Whole Brain Graded Functional Diffusion Maps (fDMs)
A sensitive biomarker for monitoring brain tumor growth and invasion
B.M. Ellingson1,2, M.G. Malkin1,3,4, S.D. Rand1,2, J.M. Connelly3, P.S. LaViolette1,5,
D.P. Bedekar1,2, and K.M. Schmainda1,2,5
1Translational
Brain Tumor Program, 2Dept. of Radiology, 3Dept. of Neurology,
4Dept. of Neurosurgery, 5Dept. of Biophysics, Medical College of Wisconsin, Milwaukee, WI
INTRODUCTION
 In neoplasms, a decrease in apparent diffusion coefficient (ADC is
believed to reflect an increase in tumor cellularity 1-6, and an increase in
ADC is believed to reflect necrosis or decreases in cellularity as a result
of successful cytotoxic treatment 2,7.
 Functional diffusion maps (fDMs) were developed to exploit these
principles on a voxel-wise basis and may be useful for predicting
response to chemotherapy and radiotherapy 8-11.
 Currently, traditional fDMs rely on a single threshold for classifying
voxels as significantly increasing or decreasing.
 We hypothesize that a graded fDM technique that stratifies voxels into
varying degrees of change, applied to the whole brain may be useful
for visualizing growing and invading tumor with high sensitivity and
specificity.
PURPOSE
To demonstrate the utility of whole brain graded functional diffusion maps (fDMs) as an biomarker for
monitoring brain tumor growth and invasion
RESULTS
BRAIN TUMOR PROGRESSION
B
A
B
C
D
Figure 2: Graded fDMs in four representative patients (A-D) with progressing glioblastoma. Graded fDMs show increasing hypercellularity
(decreasing ADC, blue voxels) over the observation period. Regions of hypocellularity (increasing ADC, red) surrounding hypercellular regions
are likely edematous regions, whereas hypocellular regions enclosed by hypercellularity likely represent areas of necrosis.
BRAIN TUMOR INVASION
TREATMENT-RELATED CHANGES
Figure 1: Calculation of graded functional diffusion maps (fDMs) from sequential ADC
maps. For each postbaseline time point, baseline ADC maps are subtracted from ADC
maps from the current day. Each voxel within an ADC difference image is stratified into
multiple categories based on the magnitude of ADC change with respect to the 95%
confidence interval for various tissue types 12.
a
A
A
b
METHODS
c
d
 Patient Population: To date, over 200 patients with gliomas have been
enrolled in this study approved by the Institutional Review Board at our
Institution.
 Clinical MRI scans included a 3D-SPGR, FLAIR, diffusion, and pre/post-contrast T1-weighted images on a 1.5T MR scanner (Excite, CVi, or
LX; GE Medical Systems, Waukesha, WI). ADC was calculated from b =
0 and 1,000 s/mm2 images.
 Functional Diffusion Maps (fDMs): All images for each patient were
registered to their own baseline, postsurgical, pretreatment, SPGR
anatomical images using a mutual information algorithm and a 12-degree
of freedom transformation using FSL (FMRIB, Oxford, UK).
a
b
B
c
B
d
C
o Voxel-wise subtraction was then performed between ADC maps
acquired at subsequent time points and the baseline, postsurgical,
pretreatment, ADC maps to create ADC images.
e
o Individual voxels were stratified into 6 categories* used to quantify
the degree of hyper-/hypocellularity:
o Hypocellular: ADC = +0.25, +0.40, and +0.75 um2/ms
o Hypercellular: ADC = -0.25, -0.40, and -0.75 um2/ms
* Based on the 95% C.I. of normal appearing white matter (NAWM), NAWM and gray
matter (NAGM), NAWM+NAGM+CSF, respectively.
Acknowledgements:
Funding support was provided by NIH/NCI R01CA082500,
NIH/NCI R21 CA109280, MCW Translational Brain Tumor Program, Advancing a
Healthier Wisconsin and a Fellowship from the MCW Cancer Center.
Figure 3: Normal cytotoxic treatment changes in graded fDMs.
Baseline = Post-Sx, Post-RT, Beginning of adjuvant
temozolomide (150 to 200 mg/m2 for 5 days during a 28 day
cycle, total of 12 cycles 13). a) Patient with bifrontal
glioblastoma. b) Remote regions of hypercellularity are likely due
to cell swelling during treatment. c) 21 months following the start
of adjuvant temozolomide, regions of residual hypercellularity in
the right frontal lobe remain, suggesting residual tumor.
f
Figure 4: Three
patients with recurrent
glioblastoma (A-B)
showing spread of
hypercellularity beyond
regions of abnormal
FLAIR signal intensity.
a) FLAIR abnormal
regions along the right
lateral ventricle. b)
Hypercellular regions
detected at the edge of
the FLAIR signal using
the
ADC threshold of
0.25 um2/ms. c) Bulky
subtle FLAIR
abnormality,
suggestive of nonenhancing infiltrative
tumor. d) Large extent
of hypercellularity
detected in both
hemispheres. e) Mass
effect on the left frontal
lobe as suggested by
deformation of the
corpus callosum. f)
Regions of mass effect
contain a high degree
of hypercellularity.
REFERENCES
1
Sugahara, JMRI, 1999; 2 Lyng, MRM, 2000; 3 Chenevert, JNCI, 2000; 4 Hayashida,
AJNR, 2006; 5 Manenti, Radiol Med, 2008; 6 Gauvain, AJR, 2001; 7 Chenevert, Clin
Cancer Res, 1997; 8 Moffat, Proc Nat Acad Sci, 2005; 9 Moffat, Neoplasia, 2006; 10
Hamstra, JCO, 2008; 11 Hamstra, Proc Nat Acad Sci, 2005. 12 Ellingson, JMRI, 2010.
13 Stupp, NEJM, 2005.