Acute stroke is the third leading cause of death and the

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1 Combined Diffusion-Weighted and Perfusion-Weighted Flow Heterogeneity Magnetic Resonance Imaging in Acute Stroke Leif Østergaard, MD, MSc; A. Gregory Sorensen, MD; David A. Chesler, PhD; Robert M. Weisskoff, PhD; Walter J. Koroshetz, MD, PhD; Ona Wu, BSc; Carsten Gyldensted, MD, PhD; Bruce R. Rosen, MD, PhD Background and Purpose The heterogeneity of microvascular flows is known to be an important determinant of the efficacy of oxygen delivery to tissue. Studies in animals have demonstrated decreased flow heterogeneity (FH) in states of decreased perfusion pressure. The purpose of the present study was to assess microvascular FH changes in acute stroke with use of a novel perfusion-weighted MRI technique and to evaluate the ability of combined diffusion-weighted MRI and FH measurements to predict final infarct size. Methods Cerebral blood flow, FH, and plasma mean transit time (MTT) were measured in 11 patients who presented with acute ( 12 hours after symptom onset) stroke. Final infarct size was determined with follow-up MRI or CT scanning. Results In normal brain tissue, the distribution of relative flows was markedly skewed toward high capillary flow velocities. Within regions of decreased cerebral blood flow, plasma MTT was prolonged. Furthermore, subregions were identified with significant loss of the high-flow component of the flow distribution, thereby causing increased homogeneity of flow velocities. In parametric maps that quantify the acute deviation of FH from that of normal tissue, areas of extreme homogenization of capillary flows predicted final infarct size on follow-up scans of 10 of 11 patients. Conclusions Flow heterogeneity and MTT can be rapidly assessed as part of a routine clinical MR examination and may provide a tool for planning of individual stroke treatment, as well as in targeting and evaluation of emerging therapeutic strategies. (Stroke. 2000;31: ) Key Words: cerebral blood flow magnetic resonance imaging, diffusion-weighted magnetic resonance imaging, perfusion-weighted microcirculation Acute stroke is the third leading cause of death and the leading cause of adult disability. The goal of emerging therapeutic strategies is to minimize the progression of tissue damage in the acute phase of the disease. Methods to rapidly assess the severity and later progression of acute stroke in individual patients are therefore highly desirable for the planning of individual treatments, as well as to evaluate novel therapeutic strategies. In acute cerebral ischemia, the delivery of nutrients is severely compromised, and tissue survival therefore depends on tissue regulatory mechanisms to meet metabolic needs. Studies with PET have shown that plasma mean blood transit time (MTT) and, with a further drop in cerebral perfusion pressure, oxygen extraction fraction (OEF) are increased in tissue at risk of infarction. 1 5 Although the relationship between prolonged blood MTT and OEF remains unclear, both phenomena are believed to reflect underlying regulatory mechanisms that attempt to compensate for a decrease in perfusion pressure. One mechanism for vasoregulatory control is believed to be the ability to alter the heterogeneity of blood transit times and thereby the mean capillary concentration of substances that diffuse from blood to tissue. 6 Experiments in rats have revealed decreased flow heterogeneity (FH) during whiskerbarrel stimulation, 7 indicating that this may be the mechanism that underlies the striking ability of the normal brain to meet increased metabolic needs during functional activation. Furthermore, Hudetz et al 8 demonstrated that a graded decrease in perfusion pressure causes a progressive loss of high-flow components, thereby decreasing total FH. Decreased FH therefore seems to play a crucial role in the maintenance of sufficient concentration gradients to drive diffusion of nutrients such as oxygen from the blood into the cells. 6 This suggests that blood MTT and the degree of FH are important indices to assess and to further understand the ability of the brain to survive ischemic episodes. We previously studied the heterogeneity of flows in normal volunteers with MRI residue detection. 9 We found the prob- Received September 21, 1999; final revision received December 10, 1999; accepted February 7, From the Department of Radiology, MGH NMR Center (A.G.S., D.A.C., R.M.W., O.W., B.R.R.), Massachusetts General Hospital, Charlestown, Mass; Harvard Medical School (A.G.S., R.M.W., B.R.R., W.J.K., D.A.C.), Boston, Mass; Harvard-MIT Division of Health Sciences (R.M.W., O.W., B.R.R.), Cambridge, Mass; Stroke Unit (W.J.K.), Department of Neurology, Massachusetts General Hospital, Boston, Mass; and Department of Neuroradiology (L.Ø., C.G.), Århus University Hospital, Århus, Denmark. Correspondence to Leif Østergaard, MD, MSc, Department of Neuroradiology, Århus Kommunehospital, Nørrebrogade 44, DK-8000 Århus C, Denmark. leif@pet.auh.dk 2000 American Heart Association, Inc. Stroke is available at

2 1098 Stroke May 2000 ability density function (PDF) of relative flows to be remarkably constant within and among normal volunteers. We therefore hypothesize that areas of decreased FH can be observed with MRI in acute stroke. We further hypothesize that because FH is associated with compromised oxygen delivery, altered FH in the acute phase is associated with a high risk of subsequent infarction. In the present study, we used MR residue detection to study plasma MTTs as well as FH patterns in patients who presented with acute stroke. Furthermore, we sought to correlate these finding with later infarction by comparing the results of initial diffusion-weighted MRI (DWI) with those of follow-up MRI or CT. Subjects and Methods Patient Data All patients were treated with the best medical management but did not receive tissue plasminogen activator or other thrombolytic treatment. DWI and cerebral blood flow (CBF) results for these patients were reported previously. 10 Examinations were performed according to a protocol approved by the Massachusetts General Hospital Subcommittee on Human Studies. Before examination, informed written consent was obtained from each patient. Imaging was performed with a General Electric Signa 1.5-T imager retrofitted for echo planar imaging (EPI) capabilities (Instascan; Advanced NMR Systems). MRI Perfusion Protocol: Determination of Cerebral Blood Volume, Cerebral Blood Flow, MTT, and FH Perfusion imaging was performed using spin echo (SE) or gradient echo (GE), EPI with a time of repetition (TR) of 1.5 seconds, and a time of echo (TE) of 100 ms (50 ms for GE EPI). The slice thickness was 5 mm with an in-plane resolution of mm in a cm field of view. In 10 slices, a total of 52 images were acquired, starting 15 seconds before the intravenous injection of 0.2 (SE EPI) or 0.1 (GE EPI) mmol/kg Gd-based contrast agent. Intravascular contrast agent concentrations were quantified with the assumption of a linear relationship between concentration and change in transverse relaxation rate ( R 2 ). 11,12 The shape of the arterial input function (AIF) was determined from feeding arterial branches, either adjacent to the area of DWI abnormality or at the contralateral middle cerebral artery, and were identified in the image slice as pixels that display early concentration increase after contrast injection. 13 The tissue residue function (or impulse response function) was calculated through deconvolvation of the tissue concentration-time curve by the AIF, with single value decomposition CBF was determined as the height of the deconvolved tissue curve. Cerebral blood volume (CBV) was determined with the area under the tissue concentrationtime curve, as previously described, and the plasma MTT, formed as the ratio CBV/CBF. 21 Finally, the distribution of tissue transit times in each imaging voxel was determined as the slope of the residue function, and with the assumption of equal lengths of capillary paths, the corresponding PDF of relative flows was determined with use of the central volume theorem. 9,21 To quantify and compare the deviation of the experimentally determined PDF from that found in normal brain, a Kolmogorov-Smirnov test was performed, in which the flow PDF in a given pixel was compared with that previously determined in normal tissue (see Results; Figure 1). 9,22 The corresponding P value (null hypothesis that FH distribution is equal to that of normal tissue) was considered statistically significant at P 0.01 (without Bonferroni correction). Initial and Final Infarct Sizes At the initial scan, infarct size was assessed with DWI, 23 acquired with single-shot EPI (TR 6 s, TE 118 ms) with diffusion-weighting Figure 1. A (top), Gray-scale image of plasma MTT in 1 brain slice from patient 6. There is a significant increase in MTT corresponding to the anterior cerebral artery territory. B, Relative flow PDF for 3 regions indicated in a. The x axis displays relative flow, f, and the y axis displays the associated probability, w(f). The distribution in normal tissue is skewed toward high flows. The 2 areas in the anterior cerebral artery territory show a loss of the high-flow component, resulting in a more symmetrical flow distribution. A (bottom), Image of CBF with a color-coded overlay that indicates the probability that the PDF in a given pixel belongs to the distribution of normal tissue. Only areas with P 0.01 are shown. Note subregions displaying abnormal flow distributions within the area of prolonged MTT. applied in 6 directions. 10 With combined low (b 3 s/mm 2 ) and high (b 892 to 1221 s/mm 2 ) b values, the entire diffusion tensor was sampled. Measurements were performed in 17 to 20 slices that were 6 mm thick with a 1-mm interslice gap and an in-plane resolution of 1.56 mm to cover the whole brain. The resulting isotropic (tensor trace) DWI was used in the assessment of initial infarct size. Final infarct size was assessed on the basis of DWIs acquired 2 to 5 days after the infarct, from T2 or FLAIR MRIs acquired at least 5 days after the infarct, or from CT scans acquired 5 days after the infarct if MRI was not available. Volumetric Analysis Using a semiautomatic image analysis software package (ALICE; Hayden Image Processing Group), areas of decreased diffusion, prolonged MTT, and abnormal P values (P 0.01) were measured in each image slice by manually drawing regions of interest around the lesions on the corresponding maps. Tissue volumes were then Age, Sex, Presenting Symptoms, and Time of Initial MRI for 11 Patients With Acute Stroke Patient Age, y/sex Presenting Symptoms MRI, h After Symptom Onset 1 33/M R hemiplegia, mutism /F Aphasia /M R hemiparesis /M L hemiparesis and hemineglect /F L hemiparesis /F L arm and leg weakness /M L facial weakness /F R hemiparesis /M L hemiparesis 4.0* 10 65/M L hemiparesis /M R hemiparesis 6.5 *This patient showed spontaneous reperfusion of the occluded vessel on the follow-up MR angiography.

3 Østergaard et al Combined DWI and PWI in Acute Stroke 1099 Figure 2. Initial and follow-up data from 3 slices from patient 11, a 45-year-old man, at 6.5 hours after onset of symptoms. On the initial DWI (first row), cell death is localized to deep gray matter, whereas the acute MTT maps (second row) show prolonged MTT corresponding to the whole middle cerebral artery territory. The P map shows highly significant deviations from the normal flow PDF in anterior and posterior subregions. These subregions corresponded well with tissue that later infarcted, displayed as bright regions in the 2-month follow-up FLAIR MR images (bottom row). determined by multiplying the lesion areas by the slice thickness plus interslice gap. We did not attempt to coregister initial and follow-up studies. Results Eleven patients with acute stroke (7 men and 4 women, mean age 61 years, age range 33 to 80 years) were examined within 12 hours of symptom onset (Table). All patients showed diffusion abnormalities on the initial DWI 23 consistent with infarction before the initial scan. Furthermore, all patients showed greater volumes of decreased CBF, increased MTT, or both in the hemisphere of infarction. FH Findings Outside volumes of prolonged MTTs, the shape of the tissue flow PDF was similar to that previously found in normal volunteers: namely, a right-skewed distribution with a distinct distribution of high flow rates. Inside volumes of prolonged MTTs, the shape of the flow PDF either was like that of normal tissue or showed a distinctive loss of the high-flow portion of the PDF. To illustrate the first type, Figure 1 shows a typical pattern in patient 6. This patient, a 64-year-old woman, was examined 5.5 hours after the onset of left leg weakness and showed prolonged MTT corresponding to the anterior cerebral artery territory (Figure 1a). Figure 1b shows the FH plots for normal brain tissue as well as 2 regions of prolonged MTT (areas are indicated on the MTT map with numbers corresponding to the PDF curves). The flow PDF in normal tissue was markedly right skewed and matched the shape previously found in normal volunteers. 9 The volumes of increased MTT displayed PDFs with a more symmetric shape, with a tendency to loose the high-flow population found in normal tissue. The degree of symmetry varied within the volume of increased MTT. The deviation from the normal PDF was subsequently quantified with a Kolmogorov- Smirnov test, yielding the probability value P that the curve belongs to the distribution of relative flows of normal tissue. 9 In Figure 1c, areas with large deviations of the PDF from that of normal tissue (P 0.01) are shown with a color-coded overlay of P onto the acute CBF map. Based on our previous experience, a significance level of P 0.05 displays few PDF abnormalities in normal tissue, except in major vessels. Therefore, P 0.01 was chosen to highlight highly significant deviations from normal FH PDF. MTT, FH, and Later Infarction In 8 of 11 patients, a comparison of initial DWIs with the follow-up study showed that lesion size had increased between the initial and follow-up scans. In all 8 cases, infarction had occurred within the region that initially displayed increased MTT. Figure 2 shows this correlation in patient 11.

4 1100 Stroke May 2000 Figure 3. Initial and follow-up studies from patient 3. Notice that the initial lesion (top row) and extent of MTT prolongation (second row) are similar to those observed in Figure 2. Although the CBF was significantly decreased (third row, gray-scale image), there were only small abnormalities in the FHs (indicated by colored areas in overlay on the CBF map). The small spots correspond to vessels with homogenous flows. The final infarct size was similar to that observed on the initial DWI, indicating that the heterogeneity may again have served as a predictor of final outcome. Figure 3 shows the respective maps for patient 3. The MTT maps and initial lesions are similar to those in Figure 2. In this case, the use of MTT overestimates the final infarct size, whereas no abnormalities are seen in the P map. Maps from patient 8 demonstrate the predictive value of the P maps in cases of white matter ischemia (Figure 4). Artifacts in P Maps In 1 patient (patient 9), P maps underestimated the final infarct size. Figure 5 shows 1 slice from this patient, in which areas with P 0.1 are displayed. The high-intensity areas correspond to areas that later infarcted, whereas a number of areas showed a nonspecific increase in P. A separate evaluation of areas with P 0.01 in this patient would cause an underestimation of the final infarct size. Interestingly, follow-up MR angiography in this patient demonstrated spontaneous reperfusion between initial and follow-up scans. Prediction of Final Infarct Size: DWI Combined With FH and MTT, Respectively In Figure 6, final infarct volumes are compared with the initial abnormalities of DWI MTT and DWI P maps, respectively. In 9 of 11 patients, volumes of initial MTT abnormality were significantly larger than the later infarct volume. In 10 of 11 patients, P maps (with vessels and volumes with preserved, high-flow component excluded; see later) corresponded well with the final infarct. In the P maps, small areas of low P value were in some cases observed at the location of major vessels (Figures 2 and 4) due to the homogeneous flow pattern in vessels relative to that in tissue. These areas were not included when defining areas of abnormal tissue FH for comparison with follow-up studies. In patients 3 and 4, areas unrelated to major vessels showed low P value in a single slice, whereas adjacent tissue in neighboring slices showed no abnormalities. An analysis of the FH PDF in these single slices revealed a high-flow distribution similar to that of normal tissue, whereas the low-flow component showed flow components down to zero (unlike the relatively sharp cutoff at 0.5 observed in normal tissue; Figure 1b). We interpret this as being due to dispersion of the AIF relative to the tissue. Based on the preserved high-flow component and the normal PDF observed in adjacent tissue in neighboring slices, these areas were not included when we compared P maps with follow-up images. We discuss these phenomena further later. In general, however, CBF, MTT, and P maps were remarkably insensitive to the choice of AIF. Discussion The results of the present study demonstrate that perfusionweighted MRI can be used to demonstrate pixel-by-pixel changes in the microvascular flow distribution in the acute stages of cerebral ischemia. Our results confirm the report by Hudetz et al 8 in animals that decreased perfusion pressure (CBF/CBV ratio) is associated with the loss of high-flow components. The present study extends these findings through documentation of the loss of FH in human acute stroke and good agreement between heterogeneity changes in early ischemia and eventual tissue infarction. Our findings hence strongly support the hypothesis by Hudetz et al 8 that gradual loss of the high-flow component of the FH PDF heralds local loss of functional reserve capacity and, there-

5 Østergaard et al Combined DWI and PWI in Acute Stroke 1101 Figure 4. Patient 8, a 80-year-old woman, showed signs of white matter ischemia. Small infarcted areas are seen on the initial DWIs (top row). The MTT image shows abnormalities that extend into the white matter around the initial lesions. Again, FH changes are observed in smaller subregions, with good correspondence to the regions that later infarcted. Note the symmetrically located areas with low probability value, corresponding to vessels. fore, infarction. 8 Our finding that P maps can be used to predict final infarct size with high certainty in untreated patients suggests that MR heterogeneity measurements may prove useful for the planning of individual patient management, as well as for the evaluation of new therapeutic approaches in smaller patient populations. The hypothesis of heterogeneity changes being the driving force in the regulation of oxygen delivery to tissue 6,7 suggests a possible relationship between our findings and the OEF increase observed with PET in tissue at high risk of subsequent infarction. 1,4,5 Indeed, qualitative analysis of the kinetics of oxygen delivery shows that one should expect reduced heterogeneity of blood flow to produce an increased flow of oxygen into the tissue in states of decreased flow, as illustrated in Figure 7. The curve is a plot of the oxygen flow into tissue versus the blood flow. From the convex shape of the curve, it can be seen that OEF at a given, limited mean blood flow is greater when blood flow is homogeneous than when blood flow is more heterogeneous. The observed shifts toward a homogeneous flow distribution may therefore signal increased utilization of metabolic regulatory capacity, accounting for the risk of infarction observed in these regions of extreme flow homogenization. PET is the method of choice to demonstrate metabolic reserve capacity in cerebrovascular disease. However, future studies should focus on the relationship between MR FH measurements and OEF measured with PET to further explore this coupling of microvascular dynamics and metabolism. Infarction occurred in areas that initially displayed prolonged plasma MTTs. This is agreement with our previous Figure 5. In patient 9, initial FH changes underestimated the final infarct size. The threshold is set at P 0.1 to demonstrate the location of minor abnormalities. Although some areas showed good correspondence with later infarct, the choice of a significance level of P 0.01 would lead to an underestimation of the final infarct size. Follow-up MRA showed that the middle cerebral artery had reperfused between the initial and follow-up scans.

6 1102 Stroke May 2000 Figure 6. Predicted final infarct sizes based on initial DWI combined with MTT and P, respectively, plotted versus actual final infarct sizes based on follow-up studies. Also shown are the corresponding linear regression lines with the assumption of a zero intercept: y 0.94x (r ) for DWI and P and y 1.96x (r ) for DWI and MTT. experience with this technique, 10 as well as with studies with PET 3,5 and SPECT. 24 Although the CBV/CBF ratio (ie, 1/MTT) depends linearly on the cerebral perfusion pressure over a range of values, 25 this dependence is likely to be lost when maximum vasodilation is reached at low pressures. 1 The MTT prolongation therefore may not be directly related Figure 7. Oxygen flow into tissue versus blood flow f, related through the equation f (1 e PS/f ), where PS is the permeability to oxygen multiplied by the surface area of capillaries. 29,30 If all blood flow is at the normal mean flow, f norm, the oxygen flow into tissue is given by the height of A. If part of the flow is at f low and the rest at f high, with weightings to maintain the same mean flow, the oxygen flow into the tissue will be the height of D. Notice, as mean flow is reduced and f high and f low changed to maintain the same CMRO 2, both f low and f high approach f min, thereby decreasing the degree of heterogeneity. Notice decreased FH with constant flow will increase oxygen delivery, in parallel with the findings of Vogel et al, who found decreased heterogeneity in states of functional activation and thereby increased oxygen metabolism. 7 to the severity of the perfusion pressure drop and, hence, risk of infarction. Our findings support, however, that prolonged MTT is an early sign of decreased perfusion pressure, at a stage where regulatory mechanisms may still suffice to ensure tissue survival. Although the high-flow component seem crucial to tissue survival, the low-flow component of the FH PDF may also prove useful in the planning of therapeutic approaches. The results of intravital microscopy studies suggest that maintenance of CBVs above a fixed, lower limit is essential to avoid white blood cell plugging of capillaries. 8,26 The distributions of absolute flows in single pixels may prove useful in the assessment of leukocyte adhesion before therapeutic attempts to reperfuse tissue. In patients with cerebrovascular disease, the AIF may undergo dispersion and delays upstream of site of measurement, possibly causing an overestimation of MTT. 14,15 We sought to reduce this bias by choosing AIFs in the vascular territory affected by the vascular occlusion. Furthermore, dispersion of the AIF will tend to broaden the flow PDF. Therefore, the effects of dispersion counteract the observed homogenization of flow elements. In determination of the flow PDF, high probability values were observed near vessels (and therefore easily identifiable on the accompanying CBV maps), because major vessel flow is inherently homogeneous. Probability maps should therefore be carefully inspected for vessels on CBV maps, as well as for signs of vessel dispersion in the PDF shape in a given region. In our experience, SE EPI images are particularly well suited for this type of analysis, because large vessels are suppressed due to the inherent microvascular weighting of these images. 12,27,28 Despite the observed robustness of the technique to the choice of AIF in the image slice, it should be carefully inspected to ensure that major hemodynamic abnormalities do not lead to biased FH abnormalities according to the location of the arterial input. In 1 patient, the P maps underestimated the final infarct size. At the follow-up MRA study, this patient showed spontaneous reperfusion of the artery occluded in the acute study. We speculate that in the rare cases of spontaneous recanalization, where tissue damage may result from hyperperfusion or other causes, the FH technique may lack specificity in the prediction of the final outcome. Given these precautions, our findings indicate that MRbased assessment of FH provides a powerful tool with which to study residual metabolic reserve capacity in peri-infarct tissue. Combined conventional MRI, MRA, DWI, determination of FH, and plasma MTT can be performed in 20 minutes with most clinical MR systems. In the future, the presence of tissue with loss of FH may serve to guide individual patient management and indicate tissue that may serve as a target for novel therapeutic approaches. References 1. Powers WJ. Cerebral hemodynamics in ischemic cerebrovascular disease. Ann Neurol. 1991;29: Gibbs JM, Wise RJ, Leenders KL, Jones T. Evaluation of cerebral perfusion reserve in patients with carotid-artery occlusion. Lancet. 1984; 1:

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