HHS Public Access Author manuscript Author Manuscript
Spine (Phila Pa 1976). Author manuscript; available in PMC 2017 May 01. Published in final edited form as: Spine (Phila Pa 1976). 2016 May ; 41(9): 751–756. doi:10.1097/BRS.0000000000001337.
Magnetic Resonance Imaging Biomarker of Axon Loss Reflects Cervical Spondylotic Myelopathy Severity Rory KJ Murphy1,*, Peng Sun2,*, Junqian Xu3, Yong Wang2, Samir Sullivan2, Paul Gamble1, Joanne Wagner4, Neill N Wright1, Ian G Dorward1, Daniel Riew1,5, Paul Santiago1,5, Michael P Kelly5, Kathryn Trinkaus6, Wilson Z. Ray1,†, and Sheng-Kwei Song2
Author Manuscript
1Department
of Neurosurgery, Washington University, St. Louis, MO 63110, USA
2Department
of Radiology, Washington University, St. Louis, MO 63110, USA
3Translational
and Molecular Imaging Institute, Department of Radiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
4Department
of Physical Therapy and Athletic Training, Saint Louis University, St. Louis, MO
63104, USA 5Department 6Division
of Orthopedic Surgery, Washington University, St. Louis, MO 63110, USA
of Biostatistics, Washington University, St. Louis, MO 63110, USA
Abstract Author Manuscript
Study Design—Prospective Cohort Study Objective—In this study, we employed diffusion basis spectrum imaging (DBSI) to quantitatively assess axon/myelin injury, cellular inflammation, and axonal loss of cervical spondylotic myelopathy (CSM) spinal cords. Summary of Background Data—A major shortcoming in the management of CSM is the lack of an effective diagnostic approach to stratify treatments and to predict outcomes. No current clinical diagnostic imaging approach is capable of accurately reflecting underlying spinal cord pathologies.
Author Manuscript
Methods—Seven patients with mild (mJOA ≥ 15), five patients with moderate (14≥ mJOA ≥ 11), and two patients with severe (mJOA 0.3 μm2/ms represents non-restricted isotropic diffusion corresponding to vasogenic edema and CSF water[22-24].Since all pathology markers are derived using a single diffusion weighted MRI data set in DBSI, naturally co-registered, the inherently quantitative relationship among all DBSI metrics enables the quantification of each pathological component. In order to reflect both morphological and microscopictissue changes, two new DBSI metrics are derived: DBSI-inflammation volume (sum of restricted and hindered isotropic diffusion fractions multiplied by white matter tract volume) and DBSI-axon volume (DBSI derived fiber fraction multiplied by white matter tract volume).
Spine (Phila Pa 1976). Author manuscript; available in PMC 2017 May 01.
Murphy et al.
Page 5
Author Manuscript
Statistics— DBSI axial and radial diffusivity, fractional anisotropy, DBSI-inflammation volume, DBSI-axon volume, DTI axial and radial diffusivity and DTI fractional anisotropy were compared using nonparametric Kruskal-Wallis test. Multinomial logistic regression models were used to test for the presence and estimate the strength of association between DBSI-axon or inflammationvolume and severity of impairment.
Results
Author Manuscript
Spinal cord white matter tract AD and RD were derived using DTI and DBSI analysis on control subjects and CSM patients. As depicted in Figure 2 we observed DTI-AD decreases as severity of impairment increases. Median AD does not differ in control subjects (1.54 μm2/ms) and those with mild CSM (1.51μm2/ms), but AD is lower in moderate CSM subjects (median 1.32; p = 0.014). Median DTI-RD increases as severity of impairment increases (0.24,0.31, and 0.40 μm2/ms in control, mild and moderate CSM subjects respectively; p = 0.0041). Median DTI-FA decreases as severity of impairment increases (0.81, 0.79, and 0.63 in control, mild, and moderate CSM subjects respectively, p = 0.0022; Fig. 2). In contrast, median DBSI-AD decreases slightly as severity of impairment increases (1.81, 1.77, and 1.61 in control, mild and moderate CSM subjects; p = 0.048). Median DBSI-RD increases as severity of impairment increases (0.30, 0.32, and 0.36 in control, mild, and moderate CSM subjects; p = 0.018). Median DBSI-FA is similar in control (0.78) and mild CSM (0.78) subjects, but it is lower in moderate CSM subjects (0.74; p = 0.033; Fig. 2).
Author Manuscript
We observed decreases in DBSI-axon volume as severity of impairment increased (Figs. 3 and 4), with the highest median volume in controls (2690 μL), followed by mild CSM subjects (2111 μL),with the lowest volume in moderate CSM subjects (1533 μL; p = 0.0016). In general, there was anincrease of 60% in the odds of impairment relative to controls for each decrease of 100 μL in DBSI-axon volume. While DBSI-inflammation volumewas not clearly associated with functional impairment, patients with moderate disability do appear to have higher DBSI-inflammation volumes than the controls (Fig. 3). Median DBSI-inflammation volumewas similar in control (266 μL) and mild CSM (171 μL) subjects, with significant overlap of the middle 50% of observations (quartile 3 – quartile 1). This was in contrast tomoderate CSM subjects that had higher DBSI-inflammation volumes (382 μL; p = 0.033). DBSI-axon volume shows a strong correlation with clinical measures (r = 0.79 and 0.87 for mJOA and MDI; Fig. 4)
Author Manuscript
Discussion MDI and mJOA are standard instruments utilized by spine surgeons worldwide for assessing the neurological deficit in patients with CSM and for classifying the injury[25, 26]. Both are validated measures for clinicians to manage patients with CSM related spinal cord injury, but neither is prognostic, or provides information on the nature of the spinal cord injury[27]. There is also a concern that both MDI and mJOA may not be sensitive enough to detect subtle neurological recovery following surgical treatment [27, 28]. Neurological impairment is thought to arise from a combination of inflammation/edema, demyelination, and axonal Spine (Phila Pa 1976). Author manuscript; available in PMC 2017 May 01.
Murphy et al.
Page 6
Author Manuscript Author Manuscript
injury/loss. Standard and advanced MRI techniques cannot accurately ascertain the extent of axonal/myelin injury, cord edema, or the severity of inflammation in a patient with CSM. Prior to surgical treatment of CSM it is difficult to predict how much a patient might improve following surgery. Thus, non-invasively distinguishing and quantifying the extent of axonal/myelin injury vs. edema/inflammation may guide both patient selection and counseling prior to surgical intervention. In this manuscript we have demonstrated that DBSI-derived axonal volume correlated with mJOA and MDI. Since this is a measure of irreversible axonal injury/loss, it is our contention that early assessment of the severity of irreversible damage to the spinal cord could serve as a prognostic biomarker for CSM. In the planned subsequent studies we expect to demonstrate DBSI-derived axonal volume can provide pre-operative prognostication of functional outcome following surgical decompression based on the extent of pre-surgical axonal loss. Although we could not verify our findings histologically on the live patients, we have recently published DBSI-histology validation on autopsy spinal cord tissues from multiple sclerosis patients.[29]
Author Manuscript
Recently studies have described promising results utilizing DTI to investigate CSM [30-33]. Our current DTI findingsare consistent with the existing literature suggesting FA may be a reliable marker, reflecting clinical (mJOA) and patient perceived disability (MDI) in CSM patients. Both in vivo and in vitro studies have demonstrated that DTI metrics lose sensitivity and specificity with increasing anatomic and pathologic complexity[15, 16].In moderate CSM patients with ongoing spinal cord compression (Fig. 2), DTI derived AD and FA decreased and RD increased as compared to controls at the time of diagnosis. This may suggest the presence of both axonal injury and demyelination, as might be expected with ongoing spinal cord compression. However subsequent DBSI analysis reveals significantly increased axonal loss andinflammationwith more modest reductions in AD and FA, and increases in RD (Fig.2). We contend that DTI derived AD/RD is significantly confounded by the presence of inflammation and axonal loss. DBSI may more accurately portray underlying neuropathology. We believe that knowledge of spinal cord axonal loss and edema/inflammation as well as accurate quantification of AD, RD, and FA will offer a paradigm shift in our understanding of the differences in presentation and response to treatment amongst cohorts of CSM patients.The usefulness of DBSI for CSM rests on anchoring the DBSI metrics of inflammation, demyelination, and axonal injury/loss to physical examination findings and long-term neurologic outcomes. Our results utilizing DBSI analysis are the first to show a strong correlation of clinical measures (mJOA and MDI) to a non-invasive imaging marker of axonal loss (Fig. 4).
Author Manuscript
DBSI was developed to overcome the challenges of chronic tissue loss, edema, and cellular infiltration. DBSI quantifies diffusion parameters of each fiber tract in the spinal cord to allow accurate determination of spinal cord integrity, the percentage of preserved axons and thus the potential for recovery using universally utilized clinical diffusion acquisition schemes. While there are no reliable means to determine which patients with CSM will improve, remain stable, and who will deteriorate[34], DBSI may represent an early noninvasive biomarker of axonal injury/loss and inflammation that can eventually be used to guide treatment, predict outcomes, and serve as a biomarker for clinical trials.
Spine (Phila Pa 1976). Author manuscript; available in PMC 2017 May 01.
Murphy et al.
Page 7
Author Manuscript
Acknowledgments National Institute of Health R01NS047592, K23NS084932, and Missouri SCIRP, National Multiple Sclerosis Society (NMSS) RG 4549A4/1 and RG 5265A1 funds were received in support of this work. Relevant financial activities outside the submitted work: board membership, consultancy, grants, expert testimony, royalties, employment, stocks, payment for lectures, payment for development of educational presentations, travel/ accommodations/meeting expenses.
References
Author Manuscript Author Manuscript Author Manuscript
1. Nurick S. The natural history and the results of surgical treatment of the spinal cord disorder associated with cervical spondylosis. Brain. 1972; 95:101–8. [PubMed: 5023079] 2. Fehlings MG, Smith JS, Kopjar B, et al. Perioperative and delayed complications associated with the surgical treatment of cervical spondylotic myelopathy based on 302 patients from the AOSpine North America Cervical Spondylotic Myelopathy Study. J Neurosurg Spine. 2012; 16:425–32. [PubMed: 22324802] 3. Karadimas SK, Gatzounis G, Fehlings MG. Pathobiology of cervical spondylotic myelopathy. Eur Spine J. 2014 4. Kadanka Z, Bednarik J, Vohanka S, et al. Conservative treatment versus surgery in spondylotic cervical myelopathy: a prospective randomised study. Eur Spine J. 2000; 9:538–44. [PubMed: 11189924] 5. Nagata K, Yoshimura N, Muraki S, et al. Prevalence of cervical cord compression and its association with physical performance in a population-based cohort in Japan: the Wakayama Spine Study. Spine (Phila Pa 1976). 2012; 37:1892–8. [PubMed: 22565382] 6. Boogaarts HD, Bartels RH. Prevalence of cervical spondylotic myelopathy. Eur Spine J. 2013 7. Beattie MS, Manley GT. Tight squeeze, slow burn: inflammation and the aetiology of cervical myelopathy. Brain : a journal of neurology. 2011; 134:1259–61. [PubMed: 21596766] 8. Yuh EL, Cooper SR, Mukherjee P, et al. Diffusion Tensor Imaging for Outcome Prediction in Mild Traumatic Brain Injury: A TRACK-TBI Study. Journal of neurotrauma. 2014; 31:1457–77. [PubMed: 24742275] 9. Mac Donald CL, Johnson AM, Cooper D, et al. Detection of blast-related traumatic brain injury in U.S. military personnel. N Engl J Med. 2011; 364:2091–100. [PubMed: 21631321] 10. Song SK, Sun SW, Ju WK, et al. Diffusion tensor imaging detects and differentiates axon and myelin degeneration in mouse optic nerve after retinal ischemia. Neuroimage. 2003; 20:1714–22. [PubMed: 14642481] 11. Song SK, Sun SW, Ramsbottom MJ, et al. Dysmyelination revealed through MRI as increased radial (but unchanged axial) diffusion of water. Neuroimage. 2002; 17:1429–36. [PubMed: 12414282] 12. Song SK, Yoshino J, Le TQ, et al. Demyelination increases radial diffusivity in corpus callosum of mouse brain. Neuroimage. 2005; 26:132–40. [PubMed: 15862213] 13. Chiang CW, Wang Y, Sun P, et al. Quantifying white matter tract diffusion parameters in the presence of increased extra-fiber cellularity and vasogenic edema. Neuroimage. 2014; 101:310–9. [PubMed: 25017446] 14. Wang Y, Wang Q, Haldar JP, et al. Quantification of increased cellularity during inflammatory demyelination. Brain : a journal of neurology. 2011; 134:3590–601. [PubMed: 22171354] 15. Benzel EC, Lancon J, Kesterson L, et al. Cervical laminectomy and dentate ligament section for cervical spondylotic myelopathy. J Spinal Disord. 1991; 4:286–95. [PubMed: 1802159] 16. Ellingson BM, Salamon N, Grinstead JW, et al. Diffusion tensor imaging predicts functional impairment in mild-to-moderate cervical spondylotic myelopathy. The spine journal : official journal of the North American Spine Society. 2014 17. Casey AT, Bland JM, Crockard HA. Development of a functional scoring system for rheumatoid arthritis patients with cervical myelopathy. Annals of the rheumatic diseases. 1996; 55:901–6. [PubMed: 9014584]
Spine (Phila Pa 1976). Author manuscript; available in PMC 2017 May 01.
Murphy et al.
Page 8
Author Manuscript Author Manuscript
18. Xu J, Shimony JS, Klawiter EC, et al. Improved in vivo diffusion tensor imaging of human cervical spinal cord. Neuroimage. 2013; 67:64–76. [PubMed: 23178538] 19. Naismith RT, Xu J, Klawiter EC, et al. Spinal cord tract diffusion tensor imaging reveals disability substrate in demyelinating disease. Neurology. 2013; 80:2201–9. [PubMed: 23667060] 20. Klineberg E. Cervical spondylotic myelopathy: a review of the evidence. The Orthopedic clinics of North America. 2010; 41:193–202. [PubMed: 20399358] 21. Fehlings MG, Arvin B. Surgical management of cervical degenerative disease: the evidence related to indications, impact, and outcome. J Neurosurg Spine. 2009; 11:97–100. [PubMed: 19769487] 22. Furlan JC, Fehlings MG, Tator CH, et al. Motor and sensory assessment of patients in clinical trials for pharmacological therapy of acute spinal cord injury: psychometric properties of the ASIA Standards. J Neurotrauma. 2008; 25:1273–301. [PubMed: 19061373] 23. Krishna V, Andrews HK, Varma A, et al. Spinal cord injury: How can we improve the classification and quantification of its severity and prognosis? Journal of neurotrauma. 2013 24. Nakamura M, Fujiyoshi K, Tsuji O, et al. Clinical significance of diffusion tensor tractography as a predictor of functional recovery after laminoplasty in patients with cervical compressive myelopathy. J Neurosurg Spine. 2012; 17:147–52. [PubMed: 22681619] 25. Uda T, Takami T, Tsuyuguchi N, et al. Assessment of cervical spondylotic myelopathy using diffusion tensor magnetic resonance imaging parameter at 3.0 tesla. Spine (Phila Pa 1976). 2013; 38:407–14. [PubMed: 22914703] 26. Xiangshui M, Xiangjun C, Xiaoming Z, et al. 3 T magnetic resonance diffusion tensor imaging and fibre tracking in cervical myelopathy. Clin Radiol. 2010; 65:465–73. [PubMed: 20451014] 27. Jones JG, Cen SY, Lebel RM, et al. Diffusion tensor imaging correlates with the clinical assessment of disease severity in cervical spondylotic myelopathy and predicts outcome following surgery. AJNR Am J Neuroradiol. 2013; 34:471–8. [PubMed: 22821918] 28. Fehlings MG, Wilson JR, Kopjar B, et al. Efficacy and safety of surgical decompression in patients with cervical spondylotic myelopathy: results of the AOSpine North America prospective multicenter study. The Journal of bone and joint surgery American volume. 2013; 95:1651–8. [PubMed: 24048552]
Author Manuscript Author Manuscript Spine (Phila Pa 1976). Author manuscript; available in PMC 2017 May 01.
Murphy et al.
Page 9
Author Manuscript Figure 1.
Author Manuscript
Standard sagittal T2 weighted image from a normal control subject (A). DTI derived axial FA maps and DBSI fiber fraction maps were obtained at the location between C1 – 2 (B & E), C3 – 4 (C & F), and C5 – 6 (D & G) from the control. Standard sagittal T2 weighted imaging demonstrating focal spinal cord compression with T2 signal change in a CSM patient with focal compression at C5/6 (H). DTI derived FA and DBSI fiber fraction maps were at the location between C1 – 2 ( I & L), C3 – 4 ( J & M ), and C5 – 6 (K & N) from the CSM patient.
Author Manuscript Author Manuscript Spine (Phila Pa 1976). Author manuscript; available in PMC 2017 May 01.
Murphy et al.
Page 10
Author Manuscript Author Manuscript Author Manuscript Figure 2.
Author Manuscript
DTI derived AD (A) decreased between mild and moderate CSM but not between control and mild CSM. DTI derived RD (C) increased with worsening clinical symptoms resulting from cord compression. As a summary parameter, DTI derived FA decreased with increasing neurological impairments (E). In contrast, DBSI derived AD (B) marginally decreased as clinical symptoms worsened. DBSI derived RD (D) of the same patient cohort exhibited a more apparently increasing trend with increasing cord compression. DBSI derived FA (F) did not differ between the control and mild CSM groups while significantly decreased in moderate CSM, suggesting that DTI may overestimate the degree of axonal/myelin injury. C = control; Mi = mild CSM; and Mo = moderate + severe CSM.
Spine (Phila Pa 1976). Author manuscript; available in PMC 2017 May 01.
Murphy et al.
Page 11
Author Manuscript Author Manuscript
Figure 3.
DBSI quantification of axon volume (A) decreased while the inflammation volume (B) increased with worsening clinical symptoms. Results suggest that progression of clinical symptoms is in part due to both cellular inflammation and axonal loss. Moderate CSM patients demonstrate a higher degree of axonal loss, and inflammation profiles as mild CSM patients. Mild CSM patients have comparable inflammation and axonal volume profiles as controls. C = control; Mi = mild CSM; and Mo = moderate + severe CSM.
Author Manuscript Author Manuscript Spine (Phila Pa 1976). Author manuscript; available in PMC 2017 May 01.
Murphy et al.
Page 12
Author Manuscript Author Manuscript
Figure 4. DBSI-axon volume was correlated with both mJOA (A) and MDI (B)
There was an increase of 60% in the odds of impairment relative to controls for each decrease of 100 μL in DBSI-axon volume.
Author Manuscript Author Manuscript Spine (Phila Pa 1976). Author manuscript; available in PMC 2017 May 01.
Spine (Phila Pa 1976). Author manuscript; available in PMC 2017 May 01. Published in final edited form as: Spine (Phila Pa 1976). 2016 May ; 41(9): 751–756. doi:10.1097/BRS.0000000000001337.
Magnetic Resonance Imaging Biomarker of Axon Loss Reflects Cervical Spondylotic Myelopathy Severity Rory KJ Murphy1,*, Peng Sun2,*, Junqian Xu3, Yong Wang2, Samir Sullivan2, Paul Gamble1, Joanne Wagner4, Neill N Wright1, Ian G Dorward1, Daniel Riew1,5, Paul Santiago1,5, Michael P Kelly5, Kathryn Trinkaus6, Wilson Z. Ray1,†, and Sheng-Kwei Song2
Author Manuscript
1Department
of Neurosurgery, Washington University, St. Louis, MO 63110, USA
2Department
of Radiology, Washington University, St. Louis, MO 63110, USA
3Translational
and Molecular Imaging Institute, Department of Radiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
4Department
of Physical Therapy and Athletic Training, Saint Louis University, St. Louis, MO
63104, USA 5Department 6Division
of Orthopedic Surgery, Washington University, St. Louis, MO 63110, USA
of Biostatistics, Washington University, St. Louis, MO 63110, USA
Abstract Author Manuscript
Study Design—Prospective Cohort Study Objective—In this study, we employed diffusion basis spectrum imaging (DBSI) to quantitatively assess axon/myelin injury, cellular inflammation, and axonal loss of cervical spondylotic myelopathy (CSM) spinal cords. Summary of Background Data—A major shortcoming in the management of CSM is the lack of an effective diagnostic approach to stratify treatments and to predict outcomes. No current clinical diagnostic imaging approach is capable of accurately reflecting underlying spinal cord pathologies.
Author Manuscript
Methods—Seven patients with mild (mJOA ≥ 15), five patients with moderate (14≥ mJOA ≥ 11), and two patients with severe (mJOA 0.3 μm2/ms represents non-restricted isotropic diffusion corresponding to vasogenic edema and CSF water[22-24].Since all pathology markers are derived using a single diffusion weighted MRI data set in DBSI, naturally co-registered, the inherently quantitative relationship among all DBSI metrics enables the quantification of each pathological component. In order to reflect both morphological and microscopictissue changes, two new DBSI metrics are derived: DBSI-inflammation volume (sum of restricted and hindered isotropic diffusion fractions multiplied by white matter tract volume) and DBSI-axon volume (DBSI derived fiber fraction multiplied by white matter tract volume).
Spine (Phila Pa 1976). Author manuscript; available in PMC 2017 May 01.
Murphy et al.
Page 5
Author Manuscript
Statistics— DBSI axial and radial diffusivity, fractional anisotropy, DBSI-inflammation volume, DBSI-axon volume, DTI axial and radial diffusivity and DTI fractional anisotropy were compared using nonparametric Kruskal-Wallis test. Multinomial logistic regression models were used to test for the presence and estimate the strength of association between DBSI-axon or inflammationvolume and severity of impairment.
Results
Author Manuscript
Spinal cord white matter tract AD and RD were derived using DTI and DBSI analysis on control subjects and CSM patients. As depicted in Figure 2 we observed DTI-AD decreases as severity of impairment increases. Median AD does not differ in control subjects (1.54 μm2/ms) and those with mild CSM (1.51μm2/ms), but AD is lower in moderate CSM subjects (median 1.32; p = 0.014). Median DTI-RD increases as severity of impairment increases (0.24,0.31, and 0.40 μm2/ms in control, mild and moderate CSM subjects respectively; p = 0.0041). Median DTI-FA decreases as severity of impairment increases (0.81, 0.79, and 0.63 in control, mild, and moderate CSM subjects respectively, p = 0.0022; Fig. 2). In contrast, median DBSI-AD decreases slightly as severity of impairment increases (1.81, 1.77, and 1.61 in control, mild and moderate CSM subjects; p = 0.048). Median DBSI-RD increases as severity of impairment increases (0.30, 0.32, and 0.36 in control, mild, and moderate CSM subjects; p = 0.018). Median DBSI-FA is similar in control (0.78) and mild CSM (0.78) subjects, but it is lower in moderate CSM subjects (0.74; p = 0.033; Fig. 2).
Author Manuscript
We observed decreases in DBSI-axon volume as severity of impairment increased (Figs. 3 and 4), with the highest median volume in controls (2690 μL), followed by mild CSM subjects (2111 μL),with the lowest volume in moderate CSM subjects (1533 μL; p = 0.0016). In general, there was anincrease of 60% in the odds of impairment relative to controls for each decrease of 100 μL in DBSI-axon volume. While DBSI-inflammation volumewas not clearly associated with functional impairment, patients with moderate disability do appear to have higher DBSI-inflammation volumes than the controls (Fig. 3). Median DBSI-inflammation volumewas similar in control (266 μL) and mild CSM (171 μL) subjects, with significant overlap of the middle 50% of observations (quartile 3 – quartile 1). This was in contrast tomoderate CSM subjects that had higher DBSI-inflammation volumes (382 μL; p = 0.033). DBSI-axon volume shows a strong correlation with clinical measures (r = 0.79 and 0.87 for mJOA and MDI; Fig. 4)
Author Manuscript
Discussion MDI and mJOA are standard instruments utilized by spine surgeons worldwide for assessing the neurological deficit in patients with CSM and for classifying the injury[25, 26]. Both are validated measures for clinicians to manage patients with CSM related spinal cord injury, but neither is prognostic, or provides information on the nature of the spinal cord injury[27]. There is also a concern that both MDI and mJOA may not be sensitive enough to detect subtle neurological recovery following surgical treatment [27, 28]. Neurological impairment is thought to arise from a combination of inflammation/edema, demyelination, and axonal Spine (Phila Pa 1976). Author manuscript; available in PMC 2017 May 01.
Murphy et al.
Page 6
Author Manuscript Author Manuscript
injury/loss. Standard and advanced MRI techniques cannot accurately ascertain the extent of axonal/myelin injury, cord edema, or the severity of inflammation in a patient with CSM. Prior to surgical treatment of CSM it is difficult to predict how much a patient might improve following surgery. Thus, non-invasively distinguishing and quantifying the extent of axonal/myelin injury vs. edema/inflammation may guide both patient selection and counseling prior to surgical intervention. In this manuscript we have demonstrated that DBSI-derived axonal volume correlated with mJOA and MDI. Since this is a measure of irreversible axonal injury/loss, it is our contention that early assessment of the severity of irreversible damage to the spinal cord could serve as a prognostic biomarker for CSM. In the planned subsequent studies we expect to demonstrate DBSI-derived axonal volume can provide pre-operative prognostication of functional outcome following surgical decompression based on the extent of pre-surgical axonal loss. Although we could not verify our findings histologically on the live patients, we have recently published DBSI-histology validation on autopsy spinal cord tissues from multiple sclerosis patients.[29]
Author Manuscript
Recently studies have described promising results utilizing DTI to investigate CSM [30-33]. Our current DTI findingsare consistent with the existing literature suggesting FA may be a reliable marker, reflecting clinical (mJOA) and patient perceived disability (MDI) in CSM patients. Both in vivo and in vitro studies have demonstrated that DTI metrics lose sensitivity and specificity with increasing anatomic and pathologic complexity[15, 16].In moderate CSM patients with ongoing spinal cord compression (Fig. 2), DTI derived AD and FA decreased and RD increased as compared to controls at the time of diagnosis. This may suggest the presence of both axonal injury and demyelination, as might be expected with ongoing spinal cord compression. However subsequent DBSI analysis reveals significantly increased axonal loss andinflammationwith more modest reductions in AD and FA, and increases in RD (Fig.2). We contend that DTI derived AD/RD is significantly confounded by the presence of inflammation and axonal loss. DBSI may more accurately portray underlying neuropathology. We believe that knowledge of spinal cord axonal loss and edema/inflammation as well as accurate quantification of AD, RD, and FA will offer a paradigm shift in our understanding of the differences in presentation and response to treatment amongst cohorts of CSM patients.The usefulness of DBSI for CSM rests on anchoring the DBSI metrics of inflammation, demyelination, and axonal injury/loss to physical examination findings and long-term neurologic outcomes. Our results utilizing DBSI analysis are the first to show a strong correlation of clinical measures (mJOA and MDI) to a non-invasive imaging marker of axonal loss (Fig. 4).
Author Manuscript
DBSI was developed to overcome the challenges of chronic tissue loss, edema, and cellular infiltration. DBSI quantifies diffusion parameters of each fiber tract in the spinal cord to allow accurate determination of spinal cord integrity, the percentage of preserved axons and thus the potential for recovery using universally utilized clinical diffusion acquisition schemes. While there are no reliable means to determine which patients with CSM will improve, remain stable, and who will deteriorate[34], DBSI may represent an early noninvasive biomarker of axonal injury/loss and inflammation that can eventually be used to guide treatment, predict outcomes, and serve as a biomarker for clinical trials.
Spine (Phila Pa 1976). Author manuscript; available in PMC 2017 May 01.
Murphy et al.
Page 7
Author Manuscript
Acknowledgments National Institute of Health R01NS047592, K23NS084932, and Missouri SCIRP, National Multiple Sclerosis Society (NMSS) RG 4549A4/1 and RG 5265A1 funds were received in support of this work. Relevant financial activities outside the submitted work: board membership, consultancy, grants, expert testimony, royalties, employment, stocks, payment for lectures, payment for development of educational presentations, travel/ accommodations/meeting expenses.
References
Author Manuscript Author Manuscript Author Manuscript
1. Nurick S. The natural history and the results of surgical treatment of the spinal cord disorder associated with cervical spondylosis. Brain. 1972; 95:101–8. [PubMed: 5023079] 2. Fehlings MG, Smith JS, Kopjar B, et al. Perioperative and delayed complications associated with the surgical treatment of cervical spondylotic myelopathy based on 302 patients from the AOSpine North America Cervical Spondylotic Myelopathy Study. J Neurosurg Spine. 2012; 16:425–32. [PubMed: 22324802] 3. Karadimas SK, Gatzounis G, Fehlings MG. Pathobiology of cervical spondylotic myelopathy. Eur Spine J. 2014 4. Kadanka Z, Bednarik J, Vohanka S, et al. Conservative treatment versus surgery in spondylotic cervical myelopathy: a prospective randomised study. Eur Spine J. 2000; 9:538–44. [PubMed: 11189924] 5. Nagata K, Yoshimura N, Muraki S, et al. Prevalence of cervical cord compression and its association with physical performance in a population-based cohort in Japan: the Wakayama Spine Study. Spine (Phila Pa 1976). 2012; 37:1892–8. [PubMed: 22565382] 6. Boogaarts HD, Bartels RH. Prevalence of cervical spondylotic myelopathy. Eur Spine J. 2013 7. Beattie MS, Manley GT. Tight squeeze, slow burn: inflammation and the aetiology of cervical myelopathy. Brain : a journal of neurology. 2011; 134:1259–61. [PubMed: 21596766] 8. Yuh EL, Cooper SR, Mukherjee P, et al. Diffusion Tensor Imaging for Outcome Prediction in Mild Traumatic Brain Injury: A TRACK-TBI Study. Journal of neurotrauma. 2014; 31:1457–77. [PubMed: 24742275] 9. Mac Donald CL, Johnson AM, Cooper D, et al. Detection of blast-related traumatic brain injury in U.S. military personnel. N Engl J Med. 2011; 364:2091–100. [PubMed: 21631321] 10. Song SK, Sun SW, Ju WK, et al. Diffusion tensor imaging detects and differentiates axon and myelin degeneration in mouse optic nerve after retinal ischemia. Neuroimage. 2003; 20:1714–22. [PubMed: 14642481] 11. Song SK, Sun SW, Ramsbottom MJ, et al. Dysmyelination revealed through MRI as increased radial (but unchanged axial) diffusion of water. Neuroimage. 2002; 17:1429–36. [PubMed: 12414282] 12. Song SK, Yoshino J, Le TQ, et al. Demyelination increases radial diffusivity in corpus callosum of mouse brain. Neuroimage. 2005; 26:132–40. [PubMed: 15862213] 13. Chiang CW, Wang Y, Sun P, et al. Quantifying white matter tract diffusion parameters in the presence of increased extra-fiber cellularity and vasogenic edema. Neuroimage. 2014; 101:310–9. [PubMed: 25017446] 14. Wang Y, Wang Q, Haldar JP, et al. Quantification of increased cellularity during inflammatory demyelination. Brain : a journal of neurology. 2011; 134:3590–601. [PubMed: 22171354] 15. Benzel EC, Lancon J, Kesterson L, et al. Cervical laminectomy and dentate ligament section for cervical spondylotic myelopathy. J Spinal Disord. 1991; 4:286–95. [PubMed: 1802159] 16. Ellingson BM, Salamon N, Grinstead JW, et al. Diffusion tensor imaging predicts functional impairment in mild-to-moderate cervical spondylotic myelopathy. The spine journal : official journal of the North American Spine Society. 2014 17. Casey AT, Bland JM, Crockard HA. Development of a functional scoring system for rheumatoid arthritis patients with cervical myelopathy. Annals of the rheumatic diseases. 1996; 55:901–6. [PubMed: 9014584]
Spine (Phila Pa 1976). Author manuscript; available in PMC 2017 May 01.
Murphy et al.
Page 8
Author Manuscript Author Manuscript
18. Xu J, Shimony JS, Klawiter EC, et al. Improved in vivo diffusion tensor imaging of human cervical spinal cord. Neuroimage. 2013; 67:64–76. [PubMed: 23178538] 19. Naismith RT, Xu J, Klawiter EC, et al. Spinal cord tract diffusion tensor imaging reveals disability substrate in demyelinating disease. Neurology. 2013; 80:2201–9. [PubMed: 23667060] 20. Klineberg E. Cervical spondylotic myelopathy: a review of the evidence. The Orthopedic clinics of North America. 2010; 41:193–202. [PubMed: 20399358] 21. Fehlings MG, Arvin B. Surgical management of cervical degenerative disease: the evidence related to indications, impact, and outcome. J Neurosurg Spine. 2009; 11:97–100. [PubMed: 19769487] 22. Furlan JC, Fehlings MG, Tator CH, et al. Motor and sensory assessment of patients in clinical trials for pharmacological therapy of acute spinal cord injury: psychometric properties of the ASIA Standards. J Neurotrauma. 2008; 25:1273–301. [PubMed: 19061373] 23. Krishna V, Andrews HK, Varma A, et al. Spinal cord injury: How can we improve the classification and quantification of its severity and prognosis? Journal of neurotrauma. 2013 24. Nakamura M, Fujiyoshi K, Tsuji O, et al. Clinical significance of diffusion tensor tractography as a predictor of functional recovery after laminoplasty in patients with cervical compressive myelopathy. J Neurosurg Spine. 2012; 17:147–52. [PubMed: 22681619] 25. Uda T, Takami T, Tsuyuguchi N, et al. Assessment of cervical spondylotic myelopathy using diffusion tensor magnetic resonance imaging parameter at 3.0 tesla. Spine (Phila Pa 1976). 2013; 38:407–14. [PubMed: 22914703] 26. Xiangshui M, Xiangjun C, Xiaoming Z, et al. 3 T magnetic resonance diffusion tensor imaging and fibre tracking in cervical myelopathy. Clin Radiol. 2010; 65:465–73. [PubMed: 20451014] 27. Jones JG, Cen SY, Lebel RM, et al. Diffusion tensor imaging correlates with the clinical assessment of disease severity in cervical spondylotic myelopathy and predicts outcome following surgery. AJNR Am J Neuroradiol. 2013; 34:471–8. [PubMed: 22821918] 28. Fehlings MG, Wilson JR, Kopjar B, et al. Efficacy and safety of surgical decompression in patients with cervical spondylotic myelopathy: results of the AOSpine North America prospective multicenter study. The Journal of bone and joint surgery American volume. 2013; 95:1651–8. [PubMed: 24048552]
Author Manuscript Author Manuscript Spine (Phila Pa 1976). Author manuscript; available in PMC 2017 May 01.
Murphy et al.
Page 9
Author Manuscript Figure 1.
Author Manuscript
Standard sagittal T2 weighted image from a normal control subject (A). DTI derived axial FA maps and DBSI fiber fraction maps were obtained at the location between C1 – 2 (B & E), C3 – 4 (C & F), and C5 – 6 (D & G) from the control. Standard sagittal T2 weighted imaging demonstrating focal spinal cord compression with T2 signal change in a CSM patient with focal compression at C5/6 (H). DTI derived FA and DBSI fiber fraction maps were at the location between C1 – 2 ( I & L), C3 – 4 ( J & M ), and C5 – 6 (K & N) from the CSM patient.
Author Manuscript Author Manuscript Spine (Phila Pa 1976). Author manuscript; available in PMC 2017 May 01.
Murphy et al.
Page 10
Author Manuscript Author Manuscript Author Manuscript Figure 2.
Author Manuscript
DTI derived AD (A) decreased between mild and moderate CSM but not between control and mild CSM. DTI derived RD (C) increased with worsening clinical symptoms resulting from cord compression. As a summary parameter, DTI derived FA decreased with increasing neurological impairments (E). In contrast, DBSI derived AD (B) marginally decreased as clinical symptoms worsened. DBSI derived RD (D) of the same patient cohort exhibited a more apparently increasing trend with increasing cord compression. DBSI derived FA (F) did not differ between the control and mild CSM groups while significantly decreased in moderate CSM, suggesting that DTI may overestimate the degree of axonal/myelin injury. C = control; Mi = mild CSM; and Mo = moderate + severe CSM.
Spine (Phila Pa 1976). Author manuscript; available in PMC 2017 May 01.
Murphy et al.
Page 11
Author Manuscript Author Manuscript
Figure 3.
DBSI quantification of axon volume (A) decreased while the inflammation volume (B) increased with worsening clinical symptoms. Results suggest that progression of clinical symptoms is in part due to both cellular inflammation and axonal loss. Moderate CSM patients demonstrate a higher degree of axonal loss, and inflammation profiles as mild CSM patients. Mild CSM patients have comparable inflammation and axonal volume profiles as controls. C = control; Mi = mild CSM; and Mo = moderate + severe CSM.
Author Manuscript Author Manuscript Spine (Phila Pa 1976). Author manuscript; available in PMC 2017 May 01.
Murphy et al.
Page 12
Author Manuscript Author Manuscript
Figure 4. DBSI-axon volume was correlated with both mJOA (A) and MDI (B)
There was an increase of 60% in the odds of impairment relative to controls for each decrease of 100 μL in DBSI-axon volume.
Author Manuscript Author Manuscript Spine (Phila Pa 1976). Author manuscript; available in PMC 2017 May 01.
