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Pediatric hydrocephalus is one of the most commonly encountered pathology in Pediatric Neurosurgery with an overall incidence of 3 in 1,000 children under 2 years of age. Cerebrospinal fluid (CSF) abnormally accumulates in different regions of the brain, and can raise intracranial pressure resulting in severe brain damage or mortality if left untreated. Various etiologies of hydrocephalus exist, including intracranial hemorrhage, brain tumors, congenital brain malformations, neural tube defects, as well as others. Unfortunately, for a significant population, this condition has an unknown etiology.
Several surgical treatments are available for pediatric hydrocephalus. These include resection of lesions that physically obstruct CSF flow, or CSF diversionary surgery to control CSF accumulation and ventricular size. These options have greatly reduced the morbidity and mortality associated with this condition. However, the long-term management of optimal shunt function is a challenge especially in young children and may require multiple brain surgeries during the patient’s life time.
Research in the Mangano lab is directed at understanding pathogenesis of pediatric hydrocephalus, that will lead us to develop new surgical and medical treatment options and to improve patient outcomes and quality of life. To establish the goals, we study essential brain anatomy, neural cell types, and genes involved in pediatric hydrocephalus utilizing advanced MR imaging methods (diffusion tensor imaging), mouse genetic models, and several surgical techniques.
Two main aspects of research are currently ongoing in the lab. Each project includes active collaborations with multidisciplinary researchers across divisions at Cincinnati Children’s, including the Division of Radiology, Developmental Biology, and Human Genetics.
Our Current Projects include:
Di Nardo A, Wertz MH, Kwiatkowski E, Tsai PT, Leech JD, Greene-Colozzi E, Goto J, Dilsiz P, Talos DM, Clish CB, Kwiatkowski DJ, Sahin M. Neuronal Tsc1/2 complex controls autophagy through AMPK-dependent regulation of ULK1.Hum Mol Genet. 2014 Mar 18. PMID: 24599401.
Williams MT, Braun AA, Amos-Kroohs RM, McAllister JP 2nd, Lindquist DM, Mangano FT, Vorhees CV, Yuan W. Kaolin-induced ventriculomegaly at weaning produces long-term learning, memory, and motor deficits in rats. Int J Dev Neurosci. 2014 Mar 2;35C:7-15. PMID: 24594360.
Rajagopal A, Shimony JS, McKinstry RC, Altaye M, Maloney T, Mangano FT, Limbrick DD, Holland SK, Jones BV, Simpson S, Mercer D, Yuan W. White matter microstructural abnormality in children with hydrocephalus detected by probabilistic diffusion tractography. AJNR Am J Neuroradiol. 2013 Dec;34(12):2379-85. PMID:24072621.
Cancelliere A, Mangano FT, Air EL, Jones BV, Altaye M, Rajagopal A, Holland SK, Hertzler DA 2nd, Yuan W. DTI values in key white matter tracts from infancy through adolescence. AJNR Am J Neuroradiol. 2013 Jul;34(7):1443-9. PMID: 23370472.
Prabhakar S*, Goto J*, Zuang X, Sena-Esteves M, Bronson R, Brockmann J, Gianni D, Wojtkiewicz GR, Chen JW, Stemmer-Rachamimov A, Kwiatkowski DJ, Breakefield XO. Stochastic model of Tsc1 lesions in mouse brain. PLoS One. 2013 May 16;8(5):e64224. PMID:23696872
Yuan W, McKinstry RC, Shimony JS, Altaye M, Powell SK, Phillips JM, Limbrick DD Jr, Holland SK, Jones BV, Rajagopal A, Simpson S, Mercer D, Mangano FT. Diffusion tensor imaging properties and neurobehavioral outcomes in children with hydrocephalus. AJNR Am J Neuroradiol. 2013 Feb;34(2):439-45. PMID: 22899790.
Tsai PT, Greene-Colozzi E, Goto J, Anderl S, Kwiatkowski DJ, Sahin M. Prenatal rapamycin results in early and late behavioral abnormalities in wildtype C57BL/6 mice. Behav Genet. 2013 Jan;43(1):51-9. PMID: 23229624.
Buckley RT, Yuan W, Mangano FT, Phillips JM, Powell S, McKinstry RC, Rajagopal A, Jones BV, Holland S, Limbrick DD Jr. Longitudinal comparison of diffusion tensor imaging parameters and neuropsychological measures following endoscopic third ventriculostomy for hydrocephalus. J Neurosurg Pediatr. 2012 Jun;9(6):630-5. PMID: 22656255.
Sun M, Yuan W, Hertzler DA, Cancelliere A, Altaye M, Mangano FT. Diffusion tensor imaging findings in young children with benign external hydrocephalus differ from the normal population. Childs Nerv Syst. 2012 Feb;28(2):199-208. PMID: 22167268.
Yuan W, McAllister JP 2nd, Lindquist DM, Gill N, Holland SK, Henkel D, Rajagopal A, Mangano FT. Diffusion tensor imaging of white matter injury in a rat model of infantile hydrocephalus. Childs Nerv Syst. 2012 Jan;28(1):47-54. PMID: 21994049.
Anderl S, Freeland M, Kwiatkowski DJ, Goto J. Therapeutic value of prenatal rapamycin treatment in a mouse brain model of tuberous sclerosis complex. Hum Mol Genet. 2011 Dec 1;20(23):4597-604. PMID: 21890496.
Goto J, Talos DM, Klein P, Qin W, Chekaluk YI, Anderl S, Malinowska IA, Di Nardo A, Bronson RT, Chan JA, Vinters HV, Kernie SG, Jensen FE, Sahin M, Kwiatkowski DJ. Regulable neural progenitor-specific Tsc1 loss yields giant cells with organellar dysfunction in a model of tuberous sclerosis complex. Proc Natl Acad Sci U S A. 2011 Nov 8;108(45):E1070-9. PMID: 22025691
Malhowski AJ, Hira H, Bashiruddin S, Warburton R, Goto J, Robert B, Kwiatkowski DJ, Finlay GA. Smooth muscle protein-22-mediated deletion of Tsc1 results in cardiac hypertrophy that is mTORC1-mediated and reversed by rapamycin. Hum Mol Genet. 2011 Apr 1;20(7):1290-305. PMID: 21212099
Sun Q, Chen X, Ma J, Peng H, Wang F, Zha X, Wang Y, Jing Y, Yang H, Chen R, Chang L, Zhang Y, Goto J, Onda H, Chen T, Wang MR, Lu Y, You H, Kwiatkowski D, Zhang H. Mammalian target of rapamycin up-regulation of pyruvate kinase isoenzyme type M2 is critical for aerobic glycolysis and tumor growth. Proc Natl Acad Sci U S A. 2011 Mar 8;108(10):4129-34. PMID: 21325052.
Yuan W, Deren KE, McAllister JP 2nd, Holland SK, Lindquist DM, Cancelliere A, Mason M, Shereen A, Hertzler DA, Altaye M, Mangano FT. Diffusion tensor imaging correlates with cytopathology in a rat model of neonatal hydrocephalus. Cerebrospinal Fluid Res. 2010 Nov 5;7:19. PMID: 21054844
Yuan W, Mangano FT, Air EL, Holland SK, Jones BV, Altaye M, Bierbrauer K. Anisotropic diffusion properties in infants with hydrocephalus: a diffusion tensor imaging study. AJNR Am J Neuroradiol. 2009 Oct;30(9):1792-8. PMID: 19661167.
Goto J, Tezuka T, Nakazawa T, Sagara H, Yamamoto T. Loss of Fyn tyrosine kinase on the C57BL/6 genetic background causes hydrocephalus with defects in oligodendrocyte development. Mol Cell Neurosci. 2008 Jun;38(2):203-12. PMID: 18403215
Francesco T. Mangano, DO, FACS, FACOSAssociate Professor of Neurosurgery and PediatricsChief, Division of Pediatric NeurosurgeryCo-Director, Epilepsy Surgery Program
“The effect of hydrocephalus on SVZ progenitor proliferation” by J. Goto“Longitudinal post-surgery DTI changes in children with hydrocephalus (HCP) and its predictive value for future behavioral outcome” by F. Mangano2013 AANS/CNS Section on Pediatric Neurological SurgeryDecember 3-6, 2013 in Toronto, Ontario
“Diffusion tensor imaging” by F. ManganoBiomarkers in hydrocephalus A special research workshop the Hydrocephalus AssociationApril 27-29, 2014, The Washington University School of Medicine, in St. Louis, Missouri
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