Demyelination and degeneration in the injured human spinal cord detected with diffusion and magnetization transfer MRI
Research Highlights
► We combined DTI, magnetization transfer and atrophy measure in spinal cord injury. ► Differences in normal-appearing white matter for DTI and MTR. ► Results suggest degeneration and demyelination in SCI patients. ► DTI, MTR and atrophy can predict impairment in spinal cord injury (SCI).
Introduction
Sensorimotor impairments after spinal cord injuries (SCI) largely depend on the damage to ascending and descending myelinated tracts in the white matter that are distributed throughout the various quadrants of the spinal cord. The dorsal columns are clearly delineated and contain mainly ascending sensory pathways important for proprioception. Other tracts ascend more laterally and carry sensory information to the cerebellum (ventral and dorsal spinocerebellar tracts) or the thalamus (lateral and spinothalamic tracts). Major descending tracts are located laterally (corticospinal and rubrospinal) and ventrally and carry information mainly from the vestibular system, the reticular system and some direct ipsilateral corticospinal projections.
Traumatic lesions (including primary and secondary lesions) not only can induce a physical discontinuity of the tracts but also anterograde wallerian demyelination as well as some retrograde degeneration. After SCI, some pathways may be preserved and contribute to recovery of function. This could be achieved by regeneration of pathways or sprouting of undamaged pathways (Bareyre et al., 2004, Maier and Schwab, 2006, Rossignol et al., 2007). Whereas in the first case, pathways are replaced by regenerated fibers, in the second case, new connections are either made or strengthened through existing structures. Thus, damage to the corticospinal tract can be in part offset by sprouting new connections through propriospinal or reticulospinal pathways, which then act more or less as a new (or enhanced relay) between the cortex and the spinal cord. It is thus important to develop prognostic imaging tools that will allow the characterization of the damaged tracts and the state of residual tracts.
Diffusion-weighted (DW) magnetic resonance imaging (MRI) exploits signal attenuation of water molecules that diffuse preferentially along white matter axons. It is possible to model this diffusion profile using diffusion tensor imaging (DTI) (Basser et al., 1994) and derive metrics of fractional anisotropy (FA), mean diffusivity (MD), axial and radial diffusivities that provide sensitive biomarkers for characterizing abnormality in the white matter. Animal studies notably showed that axial and radial diffusivities are good predictors of axonal loss and demyelination, respectively (Budde et al., 2007). DTI has been applied to assess the severity of the spinal cord injury (Agosta et al., 2007, Budde et al., 2007, Cohen-Adad et al., 2008a, DeBoy et al., 2007, Deo et al., 2006, Ducreux et al., 2007, Ellingson et al., 2008, Fujiyoshi et al., 2007, Kim et al., 2007, Lammertse et al., 2007, Nevo et al., 2001, Ohgiya et al., 2007, Plank et al., 2007, Ries et al., 2000, Schwartz et al., 2005, Shen et al., 2007, Thurnher and Bammer, 2006, Valsasina et al., 2005, Vargas et al., 2008). As an extension to DTI, high angular resolution diffusion imaging (HARDI) and Q-Ball imaging (QBI) can represent more than one diffusion direction, thereby alleviating limitations of the diffusion tensor in presence of crossing fibers (Tuch, 2004). HARDI has proven efficient in the detection of subtle axonal connections in the spinal cord (Cohen-Adad et al., 2008b, Lundell et al., 2009) and HARDI-based metrics such as the generalized fractional anisotropy (GFA) might be a good surrogate of white matter pathology, as suggested in previous work (Barmpoutis et al., 2009, Cohen-Adad et al., 2009b). One limitation of DTI/HARDI in the characterization of white matter integrity however, is the lack of specificity for determining demyelination and axonal loss. Several physical parameters can influence diffusion metrics including myelination, axonal density, axonal diameter, or orientation of fiber bundles (Beaulieu, 2002, Sen and Basser, 2005). Therefore combining DW-MRI with an independent measure that is sensitive to demyelination would increase the reliability of diagnosis.
Magnetization transfer (MT) contrast is based on the interaction between hydrogen protons bounded to macromolecules (e.g. lipid constituted of axons myelin sheet), thereby providing an indirect surrogate for myelin content (Kucharczyk et al., 1994, Pike et al., 2000). One advantage of MT is its specificity to demyelination and degeneration, as assessed by histopathology (Mottershead et al., 2003, Schmierer et al., 2004). Using high resolution MT measurements in the spinal cord, it is possible to assess demyelination of specific spinal pathways, as shown in MS patients (Zackowski et al., 2009). It should however be stressed that MTR is a semi-quantitative measure that not only depends on the size of the macromolecular pool but also on the exchange rate between the bound and mobile proton pools, decreasing its specificity for myelin imaging (McCreary et al., 2009). Hence, combining measures of MT and DW-MRI is a means to become more specific to white matter pathology (Reich et al., 2007). Moreover, the high reproducibility of MT and DW-MRI in the human cervical cord at 3T suggests that these measures would provide robust assessment of white matter pathology (Smith et al., 2009).
The goal of this study was to assess the state of spinal tracts in patients with chronic SCI by combining HARDI, magnetization transfer imaging and measures of cord atrophy. We performed correlations and stepwise regressions between MRI metrics and clinical parameters. Our hypotheses were:
- 1.
HARDI metrics and MTR (measured in the normal appearing tissue as assessed using conventional T2 contrast) and cord area differ between SCI patients and age-matched controls.
- 2.
HARDI metrics and MTR correlate with clinical disability score and are specific to the tracts involved, i.e., dorsal region for sensory scores and ventrolateral regions for the motor scores.
Section snippets
Subjects
Patients with chronic cervical SCI were recruited (N = 14, age = 45 ± 14 years, three women, delay after injury = 25 ± 35 years) (see Table 1). Exclusion criteria were: significant acute and chronic medical conditions, significant psychiatric or neurological history (other than SCI for patients), use of psychoactive drugs, osteosynthesis material in the spine and standard contraindications to MRI. Most patients presented spasticity and were treated with baclofen (Lioresal, 30 mg/day). Neuropathic pains
Group differences
Significant differences were detected between SCI patients and controls for metrics measured in the normal-appearing spinal cord (see Fig. 3). Cord area was 77.5 ± 3.2 mm2 in controls and 68.8 ± 12.1 mm2 in patients. Student's T-test showed differences in FA (p < 0.0001), axial diffusivity (p = 0.0138), radial diffusivity (p = 0.0135), GFA (p < 0.0001), MTR (p < 0.0001) and atrophy index (p = 0.0201). No significant difference was detected in MD (p = 0.41), T1-weighted (p = 0.76) and T2-weighted (p = 0.09) signals.
Correlation with clinical scores
Discussion
This study shows that HARDI and MT measurements at 3T in the cervical spinal cord of chronic SCI patients detected spinal cord damage in regions where conventional imaging was negative. Moreover, some metrics (FA, GFA, radial diffusivity, MTR and atrophy) were remarkably well correlated with clinical disability. Stepwise linear regressions showed that measures of MTR in the dorsal spinal cord explained sensory disability (ASIA score) whereas measures of MTR in the ventro-lateral spinal cord
Conclusion
High angular resolution diffusion-weighted imaging (HARDI), magnetization transfer ratio and cord atrophy are sensitive markers of spinal cord pathology and clinical disability in patients with spinal cord injury. Moreover, tract-specific information could be derived to predict sensory and motor disability in the normal appearing white matter. Multi-parametric MRI provides sensitive markers of demyelination and degeneration, opening the door to longitudinal studies for testing therapeutic
Acknowledgments
We thank Dr. Maxime Descoteaux for providing the code to compute the Q-Ball ODF and Dr. Henrik Lundell for providing the code to measure the cord area. We also thank Drs. Stéphane Ouary, Olivier Freund, Kevin Nigaud, Alexandre Vignaud and Eric Bardinet for helping with the project. We thank Drs. Thierry Albert, Bertrand Baussart, Caroline Hugeron, Hugues Pascal Moussellard, Frédéric Petit and Marc-Antoine Rousseau for helping with patient recruitment and we thank all subjects. We also thank the
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