Chronic Multiple Sclerosis Lesions Research Articles

Loss of miR-145 promotes remyelination and functional recovery in a model of chronic central demyelination

Strategies for treating progressive multiple sclerosis (MS) remain limited. Here, we found that miR-145-5p is overabundant uniquely in chronic lesion tissues from secondary progressive MS patients. We induced both acute and chronic demyelination in miR-145 knockout mice to determine its contributions to remyelination failure. Following acute demyelination, no advantage to miR-145 loss could be detected. However, after chronic demyelination, animals with miR-145 loss demonstrated increased remyelination and functional recovery, coincident with altered presence of astrocytes and microglia within the corpus callosum relative to wild-type animals. This improved response in miR-145 knockout animals coincided with a pathological upregulation of miR-145-5p in wild-type animals with chronic cuprizone exposure, paralleling human chronic lesions. Furthermore, miR-145 overexpression specifically in oligodendrocytes (OLs) severely stunted differentiation and negatively impacted survival. RNAseq analysis showed altered transcriptome in these cells with downregulated major pathways involved in myelination. Our data suggest that pathological accumulation of miR-145-5p is a distinctive feature of chronic demyelination and is strongly implicated in the failure of remyelination, possibly due to the inhibition of OL differentiation together with alterations in other glial cells. This is mirrored in chronic MS lesions, and thus miR-145-5p serves as a potential relevant therapeutic target in progressive forms of MS.

Central Vein Sign and Paramagnetic Rim Lesions: Susceptibility Changes in Brain Tissues and Their Implications for the Study of Multiple Sclerosis Pathology.

Multiple sclerosis (MS) is the most common acquired inflammatory and demyelinating disease in adults. The conventional diagnostic of MS and the follow-up of inflammatory activity is based on the detection of hyperintense foci in T2 and fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) and lesions with brain-blood barrier (BBB) disruption in the central nervous system (CNS) parenchyma. However, T2/FLAIR hyperintense lesions are not specific to MS and the MS pathology and inflammatory processes go far beyond focal lesions and can be independent of BBB disruption. MRI techniques based on the magnetic susceptibility properties of the tissue, such as T2*, susceptibility-weighted images (SWI), and quantitative susceptibility mapping (QSM) offer tools for advanced MS diagnostic, follow-up, and the assessment of more detailed features of MS dynamic pathology. Susceptibility-weighted techniques are sensitive to the paramagnetic components of biological tissues, such as deoxyhemoglobin. This capability enables the visualization of brain parenchymal veins. Consequently, it presents an opportunity to identify veins within the core of multiple sclerosis (MS) lesions, thereby affirming their venocentric characteristics. This advancement significantly enhances the accuracy of the differential diagnostic process. Another important paramagnetic component in biological tissues is iron. In MS, the dynamic trafficking of iron between different cells, such as oligodendrocytes, astrocytes, and microglia, enables the study of different stages of demyelination and remyelination. Furthermore, the accumulation of iron in activated microglia serves as an indicator of latent inflammatory activity in chronic MS lesions, termed paramagnetic rim lesions (PRLs). PRLs have been correlated with disease progression and degenerative processes, underscoring their significance in MS pathology. This review will elucidate the underlying physical principles of magnetic susceptibility and their implications for the formation and interpretation of T2*, SWI, and QSM sequences. Additionally, it will explore their applications in multiple sclerosis (MS), particularly in detecting the central vein sign (CVS) and PRLs, and assessing iron metabolism. Furthermore, the review will discuss their role in advancing early and precise MS diagnosis and prognostic evaluation, as well as their utility in studying chronic active inflammation and degenerative processes.

Disease-associated astrocyte epigenetic memory promotes CNS pathology.

Disease-associated astrocyte subsets contribute to the pathology of neurologic diseases, including multiple sclerosis and experimental autoimmune encephalomyelitis1-8 (EAE), an experimental model for multiple sclerosis. However, little is known about the stability of these astrocyte subsets and their ability to integrate past stimulation events. Here we report the identification of an epigenetically controlled memory astrocyte subset that exhibits exacerbated pro-inflammatory responses upon rechallenge. Specifically, using a combination of single-cell RNA sequencing, assay for transposase-accessible chromatin with sequencing, chromatin immunoprecipitation with sequencing, focused interrogation of cells by nucleic acid detection and sequencing, and cell-specific in vivo CRISPR-Cas9-based genetic perturbation studies we established that astrocyte memory is controlled by the metabolic enzyme ATP-citrate lyase (ACLY), which produces acetyl coenzyme A (acetyl-CoA) that is used by histone acetyltransferase p300 to control chromatin accessibility. The number of ACLY+p300+ memory astrocytes is increased in acute and chronic EAE models, and their genetic inactivation ameliorated EAE. We also detected the pro-inflammatory memory phenotype in human astrocytes in vitro; single-cell RNA sequencing and immunohistochemistry studies detected increased numbers of ACLY+p300+ astrocytes in chronic multiple sclerosis lesions. In summary, these studies define an epigenetically controlled memory astrocyte subset that promotes CNS pathology in EAE and, potentially, multiple sclerosis. These findings may guide novel therapeutic approaches for multiple sclerosis and other neurologic diseases.

Ferroptosis contributes to multiple sclerosis and its pharmacological targeting suppresses experimental disease progression

Multiple sclerosis (MS) is a chronic autoimmune disorder characterized by central nervous (CNS) demyelination resulting in axonal injury and neurological deficits. Essentially, MS is driven by an auto-amplifying mechanism of inflammation and cell death. Current therapies mainly focus on disease modification by immunosuppression, while no treatment specifically focuses on controlling cell death injury. Here, we report that ferroptosis, an iron-catalyzed mode of regulated cell death (RCD), contributes to MS disease progression. Active and chronic MS lesions and cerebrospinal fluid (CSF) of MS patients revealed several signs of ferroptosis, reflected by the presence of elevated levels of (labile) iron, peroxidized phospholipids and lipid degradation products. Treatment with our candidate lead ferroptosis inhibitor, UAMC-3203, strongly delays relapse and ameliorates disease progression in a preclinical model of relapsing-remitting MS. In conclusion, the results identify ferroptosis as a detrimental and targetable factor in MS. These findings create novel treatment options for MS patients, along with current immunosuppressive strategies.

B cell depletion therapy does not resolve chronic active multiple sclerosis lesions.

Chronic active lesions (CAL) in multiple sclerosis (MS) have been observed even in patients taking high-efficacy disease-modifying therapy, including B-cell depletion. Given that CAL are a major determinant of clinical progression, including progression independent of relapse activity (PIRA), understanding the predicted activity and real-world effects of targeting specific lymphocyte populations is critical for designing next-generation treatments to mitigate chronic inflammation in MS. We analyzed published lymphocyte single-cell transcriptomes from MS lesions and bioinformatically predicted the effects of depleting lymphocyte subpopulations (including CD20 B-cells) from CAL via gene-regulatory-network machine-learning analysis. Motivated by the results, we performed invivo MRI assessment of PRL changes in 72 adults with MS, 46 treated with anti-CD20 antibodies and 26 untreated, over ∼2 years. Although only 4.3% of lymphocytes in CAL were CD20 B-cells, their depletion is predicted to affect microglial genes involved in iron/heme metabolism, hypoxia, and antigen presentation. Invivo, tracking 202 PRL (150 treated) and 175 non-PRL (124 treated), none of the treated paramagnetic rims disappeared at follow-up, nor was there a treatment effect on PRL for lesion volume, magnetic susceptibility, or T1 time. PIRA occurred in 20% of treated patients, more frequently in those with ≥4 PRL (p=0.027). Despite predicted effects on microglia-mediated inflammatory networks in CAL and iron metabolism, anti-CD20 therapies do not fully resolve PRL after 2-year MRI follow up. Limited tissue turnover of B-cells, inefficient passage of anti-CD20 antibodies across the blood-brain-barrier, and a paucity of B-cells in CAL could explain our findings. Intramural Research Program of NINDS, NIH; NINDS grants R01NS082347 and R01NS082347; Dr. Miriam and Sheldon G. Adelson Medical Research Foundation; Cariplo Foundation (grant #1677), FRRB Early Career Award (grant #1750327); Fund for Scientific Research (FNRS).

TSPO-Detectable Chronic Active Lesions Predict Disease Progression in Multiple Sclerosis.

In the multiple sclerosis (MS) brain, chronic active lesions can be detected using MRI- and PET-based methods. In this study, we investigated whether the frequency of TSPO-PET-detectable chronic active lesions associates with disease progression measured using the Expanded Disability Status Scale (EDSS) at 5-year follow-up. Chronic lesion-associated innate immune cell activation was evaluated using TSPO-PET in 82 patients with MS. Chronic lesions were categorized into rim-active, inactive, and overall active lesion subtypes based on innate immune cell activation patterns in the lesion core and at the 2-mm perilesional rim. Logistic regression was used to identify best predictors of progression. Twenty-one patients experienced disability progression during the follow-up. These patients had a significantly higher proportion of rim-active lesions (p < 0.001) and a significantly lower proportion of inactive lesions (p = 0.001) compared with nonprogressed patients. The results were similar in the patient group having no relapses during the follow-up (60 patients, 14 experienced progression). In logistic regression modeling, the categorized variable "patients with >10% rim-active lesions and ≤50% inactive lesions of all chronic lesions" predicted disease progression in the entire cohort (OR = 26.8, p < 0.001) and in the group free of relapses (OR = 34.8, p = 0.002). The results show that single TSPO-PET-based in vivo lesion phenotyping of chronic MS lesions provides a strong predictor for MS disease progression. This emphasizes the significance of chronic active lesions in disability accumulation in MS.

African Americans with multiple sclerosis (MS) are more likely to have paramagnetic rim lesions (PRLs) compared to Caucasians (P11-3.017)

<h3>Objective:</h3> To determine the prevalence of paramagnetic rim lesions (PRLs) in African American patients with multiple sclerosis (AAwMS) compared to Caucasian (CAwMS). <h3>Background:</h3> PRLs are a subset of chronic active MS lesions with a rim of iron-laden innate immune cells and their presence has been associated with higher disability. AAwMS have been clinically observed to have higher disability and more severe symptoms as compared to other racial groups. <h3>Design/Methods:</h3> In this retrospective study of 139 AAwMS and 132 CAwMS quantitative susceptibility mapping (QSM), an MRI approach sensitive to iron, was used to identify PRLs. A linear model assessed the relationship between EDSS and race, adjusting for total lesion number (TLN), sex, age and disease duration (DD). The association of PRL per patient and race was modeled, adjusting for clinical variables and total lesions, using a zero-inflated Poisson regression. <h3>Results:</h3> The cohorts were well matched on all clinical variables and TLN. In a linear model, AAwMS had a higher EDSS (p-value &lt;0.001) with, on average, a 1.16-point higher EDSS (95% CI: [0.73, 1.60] than CAwMS. AAwMS had a mean of 1.3 (2.72) PRL whereas CAwMS had 0.82 (1.69), p=0.085. In the zero-inflated Poisson model, the log odds ratio of having no PRL was 0.53 (95% CI: [0.29, 0.97], p-value = 0.039) for AAwMS, indicating more patients have at least one PRL. In the Poisson model, only TLN (p = 0.021) and gender (p = 0.046) were found to be significant, which indicates that AAwMS were more likely to have one PRL, however among all patients with PRL, the total number of PRL did not depend on race. <h3>Conclusions:</h3> This is the first study to explore racial differences in the occurrence of chronic active lesions and provides preliminary evidence that PRL could relate to racial specific differences in disease pathology, an area which has been significantly understudied. <b>Disclosure:</b> Dr. Michaelson has nothing to disclose. Ms. Marcille has nothing to disclose. Dr. Sweeney has nothing to disclose. Dr. Kaunzner has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Dr. Kaunzner has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Medlearning. Jai Perumal has nothing to disclose. Dr. Nealon has nothing to disclose. Thanh Nguyen has nothing to disclose. Dr. Gauthier has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Gnenetech. The institution of Dr. Gauthier has received research support from Genentech.

Single-timepoint low-dimensional characterization and classification of acute versus chronic multiple sclerosis lesions using machine learning

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.

Identification of potential regulatory long non-coding RNA-associated competing endogenous RNA axes in periplaque regions in multiple sclerosis.

Slow-burning inflammation at the lesion rim is connected to the expansion of chronic multiple sclerosis (MS) lesions. However, the underlying processes causing expansion are not clearly realized. In this context, the current study used a bioinformatics approach to identify the expression profiles and related lncRNA-associated ceRNA regulatory axes in the periplaque region in MS patients. Expression data (GSE52139) from periplaque regions in the secondary progressive MS spinal cord and controls were downloaded from the Gene Expression Omnibus database (GEO), which has details on mRNAs and lncRNAs. Using the R software's limma package, the differentially expressed lncRNAs (DElncRNAs) and mRNAs (DEmRNAs) were found. The RNA interactions were also found using the DIANA-LncBase, miRTarBase, and HMDD databases. The Pearson correlation coefficient was used to determine whether there were any positive correlations between DEmRNAs and DElncRNAs in the ceRNA network. Finally, lncRNA-associated ceRNA axes were created based on co-expression and connections between DElncRNA, miRNA, and DEmRNA. We used the Enrichr tool to enrich the biological process, molecular function, and pathways for DEmRNAs and DElncRNAs. A network of DEmRNAs' protein-protein interactions was developed, and the top five hub genes were found using Cytoscape and STRING. The current study indicates that 15 DEmRNAs, including FOS, GJA1, NTRK2, CTNND1, and SP3, are connected to the MS ceRNA network. Additionally, four DElncRNAs (such as TUG1, ASB16-AS1, and LINC01094) that regulated the aforementioned mRNAs by sponging 14 MS-related miRNAs (e.g., hsa-miR-145-5p, hsa-miR-200a-3p, hsa-miR-20a-5p, hsa-miR-22-3p, hsa-miR-23a-3p, hsa-miR-27a-3p, hsa-miR-29b-3p, hsa-miR-29c-3p, hsa-miR-34a-5p) were found. In addition, the analysis of pathway enrichment revealed that DEmRNAs were enriched in the pathways for the "MAPK signaling pathway", "Kaposi sarcoma-associated herpesvirus infection", "Human immunodeficiency virus one infection", "Lipid and atherosclerosis", and "Amphetamine addiction". Even though the function of these ceRNA axes needs to be investigated further, this study provides research targets for studying ceRNA-mediated molecular mechanisms related to periplaque demyelination in MS.

Choroid plexus volume in multiple sclerosis predicts expansion of chronic lesions and brain atrophy.

ObjectivesRecent studies suggested that the expansion of long‐standing multiple sclerosis (MS) lesions and an enlargement of choroid plexus may be linked to chronic inflammation and microglial activation. We investigated the potential association between plexus volume and subsequent lesion expansion in patients with relapsing‐remitting MS.MethodsPre‐ and post‐gadolinium 3D‐T1, 3D FLAIR and diffusion tensor images were acquired from 49 patients. Choroid plexus (CP) volume (normalised by Total Intracranial Volume, TIV) and lesion activity were analysed between baseline and 48 months. In addition, plexus volume was measured in 40 healthy controls of similar age and gender.ResultsBaseline CP/TIV ratio was significantly larger in RRMS patients compared to normal controls (p < 0.001). CP/TIV ratio remained stable in RRMS patients during follow‐up period. There was a strong correlation between baseline CP/TIV ratio and subsequent rate of chronic lesion expansion (p < 0.001), which was stronger in close proximity to CSF. A cut‐off of 98 × 10−5 CP/TIV ratio predicted future lesion expansion with a sensitivity of 85% and specificity of 76%. CP/TIV ratio larger than a cut‐off was associated with >8‐fold increased risk of chronic lesion expansion. Baseline CP/TIV ratio was also associated with change in Mean Diffusivity (MD) inside of chronic lesions. Furthermore, baseline CP/TIV ratio significantly correlated with central brain atrophy. There was, however, no correlation between CP/TIV ratio and volume of new lesions.InterpretationOur data demonstrate that baseline CP/TIV ratio predicts subsequent expansion of chronic periventricular MS lesions and associated tissue damage within and outside of chronic lesions.

GABAB receptor agonist baclofen promotes central nervous system remyelination.

Promoting remyelination is considered as a potential neurorepair strategy to prevent/limit the development of permanent neurological disability in patients with multiple sclerosis (MS). To this end, a number of clinical trials are investigating the potential of existing drugs to enhance oligodendrocyte progenitor cell (OPC) differentiation, a process that fails in chronic MS lesions. We previously reported that oligodendroglia express GABAB receptors (GABAB Rs) both in vitro and in vivo, and that GABAB R-mediated signaling enhances OPC differentiation and myelin protein expression in vitro. Our goal here was to evaluate the pro-remyelinating potential of GABAB R agonist baclofen (Bac), a clinically approved drug to treat spasticity in patients with MS. We first demonstrated that Bac increases myelin protein production in lysolecithin (LPC)-treated cerebellar slices. Importantly, Bac administration to adult mice following induction of demyelination by LPC injection in the spinal cord resulted in enhanced OPC differentiation and remyelination. Thus, our results suggest that Bac repurposing should be considered as a potential therapeutic strategy to stimulate remyelination in patients with MS.

A New Advanced MRI Biomarker for Remyelinated Lesions in Multiple Sclerosis.

ObjectivesNeuropathological studies have shown that multiple sclerosis (MS) lesions are heterogeneous in terms of myelin/axon damage and repair as well as iron content. However, it remains a challenge to identify specific chronic lesion types, especially remyelinated lesions, in vivo in patients with MS.MethodsWe performed 3 studies: (1) a cross‐sectional study in a prospective cohort of 115 patients with MS and 76 healthy controls, who underwent 3 T magnetic resonance imaging (MRI) for quantitative susceptibility mapping (QSM), myelin water fraction (MWF), and neurite density index (NDI) maps. White matter (WM) lesions in QSM were classified into 5 QSM lesion types (iso‐intense, hypo‐intense, hyperintense, lesions with hypo‐intense rims, and lesions with paramagnetic rim legions [PRLs]); (2) a longitudinal study of 40 patients with MS to study the evolution of lesions over 2 years; (3) a postmortem histopathology‐QSM validation study in 3 brains of patients with MS to assess the accuracy of QSM classification to identify neuropathological lesion types in 63 WM lesions.ResultsAt baseline, hypo‐ and isointense lesions showed higher mean MWF and NDI values compared to other QSM lesion types (p < 0.0001). Further, at 2‐year follow‐up, hypo‐/iso‐intense lesions showed an increase in MWF. Postmortem analyses revealed that QSM highly accurately identifies (1) fully remyelinated areas as hypo‐/iso‐intense (sensitivity = 88.89% and specificity = 100%), (2) chronic inactive lesions as hyperintense (sensitivity = 71.43% and specificity = 92.00%), and (3) chronic active/smoldering lesions as PRLs (sensitivity = 92.86% and specificity = 86.36%).InterpretationThese results provide the first evidence that it is possible to distinguish chronic MS lesions in a clinical setting, hereby supporting with new biomarkers to develop and assess remyelinating treatments. ANN NEUROL 2022;92:486–502

The expansion and severity of chronic MS lesions follows a periventricular gradient

Background and Objectives: Expansion of chronic lesions in multiple sclerosis (MS) patients and recently described cerebrospinal fluid (CSF)-related gradient of tissue damage are linked to microglial activation. The aim of this study was to investigate whether lesion expansion is associated with proximity to ventricular CSF spaces. Methods: Pre- and post-gadolinium three-dimensional (3D)-T1, 3D FLAIR and diffusion tensor images were acquired from 36 relapsing-remitting MS (RRMS) patients. Lesional activity was analysed between baseline and 48 months at different distances from the CSF using successive 1 mm thick concentric bands radiating from the ventricles. Results: Voxel-based analysis of the rate of lesion expansion demonstrated a clear periventricular gradient decreasing away from the ventricles. This was particularly apparent when lesions of equal diameter were analysed. Periventricular lesional tissue showed higher degree of tissue destruction at baseline that significantly increased during follow-up in bands close to CSF. This longitudinal change was proportional to degree of lesion expansion. Lesion-wise analysis revealed a gradual, centrifugal decrease in the proportion of expanding lesions from the immediate periventricular zone. Discussion: Our data suggest that chronic white matter lesions in close proximity to the ventricles are more destructive, show a higher degree of expansion at the lesion border and accelerated tissue loss in the lesion core.

Dimethyl Fumarate Reduces Inflammation in Chronic Active Multiple Sclerosis Lesions.

Background and ObjectivesTo determine the effects of dimethyl fumarate (DMF) and glatiramer acetate on iron content in chronic active lesions in patients with multiple sclerosis (MS) and in human microglia in vitro.MethodsThis was a retrospective observational study of 34 patients with relapsing-remitting MS and clinically isolated syndrome treated with DMF or glatiramer acetate. Patients had lesions with hyperintense rims on quantitative susceptibility mapping, were treated with DMF or glatiramer acetate (GA), and had a minimum of 2 on-treatment scans. Changes in susceptibility in rim lesions were compared among treatment groups in a linear mixed effects model. In a separate in vitro study, induced pluripotent stem cell–derived human microglia were treated with DMF or GA, and treatment-induced changes in iron content and activation state of microglia were compared.ResultsRim lesions in patients treated with DMF had on average a 2.77-unit reduction in susceptibility per year over rim lesions in patients treated with GA (bootstrapped 95% CI −5.87 to −0.01), holding all other variables constant. Moreover, DMF but not GA reduced inflammatory activation and concomitantly iron content in human microglia in vitro.DiscussionTogether, our data indicate that DMF-induced reduction of susceptibility in MS lesions is associated with a decreased activation state in microglial cells. We have demonstrated that a specific disease modifying therapy, DMF, decreases glial activity in chronic active lesions. Susceptibility changes in rim lesions provide an in vivo biomarker for the effect of DMF on microglial activity.Classification of EvidenceThis study provided Class III evidence that DMF is superior to GA in the presence of iron as a marker of inflammation as measured by MRI quantitative susceptibility mapping.

Consistency of the “central vein sign” in chronic multiple sclerosis lesions

BackgroundIn recent years, there has been an increasing interest in the central vein sign (CVS) as a new imaging marker and previous cross-sectional studies demonstrated that the CVS has the potential to discriminate multiple sclerosis (MS) lesions from non-MS lesions. The aim of this study was to investigate the consistency of the CVS in a longitudinal magnetic resonance imaging (MRI) data set. Methods3T MRI datasets from seventy-one people with MS acquired at baseline and after 12 months-follow-up were analyzed. Chronic lesions were identified on fluid-attenuated inversion recovery (FLAIR) images. Co-registered susceptibility-weighted/FLAIR images were analyzed for the presence of a CVS at baseline and follow-up. ResultsA total of 183 chronic lesions were included in the final analysis. At baseline MRI, a CVS was detectable in 141/183 (77%) lesions. Overall, the CVS was consistent in 114/141 (81%) lesions (Cohen's kappa = 0.46, standard error = 0.07). ConclusionThe CVS is a rather stable feature in chronic MS lesions and therefore represents a robust imaging marker that could increase the specificity of MRI in MS.

QSMRim-Net: Imbalance-aware learning for identification of chronic active multiple sclerosis lesions on quantitative susceptibility maps

Background and PurposeChronic active multiple sclerosis (MS) lesions are characterized by a paramagnetic rim at the edge of the lesion and are associated with increased disability in patients. Quantitative susceptibility mapping (QSM) is an MRI technique that is sensitive to chronic active lesions, termed rim + lesions on the QSM. We present QSMRim-Net, a data imbalance-aware deep neural network that fuses lesion-level radiomic and convolutional image features for automated identification of rim + lesions on QSM. MethodsQSM and T2-weighted-Fluid-Attenuated Inversion Recovery (T2-FLAIR) MRI of the brain were collected at 3 T for 172 MS patients. Rim + lesions were manually annotated by two human experts, followed by consensus from a third expert, for a total of 177 rim + and 3986 rim negative (rim−) lesions. Our automated rim + detection algorithm, QSMRim-Net, consists of a two-branch feature extraction network and a synthetic minority oversampling network to classify rim + lesions. The first network branch is for image feature extraction from the QSM and T2-FLAIR, and the second network branch is a fully connected network for QSM lesion-level radiomic feature extraction. The oversampling network is designed to increase classification performance with imbalanced data. ResultsOn a lesion-level, in a five-fold cross validation framework, the proposed QSMRim-Net detected rim + lesions with a partial area under the receiver operating characteristic curve (pROC AUC) of 0.760, where clinically relevant false positive rates of less than 0.1 were considered. The method attained an area under the precision recall curve (PR AUC) of 0.704. QSMRim-Net out-performed other state-of-the-art methods applied to the QSM on both pROC AUC and PR AUC. On a subject-level, comparing the predicted rim + lesion count and the human expert annotated count, QSMRim-Net achieved the lowest mean square error of 0.98 and the highest correlation of 0.89 (95% CI: 0.86, 0.92). ConclusionThis study develops a novel automated deep neural network for rim + MS lesion identification using T2-FLAIR and QSM images.

Phenotyping of multiple sclerosis lesions according to innate immune cell activation using 18 kDa translocator protein-PET.

Chronic active lesions are promotors of neurodegeneration and disease progression in multiple sclerosis. They harbour a dense rim of activated innate immune cells at the lesion edge, which promotes lesion growth and thereby induces damage. Conventional MRI is of limited help in identifying the chronic active lesions, so alternative imaging modalities are needed. Objectives were to develop a PET-based automated analysis method for phenotyping of chronic lesions based on lesion-associated innate immune cell activation and to comprehensively evaluate the prevalence of these lesions in the various clinical subtypes of multiple sclerosis, and their association with disability. In this work, we use 18 kDa translocator protein-PET imaging for phenotyping chronic multiple sclerosis lesions at a large scale. For this, we identified 1510 white matter T1-hypointense lesions from 91 multiple sclerosis patients (67 relapsing–remitting patients and 24 secondary progressive patients). Innate immune cell activation at the lesion rim was measured using PET imaging and the 18 kDa translocator protein-binding radioligand 11C-PK11195. A T1-hypointense lesion was classified as rim-active if the distribution volume ratio of 11C-PK11195-binding was low in the plaque core and considerably higher at the plaque edge. If no significant ligand binding was observed, the lesion was classified as inactive. Plaques that had considerable ligand binding both in the core and at the rim were classified as overall-active. Conventional MRI and disability assessment using the Expanded Disability Status Scale were performed at the time of PET imaging. In the secondary progressive cohort, an average of 19% (median, interquartile range: 11–26) of T1 lesions were rim-active in each individual patient, compared to 10% (interquartile range: 0–20) among relapsing–remitting patients (P = 0.009). Secondary progressive patients had a median of 3 (range: 0–11) rim-active lesions, versus 1 (range: 0–18) among relapsing–remitting patients (P = 0.029). Among those patients who had rim-active lesions (n = 63), the average number of active voxels at the rim was higher among secondary progressive compared to relapsing–remitting patients (median 158 versus 74; P = 0.022). The number of active voxels at the rim correlated significantly with the Expanded Disability Status Scale (R = 0.43, P < 0.001), and the volume of the rim-active lesions similarly correlated with the Expanded Disability Status Scale (R = 0.45, P < 0.001). Our study is the first to report in vivo phenotyping of chronic lesions at large scale, based on 18 kDa translocator protein-PET. Patients with higher disability displayed a higher proportion of rim-active lesions. The in vivo lesion phenotyping methodology offers a new tool for individual assessment of smouldering (rim-active) lesion burden.

Long-term dynamics of multiple sclerosis iron rim lesions

BackgroundSeveral studies have pointed out that seemingly chronic multiple sclerosis (MS) lesions may also be in inflammatory states. In pathological studies, up to 40% of chronic MS lesions are characterized as “chronic active” or “smoldering” lesions that are characterized by a rim of iron-laden proinflammatory macrophages/microglial cells at the lesion edge with low-grade continuous myelin breakdown. In vivo, these lesions can be visualized as “iron rim lesions” (IRLs) on susceptibility-weighted imaging (SWI). The aim of this study was to investigate the long-term dynamics of IRLs in vivo for a more detailed evolution of dynamic lesion volume changes occurring over time. MethodsWe retrospectively identified patients with MS who were followed for at least 36 months (up to 72 months) and underwent at least an annual MRI on the same 3 Tsystem. Using Voxel-Guided Morphometry (VGM) we investigated regional volume changes within lesions and correlated these findings with SWI for the presence of a characteristic hypointense lesion rim. To estimate tissue damage, apparent diffusion coefficient (ADC) values for every lesion at baseline and follow-up MRIs were determined. ResultsForty-three patients were included in the study. Overall, we identified 302 supratentorial non-confluent MS lesions (52 persistent IRLs, nine transient IRLs, 228 non-IRLs and 13 acute contrast-enhancing lesions). During follow-up, persistent IRLs significantly enlarged, whereas non-IRLs showed a tendency to shrink. At baseline MRI, ADC values were significantly higher in persistent IRLs (1.23 × 10−3 mm/s2) compared to non-IRLs (1.01 × 10−3 mm/s2; p < 0.001), but not compared to transient IRLs (1.06 × 10−3 mm/s2; p = 0.15) and contrast-enhancing lesions (1.15 × 10−3 mm/s2; p = 1.0). During follow-up, ADC values significantly increased more often in persistent IRLs compared to all other lesion types (p < 0.0001). ConclusionsOur long-term data demonstrate that persistent IRLs enlarge during disease duration, whereas non-IRLs show a tendency to shrink. Furthermore, IRLs are associated with sustained tissue damage, supporting the notion that IRLs could represent a new imaging biomarker in MS.

7T MRI Differentiates Remyelinated from Demyelinated Multiple Sclerosis Lesions.

ObjectiveTo noninvasively assess myelin status in chronic white matter lesions of multiple sclerosis (MS), we developed and evaluated a simple classification scheme based on T1 relaxation time maps derived from 7‐tesla postmortem and in vivo MRI.MethodsUsing the MP2RAGE MRI sequence, we classified 36 lesions from 4 postmortem MS brains as “long‐T1,” “short‐T1,” and “mixed‐T1” by visual comparison to neocortex. Within these groups, we compared T1 times to histologically derived measures of myelin and axons. We performed similar analysis of 235 chronic lesions with known date of onset in 25 MS cases in vivo and in a validation cohort of 222 lesions from 66 MS cases, investigating associations with clinical and radiological outcomes.ResultsPostmortem, lesions classified qualitatively as long‐T1, short‐T1, and mixed‐T1 corresponded to fully demyelinated, fully remyelinated, and mixed demyelinated/remyelinated lesions, respectively (p ≤ 0.001). Demyelination (rather than axon loss) dominantly contributed to initial T1 prolongation. We observed lesions with similar characteristics in vivo, allowing manual classification with substantial interrater and excellent intrarater reliability. Short‐T1 lesions were most common in the deep white matter, whereas long‐T1 and mixed‐T1 lesions were prevalent in the juxtacortical and periventricular white matter (p = 0.02) and were much more likely to have paramagnetic rims suggesting chronic inflammation (p < 0.001). Older age at the time of lesion formation portended less remyelination (p = 0.007).Interpretation7‐tesla T1 mapping with MP2RAGE, a clinically available MRI method, allows qualitative and quantitative classification of chronic MS lesions according to myelin content, rendering straightforward the tracking of lesional myelination changes over time. ANN NEUROL 2021;90:612–626

Expansion of chronic MS lesions is associated with an increase of radial diffusivity in periplaque white matter

Background: Expansion of chronic multiple sclerosis (MS) lesion is associated with slow-burning inflammation at lesion rim. However, the underlying mechanisms leading to expansion are not fully understood. Objective: To investigate the relationship between diffusivity markers of demyelination and axonal loss in perilesional white matter and lesion expansion in relapsing-remitting MS (RRMS). Methods: T1, FLAIR and diffusion tensor images were acquired from 30 patients. Novel single-streamline technique was used to estimate diffusivity in lesions, perilesional white matter and normal-appearing white matter (NAWM). Results: Significant association was found between baseline periplaque radial diffusivity (RD) and subsequent lesion expansion. Conversely, periplaque axial diffusivity (AD) did not correlate with lesion growth. Baseline RD (but not AD) in periplaque white matter of expanding lesions was significantly higher compared with non-expanding lesions. Correlation between increase of both RD and AD in the periplaque area during follow-up period and lesion expansion was noticeably stronger for RD. Increase of RD in periplaque area was also much higher compared to AD. There was significant increase of AD and RD in the periplaque area of expanding, but not in non-expanding, lesions. Conclusion: Periplaque demyelination is likely to be an initial step in a process of lesion expansion and, as such, potentially represents a suitable target for remyelinating therapies.