Magnetic resonance water diffusion imaging can detect early ischemic changes in stroke. Using a middle cerebral artery occlusion model, we examined which range of values of the orientation-independent diffusion quantity D-av = 1/3Trace(D) = 1/3(D-xx + D-yy + D-zz) is an early noninvasive indicator of reduced cerebral perfusion and focal brain injury. Cats underwent either a 30-min occlusion followed by 3.5 h reperfusion (n = 7) or a 60-min occlusion followed by 4-h reperfusion (n = 6). Repeated measurements of CBF were made with radiolabeled microspheres, and acute focal injury was measured with triphenyltetrazolium chloride (TTC) staining. During occlusion, the decrease in D-av correlated with CBF for caudate [30-min occlusion (n = 13): p < 0.0001; 60-min occlusion (n = 6): p < 0.02] and for cortex [30-min occlusion(n = 12): p < 0.0001; 60-min occlusion (n = 5): p < 0.04]. Variable caudate and hemispheric injury levels were found among cats in both groups, The area of tissue injury demarcated by TTC began to correlate with the area of reduced D-av by 30 min of occlusion (p < 0.02), and this correlation improved (p < 0.0001) at 1, 1.5, and 2.0 h after the onset of occlusion. The time necessary to reach a one-to-one correspondence between the percent of hemisphere injured and the percent of hemispheric area with D-av < 0.65 x 10(-9) m(2)/s was 2 h after occlusion. Thus, the absolute value of D-av is a good indicator of the risk of tissue injury, whereas the combination of D,,, and the length of time of D-av reduction is an excellent predictor of acute focal tissue injury demarcated by TTC staining.