Imaging of Pulmonary Perfusion 37

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C. Fink, MD

Department of Clinical Radiology, University Hospitals – Gross hadern, Ludwig Maximilian University of Munich, Marchioni nistr. 15, 81377 Munich, Germany

C O N T E N T S

37.1 Introduction 417 37.2 Imaging Technique and Feasibility Studies 418

37.3 Quantiﬁ cation of Pulmonary Perfusion 420 37.4 Clinical Applications 422

37.4.1 Pulmonary Embolism and Pulmonary Hypertension 422 37.4.2 Cystic Fibrosis 424

37.5 Future Developments 424 References 425

Imaging of Pulmonary Perfusion 37

Christian Fink

37.1

Introduction

Pulmonary blood fl ow (perfusion) is essential for an effi cient gas exchange in the lungs. The balance between ventilation and perfusion is pathologically altered in a variety of lung diseases. In pulmonary vascular diseases pulmonary perfusion is changed by a reduction of blood fl ow either in the pulmonary arterial system [e.g., pulmonary embolism (PE), pulmonary hypertension (PH) or venous system (e.g., venoocclusive disease)] (Bailey et al. 2000;

Fazio and Wollmer 1981). Apart from pulmonary vascular disease, pulmonary perfusion can also be reduced by a regional destruction or displacement of the capillary bed in parenchymal lung disease (e.g., tumor; ﬁ brosis). Finally, pulmonary perfusion can

be reduced in a regulatory way by the mechanism of hypoxic vasoconstriction. Pulmonary hypoxic vasoconstriction, which was initially described by Euler and Liljestrand (1946), leads to a reduction of perfusion in non-ventilated lung and is therefore frequently observed in airway diseases such as chronic obstructive pulmonary disease (COPD).

There are several motivations for a better knowledge of the regional lung perfusion in all of these disease entities: First of all, perfusion imaging may be used to establish the diagnosis by the demonstration of a characteristic perfusion pattern. One example is pulmonary embolism, in which peripheral wedge- shaped perfusion defects are a characteristic ﬁ nding (Fazio and Wollmer 1981).

Furthermore, knowledge of pulmonary perfusion may be essential for the planning of lung surgery. In patients with non-small-cell lung cancer, perfusion imaging is frequently used to estimate the postoperative lung function (Bollinger et al. 2002). Perfusion imaging is also used in patients with emphysema to determine the extent of volume-reduction surgery of the lung (Hunsacker et al. 2002).

In clinical medicine, pulmonary perfusion has traditionally been assessed by radionuclide lung scintigraphy after intravenous administration of radioactively labeled macroaggregates (^99mTc-MAA) (Fazio and Wollmer 1981). Using conventional planar scintigraphy, the method is limited by a poor spatial resolution and the disadvantages of a projection method. A certain improvement is achieved with single-photon-emission computed tomography (SPECT) imaging; however, other disadvantages of the method such as a lack of anatomical and temporal information remain. For a quantitative approach to perfusion imaging of the lung, H₂¹⁵O positron-emission tomography (PET) has been proposed (Schus- ter et al. 1995; Serizawa et al. 1994). However, the method is technically complex and requires a cyclo- tron production of the tracer with an extremely short half-life. Consequently, this method has been limited to a research setting.

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37.2

Imaging Technique and Feasibility Studies

Similar to other body regions such as the heart or brain, contrast-enhanced perfusion MRI has also been attempted in the lungs. Technically, pulmonary perfusion MRI is realized by rapid T1-weighted MR imaging of the ﬁ rst pass of a contrast agent bolus through the lungs following peripheral intravenous injection. Due to the requirement of very rapid imaging to visualize the pulmonary transit of the contrast agent bolus, the majority of the initial studies of pulmonary perfusion MRI have been limited to two-dimensional single-slice or multi-slice MRI (Uematsu et al. 2004). For a potential clinical use, however, 2D MRI provides only a poor through-plane spatial resolution and anatomic coverage and therefore may not allow for the detection of minor perfusion abnormalities, such as segmental or subsegmental perfusion defects in PE. With the availability of high-performance gradient systems, time-resolved 3D MRI of the lungs has become feasible (Goyen et al. 2001; Schoenberg et al. 1999). Consequently, this technique has also been proposed for the assessment of lung perfusion by several groups. However, spatial and temporal resolution of pulmonary perfusion MRI in these studies was still insufﬁ cient to be clinically acceptable. Typically, the partition thickness ranged between 10 and 30 mm, while a temporal resolution between 5 and 7 s was achieved (Iwasawa et al. 2002;

Matsuoka et al. 2001; Makagawa et al. 2001).

With the application of parallel-imaging techniques in combination with improved high-performance gradient systems, the spatial and temporal resolution of MRI can be signiﬁ cantly improved. Consequently, this technical improvement has also been utilized for qualitative and semi-quantitative perfusion MRI of the lungs.

In one feasibility study, 2 volunteers and 14 patients with different lung diseases (mainly COPD) were examined with a contrast-enhanced pulmonary perfusion MRI technique using the generalized autocalibrating partially parallel acquisitions (GRAPPA) technique (Griswold et al. 2002). In general, the GRAPPA algo- rithm can be expected to be advantageous compared to a SENSE approach for imaging lung tissue, because of the low intrinsic signal intensity of the lung parenchyma. In the lung tissue, coil sensitivity proﬁ les in image space as required for the SENSE reconstruction may be affected by substantial errors, cf. Chap. 2. Using a parallel imaging acceleration factor of R=2 and a short repetition time (TR=1.9 ms), a 3D volume with 32 coro-

nal partitions (spatial resolution of 3.6×2.0×5.0 mm³) covering the entire lungs could be acquired in 1.5 s. For 10 of the 14 patients of this study, conventional perfusion scintigraphy was available for comparison. Per- fusion MRI with parallel imaging allowed the acquisition of perfusion data with a spatial resolution that was sufﬁ cient to differentiate perfusion abnormalities from normally perfused lung (Figs. 37.1 and 37.2). When the results of the perfusion-weighted MRI data were compared to scintigraphy, a good inter-modality agreement was observed (κ=0.74) (Fink et al. 2003).

To assess the reproducibility of these ﬁ ndings, another study with identical imaging technique was performed in 7 healthy volunteers and 20 consecutive patients with suspected lung cancer or metasta- sis. All patients had previously been examined with perfusion scintigraphy. In this study, pulmonary perfusion MRI allowed for the detection of perfusion defects with a high accuracy (sensitivity 88% to 94%, speciﬁ city 100%) compared to the gold-standard perfusion scintigraphy. In all volunteers and three patients without perfusion defects at perfusion scintigraphy, MRI also showed no perfusion abnormalities. A very good interobserver agreement (κ=0.86) of pulmonary perfusion MRI for the detection of perfusion defects was found (Fink et al. 2004c).

Although the temporal and spatial resolution of pulmonary perfusion MRI has been substantially improved by parallel imaging, some applications (e.g., absolute quantiﬁ cation, pediatric imaging) might even require a higher spatial or temporal resolution.

This can be achieved by combining parallel imaging with other k-space sampling methods that result in a reduction of the imaging time of MRI.

One example of these alternative k-space sampling methods is view sharing, which has already been used to improve the temporal resolution of time-resolved 3D MRA (Korosec et al. 1996); cf. Chaps. 7 and 11.

By sampling center parts of k-space more frequently than k-space periphery, the total acquisition time of MRI is reduced with view sharing. In detail, the low-frequency k-space data that contribute most sig- niﬁ cantly to the image contrast are sampled more frequently than the high-frequency k-space data, which are interpolated between consecutive time frames.

Recently, a 3D FLASH imaging sequence combining view sharing with parallel imaging has become available under the acronym TREAT (time-resolved echo-shared angiographic technique) (Fink et al.

2005a). In a feasibility study, the potential beneﬁ t of the combination of parallel imaging with view sharing for contrast-enhanced MRA and perfusion MRI

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was evaluated. Since depending on the reduction rate of acquired high-frequency k-space data, blurring artefacts of enhancing structures can occur with view sharing, the initial step was a simulation of the effect of different k-space segmentation factors (n=3- 6) on the image quality of the TREAT acquisition. It was shown that a view-sharing factor of n=3, corre- sponding to an increase of the temporal resolution by a factor of 1.5, achieves a satisfactory image quality without an increased rate of blurring artefacts.

In a clinical study in 36 patients with different car- diovascular or pulmonary disease, the image data of TREAT were compared to image data acquired in a

patient group with a similar distribution of age and disease state using time-resolved MRI with parallel imaging, but without view sharing. Both sequences used the same imaging parameters, except that the spatial resolution was improved with TREAT by 33%.

In this comparison, the image quality of TREAT was rated signiﬁ cantly higher than that of the parallel MR sequence without view sharing (Fink et al. 2005a).

These results of the initial report were recently also conﬁ rmed in an interindividual comparison of view- shared and non-view-shared time-resolved MRA (Fink et al. 2005c). In practice, a combination of parallel imaging and view sharing might allow for a spatial

Fig. 37.1a–g. Pulmonary perfusion MRI in a 56-year-old male with lung cancer. a-c.

Coronal, sagittal, and axial T1-weighted MRI showing the cancer in the right upper lobe (arrows). d-f Corresponding multiplanar reformats (MPR) of 3D pulmonary per- fusion MRI showing the perfusion defect caused by the lung tumor (arrows). g Due to the lower spatial resolution conventional perfusion scintigraphy shows a more ill- deﬁ ned border between the perfusion defect and the normally perfused lung (arrow).

Reprinted with permission from (Fink et al. 2003) c b

a

d e f

g

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Fig. 37.2a–f. MRI of lung perfusion in a 63-year-old male with emphysema. a Coronal HASTE MRI shows emphysematous “barrel chest” aspect of the thorax. b High-resolution 3D MRA demonstrates tapering of right lower lobe artery and hypovascularity of right lung due to emphysema. c-e Pulmonary perfusion MRI shows bilateral perfusion defects most likely caused by paren- chymal distortion and hypoxic vasoconstriction. f As a projection method, planar perfusion scintigraphy falsely demonstrates a more homogenous perfusion pattern. Reprinted with permission from (Fink et al. 2003)

c b

a

d e f

resolution sufﬁ cient to detect even subtle perfusion defects that might be undetectable at conventional perfusion scintigraphy. In addition, view sharing may be used to further decrease the scan time for special applications such as quantitative perfusion MRI.

A major drawback of parallel imaging is the increase of image noise. For the visualization of lung perfusion, the time-resolved image data are usually post-processed by subtraction of a pre-contrast data set from the data set with the peak enhancement of the lung parenchyma. Unfortunately, this results in an additional increase of the noise in the image data.

Correlation analysis has previously been proposed for time-resolved MRA to improve image background suppression and arteriovenous separation (Bock et al. 2000; Strecker et al. 2000). In these studies, it has also been demonstrated that the SNR of time-resolved MRI processed with correlation analysis is superior compared to image data processed with subtraction.

Therefore, correlation analysis has recently also been evaluated for the post-processing of pulmonary per-

fusion MRI. Compared to subtraction an approxi- mately 1.8 higher SNR of perfused lung parenchyma was achieved with correlation analysis in comparison to subtraction (Fink et al. 2004b). In addition, it has been shown that correlation analysis might also be used for the suppression of the signal of intrapulmo- nary blood vessels, which is not only useful for the assessment of qualitative pulmonary perfusion MRI, but also for quantiﬁ cation of perfusion from MRI (Risse et al. 2004).

37.3

Quantiﬁ cation of Pulmonary Perfusion

Apart from a qualitative assessment of lung perfusion, also a quantiﬁ cation of perfusion on the basis of indicator-dilution theory has been proposed for pulmonary perfusion MRI. Assuming no

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relevant extravasation of the contrast agent during the fi rst-pass through the lungs, pulmonary blood fl ow (PBF) can be quantifi ed from the knowledge of the arterial input function (AIF) and tissue concen- tration-time curve C(t) using deconvolution analysis (Ostergaard et al. 1996; Weisskoff et al. 1993):

C t( )PBF AIF R t( )PBF AIF

°

( )^T sR t( - )^{T T}d

Neglecting differences in arterial and capillary hematocrit and tissue density, the pulmonary blood volume (PBV) can be calculated as the area under the concentration-time curve C(t) normalized to the area under the AIF:

PBV

°

AIF

°

C d d ( )

( ) T T

T T

According to the central volume theorem, the mean transit time (MTT) can be calculated from PBF and PBV:

MTT PBV

PBF

In a pig model, Hatabu et al. (1999) demonstrated a very good correlation between perfusion parameters obtained from perfusion MRI and microsphere perfusion measurements. Initial experiments with this technique in human volunteers have shown the feasibility of MRI to demonstrate regional differences of lung perfusion parameters in different lung regions (e.g., gravity-dependent vs. non-gravity-dependent lung) (Levin et al. 2001). However, to achieve a temporal resolution sufﬁ cient for perfusion quantiﬁ cation, both of these initial studies were limited to 2D MRI with a mod- erate in-plane and through-plane spatial resolution.

In a more clinically orientated approach, Ohno et al. (2004) have recently also proposed perfusion quantifi cation of the entire lung in patients with pulmonary hypertension or lung cancer using time- resolved 3D MRI. However, without the availability of parallel-imaging techniques, the spatial resolution in these studies had to be reduced (i.e., the lungs were covered with only ten coronal partitions with a thickness of 10 mm to 20 mm) to allow for a suffi cient temporal resolution for perfusion quantifi cation.

More recently, two groups have evaluated the use of parallel imaging to improve the temporal and spatial resolution for quantitative pulmonary perfusion MRI. In a pilot study, we evaluated the feasibility of 3D quantitative perfusion MRI in eight patients with PE or PH (Fink et al. 2004d). In patients with PE or

chronic thromboembolic PH (CTEPH) characteristic wedge-shaped perfusion defects with decreased PBF and PBV and increased MTT were observed (Fig. 37.3). Patients with primary PH (PPH) or Eisen- menger syndrome showed a more homogeneous perfusion pattern. Although showing a quite large interindividual variation, the mean PBF and PBV found in this pilot study (PBF: 104–322 ml/100 ml/min; PBV:

8–21 ml/100 ml) were comparable to values previously obtained by H₂¹⁵O PET (Schuster et al. 1995;

Serizawa et al. 1994).

In another study, the effect of breath-holding on pulmonary perfusion was investigated (Fink et al.

2005b). Therefore, nine healthy volunteers were examined with pulmonary perfusion MRI with parallel imaging during end-inspiratory and end-expiratory breath-holds. It was shown that perfusion was sig- nifi cantly increased at expiratory breath-hold when compared to inspiratory measurements. This was also confi rmed by phase-contrast MR measurements of the macroscopic blood fl ow in the pulmonary arteries. The fi ndings of this study can be explained by the well-known effect that lung infl ation causes a compression of the alveolar blood vessels. As a con- sequence, pulmonary vascular resistance is increased and pulmonary perfusion is reduced during inspiratory breath-hold (Brower et al. 1985; Hakim et al.

1982; Raj et al. 1987).

The aim of a study by Nikolaou et al. (2004) was to determine the optimum contrast agent dose for quantitative pulmonary perfusion MRI. The rationale behind this study was that a potential source of error of quantitative perfusion MRI results from a missing linearity between the local MR contrast-agent concentration and observed signal-intensity changes.

Especially for the determination of the arterial-input function, there may be a non-linear relation between the contrast-agent concentration and signal-intensity changes. On the other hand, the contrast-agent dose may not be arbitrarily reduced, since pulmonary perfusion MRI, especially if combined with parallel imaging, suffers from a poor SNR. In a phantom experi- ment with a 3D FLASH pulse sequence (TR=1.7 ms;

TE=0.6 ms; α=25°) with GRAPPA (acceleration factor R=2), Nikolaou et al. could demonstrate a linear relation between relative signal increase and contrast agent concentration up to 5.0 mmol/l. In a subsequent volunteer study, three different contrast agent doses (2, 4, and 8 ml Gadodiamide equivalent to a dose of 0.014, 0.029, and 0.057 mmol/kg body weight in a 70 kg volunteer) were compared. It was shown that the doses of 0.029 and 0.057 mmol/kg

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body weight yielded the best agreement with the ref- erence value from the literature. Finally, using a dose of 0.057 mmol/kg body weight, quantiﬁ cation of pulmonary perfusion was reproducible in 16 volunteers, indicating a potential for a clinical use.

37.4

Clinical Applications

37.4.1

Pulmonary Embolism and Pulmonary Hypertension

In a study in 48 patients with suspected PE, Ohno et al. (2004) compared the diagnostic accuracy of time- resolved 3D MRA using SENSE parallel imaging with

multi-detector CT (MDCT) and ventilation-perfusion scintigraphy (VQ scan). Conventional pulmonary angiography served as the gold standard. PE was diag- nosed when an area of decreased perfusion in the lung parenchyma with or without a corresponding ﬁ lling defect in the pulmonary artery was observed. In this study it was shown that time-resolved MRA had a higher diagnostic accuracy for the detection of PE when compared to MDCT and VQ scan. In detail, the sensitivity of time-resolved MRA was 92% compared to 83% (MDCT) and 67% (VQ scan). Similarly, the speciﬁ city of time-resolved MRA was 94% compared to 94% (MDCT) and 78% (VQ scan). Both the posi- tive and negative predictive value (PPV and NPV) of time-resolved MRA was superior to MDCT and scintigraphy [PPV: 85% (MRA), 83% (MDCT), and 50%

(VQ scan); NPV: 97% (MRA), 94% (MDCT), and 88%

(VQ scan)]. Based on these results, a comprehensive imaging of PE by MRI using parallel imaging might be

Fig. 37.3a–c. Quantitative pulmonary perfusion MRI in a patient with acute pulmonary embolism. a High-resolution MRA shows acute pulmonary embolism in the lobar artery of the left lower lobe and subsegmental embolism in the right lower and middle lobe (arrows).

b-c Coronal and axial color-coded para- metric maps of the regional pulmonary blood ﬂ ow (PBF) obtained by quantitative pulmonary perfusion MRI show typ- ical wedge-shaped perfusion defects (ar- rows) caused by pulmonary embolism c

b a

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considered more frequently in the future. This includes the group of patients with low clinical probability for PE, especially if of young age, which in clinical practice is frequently exposed to the substantial radiation dose of MDCT of up to 4 mSv to 8 mSv, despite an overall prevalence of PE of only 3.4% (Wells et al. 1998). In addition, pulmonary perfusion MRI as a radiation- free method might be used to assess the resolution of thromboembolism during anticoagulative therapy.

Apart from PE, pulmonary perfusion MRI might be used for the differentiation of primary or sec- ondary (i.e., chronic thromboembolic) PH (Ley et al. 2004; Nicolaou et al. 2004). Whereas chronic thromboembolic PH features segmental perfusion defects, primary PH (PPH) often shows a more dif- fuse and patchy perfusion pattern (Fink et al. 2005b;

Nicolaou et al. 2005; Ley et al. 2004) (Fig. 37.4).

The differentiation of PPH and CTEPH is of clini-

Fig. 37.4a–c. Pulmonary perfusion MRI for the differentiation of different entities of pulmonary hypertension. Pulmonary perfusion MRI a and high-resolution MRA b of a patient with chronic thromboembolic pulmonary hypertension shows typi- cal segmental perfusion defects of the lung (arrows) caused by chronic thromboembolism. The MRA shows typical features of CTEPH such as central arterial dilatation and peripheral webs and bands (open arrow). In contrast, pulmonary perfusion MRI c of a patient with PPH shows a more homogeneous perfusion pattern without segmental distribution of the perfusion defects.

MRA in this patient also reveals dilatated central pulmonary arteries as a typical feature of PH c

b a

d

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cal relevance since effective but diverse therapeutic options (i.e., medical vs. surgical) are available for both disease entities.

In a study by Nikolaou et al. (2005) in 29 patients with PH, the accuracy of a combined MR protocol of pulmonary perfusion MRI and high-spatial-resolution MRA with parallel imaging for the differentiation of different forms of PH was assessed. For comparison perfusion scintigraphy was available in the majority of patients. It was shown that, using the comprehensive MR imaging protocol, a correct differentiation of PPH and CTEPH could be made in 90% of the patients. MR perfusion imaging showed an agreement (i.e., identical diagnosis on a per patient basis) of 79% to perfusion scintigraphy. The interobserver agreement was good (κ=0.63). Further studies are required to evaluate the potential of pulmonary perfusion MRI for the assessment of patients with PH. Apart from the differentiation between different entities of PH, pulmonary perfusion MRI might be used for the functional staging of PH and might be integrated into comprehensive imaging protocols of PH (Kreitner et al. 2004; Ley et al. 2004; Nikolaou et al. 2005).

37.4.2

Cystic Fibrosis

Even more than in adults, the radiation dose is a criti- cal factor in pediatric imaging. Therefore, radiation- free imaging techniques, such as MRI, are a desirable alternative to conventional imaging methods.

This holds especially true for patients with chronic diseases in which frequent follow-up exams are usually required in the course of the disease. One typical example is patients with cystic ﬁ brosis (CF), in which the life expectancy is mainly determined by the course of pulmonary complications.

In a pilot study, the correlation of lung perfusion changes with structural abnormalities of the lung was assessed in 11 children with CF. In addition to morphologic imaging, the regional lung perfusion changes were assessed with a time-resolved 3D-FLASH sequence with GRAPPA (acceleration factor R=2). In total 198 lung segments were ana- lyzed by two radiologists in consensus and scored for changes of the lung morphology (1= normal;

2= mild; 3= severe) as well as for perfusion changes (0=normal; 1=defect). Segmental perfusion defects were observed in all patients and were predomi- nantly located in the upper lobes (80%). Normal

lung parenchyma showed a homogenous perfusion in 86% of analyzed lung segments, while in 97% of the cases severe morphological changes (e.g., severe bronchiectasis and ﬁ brotic changes) led to perfusion defects (P<0.0001) (Fig. 37.5). Segments with mild morphological changes showed either normal (53%) or impaired perfusion (47%). Although more studies are required to further assess the potential of pulmonary perfusion MRI in CF, the results of this pilot study indicate that perfusion MRI might help to identify patients in which intensiﬁ ed therapy might improve the lung function and possibly prevent irre- versible loss of tissue structure and lung function (Eichinger et al. 2004).

37.5

Future Developments

The relevance of higher magnetic fi eld strengths (B₀≥3 T) for pulmonary MRI has not yet been clinically evaluated. On the one hand, an increased fi eld strength should result in a proportionally better SNR, which is especially desirable in the lung parenchyma with intrinsic low signal. On the other hand, the increased signal might be canceled due to the higher susceptibility effects in the heterogene- ous lung tissue resulting in reduced T2* relaxation times at 3 T. Especially the combination of high fi eld strength with higher parallel imaging acceleration factors should lead to synergistic effects and requires further research. Due to the coronal orientation of the acquired 3D slabs in lung perfusion imaging, acceleration factors greater than 2 should be feasible with typical phased-array surface coil systems that are positioned on top of the patient’s chest and pro- vide several coil elements with distinct coil sensitivity profi les in left-right direction.

Moreover, new parallel-imaging reconstruction algorithms, which do not require repeated measurements of the coil sensitivity proﬁ les (e.g. TSENSE), are another promising development for pulmonary perfusion MRI with increased temporal resolution.

Apart from MR hardware and software developments, further improvement of pulmonary perfusion MRI might be achieved with intravascular gadolin- ium-based MR contrast agents, which will become clinically available in the near future. In addition to the higher T1 relaxivity that will improve the signal characteristics of perfused lung, comprehensive

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Fig. 37.5a–d. Pulmonary perfusion MRI in children with cystic ﬁ brosis. Excellent correlation of severe perfusion changes demon- strated by pulmonary perfusion MRI a and severe morphologic (e.g., bronchiectatic) changes as revealed by HASTE-MRI b in a child with severe cystic ﬁ brosis. Similarly minor perfusion changes in the upper lobes c correlate well with minor morphologic tissue changes in another child with CF d

imaging protocols comprising ﬁ rst-pass perfusion MRI and steady-state high-spatial-resolution MRA may be realized (Fink et al. 2004b).

In conclusion, parallel imaging has signiﬁ cantly improved the potential of non-invasive imaging of pulmonary perfusion using MRI. Despite the promising results of initial pilot studies in various pulmonary diseases, further studies evaluating pulmonary perfusion MRI for the clinical assessment of pulmonary disease are required.

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