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adiología. 2012;54(3):208---220

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PDATE IN RADIOLOGY

tudying cerebral perfusion using magnetic susceptibilityechniques: Technique and applications�

.A. Guzmán-de-Villoriaa,b,∗, P. Fernández-Garcíaa, J.M. Mateos-Pérezb,c, M. Descob,c,d

Servicio de Radiodiagnóstico. Hospital General Universitario Gregorio Maranón, Madrid, SpainCentro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, SpainUnidad de Medicina y Cirugía Experimental, Hospital General Universitario Gregorio Maranón, Madrid, SpainDepartamento de Bioingeniería e Ingeniería Aeroespacial, Universidad Carlos III, Madrid, Spain

eceived 27 March 2011; accepted 27 June 2011

KEYWORDSPerfusion magneticresonance imaging;Brain tumors;Multiple sclerosis;Cerebral thrombosis

Abstract Perfusion MRI makes it possible to evaluate the cerebral microvasculature throughchanges in signal due to a tracer passing through blood vessels. The most commonly used tech-nique is based on the magnetic susceptibility of gadolinium in T2*-weighted sequences, andthe most commonly evaluated parameters are cerebral blood volume, cerebral blood flow,and mean transit time. Diverse technical aspects, like the sequence used, and the dose andspeed of contrast material injection, must be taken into account in perfusion MRI studies. It isalso essential to consider possible sources of error like contrast material leaks due to changesin the permeability of the blood---brain barrier. The most widely used clinical applications ofperfusion MRI include the determination of the degree of aggressiveness of gliomas, the dif-ferentiation of some histological types of tumors or pseudotumors, and the evaluation of thepenumbral area in acute ischemia.© 2011 SERAM. Published by Elsevier España, S.L. All rights reserved.

PALABRAS CLAVEImagen de perfusión

Estudio de la perfusión cerebral mediante técnicas de susceptibilidad magnética:técnica y aplicaciones

ded from http://zl.elsevier.es, day 14/08/2014. This copy is for personal use. Any transmission of this document by any media or format is strictly prohibited.

por resonanciamagnética;Tumores cerebrales;Esclerosis múltiple;

Resumen Las técnicas de perfusión por RM (PRM) permiten la valoración de la microvascu-latura cerebral mediante los cambios de senal debidos al paso intravascular de un trazador.La técnica más empleada se basa en la susceptibilidad magnética del gadolinio en secuenciasT2* y los parámetros más comúnmente valorados son: el volumen sanguíneo cerebral, el flujo
Trombosis cerebral sanguíneo cerebral y el tiempo de tránsito medio. En los estudios de PRM deben considerarse
� Please cite this article as: Guzmán-de-Villoria JA, et al. Estudio de la perfusión cerebral mediante técnicas de susceptibilidadagnética: técnica y aplicaciones. Radiología. 2012;54(3):208---20.∗ Corresponding author.

E-mail address: [email protected] (J.A. Guzmán-de-Villoria).

173-5107/$ – see front matter © 2011 SERAM. Published by Elsevier España, S.L. All rights reserved.

dx.doi.org/10.1016/j.rxeng.2011.06.004

http://www.elsevier.es/rx

mailto:[email protected]

Studying cerebral perfusion using magnetic susceptibility techniques: Technique and applications 209

diversos aspectos técnicos como la secuencia empleada, la dosis o la velocidad de inyección delcontraste. También debe valorarse la existencia de fuentes de error como las debidas a la fugade contraste por alteración en la permeabilidad de la barrera hematoencefálica. Las aplica-ciones clínicas más extendidas de la PRM incluyen la determinación del grado de agresividad degliomas, la diferenciación de algunos tipos histológicos tumorales o de lesiones pseudotumoralesy la valoración del área de penumbra en la isquemia aguda.© 2011 SERAM. Publicado por Elsevier España, S.L. Todos los derechos reservados.

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Document downloaded from http://zl.elsevier.es, day 14/08/2014. This copy is for personal use. Any transmission of this document by any media or format is strictly prohibited.

Introduction

Strictly, cerebral perfusion is defined as the steady-statedelivery of nutrients and oxygen via blood per unit volumeor mass and is typically measured in milliliters per 100 g oftissue per minute.1 However, in perfusion MR (PMR) imaging,the term has broadened1 to include multiple tissue microcir-culatory parameters, such as cerebral blood volume (CBV),cerebral blood flow (CBF), mean transit time (MTT), time topeak (TTP), and maximum time (Tmax).

Technical considerations

Modalities of perfusion MR imaging. T2*-weighteddynamic magnetic susceptibility imaging

The three main techniques used to perform PMR imaging areT2*-weighted dynamic magnetic susceptibility, T1-weighteddynamic perfusion, and arterial spin labeling.2 All threetechniques are based on the signal changes that accom-pany the passage of a tracer through the cerebrovascularsystem.1 This tracer can be endogenous (water) or exoge-nous (gadolinium chelates).

The most commonly used technique is T2*-weighteddynamic magnetic susceptibility, which relies on the para-magnetic property of gadolinium contrast agents when theypass through the cerebrovascular system leading to a T2 sig-nal drop, and mainly T2*, due to the differences in localmagnetic susceptibility (Fig. 1).1,3

Intravenous gadolinium chelate is a nondiffusible tracerfrom the vascular bed to the cerebral parenchyma.1 Thisconfinement to the vascular space leads to the dominanteffect of magnetic susceptibility. Therefore, the para-magnetic agent acts as a series of magnetic cylinders thatinfluence the surrounding tissue altering the local magneticfields.4 If the magnetic field is perfectly homogeneous, allwater molecules precess at the same frequency; nonethe-less, when the paramagnetic gadolinium agent alters themagnetic field, water molecules of the surrounding tissueprecess at different frequencies.4

Research has shown a linear relationship between con-trast agent concentration and T2 signal rate change.3 Thus,contrast agent concentration is proportional to the changesin the relaxation rate [�R2*], according to the equation
�R2* (t) = {−ln[S(t)/S0]}/TE}, where S(t) is the signal inten-sity in a given t time, S0 is the precontrast signal intensity,TE is echo time, and �R2* represents the changes inrelaxation rate, which is assumed to be proportional to
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issue contrast agent concentration,1 provided that there iso contrast agent recirculation or leakage.4 Therefore, a tis-ue contrast concentration---time curve can be derived fromhe shortening of T2* during the passage of the bolus ofadolinium, allowing estimates of the different parameters.

equences used in T2*-weighted dynamic magneticusceptibility imaging

he sequences should have an appropriate temporal res-lution, so that images of a dynamic series are acquiredt approximately one-second intervals.1 Longer inter-als provide less accurate measurements of the signalntensity---time curve. For this reason, most studies usecho planar imaging (EPI), capable of generating approxi-ately 10 MR images every second, making it ideal for rapidynamic imaging.1

The use of gradient echo (GE) or spin echo (SE) sequencesor acquisition of perfusion data will depend on many fac-ors such as the signal-to-noise ratio, contrast agent doser size of the vessels to be evaluated.5 GE sequencesrovide a better signal-to-noise ratio, higher signal changess a function of contrast agent concentration, and ainear behavior at large concentrations.5 These sequencesrovide information from all sizes of vessels, but theyre more sensitive to macrovessels. Therefore, signalhanges increase as vessel size increase, until they reach

plateau and remain independent of vessel size for sizes3---4 �m.6

On the other hand, SE sequences are particularly sen-itive for the evaluation of small vessels, at capillary level,ith the signal changes peaking for vessels of 1---2 �m.6 Some

tudies have suggested that GE sequences are superior to SEequences in the evaluation of brain tumors using perfusionR imaging.6,7 Sugahara et al.6 showed that for high-gradeliomas the maximum relative CBV (rCBV) ratios obtainedith GE-EPI were higher that those acquired with SE-EPI. In

his respect, most published studies used T2*-weighted GEmaging for the determination of the preoperative grade ofrain tumors.8---15

Another consideration is the type of contrast agentsed. Because of their properties, the currently availableadolinium-based contrast agents are especially suited forerfusion MR studies. Compared with conventional 0.5 mol/L
ormulations, 1.0 mol/L gadobutrol (Gd-BT-DO3A; Gadovist®
ayer-Schering AG, Berlin, Germany) has a two times higheroncentration of gadolinium, allowing the administrationf the same amount of gadolinium with a lower volume

210 J.A. Guzmán-de-Villoria et al.

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aramagnetic agent in the vessels produces local magnetic fiolecules and signal loss on T2*-weighted sequences. This mod

f bolus. This facilitates more appropriate bolus geometry,ith sharper bolus peak and an increased first-pass gadolin-

um concentration in blood.16 Gadobenate dimeglumineGd-BOPTA; MultiHance®; Bracco Imaging SpA, Milan, Italy)s another contrast agent especially useful for PMR imaging.his agent has a two-fold higher T1 and T2 relaxivity values

n blood due to a weak and transient interaction of Gd-OPTA with serum proteins.17 Standard doses of gadobenateimeglumine and gadobutrol provide similar signal reduc-ion (approximately 30%), but substantially higher than theignal drop obtained with conventional contrast agents.17

oth gadobenate dimeglumine and gadobutrol allow forhe acquisition of high-quality perfusion maps for CBV andBF quantification, without significant differences betweenhem.17

Although some studies have used doses ≥0.3 mmol/kg
f gadobutrol for PMR imaging,16 Essig et al.17 demon-trated that 0.2 mmol/kg doses of both agents produceetter image quality but with no clinical benefit over these of 0.1 mmol/kg doses.
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igure 2 Example of acquisition of parametric color maps of cerlood flow (CBF) from the convolution of the arterial input functions adjusted to these results (higher values in red and lower values igure legend, the reader is referred to the web version of the articl

in the surrounding tissue that results in dephasing of watersumes that no contrast agent leakage occurs.

arameters estimated using perfusionagnetic resonance: CBV, CBF, MTT, TTP

nd Tmax

BV is defined as the total volume of blood traversing aiven region of brain, measured in milliliters of blood per00 grams of brain tissue (ml/100 g).2 CBF is defined ashe volume of blood traversing a given region of brain pernit time, measured in milliliters of blood per 100 grams ofrain tissue per minute (ml/100 g/min).2 MTT is the averageime that blood takes to pass from arterial inflow to venousutflow, measured in seconds.2 The parameters correlateccording to the equation MTT = CBV/CBF (Fig. 2).

Calculation of CBF and MTT requires knowledge of therterial input function (AIF) (Fig. 3). This function represents
he concentration of contrast agent in the arterial inflowhat supplies a given tissue, as a function of time.4 Hence,nowing the AIF, a convolution algorithm is used to createBF and MTT cerebral maps.2 As for CBV, the estimates can
t time Cerebral blood flow(CBF)

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ebral blood volume (CBV), mean transit time (MTT), cerebral (AIF). Values for each parameter are absolute and color scalen green). (For interpretation of the references to color in thise.)


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Figure 3 Calculation of perfusion parameters from the signal drop (S)---time (t) curve in dynamic T2*-weighted images. The areaunder the curve represents the cerebral blood flow (CBV). Mean transit time (MTT) is the time elapsed from the injection of thetracer to the time the half-width of the curve is reached. Cerebral blood flow (CBF) is calculated dividing CBV by MTT. Using this

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be simplified using the rCBV value, obtained by calculat-ing the area under the concentration---time curve computedon a voxel-by-voxel basis from the intensity---time curve.2,5

Since rCBV is a ‘‘relative’’ measurement, the AIF is not usedin its calculation.2,4,5 Nonetheless, quantitation of rCBV isless precise because some of the factors that vary betweenpatients (e.g., the underlying vascular architecture), physi-ologic factors (e.g., cardiac output) or aspects related to theacquisition of MR images (e.g., contrast injection conditions)are obviated.5

In order to simplify comparison between patients, rCBVvalues are normalized to the contralateral tissue,2,8 usu-ally the white matter of the uninvolved contralateralregion.3,6,8,13,18---23 Other authors use as standard reference acontralateral homologous region.1,24 The use of gray matteras standard reference is unusual.15

Although CBV maps are good indicators of hypervascularregions, values calculated on a pixel-by-pixel basis have apoor signal-to-noise ratio. It is therefore preferable to cal-culate CBV values from region of interests (ROI) within theregions with maximum CBV value.1

TTP is the time between the tracer injection and themaximum signal change. TTP can be derived from thesignal---time curve with magnetic susceptibility imagingwithout knowledge of the AIF.25 Tmax is an estimation of TTPafter a deconvolution with the AIF.26

Pitfalls and artifacts

Even using an optimal PMR imaging protocol, there might bepotential confusing factors in the interpretation of perfusionmaps. An important source of errors is a low cardiac output
or a low contrast injection rate.5 In these cases, the insuf-ficient contrast agent concentration does not induce thesignal change required to produce the appropriate perfusionmaps.
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d, but the obtained values are relative to a reference area.

When assessing contrast injection rate, it should beonsidered that rates <3 ml/s lead to underestimationf CBV, while rates >5 ml/s show no benefits for CBVetermination.27 Most published articles use injection ratesetween 3 and 5 ml/s,6,8,11,12,14,23,24,28---32 with 6 ml/s beingimit of the injection rate.9,20,33

Another potential artifact arises as a result oflood---brain barrier (BBB) breakdown. T2*-weighted PMRmaging assumes that contrast agent remains intravascular,ut once this assumption is not valid, the linear relationships not assumed between contrast agent concentration andignal drop.5

In addition, in cases of increased BBB permeability, theeakage effect appears on both T1 and T2 or T2* as a sourcef error for perfusion parameter calculations34 (Fig. 4). T1eakage effect is due to the fact that gadolinium-based con-rast agents have T1 effect in addition to the T2* effect.his unwanted T1 effect is caused by extravasated contrastaterial and is identified as a rise in signal intensity aboveaseline after the initial drop33 (Fig. 5). The area above theaseline is interpreted by the algorithm as negative bloodolume, which is subtracted from the area below the base-ine caused by the T2* signal,2 resulting in underestimationf CBV.2,5,33

In case of T2 leakage, there will be an addi-ional signal drop, subsequent to the one caused byhe arrival of the bolus of contrast to the cerebralarenchyma (Fig. 6), resulting in an overestimation ofBV.34

Techniques of gamma-variate fitting only minimizehis unwanted T1 or T2 effect.33 Several methods haveherefore been proposed to minimize these sources ofrrors.34 One approach, which would avoid T1 leakage
ffect, is to use dysprosium-based contrast agents, whichave stronger T2* effect but negligible T1 effect.2,35
onetheless, this type of contrast is not easily avail-ble.


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Figure 4 (A) Conditions with increased blood---brain barrier permeability lead to contrast passage from microvasculature tointerstitium. (B) This may lead to T1 leakage effect that translates into a rise in signal intensity (S) after a signal drop. (C) Theremight also be T2 leakage effect that results in an additional signal drop, subsequent to the one caused by the arrival of the boluso imat

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f contrast to the cerebral parenchyma, resulting in an overest

The use of contrast with double concentration, such as.0 mol/L gadobutrol, allows lower injection volume com-ared to standard 0.5 mol/L concentrations. This will in turneduce the volume of extravasated contrast material sec-ndary to altered BBB permeability.

Another approach to minimize this source of errors is toncrease the repetition time (RT), which reduces T1 effects.owever, such approach leads to increased scan times and

ower temporal resolution if parameters such as the num-er of dynamic series or the number of sections in eacheries are maintained.2 The use of a small flip angle alsoeduces T1 effect, but it also reduces the signal-to-noiseatio of the PMR Image 34. Another approach is to preinject

small dose of gadolinium (0.25---0.05 mmol/kg) 5---10 minefore the intravenous administration of the bolus to pre-aturate the interstitium and elevate the baseline beforehe dynamic acquisition.2,5 Although this method is very use-ul to reduce T1 leakage effects,34 it may be impracticaln real clinical practice.2 An interesting alternative is thecquisition of dynamic T1 susceptibility MR images prior to2* susceptibility MR imaging. In this way, T1 effect cane minimized and, at the same time, an estimation of BBBermeability can be obtained (with dynamic T1 imaging) asell as of the rest of perfusion parameters calculated usingynamic T2* Images.36

Other alternative is to correct the T1 effect using differ-nt mathematical models or postprocessing methods.2,5,33---35

One of the problems with the quantification of per-
usion parameters is the lack of standardized acquisition andostprocessing of data.34 This section includes the use ofifferent deconvolution algorithms used with conventionaloftware programs provided by various manufacturers,37
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ion of cerebral blood volume.

hich hinders the comparison of intra- and intersubjectata.

Moreover, an essential aspect in the calculation of abso-ute values for CBF is the determination of a vasculartructure appropriate for the evaluation of AIF. In order torevent partial volume effects, the most appropriate is aarge cerebral vessel oriented parallel to the main magneticeld.5 Stenotic or occluded vessels should be avoided.

Parametric color maps, usually used for visual analysisnd ROI placement, are not very accurate, increasing theampling error inherent to this type of analysis.38 In addition,heir assessment depends on factors such as window levelnd window width or the color scale used.

Lastly, magnetic susceptibility PMR imaging requiresadolinium administration, with the associated risk ofephrogenic systemic fibrosis in patients with impairedenal function. This complication seems to be less pre-ictable with cyclic chelates than with linear chelatesecause the latter have less kinetic stability, and releasef free gadolinium from the chelate is thus moreikely.39

linical applications of perfusion magneticesonance imaging

umor application. General characteristics

he basic principle of PMR in oncologic imaging is that as tumor grows its metabolic demands increase due to rapidell growth and increased cell turnover.2 Angiogenic activitys stimulated by hypoxia and hypoglycemia through cytokine


Figure 5 An example of T1 leakage effect in perfusion magnetic resonance (MR) imaging study due to magnetic susceptibilityof the contrast agent. (A) Axial gadolinium-enhanced T1-weighted MR image shows a right parietal meningioma with hyperintensesolid component. (B) Moderate increase of cerebral blood volume observed in the parametric color map. (C) Perfusion curve showsa rise in signal intensity above baseline after the initial drop, caused by T1 effect secondary to extravasation of gadolinium intothe interstitium. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of thearticle.)

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Figure 6 An example of T2 leakage effect in perfusion magnetic resonance (MR) imaging study due to magnetic susceptibility ofthe contrast agent in a patient diagnosed with left frontal parasagittal meningioma. (A) Axial EPI T2*-weighted perfusion imagesrepresent the same axial plane in consecutive dynamic images. (B) Perfusion curves with the indicator of the corresponding dynamicimage. Due to the T2 effect, a continuation of the signal drop is identified in the neoplasm after the first pass of contrast agentthrough the cerebral microvasculature. On EPI T2*-weighted images, this effect translates into a marked tumor hypointensity on

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all dynamic images obtained after contrast agent arrival.

production.40 As a result, these tumors show a higher pro-portion of immature vessels and, therefore, an abnormallyincreased permeability.36 This neoangiogenesis can be quan-tified by PMR imaging.

Nonetheless, increased tumor vascularization does notnecessarily indicate malignancy, the main exception beingextraaxial tumors (choroid plexus papillomas, neurinomasor meningiomas).1,2,36,41 Hemangioblastoma is an exampleof benign intraaxial lesion with increased vascularity and
increased CBV values,41 despite being classed as WorldHealth Organization (WHO) grade I lesions. This is due tothe histological features of hemangioblastomas that includethe presence of numerous capillaries.42,43
mmr(

It is worth noting that areas with increased perfusiono not necessarily correlate with contrast enhanced areasn T1-weighted Images 1, 3, and 8. Enhancement areas on1-weighted sequences are indicative of altered BBB per-eability.

lioma grading

rading of brain tumors has great significance because, in
ost cases, high-grade tumors (WHO grade III and IV andetastases) are usually treated with adjuvant chemo- or
adiotherapy after surgery, whereas in low-grade tumorsgrade I and II) the use of adjuvant therapy after resection


Figure 7 Determination of the degree of aggressiveness of gliomas. Low-grade astrocytoma (A---C) in left postcentral gyrus.(A) Tumor appears hyperintense on the T2-weighted sequence with no edema or necrosis. (B) There is no enhancement on theT1-weighted sequence after gadolinium administration. (C) Parametric color map shows cerebral blood volume values similar tothose of the contralateral white matter. Bilateral high-grade astrocytoma (D---F) in the frontal lobe with transcallosal involvement.(D) Coronal T2-weighted image shows signs of highly aggressive tumor (edema, necrosis and heterogeneity). (E) T1-weightedsequence shows areas of ring enhancement after contrast administration. (F) Volumetric map shows a rise in cerebral blood volumewithin the area of enhancement. (For interpretation of the references to color in this figure legend, the reader is referred to thew

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s controversial.44,45 Tumor grade is also associated with dis-ase outcome because survival time is significantly lower inigh-grade tumors.46---49

Most published articles on tumor grade determi-ation refer to gliomas. CBV values are significantlyigher in high-grade tumors (Fig. 7). For rCBV cutoffalues between 1.16 and 3.9, the sensitivity and speci-city for tumor grading were 100---72.5% and 96.8---55%,espectively.9,11,18,23,24,28,31,50,51

Oligodendrogliomas represent a special case becausehey have high CBV values regardless their degree of aggres-iveness, so that a portion of low-grade oligodendrogliomashow increased CBV values, higher than low-grade diffusestrocytomas.10,28,44,52 This is due to the dense network ofapillaries found in oligodendrogliomas, even in low-gradenes.44,53

ifferentiation of tumor histological type

erebral perfusion findings may provide useful informa-ion for the differentiation of certain histological types ofumors.

Lymphomas show relatively low values of CBV despite
heir histological aggressiveness, which may be help-ul to differentiate them from other neoplasms21,41,54---56
Fig. 8). This is explained by the angiocentric infiltrationattern of lymphomas, where tumor cells are arranged

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n concentric perivascular layers, without neovascular-zation being a prominent finding.42 Nonetheless, morehan 23.1---25% of patients show relatively high rCBValues.54,56

Perfusion MR imaging has also been used in the differ-ntiation between cerebral metastases and high-grade glialumors. Some authors found no differences in CBV valuesn the solid portion of the tumor.11,57,58 This is becauseetastatic tumors spread via hematogenous dissemination

hrough the central nervous system and stimulate neo-ascularization. These neovessels are similar to those ofalignant gliomas, showing cell gap junctions, fenestra-

ions of membranes, and open endothelial junctions.59 Inontrast, Bulakbasi et al.9 found higher rCBV values foretastases than for high-grade gliomas, but with no clear

utoff value for their differentiation. Kremer et al.55 demon-trated significant differences only between gliomas andetastases from kidney or melanoma, possibly due to

he extensive vasculature of these lesions. However, dueo the small number of cases, no conclusions could berawn.

In addition, statistically significant differences in CBV val-es were found in peritumoral edema because these valuesre significantly increased in gliomas in comparison with
etastases.60 In metastatic brain tumors, the associated
asogenic edema consists of water leakage from capillar-es but no tumor cells are present outside the tumor mass.igration of this fluid from the vascular system results in


Figure 8 Brain lymphoma. (A) T2-weighted image shows a left periventricular mass with intermediate signal, a central necroticarea and associated edema. There is involvement of the corpus callosum. (B) After gadolinium injection there is peripheral enhance-ment on T1-weighted sequences. (C) Significantly decreased apparent diffusion coefficients, characteristic of this type of tumors.(D) On color maps, cerebral blood volume values are similar or slightly higher to those of the contralateral white matter. (Forinterpretation of the references to color in this figure legend, the reader is referred to the web version of the article.)

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destruction of the microvasculature and decreased cerebralblood flow. In gliomas, however, tumor cells are present inperitumoral edema and vascularity is therefore relativelypreserved in this area.60

Differentiation with non neoplastic lesions:Tumefactive demyelinating lesions

PMR imaging can provide essential information for the dif-ferentiation of lesions that can mimic intracraneal tumorson conventional MR imaging.

Tumefactive demyelinating lesions (TDL) and aggressiveneoplasms can both show mass effect, areas of contrastenhancement and necrosis/cysts.61 Nonetheless, Cha et al.61

have demonstrated significantly lower rCBV values for TDLsthan for high-grade gliomas or even lymphomas. All casesin that series had rCBV values <2. These results can bejustified by the absence of marked angiogenesis in histolog-ical specimens.62 In addition, these authors have observed
distinguishing vascular structures in TDLs on dynamic T2*-weighted images, presumably veins traversing the lesionson their way toward the margin of both lateral ventricles(Fig. 9).
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pplication in cerebral ischemia: Conceptf penumbra

ecent advances in mechanical procedures and thrombolyticherapy for the treatment of acute cerebral stroke havellowed us to achieve good outcomes (modified Rankin scale2) in 25---45% of treated patients, with cerebral hemorrhageccurring in 6---11% of patients.26 Although the probabilityf a good outcome may be greater without treatment, theajority of patients remain disabled despite treatment. The

esults of several trials63---66 that aim to extend the 4.5-h win-ow for thrombolytic therapy from the onset of symptomsave been published.67 In case of thrombectomy, there iso strict time window, but the decision is made on an indi-idual basis and based on the evaluation of the potentiallyalvageable tissue.68

These facts indicate the need for selecting by imagingechniques those patients that can benefit from early acutetroke therapy, increasing the yield of good clinical out-ome and reducing the risk of symptomatic hemorrhage
rrespective of the time elapsed since the onset of theschemic episode. To this end, the concept of ischemicenumbra has been defined as the functionally impairedut potentially viable tissue usually surrounding the area


Figure 9 tumefactive demyelinating lesions. (A) T2-weighted images show hyperintense periventricular lesion with associatededema that extends into the corpus callosum. (B) IV contrast-enhanced T1-weighted sequence shows incomplete peripheral enhance-ment at the medial margin of the lesion. (C) Dynamic EPI T2-weighted image obtained during first pass of contrast agent throughthe cerebral microvasculature shows linear structures (arrowheads) traversing the lesion on its way toward the margin of the lateralventricle that presumably corresponds to subependymal veins. (D) Parametric color map demonstrates that cerebral blood volumein the lesion is similar to that found in the left centrum semiovale. (For interpretation of the references to color in this figurel .)

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egend, the reader is referred to the web version of the article

f early stroke.69 In humans, the duration of penumbra istill unclear, but PET imaging has demonstrated a dura-ion >24---48 h.69 Nonetheless, the penumbra area drasticallyecreases with time so that 6 h after the stroke there is lesshan 20% of penumbra.70

The most widely accepted form for identification ofschemic penumbra is the calculation of the differenceetween the volume in the area of decreased appar-nt diffusion coefficient (ADC) determined by diffusionR (DMR) imaging----that represents the core of the

nfarct----and the volume in the hypoperfusion area, usuallyarger, assessed by PMR imaging.69 This difference in vol-me is known as perfusion---diffusion mismatch (Fig. 10).onetheless, Parsons et al.71 consider that response tohrombolytic therapy and progression to stroke reliesore on the volumes individually assessed by PMR andMR imaging than on the degree of perfusion---diffusionismatch.DMR imaging abnormalities usually represent the area

f cytotoxic edema and irreversible infarct.26 In someases, however, DMR imaging abnormalities may beeversible.26,68

usi

On the other hand, PMR imaging abnormalities of acuteerebral infarct tend to overestimate the penumbra zoneecause they include both ischemic areas and areas ofenign oligemia that are not at risk of progression toschemic lesion.26

Nonetheless, the parameter and corresponding thresh-ld to differentiate infarcted and penumbral tissue fromligemia has not been established yet.68 The most frequentlysed parameters in the literature are TTP, MTT or Tmax.26,72

or the analysis of these parameters visual assessment cane used64,65,73 as well as quantitative thresholds of 4---6 s forTP or MTT72 or a Tmax delay ≥2 s63,66 for the determinationf the penumbra area. Nonetheless, some authors considerhat the Tmax ≥ 2 s threshold used in most clinical trials over-stimates the volume of penumbral tissue and, for thiseason, they establish higher cutoff values (Tmax ≥ 6---8 s)74

o differentiate irreversible infarction from penumbra, oralues ≥4 s to differentiate penumbral from oligemic area.75

The results of several clinical trials that evaluated the
se of thrombolytic therapy more than 3 h after stroke onsetuggest that the presence of diffusion---perfusion mismatchs better predictor of favorable therapeutic response than


Figure 10 Ischemic penumbra. (A) It is identified as a hyperintense area on diffusion-weighted imaging that corresponds withan area of decreased apparent diffusion coefficients (B) located in left corona radiata and that theoretically represents the areaof cytotoxic edema and irreversible infarct. (C) A hypoperfused region is identified on the parametric color map with increasedmean transit time in the left hemisphere extending beyond the area of restricted diffusion (Image provided by Dr. Sebastià RemolloFriedemann from Hospital Universitario Doctor Josep Trueta, Gerona). (For interpretation of the references to color in this figure

.)

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legend, the reader is referred to the web version of the article

the duration of symptoms.63,65,66,73 In those references, theterm mismatch is defined as a PMR imaging lesion ≥120%of the DMR imaging lesion volume.63---66,73

Conclusion

PMR imaging techniques provide functional and additionalinformation on cerebral vasculature that complements con-ventional MR imaging. CBV can help to determine the gradeof gliomas and to differentiate them from other neoplasmssuch as lymphomas or metastases. CBV can also be use-ful in the diagnosis of TDLs. In addition, PMR imagingallows identification of penumbra areas, potentially salvage-able, as mismatch areas in patients with acute ischemicstroke.

Nonetheless, several technical aspects should be con-sidered when performing and interpreting PMR imagingstudies, such as the perfusion modality and sequence used,as well as the type of contrast or injection rate. The lim-itations inherent to this type of studies should also beconsidered, including the presence of magnetic suscepti-bility artifacts, relative quantification of CBV instead ofabsolute quantification in most cases, or problems arisingfrom contrast leakage secondary to altered BBB permeabil-ity.

An understanding of the indications and limitations ofPMR imaging techniques will allow them to be routinelyincorporated into MR imaging protocols.

Authorship

1. Responsible for the integrity of the study: JAGV.2. Conception of the study: JAGV.
3. Design of the study: JAGV, PFG, JMMP, MD.4. Acquisition of data: N/A.5. Analysis and interpretation of data: N/A.6. Statistical treatment: N/A.
7. Bibliographic search: JAGV.8. Drafting of the manuscript: JAGV.9. Critical review with intellectually relevant contrib-

utions: PFG, JMMP, MD.0. Approval of the final version: JAGV, PFG, JMMP, MD.

onflict of interest

he authors declare not having any conflict of interest.

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