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30 MATRIX METALLOPROTEINASES, THEIR ENDOGENOUS INHIBITOR AND APPARENT DIFFUSION COEFFICIENT REDUCTION ON MAGNETIC RESONANCE IMAGING: A COMPARISON OF HUMAN SERUM AND RADIOGRAPHIC MARKERS IN ACUTE ISCHEMIC STROKE
  1. M. M. Ning,
  2. N. M. Menezes,
  3. K. L. Furie,
  4. A. G. Sorensen,
  5. W. J. Koroshetz,
  6. P. J. Kelly,
  7. H. Lee,
  8. X. Wang,
  9. M. W. Zhu,
  10. C. Lopez,
  11. M. Lederer,
  12. F. Buonanno,
  13. J. P. Kistler,
  14. G. Rordorf,
  15. A. Singhal,
  16. E. H. Lo
  1. Boston, MA., 1University of Louisville
  2. Louisville VAMC

Abstract

Background Human matrix metalloproteinase-9 (MMP-9) has been studied as a biomarker in acute stroke injury and as a potential target of therapy. MMP-9 is a zinc-dependent endopeptidase that participates in extracellular matrix remodeling, and is a major mediator of t-PA-related adverse outcome and blood-brain-barrier (BBB) disruption in animal models of focal ischemia and spontaneous intracerebral hemorrhage (ICH). In vitro findings also suggest that exogenous MMP-9 inhibition may improve cerebral ischemic tissue outcome. Reduction in the apparent diffusion coefficient (ADC) on diffusion-weighted imaging (DWI) has been utilized as a quantitative radiologic marker of acute cerebral ischemic injury. Using non-invasive quantitative MRI techniques, we wish to validate MMP as a potential surrogate marker of cerebral injury in humans, by investigating the relationship between MMP-9, its endogenous inhibitor TIMP-1, and the extent of cerebral ischemic injury as measured by early ADC reduction.

Method In 36 patients with acute ischemic stroke, plasma levels of MMP-9 and TIMP-1 were measured at mean 6 hr post stroke. DWI was obtained at mean 8 hr post stroke. Within each lesion, we calculated the percent of voxels showing ADC reduction at or below each of 8 incremental thresholds, at intervals of 90 × 10-6 mm2/s, from 185 × 10-6 to 825 × 10-6 mm2/s.

Result Acute TIMP-1 level was inversely correlated to the percent of voxels with ADC reduction at or below the lowest threshold, 185 × 10-6 mm2/s (r = -0.41, p<0.02), and had a similar trend at the next two thresholds, 275 × 10-6 and 365 × 10-6 mm2/s. Acute MMP-9 level had a weak but positive trend correlating with the percent of voxels at the lowest threshold (r = 0.31, p<0.08). There is no correlation of either marker with ADC reduction at the higher thresholds.

Conclusion While MMP-9 is positively correlated, TIMP-1 is inversely related to MR evidence of cerebral injury. Although preliminary, these findings lend support to the hypothesis that TIMP-1 may be protective, whereas MMP-9 may be associated with the extent of stunned acute ischemic cerebral tissue. Early exogenous blockade of MMP-9 may improve the outcome of ischemic brain tissue. However, these hypotheses need confirmation with a larger cohort of patients, and correlation with clinical outcomes, such as hemorrhagic transformation, which also has a threshold effect on ADC reduction.

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