title: Cerebrospinal fluid matrix metalloproteinases are elevated in cerebral adrenoleukodystrophy and correlate with MRI severity and neurologic dysfunction.
abstract: BACKGROUND
  X-linked adrenoleukodystrophy results from mutations in the ABCD1 gene disrupting the metabolism of very-long-chain fatty acids. The most serious form of ALD, cerebral adrenoleukodystrophy (cALD), causes neuroinflammation and demyelination. Neuroimaging in cALD shows inflammatory changes and indicates blood-brain-barrier (BBB) disruption. We hypothesize that disruption may occur through the degradation of the extracellular matrix defining the BBB by matrix metalloproteinases (MMPs). MMPs have not been evaluated in the setting of cALD.
  
  
  RESULTS
  We used a multiplex assay to correlate the concentration of MMPs in cerebrospinal fluid and plasma to the severity of brain inflammation as determined by the ALD MRI (Loes) score and the neurologic function score. There were significant elevations of MMP2, MMP9, MMP10, TIMP1, and total protein in the CSF of boys with cALD compared to controls. Levels of MMP10, TIMP1, and total protein in CSF showed significant correlation [p<0.05 for each with pre-transplant MRI Loes Loes scores (R(2) = 0.34, 0.20, 0.55 respectively). Levels of TIMP1 and total protein in CSF significantly correlated with pre-transplant neurologic functional scores (R(2) = 0.22 and 0.48 respectively), and levels of MMP10 and total protein in CSF significantly correlated with one-year post-transplant functional scores (R(2) = 0.38 and 0.69). There was a significant elevation of MMP9 levels in plasma compared to control, but did not correlate with the MRI or neurologic function scores.
  
  
  CONCLUSIONS
  MMPs were found to be elevated in the CSF of boys with cALD and may mechanistically contribute to the breakdown of the blood-brain-barrier. MMP concentrations directly correlate to radiographic and clinical neurologic severity. Interestingly, increased total protein levels showed superior correlation to MRI score and neurologic function score before and at one year after transplant.
authors.affiliation: Division of Pediatric Blood and Marrow Transplantation, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Thibert
authors.forename: Gerald V
authors.initials: GV
authors.lastname: Raymond
authors.forename: David R
authors.initials: DR
authors.lastname: Nascene
authors.forename: Weston P
authors.initials: WP
authors.lastname: Miller
authors.forename: Jakub
authors.initials: J
authors.lastname: Tolar
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Orchard
authors.forename: Troy C
authors.initials: TC
authors.lastname: Lund
mesh_terms: D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000326:Adrenoleukodystrophy / Q000097:blood / Q000134:cerebrospinal fluid / Q000235:genetics* / Q000473:pathology; D001812:Blood-Brain Barrier / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D015870:Gene Expression; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D053506:Matrix Metalloproteinase 10 / Q000134:cerebrospinal fluid / Q000235:genetics*; D020778:Matrix Metalloproteinase 2 / Q000134:cerebrospinal fluid / Q000235:genetics*; D020780:Matrix Metalloproteinase 9 / Q000134:cerebrospinal fluid / Q000235:genetics*; D009154:Mutation; D012720:Severity of Illness Index; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000134:cerebrospinal fluid / Q000235:genetics*
chemical_list: C115572:ABCD1 protein, human; D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters; C560822:TIMP1 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; C511770:MMP10 protein, human; D053506:Matrix Metalloproteinase 10; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9