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.