title: Multiple sclerosis: myeloperoxidase immunoradiology improves detection of acute and chronic disease in experimental model.
abstract: OBJECTIVE
  To test if MPO-Gd, a gadolinium-based magnetic resonance (MR) imaging probe that is sensitive and specific for the proinflammatory and oxidative enzyme myeloperoxidase (MPO), which is secreted by certain inflammatory cells, is more sensitive than diethylenetriaminepentaacetic acid (DTPA)-Gd in revealing early subclinical and chronic disease activity in the brain in experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis.
  
  
  METHODS
  The protocol for animal experiments was approved by the institutional animal care committee. A total of 61 female SJL mice were induced with EAE. Mice underwent MPO-Gd- or DTPA-Gd-enhanced MR imaging on days 6, 8, and 10 after induction, before clinical disease develops, and during chronic disease at remission and the first relapse. Brains were harvested at these time points for flow cytometric evaluation of immune cell subtypes and immunohistochemistry. Statistical analysis was performed, and P < .05 was considered to indicate a significant difference.
  
  
  RESULTS
  MPO-Gd helps detect earlier (5.2 vs 2.3 days before symptom onset, P = .004) and more (3.1 vs 0.3, P = .008) subclinical inflammatory lesions compared with DTPA-Gd, including in cases in which there was no evidence of overt blood-brain barrier (BBB) breakdown detected with DTPA-Gd enhancement. The number of MPO-Gd-enhancing lesions correlated with early infiltration of MPO-secreting monocytes and neutrophils into the brain (r = 0.91). MPO-Gd also helped detect more lesions during subclinical disease at remission (5.5 vs 1.3, P = .006) and at the first relapse (9.0 vs 2.7, P = .03) than DTPA-Gd, which also correlated well with the presence and accumulation of MPO-secreting inflammatory cells in the brain (r = 0.93).
  
  
  CONCLUSIONS
  MPO-Gd specifically reveals lesions with inflammatory monocytes and neutrophils, which actively secrete MPO. These results demonstrate the feasibility of detection of subclinical inflammatory disease activity in vivo, which is different from overt BBB breakdown.
authors.affiliation: From the Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, 185 Cambridge St, Boston, MA 02114 (B.P., L.B., G.R.W., Y.I., M.A., D.L., S.S., K.L.C.H., J.W.C.); Department of Radiology, Massachusetts General Hospital, Boston, Mass (B.P., J.W.C.); and European Institute for Molecular Imaging, University of Münster, Münster, Germany (A.H.J.).
authors.forename: Benjamin
authors.initials: B
authors.lastname: Pulli
authors.forename: Lionel
authors.initials: L
authors.lastname: Bure
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Wojtkiewicz
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Iwamoto
authors.forename: Muhammad
authors.initials: M
authors.lastname: Ali
authors.forename: Dan
authors.initials: D
authors.lastname: Li
authors.forename: Stefan
authors.initials: S
authors.lastname: Schob
authors.forename: Kevin Li-Chun
authors.initials: KL
authors.lastname: Hsieh
authors.forename: Andreas H
authors.initials: AH
authors.lastname: Jacobs
authors.forename: John W
authors.initials: JW
authors.lastname: Chen
mesh_terms: D000208:Acute Disease; D000818:Animals; D002908:Chronic Disease; D003287:Contrast Media; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental; D005260:Female; D019786:Gadolinium DTPA; D051379:Mice; D009103:Multiple Sclerosis / Q000000981:diagnostic imaging* / Q000276:immunology*; D009195:Peroxidase / Q000032:analysis*; D011877:Radionuclide Imaging
chemical_list: D003287:Contrast Media; D009195:Peroxidase; D019786:Gadolinium DTPA