title: Micro-computed tomography in murine models of cerebral cavernous malformations as a paradigm for brain disease.
abstract: Cerebral cavernous malformations (CCMs) are hemorrhagic brain lesions, where murine models allow major mechanistic discoveries, ushering genetic manipulations and preclinical assessment of therapies. Histology for lesion counting and morphometry is essential yet tedious and time consuming. We herein describe the application and validations of X-ray micro-computed tomography (micro-CT), a non-destructive technique allowing three-dimensional CCM lesion count and volumetric measurements, in transgenic murine brains.
  
  
  
  We hereby describe a new contrast soaking technique not previously applied to murine models of CCM disease. Volumetric segmentation and image processing paradigm allowed for histologic correlations and quantitative validations not previously reported with the micro-CT technique in brain vascular disease.
  
  
  
  Twenty-two hyper-dense areas on micro-CT images, identified as CCM lesions, were matched by histology. The inter-rater reliability analysis showed strong consistency in the CCM lesion identification and staging (K=0.89, p<0.0001) between the two techniques. Micro-CT revealed a 29% greater CCM lesion detection efficiency, and 80% improved time efficiency.
  
  
  
  Serial integrated lesional area by histology showed a strong positive correlation with micro-CT estimated volume (r(2)=0.84, p<0.0001).
  
  
  
  Micro-CT allows high throughput assessment of lesion count and volume in pre-clinical murine models of CCM. This approach complements histology with improved accuracy and efficiency, and can be applied for lesion burden assessment in other brain diseases.
authors.affiliation: Neurovascular Surgery Program, Section of Neurosurgery, The University of Chicago Medicine and Biological Sciences, Chicago, IL, USA.
authors.forename: Romuald
authors.initials: R
authors.lastname: Girard
authors.affiliation: Neurovascular Surgery Program, Section of Neurosurgery, The University of Chicago Medicine and Biological Sciences, Chicago, IL, USA.
authors.forename: Hussein A
authors.initials: HA
authors.lastname: Zeineddine
authors.affiliation: Department of Organismal Biology and Anatomy, The University of Chicago Medicine and Biological Sciences, Chicago, IL, USA.
authors.forename: Courtney
authors.initials: C
authors.lastname: Orsbon
authors.affiliation: Neurovascular Surgery Program, Section of Neurosurgery, The University of Chicago Medicine and Biological Sciences, Chicago, IL, USA.
authors.forename: Huan
authors.initials: H
authors.lastname: Tan
authors.affiliation: Neurovascular Surgery Program, Section of Neurosurgery, The University of Chicago Medicine and Biological Sciences, Chicago, IL, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Moore
authors.affiliation: Neurovascular Surgery Program, Section of Neurosurgery, The University of Chicago Medicine and Biological Sciences, Chicago, IL, USA.
authors.forename: Nick
authors.initials: N
authors.lastname: Hobson
authors.affiliation: Neurovascular Surgery Program, Section of Neurosurgery, The University of Chicago Medicine and Biological Sciences, Chicago, IL, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Shenkar
authors.affiliation: Neurovascular Surgery Program, Section of Neurosurgery, The University of Chicago Medicine and Biological Sciences, Chicago, IL, USA.
authors.forename: Rhonda
authors.initials: R
authors.lastname: Lightle
authors.affiliation: Neurovascular Surgery Program, Section of Neurosurgery, The University of Chicago Medicine and Biological Sciences, Chicago, IL, USA.
authors.forename: Changbin
authors.initials: C
authors.lastname: Shi
authors.affiliation: Neurovascular Surgery Program, Section of Neurosurgery, The University of Chicago Medicine and Biological Sciences, Chicago, IL, USA.
authors.forename: Maged D
authors.initials: MD
authors.lastname: Fam
authors.affiliation: Neurovascular Surgery Program, Section of Neurosurgery, The University of Chicago Medicine and Biological Sciences, Chicago, IL, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Neurovascular Surgery Program, Section of Neurosurgery, The University of Chicago Medicine and Biological Sciences, Chicago, IL, USA; Department of Pathology, The University of Chicago Medicine and Biological Sciences, Chicago, IL, USA.
authors.forename: Le
authors.initials: L
authors.lastname: Shen
authors.affiliation: Department of Organismal Biology and Anatomy, The University of Chicago Medicine and Biological Sciences, Chicago, IL, USA.
authors.forename: April I
authors.initials: AI
authors.lastname: Neander
authors.affiliation: Molecular Genetics and Microbiology Department, Duke University Medical Center, Durham, NC, USA.
authors.forename: Autumn
authors.initials: A
authors.lastname: Rorrer
authors.affiliation: Molecular Genetics and Microbiology Department, Duke University Medical Center, Durham, NC, USA.
authors.forename: Carol
authors.initials: C
authors.lastname: Gallione
authors.affiliation: Department of Medicine and Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Alan T
authors.initials: AT
authors.lastname: Tang
authors.affiliation: Department of Medicine and Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Mark L
authors.initials: ML
authors.lastname: Kahn
authors.affiliation: Molecular Genetics and Microbiology Department, Duke University Medical Center, Durham, NC, USA.
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Marchuk
authors.affiliation: Department of Organismal Biology and Anatomy, The University of Chicago Medicine and Biological Sciences, Chicago, IL, USA.
authors.forename: Zhe-Xi
authors.initials: ZX
authors.lastname: Luo
authors.affiliation: Neurovascular Surgery Program, Section of Neurosurgery, The University of Chicago Medicine and Biological Sciences, Chicago, IL, USA. Electronic address: iawad@uchicago.edu.
authors.forename: Issam A
authors.initials: IA
authors.lastname: Awad
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins; D001921:Brain / Q000000981:diagnostic imaging*; D003287:Contrast Media; D004195:Disease Models, Animal; D005260:Female; D020786:Hemangioma, Cavernous, Central Nervous System / Q000000981:diagnostic imaging*; D006652:Histological Techniques; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D007455:Iodine; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D015588:Observer Variation; D009929:Organ Size; D015203:Reproducibility of Results; D013997:Time Factors; D055114:X-Ray Microtomography / Q000379:methods*; D054460:rho-Associated Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D003287:Contrast Media; D047908:Intracellular Signaling Peptides and Proteins; C559318:PDCD10 protein, mouse; D007455:Iodine; C515854:Rock1 protein, mouse; C515855:Rock2 protein, mouse; D054460:rho-Associated Kinases
keywords: Cerebral cavernous malformation; Iodine contrast; Micro-CT; Morphometry