Dataset Information

Structural disconnectivity from paramagnetic rim lesions is related to disability in multiple sclerosis.

ABSTRACT:

Background

In people with multiple sclerosis (pwMS), lesions with a hyperintense rim (rim+) on Quantitative Susceptibility Mapping (QSM) have been shown to have greater myelin damage compared to rim- lesions, but their association with disability has not yet been investigated. Furthermore, how QSM rim+ and rim- lesions differentially impact disability through their disruptions to structural connectivity has not been explored. We test the hypothesis that structural disconnectivity due to rim+ lesions is more predictive of disability compared to structural disconnectivity due to rim- lesions.

Methods

Ninety-six pwMS were included in our study. Individuals with Expanded Disability Status Scale (EDSS) <2 were considered to have lower disability (n = 59). For each gray matter region, a Change in Connectivity (ChaCo) score, that is, the percent of connecting streamlines also passing through a rim- or rim+ lesion, was computed. Adaptive Boosting was used to classify the pwMS into lower versus greater disability groups based on ChaCo scores from rim+ and rim- lesions. Classification performance was assessed using the area under ROC curve (AUC).

Results

The model based on ChaCo from rim+ lesions outperformed the model based on ChaCo from rim- lesions (AUC = 0.67 vs 0.63, p-value < .05). The left thalamus and left cerebellum were the most important regions in classifying pwMS into disability categories.

Conclusion

rim+ lesions may be more influential on disability through their disruptions to the structural connectome than rim- lesions. This study provides a deeper understanding of how rim+ lesion location/size and resulting disruption to the structural connectome can contribute to MS-related disability.

SUBMITTER: Tozlu C

PROVIDER: S-EPMC8553317 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Publications

Structural disconnectivity from paramagnetic rim lesions is related to disability in multiple sclerosis.

Tozlu Ceren C Jamison Keith K Nguyen Thanh T Zinger Nicole N Kaunzner Ulrike U Pandya Sneha S Wang Yi Y Gauthier Susan S Kuceyeski Amy A

Brain and behavior 20210908 10

<h4>Background</h4>In people with multiple sclerosis (pwMS), lesions with a hyperintense rim (rim+) on Quantitative Susceptibility Mapping (QSM) have been shown to have greater myelin damage compared to rim- lesions, but their association with disability has not yet been investigated. Furthermore, how QSM rim+ and rim- lesions differentially impact disability through their disruptions to structural connectivity has not been explored. We test the hypothesis that structural disconnectivity due to ...[more]

PMID: 34498432

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Project description:Prediction of disease progression is challenging in multiple sclerosis as the sequence of lesion development and retention of inflammation within a subset of chronic lesions is heterogeneous among patients. We investigated the sequence of lesion-related regional structural disconnectivity across the spectrum of disability and cognitive impairment in multiple sclerosis. In a full cohort of 482 multiple sclerosis patients (age: 41.83 ± 11.63 years, 71.57% females), the Expanded Disability Status Scale was used to classify patients into (i) no or mild (Expanded Disability Status Scale <3) versus (ii) moderate or severe disability groups (Expanded Disability Status Scale ≥3). In 363 out of 482 patients, quantitative susceptibility mapping was used to identify paramagnetic rim lesions, which are maintained by a rim of iron-laden innate immune cells. In 171 out of 482 patients, Brief International Cognitive Assessment was used to identify subjects as being cognitively preserved or impaired. Network Modification Tool was used to estimate the regional structural disconnectivity due to multiple sclerosis lesions. Discriminative event-based modelling was applied to investigate the sequence of regional structural disconnectivity due to (i) all representative T2 fluid-attenuated inversion recovery lesions, (ii) paramagnetic rim lesions versus non-paramagnetic rim lesions separately across disability groups ('no to mild disability' to 'moderate to severe disability'), (iii) all representative T2 fluid-attenuated inversion recovery lesions and (iv) paramagnetic rim lesions versus non-paramagnetic rim lesions separately across cognitive status ('cognitively preserved' to 'cognitively impaired'). In the full cohort, structural disconnection in the ventral attention and subcortical networks, particularly in the supramarginal and putamen regions, was an early biomarker of moderate or severe disability. The earliest biomarkers of disability progression were structural disconnections due to paramagnetic rim lesions in the motor-related regions. Subcortical structural disconnection, particularly in the ventral diencephalon and thalamus regions, was an early biomarker of cognitive impairment. Our data-driven model revealed that the structural disconnection in the subcortical regions, particularly in the thalamus, is an early biomarker for both disability and cognitive impairment in multiple sclerosis. Paramagnetic rim lesions-related structural disconnection in the motor cortex may identify the patients at risk for moderate or severe disability in multiple sclerosis. Such information might be used to identify people with multiple sclerosis who have an increased risk of disability progression or cognitive decline in order to provide personalized treatment plans.

Project description:BackgroundMultiple sclerosis (MS) paramagnetic rim lesions (PRLs) are markers of chronic active biology and exhibit complex iron and myelin changes that may complicate quantification when using conventional MRI approaches.PurposeTo conduct a multiparametric MRI analysis of PRLs.Study typeRetrospective/longitudinal.SubjectsNinety-five progressive MS subjects with at least one persistent PRL who were enrolled in the CONSONANCE trial.Field strength/sequence3-T/Susceptibility-weighted, T1-weighted, T2-weighted, and fluid-attenuated inversion recovery.AssessmentAcute/chronic PRLs and non-PRLs were measured at screening, 24, 48, and 96 weeks using quantitative magnetic susceptibility (QS), R2*, and standardized T1w/T2w ratio (sT1w/T2w). PRL analyses were performed for whole lesion, core, and rim. The correlations between PRL core and rim sT1w/T2w, QS, and R2* were assessed.Statistical testsLinear mixed models. A P-value <0.05 was considered significant.ResultsThere was a significant decrease in sT1w/T2w (-0.24 ± -5.3 × 10-3) and R2* (-3.6 ± 2.2 Hz) but a significant increase in QS (+21 ± 1.3 ppb) using whole-lesion analysis of chronic PRLs compared to non-PRLs at screening. Tissue damage accumulated at the 96-week time point was more evident in acute/chronic PRLs compared to acute/chronic non-PRLs (ΔsT1w/T2w = -0.21/-0.24 ± 0.033/0.0053; ΔR2* = -4.4/-3.6 ± 1.4/2.2 Hz). New, acute PRL sT1w/T2w significantly increased in lesion core (+4.3 × 10-3 ± 1.2 × 10-4) and rim (+5.6 × 10-3 ± 1.2 × 10-4) 24 weeks post lesion inception, suggestive of partial recovery. Chronic PRLs, contrastingly, showed significant decreases in sT1w/T2w over the initial 24 weeks for both core (-2.1 × 10-4 ± 2.0 × 10-5) and rim (-2.4 × 10-4 ± 2.0 × 10-5), indicative of irreversible tissue damage. Significant positive correlations between PRL core and rim sT1w/T2w (R2 = 0.53), R2* (R2 = 0.69) and QS (R2 = 0.52) were observed.Data conclusionMultiparametric assessment of PRLs has the potential to be a valuable tool for assessing complex iron and myelin changes in chronic active PRLs of progressive MS patients.Level of evidence2 TECHNICAL EFFICACY: Stage 3.

Project description:BackgroundRecent findings from several studies have shown that paramagnetic rim lesions identified using susceptibility-based MRI could represent potential diagnostic and prognostic biomarkers in multiple sclerosis (MS). Here, we perform a systematic review and meta-analysis of the existing literature to assess their pooled prevalence at lesion-level and patient-level.MethodsBoth database searching (PubMed and Embase) and handsearching were conducted to identify studies allowing the lesion-level and/or patient-level prevalence of rim lesions or chronic active lesions to be calculated. Pooled prevalence was estimated using the DerSimonian-Laird random-effects model. Subgroup analysis and meta-regression were performed to explore possible sources of heterogeneity. PROSPERO registration: CRD42020192282.Results29 studies comprising 1230 patients were eligible for analysis. Meta-analysis estimated pooled prevalences of 9.8% (95% CI: 6.6-14.2) and 40.6% (95% CI: 26.2-56.8) for rim lesions at lesion-level and patient-level, respectively. Pooled lesion-level and patient-level prevalences for chronic active lesions were 12.0% (95% CI: 9.0-15.8) and 64.8% (95% CI: 54.3-74.0), respectively. Considerable heterogeneity was observed across studies (I2>75%). Subgroup analysis revealed a significant difference in patient-level prevalence between studies conducted at 3T and 7T (p = 0.0312). Meta-regression analyses also showed significant differences in lesion-level prevalence with respect to age (p = 0.0018, R2 = 0.20) and disease duration (p = 0.0018, R2 = 0.48). Other moderator analyses demonstrated no significant differences according to MRI sequence, gender and expanded disability status scale (EDSS).ConclusionIn this study, we show that paramagnetic rim lesions may be present in an important proportion of MS patients, notwithstanding significant variation in their assessment across studies. In view of their possible clinical relevance, we believe that clear guidelines should be introduced to standardise their assessment across research centres to in turn facilitate future analyses.

Project description:ObjectivesThe aims of this study were to report the effectiveness and safety of teriflunomide in Chinese patients with relapsing-remitting multiple sclerosis (RRMS) and to explore the association of paramagnetic rim lesion (PRL) burden with patient outcome in the context of teriflunomide treatment and the impact of teriflunomide on PRL burden.MethodsThis is a prospective observational study. A total of 100 RRMS patients treated with teriflunomide ≥3 months were included in analyzing drug persistence and safety. Among them, 96 patients treated ≥6 months were included in assessing drug effectiveness in aspects of no evidence of disease activity (NEDA) 3. The number and total volume of PRL were calculated in 76 patients with baseline susceptibility-weighted imaging (SWI), and their association with NEDA3 failure during teriflunomide treatment was investigated.ResultsOver a treatment period of 19.7 (3.1-51.7) months, teriflunomide reduced annualized relapse rate (ARR) from 1.1 ± 0.8 to 0.3 ± 0.5, and Expanded Disability Status Scale (EDSS) scores remained stable. At month 24, the NEDA3% and drug persistence rate were 43.8% and 65.1%, respectively. In patients with a baseline SWI, 81.6% had at least 1 PRL, and 42.1% had ≥4 PRLs. The total volume of PRL per patient was 0.3 (0.0-11.5) mL, accounting for 2.3% (0.0%-49.0%) of the total T2 lesion volume. Baseline PRL number ≥ 4 (OR = 4.24, p = 0.009), younger onset age (OR = 0.94, p = 0.039), and frequent relapses in initial 2 years of disease (OR = 13.40, p = 0.026) were associated with NEDA3 failure. The PRL number and volume were not reduced (p = 0.343 and 0.051) after teriflunomide treatment for more than 24 months. No new safety concerns were identified in this study.ConclusionTeriflunomide is effective in reducing ARR in Chinese patients with RRMS. Patients with less PRL burden, less frequent relapses, and relatively older age are likely to benefit more from teriflunomide, indicating that PRL might be a valuable measurement to inform clinical treatment decision.

Dataset Information

Structural disconnectivity from paramagnetic rim lesions is related to disability in multiple sclerosis.

Background

Methods

Results

Conclusion

Publications

Structural disconnectivity from paramagnetic rim lesions is related to disability in multiple sclerosis.

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