1. Visualization of Fibers at Risk for Neuronal Tract Injury in Early MS by Streamtube Diffusion Tractography at 3 Tesla Jack H Simon 1 David E Miller 1 Mark Brown 1 John R Corboy 1 Jeffrey L Bennett 1 Song Zhang 2 David H Laidlaw 2 1 University of Colorado Health Sciences Center 2 Brown University Supported by the National MS Society (RG 3307-A-1), GE Medical Systems, and the National Science Foundation (CCR-0086065).

2. Background – Neuronal Tract Degeneration in Early MS Axonal injury in inflammatory MS Lesions Trapp et al 1998; Ferguson et al 1997 Empty myelin cylinders 2° to and distant from focal lesion Bjartmar et al 2001 Major axonal loss (and atrophy) in corpus callosum Evangelou et al 2000 Neuronal Tract Degeneration Patterns in Early MS Transcallosal Bands Corticospinal Tract Degeneration Bjartmar et al 2001 Simon et al Neurology 2000 Simon et al Neurology 2001

3. Goals/Question Develop a process to identify and then interrogate neuronal fibers that are anatomically related to focal demyelinating lesions Can we detect and measure neuronal fiber injury/degeneration in vivo ?

4. Strategy Earliest MS –Identify focal lesions at the time of a CIS Identify fibers transiting the focal lesion and reaching a distant structure (corpus callosum) Interrogate fibers (in corpus callosum) by MRI distant from focal lesion –MTR, Diffusion tensor ( ; FA) –Longitudinal MRI follow-up

5. 3T Pulse Parameters Diffusion Tensor Imaging –Echo-planar –B-value 1000, 25 gradient directions Axial plane - 3 sets of overlapping slices 5.1 mm thick with 1.7mm shifts FOV 28 x 28 cm, matrix 160 x160, 2 excitations TR/TE 6075/69.8-minimum Magnetization Transfer Imaging –3D gradient-echo MT pulse –Fermipulse; applied middle 30% of the phase encode steps (SAR) –Pulse width of 8 ms –Peak B1 field of 9.24 μT, flip angle of 670° –1200 Hz from the center frequency –TR/TE/flip angle 50/2.4(fr)/15° –FOV 22x22, matrix 256 x192, one excitation Sagittal plane 3 mm partitions

6. Patient Characteristics

7. Generate streamtubes and streamsurfaces Westin et al 2002; Zhang et al 2003 coherent white matter tracts – fastest diffusion, principal eigenvector Terminate streamtube low linear diffusion; data boundary; curvature 500,000 streamtubes Cull #1 –length; anisotropy; redundancy 2,000 streamtubes Cull # 2 - seed points within the 3D coordinates of T2-lesions Cull # 3 - intersection with corpus callosum. Calculate Diffusion tensor - non-linear approach Register data sets- affine transformations optimized by mutual information algorithm Outline of Streamtube Tractography Strategy Visualize in optimal projection – quantitative analyses

8. Visualization -Streamtubes + StreamsurfacesSegmentation & Registration AAMI (Analysis Application for Medical Imaging) David E. Miller - University of Colorado HSC Visualization Tools Song Zhang and David Laidlaw - Brown University

9. Streamtubes culled to lesion Streamsurfaces not utilized

10. Streamtubes culled to [lesion + corpus callosum]

11. Case 1 Streamtubes and StreamsurfacesCulled to Lesion Culled to [lesion + corpus callosum]

12. Culled to LesionCulled to [Lesion + Corpus Callosum] Case 2

14. Culled to [lesion + corpus callosum] Case 3

15. Case 1 Registration of culled streamtubes to sagittal representation of corpus callosum Fibers at Risk (FAR)

16. Corpus Callosum AreaMean MTR ID FAR % AAWM % All Corpus Callosum NAWM Fraction AAWM Fraction FAR Fraction CIS 121.04.148.9449.0645.9850.57 CIS 210.0049.55 49.78 CIS 330.08.748.5348.5548.3650.63 CIS 1CIS 2CIS 3

17. Conclusions Viable strategy and methodology to identify a new class of tissue called fibers at risk (FAR) –NAWM –AAWM –FAR FAR makes up a formidable percentage of corpus callosum with minimal overlap with AAWM Strategy applicable to any neuronal tract Future studies to determine injury profile over time, factors associated with more severe neuronal tract injury Assay of MS neurodegeneration to evaluate treatment ?

18. Supported by The National Multiple Sclerosis Society (RG 3307-A-1) GE Medical Systems (3T diffusion tensor MRI) National Science Foundation (CCR-0086065) University of Colorado 3T Research Instrument (ONDCP) University of Colorado Brain Imaging Research Laboratory (BIRL) Rebecca Leek and MaryJoel Meyer BIRL and Brain Imaging Center for Drug Abuse Research Deb Singel