Person:

Bakshi, Rohit

Background: The reliable and efficient measurement of spinal cord atrophy is of growing interest in monitoring disease progression in multiple sclerosis (MS). Methods: We compared T1- and T2-weighted MRI for measuring cervical spinal cord volume in 31 patients with MS and 18 age-matched controls (NC) from T1-weighted gradient recalled echo and T2-weighted fast spin-echo 1.5 T axial acquisitions. The two sequences were matched on slice thickness, signal averages and voxel size. An active surface software tool determined the normalized mean cervical cord cross-sectional area. Results: T1-derived cord areas were higher than T2 areas in the whole cohort (estimated mean difference = 7.03 mm2 (8.89 %); 95 % Confidence Interval (CI): 5.91, 8.14; p < 0.0001) and in both groups separately. There were trends for lower spinal cord areas in MS vs. NC with both sequences. For the T1 cord area, the mean difference was 3.7 mm2 (4.55 %) (95 % CI: −1.36, 8.78; p = 0.15). For the T2 cord area, the difference was larger [mean difference 4.9 mm2 (6.52 %) (95 % CI: −0.83, 10.67); p = 0.091]. The T1 and T2 cord areas showed similar weak to moderate correlations with measures of clinical status and T2 spinal cord lesion volume in the MS group. Superficial spinal cord T2 lesions had no apparent confounding effect on the outlining tool. The mean intra-rater and inter-rater coefficients of variation ranged from 0.27 to 0.91 % for T1- and 0.66 to 0.99 % for T2-derived cord areas. Conclusion: T2-weighted images may prove efficient for measuring cervical spinal cord atrophy in MS, with the added advantage of lesion detectability.

Magnetic resonance imaging (MRI) of the brain provides important outcome measures in the longitudinal evaluation of disease activity and progression in MS subjects. Two common measures derived from brain MRI scans are the brain parenchymal fraction (BPF) and T2 hyperintense lesion volume (T2LV), and these measures are routinely assessed longitudinally in clinical trials and observational studies. When measuring each outcome longitudinally, observed changes may be potentially confounded by variability in MRI acquisition parameters between scans. In order to accurately model longitudinal change, the acquisition parameters should thus be considered in statistical models. In this paper, several models for including protocol as well as individual MRI acquisition parameters in linear mixed models were compared using a large dataset of 3453 longitudinal MRI scans from 1341 subjects enrolled in the CLIMB study, and model fit indices were compared across the models. The model that best explained the variance in BPF data was a random intercept and random slope with protocol specific residual variance along with the following fixed-effects: baseline age, baseline disease duration, protocol and study time. The model that best explained the variance in T2LV was a random intercept and random slope along with the following fixed-effects: baseline age, baseline disease duration, protocol and study time. In light of these findings, future studies pertaining to BPF and T2LV outcomes should carefully account for the protocol factors within longitudinal models to ensure that the disease trajectory of MS subjects can be assessed more accurately.

Assess the sensitivity of the Magnetic Resonance Disease Severity Scale (MRDSS), based on cerebral lesions and atrophy, for treatment monitoring of glatiramer acetate (GA) in relapsing-remitting multiple sclerosis (MS). This retrospective non-randomized pilot study included patients who started daily GA [n = 23, age (median, range) 41 (26.2, 53.1) years, Expanded Disability Status Scale (EDSS) score 1.0 (0, 3.5)], or received no disease-modifying therapy (noDMT) [n = 21, age 44.8 (28.2, 55.4), EDSS 0 (0, 2.5)] for 2 years. MRDSS was the sum of z-scores (normalized to a reference sample) of T2 hyperintense lesion volume (T2LV), the ratio of T1 hypointense LV to T2LV (T1/T2), and brain parenchymal fraction (BPF) multiplied by negative 1. The two groups were compared by Wilcoxon rank sum tests; within group change was assessed by Wilcoxon signed rank tests. Glatiramer acetate subjects had less progression than noDMT on T1/T2 [(median z-score change (range), 0 (−1.07, 1.20) vs. 0.41 (−0.30, 2.51), p = 0.003)] and MRDSS [0.01 (−1.33, 1.28) vs. 0.46 (−1.57, 2.46), p = 0.01]; however, not on BPF [0.12 (−0.18, 0.58) vs. 0.10 (−1.47,0.50), p = 0.59] and T2LV [−0.03 (−0.90, 0.57) vs. 0.01 (−1.69, 0.34), p = 0.40]. While GA subjects worsened only on BPF [0.12 (−0.18, 0.58), p = 0.001], noDMT worsened on BPF [0.10 (−1.47, 0.50), p = 0.002], T1/T2 [0.41 (−0.30, 2.51), p = 0.0002], and MRDSS [0.46 (−1.57, 2.46), p = 0.0006]. These preliminary findings show the potential of two new cerebral MRI metrics to track MS therapeutic response. The T1/T2, an index of the destructive potential of lesions, may provide particular sensitivity to treatment effects.

Multiple sclerosis (MS) commonly affects occupational function. We investigated the link between brain MRI and employment status. Patients with MS (n = 100) completed a Work Productivity and Activity Impairment (WPAI) (general health version) survey measuring employment status, absenteeism, presenteeism, and overall work and daily activity impairment. Patients “working for pay” were considered employed; “temporarily not working but looking for work,” “not working or looking for work due to age,” and “not working or looking for work due to disability” were considered not employed. Brain MRI T1 hypointense (T1LV) and T2 hyperintense (T2LV) lesion volumes were quantified. To assess lesional destructive capability, we calculated each subject’s ratio of T1LV to T2LV (T1/T2). Normalized brain parenchymal volume (BPV) assessed brain atrophy. The mean (SD) age was 45.5 (9.7) years; disease duration was 12.1 (8.1) years; 75 % were women, 76 % were relapsing-remitting, and 76 % were employed. T1LV, T1/T2, Expanded Disability Status Scale (EDSS) scores, and activity impairment were lower and BPV was higher in the employed vs. not employed group (Wilcoxon tests, p < 0.05). Age, disease duration, MS clinical subtype, and T2LV did not differ between groups (p > 0.05). In multivariable logistic regression modeling, adjusting for age, sex, and disease duration, higher T1LV predicted a lower chance of employment (p < 0.05). Pearson correlations showed that EDSS was associated with activity impairment (p < 0.05). Disease duration, age, and MRI measures were not correlated with activity impairment or other WPAI outcomes (p > 0.05). We report a link between brain atrophy and lesions, particularly lesions with destructive potential, to MS employment status.

Background: Spinal cord atrophy occurs early in multiple sclerosis (MS) and impacts disability. The therapeutic effect of interferon beta-1a (IFNβ-1a) on spinal cord atrophy in patients with relapsing-remitting (RR) MS has not been explored. Methods: We retrospectively identified 16 consecutive patients receiving weekly intramuscular IFNβ-1a for 2 years [baseline age (mean ± SD) 47.7 ± 7.5 years, Expanded Disability Status Scale score median (range) 1.5 (0–2.5), timed 25-foot walk 4.6 ± 0.7 seconds; time on treatment 68.3 ± 59.9 months] and 11 sex- and age-matched normal controls (NC). The spinal cord was imaged at baseline, 1 and 2 years later with 3T MRI. C1-C5 spinal cord volume was measured by an active surface method, from which normalized spinal cord area (SCA) was calculated. Results: SCA showed no change in the MS or NC group over 2 years [mean annualized difference (95 % CI) MS: −0.604 mm2 (−1.352, 0.144), p = 0.106; NC: −0.360 mm2 (−1.576, 0.855), p = 0.524]. Between group analysis indicated no differences in on-study SCA change [MS vs. NC; year 1 vs. baseline, mean annualized difference (95 % CI) 0.400 mm2 (−3.350, 2.549), p = 0.780; year 2 vs. year 1: −1.196 mm2 (−0.875, 3.266), p = 0.245; year 2 vs. baseline −0.243 mm2 (−1.120, 1.607), p = 0.712]. Conclusion: Established IFNβ-1a therapy was not associated with ongoing spinal cord atrophy or any difference in the rate of spinal cord volume change in RRMS compared to NC over 2 years. These results may reflect a treatment effect. However, due to sample size and study design, these results should be considered preliminary and await confirmation.

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.

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.