a range of programs specializing in new onset epilepsy, the ketogenic diet, intractable epilepsy, neuroinflammation, neurogenetics, epilepsy surgery, epileptic encephalopathy and more.

The Children’s National epilepsy program is continuously working to improve care for patients through clinical innovation, growing our team and expanding access in locations throughout the region.

Epilepsy infographic

To refer a patient or learn more about our program, call 202-476-3611 or visit ChildrensNational.org/Epilepsy.

Catherine Limperopoulos

Stressful pregnancies can leave fingerprint on fetal brain

Catherine Limperopoulos

“We were alarmed by the high percentage of pregnant women with a diagnosis of a major fetal heart problem who tested positive for stress, anxiety and depression,” says Catherine Limperopoulos, Ph.D., director of the Center for the Developing Brain at Children’s National and the study’s corresponding author.

When a diagnosis of fetal congenital heart disease causes pregnant moms to test positive for stress, anxiety and depression, powerful imaging can detect impaired development in key fetal brain regions, according to Children’s National Hospital research published online Jan. 13, 2020, in JAMA Pediatrics.

While additional research is needed, the Children’s National study authors say their unprecedented findings underscore the need for universal screening for psychological distress as a routine part of prenatal care and taking other steps to support stressed-out pregnant women and safeguard their newborns’ developing brains.

“We were alarmed by the high percentage of pregnant women with a diagnosis of a major fetal heart problem who tested positive for stress, anxiety and depression,” says Catherine Limperopoulos, Ph.D., director of the Center for the Developing Brain at Children’s National and the study’s corresponding author. “Equally concerning is how prevalent psychological distress is among pregnant women generally. We report for the first time that this challenging prenatal environment impairs regions of the fetal brain that play a major role in learning, memory, coordination, and social and behavioral development, making it all the more important for us to identify these women early during pregnancy to intervene,” Limperopoulos adds.

Congenital heart disease (CHD), structural problems with the heart, is the most common birth defect. Still, it remains unclear how exposure to maternal stress impacts brain development in fetuses with CHD.

The multidisciplinary study team enrolled 48 women whose unborn fetuses had been diagnosed with CHD and 92 healthy women with uncomplicated pregnancies. Using validated screening tools, they found:

  • 65% of pregnant women expecting a baby with CHD tested positive for stress
  • 27% of women with uncomplicated pregnancies tested positive for stress
  • 44% of pregnant women expecting a baby with CHD tested positive for anxiety
  • 26% of women with uncomplicated pregnancies tested positive for anxiety
  • 29% of pregnant women expecting a baby with CHD tested positive for depression and
  • 9% women with uncomplicated pregnancies tested positive for depression

All told, they performed 223 fetal magnetic resonance imaging sessions for these 140 fetuses between 21 and 40 weeks of gestation. They measured brain volume in cubic centimeters for the total brain as well as volumetric measurements for key regions such as the cerebrum, cerebellum, brainstem, and left and right hippocampus.

Maternal stress and anxiety in the second trimester were associated with smaller left hippocampi and smaller cerebellums only in pregnancies affected by fetal CHD. What’s more, specific regions — the hippocampus head and body and the left cerebellar lobe – were more susceptible to stunted growth. The hippocampus is key to memory and learning, while the cerebellum controls motor coordination and plays a role in social and behavioral development.

The hippocampus is a brain structure that is known to be very sensitive to stress. The timing of the CHD diagnosis may have occurred at a particularly vulnerable time for the developing fetal cerebellum, which grows faster than any other brain structure in the second half of gestation, particularly in the third trimester.

“None of these women had been screened for prenatal depression or anxiety. None of them were taking medications. And none of them had received mental health interventions. In the group of women contending with fetal CHD, 81% had attended college and 75% had professional educations, so this does not appear to be an issue of insufficient resources,” Limperopoulos adds. “It’s critical that we routinely to do these screenings and provide pregnant women with access to interventions to lower their stress levels. Working with our community partners, Children’s National is doing just that to help reduce toxic prenatal stress for both the health of the mother and for the future newborns. We hope this becomes standard practice elsewhere.”

Adds Yao Wu, Ph.D., a research associate working with Limperopoulos at Children’s National and the study’s lead author: “Our next goal is exploring effective prenatal cognitive behavioral interventions to reduce psychological distress felt by pregnant women and improve neurodevelopment in babies with CHD.”

In addition to Limperopoulos and Wu , Children’s National study co-authors include Kushal Kapse, MS, staff engineer; Marni Jacobs, Ph.D., biostatistician; Nickie Niforatos-Andescavage, M.D., neonatologist; Mary T. Donofrio, M.D., director, Fetal Heart Program; Anita Krishnan, M.D., associate director, echocardiography; Gilbert Vezina, M.D., director, Neuroradiology Program; David Wessel, M.D., Executive Vice President and Chief Medical Officer; and Adré  J. du Plessis, M.B.Ch.B., director, Fetal Medicine Institute. Jessica Lynn Quistorff, MPH, Catherine Lopez, MS, and Kathryn Lee Bannantine, BSN, assisted with subject recruitment and study coordination.

Financial support for the research described in this post was provided by the National Institutes of Health under grant No. R01 HL116585-01 and the Thrasher Research Fund under Early Career award No. 14764.

sleeping baby

False negatives: Delayed Zika effects in babies who appeared normal at birth

sleeping baby

Colombian infants exposed to Zika virus in the womb showed neurodevelopmental delays as toddlers, despite having “normal” brain imaging and head circumference at birth, a finding that underscores the importance of long-term neurodevelopmental follow-up for Zika-exposed infants.

Colombian infants exposed to Zika virus in the womb showed neurodevelopmental delays as toddlers, despite having “normal” brain imaging and head circumference at birth, a finding that underscores the importance of long-term neurodevelopmental follow-up for Zika-exposed infants, according to a cohort study published online Jan. 6, 2020, in JAMA Pediatrics.

“These infants had no evidence of Zika deficits or microcephaly at birth. Neurodevelopmental deficits, including declines in mobility and social cognition, emerged in their first year of life even as their head circumference remained normal,” says Sarah B. Mulkey, M.D. Ph.D., a fetal/neonatal neurologist at Children’s National Hospital and the study’s first author. “About one-third of these newborns who underwent postnatal head ultrasound had nonspecific imaging results, which we believe are the first published results finding a link between subtle brain injuries and impaired neuromotor development in Zika-exposed children.”

The multi-institutional research group led by Children’s National enrolled pregnant women in Atlántico Department, which hugs the Caribbean coast of Colombia, who had been exposed to Zika, and performed a series of fetal magnetic resonance images (MRI) and ultrasounds as their pregnancies progressed.

Even though their mothers had laboratory-confirmed Zika infections, 77 out of 82 of their offspring were born with no sign of congenital Zika syndrome, a constellation of birth defects that includes severe brain abnormalities, eye problems and congenital contractures, and 70 underwent additional testing of neurodevelopment during infancy. These apparently normal newborns were born between Aug. 1, 2016, and Nov. 30, 2017, at the height of the Zika epidemic, and had normal head circumference.

When they were 4 to 8 months or 9 to 18 months of age, the infants’ neurodevelopment was evaluated using two validated tools, the Warner Initial Developmental Evaluation of Adaptive and Functional Skills (a 50-item test of such skills as self-care, mobility, communication and social cognition) and the Alberta Infant Motor Scale (a motor examination of infants in prone, supine, sitting and standing positions). Some infants were assessed during each time point.

Women participating in the study were highly motivated, with 91% following up with appointments, even if it meant traveling hours by bus. In addition to Children’s National faculty traveling to Colombia to train staff how to administer the screening instruments, videotaped assessments, MRIs and ultrasounds were read, analyzed and scored at Children’s National. According to the study team, the U.S. scoring of Alberta Infant Motor Scale tests administered in Colombia is also unprecedented for a research study and offers the potential of remote scoring of infants’ motor skill maturity in regions of the world where pediatric specialists, like child neurologists, are lacking.

“Normally, neurodevelopment in infants and toddlers continues for years, building a sturdy neural network that they later use to carry out complex neurologic and cognitive functions as children enter school,” Dr. Mulkey adds. “Our findings underscore the recommendations by the Centers for Disease Control and Prevention (CDC) that all infants exposed to Zika in the womb undergo long-term follow-up, providing an opportunity to intervene earlier.”

An accompanying editorial by CDC staffers concurs, saying the study reported “intriguing data” that add “to the growing evidence of the need for long-term follow-up for all children with Zika virus exposure in utero to ensure they receive the recommended clinical evaluations even when no structural defects are identified at birth.”

In addition to Dr. Mulkey, study co-authors include Margarita Arroyave-Wessel, MPH, Dorothy I. Bulas, M.D., chief of Diagnostic Imaging and Radiology, JiJi Jiang, MS, Stephanie Russo, BS, Robert McCarter, ScD, research section head, design and biostatistics,  Adré J. du Plessis, M.B.Ch.B., MPH, chief of the Division of Fetal and Transitional Medicine, and co-Senior Author, Roberta L. DeBiasi, MD, MS, chief of the Division of Pediatric Infectious Diseases, all of Children’s National; Colleen Peyton, PT, DPT, of Northwestern University; Yamil Fourzali, M.D., of Sabbag Radiologos, Barranquilla, Colombia; Michael E. Msall, M.D., of University of Chicago Comer Children’s Hospital; and co-Senior Author, Carlos Cure, M.D., BIOMELab, Barranquilla, Colombia.

Funding for the research described in this post was provided by the Thrasher Research Fund, the National Institutes of Health under award Nos. UL1TR001876 and KL2TR001877, and the Leadership Education in Neurodevelopmental and Related Disorders Training Program under grant HRSA/MCHB T73 MC11047.

4th International Symposium on hypothalamic hamartomas

Children’s National co-hosts the 4th International Symposium on hypothalamic hamartomas

The Children’s National Hospital’s Comprehensive Pediatric Epilepsy Program co-hosted the 4th International Symposium on Hypothalamic Hamartomas held in September 2019 in Washington, D.C.

The 2019 Symposium focused on the psychiatric, neuropsychological, neurological and endocrinological comorbidities of Hypothalamic Hamartomas (HH). The participants also looked at treating the whole person – in addition to the tumor – covering the cognitive, physical, emotional and intellectual impacts of HH.

4th International Symposium on hypothalamic hamartomas

Attendees at the 4th International Symposium on Hypothalamic Hamartomas.

Presenters at the Symposium included experts from around the world, such as Children’s National’s Chief of the Divisions of Child Neurology and of Epilepsy and Neurophysiology,, William D. Gaillard, M.D., who moderated the entire event and served as the HH Symposium Chair on the Symposium Steering Committee.  Dr. Gaillard also facilitated a presentation titledDeveloping a New Paradigm for Assessing, Surveilling, & Treating HH Comorbidities” and another presentation titled, “Set 3 Year Research Roadmap & Top Priorities.”

Senior Vice President for the Center for Neuroscience & Behavioral Health, Roger Packer, M.D., also presented at the event on treatments being used in other hypothalamic hamartoma syndromes which may possibly have opportunities for success with treatment of HH.

brain network illustration

$2.5M to protect the brain from metabolic insult

brain network illustration

The brain comprises only 2% of the body’s volume, but it uses more than 20% of its energy, which makes this organ particularly vulnerable to changes in metabolism.

More than 30 million Americans have diabetes, with the vast majority having Type 2 disease. Characterized by insulin resistance and persistently high blood sugar levels, poorly controlled Type 2 diabetes has a host of well-recognized complications: compared with the general population, a greatly increased risk of kidney disease, vision loss, heart attacks and strokes and lower limb amputations.

But more recently, says Nathan A. Smith, MS, Ph.D., a principal investigator in Children’s National Research Institute’s Center for Neuroscience Research, another consequence has become increasingly apparent. With increasing insulin resistance comes cognitive damage, a factor that contributes significantly to dementia diagnoses as patients age.

The brain comprises only 2% of the body’s volume, but it uses more than 20% of its energy, Smith explains – which makes this organ particularly vulnerable to changes in metabolism. Type 2 diabetes and even prediabetic changes in glucose metabolism inflict damage upon this organ in mechanisms with dangerous synergy, he adds. Insulin resistance itself stresses brain cells, slowly depriving them of fuel. As blood sugar rises, it also increases inflammation and blocks nitric oxide, which together narrow the brain’s blood vessels while also increasing blood viscosity.

When the brain’s neurons slowly starve, they become increasingly inefficient at doing their job, eventually succumbing to this deprivation. These hits don’t just affect individual cells, Smith adds. They also affect connectivity that spans across the brain, neural networks that are a major focus of his research.

While it’s well established that Type 2 diabetes significantly boosts the risk of cognitive decline, Smith says, it’s been unclear whether this process might be halted or even reversed. It’s this question that forms the basis of a collaborative Frontiers grant, $2.5 million from the National Science Foundation split between his laboratory; the lead institution, Stony Brook University; and Massachusetts General Hospital/Harvard Medical School.

Smith and colleagues at the three institutions are testing whether changing the brain’s fuel source from glucose to ketones – byproducts from fat metabolism – could potentially save neurons and neural networks over time. Ketones already have shown promise for decades in treating some types of epilepsy, a disease that sometimes stems from an imbalance in neuronal excitation and inhibition. When some patients start on a ketogenic diet – an extreme version of a popular fat-based diet – many can significantly decrease or even stop their seizures, bringing their misfiring brain cells back to health.

Principal Investigator Smith and his laboratory at the Children’s National Research Institute are using experimental models to test whether ketones could protect the brain against the ravages of insulin resistance. They’re looking specifically at interneurons, the inhibitory cells of the brain and the most energy demanding. The team is using a technique known as patch clamping to determine how either insulin resistance or insulin resistance in the presence of ketones affect these cells’ ability to fire.

They’re also looking at how calcium ions migrate in and out of the cells’ membranes, a necessary prerequisite for neurons’ electrical activity. Finally, they’re evaluating whether these potential changes to the cells’ electrophysiological properties in turn change how different parts of the brain communicate with each other, potentially restructuring the networks that are vital to every action this organ performs.

Colleagues at Athinoula A. Martinos Center for Biomedical Imaging at Massachusetts General Hospital and Harvard Medical School, led by Principal Investigator Eva-Maria Ratai, Ph.D.,  will perform parallel work in human subjects. They will use imaging to determine how these two fuel types, glucose or ketones, affect how the brain uses energy and produces the communication molecules known as neurotransmitters. They’re also investigating how these factors might affect the stability of neural networks using techniques that investigate the performance of these networks both while study subjects are at rest and performing a task.

Finally, colleagues at the Laufer Center for Physical and Quantitative Biology at Stony Brook University, led by Principal Investigator Lilianne R. Mujica-Parodi, Ph.D., will use results generated at the other two institutions to construct computational models that can accurately predict how the brain will behave under metabolic stress: how it copes when deprived of fuel and whether it might be able to retain healthy function when its cells receive ketones instead of glucose.

Collectively, Smith says, these results could help retain brain function even under glucose restraints. (For this, the research team owes a special thanks to Mujica-Parodi, who assembled the group to answer this important question, thus underscoring the importance of team science, he adds.)

“By supplying an alternate fuel source, we may eventually be able to preserve the brain even in the face of insulin resistance,” Smith says.

Dr. Kurt Newman in front of the capitol building

Making healthcare innovation for children a priority

Dr. Kurt Newman in front of the capitol building

Recently, Kurt Newman, M.D., president and CEO of Children’s National Hospital, authored an opinion piece for the popular political website, The Hill. In the article, he called upon stakeholders from across the landscape to address the significant innovation gap in children’s healthcare versus adults.

As Chair of the Board of Trustees of the Children’s Hospital Association,  Dr. Newman knows the importance of raising awareness among policy makers at the federal and state level about the healthcare needs of children. Dr. Newman believes that children’s health should be a national priority that is addressed comprehensively. With years of experience as a pediatric surgeon, he is concerned by the major inequities in the advancements of children’s medical devices and technologies versus those for adults. That’s why Children’s National is working to create collaborations, influence policies and facilitate changes that will accelerate the pace of pediatric healthcare innovation for the benefit of children everywhere. One way that the hospital is tackling this challenge is by developing the Children’s National Research & Innovation Campus, which will be the nation’s first innovation campus focused on pediatric research.

Research & Innovation Campus

Children’s National welcomes Virginia Tech to its new campus

Children’s National Hospital and Virginia Tech create formal partnership that includes the launch of a Virginia Tech biomedical research facility within the new Children’s National Research & Innovation Campus.

Children’s National Hospital and Virginia Tech recently announced a formal partnership that will include the launch of a 12,000-square-foot Virginia Tech biomedical research facility within the new Children’s National Research & Innovation Campus. The campus is an expansion of Children’s National that is located on a nearly 12-acre portion of the former Walter Reed Army Medical Center in Washington, D.C. and is set to open its first phase in December 2020. This new collaboration brings together Virginia Tech, a top tier academic research institution, with Children’s National, a U.S. News and World Report top 10 children’s hospital, on what will be the nation’s first innovation campus focused on pediatric research.

Research & Innovation Campus

“Virginia Tech is an ideal partner to help us deliver on what we promised for the Children’s National Research & Innovation Campus – an ecosystem that enables us to accelerate the translation of potential breakthrough discoveries into new treatments and technologies,” says Kurt Newman, M.D., president and CEO, Children’s National. “Our clinical expertise combined with Virginia Tech’s leadership in engineering and technology, and its growing emphasis on biomedical research, will be a significant advance in developing much needed treatment and cures to save children’s lives.”

Earlier this year, Children’s National announced a collaboration with Johnson & Johnson Innovation LLC to launch JLABS @ Washington, DC at the Research & Innovation Campus. The JLABS @ Washington, DC site will be open to pharmaceutical, medical device, consumer and health technology companies that are aiming to advance the development of new drugs, medical devices, precision diagnostics and health technologies, including applications in pediatrics.

“We are proud to welcome Virginia Tech to our historic Walter Reed campus – a campus that is shaping up to host some of the top minds, talent and innovation incubators in the world,” says Washington, D.C. Mayor Muriel Bowser. “The new Children’s National Research & Innovation Campus will exemplify why D.C. is the capital of inclusive innovation – because we are a city committed to building the public and private partnerships necessary to drive discoveries, create jobs, promote economic growth and keep D.C. at the forefront of innovation and change.”

Faculty from the Children’s National Research Institute and the Fralin Biomedical Research Institute at Virginia Tech Carilion (VTC) have worked together for more than a decade, already resulting in shared research grants, collaborative publications and shared intellectual property. Together, the two institutions will now expand their collaborations to develop new drugs, medical devices, software applications and other novel treatments for cancer, rare diseases and other disorders.

“Joining with Children’s National in the nation’s capital positions Virginia Tech to improve the health and well-being of infants and children around the world,” says Virginia Tech President Tim Sands, Ph.D. “This partnership resonates with our land-grant mission to solve big problems and create new opportunities in Virginia and D.C. through education, technology and research.”

The partnership with Children’s National adds to Virginia Tech’s growing footprint in the Washington D.C. region, which includes plans for a new graduate campus in Alexandria, Va. with a human-centered approach to technological innovation. Sands said the proximity of the two locations – just across the Potomac – will enable researchers to leverage resources, and will also create opportunities with the Virginia Tech campus in Blacksburg, Va. and the Virginia Tech Carilion Health Science and Technology campus in Roanoke, Va.

Carilion Clinic and Children’s National have an existing collaboration for provision of certain specialized pediatric clinical services. The more formalized partnership between Virginia Tech and Children’s National will drive the already strong Virginia Tech-Carilion Clinic partnership, particularly for children’s health initiatives and facilitate collaborations between all three institutions in the pediatric research and clinical service domains.

Children’s National and Virginia Tech will engage in joint faculty recruiting, joint intellectual property, joint training of students and fellows, and collaborative research projects and programs according to Michael Friedlander, Ph.D., Virginia Tech’s vice president for health sciences and technology, and executive director of the Fralin Biomedical Research Institute at VTC.

“The expansion and formalization of our partnership with Children’s National is extremely timely and vital for pediatric research innovation and for translating these innovations into practice to prevent, treat and ultimately cure nervous system cancer in children,” says Friedlander, who has collaborated with Children’s National leaders and researchers for more than 20 years. “Both Virginia Tech and Children’s National have similar values and cultures with a firm commitment to discovery and innovation in the service of society.”

“Brain and other nervous system cancers are among the most common cancers in children (alongside leukemia),” says Friedlander. “With our strength in neurobiology including adult brain cancer research in both humans and companion animals at Virginia Tech and the strength of Children’s National research in pediatric cancer, developmental neuroscience and intellectual disabilities, this is a perfect match.”

The design of the Children’s National Research & Innovation Campus not only makes it conducive for the hospital to strengthen its prestigious partnerships with Virginia Tech and Johnson & Johnson, it also fosters synergies with federal agencies like the Biomedical Advanced Research and Development Authority, which will collaborate with JLABS @ Washington, DC to establish a specialized innovation zone to develop responses to health security threats. As more partners sign on, this convergence of key public and private institutions will accelerate discoveries and bring them to market faster for the benefit of children and adults.

“The Children’s National Research & Innovation Campus pairs an inspirational mission to find new treatments for childhood illness and disease with the ideal environment for early stage companies. I am confident the campus will be a magnet for big ideas and will be an economic boost for Washington DC and the region,” says Jeff Zients, who was appointed chair of the Children’s National Board of Directors effective October 1, 2019. As a CEO and the former director of President Obama’s National Economic Council, Zients says that “When you bring together business, academia, health care and government in the right setting, you create a hotbed for innovation.”

Ranked 7th in National Institutes of Health research funding among pediatric hospitals, Children’s National continues to foster collaborations as it prepares to open its first 158,000-square-foot phase of its Research & Innovation Campus. These key partnerships will enable the hospital to fulfill its mission of keeping children top of mind for healthcare innovation and research while also contributing to Washington D.C.’s thriving innovation economy.

Xanxin Pei

Dr. Yanxin Pei receives prestigious grant from V Foundation for Cancer Research

Xanxin Pei

When asked about this award, Dr. Pei noted “I am so deeply grateful to receive this support from the V Foundation for Cancer Research…I will use these resources to aid our goal of discovering new therapies to treat medulloblastoma.”

Yanxin Pei, Ph.D., assistant professor in the Brain Tumor Institute and the Children’s Research Institute at Children’s National Hospital in Washington, D.C., has recently been awarded a prestigious grant by the V Foundation for Cancer Research to support her groundbreaking work in finding new treatments for childhood medulloblastoma.

Dr. Pei, who joined Children’s National in 2014 after training in the Wechsler-Reya lab at the Sanford-Burnham Institute in La Jolla, CA, has focused her work on the biology of medulloblastoma, the most common malignant brain tumor in children, with a major emphasis on the study of the medulloblastoma subtype most resistant to treatment. Children with this form of medulloblastoma have less than a 30% chance of survival five years from their diagnosis.

Having already developed one of the most important mouse models of this disease, Dr. Pei’s present V Foundation for Cancer Research Award, which includes becoming a V scholar, will explore the role of metabolism in the development of metastasis in MYC-amplified medulloblastomas (the most virulent form of medulloblastoma).

The V Foundation for Cancer Research Award is one of a series of prestigious awards Dr. Pei has received over the past 18 months for her work, including an NIH-sponsored 5-year award (ROI) evaluating other aspects of medulloblastoma development and resistance to therapy, and grants from the Rally Foundation, the Meghan Rose Bradley Foundation and the Children’s Cancer Foundation.

When asked about this award, Dr. Pei noted “I am so deeply grateful to receive this support from the V Foundation for Cancer Research…I will use these resources to aid our goal of discovering new therapies to treat medulloblastoma.”

Her cutting-edge work is generating national and international attention and firmly places Dr. Pei as an international leader in medulloblastoma research.

Jake and Dr. Oluigbo

Doctors at Children’s National give Jake his life back

Jake and Dr. Oluigbo

At the age of 17, Jake underwent surgery led by neurosurgeon Chima Oluigbo, M.D., where he conducted a temporal lobe resection, also called temporal lobectomy, that works to lower the number of seizures, make them less severe or stop them completely. The surgery ended up being successful and it worked to greatly improve his overall quality of life.

Since 1969, November has been considered Epilepsy Awareness Month to highlight the importance of recognizing a seizure and promoting seizure first aid. At Children’s National Hospital, doctors in the division of neurology are committed to finding treatments for epilepsy and have done just that by helping Jacob Yates, an 18-year-old patient, get his life back.

For many families the holidays are meant for spending time with loved ones and enjoying the seasonal festivities. However, the holidays were not always a joyous occasion for Jake and his family. Since he was a baby, many of his holidays were spent in a bed due to a brain disorder that caused him to have developmental delays and, at times, up to 17 seizures a day.

“The holidays were always a tough time for the family because Jake would get so excited around Christmas that it would overwhelm his system and induce seizures that took him days to recover from,” says his mom, Jennifer.

Jake was born a preemie and hours after he was born, doctors at his local hospital had identified that he was having trouble breathing. By coincidence, the Children’s National transport team was on-site to take another patient to Children’s National, but once they looked at Jake they immediately took him instead by SkyBear Air Transport, the hospital’s rapid helicopter transport service.

During his stay at Children’s National, Jake was in the neonatal intensive care unit (NICU) for 11 days and was supported by breathing machines to help with respiratory distress and other issues stemming from him being born prematurely.

“If it wasn’t for the Children’s National transport team coincidentally being at our local hospital, Jake wouldn’t have survived staying at that location,” said Jennifer.

After he was taken care of at Children’s National, he was discharged 11 days later, but at the age of three months Jake was still experiencing respiratory issues and was taken back to his local hospital in Charles County.

“When he first arrived back at the University of Maryland Charles Regional Medical Center, the doctors thought he may have had cystic fibrosis, but it came back that perhaps he was suffering from reflux and they put him on medication,” Jennifer recalls. Unfortunately, this was not the cause and it would not be the family’s last visit to the hospital.

By the age of six months, Jake had his first seizure and he was flown back to Children’s National. Over the next year he was repeatedly admitted to the hospital as his seizures had caused him to stop breathing.

Between the ages of 4 to 6 years old, Jake became a patient of William D. Gaillard, M.D., division chief of epilepsy and neurophysiology and Roger Packer, M.D., senior vice president at the Center of Neuroscience and Behavioral Health at Children’s National. After his visit, both doctors recommended surgery, but Dr. Packer recommended that Jake receive an electroencephalogram (EEG), magnetic resonance imaging (MRI) and go through a sleep study first to identify the specific causes of his seizures.

Now on a new medication, his seizures were maintained for the most part, but doctors were still recommending that it was time for surgery. When Jake was 15, his parents re-evaluated the surgery and learned that their son had a 76% chance of being seizure and medication free.

At the age of 17, Jake underwent surgery led by Chima Oluigbo, M.D., neurosurgeon at Children’s National, where he conducted a temporal lobe resection, also called temporal lobectomy, that works to lower the number of seizures, make them less severe or stop them completely. The surgery ended up being successful and it worked to greatly improve his overall quality of life.

Before the surgery, Jake didn’t speak much, experienced anxiety and had difficulty expressing his emotions. He had never told his mother that he loved her. After the surgery, Jake looked at his mother and said, “I love you babe.”

According to Jennifer, since the surgery her son is a completely different person and states that he has been seizure free for over a year. Equally, Jake and the family can now all look forward to the holidays.

“We’re so excited to have him share the holidays,” Jennifer says. “He feels better and it shows through his attitude and the way he responds to things. Words can’t express the gratitude we have for the doctors at Children’s National Hospital. They gave my son his life back.”

a necrotic muscle fiber with Duchenne’s Muscular Dystrophy

Children’s National Hospital to host 30th Annual Pediatric Neurology Update

a necrotic muscle fiber with Duchenne’s Muscular Dystrophy

The Children’s National Hospital’s Center for Neuroscience and Behavioral Medicine is proud to host the 30th Annual Pediatric Neurology Update course.

This year’s course will feature two critical areas in pediatric neuroscience: neuromuscular diseases with a special emphasis on the scientific, medical, ethical and financial implications of the new molecular genetic therapies for pediatric neuromuscular disease (including Werdnig- Hoffmann and Duchenne’s Muscular Dystrophy) and advances in neurocritical care.

We invite you to join us for presentations from renowned experts in the field during this full-day, CME accredited event on April 2, 2020.

For more information and to register, visit ChildrensNational.org/NeurologyUpdate.

t-cells

Tailored T-cell therapies neutralize viruses that threaten kids with PID

t-cells

Tailored T-cells specially designed to combat a half dozen viruses are safe and may be effective in preventing and treating multiple viral infections, according to research led by Children’s National Hospital faculty.

Catherine Bollard, M.B.Ch.B., M.D., director of the Center for Cancer and Immunology Research at Children’s National and the study’s senior author, presented the teams’ findings Nov. 8, 2019, during a second-annual symposium jointly held by Children’s National and the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH). Children’s National and NIAID formed a research partnership in 2017 to develop and conduct collaborative clinical research studies focused on young children with allergic, immunologic, infectious and inflammatory diseases. Each year, they co-host a symposium to exchange their latest research findings.

According to the NIH, more than 200 forms of primary immune deficiency diseases impact about 500,000 people in the U.S. These rare, genetic diseases so impair the person’s immune system that they experience repeated and sometimes rare infections that can be life threatening. After a hematopoietic stem cell transplantation, brand new stem cells can rebuild the person’s missing or impaired immune system. However, during the window in which the immune system rebuilds, patients can be vulnerable to a host of viral infections.

Because viral infections can be controlled by T-cells, the body’s infection-fighting white blood cells, the Children’s National first-in-humans Phase 1 dose escalation trial aimed to determine the safety of T-cells with antiviral activity against a half dozen opportunistic viruses: adenovirus, BK virus, cytomegalovirus (CMV), Epstein-Barr virus (EBV), Human Herpesvirus 6 and human parainfluenza-3 (HPIV3).

Eight patients received the hexa-valent, virus-specific T-cells after their stem cell transplants:

  • Three patients were treated for active CMV, and the T-cells resolved their viremia.
  • Two patients treated for active BK virus had complete symptom resolution, while one had hemorrhagic cystitis resolved but had fluctuating viral loads in their blood and urine.
  • Of two patients treated prophylactically, one developed EBV viremia that was treated with rituximab.

Two additional patients received the T-cell treatments under expanded access for emergency treatment, one for disseminated adenoviremia and the other for HPIV3 pneumonia. While these critically ill patients had partial clinical improvement, they were being treated with steroids which may have dampened their antiviral responses.

“These preliminary results show that hexaviral-specific, virus-specific T-cells are safe and may be effective in preventing and treating multiple viral infections,” says Michael Keller, M.D., a pediatric immunologist at Children’s National and the lead study author. “Of note, enzyme-linked immune absorbent spot assays showed evidence of antiviral T-cell activity by three months post infusion in three of four patients who could be evaluated and expansion was detectable in two patients.”

In addition to Drs. Bollard and Keller, additional study authors include Katherine Harris M.D.; Patrick J. Hanley Ph.D., assistant research professor in the Center for Cancer and Immunology; Allistair Abraham, M.D., a blood and marrow transplantation specialist; Blachy J. Dávila Saldaña, M.D., Division of Blood and Marrow Transplantation; Nan Zhang Ph.D.; Gelina Sani BS; Haili Lang MS; Richard Childs M.D.; and Richard Jones M.D.

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Children’s National-NIAID 2019 symposium presentations

“Welcome and introduction”
H. Clifford Lane, M.D., director of NIAID’s Division of Clinical Research

“Lessons and benefits from collaboration between the NIH and a free-standing children’s hospital”
Marshall L. Summar, M.D., director, Rare Disease Institute, Children’s National

“The hereditary disorders of PropionylCoA and Cobalamin Metabolism – past, present and future”
Charles P. Venditti, M.D., Ph.D., National Human Genome Research Institute Collaboration

“The road(s) to genetic precision therapeutics in pediatric neuromuscular disease: opportunities and challenges”
Carsten G. Bönnemann, M.D., National Institute of Neurological Disorders and Stroke

“Genomic diagnostics in immunologic diseases”
Helen Su, M.D., Ph.D., National Institute of Allergy and Infectious Diseases

“Update on outcomes of gene therapy clinical trials for X-SCID and X-CGD and plans for future trials”
Harry Malech, M.D., National Institute of Allergy and Infectious Diseases

“Virus-specific T-cell therapies: broadening applicability for PID patients”
Catherine Bollard, M.D., Children’s National 

“Using genetic testing to guide therapeutic decisions in Primary Immune Deficiency Disease”
Vanessa Bundy, M.D., Ph.D., Children’s National 

Panel discussion moderated by Lisa M. Guay-Woodford, M.D.
Drs. Su, Malech, Bollard and Bundy
Morgan Similuk, S.C.M., NIAID
Maren Chamorro, Parent Advocate

“Underlying mechanisms of pediatric food allergy: focus on B cells
Adora Lin, M.D., Ph.D., Children’s National 

“Pediatric Lyme outcomes study – interim update”
Roberta L. DeBiasi, M.D., MS, Children’s National 

“Molecular drivers and opportunities in neuroimmune conditions of pediatric onset”
Elizabeth Wells, M.D., Children’s National 

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Also read: Johan’s story
View: Safeguarding Johan’s future

Newborn baby laying in crib

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

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

pastel colored DNA strands

Germline microsatellite genotypes differentiate children with medulloblastoma

pastel colored DNA strands

A new study suggests that medulloblastoma-specific germline microsatellite variations mark those at-risk for medulloblastoma development.

Brian Rood, M.D., oncologist and medical director at the Brain Tumor Institute, and Harold “Skip” Garner, Ph.D., associate vice provost for research development at Edward Via College of Osteopathic Medicine, published a report in the Society for Neuro-Oncology’s Neuro-Oncology Journal about using a novel approach to identify specific markers in germline (non-tumor) DNA called microsatellites that can differentiate children who have the brain tumor medulloblastoma (MB) from those who don’t.

“Ultimately, the best way to save children from brain tumors and prevent them from bearing long-term side effects from treatment is to prevent those tumors from occurring in the first place,” says Dr. Rood. “New advancements hold the potential to finally realize the dream of cancer prevention, but we must first identify those children at-risk.”

While analyzing germline sequencing data from a training set of 120 MB subjects and 425 controls, the doctors identified 139 individual microsatellites whose genotypes differ significantly between the groups. Using a genetic algorithm, they were able to construct a subset of 43 microsatellites that distinguish MB subjects from controls with a sensitivity and specificity of 92% and 88% respectively.

“We made discoveries in an untapped part of the human genome, enabled by unique bioinformatics data mining approaches combined with clinical insight,” said Dr. Garner. “Our findings establish new genomic directions that can lead to high accuracy diagnostics for predicting susceptibility to medulloblastoma.”

What the doctors discovered and demonstrated in the study was that MB-specific germline microsatellite variations mark those at risk for MB development and suggest that other mechanisms of cancer predisposition beyond heritable mutations exist for MB.

“This work is the first to demonstrate the ability of specific DNA sequences to differentiate children with cancer from their healthy counterparts,” added Dr. Rood.

Contributing Authors to this research study included:  Brian R. Rood, M.D., Harold R. Garner, Ph.D., Samuel Rivero-Hinojosa, Ph.D., and Nicholas Kinney, Ph.D.

mitochondria

Molecular gatekeepers that regulate calcium ions key to muscle function

mitochondria

Controlled entry of calcium ions into the mitochondria, the cell’s energy powerhouses, makes the difference between whether muscles grow strong or easily tire and perish from injury, according to research published in Cell Reports.

Calcium ions are essential to how muscles work effectively, playing a starring role in how and when muscles contract, tap energy stores to keep working and self-repair damage. Not only are calcium ions vital for the repair of injured muscle fibers, their controlled entry into the mitochondria, the cell’s energy powerhouses, spells the difference between whether muscles will be healthy or if they will easily tire and perish following an injury, according to research published Oct. 29, 2019, in Cell Reports.

“Lack of the protein mitochondrial calcium uptake1 (MICU1) lowers the activation threshold for calcium uptake mediated by the mitochondrial calcium uniporter in both, muscle fibers from an experimental model and fibroblast of  a patient lacking MICU1,” says Jyoti K. Jaiswal, MSc, Ph.D., a principal investigator in the Center for Genetic Medicine Research at Children’s National Hospital and one of the paper’s corresponding authors. “Missing MICU1 also tips the calcium ion balance in the mitochondria when muscles contract or are injured, leading to more pronounced muscle weakness and myofiber death.”

Five years ago, patients with a very rare disease linked to mutations in the mitochondrial gene MICU1 were described to suffer from a neuromuscular disease with signs of muscle weakness and damage that could not be fully explained.

To determine what was going awry, the multi-institutional research team used a comprehensive approach that included fibroblasts donated by a patient lacking MICU1 and an experimental model whose MICU1 gene was deleted in the muscles.

Loss of MICU1 in skeletal muscle fibers leads to less contractile force, increased fatigue and diminished capacity to repair damage to their cell membrane, called the sarcolemma. Just like human patients, the experimental model suffers more pronounced muscle weakness, increased numbers of dead myofibers, with greater loss of muscle mass in certain muscles, like the quadriceps and triceps, the research team writes.

“What was happening to the patient’s muscles was a big riddle that our research addressed,” Jaiswal adds. “Lacking this protein is not supposed to make the muscle fiber die, like we see in patients with this rare disease. The missing protein is just supposed to cause atrophy and weakness.”

Patients with this rare disease show early muscle weakness, fluctuating levels of fatigue and lethargy, muscle aches after exercise, and elevated creatine kinase in their bloodstream, an indication of cell damage due to physical stress.

“One by one, we investigated these specific features in experimental models that look normal and have normal body weight, but also show lost muscle mass in the quadriceps and triceps,” explains Adam Horn, Ph.D., the lead researcher in Jaiswal’s lab who conducted this study. “Our experimental model lacking MICU1 only in skeletal muscles responded to muscle deficits so similar to humans that it suggests that some of the symptoms we see in patients can be attributed to MICU1 loss in skeletal muscles.”

Future research will aim to explore the details of how the impact of MICU1 deficit in muscles may be addressed therapeutically and possible implications of lacking MICU1 or its paralog in other organs.

In addition to Jaiswal and Horn, Children’s National Hospital Center for Genetic Medicine Research co-authors include Marshall W. Hogarth and Davi A. Mazala. Additional co-authors include Lead Author Valentina Debattisti, Raghavendra Singh, Erin L. Seifert, Kai Ting Huang, and Senior Author György Hajnóczky, all from Thomas Jefferson University; and Rita Horvath, from Newcastle University.

Financial support for research described in this post was provided by the National Institutes of Health under award numbers R01AR55686, U54HD090257 and RO1 GM102724; National Institute of Arthritis and Musculoskeletal and Skin Diseases under award number T32AR056993; and Foundation Leducq.

doctor checking pregnant woman's belly

Novel approach to detect fetal growth restriction

doctor checking pregnant woman's belly

Morphometric and textural analyses of magnetic resonance imaging can point out subtle architectural deviations associated with fetal growth restriction during the second half of pregnancy, a first-time finding that has the promise to lead to earlier intervention.

Morphometric and textural analyses of magnetic resonance imaging (MRI) can point out subtle architectural deviations that are associated with fetal growth restriction (FGR) during the second half of pregnancy. The first-time finding hints at the potential to spot otherwise hidden placental woes earlier and intervene in a more timely fashion, a research team led by Children’s National Hospital faculty reports in Pediatric Research.

“We found reduced placental size, as expected, but also determined that the textural metrics are accelerated in FGR when factoring in gestational age, suggesting premature placental aging in FGR,” says Nickie Andescavage, M.D., a neonatologist at Children’s National and the study’s lead author. “While morphometric and textural features can discriminate placental differences between FGR cases with and without Doppler abnormalities, the pattern of affected features differs between these sub-groups. Of note, placental insufficiency with abnormal Doppler findings have significant differences in the signal-intensity metrics, perhaps related to differences of water content within the placenta.”

The placenta, an organ shared by the pregnant woman and the developing fetus, delivers oxygen and nutrients to the developing fetus and ferries away waste products. Placental insufficiency is characterized by a placenta that develops poorly or is damaged, impairing blood flow, and can result in still birth or death shortly after birth. Surviving infants may be born preterm or suffer early brain injury; later in life, they may experience cardiovascular, metabolic or neuropsychiatric problems.

Because there are no available tools to help clinicians identify small but critical changes in placental architecture during pregnancy, placental insufficiency often is found after some damage is already done. Typically, it is discovered when FGR is diagnosed, when a fetus weighs less than 9 of 10 fetuses of the same gestational age.

“There is a growing appreciation for the prenatal origin of some neuropsychiatric disorders that manifest years to decades later. Those nine months of gestation very much define the breath of who we later become as adults,” says Catherine Limperopoulos, Ph.D., director of MRI Research of the Developing Brain at Children’s National and the study’s senior author. “By identifying better biomarkers of fetal distress at an earlier stage in pregnancy and refining our imaging toolkit to detect them, we set the stage to be able to intervene earlier and improve children’s overall outcomes.”

The research team studied 32 healthy pregnancies and compared them with 34 pregnancies complicated by FGR. These women underwent up to two MRIs between 20 weeks to 40 weeks gestation. They also had abdominal circumference, fetal head circumference and fetal femur length measured as well as fetal weight estimated.

In pregnancies complicated by FGR, placentas were smaller, thinner and shorter than uncomplicated pregnancies and had decreased placental volume. Ten of 13 textural and morphometric features that differed between the two groups were associated with absolute birth weight.

“Interestingly, when FGR is diagnosed in the second trimester, placental volume, elongation and thickness are significantly reduced compared with healthy pregnancies, whereas the late-onset of FGR only affects placental volume,” Limperopoulos adds. “We believe with early-onset FGR there is a more significant reduction in the developing placental units that is detected by gross measures of size and shape. By the third trimester, the overall shape of the placenta seems to have been well defined so that primarily volume is affected in late-onset FGR.”

In addition to Dr. Andescavage and Limperopoulos, study co-authors include Sonia Dahdouh, Sayali Yewale, Dorothy Bulas, M.D., chief of the Division of Diagnostic Imaging and Radiology, and Biostatistician, Marni Jacobs, Ph.D., MPH, all of Children’s National; Sara Iqbal, of MedStar Washington Hospital Center; and Ahmet Baschat, of Johns Hopkins Center for Fetal Therapy.

Financial support for research described in this post was provided by the National Institutes of Health under award number 1U54HD090257, R01-HL116585, UL1TR000075 and KL2TR000076, and the Clinical-Translational Science Institute-Children’s National.

little girl reaching for gun

Empowering pediatricians to reduce preventable firearm injuries and deaths

little girl reaching for gun

Lenore Jarvis, M.D., MEd, FAAP, will participate in a symposium of surgeons, neurosurgeons and emergency medicine doctors during the American Academy of Pediatrics National Conference and Exhibition – the first time these groups have come together to help reduce the number of kids hurt or killed by firearms.

Lenore Jarvis, M.D., MEd, FAAP, remembers feeling fatigue and frustration when, despite her team’s herculean efforts, a 5-year-old died from accidental gunshot wounds. The preschooler had been feeling playful: He surprised a family member who mistook him for an intruder and fired, fatally wounding the child.

As an Emergency Medicine and Trauma Services specialist at Children’s National Hospital, Dr. Jarvis has cared for kids with a range of firearm-related injuries from accidental shootings, intentional acts of violence or suicide attempts. Even when children survive such traumatic injuries, their lives are indelibly altered.

“We’re trained to save lives, but we also want to prevent childhood injuries, if possible. As I considered this young child’s life ending so prematurely and so tragically, I thought I should do more. I could do more,” recalls Dr. Jarvis, the division’s director of advocacy and health policy.

To that end, in addition to advocacy at the regional and national level, on Oct. 26, 2019, Dr. Jarvis will participate in a four-hour symposium of surgeons, neurosurgeons and emergency medicine doctors during the American Academy of Pediatrics (AAP) National Conference and Exhibition – the first time these groups have come together to explore ways they can help to reduce the number of kids hurt or killed by firearms.

Dr. Jarvis will set the stage for the day’s collective call to action when she counsels pediatricians about how they can advocate within the clinic by simple actions such as:

  • Asking families if there are firearms in the home
  • Making time for such conversations during routine care, including well-child visits
  • Paying special attention to warning signs of suicide and depression
  • Having frank conversations with parents about curious toddlers

“The safest home is a home without a firearm. If that’s not possible, the firearm should be stored in a locked cabinet with the ammunition stored separately,” she says. “Toddlers are especially curious and they actively explore their environment. An unsecured firearm can be a tragic accident waiting to happen with curious young children in the home. And if teenagers happen upon the weapon, it could be used in a homicide or suicide.”

In addition to empowering clinicians to have these conversations routinely, symposium speakers will emphasize empowering parents to ask other families: “Is there an unlocked gun in your house?”

“It’s no different than a parent of a child with a life-threatening sensitivity to peanuts asking if there are peanuts in any home that child may visit,” she adds. “As one of the leading causes of death among children and youth, unsecured firearms are even more dangerous than peanuts. And families should feel comfortable making informed decisions about whether their children will be safe as they play and socialize with friends.”

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AAP National Conference and Exhibition presentation
Saturday, Oct. 26, 2:15 p.m. to 6:15 p.m. (ET)
“AAP NCE Section on Emergency Medicine/Section on Surgery/Section on Neurosurgery gun advocacy joint program”