title: Diffusion tensor imaging with direct cytopathological validation: characterisation of decorin treatment in experimental juvenile communicating hydrocephalus.
abstract: BACKGROUND
  In an effort to develop novel treatments for communicating hydrocephalus, we have shown previously that the transforming growth factor-β antagonist, decorin, inhibits subarachnoid fibrosis mediated ventriculomegaly; however decorin's ability to prevent cerebral cytopathology in communicating hydrocephalus has not been fully examined. Furthermore, the capacity for diffusion tensor imaging to act as a proxy measure of cerebral pathology in multiple sclerosis and spinal cord injury has recently been demonstrated. However, the use of diffusion tensor imaging to investigate cytopathological changes in communicating hydrocephalus is yet to occur. Hence, this study aimed to determine whether decorin treatment influences alterations in diffusion tensor imaging parameters and cytopathology in experimental communicating hydrocephalus. Moreover, the study also explored whether diffusion tensor imaging parameters correlate with cellular pathology in communicating hydrocephalus.
  
  
  METHODS
  Accordingly, communicating hydrocephalus was induced by injecting kaolin into the basal cisterns in 3-week old rats followed immediately by 14 days of continuous intraventricular delivery of either human recombinant decorin (n = 5) or vehicle (n = 6). Four rats remained as intact controls and a further four rats served as kaolin only controls. At 14-days post-kaolin, just prior to sacrifice, routine magnetic resonance imaging and magnetic resonance diffusion tensor imaging was conducted and the mean diffusivity, fractional anisotropy, radial and axial diffusivity of seven cerebral regions were assessed by voxel-based analysis in the corpus callosum, periventricular white matter, caudal internal capsule, CA1 hippocampus, and outer and inner parietal cortex. Myelin integrity, gliosis and aquaporin-4 levels were evaluated by post-mortem immunohistochemistry in the CA3 hippocampus and in the caudal brain of the same cerebral structures analysed by diffusion tensor imaging.
  
  
  RESULTS
  Decorin significantly decreased myelin damage in the caudal internal capsule and prevented caudal periventricular white matter oedema and astrogliosis. Furthermore, decorin treatment prevented the increase in caudal periventricular white matter mean diffusivity (p = 0.032) as well as caudal corpus callosum axial diffusivity (p = 0.004) and radial diffusivity (p = 0.034). Furthermore, diffusion tensor imaging parameters correlated primarily with periventricular white matter astrocyte and aquaporin-4 levels.
  
  
  CONCLUSIONS
  Overall, these findings suggest that decorin has the therapeutic potential to reduce white matter cytopathology in hydrocephalus. Moreover, diffusion tensor imaging is a useful tool to provide surrogate measures of periventricular white matter pathology in communicating hydrocephalus.
authors.affiliation: Institute of Metabolism and Systems Research, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK.|Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, B15 2TH, UK.|Neurotrauma, College of Medicine and Dentistry, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK.
authors.forename: Anuriti
authors.initials: A
authors.lastname: Aojula
authors.affiliation: Institute of Metabolism and Systems Research, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK.|Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, B15 2TH, UK.|Neurotrauma, College of Medicine and Dentistry, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK.
authors.forename: Hannah
authors.initials: H
authors.lastname: Botfield
authors.affiliation: Department of Neurosurgery, Division of Pediatric Neurosurgery at the Washington University School of Medicine and the Saint Louis Children's Hospital, St. Louis, MO, 63110, USA. pat.mcallister@wustl.edu.
authors.forename: James Patterson
authors.identifier: http://orcid.org/0000-0003-4877-6812
authors.initials: JP
authors.lastname: McAllister
authors.affiliation: Institute of Metabolism and Systems Research, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK.|Neurotrauma, College of Medicine and Dentistry, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK.
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Gonzalez
authors.affiliation: Department of Bioengineering, University of Utah, Salt Lake City, UT, 84112, USA.
authors.forename: Osama
authors.initials: O
authors.lastname: Abdullah
authors.affiliation: Department of Bioengineering, University of Utah, Salt Lake City, UT, 84112, USA.|Neurotrauma, College of Medicine and Dentistry, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK.
authors.forename: Ann
authors.initials: A
authors.lastname: Logan
authors.affiliation: Institute of Metabolism and Systems Research, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK.|Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, B15 2TH, UK.|Neurotrauma, College of Medicine and Dentistry, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK.|Department of Neurology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, B15 2TH, UK.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Sinclair
mesh_terms: D000818:Animals; D051401:Aquaporin 4 / Q000378:metabolism; D001284:Atrophy / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002648:Child; D058575:Decorin / Q000494:pharmacology*; D038524:Diffusion Magnetic Resonance Imaging; D056324:Diffusion Tensor Imaging; D004195:Disease Models, Animal; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D006849:Hydrocephalus / Q000000981:diagnostic imaging* / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D007150:Immunohistochemistry; D007616:Kaolin; D009186:Myelin Sheath / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000494:pharmacology*; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism; D066127:White Matter / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
chemical_list: C496032:Aqp4 protein, rat; D051401:Aquaporin 4; C546878:DCN protein, human; D058575:Decorin; D005904:Glial Fibrillary Acidic Protein; D018696:Neuroprotective Agents; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D007616:Kaolin
keywords: Cytopathology; DTI; Decorin; Hydrocephalus