2
Symposium Introduction 223 P erinatal brain injury results in extraordinary costs to society, as well as to the affected individuals and their families. Despite recent advances in neonatal intensive care, its overall incidence is not declining. Premature infants have the greatest risk of perinatal brain injury, although term babies with congenital heart or respiratory disease are also susceptible. In the United States alone, about 56 000 very low birth weight (VLBW; weighing less than 1500 g) infants are born annually, of whom 90% will survive (21). Spastic motor deficits, or cerebral palsy (CP), will develop later in 5% to 10% of these survivors, while an additional 25% to 50% will have significant cognitive and neurobehavioral sequelae (21). In both the VLBW infants and term infants with cardiac or pulmonary disease, the underlying commonality is cardiorespiratory compromise and resulting hypoxia-ischemia to the vulnerable, immature brain (21). While there is a spectrum of hypoxic-ischemic lesions encountered in the developing brain, the usual underlying neuropathology as de- termined by autopsy or clinical neuroimaging comprises periventricular leukomalacia (PVL), germinal matrix (ganglionic eminence)/in- traventricular hemorrhage (IVH) with or without periventricular hemorrhagic infarction (PHI), and gray matter injury (20). is Brain Pathology symposium seeks to bring together current investigation into the mechanisms of perinatal brain injury, including excitotoxicity, common to both gray and white matter injury (13); free radical damage, here focusing on PVL (9); and the role of blood products in the tissue injury following germinal matrix hemorrhage (23). In addition, an exciting new avenue of research into the role of subplate neuron injury as a substrate for defective thalamocortical organization and function is reviewed (15). Periventricular leukomalacia (PVL) includes focal necrosis, virtually always accompanied by diffuse white matter gliosis (DWMG). As neonatal intensive care practices improve, the incidence of focally necrotic (cystic) PVL has decreased, and DWMG alone (non-cystic PVL) dominates the clinical picture (21). Factors contributing to the pathogenesis of PVL include relative zones of hypovascularity in the deep, periventricular regions (5, 17), and “pressure-passive” cerebral circulation in the immature brain (19). Oxidative and nitrative injury to immature human white matter also contributes to PVL. In particular, the developing (premyelinating) oligodendroglia (OLs), which do not yet express myelin basic protein, are especially vulnerable to this injury, and undergo apoptosis (10). ese findings, and the reasons for the susceptibility of premyelinating OLs, have been the subjects of intensive research in recent years, reviewed in detail by Haynes and Baud and colleagues, in this issue (9). Potential sources of nitrogen free radicals are discussed, along with preliminary work in human non-PVL white matter showing the expression of inducible NOS in astrocytes (9, 10). e so-called fetal inflammatory response, occurring in the setting of maternofetal infection and epidemiologically associated with PVL (14) may also have a synergistic or additive effect on hypoxia-ischemia, perhaps acting through activated microglia and astrocytes (1, 9). e impact of cytokines on PVL is, of course, under active exploration as well. e contribution of excitotoxicity to perinatal brain injury is reviewed by Johnston, in this issue (13). Maturation-dependent and cell- specific expression of different glutamate receptor subtypes likely confers differential permeability to calcium, resulting in the observed pattern of selective vulnerability of neuroanatomic regions to glutamate toxicity. With respect to PVL, for example, excitotoxic injury to oligodendroglia appears related to the downregulation of both functional activity and subunit expression of α-amino-3-hydroxy-5-meth- yl-4-isoxazolepropionate/kainate (AMPA/KA) receptors in MBP+ cells (4, 6, 18). e relationship of excitotoxicity to hypoxia-ischemia and white matter injury is further illustrated in a P7 rat model of unilateral carotid ligation and hypoxia, in which injury is prevented by administration of an AMPA/KA antagonist (7). Excitotoxic mechanisms are also important in gray matter injury, as reviewed in this issue (13). Germinal matrix/intraventricular hemorrhage remains a significant risk in the preterm infant, and is highly associated with other peri- natal brain lesions (1). Factors contributing to the pathogenesis of germinal matrix hemorrhage include the structure of vessels in this region: they consist of a single layer of endothelium, and have a high density and percent area in the germinal matrix (2). Factors such as cell proliferation have been looked at in a rat model of periventricular/IVH (22), as have the effects of transforming growth factor-β in development of posthemorrhagic hydrocephalus (3). In this issue, the article by Xue and co-workers describes new work regarding the contribution of blood components such as thrombin to the tissue injury adjacent to and resulting from germinal matrix hemorrhage, as elucidated in their model (23). Perinatal damage to gray matter encompasses lesions of the cerebral cortex, basal ganglia, thalamus, hippocampus, cerebellum, and brainstem. In general, in contrast to PVL or germinal matrix/IVH, gray matter injury more commonly affects term infants, suggesting maturation-dependent mechanisms (20). With ever more sophisticated neuroimaging techniques has come the recognition that survivors of preterm birth, with and without PVL, demonstrate significant decreases in gray matter volume, particularly affecting thalamus, hippo- campus, and cerebral cortex, when compared to term infants (11, 12). ese volume losses are distinct from overt gray matter defects due to arterial or border zone infarcts. ey may reflect much more subtle damage to subcellular structures such as dendrites and neuropil, and are postulated to underlie the cognitive and neurobehavioral deficits seen in surviving children who reach school age (21). Given that subplate neurons are critical to the proper development of the cortical plate and connections to and from the thalamus (8), and that subplate neurons are selectively vulnerable to neonatal-hypoxia-ischemia in a rodent model (16), attention in recent years has turned to this fascinating transient cell population in the immature brain, as a possible link to the subtle neurocognitive disturbances often found in survivors of prematurity. is exciting topic is comprehensively reviewed by McQuillen and Ferriero in this Symposium, on perinatal subplate neuron injury and its implications for cortical organization and function (15). Symposium Editor: Rebecca D. Folkerth

Symposium Editor: Rebecca D. Folkerth

  • View
    215

  • Download
    3

Embed Size (px)

Citation preview

Page 1: Symposium Editor: Rebecca D. Folkerth

Symposium Introduction 223

Perinatal brain injury results in extraordinary costs to society, as well as to the affected individuals and their families. Despite recent advances in neonatal intensive care, its overall incidence is not declining. Premature infants have the greatest risk of perinatal brain injury, although term babies with congenital heart or respiratory disease are also susceptible. In the United States alone, about

56 000 very low birth weight (VLBW; weighing less than 1500 g) infants are born annually, of whom 90% will survive (21). Spastic motor deficits, or cerebral palsy (CP), will develop later in 5% to 10% of these survivors, while an additional 25% to 50% will have significant cognitive and neurobehavioral sequelae (21). In both the VLBW infants and term infants with cardiac or pulmonary disease, the underlying commonality is cardiorespiratory compromise and resulting hypoxia-ischemia to the vulnerable, immature brain (21).

While there is a spectrum of hypoxic-ischemic lesions encountered in the developing brain, the usual underlying neuropathology as de-termined by autopsy or clinical neuroimaging comprises periventricular leukomalacia (PVL), germinal matrix (ganglionic eminence)/in-traventricular hemorrhage (IVH) with or without periventricular hemorrhagic infarction (PHI), and gray matter injury (20). This Brain Pathology symposium seeks to bring together current investigation into the mechanisms of perinatal brain injury, including excitotoxicity, common to both gray and white matter injury (13); free radical damage, here focusing on PVL (9); and the role of blood products in the tissue injury following germinal matrix hemorrhage (23). In addition, an exciting new avenue of research into the role of subplate neuron injury as a substrate for defective thalamocortical organization and function is reviewed (15).

Periventricular leukomalacia (PVL) includes focal necrosis, virtually always accompanied by diffuse white matter gliosis (DWMG). As neonatal intensive care practices improve, the incidence of focally necrotic (cystic) PVL has decreased, and DWMG alone (non-cystic PVL) dominates the clinical picture (21). Factors contributing to the pathogenesis of PVL include relative zones of hypovascularity in the deep, periventricular regions (5, 17), and “pressure-passive” cerebral circulation in the immature brain (19). Oxidative and nitrative injury to immature human white matter also contributes to PVL. In particular, the developing (premyelinating) oligodendroglia (OLs), which do not yet express myelin basic protein, are especially vulnerable to this injury, and undergo apoptosis (10). These findings, and the reasons for the susceptibility of premyelinating OLs, have been the subjects of intensive research in recent years, reviewed in detail by Haynes and Baud and colleagues, in this issue (9). Potential sources of nitrogen free radicals are discussed, along with preliminary work in human non-PVL white matter showing the expression of inducible NOS in astrocytes (9, 10). The so-called fetal inflammatory response, occurring in the setting of maternofetal infection and epidemiologically associated with PVL (14) may also have a synergistic or additive effect on hypoxia-ischemia, perhaps acting through activated microglia and astrocytes (1, 9). The impact of cytokines on PVL is, of course, under active exploration as well.

The contribution of excitotoxicity to perinatal brain injury is reviewed by Johnston, in this issue (13). Maturation-dependent and cell-specific expression of different glutamate receptor subtypes likely confers differential permeability to calcium, resulting in the observed pattern of selective vulnerability of neuroanatomic regions to glutamate toxicity. With respect to PVL, for example, excitotoxic injury to oligodendroglia appears related to the downregulation of both functional activity and subunit expression of α-amino-3-hydroxy-5-meth-yl-4-isoxazolepropionate/kainate (AMPA/KA) receptors in MBP+ cells (4, 6, 18). The relationship of excitotoxicity to hypoxia-ischemia and white matter injury is further illustrated in a P7 rat model of unilateral carotid ligation and hypoxia, in which injury is prevented by administration of an AMPA/KA antagonist (7). Excitotoxic mechanisms are also important in gray matter injury, as reviewed in this issue (13).

Germinal matrix/intraventricular hemorrhage remains a significant risk in the preterm infant, and is highly associated with other peri-natal brain lesions (1). Factors contributing to the pathogenesis of germinal matrix hemorrhage include the structure of vessels in this region: they consist of a single layer of endothelium, and have a high density and percent area in the germinal matrix (2). Factors such as cell proliferation have been looked at in a rat model of periventricular/IVH (22), as have the effects of transforming growth factor-β in development of posthemorrhagic hydrocephalus (3). In this issue, the article by Xue and co-workers describes new work regarding the contribution of blood components such as thrombin to the tissue injury adjacent to and resulting from germinal matrix hemorrhage, as elucidated in their model (23).

Perinatal damage to gray matter encompasses lesions of the cerebral cortex, basal ganglia, thalamus, hippocampus, cerebellum, and brainstem. In general, in contrast to PVL or germinal matrix/IVH, gray matter injury more commonly affects term infants, suggesting maturation-dependent mechanisms (20). With ever more sophisticated neuroimaging techniques has come the recognition that survivors of preterm birth, with and without PVL, demonstrate significant decreases in gray matter volume, particularly affecting thalamus, hippo-campus, and cerebral cortex, when compared to term infants (11, 12). These volume losses are distinct from overt gray matter defects due to arterial or border zone infarcts. They may reflect much more subtle damage to subcellular structures such as dendrites and neuropil, and are postulated to underlie the cognitive and neurobehavioral deficits seen in surviving children who reach school age (21). Given that subplate neurons are critical to the proper development of the cortical plate and connections to and from the thalamus (8), and that subplate neurons are selectively vulnerable to neonatal-hypoxia-ischemia in a rodent model (16), attention in recent years has turned to this fascinating transient cell population in the immature brain, as a possible link to the subtle neurocognitive disturbances often found in survivors of prematurity. This exciting topic is comprehensively reviewed by McQuillen and Ferriero in this Symposium, on perinatal subplate neuron injury and its implications for cortical organization and function (15).

Symposium Editor: Rebecca D. Folkerth

Page 2: Symposium Editor: Rebecca D. Folkerth

224 Symposium Introduction

REFERENCES1. Armstrong DL, Sauls CD, Goddard-Finegold J (1987) Neuropathologic findings in short-term survivors of intraventricular hemorrhage. Am J Dis Child 141:617-621.

2. Ballabh P, Braun A, Nedergaard M (2004) Ana-tomic analysis of blood vessels in germinal ma-trix, cerebral cortex, and white matter in devel-oping infants. Pediatr Res 56:117-124.

3. Cherian S, Whitelaw A, Thoresen M, Love S (2004) The pathogenesis of neonatal post-hem-orrhagic hydrocephalus. Brain Pathol 14:305-311.

4. Deng W, Rosenberg PA, Volpe JJ, Jensen FE (2003) Calcium-permeable AMPA/kainate recep-tors mediate toxicity and preconditioning by oxygen-glucose deprivation in oligodendrocyte precursors. Proc Natl Acad Sci U S A 100:6801-6806.

5. De Reuck J (1972) The cortico-subcortical arte-rial angio-architecture in the human brain. Acta Neurol Belg 72:323-329.

6. Fern R, Moller T (2000) Rapid ischemic cell death in immature oligodendrocytes: a fatal glutamate release feedback loop. J Neurosci 20:34-42.

7. Follett PL, Rosenberg PA, Volpe JJ, Jensen FE (2000) NBQX attenuates excitotoxic injury in de-veloping white matter. J Neurosci 20:9235-9241.

8. Ghosh A, Antonini A, McConnell SK, Shatz CJ (1990) Requirement for subplate neurons in the formation of thalamocortical connections. Na-ture 347:179-181.

9. Haynes RL, Baud O, Li J, Kinney HC, Volpe JJ, Folkerth RD (2005) Oxidative and nitrative injury in periventricular leukomalacia: A review. Brain Pathol 15:216-224.

10. Haynes RL, Folkerth RD, Keefe RJ, et al. (2003) Nitrosative and oxidative injury to premyelinat-ing oligodendrocytes in periventricular leukoma-lacia. J Neuropathol Exp Neurol 62:441-450.

11. Inder TE, Huppi PS, Warfield S, et al. (1999) Periventricular white matter injury in the prema-ture infant is associated with a reduction in ce-rebral cortical gray matter volume at term. Ann Neurol 46:755-760.

12. Inder TE, Warfield SK, Wang H, Huppi PS, Volpe JJ (2005) Abnormal cerebral structure is present at term in premature infants. Pediatrics 115:286-294.

13. Johnston MV (2005) Excitotoxicity in perinatal brain injury. Brain Pathol 15:225-231.

14. Leviton A, Paneth N, Reuss ML, et al. (1999) Maternal infection, fetal inflammatory response, and brain damage in very low birth weight in-fants. Developmental Epidemiology Network Investigators. Pediatr Res 46:566-575.

15. McQuillen PS, Ferriero DM (2005) Perinatal subplate neuron injury: Implications for cortical development and plasticity. Brain Pathol 15:241-251.

16. McQuillen PS, Sheldon RA, Shatz CJ, Ferri-ero DM (2003) Selective vulnerability of subplate neurons after early neonatal hypoxia-ischemia. J Neurosci 23:3308-3315.

17. Rorke LB (1992) Anatomical features of the developing brain implicated in pathogenesis of hypoxic-ischemic injury. Brain Pathol 2:211-221.

18. Rosenberg PA, Dai W, Gan XD, et al. (2003) Mature myelin basic protein-expressing oligo-dendrocytes are insensitive to kainate toxicity. J Neurosci Res 71:237-245.

19. Tsuji M, Saul JP, du Plessis A, et al. (2000) Ce-rebral intravascular oxygenation correlates with mean arterial pressure in critically ill premature infants. Pediatrics 106:625-632.

20. Volpe JJ (2003) Cerebral white matter injury of the premature infant-more common than you think. Pediatrics 112:176-180.

21. Volpe JJ (2001) Neurology of the Newborn. 4th ed. Philadelphia: WB Saunders Company.

22. Xue M, Balasubramaniam J, Buist RJ, Peeling J, Del Bigio MR (2003) Periventricular/intraventricu-lar hemorrhage in neonatal mouse cerebrum. J Neuropathol Exp Neurol 62:1154-1165.

23. Xue M, Balasubramaniam J, Parsons KAL, McIntyre IW, Peeling J, Del Bigio MR (2005) Does thrombin play a role in the pathogenesis of brain damage after periventricular hemorrhage? Brain Pathol 15:232-240.