Percentage Brain Volume Change Research Articles

Automatic estimation of brain parenchymal fraction in patients with multple sclerosis: a comparison between synthetic MRI and an established automated brain segmentation software based on FSL

PurposeWe aimed to validate the estimation of the brain parenchymal fraction (BPF) in patients with multiple sclerosis (MS) using synthetic magnetic resonance imaging (SyMRI) by comparison with software tools of the FMRIB Software Library (FSL). In addition to a cross-sectional method comparison, longitudinal volume changes were assessed to further elucidate the suitability of SyMRI for quantification of disease-specific changes.MethodsMRI data from 216 patients with MS and 28 control participants were included for volume estimation by SyMRI and FSL-SIENAX. Moreover, longitudinal data from 35 patients with MS were used to compare registration-based percentage brain volume changes estimated using FSL-SIENA to difference-based calculations of volume changes using SyMRI.ResultsWe observed strong correlations of estimated brain volumes between the two methods. While SyMRI overestimated grey matter and BPF compared to FSL-SIENAX, indicating a systematic bias, there was excellent agreement according to intra-class correlation coefficients for grey matter and good agreement for BPF and white matter. Bland–Altman plots suggested that the inter-method differences in BPF were smaller in patients with brain atrophy compared to those without atrophy. Longitudinal analyses revealed a tendency for higher atrophy rates for SyMRI than for SIENA, but SyMRI had a robust correlation and a good agreement with SIENA.ConclusionIn summary, BPF based on data from SyMRI and FSL-SIENAX is not directly transferable because an overestimation and higher variability of SyMRI values were observed. However, the consistency and correlations between the two methods were satisfactory, and SyMRI was suitable to quantify disease-specific atrophy in MS.

Short-term brain atrophy evolution after initiation of immunotherapy in a real-world multiple sclerosis cohort.

In multiple sclerosis (MS), brain atrophy measurements have emerged as an important biomarker reflecting neurodegeneration and disability progression. However, due to several potential confounders, investigation of brain atrophy in clinical routine and even in controlled clinical studies can be challenging. The aim of this study was to investigate the short-term dynamics of brain atrophy development after initiation of disease-modifying therapy (DMT) in a "real-world setting." In this retrospective study, we included MS patients starting DMT (natalizumab, fingolimod, dimethyl fumarate, or interferon-ß1a) or without DMT, availability of a baseline MRI, and two annual follow-up scans on the same MRI system. Two-timepoint percentage brain volume changes (PBVCs) were calculated. Fifty-five MS patients (12 patients starting DMT with natalizumab, 7 fingolimod, 14 dimethyl fumarate, 11 interferon-ß1a, and 11 patients without DMT) were included. We found the highest PBVCs in the first 12 months after initiation of natalizumab treatment. Furthermore, the PBVCs in our study were very much comparable to the results observed by other groups, as well as for fingolimod, dimethyl fumarate, and interferon-ß1a. We found PBVCs that are comparable to the results of previous studies, suggesting that brain atrophy, assessed on 3D MRI data sets acquired on the same 3T MRI, provides a robust MS biomarker.

Learning from pseudo-labels: deep networks improve consistency in longitudinal brain volume estimation.

Brain atrophy is a critical biomarker of disease progression and treatment response in neurodegenerative diseases such as multiple sclerosis (MS). Confounding factors such as inconsistent imaging acquisitions hamper the accurate measurement of brain atrophy in the clinic. This study aims to develop and validate a robust deep learning model to overcome these challenges; and to evaluate its impact on the measurement of disease progression. Voxel-wise pseudo-atrophy labels were generated using SIENA, a widely adopted tool for the measurement of brain atrophy in MS. Deformation maps were produced for 195 pairs of longitudinal 3D T1 scans from patients with MS. A 3D U-Net, namely DeepBVC, was specifically developed overcome common variances in resolution, signal-to-noise ratio and contrast ratio between baseline and follow up scans. The performance of DeepBVC was compared against SIENA using McLaren test-retest dataset and 233 in-house MS subjects with MRI from multiple time points. Clinical evaluation included disability assessment with the Expanded Disability Status Scale (EDSS) and traditional imaging metrics such as lesion burden. For 3 subjects in test-retest experiments, the median percent brain volume change (PBVC) for DeepBVC and SIENA was 0.105 vs. 0.198% (subject 1), 0.061 vs. 0.084% (subject 2), 0.104 vs. 0.408% (subject 3). For testing consistency across multiple time points in individual MS subjects, the mean (± standard deviation) PBVC difference of DeepBVC and SIENA were 0.028% (± 0.145%) and 0.031% (±0.154%), respectively. The linear correlation with baseline T2 lesion volume were r = -0.288 (p < 0.05) and r = -0.249 (p < 0.05) for DeepBVC and SIENA, respectively. There was no significant correlation of disability progression with PBVC as estimated by either method (p = 0.86, p = 0.84). DeepBVC is a deep learning powered brain volume change estimation method for assessing brain atrophy used T1-weighted images. Compared to SIENA, DeepBVC demonstrates superior performance in reproducibility and in the context of common clinical scan variances such as imaging contrast, voxel resolution, random bias field, and signal-to-noise ratio. Enhanced measurement robustness, automation, and processing speed of DeepBVC indicate its potential for utilisation in both research and clinical environments for monitoring disease progression and, potentially, evaluating treatment effectiveness.

Effect of Longer-term Ofatumumab Treatment on Disability Progression and Brain Volume Change (S16.009)

Effect of Longer-term Ofatumumab Treatment on Disability Progression and Brain Volume Change (S16.009)

Disease Outcomes With Ublituximab in Participants With Highly Active Disease: Subpopulation Analyses of the Phase 3 ULTIMATE I and II Studies in Participants With Relapsing Multiple Sclerosis (P6-3.002)

Disease Outcomes With Ublituximab in Participants With Highly Active Disease: Subpopulation Analyses of the Phase 3 ULTIMATE I and II Studies in Participants With Relapsing Multiple Sclerosis (P6-3.002)

Longitudinal Brain Volume Findings in an Outpatient Practice of Young People with MS (P11-3.001)

<h3>Objective:</h3> To assess in an outpatient setting the application of volumetrics with brain MRI among young people with multiple sclerosis (MS). <h3>Background:</h3> Research on brain atrophy in MS has illuminated how inflammation and neurodegenerative processes lead to cognitive and neurologic declines. However, brain volume assessment is rarely used in routine practice. Here, we examined predominantly pediatric onset MS and some younger adult-onset MS patients who underwent routine brain MRI including volumetrics. Our goal was to assess the impact of brain volume change on clinical outcomes including SDMT in this relatively young and stable MS subset. <h3>Design/Methods:</h3> 77 patients with pediatric or adult onset RRMS or CIS, 31 years of age or younger, were evaluated with at least two MRI studies. Volume data was computed on MRI images with icobrain ms software, compared to age- and sex-related norms and adjusted for differences across the various Siemens 3T scanners. Changes in volumes of whole brain (WB), white matter (WM), grey matter (GM), lateral ventricles (LV), and thalamus were calculated as an average annualized percent brain volume change per year. <h3>Results:</h3> The mean patient age was 21.6 years (range 12–31); 70% were female. The annual mean decrease of WB volume: −0.473%, WM: −0.390%, GM: −0.517%, thalamus: −0.552%, and annual LV volume increase: 1.78%. A total of 32.5% of patients had an annual decrease in GM volume &gt;0.8% (the 90% threshold for measurement error). 29.9% of patients had LV volumes increase &gt;3.5%. Whole brain volume loss and lateral ventricle increase was significantly correlated, r=−0.34 (p=0.002). Clinical and demographic features between those whose brain volume declined and those whose brain volumes remained stable will be presented. <h3>Conclusions:</h3> Quantitative MRI is a useful technique which has only begun to be incorporated into clinical practice. A proportion of young otherwise stable patients with RRMS show brain volume loss under computer-assisted analyses. <b>Disclosure:</b> Dr. O’Neill has nothing to disclose. Dr. Couvreur has received personal compensation in the range of $10,000-$49,999 for serving as a Intern Clinical application specialist at icometrix with The Prince Albert Fund. Dr. Hu has nothing to disclose. Mr. Zhang has nothing to disclose. Ms. Pehel has nothing to disclose. Ms. Sosa has nothing to disclose. Ms. Fade has nothing to disclose. Elayne Feld has nothing to disclose. Dr. Chen has received personal compensation for serving as an employee of icometrix. Dr. De Barros has received personal compensation for serving as an employee of Icometrix. Thibo Billiet has received personal compensation for serving as an employee of icometrix. Annemie Ribbens, 9599 has received personal compensation for serving as an employee of icometrix. Annemie Ribbens, 9599 has stock in icometrix. Dr. Krupp has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche. Dr. Krupp has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis. Dr. Krupp has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Janssen. Dr. Krupp has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Gerson Lerhman. Dr. Krupp has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for medscape. Dr. Krupp has received personal compensation in the range of $500-$4,999 for serving as a Consultant for NeuroLive. Dr. Krupp has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Eisai. Dr. Krupp has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi. Dr. Krupp has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Dr. Krupp has received personal compensation in the range of $500-$4,999 for serving as an officer or member of the Board of Directors for Cleveland Clinic. Dr. Krupp has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for MCIC. The institution of Dr. Krupp has received research support from Biogen. The institution of Dr. Krupp has received research support from National Multiple Sclerosis Society. Dr. Krupp has received intellectual property interests from a discovery or technology relating to health care.

Disability progression and worse cognitive status are associated with higher concurrent brain atrophy rates (P13-3.007)

<h3>Objective:</h3> To determine associations between brain atrophy rate and clinical outcome measures in multiple sclerosis (MS). <h3>Background:</h3> The determination and treatment of neurodegenerative aspects of MS remains a challenge. One indirect form of assessment is the whole brain atrophy rate as determined by longitudinal MRI. Integration of brain atrophy rate assessments into clinical practice is hampered by multiple technical and translational factors, including incomplete clinical validation. It remains unclear to what extent clinical assessments are reflected and associated with this measure. <h3>Design/Methods:</h3> In a large retrospective observational cohort, we used FSL-SIENA to determine annualized percent brain volume change (aPBVC) from longitudinal clinical 3T MRI obtained using a uniform hardware and software acquisition protocol. Clinical outcomes, including confirmed disability progression, the 9-hole peg test (9HPT), the symbol digit modalities test (SDMT), and the timed-25-foot walk (T25w) were determined from retrospective chart review. SDMT, 9HPT, and T25w were averaged between the first and second MRI sessions to produce a single number. Using forward regression models, we assessed clinical predictors of aPBVC, including CDP and secondary clinical outcome measures, as independent variables along with age of onset and type of MS. <h3>Results:</h3> 123 patients met inclusion criteria (102 RMS, 21 PMS; mean age = 36 ±SD 11) with available clinical and MRI data. In univariable analyses, confirmed disability progression showed the strongest association with concurrent aPBVC (β=0.31, p &lt;0.001), followed by the SDMT (β=0.27, p=0.006) whereas 9HPT and T25 were not significant (p&gt;0.05). Change in EDSS and cross-sectional SDMT both remained significantly associated in multivariable models (p=0.008 and p=0.04, respectively). <h3>Conclusions:</h3> Both disability progression as well as the SDMT are independently associated with the observed brain atrophy rate. <b>Disclosure:</b> Dr. Garcia-Dominguez has nothing to disclose. Dr. Hemond has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for VIVIO Health. Dr. Hemond has stock in VIVIO Health. The institution of Dr. Hemond has received research support from Consorium of Multiple Sclerosis Centers. The institution of Dr. Hemond has received research support from National Multiple Sclerosis Society. The institution of Dr. Hemond has received research support from National Center for Advancing Translational Sciences, National Institutes of Health. The institution of Dr. Hemond has received research support from University of Massachusetts Memorial Medical Center. The institution of Dr. Hemond has received research support from National Institute Of Neurological Disorders And Stroke of the National Institutes of Health. Dr. Hemond has received personal compensation in the range of $0-$499 for serving as a Member of Data Safety and Monitoring Board with National Institute Of Neurological Disorders And Stroke of the National Institutes of Health.

Assessing the Equivalence of Brain-Derived Measures from Two 3D T1-Weighted Acquisitions: One Covering the Brain and One Covering the Brain and Spinal Cord.

In MS, it is common to acquire brain and spinal cord MR imaging sequences separately to assess the extent of the disease. The goal of this study was to see how replacing the traditional brain T1-weighted images (brain-T1) with an acquisition that included both the brain and the cervical spinal cord (cns-T1) affected brain- and spinal cord-derived measures. Thirty-six healthy controls (HC) and 42 patients with MS were included. Of those, 18 HC and 35 patients with MS had baseline and follow-up at 1 year acquired on a 3T magnet. Two 3D T1-weighted images (brain-T1 and cns-T1) were acquired at each time point. Regional cortical thickness and volumes were determined with FastSurfer, and the percentage brain volume change per year was obtained with SIENA. The spinal cord area was estimated with the Spinal Cord Toolbox. Intraclass correlation coefficients (ICC) were calculated to check for consistency of measures obtained from brain-T1 and cns-T1. Cortical thickness measures showed an ICC >0.75 in 94% of regions in healthy controls and 80% in patients with MS. Estimated regional volumes had an ICC >0.88, and the percentage brain volume change had an ICC >0.79 for both groups. The spinal cord area measures had an ICC of 0.68 in healthy controls and 0.92 in patients with MS. Brain measurements obtained from 3D cns-T1 are highly equivalent to those obtained from a brain-T1, suggesting that it could be feasible to replace the brain-T1 with cns-T1.

Multiple sclerosis optic neuritis and trans-synaptic pathology on cortical thinning in people with multiple sclerosis.

The multi-order visual system represents an excellent testing site regarding the process of trans-synaptic degeneration. The presence and extent of global versus trans-synaptic neurodegeneration in people with multiple sclerosis(pwMS) is not clear. To explore cross-sectional and longitudinal relationships between retinal, thalamic and cortical changes in pwMS with and without MS-related optic neuritis (pwMSON and pwoMSON) using MRI and optical coherence tomography (OCT). 162 pwMS and 47 healthy controls (HCs) underwent OCT and brain MRI at baseline and 5.5-years follow-up. Peripapillary retinal nerve fiber layer (pRNFL) and macular ganglion cell inner plexiform layer (mGCIPL) thicknesses were determined. Global volume measures of brain parenchymal volume (BPV)/percent brain volume change (PBVC), thalamic volume and T2-lesion volume (LV) were derived using standard analysis protocols. Regional cortical thickness was determined using FreeSurfer. Cross-sectional and longitudinal relationship between the retinal measures, thalamic volume and cortical thickness were assessed using age, BPV/PBVC and T2-LV adjusted correlations and regressions. After age, BPV and T2-LV adjustment, the thalamic volume explained additional variance in the thickness of pericalcarine (R2 increase of 0.066, standardized β = 0.299, p = 0.039) and lateral occipital (R2 increase of 0.024, standardized β = 0.299, p = 0.039) gyrii in pwMSON. In pwoMSON, the thalamic volume was a significant predictor only of control (frontal) regions of pars opercularis. There was no relationship between thalamic atrophy and cortical thinning over the follow-up in both pwMS with and without MSON. While numerically lower in the pwMSON group, the inter-eye difference was not able to predict the presence of MSON. MSON can induce a measurable amount of trans-synaptic pathology on second-order cortical regions.

Prognostic significance of neurofilament light in Fingolimod therapy for Multiple Sclerosis: A systemic review and meta-analysis based on randomized control trials

This research was conducted to assess Neurofilament light chain (NfL) as prognostic factor for Multiple Sclerosis and effect of Fingolimod on plasma levels of NfL. A systemic search was conducted from electronic databases (PubMed/Medline, Cochrane Library, and Google Scholar) from inception to 7th September 2022. All statistical analyses were conducted in Review Manager 5.4.1. Studies meeting inclusion criteria were selected. Only those studies that involved Multiple sclerosis patients in which plasma levels of NfL was provided and Fingolimod was used in the treatment group. Fixed-effect model was used to pool the studies to assess NfL as prognostic factor, which was reported in the Hazards ratio (HR) and their corresponding 95% confidence interval (CI). Moreover, effect of Fingolimod on NfL levels was analysed qualitatively. Five Randomized Controlled Trials were used in the study. Four studies were used in quantitative analysis which showed increased NfL was related to significant increase in cognitive disability worsening (HR= 1.66 [1.35, 2.05]; p< 0.00001; I2= 0%). The qualitative analysis method was employed to evaluate the factors correlating with increased NfL levels in Multiple Sclerosis patients. Five studies evaluated that there was significant decrease in NfL levels when Fingolimod was used as compared to placebo. 4 studies were included to correlated NfL levels with clinical and MRI parameters and association was found between increasing NfL levels and relapses, active/new T2 lesions and percentage of brain volume change. The results of our meta-analysis and systematic review demonstrated statistically significant effect of NfL as a prognostic marker with its level being decreased significantly when Fingolimod was used for treating Multiple Sclerosis.

Percentage brain volume change in multiple sclerosis mainly reflects white matter and cortical volume.

Brain atrophy in multiple sclerosis (MS), as measured by percentage brain volume change (PBVC) from brain magnetic resonance imaging (MRI), has been established as an outcome parameter in clinical trials. It is unknown to what extent volume changes within different brain tissue compartments contribute to PBVC. We analyzed pairs of MRI scans (at least 6 months apart) in 600 patients with relapsing-remitting MS. Multiple regression revealed that PBVC mainly reflects volume loss of white and cortical gray matter, while deep gray matter and white matter lesions were less represented. Our findings aid the interpretation of PBVC changes in MS.

Early spinal cord pseudoatrophy in interferon-beta-treated multiple sclerosis.

Brain pseudoatrophy has been shown to play a pivotal role in the interpretation of brain atrophy measures during the first year of disease-modifying therapy in multiple sclerosis. Whether pseudoatrophy also affects the spinal cord remains unclear. The aim of this study was to analyze the extent of pseudoatrophy in the upper spinal cord during the first 2 years after therapy initiation and compare this to the brain. A total of 129 patients from a prospective longitudinal multicentric national cohort study for whom magnetic resonance imaging scans at baseline, 12 months, and 24 months were available were selected for brain and spinal cord volume quantification. Annual percentage brain volume and cord area change were calculated using SIENA (Structural Image Evaluation of Normalized Atrophy) and NeuroQLab, respectively. Linear mixed model analyses were performed to compare patients on interferon-beta therapy (n= 84) and untreated patients (n= 45). Patients treated with interferon-beta demonstrated accelerated annual percentage brain volume and cervical cord area change in the first year after treatment initiation, whereas atrophy rates stabilized to a similar and not significantly different level compared to untreated patients during the second year. These results suggest that pseudoatrophy occurs not only in the brain, but also in the spinal cord during the first year of interferon-beta treatment.

Neurofilament-light and contactin-1 association with long-term brain atrophy in natalizumab-treated relapsing-remitting multiple sclerosis

Background: Despite highly effective treatment strategies for patients with relapsing-remitting multiple sclerosis (RRMS), long-term neurodegeneration and disease progression are often considerable. Accurate blood-based biomarkers that predict long-term neurodegeneration are lacking. Objective: To assess the predictive value of serum neurofilament-light (sNfL) and serum contactin-1 (sCNTN1) for long-term magnetic resonance imaging (MRI)–derived neurodegeneration in natalizumab-treated patients with RRMS. Methods: sNfL and sCNTN1 were measured in an observational cohort of natalizumab-treated patients with RRMS at baseline (first dose) and at 3 months, Year 1, Year 2, and last follow-up (median = 5.2 years) of treatment. Disability progression was quantified using “EDSS-plus” criteria. Neurodegeneration was measured by calculating annualized percentage brain, ventricular, and thalamic volume change (PBVC, VVC, and TVC, respectively). Linear regression analysis was performed to identify longitudinal predictors of neurodegeneration. Results: In total, 88 patients (age = 37 ± 9 years, 75% female) were included, of whom 48% progressed. Year 1 sNfL level (not baseline or 3 months) was associated with PBVC (standardized (std.) β = −0.26, p = 0.013), VVC (standardized β = 0.36, p < 0.001), and TVC (standardized β = −0.24, p = 0.02). For sCNTN1, only 3-month level was associated with VVC (standardized β = −0.31, p = 0.002). Conclusion: Year 1 (but not baseline) sNfL level was predictive for long-term brain atrophy in patients treated with natalizumab. sCNTN1 level did not show a clear predictive value.

Effect of ocrelizumab on leptomeningeal inflammation and humoral response to Epstein-Barr virus in multiple sclerosis. A pilot study

BackgroundOcrelizumab is an effective treatment for relapsing and primary-progressive multiple sclerosis (MS). However, the effect of ocrelizumab on leptomeningeal (LM) inflammation is unknown. ObjectiveTo investigate whether ocrelizumab reduces LM inflammation by reducing the exposure to Epstein-Barr virus (EBV)-infected B cells in relapsing-remitting (RR) MS. MethodsThis was a Phase IV, prospective, open-label, single-center, observational, longitudinal pilot study of RRMS patients who started treatment with ocrelizumab (NCT03025269). Clinical, MRI and EBV-antibodies outcomes at baseline, 12- and 24-month of the study were evaluated. The MRI outcomes included T2, T1 and T1-contrast enhancing (CE) lesion counts and volumes, LM CE count, and percentage brain volume changes. Results27 RRMS patients started ocrelizumab and 24 remained on the treatment for whole duration of the study. Most patients remained stable (74.1%) or improved (18.5%) in their disability status. At baseline, 42.3% of patients showed LM CE lesions. The majority of patients remained stable in their LM CE status over the follow-up (72.7%). A significant decrease in percentage volume loss of cortex (p=0.009), GM (p=0.01) and thalamus (p=0.038) was detected, while T1-LV increased (p=0.02). A significant decrease of EBNA-1 IgG (p=0.013) was evidenced. An infusion-related allergic reaction led to discontinuation of the medication in one patient at first dose. ConclusionsTreatment with ocrelizumab was safe and clinically effective. Brain volume loss and accumulation of T1-LV occurred. While ocrelizumab decreased humoral response to EBV possibly by reducing B cells, it did not reduce LM inflammation.

The spatio-temporal relationship between white matter lesion volume changes and brain atrophy in clinically isolated syndrome and early multiple sclerosis

BackgroundWhite matter lesions and brain atrophy are both present early in multiple sclerosis. However, the spatio-temporal relationship between atrophy and lesion processes remains unclear. MethodsYearly magnetic resonance images were analyzed in 392 patients with clinically isolated syndrome from the 5-year REFLEX/REFLEXION studies. Patients received early treatment (from baseline; N = 262) or delayed treatment (from month-24; N = 130) with subcutaneous interferon beta-1a. Global and central atrophy were assessed using FSL-SIENA to provide yearly percentage volume change of brain and ventricles, respectively. Yearly total lesion volume change was calculated by subtracting the sum of the negative lesion volume change (disappearing + shrinking) from the positive lesion volume change (new + enlarging) for each yearly interval, as determined by an in-house developed semi-automated method. Using linear mixed models, during the period where patients had received ≥1 year of treatment, we investigated whether total lesion volume change was associated with percentage brain volume change or percentage ventricular volume change in the next year, and vice versa. ResultsHigher total lesion volume change was related to significantly faster global atrophy (percentage brain volume change) in the next year (B = − 0.113, SE = 0.022, p < 0.001). In patients receiving early treatment only, total lesion volume change was also associated with percentage ventricular volume change in the next year (B = 1.348, SE = 0.181, p < 0.001). Voxel-wise analyses showed that in patients receiving early treatment, higher total lesion volume change in years 2, 3, and 4 was related to faster atrophy in the next year, and in year 4 this relationship was stronger in patients receiving delayed treatment. Interestingly, faster atrophy was related to higher total lesion volume change in the next year (percentage brain volume change: B = − 0.136, SE = 0.062, p = 0.028; percentage ventricular volume change: B = 0.028, SE = 0.008, p < 0.001). ConclusionsHigher lesion volume changes were associated with faster atrophy in the next year. Interestingly, there was also an association between faster atrophy and higher lesion volume changes in the next year.

CONCERTO: A randomized, placebo-controlled trial of oral laquinimod in relapsing-remitting multiple sclerosis

Background: Interventions targeting the adaptive immune response are needed in multiple sclerosis (MS). Objective: Evaluate laquinimod’s efficacy, safety, and tolerability in patients with relapsing-remitting multiple sclerosis (RRMS). Methods: CONCERTO was a randomized, double-blind, placebo-controlled, phase-3 study. RRMS patients were randomized 1:1:1 to receive once-daily oral laquinimod 0.6 or 1.2 mg or placebo for ⩽24 months (n = 727, n = 732, and n = 740, respectively). Primary endpoint was time to 3-month confirmed disability progression (CDP). The laquinimod 1.2-mg dose arm was discontinued (1 January 2016) due to cardiovascular events at high doses. Safety was monitored throughout the study. Results: CONCERTO did not meet the primary endpoint of significant effect with laquinimod 0.6-mg versus placebo on 3-month CDP (hazard ratio: 0.94; 95% confidence interval: 0.67–1.31; p = 0.706). Secondary endpoint p values were nominal and non-inferential. Laquinimod 0.6 mg demonstrated 40% reduction in percent brain volume change from baseline to Month 15 versus placebo (p < 0.0001). The other secondary endpoint, time to first relapse, and annualized relapse rate (an exploratory endpoint) were numerically lower (both, p = 0.0001). No unexpected safety findings were reported with laquinimod 0.6 mg. Conclusion: Laquinimod 0.6 mg demonstrated only nominally significant effects on clinical relapses and magnetic resonance imaging (MRI) outcomes and was generally well tolerated. Clinical trial registration number: ClinicalTrials.gov (NCT01707992).

Brain atrophy rates in patients with multiple sclerosis on long term natalizumab resembles healthy controls

BackgroundClinically stable multiple sclerosis (MS) patients often have negligible inflammatory MRI changes. Brain atrophy may provide insight into subclinical disease progression. The objective was to compare brain atrophy rates in stable patients on long term natalizumab treatment vs. age and gender matched healthy non-MS controls (HC) prospectively over two-years examining brain volume, cognition, and patient reported outcomes (PROs). MethodsMS patients treated with natalizumab for a minimum of 2 years, age 18-60 were recruited and compared with age- and gender-matched healthy controls (HC). Both groups were followed prospectively to obtain two years of consecutive magnetic resonance imaging, clinical and PRO data. Baseline normalized brain volume (NBV), yearly T2 lesion volume (T2LV), and percent brain volume change (PBVC) were measured using SIENAX, JIM 6.0, and SIENA respectively. Neuropsychological tests from the MACFIMS battery were selected to optimize assessments for impairments in the domains of information processing speed and memory. Patient reported outcomes (PROs) for domains of physical, mental and social quality of life were evaluated using the NeuroQol short forms. ResultsForty-eight natalizumab and 62 HC completed all study visits. At baseline, unadjusted mean NBV (natalizumab=1508.80cm (Popescu et al., 2013) vs. HC=1539.23cm (Popescu et al., 2013); p=0.033) and median baseline T2LV (natalizumab=1724.62mm (Popescu et al., 2013) vs. HC=44.20mm (Popescu et al., 2013); p=<0.0001) were different. The mean PBVC at year 2, adjusted for gender and baseline age was -0.57% (CI: 0.7620, -0.3716) for natalizumab and -0.50% (-0.7208, -0.2831) for HC, but the difference between groups was not statistically significant (0.073%; p=0.62). Over the 2-year period, HC demonstrated mild improvements in some cognitive tests vs. natalizumab subjects. However, PROs were similar between the two groups. ConclusionStable MS patients on natalizumab have similar brain volume loss as people who do not have MS, suggesting normalization of brain atrophy.

Generating Longitudinal Atrophy Evaluation Datasets on Brain Magnetic Resonance Images Using Convolutional Neural Networks and Segmentation Priors.

Brain atrophy quantification plays a fundamental role in neuroinformatics since it permits studying brain development and neurological disorders. However, the lack of a ground truth prevents testing the accuracy of longitudinal atrophy quantification methods. We propose a deep learning framework to generate longitudinal datasets by deforming T1-w brain magnetic resonance imaging scans as requested through segmentation maps. Our proposal incorporates a cascaded multi-path U-Net optimised with a multi-objective loss which allows its paths to generate different brain regions accurately. We provided our model with baseline scans and real follow-up segmentation maps from two longitudinal datasets, ADNI and OASIS, and observed that our framework could produce synthetic follow-up scans that matched the real ones (Total scans= 584; Median absolute error: 0.03 ± 0.02; Structural similarity index: 0.98 ± 0.02; Dice similarity coefficient: 0.95 ± 0.02; Percentage of brain volume change: 0.24 ± 0.16; Jacobian integration: 1.13 ± 0.05). Compared to two relevant works generating brain lesions using U-Nets and conditional generative adversarial networks (CGAN), our proposal outperformed them significantly in most cases (p < 0.01), except in the delineation of brain edges where the CGAN took the lead (Jacobian integration: Ours - 1.13 ± 0.05 vs CGAN - 1.00 ± 0.02; p < 0.01). We examined whether changes induced with our framework were detected by FAST, SPM, SIENA, SIENAX, and the Jacobian integration method. We observed that induced and detected changes were highly correlated (Adj. R2 > 0.86). Our preliminary results on harmonised datasets showed the potential of our framework to be applied to various data collections without further adjustment.

Clinical feasibility of longitudinal lateral ventricular volume measurements on T2-FLAIR across MRI scanner changes

BackgroundGreater brain atrophy is associated with disability progression (DP) in patients with multiple sclerosis (PwMS). However, methodological challenges limit its routine clinical use. ObjectiveTo determine the feasibility of atrophy measures as markers of DP in PwMS scanned across different MRI field strengths. MethodsA total of 980 PwMS were scanned on either 1.5 T or 3.0 T MRI scanners. Demographic and clinical data were retrospectively collected, and the presence of DP was determined according to standard clinical trial criteria. Lateral ventricular volume (LVV) change was measured with the NeuroSTREAM technique on clinical routine T2-FLAIR images. Percent brain volume change (PBVC) was measured using SIENA and ventricular cerebrospinal fluid (vCSF) % change was measured using VIENA and SIENAX algorithms on 3D T1-weighted images (WI). Stable vs. DP PwMS were compared using analysis of covariance (ANCOVA). Mixed modeling determined the effect of MRI scanner change on MRI-derived atrophy measures. ResultsLongitudinal LVV analysis was successful in all PwMS. SIENA-based PBVC and VIENA-based changes failed in 37.6% of cases, while SIENAX-based vCSF failed in 12.9% of cases. PwMS with DP (n = 241) had significantly greater absolute (20.9% vs. 8.7%, d = 0.66, p < 0.001) and annualized LVV % change (4.1% vs. 2.3%, d = 0.27, p < 0.001) when compared to stable PwMS (n = 739). In subjects with both analyses available, both 3D-T1 and T2-FLAIR-based analyses differentiated PwMS with DP (n = 149). However, only NeuroSTREAM and VIENA-based LVV/vCSF were able to show greater atrophy in PwMS that were scanned on different scanners. PBVC and SIENAX-based vCSF % changes were significantly affected by scanner change (Beta = −0.16, t-statistics = −2.133, p = 0.033 and Beta = −2.08, t-statistics = −4.084, p < 0.001), whereas no MRI scanner change effects on NeuroSTREAM-based PLVVC and VIENA-based vCSF % change were noted. ConclusionsLVV-based atrophy on T2-FLAIR is a clinically relevant measure in spite of MRI scanner changes and mild disability levels.

Multimodal MRI Response to Fingolimod in Multiple Sclerosis: A Nonrandomized, Single Arm, Observational Study.

Fingolimod has a favorable effect on conventional MRI measures; however, its neuroprotective effect is not clear. We aim to investigate changes of conventional and advanced MRI measures in lesions and normal-appearing white matter (NAWM) over 2 years in fingolimod-treated patients. Fifty relapsing-remitting multiple sclerosis patients and 27 healthy controls were enrolled in the study and underwent baseline, 1-year, and 2-year 3T MRI scans. T2 lesion volume, whole brain volume, cortical gray matter volume, white matter volume, corpus callosum area, percentage brain volume change (PBVC), Expanded Disability Status Scale, gadolinium-enhancing lesions, PBVC, magnetization transfer ratio (MTR), and diffusion tensor imaging metrics (fractional anisotropy [FA] and median diffusivity [MD]) in lesions and NAWM were calculated. Longitudinal changes were examined using one-way repeated measures ANOVA. Bonferroni correction for multiple testing was used when appropriate. Conventional MRI measures were unchanged in both groups. Lesion MTR increased significantly (P < .001), but NAWM-MTR remained unchanged. Lesion FA improved significantly in year 1 (P = .003) and over the study duration (P = .05). Lesion MD changed significantly from baseline to year 1 (P < .001) and remained stable over 2 years. NAWM-FA was significant from baseline to year 1 (P = .002) and from baseline to year 2 (P < .001). NAWM-MD was significant only from baseline to year 1 (P = .001). These findings suggest a possible neuroreparative effect of fingolimod on the MS lesions and NAWM. Larger and longer randomized studies are required to confirm these results.