•Machine learning model classifies acute vs chronic multiple sclerosis (MS) lesions.•Used single timepoint non-contrast conventional T1- and T2-weighted MRI only.•Identified 16 textural radiomic ...features discriminative of MS lesion subtype.•Achieved 74% balanced accuracy with 71–76% sensitivity and 73–78% specificity.
Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease characterized by the appearance of focal lesions across the central nervous system. The discrimination of acute from chronic MS lesions may yield novel biomarkers of inflammatory disease activity which may support patient management in the clinical setting and provide endpoints in clinical trials. On a single timepoint and in the absence of a prior reference scan, existing methods for acute lesion detection rely on the segmentation of hyperintense foci on post-gadolinium T1-weighted magnetic resonance imaging (MRI), which may underestimate recent acute lesion activity. In this paper, we aim to improve the sensitivity of acute MS lesion detection in the single-timepoint setting, by developing a novel machine learning approach for the automatic detection of acute MS lesions, using single-timepoint conventional non-contrast T1- and T2-weighted brain MRI. The MRI input data are supplemented via the use of a convolutional neural network generating “lesion-free” reconstructions from original “lesion-present” scans using image inpainting. A multi-objective statistical ranking module evaluates the relevance of textural radiomic features from the core and periphery of lesion sites, compared within “lesion-free” versus “lesion-present” image pairs. Then, an ensemble classifier is optimized through a recursive loop seeking consensus both in the feature space (via a greedy feature-pruning approach) and in the classifier space (via model selection repeated after each pruning operation). This leads to the identification of a compact textural signature characterizing lesion phenotype. On the patch-level task of acute versus chronic MS lesion classification, our method achieves a balanced accuracy in the range of 74.3–74.6% on fully external validation cohorts.
Previous histopathology and MRI studies have addressed the differences between focal white matter lesions (FWML) and diffusely abnormal white matter (DAWM) in multiple sclerosis (MS). These two ...categories of white matter T2-weighted (T2w) hyperintensity show different degrees of demyelination, axonal loss and immune cell density on histopathology, potentially offering distinct correlations with symptoms.
1) To automate the separation of FWML and DAWM using T2w MRI intensity thresholds and to investigate their differences in magnetization transfer ratios (MTR), which are sensitive to myelin content; 2) to correlate MTR values in FWML and DAWM with normalized signal intensity values on fluid attenuated inversion recovery (FLAIR), T2w, and T1-weighted (T1w) contrasts, as well as with the ratio of T2w/T1w normalized values, in order to determine whether these normalized intensities can be used when MTR is not available.
We used three MRI datasets: datasets 1 and 2 had 20 MS participants each, scanned with similar 3T MRI protocols in 2 centers, including: 3D T1w (MP2RAGE), 3D FLAIR, 2D T2w, and 3D magnetization-transfer (MT) contrasts. Dataset 3 consisted of 67 scans of participants enrolled in a multisite study and had T1w and T2w contrasts. We used the first dataset to develop an automated technique to separate FWML from DAWM and the second and third to validate the automation of the technique. We applied the automatic thresholds to all datasets to assess the overlap of the manual and the automated masks using Dice kappa. We also assessed differences in mean MTR values between NAWM, DAWM and FWML, using manually and automatically derived masks in datasets 1 and 2. Finally, we used the mean intensity of manually-traced areas of NAWM on T2w images as the normalization factor for each MRI contrast, and compared these with the normalized-intensity values obtained using automated NAWM (A-NAWM) masks as the normalization factor. ANOVA assessed the MTR differences across tissue types. Paired t-test or Wilcoxon signed-ranked test assessed FWML and DAWM differences between manual and automatically derived volumes. Pearson correlations assessed the relationship between MTR and normalized intensity values in the manual and automatically derived masks.
The mean Dice-kappa values for dataset 1 were: 0.79 for DAWM masks and 0.90 for FWML masks. In dataset 2, mean Dice-kappa values were: 0.78 for DAWM and 0.87 for FWML. In dataset 3, mean Dice-kappa values were 0.72 for DAWM, and 0.87 for FWML. Manual and automated DAWM and FWML volumes were not significantly different in all datasets. MTR values were significantly lower in manually and automatically derived FWML compared with DAWM in both datasets (dataset 1 manual: F = 111,08, p < 0.0001; automated: F = 153.90, p < 0.0001; dataset 2 manual: F = 31.25, p < 0.0001; automated: F = 74.04, p < 0.0001). In both datasets, manually derived FWML and DAWM MTR values showed significant correlations with normalized T1w (r = 0.77 to 0.94) intensities.
The separation of FWML and DAWM on MRI scans of MS patients using automated intensity thresholds on T2w images is feasible. MTR values are significantly lower in FWML than DAWM, and DAWM values are significantly lower than NAWM, reflecting potentially greater demyelination within focal lesions. T1w normalized intensity values exhibit a significant correlation with MTR values in both tissues of interest and could be used as a proxy to assess demyelination when MTR or other myelin-sensitive images are not available.
•The separation of FWML and DAWM on MRIof MS patients is feasible using automatically selected intensity thresholds on T2wMRI.•MTR values, which are sensitive to myelin content, are significantly lower in FWML than DAWM.•Normalized intensity values of T1w images exhibit strong correlation with MTR values, both in DAWM areas and FWML.•The proposed FWML/DWML separation script is publicly available at http://nist.mni.mcgill.ca/?p=2394
We investigated fluctuations in brain volume throughout the day using statistical modeling of magnetic resonance imaging (MRI) from large populations. We applied fully automated image analysis ...software to measure the brain parenchymal fraction (BPF), defined as the ratio of the brain parenchymal volume and intracranial volume, thus accounting for variations in head size. The MRI data came from serial scans of multiple sclerosis (MS) patients in clinical trials (n=755, 3269 scans) and from subjects participating in the Alzheimer's Disease Neuroimaging Initiative (ADNI, n=834, 6114 scans). The percent change in BPF was modeled with a linear mixed effect (LME) model, and the model was applied separately to the MS and ADNI datasets. The LME model for the MS datasets included random subject effects (intercept and slope over time) and fixed effects for the time-of-day, time from the baseline scan, and trial, which accounted for trial-related effects (for example, different inclusion criteria and imaging protocol). The model for ADNI additionally included the demographics (baseline age, sex, subject type normal, mild cognitive impairment, or Alzheimer's disease, and interaction between subject type and time from baseline).
There was a statistically significant effect of time-of-day on the BPF change in MS clinical trial datasets (−0.180 per day, that is, 0.180% of intracranial volume, p=0.019) as well as the ADNI dataset (−0.438 per day, that is, 0.438% of intracranial volume, p<0.0001), showing that the brain volume is greater in the morning. Linearly correcting the BPF values with the time-of-day reduced the required sample size to detect a 25% treatment effect (80% power and 0.05 significance level) on change in brain volume from 2 time-points over a period of 1year by 2.6%.
Our results have significant implications for future brain volumetric studies, suggesting that there is a potential acquisition time bias that should be randomized or statistically controlled to account for the day-to-day brain volume fluctuations.
•We used large MS and ADNI datasets to investigate diurnal brain volume changes.•There was a significant diurnal effect on brain volume changes.•Brain volumes were larger in the morning.•We recommend controlling for the acquisition time in future volumetric studies.
OBJECTIVETo summarize current and emerging imaging techniques that can be used to assess neuroprotection and repair in multiple sclerosis (MS), and to provide a consensus opinion on the potential ...utility of each technique in clinical trial settings.
METHODSClinicians and scientists with expertise in the use of MRI in MS convened in Toronto, Canada, in November 2016 at a North American Imaging in Multiple Sclerosis (NAIMS) Cooperative workshop meeting. The discussion was compiled into a manuscript and circulated to all NAIMS members in attendance. Edits and feedback were incorporated until all authors were in agreement.
RESULTSA wide spectrum of imaging techniques and analysis methods in the context of specific study designs were discussed, with a focus on the utility and limitations of applying each technique to assess neuroprotection and repair. Techniques were discussed under specific themes, and included conventional imaging, magnetization transfer ratio, diffusion tensor imaging, susceptibility-weighted imaging, imaging cortical lesions, magnetic resonance spectroscopy, PET, advanced diffusion imaging, sodium imaging, multimodal techniques, imaging of special regions, statistical considerations, and study design.
CONCLUSIONSImaging biomarkers of neuroprotection and repair are an unmet need in MS. There are a number of promising techniques with different strengths and limitations, and selection of a specific technique will depend on a number of factors, notably the question the trial seeks to answer. Ongoing collaborative efforts will enable further refinement and improved methods to image the effect of novel therapeutic agents that exert benefit in MS predominately through neuroprotective and reparative mechanisms.
Although multiple sclerosis has traditionally been considered a white matter disease, extensive research documents the presence and importance of grey matter injury including cortical and deep ...regions. The deep grey matter exhibits a broad range of pathology and is uniquely suited to study the mechanisms and clinical relevance of tissue injury in multiple sclerosis using magnetic resonance techniques. Deep grey matter injury has been associated with clinical and cognitive disability. Recently, MRI characterization of deep grey matter properties, such as thalamic volume, have been tested as potential clinical trial end points associated with neurodegenerative aspects of multiple sclerosis. Given this emerging area of interest and its potential clinical trial relevance, the North American Imaging in Multiple Sclerosis (NAIMS) Cooperative held a workshop and reached consensus on imaging topics related to deep grey matter. Herein, we review current knowledge regarding deep grey matter injury in multiple sclerosis from an imaging perspective, including insights from histopathology, image acquisition and post-processing for deep grey matter. We discuss the clinical relevance of deep grey matter injury and specific regions of interest within the deep grey matter. We highlight unanswered questions and propose future directions, with the aim of focusing research priorities towards better methods, analysis, and interpretation of results.
In this trial, daclizumab high-yield process (a monoclonal antibody that binds to CD25 and modulates interleukin-2 signaling) was more effective than interferon beta-1a in patients with ...relapsing–remitting multiple sclerosis. Infection and rash were more common with daclizumab.
Daclizumab is a humanized monoclonal antibody that binds to the alpha subunit (CD25) of the high-affinity interleukin-2 receptor.
1
,
2
Daclizumab treatment prevents signaling through the high-affinity interleukin-2 receptor and increases the availability of interleukin-2 to signal at its intermediate-affinity receptor.
1
,
2
The use of daclizumab in patients with multiple sclerosis was based initially on the hypothesis that it directly antagonizes activated CD25+ effector T cells, which have long been implicated as key mediators of the pathogenic effects of multiple sclerosis.
1
,
3
Notably, effector T-cell numbers and recall responses appear to be largely unaffected by daclizumab in vivo.
3
Other clinically important . . .
OBJECTIVE:To evaluate 5-year efficacy and safety of alemtuzumab in patients with active relapsing-remitting multiple sclerosis and inadequate response to prior therapy.
METHODS:In the 2-year ...Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis (CARE-MS) II study (NCT00548405), alemtuzumab-treated patients received 2 courses (baseline and 12 months later). Patients could enter an extension (NCT00930553), with as-needed alemtuzumab retreatment for relapse or MRI activity. Annualized relapse rate (ARR), 6-month confirmed disability worsening (CDW; ≥1-point Expanded Disability Status Scale EDSS score increase ≥1.5 if baseline EDSS = 0), 6-month confirmed disability improvement (CDI; ≥1-point EDSS decrease baseline score ≥2.0), no evidence of disease activity (NEDA), brain volume loss (BVL), and adverse events (AEs) were assessed.
RESULTS:Most alemtuzumab-treated patients (92.9%) who completed CARE-MS II entered the extension; 59.8% received no alemtuzumab retreatment. ARR was low in each extension year (years 3–50.22, 0.23, 0.18). Through 5 years, 75.1% of patients were free of 6-month CDW; 42.9% achieved 6-month CDI. In years 3, 4, and 5, proportions with NEDA were 52.9%, 54.2%, and 58.2%, respectively. Median yearly BVL remained low in the extension (years 1–5−0.48%, −0.22%, −0.10%, −0.19%, −0.07%). AE exposure-adjusted incidence rates in the extension were lower than in the core study. Thyroid disorders peaked at year 3, declining thereafter.
CONCLUSIONS:Alemtuzumab provides durable efficacy through 5 years in patients with an inadequate response to prior therapy in the absence of continuous treatment.
CLASSIFICATION OF EVIDENCE:This study provides Class III evidence that alemtuzumab provides efficacy and slowing of brain atrophy through 5 years.This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
Histamine H
3
receptor blockade may enhance lesion remyelination in multiple sclerosis (MS). The efficacy (using a magnetic resonance imaging marker of myelination, magnetisation transfer ratio MTR), ...safety and pharmacokinetics of GSK239512, a potent and brain penetrant H
3
receptor antagonist/inverse agonist on lesion remyelination in relapsing-remitting MS (RRMS) were assessed. This was a phase II, randomised, parallel-group, placebo-controlled, double-blind (sponsor-unblinded), international, multicentre study (NCT01772199). Patients aged 18–50 with RRMS, receiving intramuscular interferon-β1a or glatiramer acetate, were randomised 1:1 to once-daily oral GSK239512 or placebo, up-titrated over 4–5 weeks to a maximum tolerable dose up to 80 µg and maintained until Week 48. The co-primary endpoints were mean changes in post-lesion MTR in gadolinium-enhanced (GdE) or Delta-MTR defined lesions from pre-lesion values. Adverse events (AE) and withdrawals were monitored. Of the 131 patients randomised, 114 patients completed the study (GSK239512,
n
= 51; placebo,
n
= 63) and 27 (GSK239512) and 28 (placebo) patients contributed lesions to the primary analysis. GSK239512 was associated with positive effect sizes of 0.344 90% confidence interval (CI) 0.018, 0.671 and 0.243 (90% CI −0.112, 0.598) for adjusted mean changes in the normalised MTR for GdE and Delta-MTR lesions, respectively. The overall incidence of AEs was similar between GSK239512 and placebo during the treatment phase although some AEs including insomnia were more common with GSK239512, particularly during the titration period. A small but positive effect of GSK239512 on remyelination was observed. MTR assessment represents a promising method for detecting lesion remyelination in RRMS.
Onset of MS occurs during childhood in about 5% of cases. It is unclear whether very young age at MS onset, when the nervous system is still myelinating, affects MS lesion accrual or regional ...distribution.
To compare the frequency, volume and distribution of T2 and T1 lesions in children and adults with relapsing-remitting multiple sclerosis (RRMS).
Lesions were segmented on T2- and T1-weighted MRI images from 29 children and 29 adults with RRMS, matched for disease duration.
All subjects exhibited T2-weighted brain lesions. Children had higher whole-brain T2-weighted-lesion-volume (T2LV) compared to adults (mean (SD) in cm(3): 12.76(2.7) vs. 10.03(3.4), p<0.0013). The supratentorial-T2LV was similar in children and adults (8.45(1.7) vs. 7.94(1.7), mean (SD), p = 0.2582), but adults were more likely to have supratentorial lesions (96.5% vs. 68.9%, p<0.012). Children were more likely to have infratentorial-T2-weighted lesions (75.9% vs. 43.4%, p<0.03), specifically in the brainstem (62.1% vs. 26.7%, p<0.019) and the pons (48.3% vs. 17.24%, p<0.024), had higher infratentorial-T2-weighted-lesion counts (4.1(5.6) vs. 1.45(2.3), p<0.021), a greater infratentorial-T2LV (4.31(2.7) vs. 2.08(2.4), p<0.0013), and a greater infratentorial-T1-weighted-lesion-volume (T1LV) (3.7(2.5) vs. 1.08(1.9), p<0.0007). Whole-brain-T1LV was higher in children (9.3(2.5) vs. 6.43(2.1), p>0.001). Adult MS patients had higher supratentorial-T1LV (5.5(0.92) vs. 6.41(2.1), mean (SD), p<0.034), whereas children were more likely to have infratentorial-T1-weighted lesions (58.6% vs. 23.3%, p<0.015).
Onset of MS during childhood is associated with a higher volume of brain lesions in the first few years of disease relative to adults. Children with MS are more likely than adults to have T2 and T1 lesions in the infratentorial white matter, raising the possibility of preferential immune targeting of more mature myelin. Children with MS have a lower supratentorial T1 lesion burden, possibly reflecting more effective remyelination and repair in brain regions that are still engaged in active primary myelination.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
PDF
