REVIEW
Comparison of PET and DW / PW-MRI in Acute Ischemic Stroke
W.-D. Heiss and J. Sobesky

Max Planck Institute for Neurological Research, Köln, Germany(Received for publication on November 7, 2007)(Accepted for publication on February 21, 2008)

Abstract: The penumbra - tissue perfused below the flow threshold for functional disturbance but above that for maintenance of morphological integrity - is the target for therapy
in acute ischemic stroke. Irreversible tissue damage and penumbra can be reliably identified by multitracer positron emission tomography (PET) which has severe limitations due tocomplexity, invasiveness and radiation exposure. Therefore other modalities served as surrogate markers, with diffusion / perfusion-weighted magnetic resonance imaging (DW / PW MRI) and perfusion computed tomography (PCT) being applied widely in clinical routine.
In order to evaluate the limitations of DW / PW - MRI a comparative study was performedin acute stroke patients in whom cerebral perfusion was assessed by perfusion-weighted
magnetic resonance imaging (PW-MRI) and H2 1 5O-PET, tissue damage was estimated bydiffusion-weighted magnetic resonance imaging (DW-MRI) and 11C-flumazenil (FMZ) PET
and DW / PW - MRI mismatch was related to the tissue with increased oxygen extraction
fraction (OEF) as an indicator of penumbra. The lesions in DW - MRI and in FMZ-PET werereliable predictors of final infarct on late MRI, but DW - MRI showed a high false positive
rate. PW - MRI was limited in estimating flow and yielded values comparable to H2 15O-PET
only in the range between 20 and 30 ml/100g/min. The DW / PW - MRI mismatch overestimated the penumbra as determined by increased OEF. These limitations of DW / PW - MRI
have to be considered if used for selection of patients for treatment and might have an impact on the outcome of clinical trials based on this surrogate marker. (Keio J Med 57 (3) : 125－131, september 2008)
Key words: brain ischemia, ischemic stroke, positron emission tomography, diffusion / perfusionweighted magnetic resonance imaging, oxygen extraction fraction, mismatch, stroke
therapy, thrombolysis, reperfusion

Introduction
Therapy in acute ischemic stroke can only be effective
as long as potentially salvageable tissue is present within
the brain area affected by the perfusional disturbance.
Therefore, the identification of the penumbra - tissue
perfused at a level which impairs function but preservesmorphology1-3 - and the distinction of this potentiallyreversible condition from irreversibly damaged tissue isof utmost importance for the initiation of treatment strategies targeted at reperfusion and protection of ischemically compromised but viable brain areas. Whereas themodel of regional ischemic damage with a core of fastdeveloping necrosis and a surrounding area with delayed

damage and a potential for recovery, i.e. the penumbra,
was developed from animal experiments, the transfer ofthis concept into clinical application in patients withacute ischemic stroke is limited by the inaccuracy in differentiating functional impairment from morphologicaldestruction in early stroke. Various imaging modalities
have been applied for this task: PET of regional cerebral
blood flow and energy metabolism was the first imaging
technique employed for penumbra detection, which was
defined as the region with increased oxygen extraction
fraction and termed “misery perfusion” for this purpose.4
PET is still considered the gold standard for detection of
penumbra and irreversibly damaged tissue, 5, 6 but its
availability is limited to a few centres and restricted byPresented at the 1519th meeting of the Keio Medical Society in Tokyo, May 25, 2007
Corresponding Author: Prof. Dr. W.-D. Heiss, Max Planck Institute for Neurological Research Gleueler Str. 50 50931 Köln, Phone: 49-221-4726-220
Fax:49-221-4726-349, E-mail:wdh@nf.mpg.de
125

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Heiss WD: PET and DW/PW-MRI in Stroke

the complex logistics involved. DW / PW - MRI is widely available and has become the routine method for theacute evaluation of stroke patients. The area of diffusion/ perfusion mismatch has been used as a surrogate marker of the penumbra and promising results were achieved
in identifying patients with a chance to respond to therapy.7-9 Recently also determination of perfusion by x-ray
computed tomography(CT) was successfully applied todetection of potentially salvageable ischemically compromised tissue.10
Detection of Penumbra
Severity and extent of the ischemic compromise can beclearly assessed in experimental models for which flow
thresholds for preservation of function and morphology
were defined.2, 3 Ischemic tissue is only amenable totherapy as long as the lack of blood supply did not leadto morphological destruction and only caused functional
impairment. This tissue, termed the penumbra,1 is perfused at a level within the thresholds of functional impairment and morphological integrity and has the capacity to recover if perfusion is improved. The extent of thistissue compartment is dependent on residual flow andduration of flow disturbance: It can be clearly demonstrated in animal experiments with permanent and transient occlusion of cerebral vessels11 that the volume offunctionally impaired but morphologically intact tissue islarge and involves even the centre of the vascular territory with impaired blood supply immediately after the onset of the perfusional disturbance, and it becomes progressively smaller with time elapsed since the vascular
attack.5 This concept as developed in animal experiments defines the penumbra as a dynamic process depending on residual perfusion and duration, with conversion into irreversible neuronal damage over time, progressing from the centre of dense ischemia to the surrounding tissue with less severe but still critically hypoperfused adjacent areas.
In the clinical setting of acute stroke management theassessment of the condition of the ischemically affected
tissue is extremely difficult and necessitates logisticallycomplex and expensive investigative procedures, whichcannot be performed routinely. Studies performed in selected cases with determination of regional cerebral
blood flow (rCBF), regional cerebral consumption of oxygen (rCMO 2), regional oxygen extraction fraction(rOEF), and regional cerebral metabolic rate for glucose(rCMRglc) by PET have broadened the knowledge ofpathophysiological mechanisms leading to ischemic infarction and in some instances could explain the successor failure of therapeutic interventions. In individual cases, disturbances of flow and energy metabolism in theacute stage could be related to the final fate of the tissue:
synchronous decreases of flow and oxygen consumption

below threshold values predicted infarction, whereas uncoupled decreases of flow with oxygen consumption preserved at a higher value termed “misery perfusion” by
Baron et al. (1981)1 2 indicated tissue with uncertain
prognosis, i.e. the potential for recovery or necrosis. The
determination of absolute values of thresholds in patients, however, is difficult since the necessary calculation requires arterial blood sampling. Additionally, measurements of tracer concentrations are affected by considerable variability causing especially high statisticalerrors at low count rates. As a consequence, the reported
values for the threshold of morphological damage and of
the upper limit of penumbra given by different authors
vary considerably (review in Heiss et al, 2000).13 These
values are also affected by the time of determination after the vascular attack since the variability of flow in thecourse after the attack which has a considerable effect on
outcome cannot be assessed. For preservation of morphology the necessary oxygen consumption was determined to be around 65μmol/100g/min, the flow thresholds ranged between 5 and 12 ml/100g/min. For the upper limit of the penumbra flow values between 14 and 22
ml/100g/min were reported. These values corresponded
to those assessed by other methods as PW-MRI, single
photon emission computed tomography (SPECT), andXe-enhanced computed tomography (Xe-CT).
Using flow values measured in the first hours after astroke various compartments of tissue and their contribution to the final infarct on CT/MRI can be determined. If
the threshold for probable infarction was arbitrarily set tothe conventional value of 12 ml/100g/min and that for
the upper limit of penumbra to 18 ml/100g/min14 a large
compartment of the final infarct (70%) was critically
perfused, i.e. at a level predicting necrosis; a smaller
compartment (18%) had flow values in the penumbra
range and a fairly small compartment (12%) was sufficiently perfused.15 This result carries important implications for treatment of acute stroke: a significant effectcan only be achieved if perfusion is improved before irreversible damage has occurred.
Detection of Irreversibly Damaged Tissue
The determination of rCBF is an unreliable predictor
for the assessment of irreversible damage. For that purpose quantitative measurement of CMRO2 and CBF isnecessary requiring arterial blood sampling which is prohibited when invasive strategies, e.g. thrombolysis, areplanned. Therefore, a marker of neuronal integrity isneeded which can noninvasively distinguish between viable and irreversibly damaged neurons. As such tracers
labelled ligands of central benzodiazepine receptors canbe applied which reliably differentiated infarcted from
non-infarcted cortex in animal experiments and in stroke
patients.1 6 Using 11C-flumazenil(FMZ) as a marker ofKeio J Med 2008; 57 (3): 125－131

127

neuronal integrity and H21 5O for flow determinations,the pathophysiological changes early after ischemic
stroke could be more accurately specified: 55% of thevolume of the final infarct had FMZ uptake decreased
below the limit of 95% probability for infarction at the
study in the first hours after stroke; 21% of the final infarct had flow below 14 ml/100g/min, the 95% probability threshold for survival, but FMZ above the criticalvalue, thereby indicating penumbra tissue. Only 13% of
the final infarct exhibited neuronal integrity and CBFvalues above the penumbral range. These results stressagain the crucial role of early reperfusion in the treatment of ischemic stroke. Only a rather small compartment is initially viable and sufficiently perfused, but
eventually becomes necrotic mainly owing to delayedmechanisms; only this tissue volume may benefit fromneuroprotective or other measures exclusively targeted
to secondary damage.

results across studies. More sophisticated analytical procedures may help to improve accuracy in distinguishingcore from penumbral tissue.28

Limitations of DW / PW - MRI

For the prediction of irreversible cortical damage results from DW - MRI (median 6.5 hours after symptoms
onset) and FMZ PET (median 85 min between DW MRI and PET) were compared with infarct extension 24
to 48 h later on T2-weighted MRI in 12 acute stroke patients.2 9 Cortical areas were categorised as infarction or
normal according to their appearance on follow-up MRI
and volumes of interest (VOIs) of 6-mm diameter werefitted into the cortical rim of the coregistered DW - MRI,
apparent diffusion coefficient (ADC), and FMZ images.
Across all patients’ volumes of interest, the thresholdprobability integrals of final infarction or noninfarction
were interactively computed, and positive prediction
curves were obtained on which 95% prediction limits
could be defined.1 6 These values - FMZ binding 3.2
times the mean of the contralateral white matter, DW MRI intensity 1.18 times the contralateral area, ADC
0.83 times the contralateral region - represent the 95%
probability threshold of final infarction. When the volumes of tissue beyond these thresholds were compared,
close correlations between volumes with FMZ and DW MRI beyond threshold as well as between predicted andfinal infarct volumes were obtained, but the volumes did
not completely overlap. Overall, 83.5% of the final infarct (median, 14.9 cm3) was predicted by decreased
FMZ binding, 84.7% by increased DW - MRI signal, and70.9% by reduced ADC value. However, because of theincongruities, only a small part of the final infarct was
not predicted by FMZ or DW - MRI value beyond thecritical limit (median, 1.1 cm3). The false-positive rates
showed significant differences: only a small part (median, 0; mean, 0.9 cm3) of the finally noninfarcted tissue
had initially decreased FMZ binding, whereas 5.1 cm3 offinally normal tissue showed an increased DW - MRI
signal (25.9% of the total volume of DW - MRI increase)and 3.6 cm3 showed a decreased ADC value (22.3% ofWithout doubt DW / PW - MRI is the most widely
available and most utilised method to detect tissue amenable for therapy in patients with acute stroke and it istherefore the preferred method for selection of patientsand for evaluation of treatment effects in stroke trials.1 7-1 9 However, the assumption that the diffusion /perfusion mismatch represents the penumbra as challenged by several limitations of DW / PW - MRI20:
1 The initial diffusion lesion does not only consist of irreversibly infarcted tissue; diffusion lesions may bereversed if blood flow is restored at an early time
point.7-9
2 True penumbra cannot be clearly differentiated fromtissue experiencing oligemia; the perfusion-weighted
imaging abnormality often overestimates the final infarct volume and thereby the amount of tissue atrisk.21
These facts are further accentuated by methodologicallimitations, especially perfusion techniques and data
evaluation are not truly quantitative and vary among
centres. 2 2 In order to account for these inaccuracies
Kidwell et al 20 proposed a modified model of ischemic
compromised tissue as observed by DW / PW - MRI in
which the penumbra includes the diffusion / perfusion
mismatch region, minus the region of benign oligemia as
well as a portion of the initial diffusion abnormality itself. The definition of this tissue compartment, however,remains to be controversial and several attempts havebeen made to identify perfusion or apparent diffusion coefficient thresholds for better differentiation of these regions,21, 23-27 but a consensus on the best method is still
hampered by the lack of standardisation of methodological approaches to image post processing and analysis
which restricts pooling of data and cross-comparison ofComparison of MRI and PET
Absolute or relative thresholds derived from DW / PW
- MRI are still not reliable in predicting the fate of ischemic tissue.2 8 Therefore, a validation of MR signatureson results from PET measurements might help in the interpretation of the respective finding and in the assessment of the accuracy of the various measures for predicting tissue outcome. Comparative studies with PET and
MRI were performed in 3 groups of patients with respect
to assessment of cortical damage, measurement of perfusion and delineation of penumbra tissue.
Irreversible Cortical Damage

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Heiss WD: PET and DW/PW-MRI in Stroke

total volume). These differences were significant( <0.01, Wilcoxon test). The volumes of infarcted tissue(P
not predicted by decreased FMZ or changed DW - MRI
signal were comparable. In single cases, areas withmarkedly increased DW - MRI signal did not show either impaired FMZ binding or a lesion on late MRI, asreported previously,3 0 but in most cases the differenceswith respect to FMZ binding and DW - MRI signals
were at the borderline of the ischemic territory.
Perfusion in and around the Ischemic Territory
For the assessment of perfusion within the oligemic
and ischemic territory results from PW - MRI (median 8hours after symptoms onset) were compared with cerebral blood flow measurements obtained with H215O-PET(interval 60 min between PW - MRI and PET) in 11
acute stroke patients.3 1 After coregistration of the MR
and PET images, an individual brain atlas was createdfor each patient. Then the volume of hypoperfusion of<20 ml/100 g per minute (PET CBF) was created withthe use of a voxel-based threshold function. Within thesame brain atlas, the time to peak (TTP) images were analyzed with stepwise increasing thresholds, i.e. with increasing relative TTP delays (2, 4, 6, 8, 10 seconds withrespect to the unaffected hemisphere). The volume of
CBF hypoperfusion ranged from 1.2 to 362 cm3 (median,34.5 cm3). The voxelbased 3-dimensional fusion of eachpatient’s hypoperfusion volume (CBF) and the respective
set of TTP volumes were used to create subcompartments to calculate sensitivity and specificity values foreach TTP threshold. The TTP threshold of 4 seconds reliably identified hypoperfused tissue (sensitivity, 0.827)
and excluded normoperfused tissue (specificity, 0.768).
Increasing the TTP threshold to 6 seconds impaired theability to detect hypoperfusion (sensitivity, 0.765) but
improved the rate of correctly identified normoperfusedtissue (specificity, 0.875). From this small sample size, it
can be concluded that a TTP delay between 4 and 6 seconds is useful to differentiate cerebral hypoperfusion of<20ml/100 g/ min.
Delineation of Penumbra Tissue
For the demarcation of the volume of tissue at risk
(penumbra) the areas of mismatch from DW / PW - MRI
were compared to those of increased oxygen extraction
fraction (OEF) as determined from PET of cerebral
blood flow (CBF) and cerebral metabolic rate of oxygen(CMRO2) in 5 patients with acute and 5 patients withsubacute state after stroke due to vascular stenosis.32 As
surrogate markers of the penumbra, DW / PW - MRI revealed a mismatch between the volumes of TTP prolonged beyond 4 sec and the volume of increased DW MRI signal, and volumes of increased OEF (>150%)

were calculated from CBF and CMRO2 maps measured
by PET. The comparison of the volumes identified bythese modalities demonstrated a high variability: all 10
patients showed areas of TTP prolongation on PW images (median volume, 162 cm 3; range, 8 to 450 cm 3).
However, in only 6 of 10 patients was an elevated OEF
identified on PET images (median volume, 65 cm 3;
range, 12 to 240 cm3). The areas of OEF elevation werealways located within the areas of TTP prolongation but
were significantly smaller and covered only 8% to 58%(median, 33%) of the TTP area. These preliminary data
demonstrate a high sensitivity but a low specificity of thechosen threshold to identify penumbral tissue as definedby PET: in 40% of the patients with TTP > 4, no OEF elevation was found. In the remaining 60% with OEF elevation and TTP > 4, only a third of the TTP volume corresponded to elevated OEF. These findings may explain
the poor relation between increased OEF and TTP values
in a correlation analysis based on volumes of interest.
The results of our small patient sample indicate that TTP
threshold > 4 seconds does not sufficiently discriminate
between normal and increased OEF in ischemic tissue.
These preliminary data on the comparison of PET and
DW / PW - MRI for assessment of perfusion, identification of irreversible tissue damage, and distinction of penumbra indicate that imaging with these different modalities yields complementary information on the dynamics
of pathophysiological events in ischemic brain tissue.
The findings of DW - MRI/ADC imaging correlate wellwith those of FMZ PET and predict the final infarct extension.26, 3 3 However, the increased DW - MRI signal
carries a considerable false-positive rate, a clinically important restriction of DW - MRI that was demonstrated
in previous studies of patients with transient ischemic attack and those treated with thrombolysis.7, 3 4, 3 5 PW MRI-derived TTP maps are only indirect surrogates of
CBF because they are based on a different pathophysiological approach.3 6 Hence, a TTP prolongation of > 4
seconds allows only a vague estimate of hypoperfusionof 20ml/100 g/ min.3 7 Because of this indirect assessment of perfusion from TTP prolongation, which therefore inconsistently corresponds to elevated OEF,3 8 themismatch volume in DW / PW - MRI does not reliablyreflect misery perfusion as defined by PET. Despite theimportance of MRI in clinical practice for the selectionof patients who might benefit from revascularization
procedures, the differences between the imaging methods and their specific methodological restrictions should
be taken into account when results are compared anddefinitions of various tissue conditions are transferred
between the modalities.
Effects of Treatment on the Penumbra
The efficacy of treatment in ischemic stroke can only

Keio J Med 2008; 57 (3): 125－131

be proven by controlled randomized double blind clinical trials, as successfully performed for thrombolysis
within the 3-hour-window39, 40 (The NINDS rtPA Stroke
Study Group 1995, The Atlantis 2004). Since such controlled trials require large patients’ populations collected
in many stroke centres and therefore usually take longtime and considerable funds, surrogate markers are applied to predict potential therapeutic effects in small
groups of patients. It has to be kept in mind that proveneffects on surrogate markers always must be confirmed
in controlled trials based on sufficient patients’ populations. Based on experimental results in stroke models4 1
neuroimaging has been used as a surrogate marker to indicate therapeutic effects of various treatment strategies.
Non-enhanced x-ray CT which is still the first line diagnostic procedure in management of acute ischemic
stroke42 does not reliably predict response to thrombolysis.43 Some studies demonstrated an increased risk of intracerebral hemorrhage after tPA if early ischemic signs
involved more than 1/3 of the mci-territory, but this finding was not replicated in other studies.4 4 Clinical CT
mismatch was not related to response to tPA treatment45
and the semi-quantitative analysis of early ischemic
signs by ASPECTS46 did not predict effect of tPA.47, 48
Thrombolysis is still the only approved therapy foracute ischemic stroke, and its effect was demonstrated
recently in several imaging studies, in which reperfusion
to penumbral tissue was associated with improvement inneurological deficits. In a small cohort selected from the
NINDS study, Grotta et al. (1998)49 found a significantly
greater reperfusion in the rtPA treated patients than in theplacebo group. The volume of tissue salvaged by reperfusion was established in a study in which CBF, as determined by H215O-PET within 3 hours of stroke onset, wascompared with the volume of infarction determined on
MRI 3 weeks after the ictus.50 The percentage of initially critically ischemic voxels (i.e. with a flow below thethreshold of 12 ml/100g/min) that became reperfused at
almost normal levels clearly predicted the degree of clinical improvement achieved within 3 weeks. Overall, only
22.7% of the grey matter that was initially perfused at
rates below the conventional threshold of critical ischemia became necrotic after thrombolytic therapy in thissmall sample of 12 patients. That means, that a considerable portion of the critically hypoperfused tissue wasprobably salvaged by the reperfusion therapy. AnotherPET study in 11 patients1 3 indicated that hypoperfusedtissue could benefit from reperfusion only as long as cortical flumazenil binding was not reduced to or below 3.4
times the mean uptake in white matter. This marker ofneuronal integrity can therefore serve as an indicator for
irreversibly damaged tissue that is not amenable to treatment.
Some investigators applied dynamic perfusion-CT10, 51
for the selection of patients for thrombolysis and report-

129

ed favourable outcome if a mismatch between the coreof ischemia (significant reduction of regional cerebral
blood volume, i.e. below 2.0 ml/100g/min) and the areawith decreased perfusion (regional mean transit time
above 145% of contralateral area) but maintained blood
volume (> 2 ml/100g/min) was found. Dynamic CT wasused in patients treated with intra-arterial revascularization procedures and could distinguish ischemic tissue
likely to infarct from that likely to survive.5 2 Further
studies are needed to confirm the value of this surrogate
marker for prediction of clinical outcome after treatment.
The difference in the volumes of abnormality in DW /PW - MRI - as an approximation to the zone of the penumbra - has also been used as a surrogate marker of efficacy in stroke trials.53 Several groups reported results ofserial DW and PW imaging in patients undergoing intravenous or intra-arterial thrombolysis. The main finding
proved inhibition of lesion growth in patients experiencing reperfusion compared with patients with persistentperfusion deficit.54 Normalization of PW - MRI and increases in ADC were closely associated with the reperfusion seen after thrombolytic therapy7, 5 5 and the DW /PW - MRI mismatch could be used as an effective selection criterion even in patients admitted more than 3 hours
after onset of symptoms.18 However, in some cases perfusion deficits can be resolved and DW - MRI signaturesof early ischemic injury can be reversed by prompt vessel recanalization.7 This means that the ischemic penumbra includes not only a region of diffusion / perfusion
mismatch, but also portions of the volume of initial diffusion abnormality.
The DW / PW - MRI mismatch was used for selectionof patients in several clinical trials. In patients with mismatch the outcome was more favourable after tPA treatment, especially if thrombolysis was initiated 3 - 6 hours
after stroke onset.5 6, 5 7 The diffusion / perfusion mismatch could identify subgroups of patients which might
benefit from thrombolysis 3 - 6 hours after stroke onset58
and DW / PW - MRI mismatch was more accurate thanthe clinical-diffusion-mismatch for selecting patients forreperfusion treatment.5 9 However, if only patients with
DW / PW - MRI mismatch were included into controlled
clinical trials, the outcome in the treated groups was not
improved: despite preliminary studies indicated a favourable effect for desmoteplase, 6 0, 6 1 citicholine 1 7 and
NXY-05962 the large confirmatory clinical trials did notprove the efficacy of these therapeutic regimens.63-65 In
conclusion, the various techniques that permit the identification of potentially salvageable tissue (i.e. a surrogate
measure of penumbra) have considerable limitations andcan only be applied with caution for the definition oreven extension of the window of therapeutic opportunity
in patients with acute ischemic stroke.

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Heiss WD: PET and DW/PW-MRI in Stroke

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