Neonatal Encephalopathy: Association of Cytokines with MR Spectroscopy and Outcome

Bartha, Agnes I.; Foster-Barber, Audrey; Miller, Steven P.; Vigneron, Daniel B.; Glidden, David V.; Barkovich, A. James; Ferriero, Donna M.

doi:10.1203/01.pdr.0000144819.45689.bb

Cited by 165 publications

(131 citation statements)

References 31 publications

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“…Inflammatory markers in the developing brain increase in response to H-I (26)(27)(28). To assess the level of neuroinflammation, we determined the levels of cytokines in the hippocampus of injured and noninjured hemispheres by multianalyte profiling and markers of microglia and astrocytes by immunohistochemistry in tissues of wild-type and cytNmnat1-Tg animals at P9 (2 d after H-I) and P14 (7 d after H-I), respectively.…”

Section: Resultsmentioning

confidence: 99%

Nicotinamide mononucleotide adenylyl transferase 1 protects against acute neurodegeneration in developing CNS by inhibiting excitotoxic-necrotic cell death

Verghese

Sasaki

Yang

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Hypoxic-ischemic (H-I) injury to the developing brain is a significant cause of morbidity and mortality in humans. Other than hypothermia, there is no effective treatment to prevent or lessen the consequences of neonatal H-I. Increased expression of the NAD synthesizing enzyme nicotinamide mononucleotide adenylyl transferase 1 (Nmnat1) has been shown to be neuroprotective against axonal injury in the peripheral nervous system. To investigate the neuroprotective role of Nmnat1 against acute neurodegeneration in the developing CNS, we exposed wild-type mice and mice overexpressing Nmnat1 in the cytoplasm (cytNmnat1-Tg mice) to a well-characterized model of neonatal H-I brain injury. As early as 6 h after H-I, cytNmnat1-Tg mice had strikingly less injury detected by MRI. CytNmnat1-Tg mice had markedly less injury in hippocampus, cortex, and striatum than wild-type mice as assessed by loss of tissue volume 7 d days after H-I. The dramatic protection mediated by cytNmnat1 is not mediated through modulating caspase3-dependent cell death in cytNmnat1-Tg brains. CytNmnat1 protected neuronal cell bodies and processes against NMDA-induced excitotoxicity, whereas caspase inhibition or B-cell lymphoma-extra large (Bcl-XL) protein overexpression had no protective effects in cultured cortical neurons. These results suggest that cytNmnat1 protects against neonatal HI-induced CNS injury by inhibiting excitotoxicity-induced, caspase-independent injury to neuronal processes and cell bodies. As such, the Nmnat1 protective pathway could be a useful therapeutic target for acute and chronic neurodegenerative insults mediated by excitotoxicity.

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Section: Resultsmentioning

confidence: 99%

Nicotinamide mononucleotide adenylyl transferase 1 protects against acute neurodegeneration in developing CNS by inhibiting excitotoxic-necrotic cell death

Verghese

Sasaki

Yang

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…44 Of particular note is a meta-analysis of studies examining the association between chorioamnionitis and CP, which suggests that clinical chorioamnionitis significantly increases the risk of CP amongst term-born infants, based on combined data from two small studies (relative risk [RR] 4.7; 95% CI 1.3-16.2). 45 Only one study examined the association between CP and histological chorioamnionitis, reporting a relative risk of 8.9 (95% CI 1.9-40); however, this positive association is also reflected by data from cases reviewed for medico-legal consultation, which revealed strong correlations between severe histological fetal chorioamnionitis and CP amongst infants with neurological impairments (OR 13.2, 95% CI 1.2-144).…”

Section: Observations On Placental Pathologymentioning

confidence: 99%

Inflammation‐induced sensitization of the brain in term infants

Fleiss

Tann

Degos

et al. 2015

Develop Med Child Neuro

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COXPerinatal insults are a leading cause of infant mortality and amongst survivors are frequently associated with neurocognitive impairment, cerebral palsy (CP), and seizure disorders. The events leading to perinatal brain injury are multifactorial. This review describes how one subinjurious factor affecting the brain sensitizes it to a second injurious factor, causing an exacerbated injurious cascade. We will review the clinical and experimental evidence, including observations of high rates of maternal and fetal infections in term-born infants with neonatal encephalopathy and cerebral palsy. In addition, we will discuss preclinical evidence for the sensitizing effects of inflammation on injuries, such as hypoxia-ischaemia, our current understanding of the mechanisms underpinning the sensitization process, and the possibility for neuroprotection. PERINATAL BRAIN INJURY IN THE TERM-BORN INFANTIntrapartum neonatal deaths are the third leading cause of global childhood mortality. 1 In addition, each year perinatal insults are estimated to be responsible for more than one million new cases of neonatal encephalopathy, and nearly half a million infants with impairments such as cerebral palsy (CP).2 Infants exposed to a perinatal insult typically present with encephalopathy, a descriptive term for a clinical constellation of neurological dysfunctions in the term-born that includes difficulty with initiating and maintaining respiration; depression of tone and reflexes; subnormal levels of consciousness; and seizures.3 Whilst often assumed to result solely from acute intrapartum hypoxic-ischaemia, the precise contribution of hypoxia is likely to vary according to the definition of encephalopathy used, the range of competing risks, and the care setting. 3,4 Presumed hypoxia-ischaemia is diagnosed based on reduced Apgar scores and acidosis, 5 and the combination of progressive hypoxia, hypercarbia, and acidosis is often referred to as asphyxia. 6 Encephalopathy resulting from hypoxia-ischaemia can be clearly diagnosed only in a small number of cases in which a sentinel event, such as placental abruption, uterine rupture, cord prolapse, or shoulder dystocia, is clearly present. Clinical studies have identified a number of other important antepartum and intrapartum risk factors for neonatal encephalopathy. [7][8][9][10] In low-income settings, where access to skilled birth attendants and emergency obstetric intervention is often limited, the probability of intrapartum hypoxic events contributing to neonatal encephalopathy is increased.2,9,11 However, in general, neonatal encephalopathy is likely to be a multifactorial condition with complex aetiology, encompassing several causal events, with strong evidence that fetal exposure to infection contributes. 12 CONCEPT OF INFLAMMATION-INDUCED SENSITIZATIONAn increasingly common model for the complex and multifactorial process of perinatal brain injury involves sensitization, 13-15 whereby factors not severe enough by themselves to induce significant brain damage make the developi...

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“…High interleukin (IL)-6 and IL-1␤ concentrations in amniotic fluid have been found in preterm infants with white matter (WM) lesions (1), and elevated IL-6, IL-8, and IL-1 ␤ levels in both umbilical and neonatal blood samples of preterm infants have been found to associate with intracerebral hemorrhage (2,3). Furthermore, in term infants, higher blood levels of IL-6, IL-8, and IL-1 ␤ have been reported to associate with abnormal neurodevelopmental outcome at 30 mo of age (4). In contrast, there are studies showing no association between the level of cord serum or neonatal blood proinflammatory cytokines and preterm infant's brain damage (5,6) and neurodevelopmental outcome of preterm infants at 2 y of corrected age (5).…”

mentioning

confidence: 99%

Interleukin-6 -174 and -572 Genotypes and the Volume of Deep Gray Matter in Preterm Infants

et al. 2009

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Preterm infants have smaller cerebral and cerebellar volumes at term compared with term born infants. Perinatal factors leading to the reduction in volumes are not well known. IL-6 -174 and -572 genotypes partly regulate individual immunologic responses and have also been connected with deviant neurologic development in preterm infants. Our hypothesis was that IL-6 -174 and -572 genetic polymorphisms are associated with brain lesions and regional brain volumes in very low birth weight or in very preterm infants. DNA was genotyped for IL-6 -174 and -572 polymorphisms (GG/GC/CC). Study infants (n ϭ 175) were categorized into three groups according to the most pathologic brain finding in ultrasound examinations until term. The brain MRI performed at term was analyzed for regional brain volumes. Analyzed IL-6 genotypes did not show statistically significant association with structural brain lesions. However, IL-6 -174 CC and -572 GG genotypes associated with reduced volume of one brain region, the combined volume of basal ganglia and thalami, both in univariate and in multivariate analyses (p ϭ 0.009, 0.009, respectively). The association of IL-6 -174 and -572 genetic polymorphisms with smaller volumes in deep gray matter provides us new ways to understand the processes leading to neurologic impairments in preterm infants.

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Neonatal Encephalopathy: Association of Cytokines with MR Spectroscopy and Outcome

Cited by 165 publications

References 31 publications

Nicotinamide mononucleotide adenylyl transferase 1 protects against acute neurodegeneration in developing CNS by inhibiting excitotoxic-necrotic cell death

Nicotinamide mononucleotide adenylyl transferase 1 protects against acute neurodegeneration in developing CNS by inhibiting excitotoxic-necrotic cell death

Inflammation‐induced sensitization of the brain in term infants

Interleukin-6 -174 and -572 Genotypes and the Volume of Deep Gray Matter in Preterm Infants

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