A glia-enriched stem cell 3D model of the human brain mimics the glial-immune neurodegenerative phenotypes of multiple sclerosis.

The role of central nervous system (CNS) glia in sustaining self-autonomous inflammation and driving clinical progression in multiple sclerosis (MS) is gaining scientific interest. We applied a single transcription factor (SOX10)-based protocol to accelerate oligodendrocyte differentiation from human induced pluripotent stem cell (hiPSC)-derived neural precursor cells, generating self-organizing forebrain organoids. These organoids include neurons, astrocytes, oligodendroglia, and hiPSC-derived microglia to achieve immunocompetence. Over 8 weeks, organoids reproducibly generated mature CNS cell types, exhibiting single-cell transcriptional profiles similar to the adult human brain. Exposed to inflamed cerebrospinal fluid (CSF) from patients with MS, organoids properly mimic macroglia-microglia neurodegenerative phenotypes and intercellular communication seen in chronic active MS. Oligodendrocyte vulnerability emerged by day 6 post-MS-CSF exposure, with nearly 50% reduction. Temporally resolved organoid data support and expand on the role of soluble CSF mediators in sustaining downstream events leading to oligodendrocyte death and inflammatory neurodegeneration. Such findings support the implementation of this organoid model for drug screening to halt inflammatory neurodegeneration.

New Imaging Markers in Multiple Sclerosis and Related Disorders: Smoldering Inflammation and the Central Vein Sign.

Concepts of multiple sclerosis (MS) biology continue to evolve, with observations such as "progression independent of disease activity" challenging traditional phenotypic categorization. Iron-sensitive, susceptibility-based imaging techniques are emerging as highly translatable MR imaging sequences that allow for visualization of at least 2 clinically useful biomarkers: the central vein sign and the paramagnetic rim lesion (PRL). Both biomarkers demonstrate high specificity in the discrimination of MS from other mimics and can be seen at 1.5 T and 3 T field strengths. Additionally, PRLs represent a subset of chronic active lesions engaged in "smoldering" compartmentalized inflammation behind an intact blood-brain barrier.

Enlarged perivascular spaces are associated with brain microangiopathy and aging in multiple sclerosis.

BACKGROUND: Growing evidence links brain-MRI enlarged perivascular spaces (EPVS) and multiple sclerosis (MS), but their role remains unclear. OBJECTIVE: This study aimed to investigate the cross-sectional associations of EPVS with several neuroinflammatory and neurodegenerative features in a large multicentric-MS cohort. METHODS: In total, 207 patients underwent 3T axial-T2-weighted brain-MRI for EPVS assessment (EPVS dichotomized into high/low according to ⩾ 2/< 2 rating categories). MRI biomarkers included brain-predicted age and brain-predicted age difference (brain-PAD), central vein sign (CVS)-positive lesion percentage (CVS%), paramagnetic rim and cortical lesions, T2-lesion load, and brain volumetry. The variable relative importance for EPVS-category prediction was explored using a classification random forest approach. RESULTS: High EPVS patients were older (49 vs 44 years, p = 0.003), had ⩾ 1 vascular risk factors (VRFs; p = 0.005), lower CVS% (67% vs 78%, p < 0.001), reduced brain volumes (whole brain: 0.63 vs 0.73, p = 0.01; gray matter: 0.36 vs 0.40; p = 0.002), and older brain-predicted age (58 vs 50 years, p < 0.001). No differences were found for neuroinflammatory markers. After adjusting for age and VFRs (multivariate analyses), the high EPVS category correlated with lower CVS% (odds ratio (OR) = 0.98, 95% confidence interval (CI) = 0.96-0.99; p = 0.02), lower whole brain (OR = 0.01, 95% CI = 0.0003-0.5; p = 0.02), gray matter (OR = 0.0004, 95% CI = 0.0000004-0.4; p = 0.03) volumes, and higher brain-PAD (OR = 1.05, 95% CI = 1.01-1.09; p = 0.02). Random forest identified brain-PAD as the most important predictor of high EPVS. CONCLUSION: EPVS in MS likely reflect microangiopathic disease rather than neuroinflammation, potentially contributing to accelerated neurodegeneration.

Central Vein Sign, Cortical Lesions, and Paramagnetic Rim Lesions for the Diagnostic and Prognostic Workup of Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: The diagnosis of multiple sclerosis (MS) can be challenging in clinical practice because MS presentation can be atypical and mimicked by other diseases. We evaluated the diagnostic performance, alone or in combination, of the central vein sign (CVS), paramagnetic rim lesion (PRL), and cortical lesion (CL), as well as their association with clinical outcomes. METHODS: In this multicenter observational study, we first conducted a cross-sectional analysis of the CVS (proportion of CVS-positive lesions or simplified determination of CVS in 3/6 lesions-Select3*/Select6*), PRL, and CL in MS and non-MS cases on 3T-MRI brain images, including 3D T2-FLAIR, T2*-echo-planar imaging magnitude and phase, double inversion recovery, and magnetization prepared rapid gradient echo image sequences. Then, we longitudinally analyzed the progression independent of relapse and MRI activity (PIRA) in MS cases over the 2 years after study entry. Receiver operating characteristic curves were used to test diagnostic performance and regression models to predict diagnosis and clinical outcomes. RESULTS: The presence of ≥41% CVS-positive lesions/≥1 CL/≥1 PRL (optimal cutoffs) had 96%/90%/93% specificity, 97%/84%/60% sensitivity, and 0.99/0.90/0.77 area under the curve (AUC), respectively, to distinguish MS (n = 185) from non-MS (n = 100) cases. The Select3*/Select6* algorithms showed 93%/95% specificity, 97%/89% sensitivity, and 0.95/0.92 AUC. The combination of CVS, CL, and PRL improved the diagnostic performance, especially when Select3*/Select6* were used (93%/94% specificity, 98%/96% sensitivity, 0.99/0.98 AUC; p = 0.002/p < 0.001). In MS cases (n = 185), both CL and PRL were associated with higher MS disability and severity. Longitudinal analysis (n = 61) showed that MS cases with >4 PRL at baseline were more likely to experience PIRA at 2-year follow-up (odds ratio 17.0, 95% confidence interval: 2.1-138.5; p = 0.008), whereas no association was observed between other baseline MRI measures and PIRA, including the number of CL. DISCUSSION: The combination of CVS, CL, and PRL can improve MS differential diagnosis. CL and PRL also correlated with clinical measures of poor prognosis, with PRL being a predictor of disability accrual independent of clinical/MRI activity.

Determinants and Biomarkers of Progression Independent of Relapses in Multiple Sclerosis.

Clinical, pathological, and imaging evidence in multiple sclerosis (MS) suggests that a smoldering inflammatory activity is present from the earliest stages of the disease and underlies the progression of disability, which proceeds relentlessly and independently of clinical and radiological relapses (PIRA). The complex system of pathological events driving "chronic" worsening is likely linked with the early accumulation of compartmentalized inflammation within the central nervous system as well as insufficient repair phenomena and mitochondrial failure. These mechanisms are partially lesion-independent and differ from those causing clinical relapses and the formation of new focal demyelinating lesions; they lead to neuroaxonal dysfunction and death, myelin loss, glia alterations, and finally, a neuronal network dysfunction outweighing central nervous system (CNS) compensatory mechanisms. This review aims to provide an overview of the state of the art of neuropathological, immunological, and imaging knowledge about the mechanisms underlying the smoldering disease activity, focusing on possible early biomarkers and their translation into clinical practice. ANN NEUROL 2024;96:1-20.

Comparative overview of multi-shell diffusion MRI models to characterize the microstructure of multiple sclerosis lesions and periplaques.

In multiple sclerosis (MS), accurate in vivo characterization of the heterogeneous lesional and extra-lesional tissue pathology remains challenging. Marshalling several advanced imaging techniques - quantitative relaxation time (T1) mapping, a model-free average diffusion signal approach and four multi-shell diffusion models - this study investigates the performance of multi-shell diffusion models and characterizes the microstructural damage within (i) different MS lesion types - active, chronic active, and chronic inactive - (ii) their respective periplaque white matter (WM), and (iii) the surrounding normal-appearing white matter (NAWM). In 83 MS participants (56 relapsing-remitting, 27 progressive) and 23 age and sex-matched healthy controls (HC), we analysed a total of 317 paramagnetic rim lesions (PRL+), 232 non-paramagnetic rim lesions (PRL-), 38 contrast-enhancing lesions (CEL). Consistent with previous findings and histology, our analysis revealed the ability of advanced multi-shell diffusion models to characterize the unique microstructural patterns of CEL, and to elucidate their possible evolution into a resolving (chronic inactive) vs smoldering (chronic active) inflammatory stage. In addition, we showed that the microstructural damage extends well beyond the MRI-visible lesion edge, gradually fading out while moving outward from the lesion edge into the immediate WM periplaque and the NAWM, the latter still characterized by diffuse microstructural damage in MS vs HC. This study also emphasizes the critical role of selecting appropriate diffusion models to elucidate the complex pathological architecture of MS lesions and their periplaque. More specifically, multi-compartment diffusion models based on biophysically interpretable metrics such as neurite orientation dispersion and density (NODDI; mean auc=0.8002) emerge as the preferred choice for MS applications, while simpler models based on a representation of the diffusion signal, like diffusion tensor imaging (DTI; mean auc=0.6942), consistently underperformed, also when compared to T1 mapping (mean auc=0.73375).

Metabolomics of Multiple Sclerosis Lesions Demonstrates Lipid Changes Linked to Alterations in Transcriptomics-Based Cellular Profiles.

BACKGROUND AND OBJECTIVES: People with multiple sclerosis (MS) have a dysregulated circulating metabolome, but the metabolome of MS brain lesions has not been studied. The aims of this study were to identify differences in the brain tissue metabolome in MS compared with controls and to assess its association with the cellular profile of corresponding tissue. METHODS: MS tissues included samples from the edge and core of chronic active or inactive lesions and periplaque white matter (WM). Control specimens were obtained from normal WM. Metabolomic analysis was performed using mass-spectrometry coupled with liquid/gas chromatography and subsequently integrated with single-nucleus RNA-sequencing data by correlating metabolite abundances with relative cell counts, as well as individual genes using Multiomics Factor Analysis (MOFA). RESULTS: Seventeen samples from 5 people with secondary progressive MS and 8 samples from 6 controls underwent metabolomic profiling identifying 783 metabolites. MS lesions had higher levels of sphingosines (false discovery rate-adjusted p-value[q] = 2.88E-05) and sphingomyelins and ceramides (q = 2.15E-07), but lower nucleotide (q = 0.05), energy (q = 0.001), lysophospholipid (q = 1.86E-07), and monoacylglycerol (q = 0.04) metabolite levels compared with control WM. Periplaque WM had elevated sphingomyelins and ceramides (q = 0.05) and decreased energy metabolites (q = 0.01) and lysophospholipids (q = 0.05) compared with control WM. Sphingolipids and membrane lipid metabolites were positively correlated with astrocyte and immune cell abundances and negatively correlated with oligodendrocytes. On the other hand, long-chain fatty acid, endocannabinoid, and monoacylglycerol pathways were negatively correlated with astrocyte and immune cell populations and positively correlated with oligodendrocytes. MOFA demonstrated associations between differentially expressed metabolites and genes involved in myelination and lipid biosynthesis. DISCUSSION: MS lesions and perilesional WM demonstrated a significantly altered metabolome compared with control WM. Many of the altered metabolites were associated with altered cellular composition and gene expression, indicating an important role of lipid metabolism in chronic neuroinflammation in MS.

Imaging of brain barrier inflammation and brain fluid drainage in human neurological diseases.

The intricate relationship between the central nervous system (CNS) and the immune system plays a crucial role in the pathogenesis of various neurological diseases. Understanding the interactions among the immunopathological processes at the brain borders is essential for advancing our knowledge of disease mechanisms and developing novel diagnostic and therapeutic approaches. In this review, we explore the emerging role of neuroimaging in providing valuable insights into brain barrier inflammation and brain fluid drainage in human neurological diseases. Neuroimaging techniques have enabled us not only to visualize and assess brain structures, but also to study the dynamics of the CNS in health and disease in vivo. By analyzing imaging findings, we can gain a deeper understanding of the immunopathology observed at the brain-immune interface barriers, which serve as critical gatekeepers that regulate immune cell trafficking, cytokine release, and clearance of waste products from the brain. This review explores the integration of neuroimaging data with immunopathological findings, providing valuable insights into brain barrier integrity and immune responses in neurological diseases. Such integration may lead to the development of novel diagnostic markers and targeted therapeutic approaches that can benefit patients with neurological disorders.

Association of Spinal Cord Atrophy and Brain Paramagnetic Rim Lesions With Progression Independent of Relapse Activity in People With MS.

BACKGROUND AND OBJECTIVES: Progression independent of relapse activity (PIRA) is a crucial determinant of overall disability accumulation in multiple sclerosis (MS). Accelerated brain atrophy has been shown in patients experiencing PIRA. In this study, we assessed the relation between PIRA and neurodegenerative processes reflected by (1) longitudinal spinal cord atrophy and (2) brain paramagnetic rim lesions (PRLs). Besides, the same relationship was investigated in progressive MS (PMS). Last, we explored the value of cross-sectional brain and spinal cord volumetric measurements in predicting PIRA. METHODS: From an ongoing multicentric cohort study, we selected patients with MS with (1) availability of a susceptibility-based MRI scan and (2) regular clinical and conventional MRI follow-up in the 4 years before the susceptibility-based MRI. Comparisons in spinal cord atrophy rates (explored with linear mixed-effect models) and PRL count (explored with negative binomial regression models) were performed between: (1) relapsing-remitting (RRMS) and PMS phenotypes and (2) patients experiencing PIRA and patients without confirmed disability accumulation (CDA) during follow-up (both considering the entire cohort and the subgroup of patients with RRMS). Associations between baseline MRI volumetric measurements and time to PIRA were explored with multivariable Cox regression analyses. RESULTS: In total, 445 patients with MS (64.9% female; mean [SD] age at baseline 45.0 [11.4] years; 11.2% with PMS) were enrolled. Compared with patients with RRMS, those with PMS had accelerated cervical cord atrophy (mean difference in annual percentage volume change [MD-APC] -1.41; p = 0.004) and higher PRL load (incidence rate ratio [IRR] 1.93; p = 0.005). Increased spinal cord atrophy (MD-APC -1.39; p = 0.0008) and PRL burden (IRR 1.95; p = 0.0008) were measured in patients with PIRA compared with patients without CDA; such differences were also confirmed when restricting the analysis to patients with RRMS. Baseline volumetric measurements of the cervical cord, whole brain, and cerebral cortex significantly predicted time to PIRA (all p ≤ 0.002). DISCUSSION: Our results show that PIRA is associated with both increased spinal cord atrophy and PRL burden, and this association is evident also in patients with RRMS. These findings further point to the need to develop targeted treatment strategies for PIRA to prevent irreversible neuroaxonal loss and optimize long-term outcomes of patients with MS.

Imaging chronic active lesions in multiple sclerosis: a consensus statement.

Chronic active lesions (CAL) are an important manifestation of chronic inflammation in multiple sclerosis (MS) and have implications for non-relapsing biological progression. In recent years, the discovery of innovative magnetic resonance imaging (MRI) and PET derived biomarkers has made it possible to detect CAL, and to some extent quantify them, in the brain of persons with MS, in vivo. Paramagnetic rim lesions on susceptibility-sensitive MRI sequences, MRI-defined slowly expanding lesions on T1-weighted (T1-w) and T2-w scans, and 18-kDa translocator protein-positive lesions on PET are promising candidate biomarkers of CAL. While partially overlapping, these biomarkers do not have equivalent sensitivity and specificity to histopathological CAL. Standardization in the use of available imaging measures for CAL identification, quantification, and monitoring is lacking. To fast-forward clinical translation of CAL, the North American Imaging in Multiple Sclerosis Cooperative developed a Consensus Statement, which provides guidance for the radiological definition and measurement of CAL. The proposed manuscript presents this Consensus Statement, summarizes the multistep process leading to it, and identifies the remaining major gaps in knowledge.

Diagnostic Performance of Cortical Lesions and the Central Vein Sign in Multiple Sclerosis.

Importance: Multiple sclerosis (MS) misdiagnosis remains an important issue in clinical practice. Objective: To quantify the performance of cortical lesions (CLs) and central vein sign (CVS) in distinguishing MS from other conditions showing brain lesions on magnetic resonance imaging (MRI). Design, Setting, and Participants: This was a retrospective, cross-sectional multicenter study, with clinical and MRI data acquired between January 2010 and May 2020. Centralized MRI analysis was conducted between July 2020 and December 2022 by 2 raters blinded to participants' diagnosis. Participants were recruited from 14 European centers and from a multicenter pan-European cohort. Eligible participants had a diagnosis of MS, clinically isolated syndrome (CIS), or non-MS conditions; availability of a brain 3-T MRI scan with at least 1 sequence suitable for CL and CVS assessment; presence of T2-hyperintense white matter lesions (WMLs). A total of 1051 individuals were included with either MS/CIS (n = 599; 386 [64.4%] female; mean [SD] age, 41.5 [12.3] years) or non-MS conditions (including other neuroinflammatory disorders, cerebrovascular disease, migraine, and incidental WMLs in healthy control individuals; n = 452; 302 [66.8%] female; mean [SD] age, 49.2 [14.5] years). Five individuals were excluded due to missing clinical or demographic information (n = 3) or unclear diagnosis (n = 2). Exposures: MS/CIS vs non-MS conditions. Main Outcomes and Measures: Area under the receiver operating characteristic curves (AUCs) were used to explore the diagnostic performance of CLs and the CVS in isolation and in combination; sensitivity, specificity, and accuracy were calculated for various cutoffs. The diagnostic importance of CLs and CVS compared to conventional MRI features (ie, presence of infratentorial, periventricular, and juxtacortical WMLs) was ranked with a random forest model. Results: The presence of CLs and the previously proposed 40% CVS rule had a sensitivity, specificity, and accuracy for MS of 59.0% (95% CI, 55.1-62.8), 93.6% (95% CI, 91.4-95.6), and 73.9% (95% CI, 71.6-76.3) and 78.7% (95% CI, 75.5-82.0), 86.0% (95% CI, 82.1-89.5), and 81.5% (95% CI, 78.9-83.7), respectively. The diagnostic performance of the CVS (AUC, 0.89 [95% CI, 0.86-0.91]) was superior to that of CLs (AUC, 0.77 [95% CI, 0.75-0.80]; P < .001), and was increased when combining the 2 imaging markers (AUC, 0.92 [95% CI, 0.90-0.94]; P = .04); in the random forest model, both CVS and CLs outperformed the presence of infratentorial, periventricular, and juxtacortical WMLs in supporting MS differential diagnosis. Conclusions and Relevance: The findings in this study suggest that CVS and CLs may be valuable tools to increase the accuracy of MS diagnosis.

Highly Sensitive 3-Tesla Real Inversion Recovery MRI Detects Leptomeningeal Contrast Enhancement in Chronic Active Multiple Sclerosis.

BACKGROUND: Leptomeningeal contrast enhancement (LME) on T2-weighted Fluid-Attenuated Inversion Recovery (T2-FLAIR) MRI is a reported marker of leptomeningeal inflammation, which is known to be associated with progression of multiple sclerosis (MS). However, this MRI approach, as typically implemented on clinical 3-tesla (T) systems, detects only a few enhancing foci in ~25% of patients and has thus been criticized as poorly sensitive. PURPOSE: To compare an optimized 3D real-reconstruction inversion recovery (Real-IR) MRI sequence on a clinical 3 T scanner to T2-FLAIR for prevalence, characteristics, and clinical/radiological correlations of LME. MATERIALS AND METHODS: We obtained 3D T2-FLAIR and Real-IR scans before and after administration of standard-dose gadobutrol in 177 scans of 154 participants (98 women, 64%; mean ± SD age: 49 ± 12 years), including 124 with an MS-spectrum diagnosis, 21 with other neurological and/or inflammatory disorders, and 9 without neurological history. We calculated contrast-to-noise ratios (CNR) in 20 representative LME foci and determined association of LME with cortical lesions identified at 7 T (n = 19), paramagnetic rim lesions (PRL) at 3 T (n = 105), and clinical/demographic data. RESULTS: We observed focal LME in 73% of participants on Real-IR (70% in established MS, 33% in healthy volunteers, P < 0.0001), compared to 33% on T2-FLAIR (34% vs. 11%, P = 0.0002). Real-IR showed 3.7-fold more LME foci than T2-FLAIR ( P = 0.001), including all T2-FLAIR foci. LME CNR was 2.5-fold higher by Real-IR ( P < 0.0001). The major determinant of LME status was age. Although LME was not associated with cortical lesions, the number of PRL was associated with the number of LME foci on both T2-FLAIR ( P = 0.003) and Real-IR ( P = 0.0003) after adjusting for age, sex, and white matter lesion volume. CONCLUSIONS: Real-IR a promising tool to detect, characterize, and understand the significance of LME in MS. The association between PRL and LME highlights a possible role of the leptomeninges in sustaining chronic inflammation.

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

BACKGROUND: 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. METHODS: 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 in vivo MRI assessment of PRL changes in 72 adults with MS, 46 treated with anti-CD20 antibodies and 26 untreated, over ∼2 years. FINDINGS: 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. In vivo, 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). INTERPRETATION: 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. FUNDING: 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).

Positron Emission Tomography with [18 F]-DPA-714 Unveils a Smoldering Component in Most Multiple Sclerosis Lesions which Drives Disease Progression.

OBJECTIVE: To determine the prognostic value of persisting neuroinflammation in multiple sclerosis (MS) lesions, we developed a 18 kDa-translocator-protein-positron emission tomography (PET) -based classification of each lesion according to innate immune cell content and localization. We assessed the respective predictive value of lesion phenotype and diffuse inflammation on atrophy and disability progression over 2 years. METHODS: Thirty-six people with MS (disease duration 9 ± 6 years; 12 with relapsing-remitting, 13 with secondary-progressive, and 11 with primary-progressive) and 19 healthy controls (HCs) underwent a dynamic [18 F]-DPA-714-PET. At baseline and after 2 years, the patients also underwent a magnetic resonance imaging (MRI) and neurological examination. Based on a threshold of significant inflammation defined by a comparison of [18 F]-DPA-714 binding between patients with MS and HCs, white matter lesions were classified as homogeneously active (active center), rim-active (inactive center and active periphery), or nonactive. Longitudinal cortical atrophy was measured using Jacobian integration. RESULTS: Patients with MS had higher innate inflammation in normal-appearing white matter (NAWM) and cortex than HCs (respective standardized effect size = 1.15, 0.89, p = 0.003 and < 0.001). Out of 1,335 non-gadolinium-enhancing lesions, 53% were classified as homogeneously-active (median = 17 per patient with MS), 6% rim-active (median = 1 per patient with MS), and 41% non-active (median = 14 per patient with MS). The number of homogenously-active lesions was the strongest predictor of longitudinal changes, associating with cortical atrophy (ß = 0.49, p = 0.023) and Expanded Disability Status Scale (EDSS) changes (ß = 0.35, p = 0.023) over 2 years. NAWM and cortical binding were not associated to volumetric and clinical changes. INTERPRETATION: The [18 F]-DPA-714-PET revealed that an unexpectedly high proportion of MS lesions have a smoldering component, which predicts atrophy and clinical progression. This suggests that following the acute phase, most lesions develop a chronic inflammatory component, promoting neurodegeneration and clinical progression. ANN NEUROL 2023;94:366-383.

Ageing and multiple sclerosis.

The factor that is most relevant and strongly associated with the clinical course of multiple sclerosis is chronological age. Very young patients exclusively have relapsing remitting disease, whereas those with later onset disease face a more rapid development of permanent disability. For people with progressive multiple sclerosis, the poor response to current disease modifying therapies might be related to ageing in the immune system and CNS. Ageing is also associated with increased risks of side-effects caused by some multiple sclerosis therapies. Both somatic and reproductive ageing processes might contribute to development of progressive multiple sclerosis. Understanding the role of ageing in immune and neural cell function in patients with multiple sclerosis might be key to halting non-relapse-related progression. The growing literature on potential therapies that target senescent cells and ageing processes might provide effective strategies for remyelination and neuroprotection.

BMAT: An open-source BIDS managing and analysis tool.

Magnetic Resonance Imaging (MRI) is an established technique to study in vivo neurological disorders such as Multiple Sclerosis (MS). To avoid errors on MRI data organization and automated processing, a standard called Brain Imaging Data Structure (BIDS) has been recently proposed. The BIDS standard eases data sharing and processing within or between centers by providing guidelines for their description and organization. However, the transformation from the complex unstructured non-open file data formats coming directly from the MRI scanner to a correct BIDS structure can be cumbersome and time consuming. This hinders a wider adoption of the BIDS format across different study centers. To solve this problem and ease the day-to-day use of BIDS for the neuroimaging scientific community, we present the BIDS Managing and Analysis Tool (BMAT). The BMAT software is a complete and easy-to-use local open-source neuroimaging analysis tool with a graphical user interface (GUI) that uses the BIDS format to organize and process brain MRI data for MS imaging research studies. BMAT provides the possibility to translate data from MRI scanners to the BIDS structure, create and manage BIDS datasets as well as develop and run automated processing pipelines, and is faster than its competitor. BMAT software propose the possibility to download useful analysis apps, especially applied to MS research with lesion segmentation and processing of imaging contrasts for novel disease biomarkers such as the central vein sign and the paramagnetic rim lesions.

What is the potential of paramagnetic rim lesions as diagnostic indicators in multiple sclerosis?

INTRODUCTION: In multiple sclerosis (MS), paramagnetic rim lesions (PRLs) on MRI identify a subset of chronic active lesions (CALs), which have been linked through clinical and pathological studies to more severe disease course and greater disability accumulation. Beside their prognostic relevance, increasing evidence supports the use of PRL as a diagnostic biomarker. AREAS COVERED: This review summarizes the most recent updates regarding the MRI pathophysiology of PRL, their prevalence in MS (by clinical phenotypes) vs mimicking conditions, and their potential role as diagnostic MS biomarkers. We searched PubMed with terms including 'multiple sclerosis' AND 'paramagnetic rim lesions' OR 'iron rim lesions' OR 'rim lesions' for manuscripts published between January 2008 and July 2022. EXPERT OPINION: Current research suggests that PRL can improve the diagnostic specificity and the overall accuracy of MS diagnosis when used together with the dissemination in space MRI criteria and the central vein sign. Nevertheless, future prospective multicenter studies should further define the real-world prevalence and specificity of PRL. International guidelines are needed to establish methodological criteria for PRL identification before its implementation into clinical practice.

Cortical lesions, central vein sign, and paramagnetic rim lesions in multiple sclerosis: Emerging machine learning techniques and future avenues.

The current diagnostic criteria for multiple sclerosis (MS) lack specificity, and this may lead to misdiagnosis, which remains an issue in present-day clinical practice. In addition, conventional biomarkers only moderately correlate with MS disease progression. Recently, some MS lesional imaging biomarkers such as cortical lesions (CL), the central vein sign (CVS), and paramagnetic rim lesions (PRL), visible in specialized magnetic resonance imaging (MRI) sequences, have shown higher specificity in differential diagnosis. Moreover, studies have shown that CL and PRL are potential prognostic biomarkers, the former correlating with cognitive impairments and the latter with early disability progression. As machine learning-based methods have achieved extraordinary performance in the assessment of conventional imaging biomarkers, such as white matter lesion segmentation, several automated or semi-automated methods have been proposed as well for CL, PRL, and CVS. In the present review, we first introduce these MS biomarkers and their imaging methods. Subsequently, we describe the corresponding machine learning-based methods that were proposed to tackle these clinical questions, putting them into context with respect to the challenges they are facing, including non-standardized MRI protocols, limited datasets, and moderate inter-rater variability. We conclude by presenting the current limitations that prevent their broader deployment and suggesting future research directions.

From pathology to MRI and back: Clinically relevant biomarkers of multiple sclerosis lesions.

Focal lesions in both white and gray matter are characteristic of multiple sclerosis (MS). Histopathological studies have helped define the main underlying pathological processes involved in lesion formation and evolution, serving as a gold standard for many years. However, histopathology suffers from an intrinsic bias resulting from over-reliance on tissue samples from late stages of the disease or atypical cases and is inadequate for routine patient assessment. Pathological-radiological correlative studies have established advanced MRI's sensitivity to several relevant MS-pathological substrates and its practicality for assessing dynamic changes and following lesions over time. This review focuses on novel imaging techniques that serve as biomarkers of critical pathological substrates of MS lesions: the central vein, chronic inflammation, remyelination and repair, and cortical lesions. For each pathological process, we address the correlative value of MRI to MS pathology, its contribution in elucidating MS pathology in vivo, and the clinical utility of the imaging biomarker.

Lesion size and shape in central vein sign assessment for multiple sclerosis diagnosis: An in vivo and postmortem MRI study.

BACKGROUND: The "central vein sign" (CVS), a linear hypointensity on T2*-weighted imaging corresponding to a central vein/venule, is associated with multiple sclerosis (MS) lesions. The effect of lesion-size exclusion criteria on MS diagnostic accuracy has not been extensively studied. OBJECTIVE: Investigate the optimal lesion-size exclusion criteria for CVS use in MS diagnosis. METHODS: Cross-sectional study of 163 MS and 51 non-MS, and radiological/histopathological correlation of 5 MS and 1 control autopsy cases. The effects of lesion-size exclusion on MS diagnosis using the CVS, and intralesional vein detection on histopathology were evaluated. RESULTS: CVS+ lesions were larger compared to CVS- lesions, with effect modification by MS diagnosis (mean difference +7.7 mm3, p = 0.004). CVS percentage-based criteria with no lesion-size exclusion showed the highest diagnostic accuracy in differentiating MS cases. However, a simple count of three or more CVS+ lesions greater than 3.5 mm is highly accurate and can be rapidly implemented (sensitivity 93%; specificity 88%). On magnetic resonance imaging (MRI)-histopathological correlation, the CVS had high specificity for identifying intralesional veins (0/7 false positives). CONCLUSION: Lesion-size measures add important information when using CVS+ lesion counts for MS diagnosis. The CVS is a specific biomarker corresponding to intralesional veins on histopathology.