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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