(Stroke. 2000;31:1097.)
© 2000 American Heart Association, Inc.
Original Contributions |
Combined Diffusion-Weighted and Perfusion-Weighted Flow Heterogeneity Magnetic Resonance Imaging in Acute Stroke
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. E-mail leif{at}pet.auh.dk
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Abstract |
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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.
Key Words: cerebral blood flow • magnetic resonance imaging, diffusion-weighted • magnetic resonance imaging, perfusion-weighted • microcirculation
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Introduction |
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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 2 3 4 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 whisker-barrel 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 al8 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 probability 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.
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Subjects and Methods |
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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 1.56x1.56
mm in a 40x20 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
(
R2).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.14 15 16 17
CBF was determined as the height of the deconvolved tissue curve.
Cerebral blood volume (CBV) was determined with the area under the
tissue concentration-time curve, as previously
described,18 19 20 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).
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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 applied in 6 directions.10
With combined low (b=3 s/mm2) and high (b=892 to
1221 s/mm2) 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 determined by multiplying the lesion
areas by the slice thickness plus interslice gap. We did not attempt to
coregister initial and follow-up studies.
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Results |
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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 DWI23
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.
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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.
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).
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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.
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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.
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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.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The results of the present study demonstrate that perfusion-weighted 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 al8 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 al8 that gradual loss of the high-flow component of the FH PDF heralds local loss of functional reserve capacity and, therefore, 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
tissue6 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.
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Infarction occurred in areas that initially displayed prolonged plasma MTTs. This is agreement with our previous experience with this technique,10 as well as with studies with PET3 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 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 MR-based 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.
Received September 21, 1999; revision received December 10, 1999; accepted February 7, 2000.
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