Similar Datasets
Project description:We generated a paired snRNA-seq (n= 15) and spatial transcriptomics (n=19) dataset from subcortical chronic active and chronic inactive MS lesions, identifying spatial niches and key cell interactions driving inflammation and disease progression at the lesion rim. This repository offers access to all the trancriptomics data that was used in the paper. It includes, all FASTQ files for both transcriptomics, along with the necessary files for running spatial transcriptomic samples (H&E images and JSON files), as well as the curated atlas, all derived cell subtype atlases from the main atlas and all curated ST slides.
2024-10-21 | GSE279180 | GEO
Project description:We generated a paired snRNA-seq (n= 15) and spatial transcriptomics (n=19) dataset from subcortical chronic active and chronic inactive MS lesions, identifying spatial niches and key cell interactions driving inflammation and disease progression at the lesion rim. This repository offers access to all the trancriptomics data that was used in the paper. It includes, all FASTQ files for both transcriptomics, along with the necessary files for running spatial transcriptomic samples (H&E images and JSON files), as well as the curated atlas, all derived cell subtype atlases from the main atlas and all curated ST slides.
2024-10-21 | GSE279181 | GEO
Project description:Cell type mapping reveals tissue niches and interactions in subcortical multiple sclerosis lesions.
| PRJNA1171311 | ENA
Project description:Cell type mapping reveals tissue niches and interactions in subcortical multiple sclerosis lesions [snRNA-seq]
| PRJNA1171318 | ENA
Project description:Cell type mapping reveals tissue niches and interactions in subcortical multiple sclerosis lesions [spatial transcriptomics]
| PRJNA1171322 | ENA
Project description:PurposeTo assess multiple sclerosis (MS) lesions at various ages by using quantitative susceptibility mapping (QSM) and conventional magnetic resonance (MR) imaging.Materials and methodsRetrospectively selected were 32 clinically confirmed MS patients (nine men and 23 women; 39.3 years ± 10.9) who underwent two MR examinations (interval, 0.43 years ± 0.16) with three-dimensional gradient-echo sequence from August 2011 to August 2012. To estimate the ages of MS lesions, MR examinations performed 0.3-10.6 years before study examinations were studied. Hyperintensity on T2-weighted images was used to define MS lesions. QSM images were reconstructed from gradient-echo data. Susceptibility of MS lesions and temporal rates of change were obtained from QSM images. Lesion susceptibilities were analyzed by t test with intracluster correlation adjustment and Bonferroni correction in multiple comparisons.ResultsMR imaging of 32 patients depicted 598 MS lesions, of which 162 lesions (27.1%) in 23 patients were age measurable and six (1.0%) were only visible at QSM. The susceptibilities relative to normal-appearing white matter (NAWM) were 0.53 ppb ± 3.34 for acute enhanced lesions, 38.43 ppb ± 13.0 (positive; P < .01) for early to intermediately aged nonenhanced lesions, and 4.67 ppb ± 3.18 for chronic nonenhanced lesions. Temporal rates of susceptibility changes relative to cerebrospinal fluid were 12.49 ppb/month ± 3.15 for acute enhanced lesions, 1.27 ppb/month ± 2.31 for early to intermediately aged nonenhanced lesions, and -0.004 ppb/month ± 0 for chronic nonenhanced lesions.ConclusionMagnetic susceptibility of MS lesions increased rapidly as it changed from enhanced to nonenhanced, it attained a high susceptibility value relative to NAWM during its initial few years (approximately 4 years), and it gradually dissipated back to susceptibility similar to that of NAWM as it aged, which may provide new insight into pathophysiologic features of MS lesions. Online supplemental material is available for this article.
| S-EPMC4263629 | biostudies-literature
Project description:Oxidative injury appears to play a major role in the propagation of demyelination and neurodegeneration in multiple sclerosis (MS). It has been suggested that endogenous anti-oxidant defense mechanisms within MS lesions are insufficient to prevent spreading of damage. Thus, current therapeutic approaches (e.g., fumarate treatment) target to up-regulate the expression of a key regulator of anti-oxidative defense, the transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2). In this study, we show that Nrf2 is already strongly up-regulated in active MS lesions. Nuclear Nrf2 expression was particularly observed in oligodendrocytes and its functional activity is indicated by the expression of one of its downstream targets (heme oxygenase 1) in the same cells. In contrast, only a minor number of Nrf2-positive neurons were detected, even in highly inflammatory cortical lesions presenting with extensive oxidative injury. Overall, the most pronounced Nrf2 expression was found in degenerating cells, which showed signs of apoptotic or necrotic cell death. Via whole-genome microarray analyses of MS lesions, we observed a differential expression of numerous Nrf2-responsive genes, also involved in the defense against oxidative stress, predominantly in areas of initial myelin destruction within actively demyelinating white matter lesions. Furthermore, the expression patterns of Nrf2-induced genes differed between the white matter and cortical gray matter. Our study shows that in the MS brain, Nrf2 expression varies in different cell types and is associated with active demyelination in the lesions.
| S-EPMC4503875 | 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:Objective: To assess treatment-related spatio-temporal dynamics of active MRI lesions in relapsing-remitting multiple sclerosis (RRMS) patients. Methods: We performed a post-hoc analysis of MRI data acquired at weeks 4, 8, 12, and 16, in RRMS patients from the multicenter randomized IMPROVE study, which compares patients treated with 44 mcg subcutaneous interferon ?-1a three times weekly (n = 120) versus placebo (n = 60). We created lesion probability maps (LPMs) of the cumulative combined unique active (CUA) lesions in each patient group at each time point. Group differences were tested in terms of lesion spatial distribution and frequency of occurrence. Results: Spatial distribution of CUA lesions throughout the study was less widespread in the treated than placebo group, with a 50% lower lesion accrual (24 vs. 48 cm3/month). Similar results were obtained with the WM tract analysis, with a reduction ranging from -47 to -66% in the treated group (p < 0.001). On voxel-wise analysis, CUA lesion frequency was lower in the treated group than the placebo group at week 4 (p = 0.07, corrected), becoming particularly pronounced (p ? 0.03, corrected) from week 8 onwards in large clusters of WM tracts, with peaks along fronto-parietal parts of the corticospinal tract, thalamic radiation, and superior longitudinal fascicle. Conclusion: LPM showed, in the short term, a treatment-related reduction of MRI lesion activity in RRMS patients in specific, clinically relevant brain locations. Such a quantitative approach might be a promising additional endpoint in future MS studies alongside the number and volume of WM lesions. Clinical Trial Registration: ClinicalTrials.gov identifier NCT00441103.
| S-EPMC7714945 | biostudies-literature
Project description:Chronic active multiple sclerosis lesions, characterized by a hyperintense rim of iron-enriched, activated microglia and macrophages, have been linked to greater tissue damage. Post-mortem studies have determined that chronic active lesions are primarily related to the later stages of multiple sclerosis; however, the occurrence of these lesions, and their relationship to earlier disease stages may be greatly underestimated. Detection of chronic active lesions across the patient spectrum of multiple sclerosis requires a validated imaging tool to accurately identify lesions with persistent inflammation. Quantitative susceptibility mapping provides efficient in vivo quantification of susceptibility changes related to iron deposition and the potential to identify lesions harbouring iron-laden inflammatory cells. The PET tracer 11C-PK11195 targets the translocator protein expressed by activated microglia and infiltrating macrophages. Accordingly, this study aimed to validate that lesions with a hyperintense rim on quantitative susceptibility mapping from both relapsing and progressive patients demonstrate a higher level of innate immune activation as measured on 11C-PK11195 PET. Thirty patients were enrolled in this study, 24 patients had relapsing remitting multiple sclerosis, six had progressive multiple sclerosis, and all patients had concomitant MRI with a gradient echo sequence and PET with 11C-PK11195. A total of 406 chronic lesions were detected, and 43 chronic lesions with a hyperintense rim on quantitative susceptibility mapping were identified as rim+ lesions. Susceptibility (relative to CSF) was higher in rim+ (2.42 ± 17.45 ppb) compared to rim- lesions (-14.6 ± 19.3 ppb, P < 0.0001). Among rim+ lesions, susceptibility within the rim (20.04 ± 14.28 ppb) was significantly higher compared to the core (-5.49 ± 14.44 ppb, P < 0.0001), consistent with the presence of iron. In a mixed-effects model, 11C-PK11195 uptake, representing activated microglia/macrophages, was higher in rim+ lesions compared to rim- lesions (P = 0.015). Validating our in vivo imaging results, multiple sclerosis brain slabs were imaged with quantitative susceptibility mapping and processed for immunohistochemistry. These results showed a positive translocator protein signal throughout the expansive hyperintense border of rim+ lesions, which co-localized with iron containing CD68+ microglia and macrophages. In conclusion, this study provides evidence that suggests that a hyperintense rim on quantitative susceptibility measure within a chronic lesion is a correlate for persistent inflammatory activity and that these lesions can be identified in the relapsing patients. Utilizing quantitative susceptibility measure to differentiate chronic multiple sclerosis lesion subtypes, especially chronic active lesions, would provide a method to assess the impact of these lesions on disease progression.
| S-EPMC6308309 | biostudies-literature