Neural Progenitor Cell Role in Long Term Neurodevelopmental Outcomes of Prematurely Born Infants

Mirjana Maletic-Savatic, Ph.D.

Baylor College of Medicine

Funded in June, 2008: $200000 for 3 years
LAY SUMMARY . ABSTRACT . BIOGRAPHY .

LAY SUMMARY

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Providing Evidence for Whether Neural Progenitor Cells are Involved in Human Cognition

Investigators will use H-MRS imaging to determine whether infants born extremely prematurely have an abnormally low density of neural progenitor stem cells in the brain’s hippocampus and whether this low density correlates with infants’ long-term cognitive deficits.

While full-term births occur at about the 40th week of pregnancy and the newborns weigh an average 7 lbs 6 oz, advanced neonatal intensive care techniques now enable survival of infants born at less than 30 months of gestation and weighing as little as 2.2 pounds. The more premature and lower weight infants are at the greatest risk of dying after birth, or of surviving but developing long-term cognitive and behavioral impairments. Yet it is not clear why the extent of these cognitive impairments differs among survivors.  The researchers hypothesize that the long-term cognitive outcomes correlate with the density of neural progenitor cells in the brain’s dentate gyrus. This structure is part of the hippocampus, which is involved in memory and learning.  Neural progenitor cells in the dentate gyrus evolve into differentiated brain cells during fetal development, and they also are the source of continuous neurogenesis (development of new brain cells) throughout life.

Premature birth, therefore, might limit the amount of available neural progenitor cells in the dentate gyrus, which in turn might limit full development of the dentate gyrus and the supply of neural progenitor cells needed by the brain for normal cognitive development.  As reported in the journal Science, the investigators developed a non-invasive technique to identify neural progenitor cells in the human brain, and discovered a “biomarker,” a metabolic fingerprint that exists only on these cells. Using H-MRS (proton magnetic resonance spectroscopy), they now will image the density of neural progenitor cells in two groups (20 each) of premature newborns—those under 30 weeks of gestation and those born at 30-36 weeks—with each group further categorized according to whether infants’ birth weight was extremely, very, or somewhat low.  Infants will be re-imaged when they reach normal gestational age and again at 18 months, when they will also undergo cognitive testing.  Results will be compared to those of 20 full-term birth 18 month-olds with other neurological conditions (since it is not ethical to image normal infants) to determine whether lower neural progenitor cell density correlates with cognitive deficiency.   

Significance:  This study will be the first to characterize the neural progenitor cell pool during early development and will provide the first evidence of whether these cells have a role in human cognition.  

ABSTRACT

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Neural Progenitor Cell Role in Long Term Neurodevelopmental Outcomes of Prematurely Born Infants

One of the most pressing tasks that physicians face in a daily practice is the ability to predict long-term consequences of a variety of brain insults. The challenge is even more demanding for prognosis of early brain insults, such as those that occur in extremely preterm infants. Infants born before 32 weeks of gestation represent more than 2 percent of all live births, and most of them survive with long-term disabilities, such as cerebral palsy, cognitive and behavioral impairments, and deficiencies in the sensory perceptions. The risk of long-term disabilities increases with both decreased gestational age at birth (<30 weeks of gestation) and birth weight (<1000g). However, it is still not clear why the extent of long-term outcomes differs, particularly why only some of the children develop severe cognitive impairments compared to others.

We hypothesize that the cognitive outcome of prematurely born children correlates with the density of neural progenitor cells (NPC) in the dentate gyrus. NPC reside in the subgranular zone of the dentate gyrus in the human brain and are the source of continuous neurogenesis throughout life. In the dentate gyrus, neurogenesis has been implicated in learning and memory. In addition, dentate gyrus, being a part of the hippocampal formation, is selectively vulnerable to ischemia and other insults. Therefore, premature birth and brain injury might influence the amount of available NPC in this region. Lack of the sufficient quantity of NPC might influence the capability of the dentate region to develop fully and, therefore, might contribute to the long-term development of cognitive impairments.

In order to test our hypothesis, we have developed a non-invasive methodology to identify NPC in the human brain. We have discovered a metabolic biomarker of NPC which enables their detection by proton magnetic resonance spectroscopy (1H-MRS). We have also developed new signal processing algorithms that enable NPC biomarker detection despite its low concentration in the human brain. In this study, a cohort of prospectively studied preterm infants, divided into infants born before 30 weeks of gestation and those born between 30-36 weeks of gestation, as well as those with extremely low birth weight (BW; <1000g), very low BW (<1500g) and low BW (<2500g) subjects, will be imaged within first week of birth and at their term equivalent. Control subjects will be sex matched full term infants with no neurological complications.

To test if the NPC density correlates with the long-term cognitive deficiency, the prospectively followed prematurely born subjects will have 1H-MRS of the hippocampus at 18 months of life, along with a comprehensive neuropsychological evaluation. Control subjects for this group will be healthy, sex-matched 18-month-old children with appropriate cognitive development based on the same neuropsychological tests.

This is a first study that will investigate the NPC in the human brain. It will give us not only the first insight into the NPC pool in the human brain during early development, but will also have important implications for clinical practice, including the ability to monitor the fundamental changes of the NPC that might occur during a critical period of brain growth. Furthermore, this study might lead to better interventional methodologies aimed to prevent long-term impairments in the group of infants who are at very high risk for development of learning disabilities and mental retardation.

INVESTIGATOR BIOGRAPHIES

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Mirjana Maletic-Savatic, Ph.D.

Dr. Mirjana Maletic-Savatic, Assistant Professor, Baylor College of Medicine, is a Child Neurologist who obtained her M.D. and Ph.D. degrees at the University of Belgrade, Serbia. She continued with her postdoctoral training in the laboratory of Roberto Malinow at Cold Spring Harbor Laboratory, and clinical training in child neurology at Stony Brook University, New York. Her primary scientific interest is to investigate the mechanisms that underlie brain plasticity in health and disease. More specifically, she is interested in the molecular mechanisms that lead to differentiation of neural progenitor cells into neuronal lineages, as well as in the development of new technologies that aim to detect these cells in the live human brain. She is also interested in applying her basic science research into clinical practice, which mostly consists of children affected by early developmental disorders and autism.

Utilizing Metabolomics, a developing field aimed to investigate small molecules that are at the interface of genetically determined expression and environmentally influenced cell responses, she has formulated a unique strategy that can be utilized at cellular and systems level, in vitro and in animal models as well as human subjects in vivo. Such combination of basic neuroscience research, neuroimaging, and clinical research might ultimately lead to novel diagnostic, therapeutic, and prognostic measures for the benefit of children suffering from neurological insults.