The challenge of understanding cerebral white matter injury in the premature infant

Abstract

White matter injury in the premature infant leads to motor and more commonly behavioral and cognitive problems that are a tremendous burden to society. While there has been much progress in understanding unique vulnerabilities of developing oligodendrocytes over the past 30years, there remain no proven therapies for the premature infant beyond supportive care. The lack of translational progress may be partially explained by the challenge of developing relevant animal models when the etiology remains unclear, as is the case in this disorder. There has been an emphasis on hypoxia-ischemia and infection/inflammation as upstream etiologies, but less consideration of other contributory factors. This review highlights the evolution of white matter pathology in the premature infant, discusses the prevailing proposed etiologies, critically analyzes a sampling of common animal models and provides detailed support for our hypothesis that nutritional and hormonal deprivation may be additional factors playing critical and overlooked roles in white matter pathology in the premature infant.

Keywords: cerebral palsy; glutamate; nutrition; oligodendrocyte; prematurity; white matter.

Figure 1. MRI showing diffuse white matter injury

Magnetic resonance images of diffuse white matter injury in a former 24 weeks gestational age infant studied at 12 months of age (A&C) and an age-matched control (B&D). Sagittal T1 images in the injured infant (A) compared to the control infant (B) demonstrate diffuse thinning of the corpus callosum (arrow). Axial T2 fluid-attentuated inversion-recovery (FLAIR) images (C&D) demonstrate diffusely increased signal in the periventricular white matter (arrows) and ventriculomegaly in the injured infant (C) compared to the control infant (D). This injured child developed mild spastic diparesis and later cognitive problems in school. [Images courtesy of Dr. Janet Soul]

Figure 2. Oligodendrocyte Lineage

Progression of the oligodendroglial lineage (OL) through the four major developmental stages. A2B5 identifies OL progenitors, O4 identifies Pre-OLs, O1 identifies Immature OLs and MBP identifies Mature OLs. The predominant form in cerebral white matter of the premature infant is the O4-positive pre-oligodendrocyte. [from: Volpe JJ, Kinney HC, Jensen FE, Rosenberg PA (2011) The developing oligodendrocyte: key cellular target in brain injury in the premature infant. International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience 29:423–440. Figure 2]

Figure 3. Spectrum of Injury in Rice-Vannucci Model

A–D, Nissl stains of coronal brain sections from rat sacrificed on P14 after left carotid artery ligation and subsequent two-hour hypoxia on P7. Panel A, B, C and D represents two coronal brain sections illustrating the brain injury score of 0, 1, 2, and 3, respectively. [from: Lai PC, Huang YT, Wu CC, Lai CJ, Wang PJ, Chiu TH (2011) Ceftriaxone attenuates hypoxic-ischemic brain injury in neonatal rats. Journal of biomedical science 18:69. Figure 1]

Figure 4. Brain Growth Spurt

The brain growth spurts of 7 mammalian species expressed as first-order velocity curves of the increase in weight with age. The units of time for each species are as follows: guinea pig: days; rhesus monkey: 4 days; sheep: 5 days; pig: weeks; man: months; rabbit: 2 days; rat: days. Rates are expressed as weight gain as a percentage of adult weight for each unit of time. [from: Dobbing J, Sands J (1979) Comparative aspects of the brain growth spurt. Early human development 3:79–83. Figure 1]

Figure 5. Human Myelination is Mostly Postnatal

Median age when mature myelin (degree 3) is reached. *age in postconceptional weeks at which 50% of infants attain mature myelin. †myelin maturity interval, i.e. the time interval in weeks from the age at which 50% of infants reach degree 1 myelin to the age at which 50% reach degree 3 myelin at an individual white matter site. [from: Kinney HC, Brody BA, Kloman AS, Gilles FH (1988) Sequence of central nervous system myelination in human infancy. II. Patterns of myelination in autopsied infants. Journal of neuropathology and experimental neurology 47:217–234. Table 3]

Figure 6. Components of Myelin

Lipid and protein composition of central nervous system myelin. [from: Deber CM, Reynolds SJ (1991) Central nervous system myelin: structure, function, and pathology. Clinical biochemistry 24:113–134. Table 2]

Figure 7. White Matter Volume in Premature and Mature Newborns

(A) The scatterplot shows the relative volume of myelinated WM as a percentage of intracranial volume in single gestation preterm and full-term infants (n = 35). The polynomial function fits the data. (Myelinated WM = 0.002 x postconceptional age [weeks] − 0.22 x postconceptional age [weeks] + 6.3 x postconceptional age [weeks] − 60.2.) A logarithmic transform of myelinated WM was used for the calculation of the linear regression model with r² = 0.6 and p < 0.001. (B) The scatterplot shows the absolute volume of myelinated WM in single-gestation preterm and full-term infants (n = 35). The polynomial finction fits the data. (Myelinated WM = 0.006 X postconceptional age [weeks] − 0.5 x postconceptional age [weeks] + 13.5 x postconceptional age [weeks] − 111.3.) Log (myelinated WM) was used for the calculation of the linear regression model with r² =0.8 and p < 0.001. [from: Huppi PS, Warfield S, Kikinis R, Barnes PD, Zientara GP, Jolesz FA, Tsuji MK, Volpe JJ (1998) Quantitative magnetic resonance imaging of brain development in premature and mature newborns. Annals of neurology 43:224–235. Figure 8]

Figure 8. Accretion of Plasmalogens and Other Lipids in the Human Brain

A) Concentration profile of total plasmalogens in the human forebrain and cerebellum, in μmole/g wet tissue plotted with gestational age (weeks) and postnatal age (months). In the cerebrum the increase before 32 weeks is not significant, while it is very rapid and significant between this point and the limit of the prenatal period(r=0.94; P<0.001). In the cerebellum, the plasmalogen concentration profile during the prenatal period is parabolic and highly signficant (r=0.89, P<0.001). [from: Martinez M, Ballabriga A (1978) A chemical study on the development of the human forebrain and cerebellum during the brain ‘growth spurt’ period. I. Gangliosides and plasmalogens. Brain research 159:351–362. Figures 2 and 3]

Figure 9. Accumulation of Brain Lipids and Myelination

Lecithin (unfilled circles) and plasmalogen (filled circles) content of rate brain during development with intensity of myelin staining shown by luxol fast blue staining. [from: Cuzner ML, Davison AN, Gregson NA (1965) Chemical and Metabolic Studies of Rat Myelin of the Central Nervous System. Annals of the New York Academy of Sciences 122:86–94. Figure 3]

Figure 10. Myelin Protein in Well Nourished and Undernourished Rats

Recovery of myelin protein from brains of well-nourished (open circles) and undernourished (closed circles) rats. Each point represents a single preparation of myelin from two or more animals. [from: Wiggins RC, Miller SL, Benjamins JA, Krigman MR, Morell P (1976) Myelin synthesis during postnatal nutritional deprivation and subsequent rehabilitation. Brain research 107:257–273. Figure 1]

Figure 11. Below Goal Growth Velocity in 30–35 Week Gestation Infants

Growth velocity (g/k/d) from 15 NICUs from birth to discharge. *p<0.01 vs “best net growth” NICU #1. Differences between NICUs remain significant after controlling for BW, BW Z-score, GA and gender and LOS. Gray box indicates goal growth 15–20g/kg/day. [from: Blackwell MT, Eichenwald EC, McAlmon K, Petit K, Linton PT, McCormick MC, Richardson DK (2005) Interneonatal intensive care unit variation in growth rates and feeding practices in healthy moderately premature infants. Journal of perinatology : official journal of the California Perinatal Association 25:478–485. Figure 2D]

Figure 12. Cumulative Energy Deficit Leads to Extrauterine Growth Restriction

Energy intake, cumulative energy deficit and change in Z-score for body weight during the first 7 weeks of life. It takes 1 to 2 weeks to establish adequate dietary intakes with the result that all infants accrue a significant energy deficit, which is paralleled by significant postnatal growth retardation. [from: Cooke R (2005) Postnatal growth in preterm infants: have we got it right? Journal of perinatology : official journal of the California Perinatal Association 25 Suppl 2:S12–14. Figure 1]

Figure 13. Neurodevelopmental Outcome and In-Hospital Growth

Relation between in-hospital growth velocity and neurodevelopment in a cohort of North American neonatal intensive care unit infants with a birth weight between 501 and 1000 g. Weight-gain quartiles were divided into 12 (n = 124), 15.6 (n = 122), 17.8 (n = 123), and 21.2 (n = 121) g•kg⁻¹•d⁻¹. Weight-gain quartiles were compared by using Mantel-Haenszel chi-square test. MDI, motor developmental index; PDI, physical developmental index. [from: Lafeber HN, van de Lagemaat M, Rotteveel J, van Weissenbruch M (2013) Timing of nutritional interventions in very-low-birth-weight infants: optimal neurodevelopment compared with the onset of the metabolic syndrome. The American journal of clinical nutrition. Figure 1, adapted from Ehrenkranz et al., 2006]

Figure 14. IGF-1 Concentrations Increase with Gestational Age

Individual values of fetal insulin-like growth factor-I (IGF-I) (μg/l) and the range for gestational age (mean, fifth and 95th confidence intervals). [from: Langford K, Nicolaides K, Miell JP (1998) Maternal and fetal insulin-like growth factors and their binding proteins in the second and third trimesters of human pregnancy. Human reproduction 13:1389–1393. Figure 1]

Figure 15. Sudden Drop of Estrogen After Birth

During pregnancy, maternal 17b-estradiol (E2) plasma levels increase up to 100-fold (15,000 pg/mL, approximately 55 nM), largely because of placental aromatization of C-19 steroids produced by fetal adrenal glands, compared with plasma estrogen concentrations in nonpregnant females. After birth, E2 decreases to low levels (5–35 pg/mL, or 20–130 pM) within 24 hr. [Courtesy B. Gerstner, adapted from: Tulchinsky D, Hobel CJ, Yeager E, Marshall JR (1972) Plasma estrone, estradiol, estriol, progesterone, and 17-hydroxyprogesterone in human pregnancy. I. Normal pregnancy. American journal of obstetrics and gynecology 112:1095–1100 and Ishida T, Seo F, Hirato K, Fukuda T, Yanaihara T, Araki H, Nakayama T (1985) Changes in placental enzymatic activities in relation to estrogen production during pregnancy. Nihon Sanka Fujinka Gakkai zasshi 37:547–554].

Figure 16. Hypothyroidism Decreases Myelin Lipids

Proteolipid content in brains of hypothyroid and control rats during the critical period for myelination. [from: Rosman NP, Malone MJ, Helfenstein M, Kraft E (1972) The effect of thyroid deficiency on myelination of brain. A morphological and biochemical study. Neurology 22: 99–106. Figure 9]