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Appl Radiol. Author manuscript; available in PMC 2015 October 09.
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Published in final edited form as:

Appl Radiol. 2014 July ; 43(7): 22–29.

The basics of diffusion and perfusion imaging in brain tumors

Panagiotis Korfiatis, PhD and Bradley Erickson, MD, PhD
Department of Radiology, Mayo Clinic, Rochester, MN 55905

Perfusion and diffusion magnetic resonance imaging (MRI) are commonly used by
neuroradiologists in everyday clinical practice. These techniques provide information not
available with conventional MRI. Response Assessment in Neuro-Oncology Criteria
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(RANO)1 and Macdonald2 criteria have been used extensively to evaluate tumor response
based on measurement of T1 postcontrast images. However, relying on these changes can
lead to misinterpretation of treatment response, since enhancement volume is a relatively
nonspecific feature of tumor behavior.3

Perfusion and diffusion imaging are recent advances that can help predict tumor type and
grade, as well as predict patient survival and optimal therapeutic options.4 This article will
present the basic principles of perfusion and diffusion imaging, and provide clinical
examples of their application.

Perfusion dynamic susceptibility contrast (DSC)-MRI: How it works

Perfusion imaging with dynamic susceptibility contrast (DSC)-MRI is based on the
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principles of tracer kinetic modeling to assess the cerebral microvasculature.5 In DSC

perfusion imaging, a contrast agent is injected into the blood and monitored as it passes
through the microvasculature. The vasculature is a key feature in the histopathology
diagnosis of gliomas and permits imaging associations with grade through perfusion-
weighted imaging. Blood vessels are present in higher numbers within tumors than in
normal brain tissue, and they tend to have a larger volume. In general, higher-grade tumors
also tend to have higher blood volume. In higher-grade tumors, the degradation and
remodeling of extracellular matrix macromolecules results in loss of blood-brain barrier
(BBB) integrity,6,7 which is seen as contrast leakage or enhancement.

By kinetic analysis of these data, one may compute cerebral blood flow and volume, as well
as mean transit time. These measures can capture the degree of tumor angiogenesis, an
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important biologic marker of tumor grade, histology, and prognosis, particularly in gliomas.

Perfusion imaging is based on rapid imaging (echo planar imaging) of the first pass of the
contrast agent and can be performed by using either a gradient-echo or a spin-echo pulse
sequence. In DSC imaging, the intensity decreases in areas of greater contrast concentration
due to changes in local susceptibility. This differs from dynamic contrast-enhanced (DCE)

Corresponding Author: Bradley Erickson, Mayo Building E2, 200 First St SW, Rochester, MN 55905, BJE@Mayo.edu, Phone:
507-284-8548.
 Korfiatis and Erickson Page 2

MRI, in which a T1-weighted sequence detects an increase in intensity proportional to

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contrast concentration.

Quantitative assessment
Calculating imaging biomarkers from perfusion signal time curves involves several steps;
Figure 1 depicts the most commonly used steps. MRI perfusion imaging is capable of
estimating the volume of blood that passes through the capillary bed per unit of time. The
quantification can be performed in a relative or absolute manner. Although absolute
quantification is preferable, it is much more challenging to perform in clinical practice due
to many potential imaging and data processing artifacts. Thus, DSC typically produces
images that are visually reviewed, and any measurements are expressed as a ratio to normal-
appearing white matter. Relative cerebral blood volume (rCBV) measurements have been
shown to correlate with tumor grade and histologic findings of increased tumor vascularity.8
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They have also been shown to be useful in differentiating between progression and pseudo
progression.9,10 However, the selection of the reference region of interest (ROI) still remains
an open issue in both clinical practice and longitudinal studies.11

After the data are acquired, the baseline is defined; this often includes removal of the first 3
time points due to saturation effects. The start and end points of the bolus are calculated.
Subsequently, the baseline signal intensity is calculated and the signal-time curves are
converted to concentration-time curves. This is done for each voxel in the imaging volume.
The rCBV image is the most important of the perfusion images for analyzing brain tumors
and is computed by integrating the area under the time-concentration curve.12 Some
additional image types that can be computed include percent signal recovery, a measure of
tumor leakiness; time to peak; bolus start and end time; and mean transit time. The latter two
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measures are frequently used in stroke imaging, but are of limited value in tumors.

Qualitative assessment
Several commercial software packages are available for calculating parametric maps like
CBV from DSC-MRI. For routine clinical practice, visually inspecting the color maps can
help to detect normal versus abnormal regions (Figure 2). This kind of assessment can be
very useful in the clinical setting, but it depends on the windowing technique parameters
used to present the data.

BBB disruption and leakage correction

One of the main challenges of DSC-MRI data analysis is contrast-agent extravasation due to
BBB disruption. Figure 3 demonstrates the effect of this phenomenon on time-intensity
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curves. Instead of returning to baseline, the signal returns to a point higher than the initial
baseline due to T1 effects, resulting in underestimation of the integration area. However,
depending on the pulse sequence used, T2 or T2* leakage effects can predominate, resulting
in overestimation of the rCBV value.12

The sequence type and parameters can affect how the concentration-time curves are
distorted. A one-dimensional leakage simulation study performed by Quarles et al13

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demonstrated that when T1 effects were removed, such as with the use of a dual-/multi-echo
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sequence, the measured transverse relaxation-rate-time course overestimated the true

transverse relaxation–rate-time course. Therefore, the CBV would be overestimated. When
T1 effects dominated (eg, when high flip angle and short repetition time were used), the
measured transverse relaxation-rate-time course underestimated the true transverse
relaxation-rate-time course; thus, the CBV would be underestimated.14

One technique is to minimize the contrast leakage effect by administering a contrast agent
before acquiring the DSC images (referred to as ‘preloading’). However, animal studies
suggest preloading is not very effective.15 The more popular and effective method is to
apply mathematical models of the leakage during DSC data analysis.16 Figure 4 depicts an
example of uncorrected and corrected CBV maps as well as the K2 image, a byproduct of
the mathematical correction process. K2 refers to the leakage rate detected during DSC
tumor imaging.
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Spin echo vs gradient echo

Just as gradient-echo (GE) and spin-echo (SE) techniques can produce anatomical images,
both GE and SE echo planar images (EPI) can be used for DSC-MRI. GE-DSC sequences
tend to be more sensitive to larger vessels, such as veins, while SE-DSC techniques tend to
show greater sensitivity to smaller vessels (capillaries) that should be more specific for
tumor vessels.17 In actual practice, it appears that the vessels in tumors are large enough that
GE imaging better demonstrates tumor vessels than SE imaging. However, imaging patients
with GE sequences can be challenging after surgery because hemorrhage or metallic foreign
bodies can produce signal loss and artifact.

Recently, a combination of the two techniques has been emerging, since it can provide
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simultaneous perfusion and permeability measurements.18,19 These are referred to as a spin-

and gradient-echo echo-planar imaging (SAGE EPI) MRI.

3T vs 1.5T
Transitioning DSC perfusion imaging from 1.5T to 3T creates a proportional increase in
magnetic susceptibility. Practically, this means a higher signal-to-noise ratio (SNR) for a
given dose of contrast20 or that less contrast can be used in patients with limited renal
function. 3T imaging’s increased sensitivity to contrast enhancement is well known. The
correlate is that increased field strength leads to greater enhancement of T2 effect compared
to 1.5T (the post-bolus baseline returned to a level above the baseline),21 also resulting in a
higher SNR in CBV images. Because of the increased T1 effects at higher field, leakage is
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underestimated.22 Thus, field strength should be taken into account when comparing rCBV
maps acquired at different field strengths.

Diffusion imaging: How it works

Due to their thermal energy, water molecules in tissue undergo a continuous random motion
referred to as Brownian motion. While diffusion technically refers to the movement or
transport of some substance without bulk motion within a medium like water, it also refers

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to the motion of water that occurs without bulk motion. Because water spins will run into
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constituents of cells, and because those cellular components have different concentrations in
different parts, they will spread at different rates and not behave in the same way when
moving in different directions.23 For example, the membranes of cells restrict diffusion, and
in acute stroke, where cells are not able to pump out enough water, the water that is present
sees greater diffusion restriction because the interior of the cell has many more membranes
and restricting structures than does the extracellular space.

The basic idea behind diffusion imaging is to use paired magnetic-field gradients to
“encode,” and subsequently decode, the spatial motion of the molecules. Signal intensity is
represented by the following equation:

(Eq.1)
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In this equation, ADC is the apparent diffusion coefficient and b is the gradient factor
commonly referred to as the b-factor. Sensitivity to diffusion-based contrast is controlled
primarily by the b value. S_0 is the signal intensity when no diffusion gradients are used.
The apparent diffusion coefficient is an average of the diffusion process occurring in the
tissues. Qualitatively, Eq.1 means that the measured signal is reduced when diffusion
gradients (b≠0) are applied.

As the diffusing spins move inside the field, they are affected differently by the field; thus,
their alignment with each other is destroyed. Since the measured signal is a summation of
tiny signals from all individual spins, the misalignment, or “dephasing,” caused by the
gradient pulses results in a drop in signal intensity; the longer the diffusion distance, the
greater the signal loss. Based on Eq.1, for a fixed b-factor, high ADC values translate to low
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signal. A parametric ADC map (commonly referred to simply as an ADC map) can be
generated after the application of different b-values as well as one image with no b-
weighting (often referred to as the ‘b0 image’). The b-value is a factor in diffusion-weighted
sequences. The b-factor summarizes the influence of the gradients on the diffusion-weighted
images. Image intensities in the ADC map correspond to diffusion strength in the pixels.23
Figure 5 depicts an ADC map and the images corresponding to two different b-values, as
well as the corresponding T1 postcontrast image.

Although typical diffusion images have a spatial resolution of a few millimeters, they reflect
events happening at the molecular level. As noted previously, when diffusing spins run into
cellular constituents and membranes, the ADC value will be reduced when compared with
diffusion in bulk water like cerebrospinal fluid (CSF).24 Diffusion measurements become
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more complex when the structures restricting water diffusion have a structure themselves.
For instance, axons restrict water diffusion perpendicular to their long axis, but not in the
direction of the axon. This difference in magnitude of diffusion in different directions is
referred to as diffusion anisotropy. What makes this more complex is that unless the axon is
aligned with the imaging gradient, the reduction in signal will be seen in all 3 directions.
When diffusion is to be measured in an anisotropic environment, diffusion tensor imaging is
needed for a complete description.

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Tumor cells are known to have many more membranes that both restrict motion and displace
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structures like axons that tend to have higher anisotropy. For that reason, there is great
interest in using diffusion imaging in brain tumors. ADC has been found to correlate with
tumor cellularity25,26 and tumor grade,27,28 with high-grade tumors having high cellular
density and decreased ADC. Overlap in ADC values in high-grade tumors and low-grade
tumors, however, has also been reported.25 ADC values have been reported to predict
responsiveness of temozolomide-refractory malignant glioma to bevacizumab treatment.29

Studies30-32 also indicate that recurrent tumors have lower ADC values than
pseudoprogression, likely reflecting less water diffusion when there are many cells and cell
membranes vs necrotic tissue or edema, where water is more able to diffuse. Finally, tumors
in patients treated with anti-angiogenic agents often have reduced contrast enhancement,
even when the tumor is progressing (referred to as pseudoresponse). ADC images appear to
help detect this phenomenon. If one sees an enlarging area of low ADC values in a patient
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being treated with anti-angiogenic agents, tumor pseudoresponse should be considered.

Qualitative assessment
Diffusion imaging can be visually analyzed to identify underlying pathology (Figure 6). For
the clinically used b-values, white and gray matter have similar ADC values, while a tumor
takes a range of ADC values. As one would expect, cellular areas of tumors have low signal
on ADC maps due to restricted diffusion. An inverse relationship between ADC values and
tumor grade has been reported in the literature.33 The destruction of cell membranes in
necrotic brain lesions allows for virtually unhindered diffusion, yielding areas of elevated
ADC values. Thus, areas of necrosis can be detected as elevated ADC within the tumor
lesion.34 However, the coarse resolution of diffusion MRI restricts detection of small areas
of necrosis.35 Very high diffusion values in peritumoral edema of high-grade gliomas may
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reflect fluid leakage into the extracellular space and destruction of the extracellular matrix
ultra-structure by malignant cell infiltration.36

Quantitative assessment
ADC maps can provide additional information for tumor grading and assessing the effects of
therapy in cases where T1- and T2-weighted images alone provide insufficient diagnostic
information.35 Histogram analysis based on the ADC of the enhancing tumor has been
reported to assist in differentiating true progression from pseudoprogression in
glioblastomas.37,38 However, biomarkers such as percentile values of the cumulative ADC
histogram must also be investigated. In differentiating between progression and
pseudoprogression, the underlying hypothesis is that the part of the histogram corresponding
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to lower values is related to the viable component of the tumor, while the higher part is
related to edematous/necrotic tissue.39 This approach is adapted to the heterogeneous nature
of tumors that include areas of active tumor and necrotic or “dying” portions. An example of
pseudoprogression with an enlarging region of low ADC is shown in Figure 7.

There is also interest in studying components immediately adjacent to the contrast-

enhancing portion of the tumor (which traditionally has been the focus). In this case, the
tumor is subdivided into three layers (central core, peripheral enhancement, and peritumoral

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layer), and the tumor status is determined according to the pattern of values in the three
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layers.40

Additionally, monitoring the differences in ADC values (capturing fluid-volume changes in

intra- and extracellular compartments) of the enhancing regions during post-therapy imaging
has the potential to differentiate radiation effects from tumor recurrence or progression.30

Choosing a b-value
White and gray matter exhibit very similar ADC values, while different tumor types have
been observed to exhibit dissimilar diffusion values35 for typically employed b-values. A b-
factor around 1000 is the most commonly utilized value for brain imaging in clinical and
research settings. This value has been shown to be sensitive to detecting and delineating
restricted diffusion since it provides the best tradeoff between signal attenuation from
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diffusion and background noise.41

ADC maps created with larger b-values, however, have been reported to better differentiate
progression from pseudoprogression38 and to correlate with microstructure. Diffusion
imaging with a higher b-value yields better contrast and less T2 shine-through effect42 than
reduced SNR, leading to longer acquisition times and, therefore more motion artifacts.43

A limited number of studies have compared multiple imaging approaches to explore therapy
outcome. However, the value of combining rCBV- and ADC-based biomarkers has been
recognized in several papers.40 For instance, increased rCBV values and decreased ADCs
appear to help separate true progression from pseudoprogression.

A challenge to clinical implementation of DSC-MRI-based biomarkers is the lack of

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standardized approaches to data acquisition, measurement, and analysis,24 with resulting

decreased reproducibility. Accurate CBV quantification is difficult, especially in cases of
glioblastoma (GBM) where the BBB has been interrupted and contrast leakage occurs.
Perfusion-analysis software is widely available in clinical practice; however, it is often
treated as a black box tool. Some of this software incorporates mathematical techniques to
deal with contrast agent leakage. The values produced are generally accepted, but validation
is challenging.

Assessing the accuracy and reliability of leakage-correction methods can be achieved only
with an appropriate phantom. However, creating a phantom that accurately reflects biology
is very difficult, if not impossible; development of digital phantoms that simulate contrast
extravasation remains an open research issue.
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The rCBV thresholds for differentiating progression vs pseudoprogression or tumor grading

are often not the same across different perfusion-analysis software packages because
different software packages utilize different methodologies for estimating bolus entrance
and exit times, and determining baselines, model fitting, integration methods, and
mathematical models to correct for contrast-agent extravasation.

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Most approaches to measuring rCBV use a normal-appearing region in contralateral white

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matter as a control region; however, no standardized criteria exist on how these regions of
interest (ROI) are chosen. To reduce variability in rCBV measurements, ROI selection must
also be standardized.

Tumor ROI selection delineation is also critical; areas of necrosis must be excluded from
analyses of tumor ADCs or CBV. Necrotic regions are common in high-grade tumors, and
in ADC analysis, for example, they can contribute to raising the mean ADC values of the
tumor. Necrotic areas are also known to have contrast enhancement, making ROI
determination very challenging. Furthermore, when defining ROIs using T1 images aligning
the T1 images with the diffusion or perfusion images is necessary, but not always
straightforward.

Conclusions
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DSC-MRI perfusion and diffusion MRI have already contributed to our understanding of
brain tumors and the effects of therapy. The key points are that rCBV images can give
strong indications that a tumor may be of a higher grade than contrast images might suggest;
rCBV images can help to distinguish treatment effects from true tumor progression; and
ADC images can be helpful when interpreting images of patients treated with anti-
angiogenic agents. Much still remains to be learned about these imaging methods for brain
tumors, and investigation is required to define their role in everyday clinical practice and
clinical trials.

Acknowledgments
This work was partly funded by NCI U01-160045.
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References
1. Wen PY, Macdonald DR, Reardon DA, et al. Updated response assessment criteria for high-grade
gliomas: Response assessment in neuro-oncology working group. J Clin Oncol. 2010; 28:1963–
1972. [PubMed: 20231676]
2. Macdonald DR, Cascino TL, Schold SC Jr, et al. Response criteria for phase II studies of
supratentorial malignant glioma. J Clin Oncol. 1990; 8:1277–1280. [PubMed: 2358840]
3. Provenzale JM, Mukundan S, Barboriak DP. Diffusion-weighted and perfusion MR imaging for
brain tumor characterization and assessment of treatment response. Radiology. 2006; 239:632–649.
[PubMed: 16714455]
4. Brandao LA, Shiroishi MS, Law M. BrainTumors. A multimodality approach with diffusion-
weighted imaging, diffusion tensor imaging, magnetic resonance spectroscopy, dynamic
susceptibility contrast and dynamic contrast-enhanced magnetic resonance imaging. Magn Reson
Author Manuscript

Imaging Clin N Am. 2013; 21:199–239. [PubMed: 23642551]

5. Rosen BR, Belliveau JW, Vevea JM, et al. Perfusion imaging with NMR contrast agents. Magn
Reson Med. 1990; 14:249–265. [PubMed: 2345506]
6. Walker C, Baborie A, Crooks D, et al. Biology, genetics and imaging of glial cell tumours. Br J
Radiol. 2011; 84(Spec No 2):S90–106. [PubMed: 22433833]
7. Jain RK, di Tomaso E, Duda DG, et al. Angiogenesis in brain tumours. Nat Rev Neurosci. 2007;
8:610–622. [PubMed: 17643088]

Appl Radiol. Author manuscript; available in PMC 2015 October 09.

 Korfiatis and Erickson Page 8

8. Law M, Yang S, Wang H, et al. Glioma grading: Sensitivity, specificity, and predictive values of
perfusion MR imaging and proton MR spectroscopic imaging compared with conventional MR
Author Manuscript

imaging. AJNR Am J Neuroradiol. 2003; 24:1989–1998. [PubMed: 14625221]

9. Hu LS, Eschbacher JM, Heiserman JE, et al. Reevaluating the imaging definition of tumor
progression: Perfusion MRI quantifies recurrent glioblastoma tumor fraction, pseudoprogression,
and radiation necrosis to predict survival. Neuro Oncol. 2012; 14:919–930. [PubMed: 22561797]
10. Essig M, Shiroishi MS, Nguyen TB, et al. Perfusion MRI: The five most frequently asked technical
questions. AJR Am J Roentgenol. 2013; 200:24–34. [PubMed: 23255738]
11. Bedekar D, Jensen T, Schmainda KM. Standardization of relative cerebral blood volume (rCBV)
image maps for ease of both inter- and intrapatient comparisons. Magn Reson Med. 2010; 64:907–
913. [PubMed: 20806381]
12. Paulson ES, Schmainda KM. Comparison of dynamic susceptibility-weighted contrast-enhanced
MR methods: Recommendations for measuring relative cerebral blood volume in brain tumors.
Radiology. 2008; 249:601–613. [PubMed: 18780827]
13. Quarles CC, Gochberg DF, Gore JC, et al. A theoretical framework to model DSC-MRI data
acquired in the presence of contrast agent extravasation. Phys Med Biol. 2009; 54:5749–5766.
Author Manuscript

[PubMed: 19729712]
14. Willats L, Calamante F. The 39 steps: Evading error and deciphering the secrets for accurate
dynamic susceptibility contrast MRI. NMR Biomed. 2013; 26:913–931. [PubMed: 22782914]
15. Gahramanov S, Muldoon LL, Li X, et al. Improved perfusion MR imaging assessment of
intracerebral tumor blood volume and antiangiogenic therapy efficacy in a rat model with
Ferumoxytol. Radiology. 2011; 261:796–804. [PubMed: 21940504]
16. Boxerman JL, Schmainda KM, Weisskoff RM. Relative cerebral blood volume maps corrected for
contrast agent extravasation significantly correlate with glioma tumor grade, whereas uncorrected
maps do not. AJNR Am J Neuroradiol. 2006; 27:859–867. [PubMed: 16611779]
17. Speck O, Chang L, DeSilva NM, et al. Perfusion MRI of the human brain with dynamic
susceptibility contrast: Gradient-echo versus spin-echo techniques. J Magn ResonImaging. 2000;
12:381–387.
18. Schmiedeskamp H, Andre JB, Straka M, et al. Simultaneous perfusion and permeability
measurements using combined spin- and gradient-echo MRI. J Cereb Blood Flow Metab. 2013;
33:732–743. [PubMed: 23462570]
Author Manuscript

19. Schmiedeskamp H, Straka M, Newbould RD, et al. Combined spin- and gradient-echo perfusion-
weighted imaging. Magn Reson Med. 2012; 68:30–40. [PubMed: 22114040]
20. Alvarez-Linera J. 3T MRI: Advances in brain imaging. Eur J Radiol. 2008; 67:415–426. [PubMed:
18455895]
21. Liu HL, Wu YY, Yang WS, et al. Is Weisskoff model valid for the correction of contrast agent
extravasation with combined T-1 and T-2* effects in dynamic susceptibility contrast MRI? Med
Phys. 2011; 38:802–809. [PubMed: 21452717]
22. Mauz N, Krainik A, Tropres I, et al. Perfusion magnetic resonance imaging: Comparison of
semiologic characteristics in first-pass perfusion of brain tumors at 1.5 and 3 Tesla. J Neuroradiol.
2012; 39:308–316. [PubMed: 22341619]
23. Hagmann P, Jonasson L, Maeder P, et al. Understanding diffusion MR imaging techniques: From
scalar diffusion-weighted imaging to diffusion tensor imaging and beyond. Radiographics. 2006;
26(Suppl 1):S205–223. [PubMed: 17050517]
24. Padhani AR, Liu G, Koh DM, et al. Diffusion-weighted magnetic resonance imaging as a cancer
Author Manuscript

biomarker: Consensus and recommendations. Neoplasia. 2009; 11:102–125. [PubMed: 19186405]

25. Kono K, Inoue Y, Nakayama K, et al. The role of diffusion-weighted imaging in patients with
brain tumors. AJNR Am J Neuroradiol. 2001; 22:1081–1088. [PubMed: 11415902]
26. Stadnik TW, Demaerel P, Luypaert RR, et al. Imaging tutorial: Differential diagnosis of bright
lesions on diffusion-weighted MR images. Radiographics. 2003; 23:e7. [PubMed: 12886888]
27. Bulakbasi N, Kocaoglu M, Ors F, et al. Combination of single-voxel proton MR spectroscopy and
apparent diffusion coefficient calculation in the evaluation of common brain tumors. AJNR Am J
Neuroradiol. 2003; 24:225–233. [PubMed: 12591638]

Appl Radiol. Author manuscript; available in PMC 2015 October 09.

 Korfiatis and Erickson Page 9

28. Yamasaki F, Kurisu K, Satoh K, et al. Apparent diffusion coefficient of human brain tumors at MR
imaging. Radiology. 2005; 235:985–991. [PubMed: 15833979]
Author Manuscript

29. Nagane M, Kobayashi K, Tanaka M, et al. Predictive significance of mean apparent diffusion
coefficient value for responsiveness of temozolomide-refractory malignant glioma to
bevacizumab: Preliminary report. Int J Clin Oncol. 2013 Epub ahead of print.
30. Hein PA, Eskey CJ, Dunn JF, et al. Diffusion-weighted imaging in the follow-up of treated high-
grade gliomas: Tumor recurrence versus radiation injury. AJNR Am J Neuroradiol. 2004; 25:201–
209. [PubMed: 14970018]
31. Lee WJ, Choi SH, Park CK, et al. Diffusion-weighted MR imaging for the differentiation of true
progression from pseudoprogression following concomitant radiotherapy with temozolomide in
patients with newly diagnosed high-grade gliomas. Acad Radiol. 2012; 19:1353–1361. [PubMed:
22884399]
32. Zeng QS, Li CF, Liu H, Z, et al. Distinction between recurrent glioma and radiation injury using
magnetic resonance spectroscopy in combination with diffusion-weighted imaging. Int J Radiat
Oncol Biol Phys. 2007; 68:151–158. [PubMed: 17289287]
33. Hayashida Y, Hirai T, Morishita S, et al. Diffusion-weighted imaging of metastatic brain tumors:
Author Manuscript

Comparison with histologic type and tumor cellularity. AJNR Am J Neuroradiol. 2006; 27:1419–
1425. [PubMed: 16908550]
34. Lyng H, Haraldseth O, Rofstad EK. Measurement of cell density and necrotic fraction in human
melanoma xenografts by diffusion weighted magnetic resonance imaging. Magn Reson Med.
2000; 43:828–836. [PubMed: 10861877]
35. Maier SE, Sun Y, Mulkern RV. Diffusion imaging of brain tumors. NMR Biomed. 2010; 23:849–
864. [PubMed: 20886568]
36. Morita KI, Matsuzawa H, Fujii Y, et al. Diffusion tensor analysis of peritumoral edema using
lambda chart analysis indicative of the heterogeneity of the microstructure within edema. J
Neurosurg. 2005; 102:336–341. [PubMed: 15739563]
37. Pope WB, Qiao XJ, Kim HJ, et al. Apparent diffusion coefficient histogram analysis stratifies
progression-free and overall survival in patients with recurrent GBM treated with bevacizumab: A
multi-center study. J Neurooncol. 2012; 108:491–498. [PubMed: 22426926]
38. Chu HH, Choi SH, Ryoo I, et al. Differentiation of true progression from pseudoprogression in
glioblastoma treated with radiation therapy and concomitant temozolomide: Comparison study of
Author Manuscript

standard and high-b-value diffusion-weighted imaging. Radiology. Epub ahead of print Jun 14,
2013.
39. Pope WB, Qiao XJ, Kim HJ, et al. Apparent diffusion coefficient histogram analysis stratifies
progression-free and overall survival in patients with recurrent GBM treated with bevacizumab: A
multi-center study. J Neurooncol. 2012; 108:491–498. [PubMed: 22426926]
40. Cha J, Kim ST, Kim HJ, et al. Analysis of the layering pattern of the apparent diffusion coefficient
(ADC) for differentiation of radiation necrosis from tumour progression. Eur Radiol. 2013;
23:879–886. [PubMed: 22903642]
41. Xing D, Papadakis NG, Huang CL, et al. Optimised diffusion-weighting for measurement of
apparent diffusion coefficient (ADC) in human brain. Magn Reson Imaging. 1997; 15:771–784.
[PubMed: 9309608]
42. Burdette JH, Durden DD, Elster AD, et al. High b-value diffusion-weighted MRI of normal brain. J
Comput Assist Tomogr. 2001; 25:515–519. [PubMed: 11473179]
43. Ben-Amitay S, Jones DK, Assaf Y. Motion correction and registration of high b-value diffusion
Author Manuscript

weighted images. Magn Reson Med. 2012; 67:1694–1702. [PubMed: 22183784]

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Figure 1.
A generalized model of the DSC data-processing pipeline.
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Figure 2.
The tumor region (A, B, and C) is easily detectable in the CBV image as an area of
increased blood volume, reflecting angiogenesis. Higher-grade tumors tend to have higher
values, as in this glioblastoma.
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Figure 3.
Blood-brain barrier leakage (A) and its effect on signal intensity (B). The curve corresponds
to the tumor-enhancing region in the T1 postcontrast image.
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Figure 4.
A T1 postcontrast image (A), one time-point from the perfusion image (B), the ADC map
(C), CBV (D), K2 leakage map (E), and the leakage-corrected (F) CBV maps.
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Figure 5.
T1 postcontrast imaging in a brain tumor patient (A). B0 image (B) and diffusion-weighted
image (C) computed from the 3-direction diffusion gradient images. The ADC map (D) is
computed from the diffusion-weighted image and the b0 image. It can be valuable because
high T2-signal intensity can”shine through” the diffusion-weighted image, suggesting
restricted diffusion.
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Figure 6.
(A) Postcontrast image in a patient with an anaplastic astrocytoma. (B) FLAIR image. (C)
ADC map. (D) FLAIR image in a patient with grade-2 oligoastrocytoma. (E) Postcontrast
image shows no definite contrast enhancement. (F) ADC map shows a small focus of
reduced diffusion (circle) that could represent a focus of a higher-grade or more cellular
tumor that should be considered for biopsy.
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Figure 7.
Images from a patient with a glioblastoma being treated with Avastin. Interpreting these is
challenging because the anti-angiogenic agent will result in restoration of the BBB even
when the tumor remains viable. These images demonstrate the pseudoresponse phenomenon
of decreased enhancement, mass effect, and CBV, even though the tumor is growing. Upper-
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row images were obtained when Avastin was started, and lower-row images were obtained 1
month later. Note the increasing area of low ADC, which represents the enlarging tumor.
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Appl Radiol. Author manuscript; available in PMC 2015 October 09.