Short-term MRI measurements as predictors of EDSS progression in relapsing-remitting multiple sclerosis: grey matter atrophy but not lesions are predictive in a real-life setting

ABSTRACT Background. Magnetic resonance imaging (MRI) is the best biomarker of inflammatory disease activity in relapsing remitting Multiple Sclerosis (RRMS) so far but the association with disability is weak. Appearance of new MRI-lesions is used to evaluate response to immunotherapies in individual patients as well as being the most common primary outcome in phase-2 trials. Measurements of brain atrophy show promising outcomes in natural cohort studies and some phase-2 trials. From a theoretical perspective they might represent irreversible neurodegeneration and be more closely associated with disability. However, these atrophy measurements are not yet established as prognostic factors in real-life clinical routine. High field MRI has improved image quality and resolution and new methods to measure atrophy dynamics have become available. Objective. To investigate the predictive value of MRI classification criteria in to high/low atrophy and inflammation groups, and to explore predictive capacity of two consecutive routine MRI scans for disability progression in RRMS in a real-life prospective cohort. Methods. 82 RRMS-patients (40 untreated, 42 treated with immunotherapies, mean age 40 years, median Expanded Disability Status Scale (EDSS) of 2, underwent two clinically indicated MRI scans (3 Tesla) within 5-14 months, and EDSS assessment after a mean of 3.0 (1.5-4.2) years. We investigated the predictive value of predefined classifications in low/high inflammatory and atrophy groups for EDSS progression (≥1.5 if baseline EDSS = 0, ≥1.0 if baseline EDSS <5, ≥0.5 for other) by chi-square tests and by analysis of variance (ANOVA). The classifications were based on current scientific or clinical recommendation (e.g., treatment response criteria). Brain atrophy was assessed with three different methods (SIENA, SIENAX, and FreeSurfer). Post-hoc analyses aime

Quantitative T2*mapping reveals early temporo-spatial dynamics in an ischemic stroke model

Background: Oxyhemoglobin-sensitive sequences, namely T2*, can indirectly depict changes in oxygen extraction. Purpose of this study was to investigate the dynamics of T2* changes in ischemic tissue. New method: We investigated earliest temporo-spatial dynamics within ischemic tissue, measured with quantitative T2* imaging in the histologically defined infarct core and surrounding surviving tissue. Middle cerebral artery occlusion (MCAO) was induced by a filament model in mice. Serial multiple gradient-echo T2* sequences and diffusion-weighted images were acquired for 60 min after MCAO and repeated for 60 min after recanalization. T2* maps were co-registered with histology and T2* changes were compared to the contralateral hemisphere. Results: Within the histologically defined infarct core, relative T2* values decreased significantly by -10.8 +/- 2.8% (P = 0.003) compared to the contralateral hemisphere within 3.5 +/- 0.7 min after MCAO. Relative T2* values in volume exceeding the histologically determined infarct core were significantly less decreased (-6.7 +/- 2.1%; P = 0.02) and increased after recanalization (+3.9 +/- 1.9%; P = 0.045). Volume with T2* decrease showed continuous growth over 60 min after MCAO (P = 0.002) and decreased during 60 min after recanalization (P = 0.026), showing most significant correlations between infarct core volume and T2* abnormality volume (r = 0.66; P = 0.037) of the last image acquired after recanalization. Comparison with existing method(s): To our best knowledge, this is the first application of non-invasive quantitative T2* measurements to assess changes in levels of deoxyhemoglobin as an indirect biomarker for metabolic impairment in ischemic tissue. Conclusions: Quantitative T2* imaging might be a feasible tool to indicate change of oxygenation in acute stroke imaging, without administration of contrast agent. (C) 2015 Elsevier B.V. All rights reserved

T1- Thresholds in Black Holes Increase Clinical-Radiological Correlation in Multiple Sclerosis Patients.

Magnetic Resonance Imaging (MRI) is an established tool in diagnosing and evaluating disease activity in Multiple Sclerosis (MS). While clinical-radiological correlations are limited in general, hypointense T1 lesions (also known as Black Holes (BH)) have shown some promising results. The definition of BHs is very heterogeneous and depends on subjective visual evaluation.We aimed to improve clinical-radiological correlations by defining BHs using T1 relaxation time (T1-RT) thresholds to achieve best possible correlation between BH lesion volume and clinical disability.40 patients with mainly relapsing-remitting MS underwent MRI including 3-dimensional fluid attenuated inversion recovery (FLAIR), magnetization-prepared rapid gradient echo (MPRAGE) before and after Gadolinium (GD) injection and double inversion-contrast magnetization-prepared rapid gradient echo (MP2RAGE) sequences. BHs (BHvis) were marked by two raters on native T1-weighted (T1w)-MPRAGE, contrast-enhancing lesions (CE lesions) on T1w-MPRAGE after GD and FLAIR lesions (total-FLAIR lesions) were detected separately. BHvis and total-FLAIR lesion maps were registered to MP2RAGE images, and the mean T1-RT were calculated for all lesion ROIs. Mean T1 values of the cortex (CTX) were calculated for each patient. Subsequently, Spearman rank correlations between clinical scores (Expanded Disability Status Scale and Multiple Sclerosis Functional Composite) and lesion volume were determined for different T1-RT thresholds.Significant differences in T1-RT were obtained between all different lesion types with highest T1 values in visually marked BHs (BHvis: 1453.3±213.4 ms, total-FLAIR lesions: 1394.33±187.38 ms, CTX: 1305.6±35.8 ms; p1500 ms (Expanded Disability Status Scale vs. lesion volume: rBHvis = 0.442 and rtotal-FLAIR = 0.497, p<0.05; Multiple Sclerosis Functional Composite vs. lesion volume: rBHvis = -0.53 and rtotal-FLAIR = -0.627, p<0.05).Clinical-radiological correlations in MS patients are increased by application of T1-RT thresholds. With the short acquisition time of the MP2RAGE sequences, quantitative T1 maps could be easily established in clinical studies

Regression to the Mean and Predictors of MRI Disease Activity in RRMS Placebo Cohorts - Is There a Place for Baseline-to-Treatment Studies in MS?

<div><p>Background</p><p>Gadolinium-enhancing (GD+) lesions and T2 lesions are MRI outcomes for phase-2 treatment trials in relapsing-remitting Multiple Sclerosis (RRMS). Little is known about predictors of lesion development and regression-to-the-mean, which is an important aspect in early baseline-to-treatment trials.</p><p>Objectives</p><p>To quantify regression-to-the-mean and identify predictors of MRI lesion development in placebo cohorts.</p><p>Methods</p><p>21 Phase-2 and Phase-3 trials were identified by a systematic literature research. Random-effects meta-analyses were performed to estimate development of T2 and GD+ after 6 months (phase-2) or 2 years (phase-3). Predictors of lesion development were evaluated with mixed-effect meta-regression.</p><p>Results</p><p>The mean number of GD+-lesions per scan was similar after 6 months (1.19, 95%CI: 0.87-1.51) and 2 years (1.19, 95%CI: 1.00-1.39). 39% of the patients were without new T2-lesion after 6 month and 19% after 2 years (95%CI: 12-25%). Mean number of baseline GD+-lesions was the best predictor for new lesions after 6 months.</p><p>Conclusion</p><p>Baseline GD-enhancing lesions predict evolution of Gd- and T2 lesions after 6 months and might be used to control for regression to the mean effects. Overall, proof-of-concept studies with a baseline to treatment design have to face a regression to 1.2 GD+lesions per scan within 6 months.</p></div

Reduced rich-club connectivity is related to disability in primary progressive MS

International audienceObjective: To investigate whether the structural connectivity of the brain's rich-club organization is altered in patients with primary progressive MS and whether such changes to this fundamental network feature are associated with disability measures. Methods: We recruited 37 patients with primary progressive MS and 21 healthy controls for an observational cohort study. Structural connectomes were reconstructed based on diffusionweighted imaging data using probabilistic tractography and analyzed with graph theory. Results: We observed the same topological organization of brain networks in patients and controls. Consistent with the originally defined rich-club regions, we identified superior frontal, precuneus, superior parietal, and insular cortex in both hemispheres as rich-club nodes. Connectivity within the rich club was significantly reduced in patients with MS (p 5 0.039). The extent of reduced rich-club connectivity correlated with clinical measurements of mobility (Kendall rank correlation coefficient t 5 20.20, p 5 0.047), hand function (t 5 20.26, p 5 0.014), and information processing speed (t 5 20.20, p 5 0.049). Conclusions: In patients with primary progressive MS, the fundamental organization of the structural connectome in rich-club and peripheral nodes was preserved and did not differ from healthy controls. The proportion of rich-club connections was altered and correlated with disability measures. Thus, the rich-club organization of the brain may be a promising network phenotype for understanding the patterns and mechanisms of neurodegeneration in MS

Increased Perfusion in Normal Appearing White Matter in High Inflammatory Multiple Sclerosis Patients

<div><p>Purpose</p><p>Although cerebral perfusion alterations have long been acknowledged in multiple sclerosis (MS), the relationship between measurable perfusion changes and the status of highly active MS has not been examined. We hypothesized that alteration of perfusion can be detected in normal appearing white matter and is increased in high inflammatory patients.</p><p>Materials and Methods</p><p>Thirty-three patients with relapsing-remitting MS underwent four monthly 3T MRI scans including dynamic susceptibility contrast perfusion-weighted MRI. Cerebral blood flow (CBF) and cerebral blood volume (CBV) were measured in normal appearing white matter. Patients were stratified in a high- and low-inflammatory group according to the number of new contrast enhancing lesions.</p><p>Results</p><p>Thirteen patients were classified as high-inflammatory. Compared to low-inflammatory patients, the high-inflammatory group demonstrated significantly higher CBV (p = 0.001) and CBF (p = 0.014) values. A mixed model analysis to assess independent variables associated with CBV and CBF revealed that white matter lesion load and atrophy measurements had no significant influence on CBF and CBV.</p><p>Conclusion</p><p>This work provides evidence that high inflammatory lesion load is associated with increased CBV and CBF, underlining the role of global modified microcirculation prior to leakage of the blood-brain barrier in the pathophysiology of MS. Perfusion changes might therefore be sensitive to active inflammation apart from lesion development without local blood–brain barrier breakdown, and could be utilized to further assess the metabolic aspect of current inflammation.</p></div

Placebo cohorts of RRMS trials 1996–2013 (n = 21).

<p>RRMS = Relapsing-remitting Multiple Sclerosis, Pub.Year = Year of Publication, N = patients in placebo cohort, Age = mean Age at baseline, Relapse Rate = annualized pre-study relapse rate, EDSS = mean EDSS at baseline, Gd = Gd-enhancing lesion, T2 = T2 hyper intense lesion, Diag. Criteria = Diagnostic Criteria (Poser, 2001 = McDonald 2001, 2005 = McDonald 2005), Summary data are presented as median, Comparison of phase2 and 3 baseline data with Mann-Whitney test except for diagnostic criteria (chi square test),</p><p>* = p<0.05</p><p>Placebo cohorts of RRMS trials 1996–2013 (n = 21).</p

PRISMA 2009 Flow chart—Study selection for meta-analyses.

<p>According to the PRISMA guidelines [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0116559#pone.0116559.ref015" target="_blank">15</a>].</p

T1w dark blood imaging improves detection of contrast enhancing lesions in multiple sclerosis

<div><p>Purpose</p><p>In multiple sclerosis (MS) the sensitivity for detection of contrast enhancing lesions (CEL) in T1-weighted scans is essential for diagnostics and therapy decisions. The purpose of our study was to evaluate the sensitivity of T1w MPRAGE scans in comparison to T1w dark blood technique (T1-DB) for CEL in MS.</p><p>Materials and methods</p><p>3T MR imaging was performed in 37 MS patients, including T2-weighted imaging, T1w MPRAGE before and after gadolinium injection (unenhanced-T1 and T1-CE) and T1-DB imaging. After gadolinium application, the T1-DB scan was performed prior to T1-CE. From unenhanced-T1 and T1-CE scans, subtraction images (T1-SUB) were calculated. The number of CEL was determined separately on T1-CE and T1-DB by two raters independently. Lesions only detected on T1-DB scans then were verified on T1-SUB. Only lesions detected by both raters were included in further analysis.</p><p>Results</p><p>In 16 patients, at least one CEL was detected by both rater, either on T1-CE or T1-DB. All lesions that were detected on T1-CE were also detected on T1-DB images. The total number of contrast enhancing lesions detected on T1-DB images (n = 54) by both raters was significantly higher than the corresponding number of lesions identified on T1-CE (n = 27) (p = 0.01); all of these lesions could be verified on SUB images. In 21 patients, no CEL was detected in any of the sequences.</p><p>Conclusions</p><p>The application of T1-DB technique increases the sensitivity for CEL in MS, especially for those lesions that show only subtle increase in intensity after Gadolinium application but remain hypo- or iso-intense to surrounding tissue.</p></div

Meta-regression: Association of Variables and Outcomes.

<p>Results of mixed-effects models with at least 4 studies. Outcomes are bold. Coefficients indicate positive or negative association, *(p<0.001). tau² is the estimate of residual heterogeneity compared to the simple random-effects model, § indicates no significant residual heterogeneity in the mixed effect model with p>0.05. A higher reduction of tau² within the mixed-effect models indicate a higher association with outcome. CI = Confidence interval.</p><p>Meta-regression: Association of Variables and Outcomes.</p