Disclosures Paid Consultant, MedQIA LLC Paid Consultant, Agios Pharmaceuticals, Inc. Consultant, Genentech Consultant, Siemens Medical Systems B.M. Ellingson,

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Disclosures Paid Consultant, MedQIA LLC Paid Consultant, Agios Pharmaceuticals, Inc. Consultant, Genentech Consultant, Siemens Medical Systems B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLAISMRM, Montreal, 2011

Degenerative changes in the cervical spine (spondylosis) occurs >50% of people over 55 (Hughes,1965; Irvine, 1965; Pallis, 1954) and >75% of people over age 65 (Larocca, 1988) Cervical Spondylotic Myelopathy B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLAISMRM, Montreal, 2011

Degenerative changes in the cervical spine (spondylosis) occurs >50% of people over 55 (Hughes,1965; Irvine, 1965; Pallis, 1954) and >75% of people over age 65 (Larocca, 1988) Cervical spondylotic myelopathy (CSM) is the most common cause of spinal dysfunction in the elderly (Young, 2000; Baron, 2007) Cervical Spondylotic Myelopathy B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLAISMRM, Montreal, 2011

Degenerative changes in the cervical spine (spondylosis) occurs >50% of people over 55 (Hughes,1965; Irvine, 1965; Pallis, 1954) and >75% of people over age 65 (Larocca, 1988) Cervical spondylotic myelopathy (CSM) is the most common cause of spinal dysfunction in the elderly (Young, 2000; Baron, 2007) Pathogenesis (Baron, 2007) Cervical Spondylotic Myelopathy B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLAISMRM, Montreal, 2011

Degenerative changes in the cervical spine (spondylosis) occurs >50% of people over 55 (Hughes,1965; Irvine, 1965; Pallis, 1954) and >75% of people over age 65 (Larocca, 1988) Cervical spondylotic myelopathy (CSM) is the most common cause of spinal dysfunction in the elderly (Young, 2000; Baron, 2007) Pathogenesis (Baron, 2007) Cervical Spondylotic Myelopathy B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLAISMRM, Montreal, 2011 Disc Degeneration (Photos courtesy of Arin Ellingson, University of Minnesota)

Degenerative changes in the cervical spine (spondylosis) occurs >50% of people over 55 (Hughes,1965; Irvine, 1965; Pallis, 1954) and >75% of people over age 65 (Larocca, 1988) Cervical spondylotic myelopathy (CSM) is the most common cause of spinal dysfunction in the elderly (Young, 2000; Baron, 2007) Pathogenesis (Baron, 2007) Cervical Spondylotic Myelopathy B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLAISMRM, Montreal, 2011 Disc Degeneration Increased Stresses on Endplates

Degenerative changes in the cervical spine (spondylosis) occurs >50% of people over 55 (Hughes,1965; Irvine, 1965; Pallis, 1954) and >75% of people over age 65 (Larocca, 1988) Cervical spondylotic myelopathy (CSM) is the most common cause of spinal dysfunction in the elderly (Young, 2000; Baron, 2007) Pathogenesis (Baron, 2007) Cervical Spondylotic Myelopathy B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLAISMRM, Montreal, 2011 Disc Degeneration Increased Stresses on Endplates Subperiosteal Bone and Osteophytic Bar Formation

Degenerative changes in the cervical spine (spondylosis) occurs >50% of people over 55 (Hughes,1965; Irvine, 1965; Pallis, 1954) and >75% of people over age 65 (Larocca, 1988) Cervical spondylotic myelopathy (CSM) is the most common cause of spinal dysfunction in the elderly (Young, 2000; Baron, 2007) Pathogenesis (Baron, 2007) Cervical Spondylotic Myelopathy B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLAISMRM, Montreal, 2011 Disc Degeneration Increased Stresses on Endplates Subperiosteal Bone and Osteophytic Bar Formation Encroachment On Spinal Cord

Degenerative changes in the cervical spine (spondylosis) occurs >50% of people over 55 (Hughes,1965; Irvine, 1965; Pallis, 1954) and >75% of people over age 65 (Larocca, 1988) Cervical spondylotic myelopathy (CSM) is the most common cause of spinal dysfunction in the elderly (Young, 2000; Baron, 2007) Pathogenesis (Baron, 2007) Cervical Spondylotic Myelopathy B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLAISMRM, Montreal, 2011 Disc Degeneration Increased Stresses on Endplates Subperiosteal Bone and Osteophytic Bar Formation Encroachment On Spinal Cord Neurological Impairment

Cervical Spondylotic Myelopathy B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLAISMRM, Montreal, 2011 Bernhardt, J Bone Joint Surg, 1993

Heterogeneity in CSM progression: Need for a Sensitive Imaging Biomarker B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLAISMRM, Montreal, 2011

Heterogeneity in CSM progression: Need for a Sensitive Imaging Biomarker B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLAISMRM, Montreal, 2011 Bernhardt, J Bone Joint Surg, 1993

Heterogeneity in CSM progression: Need for a Sensitive Imaging Biomarker B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLAISMRM, Montreal, 2011 Neurologically IntactNeurologically Impaired

Heterogeneity in CSM progression: Surgeons are more likely to operate on the basis of imaging even without clinical impairment (Irwin, 2005) Need for a Sensitive Imaging Biomarker B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLAISMRM, Montreal, 2011

Heterogeneity in CSM progression: Surgeons are more likely to operate on the basis of imaging even without clinical impairment (Irwin, 2005) Conventional MRI findings do not consistently correlate with outcomes after treatment (Morio, 1994; 2001; Yukawa, 2007; 2008; Matsuda, 1991; Mastronardi, 2007; Matsumoto, 2000; Fernandez de Rota, 2007; Puzzilli, 1999; Takahashi, 1989; Mehalic, 1990) Need for a Sensitive Imaging Biomarker B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLAISMRM, Montreal, 2011

Heterogeneity in CSM progression: Surgeons are more likely to operate on the basis of imaging even without clinical impairment (Irwin, 2005) Conventional MRI findings do not consistently correlate with outcomes after treatment (Morio, 1994; 2001; Yukawa, 2007; 2008; Matsuda, 1991; Mastronardi, 2007; Matsumoto, 2000; Fernandez de Rota, 2007; Puzzilli, 1999; Takahashi, 1989; Mehalic, 1990) Diffusion tensor imaging (DTI) has shown promise as a biomarker for spinal cord health Need for a Sensitive Imaging Biomarker B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLAISMRM, Montreal, 2011

Heterogeneity in CSM progression: Surgeons are more likely to operate on the basis of imaging even without clinical impairment (Irwin, 2005) Conventional MRI findings do not consistently correlate with outcomes after treatment (Morio, 1994; 2001; Yukawa, 2007; 2008; Matsuda, 1991; Mastronardi, 2007; Matsumoto, 2000; Fernandez de Rota, 2007; Puzzilli, 1999; Takahashi, 1989; Mehalic, 1990) Diffusion tensor imaging (DTI) has shown promise as a biomarker for spinal cord health –Sensitive to tissue integrity and architecture (Schwartz, 2005; Ford, 1994) Need for a Sensitive Imaging Biomarker B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLAISMRM, Montreal, 2011

Heterogeneity in CSM progression: Surgeons are more likely to operate on the basis of imaging even without clinical impairment (Irwin, 2005) Conventional MRI findings do not consistently correlate with outcomes after treatment (Morio, 1994; 2001; Yukawa, 2007; 2008; Matsuda, 1991; Mastronardi, 2007; Matsumoto, 2000; Fernandez de Rota, 2007; Puzzilli, 1999; Takahashi, 1989; Mehalic, 1990) Diffusion tensor imaging (DTI) has shown promise as a biomarker for spinal cord health –Sensitive to tissue integrity and architecture (Schwartz, 2005; Ford, 1994) –More sensitive to specific abnormalities of the cord than conventional MR (Schwartz, 2005; Herrera, 2007; Ellingson, 2010) Need for a Sensitive Imaging Biomarker B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLAISMRM, Montreal, 2011

Heterogeneity in CSM progression: Surgeons are more likely to operate on the basis of imaging even without clinical impairment (Irwin, 2005) Conventional MRI findings do not consistently correlate with outcomes after treatment (Morio, 1994; 2001; Yukawa, 2007; 2008; Matsuda, 1991; Mastronardi, 2007; Matsumoto, 2000; Fernandez de Rota, 2007; Puzzilli, 1999; Takahashi, 1989; Mehalic, 1990) Diffusion tensor imaging (DTI) has shown promise as a biomarker for spinal cord health –Sensitive to tissue integrity and architecture (Schwartz, 2005; Ford, 1994) –More sensitive to specific abnormalities of the cord than conventional MR (Schwartz, 2005; Herrera, 2007; Ellingson, 2010) –Preliminary results suggest DTI might be of diagnostic utility in CSM (Bammer, 2000; Ries, 2000; Demir, 2003; Facon, 2005; Mamata, 2005; Hori, 2006; Ellingson, 2010) Need for a Sensitive Imaging Biomarker B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLAISMRM, Montreal, 2011

Heterogeneity in CSM progression: Surgeons are more likely to operate on the basis of imaging even without clinical impairment (Irwin, 2005) Conventional MRI findings do not consistently correlate with outcomes after treatment (Morio, 1994; 2001; Yukawa, 2007; 2008; Matsuda, 1991; Mastronardi, 2007; Matsumoto, 2000; Fernandez de Rota, 2007; Puzzilli, 1999; Takahashi, 1989; Mehalic, 1990) Diffusion tensor imaging (DTI) has shown promise as a biomarker for spinal cord health –Sensitive to tissue integrity and architecture (Schwartz, 2005; Ford, 1994) –More sensitive to specific abnormalities of the cord than conventional MR (Schwartz, 2005; Herrera, 2007; Ellingson, 2010) –Preliminary results suggest DTI might be of diagnostic utility in CSM (Bammer, 2000; Ries, 2000; Demir, 2003; Facon, 2005; Mamata, 2005; Hori, 2006; Ellingson, 2010) However, spinal cord DTI suffers from many “issues” –Small size of cord –Motion artifact –Magnetic susceptibility distortions from surrounding bone –Chemical shift artifacts from fat Need for a Sensitive Imaging Biomarker B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLAISMRM, Montreal, 2011

Hypotheses B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLAISMRM, Montreal, D spatially-selective RF excitation pulse + reduced FOV EPI readout  reduced echo train length / less distortion = High Quality Spinal Cord DTI (Saritas, 2008; Finsterbusch, 2009)

Hypotheses B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLAISMRM, Montreal, D spatially-selective RF excitation pulse + reduced FOV EPI readout  reduced echo train length / less distortion = High Quality Spinal Cord DTI (Saritas, 2008; Finsterbusch, 2009) 2.Fractional Anisotropy will be reduced at the site of compression in neurologically- impaired patients (Demir, 2003; Mamata, 2005; Facon, 2005)

Hypotheses B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLAISMRM, Montreal, D spatially-selective RF excitation pulse + reduced FOV EPI readout  reduced echo train length / less distortion = High Quality Spinal Cord DTI (Saritas, 2008; Finsterbusch, 2009) 2.Fractional Anisotropy will be reduced at the site of compression in neurologically- impaired patients (Demir, 2003; Mamata, 2005; Facon, 2005) 3.lADC (parallel ADC) will be reduced in neurologically-impaired patients (Ellingson, 2008), whereas stenosis w/o myelpathy will have elevated tADC (transverse ADC) (Song, 2002; Sun, 2003; Klawiter, 2011)

Hypotheses B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLAISMRM, Montreal, D spatially-selective RF excitation pulse + reduced FOV EPI readout  reduced echo train length / less distortion = High Quality Spinal Cord DTI (Saritas, 2008; Finsterbusch, 2009) 2.Fractional Anisotropy will be reduced at the site of compression in neurologically- impaired patients (Demir, 2003; Mamata, 2005; Facon, 2005) 3.lADC (parallel ADC) will be reduced in neurologically-impaired patients (Ellingson, 2008), whereas stenosis w/o myelpathy will have elevated tADC (transverse ADC) (Song, 2002; Sun, 2003; Klawiter, 2011) 4.DTI parameters correlate with neurological impairment (mJOA)

Patients: –9 neurologically intact control subjects (age range 30 – 54, mean = 36) –12 patients with cervical stenosis with (n = 7) and without (n = 5) mild myelopathy All patients gave approved written consent to participate All procedures were approved by the IRB at UCLA Methods B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLAISMRM, Montreal, 2011

Methods B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLAISMRM, Montreal, 2011 MRI: 3T MR System (Siemens Trio TIM) & array coil Sagittal and Axial T1w and T2w DTI was acquired in 6 directions, b = 0 and 500 s/mm 2 NEX = 15 TE = 67ms TR = 3000ms ~ 1mm x 1mm in-plane resolution Slice thickness = 4mm

Methods B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLAISMRM, Montreal, 2011  2D RF pulse used for slab excitation:  Duration 11.7 ms  25 lines / echo spacing 0.45 ms  EPI trajectory with ramp sampling  48 x 128 matrix, 53 x 140 mm 2 SS PE RO FoV rFoV  Reduced Field of Excitation in PE uses same direction as rFOV (receive) Reduced FoV Full FoV

Methods B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLAISMRM, Montreal, 2011 Tractography: Diffusion Toolkit and TrackVis (MGH) –“Tensorline” propagation algorithm (Weinstein, 1999), angle threshold = 90 degrees –ROI placed to encompass whole cord

Results B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLAISMRM, Montreal, 2011 Conventional MR and Morphometry Stenosis Stenosis + MyelopathyNormal Control

Results B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLAISMRM, Montreal, 2011 Conventional MR and Morphometry * Two-way ANOVA (Group, P < ; Level, P < ) * Stenosis vs. Normal, P < 0.05 for levels C2-3 through C6-7 * No detected diff for Myelopathy

Results B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLAISMRM, Montreal, 2011 * SNR FWHM = 20mm

Results B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLAISMRM, Montreal, 2011 Mean Diffusivity

Results B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLAISMRM, Montreal, 2011 Fractional Anisotropy

Results B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLAISMRM, Montreal, 2011 FA Color Map

Results B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLAISMRM, Montreal, 2011

Results B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLAISMRM, Montreal, 2011

Results B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLAISMRM, Montreal, 2011 DTI vs. Compression Site Two-way ANOVA; Groups, P < Level of Compression: Normal vs. Stenosis, P < Normal vs. Stenosis+Myelopathy, P < Stenosis vs. Stenosis+Myelopathy, P < 0.05 Two-way ANOVA Level of Compression: Normal vs. Stenosis, P < Normal vs. Stenosis+Myelopathy, P < Stenosis vs. Stenosis+Myelopathy, N.S.

Results B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLAISMRM, Montreal, 2011 DTI vs. mJOA R 2 = P = R 2 = P =

Results B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLAISMRM, Montreal, 2011 Tractography Control CSM

Results B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLAISMRM, Montreal, 2011 Tractography

Results B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLAISMRM, Montreal, 2011 Tractography P < 0.05 vs. Stenosis P < 0.05 vs. Normal

Results B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLAISMRM, Montreal, 2011 Tractography vs. mJOA R 2 = P =

Conclusions B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLAISMRM, Montreal, D spatially-selective RF excitation pulse + reduced FOV EPI readout  reduced echo train length / less distortion = High Quality Spinal Cord DTI

Conclusions B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLAISMRM, Montreal, D spatially-selective RF excitation pulse + reduced FOV EPI readout  reduced echo train length / less distortion = High Quality Spinal Cord DTI 2.FA is reduced and MD is increased at the site of compression

Conclusions B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLAISMRM, Montreal, D spatially-selective RF excitation pulse + reduced FOV EPI readout  reduced echo train length / less distortion = High Quality Spinal Cord DTI 2.FA is reduced and MD is increased at the site of compression 3.lADC (parallel ADC) is reduced in neurologically-impaired patients whereas tADC (transverse ADC) is elevated in stenosis w/o myelopathy patients

Conclusions B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLAISMRM, Montreal, D spatially-selective RF excitation pulse + reduced FOV EPI readout  reduced echo train length / less distortion = High Quality Spinal Cord DTI 2.FA is reduced and MD is increased at the site of compression 3.lADC (parallel ADC) is reduced in neurologically-impaired patients whereas tADC (transverse ADC) is elevated in stenosis w/o myelopathy patients 4.DTI parameters correlate with neurological impairment (mJOA)

Conclusions B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLAISMRM, Montreal, D spatially-selective RF excitation pulse + reduced FOV EPI readout  reduced echo train length / less distortion = High Quality Spinal Cord DTI 2.FA is reduced and MD is increased at the site of compression 3.lADC (parallel ADC) is reduced in neurologically-impaired patients whereas tADC (transverse ADC) is elevated in stenosis w/o myelopathy patients 4.DTI parameters correlate with neurological impairment (mJOA) DTI shows great potential as a biomarker for degree of neurological impairment and may be useful for choosing surgical candidates

Thank You! B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLAISMRM, Montreal, 2011