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ISMRM 2011 E-Poster #4643. mcDESPOT-Derived MWF Improves EDSS Prediction in MS Patients Compared to Atrophy Measures Alone. J. Su 1 , H.H.Kitzler 2 , M. Zeineh 1 , S.C .Deoni 3 , C.Harper-Little 2 , A.Leung 2 , M.Kremenchutzky 2 , and B.K .Rutt 1 - PowerPoint PPT Presentation
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Declaration of Conflict of Interest or RelationshipI have no conflicts of interest to disclose with regard to the subject matter of this presentation.
MCDESPOT-DERIVED MWF IMPROVES EDSS PREDICTION IN MS PATIENTS COMPARED TO ATROPHY MEASURES ALONEJ.Su1, H.H.Kitzler2, M.Zeineh1, S.C.Deoni3, C.Harper-Little2, A.Leung2, M.Kremenchutzky2, and B.K.Rutt1
1Stanford U, CA, USA, 2TU Dresden, SN, Germany, 2U of Western Ontario, ON, Canada, 3Brown U, RI, USA
ISMRM 2011 E-POSTER #4643
Background
• Conventional MRI measures such as lesion load have been criticized with adding little new information on top of clinical scores for multiple sclerosis (MS) patients
• Measures that quantify the hidden burden of disease in white matter are urgently needed
MCDESPOT-DERIVED MWF IMPROVES EDSS PREDICTION IN MS PATIENTS COMPARED TO ATROPHY MEASURES ALONEISMRM 2011 #4643
Purpose
• To apply mcDESPOT, a whole-brain, myelin-selective, multi-component relaxometric imaging method, in a pilot MS study
• Assess if the method can explain differences in disease course and severity by uncovering the burden of disease in normal-appearing white matter (NAWM)
MCDESPOT-DERIVED MWF IMPROVES EDSS PREDICTION IN MS PATIENTS COMPARED TO ATROPHY MEASURES ALONEISMRM 2011 #4643
Study
Demographic Data Healthy Controls
All Patients CIS RRMS SPMS PPMS
N 26 26 10 5 6 5
Mean age, yr(SD)
42(13)
49(12)
41(12)
48(12)
58(7)
55(7)
Male/Female ratio 10/16 7/19 3/7 0/5 0/6 4/1
Mean disease duration, yr(SD)
—14
(13)2
(2)15
(10)28(8)
20(12)
Mean EDSS score(SD) —
3.6(2.4)
1.7(0.9)
2.0(1.7)
6.4(1.1)
5.6(1.1)
MCDESPOT-DERIVED MWF IMPROVES EDSS PREDICTION IN MS PATIENTS COMPARED TO ATROPHY MEASURES ALONEISMRM 2011 #4643
Scanning Methods• 1.5T GE Signa HDx, 8-channel head RF coil
• mcDESPOT: 2mm3 isotropic covering whole brain, about 15 min.– SPGR: TE/TR = 2.1/6.7ms, α = {3,4,5,6,7,8,11,13,18}°– bSSFP: TE/TR = 1.8/3.6ms, α = {11,14,20,24,28,34,41,51,67}°
• 2D T2 FLAIR: 0.86 mm2 in-plane and 3mm slice resolution
• 3D T1 IR-SPGR: 1mm3 resolution with pre/post Gd contrast
MCDESPOT-DERIVED MWF IMPROVES EDSS PREDICTION IN MS PATIENTS COMPARED TO ATROPHY MEASURES ALONEISMRM 2011 #4643
Processing Methods: MWF
• Linearly coregister and brain extract mcDESPOT SPGR and SSFP images with FSL1
• Find myelin water fraction maps using the established mcDESPOT fitting algorithm2
Myelin Water Fraction
1FMRIB Software Library. 2Deoni et al., Magn Reson Med. 2008 Dec;60(6):1372-87
MCDESPOT-DERIVED MWF IMPROVES EDSS PREDICTION IN MS PATIENTS COMPARED TO ATROPHY MEASURES ALONEISMRM 2011 #4643
Processing Methods: Demyelination
• Non-linearly register mcDESPOT MWF maps to MNI152 standard space
• Combine normals together to form mean and standard deviation MWF volumes
• For each subject, calculate a z-score ([x – μ]/σ) at every voxel to determine if it is significantly demyelinated, i.e. MWF < -4σ below the mean
Demyelinated Voxels
MCDESPOT-DERIVED MWF IMPROVES EDSS PREDICTION IN MS PATIENTS COMPARED TO ATROPHY MEASURES ALONEISMRM 2011 #4643
Processing Methods: WM• Brain extract MPRAGE images
• Segment white and gray matter with SPM83
• Filter tissue masks to reduce noise then manually edit by a trained neuroradiologist
• Calculate parenchymal volume fraction (PVF) as WM+GM divided by the brain mask volume
FLAIR WM
MCDESPOT-DERIVED MWF IMPROVES EDSS PREDICTION IN MS PATIENTS COMPARED TO ATROPHY MEASURES ALONEISMRM 2011 #4643
3Statistical Parametric Mapping software package.
Processing Methods: Lesions & DAWM
• Non-linearly register T2-FLAIR images to MNI152 standard space
• Combine normals together to form mean and standard deviation volumes
• Segment lesions as those voxels with z-score > +4 and diffusely abnormal white matter > +2
• Edit masks by a trained neurologist
DAWM Lesions
MCDESPOT-DERIVED MWF IMPROVES EDSS PREDICTION IN MS PATIENTS COMPARED TO ATROPHY MEASURES ALONEISMRM 2011 #4643
Processing Methods: NAWM & DVF• Segment normal-appearing
white matter (NAWM) as WM – DAWM – lesions
• Find demyelinated volume fraction (DVF)– Sum the volume of demyelinated
voxels in each tissue compartment and normalize by the compartment’s volume
– # demy. voxels in compartment * voxel volume / compartment volume
Normal-AppearingWhite Matter
MCDESPOT-DERIVED MWF IMPROVES EDSS PREDICTION IN MS PATIENTS COMPARED TO ATROPHY MEASURES ALONEISMRM 2011 #4643
Segmentations and DVFLAIR NAWM DAWM Lesions
MWF DemyelinatedVoxels
WM
DV in NAWM DV in DAWM DV in Lesions
MCDESPOT-DERIVED MWF IMPROVES EDSS PREDICTION IN MS PATIENTS COMPARED TO ATROPHY MEASURES ALONEISMRM 2011 #4643
Statistical Methods• Use rank sum tests to compare patient groups to normals along
different measures
• Perform an exhaustive search to find the best multiple linear regression model for EDSS using Mallows’ Cp4 criterion among 21 possible image-derived predictors:– PVF– log-DVF in whole brain, log-DVF in WM, log-DVF in NAWM, log-DVF in lesions– log-DV in those four compartments– mean MWF in those four compartments– volumes of those four compartments (lesion volume = T2 lesion load)– volume fractions of those four compartments with respect to the whole
brain mask volume
MCDESPOT-DERIVED MWF IMPROVES EDSS PREDICTION IN MS PATIENTS COMPARED TO ATROPHY MEASURES ALONEISMRM 2011 #4643
4Mallows C. Some comments on Cp. Technometrics. 1973;15(4):661-75.
Results: Mean MWF in Compartments
• Dotted line shows mean MWF in WM for normals. Rank sum testing was done for each bar against this
• Testing was also done for RRMS vs. SPMS and CIS vs. RRMS, any significant differences are shown with a connecting bracket
• Significance levels:* p < 0.05** p < 0.01*** p < 0.001.
MCDESPOT-DERIVED MWF IMPROVES EDSS PREDICTION IN MS PATIENTS COMPARED TO ATROPHY MEASURES ALONEISMRM 2011 #4643
Results: DVF in Compartments• Dotted line shows
demyelinated volume fraction in WM for healthy controls
• With DVF, all patient subclasses were significantly different from healthy controls
• PVF, however, fails to distinguish CIS and RR patients from normals
MCDESPOT-DERIVED MWF IMPROVES EDSS PREDICTION IN MS PATIENTS COMPARED TO ATROPHY MEASURES ALONEISMRM 2011 #4643
Results: Correlations with EDSS• Lesion load correlates
poorly with EDSS
• PVF and DVF are stronger indicators of decline
MCDESPOT-DERIVED MWF IMPROVES EDSS PREDICTION IN MS PATIENTS COMPARED TO ATROPHY MEASURES ALONEISMRM 2011 #4643
Results: Multiple Linear Regression
• The best linear model for EDSS contains PVF (p < 0.001), mean MWF in whole brain (p < 0.001), and WM volume fraction (p < 0.01)
• Whole-brain MWF and WM volume fraction significantly improve the prediction of EDSS over that produced by PVF alone
• Explains 76% of the variance in EDSS (R2 = 0.76, adjusted R2 = 0.73) compared to 56% with only PVF
MCDESPOT-DERIVED MWF IMPROVES EDSS PREDICTION IN MS PATIENTS COMPARED TO ATROPHY MEASURES ALONEISMRM 2011 #4643
Discussion & Conclusions• DVF is able to differentiate CIS and RRMS patients from
normals, whereas other measures such as PVF and mean MWF cannot
• The invisible burden of disease may be more important than lesions in determining disability, since we observe a higher correlation of EDSS with DVF in NAWM than lesion load
• A combination of established atrophy measures with new mcDESPOT-derived MWF are more capable in accurately estimating disability than either quantity alone
MCDESPOT-DERIVED MWF IMPROVES EDSS PREDICTION IN MS PATIENTS COMPARED TO ATROPHY MEASURES ALONEISMRM 2011 #4643