Broad rim lesions are a novel pathological / morphological and imaging biomarker for rapid disease progression in Multiple Sclerosis
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE281807 | GEO | 2025/02/12
REPOSITORIES: GEO
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Project description:Current Multiple Sclerosis (MS) treatments reduce relapse activity but have limited impact on disease progression. Clinical trials targeting progression often fail due to insufficient understanding of its underlying mechanisms. This study analyzes a clinically well-characterized MS autopsy cohort comparing selected individuals with opposite disease trajectories of slow versus rapid progression by extensive unbiased histology and spatial transcriptomics. It unveils a novel lesion type marked by an extensive myeloid cell rim with cellular and transcriptional signatures of inflammation, enhanced antigen presentation and lymphocyte activation that is strongly linked to rapid progression. Validation through an independent TSPO-PET study confirms the association between lesions with a broad myeloid cell rim and disease progression. These findings offer crucial insights into the mechanisms behind MS progression, identifying broad rim lesions as a biomarker for rapid disease progression and potentially guiding patient selection for future therapeutic trials targeting CNS intrinsic inflammation.
2025-02-12 | GSE281805 | GEO
Project description:Current Multiple Sclerosis (MS) treatments reduce relapse activity but have limited impact on disease progression. Clinical trials targeting progression often fail due to insufficient understanding of its underlying mechanisms. This study analyzes a clinically well-characterized MS autopsy cohort comparing selected individuals with opposite disease trajectories of slow versus rapid progression by extensive unbiased histology and spatial transcriptomics. It unveils a novel lesion type marked by an extensive myeloid cell rim with cellular and transcriptional signatures of inflammation, enhanced antigen presentation and lymphocyte activation that is strongly linked to rapid progression. Validation through an independent TSPO-PET study confirms the association between lesions with a broad myeloid cell rim and disease progression. These findings offer crucial insights into the mechanisms behind MS progression, identifying broad rim lesions as a biomarker for rapid disease progression and potentially guiding patient selection for future therapeutic trials targeting CNS intrinsic inflammation.
2025-02-12 | GSE264094 | GEO
Project description:Broad rim lesions are a novel pathological / morphological and imaging biomarker for rapid disease progression in Multiple Sclerosis
| PRJNA1185732 | ENA
Project description:Broad rim lesions are a novel pathological / morphological and imaging biomarker for rapid disease progression in Multiple Sclerosis (part 2)
| PRJNA1185739 | ENA
Project description:Broad rim lesions are a novel pathological / morphologicaland imaging biomarker for rapid disease progression in Multiple Sclerosis (part 1)
| PRJNA1100974 | ENA
Project description:In multiple sclerosis (MS), iron accumulates inside activated microglia/macrophages at edges of some chronic demyelinated lesions, forming rims. In susceptibility-based magnetic resonance imaging at 7 T, iron-laden microglia/macrophages induce a rim of decreased signal at lesion edges and have been associated with slowly expanding lesions. We aimed to determine (1) what lesion types and stages are associated with iron accumulation at their edges, (2) what cells at the lesion edges accumulate iron and what is their activation status, (3) how reliably can iron accumulation at the lesion edge be detected by 7 T magnetic resonance imaging (MRI), and (4) if lesions with rims enlarge over time in vivo, when compared to lesions without rims. Double-hemispheric brain sections of 28 MS cases were stained for iron, myelin, and microglia/macrophages. Prior to histology, 4 of these 28 cases were imaged at 7 T using post-mortem susceptibility-weighted imaging. In vivo, seven MS patients underwent annual neurological examinations and 7 T MRI for 3.5 years, using a fluid attenuated inversion recovery/susceptibility-weighted imaging fusion sequence. Pathologically, we found iron rims around slowly expanding and some inactive lesions but hardly around remyelinated shadow plaques. Iron in rims was mainly present in microglia/macrophages with a pro-inflammatory activation status, but only very rarely in astrocytes. Histological validation of post-mortem susceptibility-weighted imaging revealed a quantitative threshold of iron-laden microglia when a rim was visible. Slowly expanding lesions significantly exceeded this threshold, when compared with inactive lesions (p = 0.003). We show for the first time that rim lesions significantly expanded in vivo after 3.5 years, compared to lesions without rims (p = 0.003). Thus, slow expansion of MS lesions with rims, which reflects chronic lesion activity, may, in the future, become an MRI marker for disease activity in MS.
| S-EPMC5209400 | biostudies-literature
Project description:BackgroundMagnetic resonance imaging (MRI) markers for chronic active lesions in MS include slowly expanding lesions (SELs) and paramagnetic rim lesions (PRLs).ObjectivesTo identify the relationship between SELs and PRLs in MS, and their association with disability.Methods61 people with MS (pwMS) followed retrospectively with MRI including baseline susceptibility-weighted imaging, and longitudinal T1 and T2-weighted scans. SELs were computed using deformation field maps; PRLs were visually identified. Mixed-effects models assessed differences in Expanded Disability Status Scale (EDSS) score changes between the group defined by the presence of SELs and or PRLs.ResultsThe median follow-up time was 3.2 years. At baseline, out of 1492 lesions, 616 were classified as SELs, and 80 as PRLs. 92% of patients had ⩾ 1 SEL, 56% had ⩾ 1 PRL, while both were found in 51%. SELs compared to non-SELs were more likely to also be PRLs (7% vs. 4%, p = 0.027). PRL counts positively correlated with SEL counts (ρ= 0.28, p = 0.03). SEL + PRL + patients had greater increases in EDSS over time (beta = 0.15/year, 95% confidence interval (0.04, 0.27), p = 0.009) than SEL+PRL-patients.ConclusionSELs are more numerous than PRLs in pwMS. Compared with either SELs or PRLs found in isolation, their joint occurrence was associated with greater clinical progression.
| S-EPMC9972234 | biostudies-literature
Project description:Quantitative susceptibility mapping (QSM), an imaging technique sensitive to brain iron, has been used to detect paramagnetic rims of iron-laden active microglia and macrophages in a subset of multiple sclerosis (MS) lesions, known as rim+ lesions, that are consistent with chronic active lesions. Because of the potential impact of rim+ lesions on disease progression and tissue damage, investigating their influence on disability and neurodegeneration is critical to establish the impact of these lesions on the disease course. This study aimed to explore the relationship between chronic active rim+ lesions, identified as having a hyperintense rim on QSM, and both clinical disability and imaging measures of neurodegeneration in patients with MS. The patient cohort was composed of 159 relapsing-remitting multiple sclerosis patients. The Expanded Disability Status Scale (EDSS) and Brief International Cognitive Assessment for Multiple Sclerosis, which includes both the Symbol Digit Modalities Test and California Verbal Learning Test-II, were used to assess clinical disability. Cortical thickness and thalamic volume were evaluated as imaging measures of neurodegeneration. A total of 4469 MS lesions were identified, of which 171 QSM rim+ (3.8%) lesions were identified among 57 patients (35.8%). In a multivariate regression model, as the overall total lesion burden increased, patients with at least one rim+ lesion on QSM performed worse on both physical disability and cognitive assessments, specifically the Symbol Digit Modalities Test (p = 0.010), California Verbal Learning Test-II (p = 0.030), and EDSS (p = 0.001). In a separate univariate regression model, controlling for age (p < 0.001) and having at least one rim+ lesion was related to more cortical thinning (p = 0.03) in younger patients (< 45 years). Lower thalamic volume was associated with older patients (p = 0.038) and larger total lesion burden (p < 0.001); however, the association did not remain significant with rim+ lesions (p = 0.10). Our findings demonstrate a novel observation that chronic active lesions, as identified on QSM, modify the impact of lesion burden on clinical disability in MS patients. These results support further exploration of rim+ lesions for therapeutic targeting in MS to reduce disability and subsequent neurodegeneration.
| S-EPMC8924224 | biostudies-literature
Project description:BackgroundIn 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.MethodsNinety-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).ResultsThe 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.Conclusionrim+ 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.
| S-EPMC8553317 | biostudies-literature
Project description:In some active multiple sclerosis (MS) lesions, a strong immune reaction at the lesion edge may contain growth and thereby isolate the lesion from the surrounding parenchyma. Our previous studies suggest that this process involves opening of the blood-brain barrier in capillaries at the lesion edge, seen on MRI as centripetal contrast enhancement and a colocalized phase rim. We hypothesized that using these features to characterize early lesion evolution will allow in vivo tracking of tissue degeneration and/or repair, thus improving the evaluation of potential therapies for chronic active lesions.Centripetally and centrifugally enhancing lesions were studied in 17 patients with MS using 7-tesla MRI. High-resolution, susceptibility-weighted, T1-weighted (before/after gadolinium), and dynamic contrast-enhanced scans were acquired at baseline and months 1, 3, 6, and 12. For each lesion, time evolution of the phase rim, lesion volume, and T1 hypointensity were assessed. In autopsies of 3 progressive MS cases, the histopathology of the phase rim was determined.In centripetal lesions, a phase rim colocalized with initial contrast enhancement. In 12 of 22, this phase rim persisted after enhancement resolved. Compared with centripetal lesions with transient rim, those with persistent rim had less volume shrinkage and became more T1 hypointense between months 3 and 12. No centrifugal lesions developed phase rims at any time point. Pathologically, persistent rims corresponded to an iron-laden inflammatory myeloid cell population at the edge of chronic demyelinated lesions.In early lesion evolution, a persistent phase rim in lesions that shrink least and become more T1 hypointense over time suggests that the rim might mark failure of early lesion repair and/or irreversible tissue damage. In later stages of MS, phase rim lesions continue to smolder, exerting detrimental effects on affected brain tissue.NCT00001248.The Intramural Research Program of NINDS supported this study.
| S-EPMC4922708 | biostudies-literature