Spinal cord grey matter abnormalities are associated with secondary progression and physical disability in multiple sclerosis

Kearney, Hugh; Schneider, Torben; Yiannakas, Marios C.; Altmann, Daniel R.; Wheeler-Kingshott, Claudia A. M.; Ciccarelli, Olga; Miller, David H.

doi:10.1136/jnnp-2014-308241

Cited by 66 publications

(67 citation statements)

References 37 publications

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“…CSA and GBSI provided similar rates of spinal cord atrophy in each MS subtype, but CSA yielded a larger variability (standard deviation) when compared with GBSI (eg, in RRMS AE4.02% vs AE2.57%, respectively), implying that GBSI measurements are more precise. [3][4][5] In line with this, the percentage spinal cord decline measured with GBSI was associated with EDSS progression and with disease subtype, and performed better than CSA-derived spinal cord atrophy in detecting more disabled patients. 34 Of note, a higher percentage of spinal cord decline (and a lower standard deviation) was found in PMS when using GBSI than when using CSA (−2.29 AE 2.40% vs −1.29 AE 3.20%), and this was probably due to the relatively small sample in this MS subtype, further highlighting the higher measurement precision of GBSI.…”

Section: Discussionsupporting

confidence: 60%

“…The rates of spinal cord loss over 1 year obtained with GBSI were similar to those obtained with CSA, but they were associated with lower variability, greater ability to distinguish between MS patients and controls, and more robust clinical correlates, thereby holding promise for future MS research on spinal cord imaging. [3][4][5] Spinal cord atrophy occurs from the early stages of MS (eg, CIS), is more obvious in progressive patients than relapsing types of MS, and progresses faster than brain atrophy. CSA and GBSI provided similar rates of spinal cord atrophy in each MS subtype, but CSA yielded a larger variability (standard deviation) when compared with GBSI (eg, in RRMS AE4.02% vs AE2.57%, respectively), implying that GBSI measurements are more precise.…”

Section: Discussionmentioning

confidence: 99%

“…Use of GBSI yielded increased statistical power to detect treatment changes, suggesting that future treatment trials-particularly those testing neuroprotective agents-could include spinal cord atrophy as a primary outcome measure. [3][4][5] The risk of disability progression increases with the rate of spinal cord atrophy, 7 accounting for up to 77% of motor disability, as measured by the EDSS. Similarly, when images were acquired in a scan-rescan fashion, GBSI presented a lower coefficient of variation when compared with CSA, indicating higher precision; the median absolute deviation (0.21%) was similar to what has been previously described in the validation of a registration-based method for brain atrophy (0.15-0.20% for SIENA [Structural Image Evaluation Using Normalization of Atrophy]).…”

Section: Discussionmentioning

confidence: 99%

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Longitudinal spinal cord atrophy in multiple sclerosis using the generalized boundary shift integral

Moccia

Prados

Filippi

et al. 2019

Annals of Neurology

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Objective: Spinal cord atrophy is a clinically relevant feature of multiple sclerosis (MS), but longitudinal assessments on magnetic resonance imaging using segmentation-based methods suffer from measurement variability, especially in multicenter studies. We compared the generalized boundary shift integral (GBSI), a registration-based method, with a standard segmentation-based method. Methods: Baseline and 1-year spinal cord 3-dimensional T1-weighted images (1mm isotropic) were obtained from 282 patients (52 clinically isolated syndrome [CIS], 196 relapsing-remitting MS [RRMS], 34 progressive MS [PMS]), and 82 controls from 8 MAGNIMS (Magnetic Resonance Imaging in Multiple Sclerosis) sites on multimanufacturer and multi-field-strength scans. Spinal Cord Toolbox was used for C2-5 segmentation and cross-sectional area (CSA) calculation. After cord straightening and registration, GBSI measured atrophy based on the probabilistic boundary-shift region of interest. CSA and GBSI percentage annual volume change was calculated. Results: GBSI provided similar rates of atrophy, but reduced measurement variability compared to CSA in all MS subtypes (CIS: −0.95 AE 2.11% vs −1.19 AE 3.67%; RRMS: −1.74 AE 2.57% vs −1.74 AE 4.02%; PMS: −2.29 AE 2.40% vs −1.29 AE 3.20%) and healthy controls (0.02 AE 2.39% vs −0.56 AE 3.77%). GBSI performed better than CSA in differentiating healthy controls from CIS (area under the curve [AUC] = 0.66 vs 0.53; p = 0.03), RRMS (AUC = 0.73 vs 0.59; p < 0.001), PMS (AUC = 0.77 vs 0.53; p < 0.001), and patients with disability progression from patients without View this article online at wileyonlinelibrary.com.

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Section: Discussionsupporting

confidence: 60%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Longitudinal spinal cord atrophy in multiple sclerosis using the generalized boundary shift integral

Moccia

Prados

Filippi

et al. 2019

Annals of Neurology

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“…These studies demonstrated a high association with MS disability, particularly in progressive MS. 39,40 …”

Section: Discussionmentioning

confidence: 99%

Association Between Thoracic Spinal Cord Gray Matter Atrophy and Disability in Multiple Sclerosis

et al. 2015

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IMPORTANCE In multiple sclerosis (MS), upper cervical cord gray matter (GM) atrophy correlates more strongly with disability than does brain or cord white matter (WM) atrophy. The corresponding relationships in the thoracic cord are unknown owing to technical difficulties in assessing GM and WM compartments by conventional magnetic resonance imaging techniques.OBJECTIVES To investigate the associations between MS disability and disease type with lower thoracic cord GM and WM areas using phase-sensitive inversion recovery magnetic resonance imaging at 3T, as well as to compare these relationships with those obtained at upper cervical levels. DESIGN, SETTING, AND PARTICIPANTSBetween July 2013 and March 2014, a total of 142 patients with MS (aged 25-75 years; 86 women) and 20 healthy control individuals were included in this cross-sectional observational study conducted at an academic university hospital. MAIN OUTCOMES AND MEASURESTotal cord areas (TCAs), GM areas, and WM areas at the disc levels C2/C3, C3/C4, T8/9, and T9/10. Area differences between groups were assessed, with age and sex as covariates.RESULTS Patients with relapsing MS (RMS) had smaller thoracic cord GM areas than did ageand sex-matched control individuals (mean differences [coefficient of variation (COV)]: 0.98 mm 2 [9.2%]; P = .003 at T8/T9 and 0.93 mm 2 [8.0%]; P = .01 at T9/T10); however, there were no significant differences in either the WM area or TCA. Patients with progressive MS showed smaller GM areas (mean differences [COV]: 1.02 mm 2 [10.6%]; P < .001 at T8/T9 and 1.37 mm 2 [13.2%]; P < .001 at T9/T10) and TCAs (mean differences [COV]: 3.66 mm 2 [9.0%]; P < .001 at T8/T9 and 3.04 mm 2 [7.2%]; P = .004 at T9/T10) compared with patients with RMS. All measurements (GM, WM, and TCA) were inversely correlated with Expanded Disability Status Scale score. Thoracic cord GM areas were correlated with lower limb function. In multivariable models (which also included cord WM areas and T2 lesion number, brain WM volumes, brain T1 and fluid-attenuated inversion recovery lesion loads, age, sex, and disease duration), cervical cord GM areas had the strongest correlation with Expanded Disability Status Scale score followed by thoracic cord GM area and brain GM volume.CONCLUSIONS AND RELEVANCE Thoracic cord GM atrophy can be detected in vivo in the absence of WM atrophy in RMS. This atrophy is more pronounced in progressive MS than RMS and correlates with disability and lower limb function. Our results indicate that remarkable cord GM atrophy is present at multiple cervical and lower thoracic levels and, therefore, may reflect widespread cord GM degeneration.

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“…Afterwards, manual grey matter (GM) outlining was carried out on the average DW volume obtained according to the procedure described in Kearney et al (2014). The GM and WM masks were obtained directly from the manually drawn outlines and were limited to voxels within the whole-cord mask.…”

Section: Segmentationmentioning

confidence: 99%

Neurite orientation dispersion and density imaging of the healthy cervical spinal cord in vivo

et al. 2015

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Here we present the application of neurite orientation dispersion and density imaging (NODDI) to the healthy spinal cord in vivo. NODDI provides maps such as the intra-neurite tissue volume fraction (vin), the orientation dispersion index (ODI) and the isotropic volume fraction (viso), and here we investigate their potential for spinal cord imaging. We scanned five healthy volunteers, four of whom twice, on a 3T MRI system with a ZOOM-EPI sequence. In accordance to the published NODDI protocol, multiple b-shells were acquired at cervical level and both NODDI and diffusion tensor imaging (DTI) metrics were obtained and analysed to: i) characterise differences in grey and white matter (GM/WM); ii) assess the scan-rescan reproducibility of NODDI; iii) investigate the relationship between NODDI and DTI; and iv) compare the quality of fit of NODDI and DTI. Our results demonstrated that: i) anatomical features can be identified in NODDI maps, such as clear contrast between GM and WM in ODI; ii) the variabilities of vin and ODI are comparable to that of DTI and are driven by biological differences between subjects for ODI, have similar contribution from measurement errors and biological variation for vin, whereas viso shows higher variability, driven by measurement errors; iii) NODDI identifies potential sources contributing to DTI indices, as in the brain; and iv) NODDI outperforms DTI in terms of quality of fit. In conclusion, this work shows that NODDI is a useful model for in vivo diffusion MRI of the spinal cord, providing metrics closely related to tissue microstructure, in line with findings in the brain.

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Spinal cord grey matter abnormalities are associated with secondary progression and physical disability in multiple sclerosis

Abstract: The study findings suggest that pathological involvement of the spinal cord GM contributes significantly to physical disability in relapse-onset MS and SPMS in particular.

Cited by 66 publications

References 37 publications

Longitudinal spinal cord atrophy in multiple sclerosis using the generalized boundary shift integral

Longitudinal spinal cord atrophy in multiple sclerosis using the generalized boundary shift integral

Association Between Thoracic Spinal Cord Gray Matter Atrophy and Disability in Multiple Sclerosis

Neurite orientation dispersion and density imaging of the healthy cervical spinal cord in vivo

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