N e u r o r a d i o l o g y / H e a d a n d N e c k I m a g i n g • R ev i ew

Rueda-Lopes et al.
Diffusion-Weighted Imaging of Demyelinating Diseases

Neuroradiology/Head and Neck Imaging

Review
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Diffusion-Weighted Imaging
and Demyelinating Diseases:
FOCUS ON:

New Aspects of an Old

Advanced Sequence
Fernanda C. Rueda-Lopes1 OBJECTIVE. The purpose of this article is to discuss classic applications in diffusion-
Luiz C. Hygino da Cruz, Jr. weighted imaging (DWI) in demyelinating disease and progression of DWI in the near future.
Thomas M. Doring CONCLUSION. DWI is an advanced technique used in the follow-up of demyelinating
Emerson L. Gasparetto disease patients, focusing on the diagnosis of a new lesion before contrast enhancement. With
technical advances, diffusion-tensor imaging; new postprocessing techniques, such as tract-
Rueda-Lopes FC, Hygino da Cruz LC Jr, Doring TM, based spatial statistics; new ways of calculating diffusion, such as kurtosis; and new applica-
Gasparetto EL tions for DWI and its spectrum are about to arise.

Keywords: demyelinating, diffusion-tensor imaging,
diffusion-weighted imaging, kurtosis, tract-based spatial
statistics (TBSS)
DOI:10.2214/AJR.13.11400
Received June 17, 2013; accepted after revision
August 25, 2013.
1 disease. Conventional T2-weighted images
All authors: Department of Radiology, Federal University
of Rio de Janeiro, Clinica de Diagnostico por imagem–
CDPI/DASA, Rua: Eneida de Morais, 141/203. Ilha do
Governador, Rio de Janeiro, RJ, Brazil, CEP 21920-230.
Address correspondence to F. C. Rueda-Lopes
(frueda81@hotmail.com).
WEB
This is a web exclusive article.
AJR 2014; 202:W34–W42
0361–803X/14/2021–W34
© American Roentgen Ray Society
D
iffusion-weighted imaging (DWI),
one of the first advanced MRI
techniques, has rapidly ascended
on the basis of its applicability in
strokes and some infectious diseases [1–4].
Restricted diffusion is significant informa-
tion in the context of vascular ischemia, help-
ing to delimit the brain-damaged area [5].
Nonetheless, the utility of DWI in assessing
demyelinating disease has always been ques-
tionable, and the main clinical utility of this
sequence could be in helping with the differ-
ential diagnosis [1–5]. The most described
aspect of demyelinating disease in DWI is fa-
cilitated diffusion [5, 6]. However, restricted
diffusion may occur at early stages of lesion
progression [6]. The apparent diffusion coef-
ficient (ADC), a map calculated from DWI
data, has also been extensively investigated
to establish a connection with disease severi-
ty and clinical correlation. Another applica-
tion for DWI is its capacity to evaluate tissue
characteristics in patients with demyelinating
are highly sensitive in depicting focal demy-
elinating lesions but lack histopathologic
specificity, such as inflammation, edema, gli-
osis, and axonal loss, which are all represent-
ed as areas of high signal intensity. Because
of this lack of specificity, T2-weighted imag-
ing does not provide information that can be
reliably associated with the pathologic sub-
strate and clinical status of the patient, which
can be determined using DWI [7].
Over the past decade, new insight has been
gained into DWI. The use of diffusion tensor
imaging (DTI) with its various parameters,
including axial and radial diffusion, has al-
lowed the description of intrinsic white mat-
ter (WM) damage [8, 9]. The demyelination
process and neuronal loss are now part of the
context of imaging findings. Postprocessing
techniques, such as tract-based spatial statis-
tics (TBSS) [10], have provided new research
opportunities, including mapping normal-
appearing WM damage, reflecting its greater
sensitivity for detecting initial WM lesions
compared with conventional MRI [11].
A new era of diffusion is about to begin.
Diffusion kurtosis imaging (DKI) is a new
DWI approach considered even more sensi-
tive than DTI and TBSS for microscopic WM
lesion detection. Some reports are appearing
on this topic, and DKI seems to be better than
DWI in assessing WM [12, 13]. Taking into
account all this advancement of DWI and its
related aspects, we will discuss the main ap-
plications for clinical aspects and research.
Diffusion-Weighted Imaging
Principles and Acquisition
Diffusion describes the transfer of water
molecules from one spatial location to other
locations, increased by thermal agitation in-
side a sample of biologic tissue [8, 9]. Random
movement, or Brownian motion, is the result
of a movement without a preferred direction,
in which molecules collide randomly, typical
of diffusion in pure water. This nondirected
movement is also called “isotropic diffusion”
in which water molecules move equally in all
directions. In biologic tissue, especially brain

W34 AJR:202, January 2014

 Diffusion-Weighted Imaging of Demyelinating Diseases

tissue in which the WM tracts may serve as
pathways that the water molecules are able
to follow, a directed movement occurs. This
property is called “anisotropic diffusion.”
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including intramyelinic edema (cytotoxic oli- gies, which are quick, efficient, and insensi-
godendroglia edema) or myelin vacuolation tive to small motion, with the incorporation
and reversible reduced vascular input. Myelin of a diffusion-sensitized module [8]. This
breakdown and inflammatory cell infiltration sensitization scheme can be achieved by a bi-

The diffusion of water in biologic tissues oc-
curs inside, outside, around, and through cel-
lular structures [8]. Nonetheless, when water
molecules encounter structures, such as mye-
lin sheaths, axonal membranes, or subcellular
organelles, their continued motion in a partic-
ular direction can be impeded [14].
Reduction of the motion along pathways re-
flects the interaction between the water mole-
cules and the damaged structures, called “re-
stricted diffusion.” There are many causes for
restricted diffusion in demyelinating diseases,
may reduce water movement in the extracel-
lular space because of reduced fiber tract or-
ganization. Likewise, this inflammatory influx
can lead to disturbances of energy metabolism,
namely mitochondrial dysfunction, notably
in acute lesions [5, 6, 15, 16]. The presence of
iron-laden macrophages in this inflammatory
process can result in an overall lack of DWI
signal because of very rapid T2* relaxation,
the same as seen in the center of an abscess [5].
DWI is acquired most commonly with sin-
gle-shot echo-planar imaging (EPI) strate-
polar gradient waveform before and after the
180° refocusing radiofrequency pulse. The
first gradient pulse dephases the magnetiza-
tion across the sample and the second pulse
rephases the magnetization. For nondiffusing
molecules representing restricted diffusion,
the phases induced by both gradients will be
completely canceled, the magnetization will
be maximally coherent, and there will be no
signal attenuation from diffusion, represent-
ing the high signal intensity on a classic DWI
map [8, 9].

30

15

4 3 2 1

A B C

D E F
Fig. 1—Tumefactive demyelinating plaque in 41-year-old man.
A–C, FLAIR (A) and contrast-enhanced T1-weighted (B) images show expansive lesion with hypersignal intensity on FLAIR and irregular rim of contrast enhancement
located in right centrum semiovale. Notice increased choline peak on spectroscopy image (C).
D and E, Enhancing ring corresponds with area of restricted diffusion on trace image (D) and apparent diffusion coefficient map (E).
F, Susceptibility weighted image shows many small venosus vessels penetrating lesion.

AJR:202, January 2014 W35

 Rueda-Lopes et al.

The sensitization profile of the gradient is
determined by the b factor. The higher the b
factor, the more diffusion weighted the im-
age will be. A typical DWI sequence for rou-
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such as lymphoma and small cell carcino- T2-weighted image alterations, in the course
ma of the lung; and hyperacute hemorrhage of disease (Fig. 2). ADC reduction may be a
can have restricted diffusion [2–4]. Howev- transient alteration in the hyperacute phase
er, DWI findings may vary from normal to of a demyelinating lesion. To depict such an

tine brain MRI protocols includes a b factor
of 1000 s/mm2 (ideal between 700 and 1300
s/mm2). At high b values, the signal intensi-
ty will be reduced. A b value of zero means
application of the normal single-shot EPI se-
quence without diffusion weighting. In prac-
tice, it is denominated as a b 0 image and is
similar to a T2-weighted image. To evalu-
ate diffusion properties of the tissue, the se-
quences have to be sensitized in three dif-
ferent dimensions. The diffusion coefficient
generated is proportional to the displacement
of water molecules (which may be tortuous
depending on membrane barriers) and is di-
vided by the number of dimensions, usual-
ly three. Trace diffusion imaging and ADC
maps, representing the magnitude of the dif-
fusion and the trace divided by three, are cal-
culated from the raw diffusion images of the
scanner. In practice, the restricted diffusion
represents a decrease in the apparent diffu-
sivity of water [8, 17].
Clinical Applications
An important clinical application for DWI
in demyelinating disease is in establishing a
differential diagnosis with other pathologies.
In some circumstances, tumefactive inflam-
matory lesions may mimic a cerebral neo-
plasm, infectious abscess, or vascular isch-
emia. Most high-grade gliomas; metastases;
tumors with high nuclear-cytoplasmic ratios,
facilitated diffusibility within neoplastic le-
sions [2–4]. Intracerebral abscesses usually
have restricted diffusion centrally after com-
plete formation. In the early stages, abscesses
may have peripheral restricted diffusion [1].
Diffusion restriction is found throughout the
ischemic tissue, with the lowest ADC values
detected in the infarct core [5]. There is no es-
tablished diffusion pattern for demyelinating
plaques, but variable ADC patterns in a sin-
gle MRI study (representing different stages
of lesion progression) and rapid changes in
such patterns on previous reports are high-
ly suggestive of demyelinating disease. The
most common ADC finding is homogeneous-
ly facilitated because of vasogenic edema [5,
6, 17]. However, homogeneous restriction,
peripheral restriction with a partial or com-
plete dark ring surrounding a bright center, or
central facilitation with an isointense periph-
eral ring or homogeneously isointense can
also be seen [5]. In our practice, the incom-
plete peripheral restriction ring usually en-
hances with contrast administration, notably
in the medial zone of an acute lesion (Fig. 1).
Thin slices of sagittal FLAIR sequences,
including the corpus callosum are useful for
early diagnosis of multiple sclerosis (MS)
[17]. But in some specific and rare situations,
restricted diffusion can be the first marker
for a demyelinating lesion, preceding con-
trast enhancement and associated with subtle
abnormality, MRI should be performed in
the early phase after clinical symptom onset
(from hours up to 2 days) or even before the
symptoms [6]. By this time, T2-weighted im-
aging abnormalities are not yet significant and
the lack of contrast enhancement reflects that
the increased permeability of the blood-brain
barrier and the edematous tissue changes are
not fully developed. Within gradual develop-
ment of signals of prominent inflammatory
edematous changes, which enlarge the extra-
cellular space, ADC reaches a brief pseudo-
normalization and subsequent increase of val-
ues, usually 3–7 days after symptom onset
[15]. Different case descriptions confirm the
changing pattern of ADC within a demyelin-
ating lesion. Acute disseminated encephalo-
myelitis and relapsing-remitting MS patients
may have acute lesions showing decreased
ADC values, which become facilitated dur-
ing the subacute stage [16, 18].
ADC is a potential marker for disease se-
verity. Low signal intensity on ADC, which
represents restricted diffusion, is associated
with higher expanded disability status scale
(EDSS) score at the index attack. Moreover,
neurologic deterioration may be accompanied
with ADC variation from homogeneously fa-
cilitated to a dark or isointense ring pattern.
This restricted diffusion could reflect a great-
er extent of inflammation and tissue dam-
age in such patients [5]. The damage severity

A B C
Fig. 2—25-year-old woman with demyelinating lesion.
A–C, Demyelinating plaque is seen in left middle cerebellar peduncle (green circle) showing restricted diffusion with hypointense signal intensity on apparent diffusion
coefficient (ADC) map (A) and hyperintense signal intensity on trace image (B). Notice no contrast enhancement is seen in that location on contrast-enhanced T1-
weighted image (C), reflecting hyperacute demyelinating plaque. On same contrast-enhanced T1-weighted image, there is another focus of enhancement (blue circle, C),
located in right cerebellar peduncle close to fourth ventricle wall, with hyperintense signal on trace image (blue circle, B) and isointense signal on ADC map (blue circle,
A), representing most common demyelinating lesion behavior on diffusion-weighted imaging.

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 Diffusion-Weighted Imaging of Demyelinating Diseases
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A B C
Fig. 3—37-year-old man with spinal cord demyelinating lesions.
A, Sagittal STIR image of dorsal spinal cord shows demyelinating plaque in inferior dorsal segment (red circle) and normal-appearing white matter (WM) damage in
superior segment (green circle).
B and C, Fractional anisotropy colored map (B) of dorsal spinal cord and corresponding apparent diffusion coefficient (ADC) map (C) show dorsal WM tracts are highly
anisotropic and main diffusion direction is in head-to-foot orientation (blue, B). Notice that fractional anisotropy value is lower in plaque (0.56 ± 0.11) and mean diffusivity
(1.30 ± 0.17 × 10 −3 mm2 /s) compared with normal-appearing WM damage fractional anisotropy (0.83 ± 0.28) and mean diffusivity (0.84 ± 0.05 × 10 −3 mm2 /s), and opposite
holds true for ADC value.

and ADC value correlation was confirmed by
comparison between low-signal-intensity le-
sions on T1-weighted imaging and ADC val-
ues on secondary progressive MS patients.
The lower the signal intensity on T1-weighted
imaging, the higher ADC tends to be, repre-
senting the so-called “black holes,” which are
related to significant tissue destruction, prob-
ably secondary to axonal loss [7].
Diffusion Tensor Imaging
Principles and Acquisition
In WM, water diffusion is relatively un-
impeded parallel to the fiber orientation and
relatively restricted perpendicular to its fi-
bers, defined as anisotropism. DTI will allow
the measurement of orientation of diffusivi-
ty, including on the parallel and perpendicu-
lar axes. The diffusion tensor may be visu-
alized as an ellipsoid, with the eigenvectors
defining the directions of the principal axis
and the eigenvalues (‫ג‬1, ‫ג‬2, ‫ג‬3) the diffusion
coefficients in the main directions. To char-
acterize diffusion as anisotropic, the eigen-
values are different in magnitude along dif-
ferent axes, and the eigenvector parallel to
the WM tracts is the principal eigenvector.
This magnitude may be affected by local tis-
sue injury, modifying the diffusion param-
eter values and thus helping to characterize
abnormal microstructure [8, 9, 19, 20].
To perform DTI, a minimum of six noncol-
linear diffusion-encoding directions is neces-
sary. If the number of encoding directions or
the number of averages is increased, DTI ac-
curacy will improve, but the scanning time
will increase [8]. The use of 3-T scanners,
with a higher signal-to-noise ratio, may also
improve the sequence acquisition. DTI tech-
nique also should be position-invariant but
only for a voxel with the size of a point; for
all other applications, head angulation does
matter and should be standardized. The pa-
rameters provided by DTI using the eigen-
vectors and eigenvalues are mean diffusivi-
ty, which is quite similar to ADC, fractional
anisotropy, radial diffusivity, and axial dif-
fusivity. The mean diffusivity gives an over-
all measure of the water diffusion in a vox-
el or region, whereas fractional anisotropy is
a measure of the degree of anisotropy. Frac-

AJR:202, January 2014 W37


tional anisotropy ranges from 1 (anisotropic
diffusion) to 0 (isotropic diffusion). The radial
diffusivity [(‫ג‬2 + ‫ג‬3) / 2] and axial diffusivity
(‫ג‬1) are measures of the orthogonal and paral-
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lel diffusivities, respectively, to the main dif-
fusion directions [8, 9, 19, 20]. Radial diffu-
sivity is modulated by myelin in white matter,
whereas axial diffusivity is more specific to
axonal degeneration [8, 19, 21]. When applied
together, these DTI parameters will evaluate
the WM tracts, indicating areas of lesions not
detected on conventional MRI and identifying
damage in the normal-appearing WM [9, 20].
Clinical and Research Applications
The investigation of the normal-appear-
ing WM damage using DWI and DTI tech-
niques gave a new direction to the radiologic
approach concerning demyelinating disease.
As previously mentioned, in clinical prac-
tice, DWI can be helpful in identifying ac-
tive demyelinating lesions [5, 17, 18] and for
differential diagnosis with some conditions
that can mimic demyelinating disease [1–5].
DTI application clarified the general under-
standing about some histopathologic aspects
of the structural WM damage in demyelinat-
ing disease [19, 20]. DTI can identify a broad
area of a WM lesion not identified by conven-
tional MRI techniques and that could only
be accessed by histopathologic examination.
In general, MS lesions have decreased frac-
tional anisotropy values and increased mean
diffusivity values compared with the con-
tralateral normal-appearing WM damage
and healthy control subjects [17]. Reduced
fractional anisotropy values in the normal-
appearing WM damage surrounding demy-
elinating plaques reflect wide involvement
because the lesion is greater than it seems to
be on conventional sequences [9, 14, 22–26].
Within other DTI parameters, such as ra-
dial diffusivity and axial diffusivity, the con-
tribution of demyelination and axonal loss
for this damage may be estimated. The cor-
pus callosum has been extensively studied by
DTI parameters [27, 28], and the results may
also be used as a tool to differentiate MS
from other demyelinating diseases, such as
neuromyelitis optica (NMO) [29]. However,
more effort is needed in this field to make
DTI a useful technique for demyelinating
disease follow-up.
DTI parameters have also been evaluated
in the spinal cord [30, 31] (Fig. 3). There are
many technical issues regarding DTI acquisi-
tion in the cord because there is extensive bone
structure surrounding the neural tissue and re-
W38 AJR:202, January 2014
Rueda-Lopes et al.
Fig. 4—Tract-based spatial statistics. Corrected p maps overlaid on skeleton (green) and mean fractional
anisotropy image (gray scale). Skeleton shows main tracts where statistical analysis was carried out. Orange
areas show fractional anisotropy is significantly reduced (p < 0.05) in one group compared with another.
spiratory movement artifacts. Some articles in
this field reflect the same brain findings. There
is extensive damage of the normal-appearing
WM, reflected by decreased fractional anisotro-
py values and increased mean diffusivity values
[30, 31], including in patients with NMO [31].
The majority of previous studies assessing
DTI findings in demyelinating disease have
used region of interest (ROI)-based analysis.
Standard limitations of the ROI approach are
that the method is subjective, presents diffi-
culties in reapplication, and is necessarily hy-
pothesis driven; thus, the entire WM is not
assessed [28, 29, 32]. A new approach, vox-
el-based analysis, is more general and robust;
the statistical analysis is more reliable; and
the total brain tissue is evaluated, which is
proportioned by TBSS [10].
Tract-Based Spatial Statistics
Postprocessing Principles
TBSS is an observer-independent and hy-
pothesis-free method that provides the abil-
ity to spatially locate group differences in
the DTI data. In such a technique, fraction-
al anisotropy data for individual subjects are
projected on a common space in a way that
does not depend on perfect nonlinear record-
ing, differing from the other voxel analysis
tool. This is achieved through the use of an
initial approximate nonlinear recording, fol-
lowed by projection on an alignment-invari-
ant tract representation (the ‘‘mean fractional
anisotropy skeleton’’). The skeleton repre-
sents the centers of all fiber bundles that are
generally common to the subject involved in
a study. Each subject’s fractional anisotropy
data are then projected on the mean fractional
anisotropy skeleton in such a way that each
skeleton voxel takes the fractional anisotropy
value from the local center of the nearest rel-
evant tract [10] (Fig. 4).
The results are significant maps correct-
ed for multiple comparisons, which can show
significant alterations in diffusion param-
eters between groups of study. All DTI pa-
rameters are analyzed, including fractional
anisotropy, mean diffusivity, axial diffusiv-
ity, and radial diffusivity [10].
Research Applications
TBSS is a postprocessing technique pre-
dominantly used for research purposes. TBSS
allows group analysis of all major WM tracts,
providing an overview of WM damage, in-
cluding normal-appearing WM damage. In-
deed, TBSS is helping in the identification
of the histopathogenesis behind all structural
damage in a noninvasive manner, contributing
toward the general knowledge of demyelinat-
ing disease evolution. With this technique, dif-
ferent groups of diseases can be studied and
compared, highlighting the differences be-
tween phenotypes, clinical course, age of on-
set, and so on [32–34].
Studies using TBSS have revealed that WM
damage is already widespread when detected
in pediatric MS onset (patients younger than
18 years at onset). The most common plac-
es for fractional anisotropy reduction are the
splenium of the corpus callosum and parietal
areas, which correlate with disease duration
[33]. But pediatric onset itself is also a predic-
tor of WM damage. The premature beginning
of MS is worse, and such patients have exten-
sive lower fractional anisotropy when com-
pared with groups of patients matched for age
and disease duration [34].
Clinically isolated syndrome patients are an-
other important group for analysis by TBSS.
Decreased fractional anisotropy values in-
volving the most significant WM pathways,
including the corticospinal tracts, corpus cal-
losum, and longitudinal fasciculi, when com-
 Diffusion-Weighted Imaging of Demyelinating Diseases
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A B
D E
G H
pared with control subjects are described in year of conversion [37], but they definitely in-
clinically isolated syndrome [35]. These struc- crease during disease progression [11, 36].
tural changes may not be significant at the be- The detection of microstructure damage is
ginning of the disease [36] or during the next also important in the correlation with clinical
AJR:202, January 2014 W39
C
F
Fig. 5—Parametric DKI maps. Values of parameters
are described in Table 1.
A–D, Proton density image (A) shows hypersignal
intensity representing demyelinating lesion on the
ROI located in right frontal side. ROI in left side
represents NAWM. Other maps are axial diffusivity
(B), radial diffusivity (C) and mean diffusivity (D)
maps.
E–H, Fractional anisotropy map (E) and diffusion
kurtosis imaging maps of axial kurtosis (F), radial
kurtosis (G), and mean kurtosis (H).
aspects, mostly cognition impairment [11, 38–
40]. Since the first descriptions of MS, the cor-
pus callosum has been described as the center
of demyelinating lesions, and good judgment
for radiologic MS diagnosis includes consid-
ering lesions in this location highly sugges-
tive of MS [27, 28]. But corpus callosum le-
sions or any other lesions are not necessarily
evident as causes for disturbances in MS, re-
flecting the contribution of normal-appearing
WM damage in cognitive abnormality [11,
38]. Fractional anisotropy variations in the
 Rueda-Lopes et al.

normal-appearing WM damage of the corpus
callosum have already been detected by ROI
analysis [27, 28], but its correlation with cog-
nitive impairment is mostly described using
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mains is predicted [39]. Again, corpus cal- sion barriers, thus causing water diffusion to
losum damage may result in a disconnection deviate from gaussianity. So, DKI is theoreti-
syndrome that contributes to long-term MS cally better able to characterize microstructur-
disability [39]. al brain tissue [44]. One main difference with

a voxel-based analysis method [11, 38–40].
The corpus callosum is one of the main impor-
tant structures connecting both cerebral hemi-
spheres, and its disconnection may be a po-
tential mechanism for physical and cognitive
disability in MS [38, 39]. Different cognitive
domains are impaired in MS patients, includ-
ing processing speed, which is correlated with
abnormal fractional anisotropy in the corpus
callosum [11]. This same domain is correlat-
ed with fractional anisotropy reduction main-
ly associated with variations in radial diffusiv-
ity and reflecting myelin disarrangement as
a significant contributor to the damage [40].
Sustained attention, working memory, visu-
al working memory, and verbal learning and
recall are associated with differential patterns
of fractional anisotropy reduction. Likewise,
these damaged tracts interconnect cortical re-
gions thought to be involved with processing
in these cognitive domains or even in possible
compensatory pathways [38].
Correlations between TBSS parameters
and motor index are also possible. Increasing
EDSS scores and decreasing fractional an-
isotropy values can be found in the splenium
of the corpus callosum and along the cortico-
spinal tract. The correlation of changes with
radial diffusivity points toward the myelin
process as the major participant in damage
[41, 42]. TBSS parameters may serve as pre-
dictors for motor outcome in primary pro-
gressive MS. Lower fractional anisotropy in
the splenium of the corpus callosum predicts
a greater progression of disability in 5 years
of follow-up. When the fractional anisotro-
py reduction of the entire corpus callosum is
noted, worsening of the major cognitive do-
In NMO patients, TBSS revealed a new facet
of brain involvement [32, 43]. Widespread WM
damage was detected in the normal-appearing
WM damage, including the corpus callosum,
internal and external capsules, and both longi-
tudinal fasciculi. Typically, this damage is not
merely affecting visual and motor pathways
secondary to Wallerian degeneration from op-
tical neuritis and spinal cord affection, but also
this in situ WM lesion, mostly correlated with
demyelination, provides significant new infor-
mation about such a condition [32].
With improvements in TBSS and continu-
ous evaluation of different demyelinating dis-
ease cohorts, it will be possible to map the
most common areas of normal-appearing WM
damage lesions and the way in which the dam-
age progresses over the years, and it may be
possible to use this technique for radiologic
follow-up of patients and medication trials.
Diffusion Kurtosis Imaging
Principles and Differences Between DTI
and DKI
Diffusion kurtosis imaging (DKI) is a novel
imaging technique and an extension of the DTI
model that allows simultaneous estimation of
diffusion and kurtosis parameters [12]. DKI
enables a more accurate description of pro-
ton diffusion than DTI, considering that diffu-
sion occurs differently from that described by
a gaussian diffusion probability distribution
for free diffusion. Actually, gaussian diffusion
of the water is only seen in homogeneous so-
lutions. Water diffusibility in biologic tissues,
such as brain, often shows nongaussian behav-
ior [13] because neurologic tissue is more mi-
crostructurally complex and has more diffu-
DTI is that the signal decay is not monolog-
arithmic but includes a logarithmic extension
that incorporates diffusion kurtosis [13, 45],
a unitless quantitative measure of the devia-
tion from the gaussian distribution (in other
words, the degree of restricted diffusion). Not
only six—as necessary in DTI—but at least 15
independent diffusion directions (gradients)
within three different b values have to be ac-
quired to completely calculate diffusion kur-
tosis parameters. Unlike DTI, the maximum b
value is higher in DKI, therefore commonly
used b values are 0, 1000, and 2000 s/mm2. In
a typical DKI acquisition, besides the com-
mon diffusion parameters, such as mean dif-
fusivity, axial diffusivity, radial diffusivity,
and fractional anisotropy, diffusion kurtosis
parameters are estimated, including the mean
kurtosis and the two directional kurtosis pa-
rameters, radial kurtosis and axial kurtosis [13,
45] (Fig. 5 and Table 1).
Interpretation of Diffusion Kurtosis Imaging
Parameters and Main Applications
Mean kurtosis gives an overall measure-
ment of diffusion kurtosis in the ROI. When
anisotropic diffusion occurs—for example
within the nerve fibers—the directional kurto-
sis parameters, such as radial kurtosis and ax-
ial kurtosis, can respectively describe the dif-
fusion kurtosis perpendicular to and along the
main eigenvector. In a previous study apply-
ing DKI to correlate kurtosis parameters with
brain maturation and the myelination process
in rat brains, the authors showed that the diffu-
sion kurtosis parameters, especially radial kur-
tosis, showed higher sensitivity to the degree
of myelination [46]. This is reflected by an in-

TABLE 1: Values for Diffusion Tensor Imaging and Diffusion Kurtosis Imaging for Lesions Described on Proton Density
Image and Contralateral Normal-Appearing White Matter Damage
Region of Fractional
Interest Anisotropy Mean Diffusivity Mean Kurtosis Axial Diffusivity Axial Kurtosis Radial Diffusivity Radial Kurtosis
Lesion
a 0.296 1.155 0.665 1.524 0.736 0.955 0.678
std 0.09 0.085 0.041 0.220 0.155 0.073 0.081
Contralateral
a 0.535 0.907 0.851 1.528 0.776 0.597 0.804
std 0.05 0.03 0.037 0.107 0.080 0.026 0.086
Note—Fractional anisotropy values are lower in the lesion compared with contralateral ROI. The mean kurtosis and radial kurtosis values vary in an opposite
manner. There are increased mean diffusivity and radial diffusivity values and decreased mean kurtosis and radial kurtosis values within the lesion, as
described in the text. Axial diffusivity and axial kurtosis values are not different between lesion and normal-appearing WM damage, probably reflecting
predominance of demyelination in such lesions. a = average, std = standard deviation.

W40 AJR:202, January 2014

 Diffusion-Weighted Imaging of Demyelinating Diseases
crease in radial kurtosis because the diffusion
is more restricted perpendicular to the axon
due to the growing myelin shell. Inversely,
during the demyelination process, commonly
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seen in demyelinating diseases, radial kurto-
sis decreases because diffusion occurs more
freely, and DTI radial diffusivity will increase.
An advantage of DKI over DTI in the as-
sessment of demyelinating disease is the eval-
uation of fiber crossing regions. Mean kur-
tosis values are relatively preserved in these
regions, whereas fractional anisotropy values
are mistakenly lower in crossing fibers com-
pared with the surrounding normal WM [47].
This DKI advantage might be useful in the
evaluation of normal-appearing WM damage
because the kurtosis values are less affected by
the influence of crossing fibers.
Another application for DKI in demyelinat-
ing disease is the evaluation of normal-appear-
ing gray matter (GM). Because GM has more
free space for diffusion, measurement of frac-
tional anisotropy is more difficult. Because of
this tissue property, evaluating the nongauss-
ian probability of diffusion could be a better
method to explain cortical diffusion [48].
Our group (Doring TM, et al., presented at
2013 annual meeting of the Radiological Soci-
ety of North America) evaluated the benefits of
DKI in the assessment of patients with NMO.
Using an ROI-based analysis, DKI showed
sensitivity in detecting normal-appearing WM
damage in two parameters, radial kurtosis and
mean kurtosis. We found that radial kurtosis
was significantly reduced (p < 0.05) in the cor-
pus callosum and there was a tendency toward
reduction in the right optic radiation (p < 0.1).
These same areas were evaluated by DTI pa-
rameters, and radial diffusivity was increased,
corroborating the idea that radial kurtosis and
radial diffusivity strongly correlate negatively
(r = −0.797, Pearson correlation coefficient).
The mean kurtosis was significantly increased
in the right corticospinal tract (p = 0.004), but
no alterations were found in the DTI param-
eters. This may reflect that DKI variations are
detected earlier than DTI variations. Thus, we
infer that in this preliminary study, DKI was
more sensitive in depicting abnormalities in
the normal-appearing brain parenchyma in de-
myelinating processes.
Other Techniques
Continuous technical improvement is nec-
essary to solve the common problems already
described in the previous topics. High-angu-
lar-resolution diffusion imaging acquisitions
collect DWI with many more gradient direc-
AJR:202, January 2014 W41
tions than DTI, giving more stability and re-
liability to the tensor. Boundaries between dif-
ferent tissue types, crossing WM pathways and
fiber orientation distribution, axon diameter,
and density are better analyzed by high-angu-
lar-resolution diffusion imaging than DTI. For
cortex tissue evaluation, where the dominant
orientation varies widely, Q-Ball orientation
distribution function may be a better choice.
This feature is independent of orientation and
so is able to associate voxels with similar mi-
crostructure but different orientation [49].
Conclusion
DWI is an interesting technique for evaluat-
ing demyelinating disease. Although it is fre-
quently used in brain MRI protocols, with its
new applications, postprocessing techniques,
and future promises, DWI and other parame-
ters will reveal many different aspects of de-
myelinating disease.
The most significant clinical application
for DWI in demyelinating disease is to estab-
lish a differential diagnosis with other abnor-
malities, such as neoplasms, infectious dis-
eases, and ischemic lesions. Although there
is no established diffusion pattern for demy-
elinating plaques, variable ADC patterns in
a single MRI and rapid changes in such pat-
terns from previous reports are highly sug-
gestive of demyelinating disease. A second
clinical application is related to the early di-
agnosis because restricted diffusion can be
the first marker for a demyelinating lesion,
preceding contrast enhancement, associat-
ed with subtle T2-weighted imaging altera-
tions. The third most significant DWI clini-
cal application is the ADC potential marker
for disease severity because restricted diffu-
sion is associated with a higher EDSS score
at the index attack. Moreover, ADC variation
from a homogeneously facilitated pattern to a
dark-isointense ring pattern is correlated with
neurologic deterioration. DTI parameters
contribute to the evaluation of normal-ap-
pearing WM damage, which has previously
only been investigated using histopatholog-
ic intervention. An evolution from the ROI
analysis to group analysis was performed by
TBSS. This group analysis of all major WM
tracts provides an overview of WM dam-
age, including normal-appearing WM damage.
Thus, it is a robust way to investigate demye-
linating disease in groups of patients. DKI is a
new technique that measures the nongaussian
behavior of diffusivity, which mostly occurs
in the brain. It is more accurate than DTI pa-
rameters for evaluating fiber-crossing areas
and it appears to be more useful for provid-
ing cortex diffusion measurements.
In the near future, radiologic and thera-
peutic trial follow-up techniques and pat-
terns of diffuse WM involvement may be es-
tablished using these advanced techniques to
highlight the damage that is not revealed by
conventional sequences.
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