Abstract
Introduction
Punctate white matter lesions (pWMLs) and diffuse excessive high signal intensity (DEHSI) are commonly observed signal abnormalities on MRI scans of high-risk preterm infants near term-equivalent age. To establish whether these features are indicative abnormalities in axonal development or astroglia, we compared pWMLs and DEHSI to markers of axons and astrogliosis, derived from magnetic resonance spectroscopy (MRS).
Methods
Data from 108 preterm infants (gestational age at birth 31.0 weeks ± 4.3; age at scan 41.2 weeks ± 6.0) who underwent MR examinations under clinical indications were included in this study. Linear regression analyses were used to test the effects of pWMLs and DEHSI on N-acetyl-aspartate (NAA) and myoinositol concentrations, respectively.
Results
Across the full sample, pWMLs were associated with a reduction in NAA whereas moderate to severe DEHSI altered the normal age-dependent changes in myoinositol such that myoinositol levels were lower at younger ages with no change during the perinatal period. Subgroup analyses indicated that the above associations were driven by the subgroup of neonates with both pWMLs and moderate to severe DEHSI.
Conclusion
Overall, these findings suggest that pWMLs in conjunction with moderate/severe DEHSI may signify a population of infants at risk for long-term adverse neurodevelopmental outcome due to white matter injury and associated axonopathy. The loss of normal age-associated changes in myoinositol further suggests disrupted astroglial function and/or osmotic dysregulation.
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References
Maalouf E, Duggan P, Rutherford M, Counsell S, Fletcher A, Battin M, Cowan F, Edwards A (1999) Magnetic resonance imaging of the brain in a cohort of extremely preterm infants. J Pediatr 135:351–357
Woodward LJ, Anderson PJ, Austin NC, Howard K, Inder TE (2006) Neonatal MRI to predict neurodevelopmental outcomes in preterm infants. N Engl J Med 355:685–694
Plaisier A, Govaert P, Lequin MH, Dudink J (2013) Optimal timing of cerebral MRI in preterm infants to predict long-term neurodevelopmental outcome: a systematic review. AJNR Am J Neuroradiol. doi:10.3174/ajnr.A3513
de Bruine FT, van den Berg-Huysmans AA, Leijser LM, Rijken M, Steggerda SJ, van der Grond J, van Wezel-Meijler G (2011) Clinical implications of MR imaging findings in the white matter in very preterm infants: a 2-year follow-up study. Radiology 261:899–906
Jeon TY, Kim JH, Yoo SY, Eo H, Kwon JY, Lee J, Lee M, Chang YS, Park WS (2012) Neurodevelopmental outcomes in preterm infants: comparison of infants with and without diffuse excessive high signal intensity on MR images at near-term-equivalent age. Radiology 263:518–526
Cornette LG, Tanner SF, Ramenghi LA, Miall LS, Childs AM, Arthur RJ, Martinez D, Levene MI (2002) Magnetic resonance imaging of the infant brain: anatomical characteristics and clinical significance of punctate lesions. Arch Dis Child Fetal Neonatal Ed 86:F171–F177
Miller SP, Ferriero DM (2009) From selective vulnerability to connectivity: insights from newborn brain imaging. Trends Neurosci 32:496–505
Haynes RL, Billiards SS, Borenstein NS, Volpe JJ, Kinney HC (2008) Diffuse axonal injury in periventricular leukomalacia as determined by apoptotic marker fractin. Pediatr Res 63:656–661
Riddle A, Maire J, Gong X, Chen KX, Kroenke CD, Hohimer AR, Back SA (2012) Differential susceptibility to axonopathy in necrotic and non-necrotic perinatal white matter injury. Stroke 43:178–184
Griffith JL, Shimony JS, Cousins SA, Rees SE, McCurnin DC, Inder TE, Neil JJ (2012) MR imaging correlates of white-matter pathology in a preterm baboon model. Pediatr Res 71:185–191
Riddle A, Dean J, Buser JR, Gong X, Maire J, Chen K, Ahmad T, Cai V, Nguyen T, Kroenke CD, Hohimer AR, Back SA (2011) Histopathological correlates of magnetic resonance imaging-defined chronic perinatal white matter injury. Ann Neurol 70:493–507
Buser JR, Maire J, Riddle A, Gong X, Nguyen T, Nelson K, Luo NL, Ren J, Struve J, Sherman LS, Miller SP, Chau V, Hendson G, Ballabh P, Grafe MR, Back SA (2012) Arrested preoligodendrocyte maturation contributes to myelination failure in premature infants. Ann Neurol 71:93–109
Pierson CR, Folkerth RD, Billiards SS, Trachtenberg FL, Drinkwater ME, Volpe JJ, Kinney HC (2007) Gray matter injury associated with periventricular leukomalacia in the premature infant. Acta Neuropathol 114:619–631
Dyet L, Kennea N, Counsell S, Maalouf E, Ajayi-Obe M, Duggan P, Harrison M, Allsop J, Hajnal J, Herlihy A, Edwards B, Laroche S, Cowan F, Rutherford M, Edwards A (2006) Natural history of brain lesions in extremely preterm infants studied with serial magnetic resonance imaging from birth and neurodevelopmental assessment. Pediatrics 118:536–548
Miller SP, Ferriero DM, Leonard C, Piecuch R, Glidden DV, Partridge JC, Perez M, Mukherjee P, Vigneron DB, Barkovich AJ (2005) Early brain injury in premature newborns detected with magnetic resonance imaging is associated with adverse early neurodevelopmental outcome. J Pediatr 147:609–616
Skiold B, Vollmer B, Bohm B, Hallberg B, Horsch S, Mosskin M, Lagercrantz H, Aden U, Blennow M (2012) Neonatal magnetic resonance imaging and outcome at age 30 months in extremely preterm infants. J Pediatr 160:559–566, e551
Wisnowski JL, Bluml S, Paquette L, Zelinski E, Nelson MD, Jr., Painter MJ, Damasio H, Gilles F, Panigrahy A (2013) Altered glutamatergic metabolism associated with punctate white matter lesions in preterm infants. PLoS One 8:e56880
Clark JB (1998) N-acetyl aspartate: a marker for neuronal loss or mitochondrial dysfunction. Dev Neurosci 20:271–276
Bhakoo KK, Williams IT, Williams SR, Gadian DG, Noble MD (1996) Proton nuclear magnetic resonance spectroscopy of primary cells derived from nervous tissue. J Neurochem 66:1254–1263
Ross BD, Ernst T, Kreis R, Haseler LJ, Bayer S, Danielsen E, Bluml S, Shonk T, Mandigo JC, Caton W, Clark C, Jensen SW, Lehman NL, Arcinue E, Pudenz R, Shelden CH (1998) 1H MRS in acute traumatic brain injury. J Magn Reson Imaging 8:829–840
Gideon P, Henriksen O, Sperling BK, Christiansen P, Olsen TS, Jorgensen HS, Arlien-Soborg P (1993) Magnetic resonance spectroscopy of acute cerebral infarctions. Ugeskr Laeger 155:3194–3199
Barkovich AJ, Baranski K, Vigneron D, Partridge JC, Hallam DK, Hajnal BL, Ferriero DM (1999) Proton MR spectroscopy for the evaluation of brain injury in asphyxiated, term neonates. AJNR Am J Neuroradiol 20:1399–1405
Bitsch A, Bruhn H, Vougioukas V, Stringaris A, Lassmann H, Frahm J, Bruck W (1999) Inflammatory CNS demyelination: histopathologic correlation with in vivo quantitative proton MR spectroscopy. AJNR Am J Neuroradiol 20:1619–1627
Chang L, Munsaka SM, Kraft-Terry S, Ernst T (2013) Magnetic resonance spectroscopy to assess neuroinflammation and neuropathic pain. J Neuroimmune Pharm 8:576–593
Kapeller P, Ropele S, Enzinger C, Lahousen T, Strasser-Fuchs S, Schmidt R, Fazekas F (2005) Discrimination of white matter lesions and multiple sclerosis plaques by short echo quantitative 1H-magnetic resonance spectroscopy. J Neurol 252:1229–1234
Panigrahy A, Krieger MD, Gonzalez-Gomez I, Liu X, McComb JG, Finlay JL, Nelson MD, Gilles FH, Bluml S (2006) Quantitative short echo time H-1-MR spectroscopy of untreated pediatric brain tumors: preoperative diagnosis and characterization. Am J Neuroradiol 27:560–572
Haynes RL, Borenstein NS, Desilva TM, Folkerth RD, Liu LG, Volpe JJ, Kinney HC (2005) Axonal development in the cerebral white matter of the human fetus and infant. J Comp Neurol 484:156–167
Volpe JJ (1998) Brain injury in the premature infant: overview of clinical aspects, neuropathology, and pathogenesis. Semin Pediatr Neurol 5:135–151
Bluml S, Wisnowski JL, Nelson MD, Jr., Paquette L, Gilles FH, Kinney HC, Panigrahy A (2012) Metabolic maturation of the human brain from birth through adolescence: insights from in vivo magnetic resonance spectroscopy. Cereb Cortex
Bluml S, Wisnowski JL, Nelson MD, Jr., Paquette L, Panigrahy A (2014) Metabolic maturation of white matter is altered in preterm infants. PLoS One 9: e85829
Girard N, Fogliarini C, Viola A, Confort-Gouny S, Fur YL, Viout P, Chapon F, Levrier O, Cozzone P (2006) MRS of normal and impaired fetal brain development. Eur J Radiol 57:217–225
Card D, Nossin-Manor R, Moore AM, Raybaud C, Sled JG, Taylor MJ (2013) Brain metabolite concentrations are associated with illness severity scores and white matter abnormalities in very preterm infants. Pediatr Res 74:75–81
Hamrick SE, Miller SP, Leonard C, Glidden DV, Goldstein R, Ramaswamy V, Piecuch R, Ferriero DM (2004) Trends in severe brain injury and neurodevelopmental outcome in premature newborn infants: the role of cystic periventricular leukomalacia. J Pediatr 145:593–599
Bassi L, Chew A, Merchant N, Ball G, Ramenghi L, Boardman J, Allsop JM, Doria V, Arichi T, Mosca F, Edwards AD, Cowan FM, Rutherford MA, Counsell SJ (2011) Diffusion tensor imaging in preterm infants with punctate white matter lesions. Pediatr Res 69:561–566
Lohr JW, McReynolds J, Grimaldi T, Acara M (1988) Effect of acute and chronic hypernatremia on myoinositol and sorbitol concentration in rat brain and kidney. Life Sci 43:271–276
Paredes A, McManus M, Kwon HM, Strange K (1992) Osmoregulation of Na(+)-inositol cotransporter activity and mRNA levels in brain glial cells. Am J Physiol 263:C1282–C1288
Counsell SJ, Allsop JM, Harrison MC, Larkman DJ, Kennea NL, Kapellou O, Cowan FM, Hajnal JV, Edwards AD, Rutherford MA (2003) Diffusion-weighted imaging of the brain in preterm infants with focal and diffuse white matter abnormality. Pediatrics 112:1–7
He L, Parikh NA (2013) Automated detection of white matter signal abnormality using T2 relaxometry: application to brain segmentation on term MRI in very preterm infants. Neuroimage 64:328–340
Urenjak J, Williams SR, Gadian DG, Noble M, Department of Biophysics HIRCoSoELE (1992) Specific expression of N-acetylaspartate in neurons, oligodendrocyte-type-2 astrocyte progenitors, and immature oligodendrocytes in vitro. J Neurochem 59(1):55–61
Kidokoro H, Anderson PJ, Doyle LW, Neil JJ, Inder TE (2011) High signal intensity on T2-weighted MR imaging at term-equivalent age in preterm infants does not predict 2-year neurodevelopmental outcomes. AJNR Am J Neuroradiol 32:2005–2010
Robertson NJ, Kuint J, Counsell TJ, Rutherford TA, Coutts A, Cox IJ, Edwards AD (2000) Characterization of cerebral white matter damage in preterm infants using 1H and 31P magnetic resonance spectroscopy. J Cereb Blood Flow Metab 20:1446–1456
Miller SP, McQuillen PS, Hamrick S, Xu D, Glidden DV, Charlton N, Karl T, Azakie A, Ferriero DM, Barkovich AJ, Vigneron DB (2007) Abnormal brain development in newborns with congenital heart disease. N Engl J Med 357:1928–1938
Limperopoulos C, Tworetzky W, McElhinney DB, Newburger JW, Brown DW, Robertson RL Jr, Guizard N, McGrath E, Geva J, Annese D, Dunbar-Masterson C, Trainor B, Laussen PC, du Plessis AJ (2010) Brain volume and metabolism in fetuses with congenital heart disease: evaluation with quantitative magnetic resonance imaging and spectroscopy. Circulation 121:26–33
Billiards SS, Haynes RL, Folkerth RD, Trachtenberg FL, Liu LG, Volpe JJ, Kinney HC (2006) Development of microglia in the cerebral white matter of the human fetus and infant. J Comp Neurol 497:199–208
Raybaud C, Ahmad T, Rastegar N, Shroff M, Al Nassar M (2013) The premature brain: developmental and lesional anatomy. Neuroradiology 55(Suppl 2):23–40
Acknowledgments
Support is provided by the National Institutes of Health (K23NS063371), the Rudi Schulte Research Institute, The Ian Harrison Neonatal Neurology Program at the Children's Hospital of Pittsburgh of UPMC, and the Children's Hospital of Pittsburgh Foundation. The authors would like to thank Hannah Kinney for her helpful comments on earlier drafts of this manuscript and Julia Castro for organizing the data.
Ethical standards and patient consent
We declare that all human and animal studies have been approved by the Children's Hospital Los Angeles and the University of Pittsburgh and have therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. We declare that all patients gave informed consent prior to inclusion in this study.
Conflict of interest
We declare that we have no conflict of interest.
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Wisnowski, J.L., Schmithorst, V.J., Rosser, T. et al. Magnetic resonance spectroscopy markers of axons and astrogliosis in relation to specific features of white matter injury in preterm infants. Neuroradiology 56, 771–779 (2014). https://doi.org/10.1007/s00234-014-1380-9
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DOI: https://doi.org/10.1007/s00234-014-1380-9