Cervical spinal cord atrophy profile in adult SMN1-linked SMA

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Inhomogeneous magnetic field environment

The spinal cord is surrounded by bones and cartilaginous disks. It is also close to the lungs, each containing air. These three elements each have a different magnetic susceptibility. The magnetic field in the spinal cord region is therefore inhomogeneous, leading to geometric distortions and signal intensity loss. These artifacts can be counteracted with shimming. Shimming consists of compensating for the main field inhomogeneities by creating an auxiliary magnetic field via shim coils (Anderson, 1961; Romeo and Hoult, 1984). However, while volume shimming improves the field homogeneity, it is limited to smooth variations across space and cannot fully compensate for small and localized field variations, such as at cartilaginous discs between vertebral bodies. Echo planar imaging sequence, i.e. diffusion tensor imaging (DTI) (Figure 10), is particularly sensitive to geometric distortions in regions around vertebral disks. In addition to shimming, parallel imaging as well as slices positioning should be considered to limit magnetic field inhomogeneity, i.e. slices centered in the middle of each vertebral body and perpendicular to the spinal cord (Cohen-Adad et al., 2011). The geometry of the magnetic field inhomogeneity should be considered to correct its effect (Zeng et al., 2002; Samson et al., 2013).

Spinal cord atrophy quantification from MR images

In spinal cord disorders, axons and/or motoneurons loss can be assessed in vivo indirectly from MR images by quantifying spinal cord atrophy at a given cord level. The estimation of spinal cord cross-sectional area at given level was, for more than a decade, the most used approach to investigate atrophy in the pathological context, mainly in MS, that represents the main body of the scientific research on spinal cord pathologies. The cross-sectional approach consists of estimating a mean cord surface over a representative number of slices at a given vertebral level, typically five continuous thick slices perpendicular to the spinal cord at C2 vertebral level (Losseff et al., 1996). There were three main reasons that explain such a choice of vertebral level: i) the high contrast between the CSF and the spinal cord, as well as the large CSF space, low cross-sectional area variability, low cerebrospinal fluid flow speeds and less cord motion, which increases atrophy quantification methods’ reproducibility and accuracy at this level using a variety of magnetic strength, coils and MRI sequences; ii) The brain and the upper cervical spinal cord could be imaged in same FOV with relatively high resolution, SNR and CNR; iii) Pathological studies using cross-sectional area approach have shown pronounced cord atrophy from MR images at C2 vertebral level correlating with clinical disability mainly in MS (Kearney et al., 2015) and, to a lesser extent, in ALS (Valsasina et al., 2007; Branco et al., 2014), SCI (Cohen-Adad et al., 2011; Freund et al., 2011, 2013; Lundell et al., 2011), Huntington’s disease (Mühlau et al., 2014), Friedreich’s Ataxia (Chevis et al., 2013), and spinocerebellar ataxia (Lukas et al., 2008). For instance, apart from our MND studies, the two existing cross-sectional studies in sporadic ALS which investigated cord atrophy at C2 vertebral level (Valsasina et al., 2007; Branco et al., 2014), showed a high significant difference in cross-sectional area between ALS patients and age and sex matched controls (28/25 ALS patients versus 20/43 age- and gender-matched healthy controls; p < 0.001), with moderate correlation with the ALS Functional Rating Scale (ALSFRS) (Valsasina et al., 2007), revised ALSFRS (ALSFRS-R) and ALS severity scale (p # 0.05) and high correlation with disease duration (p < 0.001) (Branco et al., 2014). The only existing longitudinal study in ALS (Agosta et al., 2009), showed a significant cord area change between the baseline and a mean follow-up of 9 months (17 ALS patients; p = 0.003) with no correlations with the ALSFRS changes. Alternatively, some studies proposed a variety of indexes derived from cross-sectional approach (Figure 12):
– Cord anterior-posterior width (APW) and left-right width (LRW) (Lundell et al., 2011). These indexes provide, in the pathological context, information on cord flattening.
– Cord eccentricity (CE), which is defined as the square root of 1 – (APW/LRW)2. CE index provides, in the pathological context, information on cord flattening (Fahl et al., 2015; Branco et al., 2014).
– Cord radial distance, which is defined as the angular variation of the spinal cord radius over the full circle (Lundell et al., 2011).

Magnetization transfer imaging

Hydrogen nuclei linked to macromolecules such as proteins and lipids constituted of axons myelin sheet (70-80% of lipids and 20-30% of proteins), have an extremely short T2 signal (~10-5 s). These macromolecules are not directly detectable with standard MRI sequences. First, macromolecular spins are saturated using an off-resonance RF pulse, then transfer of magnetization between bound and free pools occurs by means of cross relaxation processes (dipole-dipole interactions, chemical exchange, etc.). This transfer to the « free » pool induces a signal decrease that can be indirectly measured, known as MT imaging (Filippi and Rocca, 2007; Smith et al., 2006; Wolf and Balaban, 1989). The latter interaction and/or exchange can be quantified using a magnetization transfer ratio (MTR), which is calculated as the percentage difference of MT images with macromolecules signal saturation (MS) and one without (M0): ! »# = 100×!! − !! The MTR enables inferring on myelin content, axonal count and density as shown by three MS histological studies at the brain and spinal cord levels, and thus to assess demyelination/remyelination and degeneration (Schmierer et al., 2007, 2004; Mottershead et al., 2003).
Magnetization transfer imaging was widely used at brain and spinal cord levels in demyelinating diseases. By contrast, only few studies used MT imaging at the brain level in the context of ALS, and reported change in MTR index of the CST (Carrara et al., 2012; Tanabe et al., 1998; Kato et al., 1997). At the spinal cord level, to our knowledge, there is only one study in ALS patients that used MT imaging and is from our research group (Cohen-Adad et al., 2013). In our study, we detected a significant difference between patients (n = 29) and age-matched controls (n = 21) for MTR in the CST and dorsal column of the cervical spinal cord. However, there were no correlations between MTR measured in the CST and ALSFRS-R, neither between MTR and TMS measurements. For an exhaustive description of MT imaging applications in spinal cord diseases, the reader is referred to the review from Martin et al. (2015).

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Fast and accurate semi-automated segmentation method of spinal cord MR images at 3T applied to the construction of a cervical spinal cord template

In Study 1, we showed that the semi-automated method by Losseff et al. (1996) demonstrated high reproducibility and accuracy for measuring spinal cord cross-sectional area in both cervical and thoracic regions at 3T in normal subjects and in patients with MND and SCI. Improved image spatial resolution obtained at 3T allowed higher segmentation performances than reported previously. More interestingly, full automation of the method seems possible given its low sensitivity to the initialization steps. Losseff’s segmentation method is a semi-automated method, and thus needs a large manual intervention from an operator, which restrains its use to quantify atrophy in few representative slices of the cord region of interest.
In clinical practice, it is often difficult to visually determine spinal cord atrophy. The growing interest in assessing spinal cord atrophy using MRI therefore underlines the need for a fast and accurate segmentation method of the spinal cord with limited manual intervention. This method would also enable segmentation of large data sets in a limited time, thus facilitating investigating in large cord regions using either volume or cross-sectional area measurements. Particularly, this method would enable investigation of the topography of spinal cord atrophy in spinal cord diseases using morphometry methods (Morra et al., 2009; Wang et al., 2010, 2011). Furthermore, to be used, advanced processing methods require an additional step of data normalization. The idea behind data normalization is to adjust for intersubject variability that is not related to the studied pathophysiological process (Mazziotta et al., 2001), as well as to realign all data in the same reference, i.e. template, for statistical comparisons between groups (Vasasina et al., 2012). Several methods have been proposed to construct a template of the cervical spinal cord (Fonov et al., 2014; Valsasina et al., 2012; Stroman et al., 2008). However, the proposed spinal cord templates lacked resolution and accuracy in the construction procedure or used a limited sample of healthy volunteers.
This second study was designed to address two main objectives: i) to construct and validate a new fast and accurate segmentation method with minimal manual intervention benefitting from the high robustness of Losseff’s method to its initialization procedure; ii) as an application, we extended the existing work at 1.5 and 3T (Fonov et al., 2014; Valsasina et al., 2012) to data normalization and the construction of an accurate MRI template of the cervical spinal cord using a large sample of 3T images.

Atrophy quantification in neurodegenerative diseases and trauma

Grey and white matter could not be differentiated in the acquired images due to insufficient contrast inside the spinal cord. However, as mentioned before, atrophy may predominate in a particular direction in neurodegenerative diseases and trauma. This preferential direction of cord atrophy may be detected in group analysis using surface-based morphometry techniques on spinal cord masks normalized to the template space instead of using voxel-based morphom-etry. For instance, morphological changes have been successfully detected in the hippocampus and ventricles in Alzheimer’s disease using radial distance approach and tensor-based mor-phometry [59, 60] and in the lateral ventricles in HIV/AIDS patients using multivariate tensor-based morphometry [61], as well as in the basal ganglia in ALS patients using surface-based vertex approach [62]. Our segmentation method may also measure accurately CSA and spinal cord volumes in a large range of pathologies.

Table of contents :

Contents
Remerciements
List of Tables
List of Figures
Glossary
Abstract
Publications
Articles arising from this work
Additional contributions
1. Introduction
2. Background
Motor neuron diseases
Historical setting
Amyotrophic lateral sclerosis
Spinal muscular atrophy
Spinal cord MRI
Principals of MRI
Challenges
Clinical setting
Research setting
Advanced MRI
3. Objectives
4. Results
Methodological studies
Study 1 – Validation of a semi-automated spinal cord segmentation method
Study 2 – Fast and accurate semi-automated segmentation method of spinal cord MR images at 3T applied to the construction of a cervical spinal cord template
Multi-parametric MRI studies in MND
Study 3 – Electrophysiological and spinal imaging evidence for sensory dysfunction in amyotrophic lateral sclerosis
Study 4 – Multi-parametric spinal cord MRI as potential progression marker in amyotrophic lateral sclerosis
Study 5 – Cervical spinal cord atrophy profile in adult SMN1-linked SMA
5. Discussion
Methodological developments
Multi-parametric MRI studies in MND
Perspectives
Annex A
Annex B
References

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