1. Declaration of Conflict of Interest or Relationship I have no conflicts of interest to disclose with regard to the subject matter of this presentation. S ENSITIVE D ETECTION OF M YELINATION C HANGE IN M ULTIPLE S CLEROSIS BY MC DESPOT 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 1 Stanford U, CA, USA, 2 TU Dresden, SN, Germany, 2 U of Western Ontario, ON, Canada, 3 Brown U, RI, USA ISMRM 2011 E-P OSTER #7224

2. Background There is a growing demand for metrics that can provide more detailed, spatially localized, and sensitive tracking of disease progression in multiple sclerosis (MS) than common clinical scoring methods such as EDSS Quantitative MR techniques are promising in this regard because they offer the possibility of detecting changes in normal-appearing white matter S ENSITIVE D ETECTION OF M YELINATION C HANGE IN M ULTIPLE S CLEROSIS BY MC DESPOTISMRM 2011 #7224

3. Purpose To apply mcDESPOT, a whole-brain, myelin- selective, multi-component relaxometric imaging method, in a 1-year longitudinal pilot MS study Assess the ability of the method to sense different rates of demyelination for different MS courses and compare it to changes in EDSS S ENSITIVE D ETECTION OF M YELINATION C HANGE IN M ULTIPLE S CLEROSIS BY MC DESPOTISMRM 2011 #7224

4. Study Demographic Data Healthy Controls All Patients CISRRMSSPMSPPMS N at baseline26 10565 N at 1-year4239464 Mean age at baseline, yr (SD) 42 (13) 49 (12) 41 (12) 48 (12) 58 (7) 55 (7) Mean disease duration at baseline, yr (SD) — 14 (13) 2 (2) 15 (10) 28 (8) 20 (12) Mean EDSS score at baseline (SD) — 3.6 (2.4) 1.7 (0.9) 2.0 (1.7) 6.4 (1.1) 5.6 (1.1) N with EDSS change—31002 S ENSITIVE D ETECTION OF M YELINATION C HANGE IN M ULTIPLE S CLEROSIS BY MC DESPOTISMRM 2011 #7224

5. Scanning Methods 1.5T GE Signa HDx, 8-channel head RF coil mcDESPOT: 2mm 3 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 mm 2 in-plane and 3mm slice resolution 3D T1 IR-SPGR: 1mm 3 resolution with pre/post Gd contrast S ENSITIVE D ETECTION OF M YELINATION C HANGE IN M ULTIPLE S CLEROSIS BY MC DESPOTISMRM 2011 #7224

6. Processing Methods: MWF Linearly coregister and brain extract mcDESPOT SPGR and SSFP images with FSL 1 Find myelin water fraction maps using the established mcDESPOT fitting algorithm 2 Myelin Water Fraction S ENSITIVE D ETECTION OF M YELINATION C HANGE IN M ULTIPLE S CLEROSIS BY MC DESPOTISMRM 2011 #7224 1 FMRIB Software Library. 2 Deoni et al., Magn Reson Med. 2008 Dec;60(6):1372-87

7. 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 S ENSITIVE D ETECTION OF M YELINATION C HANGE IN M ULTIPLE S CLEROSIS BY MC DESPOTISMRM 2011 #7224

8. Processing Methods: 1-year & DVF At 1-year, demyelinated voxels are based on z- scores with respect to the baseline normal distribution Find demyelinated volume fraction (DVF) – Sum the volume of demyelinated voxels and normalize by brain mask volume – # demy. voxels in compartment * voxel volume / compartment volume S ENSITIVE D ETECTION OF M YELINATION C HANGE IN M ULTIPLE S CLEROSIS BY MC DESPOTISMRM 2011 #7224

9. Results: Mean MWF in Whole Brain Dotted line shows mean MWF for normals. Rank sum testing was done for each bar against this value 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. S ENSITIVE D ETECTION OF M YELINATION C HANGE IN M ULTIPLE S CLEROSIS BY MC DESPOTISMRM 2011 #7224

10. Results: DVF Change Colors denote subject type Arrowheads indicate the direction of change and the DVF at 1-year Dashed lines show subjects who also had a change in EDSS S ENSITIVE D ETECTION OF M YELINATION C HANGE IN M ULTIPLE S CLEROSIS BY MC DESPOTISMRM 2011 #7224 Normals CIS RRMS SPMS PPMS

11. Results: DVF in Whole Brain Dotted line shows mean demyelinated volume fraction change for normals Definite MS patients are losing significantly more myelin than normals Progressive patients have a greater rate of demyelination S ENSITIVE D ETECTION OF M YELINATION C HANGE IN M ULTIPLE S CLEROSIS BY MC DESPOTISMRM 2011 #7224

12. Discussion & Conclusions The normal pool at 1-year is currently too small to show significance for the changes in mean MWF DVF, however, is sensitive enough to show statistically significant changes in brain myelination over the study period Progressive patients show greater disease decline that are not reflected in their EDSS disability score EDSS and DVF measure different aspects of the disease. Patients with changes in EDSS did not actually have the largest demyelination changes S ENSITIVE D ETECTION OF M YELINATION C HANGE IN M ULTIPLE S CLEROSIS BY MC DESPOTISMRM 2011 #7224