The Contribution of Cortical Lesions to a Composite MRI Scale of Disease Severity in Multiple Sclerosis

Objective: To test a new version of the Magnetic Resonance Disease Severity Scale (v.3 = MRDSS3) for multiple sclerosis (MS), incorporating cortical gray matter lesions (CLs) from 3T magnetic resonance imaging (MRI). Background: MRDSS1 was a cerebral MRI-defined composite scale of MS disease severity combining T2 lesion volume (T2LV), the ratio of T1 to T2LV (T1/T2), and whole brain atrophy [brain parenchymal fraction (BPF)]. MRDSS2 expanded the scale to include cerebral gray matter fraction (GMF) and upper cervical spinal cord area (UCCA). We tested the contribution of CLs to the scale (MRDSS3) in modeling the MRI relationship to clinical status. Methods: We studied 51 patients [3 clinically isolated syndrome, 43 relapsing-remitting, 5 progressive forms, age (mean ± SD) 40.7 ± 9.1 years, Expanded Disability Status Scale (EDSS) score 1.6 ± 1.7] and 20 normal controls by high-resolution cerebrospinal MRI. CLs required visibility on both fluid-attenuated inversion-recovery (FLAIR) and modified driven equilibrium Fourier transform sequences. The MACFIMS battery defined cognitively impaired (n = 18) vs. preserved (n = 33) MS subgroups. Results: EDSS significantly correlated with only BPF, UCCA, MRDSS2, and MRDSS3 (all p < 0.05). After adjusting for depressive symptoms, the cognitively impaired group had higher severity of MRI metrics than the cognitively preserved group in regard to only BPF, GMF, T1/T2, MRDSS1, and MRDSS2 (all p < 0.05). CL number was not significantly related to EDSS score or cognition status. Conclusion: CLs from 3T MRI did not appear to improve the validity of the MRDSS. Further studies employing advanced sequences or higher field strengths may show more utility for the incorporation of CLs into composite scales

Automated segmentation of cerebral deep gray matter from MRI scans: effect of field strength on sensitivity and reliability

Background: The cerebral subcortical deep gray matter nuclei (DGM) are a common, early, and clinically-relevant site of atrophy in multiple sclerosis (MS). Robust and reliable DGM segmentation could prove useful to evaluate putative neuroprotective MS therapies. The objective of the study was to compare the sensitivity and reliability of DGM volumes obtained from 1.5T vs. 3T MRI. Methods: Fourteen patients with MS [age (mean, range) 50.2 (32.0–60.8) years, disease duration 18.4 (8.2–35.5) years, Expanded Disability Status Scale score 3.1 (0–6), median 3.0] and 15 normal controls (NC) underwent brain 3D T1-weighted paired scan-rescans at 1.5T and 3T. DGM (caudate, thalamus, globus pallidus, and putamen) segmentation was obtained by the fully automated FSL-FIRST pipeline. Both raw and normalized volumes were derived. Results: DGM volumes were generally higher at 3T vs. 1.5T in both groups. For raw volumes, 3T showed slightly better sensitivity (thalamus: p = 0.02; caudate: p = 0.10; putamen: p = 0.02; globus pallidus: p = 0.0004; total DGM: p = 0.01) than 1.5T (thalamus: p = 0.05; caudate: p = 0.09; putamen: p = 0.03; globus pallidus: p = 0.0006; total DGM: p = 0.02) for detecting DGM atrophy in MS vs. NC. For normalized volumes, 3T but not 1.5T detected atrophy in the globus pallidus in the MS group. Across all subjects, scan-rescan reliability was generally very high for both platforms, showing slightly higher reliability for some DGM volumes at 3T. Raw volumes showed higher reliability than normalized volumes. Raw DGM volume showed higher reliability than the individual structures. Conclusions: These results suggest somewhat higher sensitivity and reliability of DGM volumes obtained from 3T vs. 1.5T MRI. Further studies should assess the role of this 3T pipeline in tracking potential MS neurotherapeutic effects

Enhancing the Detection of BOLD Signal in fMRI by Reducing the Partial Volume Effect

Purpose. To investigate the advantages of reducing the partial volume effect (PVE) to enhance the detection of the BOLD signal in fMRI. Methods. A linear phase term was added in k-space to obtain half-voxel shifting of 64 × 64 T2*-weighted echo-planar images. Three sets of image data shifted in the x, y, and diagonal direction, respectively, are combined with the original 64 × 64 data to form the 128 × 128 voxel-shifted interpolated data. Results. A simulation of a synthetic fMRI dataset shows that the voxel-shifted interpolation (VSI) can increase the t-score up to 50% in single-voxel activations. An fMRI study (n=7) demonstrates that 20.4% of the interpolated voxels have higher t-scores than their nearest neighboring voxels in the original maps. The average increase of the t-score in these interpolated voxels is 13.3%. Conclusion. VSI yields increased sensitivity in detecting voxel-size BOLD activations, improved spatial accuracy of activated regions, and improved detection of the peak BOLD signal of an activated region. VSI can potentially be used as an alternative to the high-resolution fMRI studies in which reduction in SNR and increase in imaging time become prohibitive

The Effect of Dimethyl Fumarate on Cerebral Gray Matter Atrophy in Multiple Sclerosis

Introduction: The objective of this pilot study was to compare cerebral gray matter (GM) atrophy over 1 year in patients starting dimethyl fumarate (DMF) for multiple sclerosis (MS) to that of patients on no disease-modifying treatment (noDMT). DMF is an established therapy for relapsing–remitting (RR) MS. Methods: We retrospectively analyzed 20 patients with RRMS at the start of DMF [age (mean ± SD) 46.1 ± 10.2 years, Expanded Disability Status Scale (EDSS) score 1.1 ± 1.2, timed 25-foot walk (T25FW) 4.6 ± 0.8 s] and eight patients on noDMT (age 42.5 ± 6.6 years, EDSS 1.7 ± 1.1, T25FW 4.4 ± 0.6 s). Baseline and 1-year 3D T1-weighted 3T MRI was processed with automated pipelines (SIENA, FSL-FIRST) to assess percentage whole brain volume change (PBVC) and deep GM (DGM) atrophy. Group differences were assessed by analysis of covariance, with time between MRI scans as a covariate. Results: Over 1 year, the DMF group showed a lower rate of whole brain atrophy than the noDMT group (PBVC: −0.37 ± 0.49% vs. −1.04 ± 0.67%, p = 0.005). The DMF group also had less change in putamen volume (−0.06 ± 0.22 vs. −0.32 ± 0.28 ml, p = 0.02). There were no significant on-study differences between groups in caudate, globus pallidus, thalamus, total DGM volume, T2 lesion volume, EDSS, or T25FW (all p > 0.20). Conclusions: These results suggest a treatment effect of DMF on GM atrophy appearing at 1 year after starting therapy. However, due to the retrospective study design and sample size, these findings should be considered preliminary, and require confirmation in future investigations. Funding Biogen

Whole brain and deep gray matter atrophy detection over 5 years with 3T MRI in multiple sclerosis using a variety of automated segmentation pipelines.

BACKGROUND:Cerebral atrophy is common in multiple sclerosis (MS) and selectively involves gray matter (GM). Several fully automated methods are available to measure whole brain and regional deep GM (DGM) atrophy from MRI. OBJECTIVE:To assess the sensitivity of fully automated MRI segmentation pipelines in detecting brain atrophy in patients with relapsing-remitting (RR) MS and normal controls (NC) over five years. METHODS:Consistent 3D T1-weighted sequences were performed on a 3T GE unit in 16 mildly disabled patients with RRMS and 16 age-matched NC at baseline and five years. All patients received disease-modifying immunotherapy on-study. Images were applied to two pipelines to assess whole brain atrophy [brain parenchymal fraction (BPF) from SPM12; percentage brain volume change (PBVC) from SIENA] and two other pipelines (FSL-FIRST; FreeSurfer) to assess DGM atrophy (thalamus, caudate, globus pallidus, putamen). MRI change was compared by two sample t-tests. Expanded Disability Status Scale (EDSS) and timed 25-foot walk (T25FW) change was compared by repeated measures proportional odds models. RESULTS:Using FreeSurfer, the MS group had a ~10-fold acceleration in on-study volume loss than NC in the caudate (mean decrease 0.51 vs. 0.05 ml, p = 0.022). In contrast, caudate atrophy was not detected by FSL-FIRST (mean decrease 0.21 vs. 0.12 ml, p = 0.53). None of the other pipelines showed any difference in volume loss between groups, for whole brain or regional DGM atrophy (all p>0.38). The MS group showed on-study stability on EDSS (p = 0.47) but slight worsening of T25FW (p = 0.054). CONCLUSIONS:In this real-world cohort of mildly disabled treated patients with RRMS, we identified ongoing atrophy of the caudate nucleus over five years, despite the lack of any significant whole brain atrophy, compared to healthy controls. The detectability of caudate atrophy was dependent on the MRI segmentation pipeline employed. These findings underscore the increased sensitivity gained when assessing DGM atrophy in monitoring MS

MRI detection of hypointense brain lesions in patients with multiple sclerosis: T1 spin-echo vs. gradient-echo

Objective Compare T1 spin-echo (T1SE) and T1 gradient-echo (T1GE) sequences in detecting hypointense brain lesions in multiple sclerosis (MS). Background Chronic hypointense lesions on T1SE MRI scans are a surrogate of severe demyelination and axonal loss in MS. The role of T1GE images in the detection of such lesions has not been clarified. Design/methods In 45 patients with MS [Expanded Disability Status Scale (EDSS) score (mean ± SD) 3.5 ± 2.0; 37 relapsing-remitting (RR); 8 secondary progressive (SP)], cerebral T1SE, T1GE, and T2-weighted fluid-attenuated inversion-recovery (FLAIR) images were acquired on a 1.5 T MRI scanner. Images were re-sampled to axial 5 mm slices before directly comparing lesion detectability using Jim (v.7, Xinapse Systems). Statistical methods included Wilcoxon signed rank tests to compare sequences and Spearman correlations to test associations. Results Considering the entire cohort, T1GE detected a higher lesion volume (5.90 ± 6.21 vs. 4.17 ± 4.84 ml, p < 0.0001) and higher lesion number (27.82 ± 20.66 vs. 25.20 ± 20.43, p < 0.05) than T1SE. Lesion volume differences persisted when considering RR and SP patients separately (both p < 0.01). A higher lesion number by T1GE was seen only in the RR group (p < 0.05). When comparing correlations between lesion volume and overall neurologic disability (EDSS score), T1SE correlated with EDSS (Spearman r = 0.29, p < 0.05) while T1GE (r = 0.23, p = 0.13) and FLAIR (r = 0.24, p = 0.12) did not. Conclusion Our data suggest that hypointense lesions on T1SE and T1GE are not interchangeable in patients with MS. Based on these results, we hypothesize that T1GE shows more sensitivity to lesions at the expense of less pathologic specificity for tissue destruction than T1SE