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1.
Mult Scler ; : 13524585241271988, 2024 Sep 05.
Artículo en Inglés | MEDLINE | ID: mdl-39234802

RESUMEN

BACKGROUND: Cerebrospinal fluid (CSF) oligoclonal bands (OCB) are a diagnostic biomarker in multiple sclerosis (MS). The central vein sign (CVS) is an imaging biomarker for MS that may improve diagnostic accuracy. OBJECTIVES: The objective of the study is to examine the diagnostic performance of simplified CVS methods in comparison to OCB in participants with clinical or radiological suspicion for MS. METHODS: Participants from the CentrAl Vein Sign in MS (CAVS-MS) pilot study with CSF testing were included. Select-3 and Select-6 (counting up to three or six CVS+ lesions per scan) were rated on post-gadolinium FLAIR* images. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value for Select-3, Select-6, OCB, and combinations thereof were calculated for MS diagnosis at baseline and at 12 months. RESULTS: Of 53 participants, 25 were OCB+. At baseline, sensitivity for MS diagnosis was 0.75 for OCB, 0.83 for Select-3, and 0.71 for Select-6. Specificity for MS diagnosis was 0.76 for OCB, 0.48 for Select-3, and 0.86 for Select-6. At 12 months, PPV for MS diagnosis was 0.95 for Select-6 and 1.00 for Select-6 with OCB+ status. DISCUSSION: Results suggest similar diagnostic performance of simplified CVS methods and OCB. Ongoing studies will refine whether CVS could be used in replacement or in conjunction with OCB.

2.
Cell Rep Med ; 5(8): 101680, 2024 Aug 20.
Artículo en Inglés | MEDLINE | ID: mdl-39121861

RESUMEN

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.


Asunto(s)
Encéfalo , Diferenciación Celular , Células Madre Pluripotentes Inducidas , Esclerosis Múltiple , Neuroglía , Organoides , Fenotipo , Humanos , Esclerosis Múltiple/patología , Esclerosis Múltiple/metabolismo , Células Madre Pluripotentes Inducidas/metabolismo , Células Madre Pluripotentes Inducidas/patología , Organoides/patología , Organoides/metabolismo , Neuroglía/metabolismo , Neuroglía/patología , Encéfalo/patología , Encéfalo/metabolismo , Oligodendroglía/metabolismo , Oligodendroglía/patología , Células-Madre Neurales/metabolismo , Células-Madre Neurales/patología , Microglía/metabolismo , Microglía/patología
3.
PLoS Comput Biol ; 20(7): e1012241, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38985831

RESUMEN

Dimension reduction tools preserving similarity and graph structure such as t-SNE and UMAP can capture complex biological patterns in high-dimensional data. However, these tools typically are not designed to separate effects of interest from unwanted effects due to confounders. We introduce the partial embedding (PARE) framework, which enables removal of confounders from any distance-based dimension reduction method. We then develop partial t-SNE and partial UMAP and apply these methods to genomic and neuroimaging data. For lower-dimensional visualization, our results show that the PARE framework can remove batch effects in single-cell sequencing data as well as separate clinical and technical variability in neuroimaging measures. We demonstrate that the PARE framework extends dimension reduction methods to highlight biological patterns of interest while effectively removing confounding effects.


Asunto(s)
Algoritmos , Biología Computacional , Neuroimagen , Humanos , Neuroimagen/métodos , Biología Computacional/métodos , Genómica/métodos , Genómica/estadística & datos numéricos , Análisis de la Célula Individual/métodos , Análisis de la Célula Individual/estadística & datos numéricos
4.
Neuron ; 2024 Jun 07.
Artículo en Inglés | MEDLINE | ID: mdl-38889714

RESUMEN

Progressive multiple sclerosis (PMS) is an immune-initiated neurodegenerative condition that lacks effective therapies. Although peripheral immune infiltration is a hallmark of relapsing-remitting MS (RRMS), PMS is associated with chronic, tissue-restricted inflammation and disease-associated reactive glial states. The effector functions of disease-associated microglia, astrocytes, and oligodendrocyte lineage cells are beginning to be defined, and recent studies have made significant progress in uncovering their pathologic implications. In this review, we discuss the immune-glia interactions that underlie demyelination, failed remyelination, and neurodegeneration with a focus on PMS. We highlight the common and divergent immune mechanisms by which glial cells acquire disease-associated phenotypes. Finally, we discuss recent advances that have revealed promising novel therapeutic targets for the treatment of PMS and other neurodegenerative diseases.

5.
Neurol Neuroimmunol Neuroinflamm ; 11(5): e200269, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-38941572

RESUMEN

BACKGROUND AND OBJECTIVES: Retinal optical coherence tomography (OCT) provides promising prognostic imaging biomarkers for future disease activity in multiple sclerosis (MS). However, raw OCT-derived measures have multiple dependencies, supporting the need for establishing reference values adjusted for possible confounders. The purpose of this study was to investigate the capacity for age-adjusted z scores of OCT-derived measures to prognosticate future disease activity and disability worsening in people with MS (PwMS). METHODS: We established age-adjusted OCT reference data using generalized additive models for location, scale, and shape for peripapillary retinal nerve fiber layer (pRNFL) and ganglion cell-inner plexiform layer (GCIP) thicknesses, involving 910 and 423 healthy eyes, respectively. Next, we transformed the retinal layer thickness of PwMS from 3 published studies into age-adjusted z scores (pRNFL-z and GCIP-z) based on the reference data. Finally, we investigated the association of pRNFL-z or GCIP-z as predictors with future confirmed disability worsening (Expanded Disability Status Scale score increase) or disease activity (failing of the no evidence of disease activity [NEDA-3] criteria) as outcomes. Cox proportional hazards models or logistic regression analyses were applied according to the original studies. Optimal cutoffs were identified using the Akaike information criterion as well as location with the log-rank and likelihood-ratio tests. RESULTS: In the first cohort (n = 863), 172 PwMS (24%) had disability worsening over a median observational period of 2.0 (interquartile range [IQR]:1.0-3.0) years. Low pRNFL-z (≤-2.04) were associated with an increased risk of disability worsening (adjusted hazard ratio (aHR) [95% CI] = 2.08 [1.47-2.95], p = 3.82e-5). In the second cohort (n = 170), logistic regression analyses revealed that lower pRNFL-z showed a higher likelihood for disability accumulation at the two-year follow-up (reciprocal odds ratio [95% CI] = 1.51[1.06-2.15], p = 0.03). In the third cohort (n = 78), 46 PwMS (59%) did not maintain the NEDA-3 status over a median follow-up of 2.0 (IQR: 1.9-2.1) years. PwMS with low GCIP-z (≤-1.03) had a higher risk of showing disease activity (aHR [95% CI] = 2.14 [1.03-4.43], p = 0.04). Compared with raw values with arbitrary cutoffs, applying the z score approach with optimal cutoffs showed better performance in discrimination and calibration (higher Harrell's concordance index and lower integrated Brier score). DISCUSSION: In conclusion, our work demonstrated reference cohort-based z scores that account for age, a major driver for disease progression in MS, to be a promising approach for creating OCT-derived measures useable across devices and toward individualized prognostication.


Asunto(s)
Progresión de la Enfermedad , Esclerosis Múltiple , Tomografía de Coherencia Óptica , Humanos , Femenino , Masculino , Adulto , Persona de Mediana Edad , Pronóstico , Esclerosis Múltiple/fisiopatología , Esclerosis Múltiple/diagnóstico por imagen , Retina/diagnóstico por imagen , Retina/patología , Retina/fisiopatología , Índice de Severidad de la Enfermedad
6.
J Neuroinflammation ; 21(1): 154, 2024 Jun 08.
Artículo en Inglés | MEDLINE | ID: mdl-38851724

RESUMEN

Extracellular vesicles (EVs) are released by all cells, can cross the blood-brain barrier, and have been shown to play an important role in cellular communication, substance shuttling, and immune modulation. In recent years EVs have shifted into focus in multiple sclerosis (MS) research as potential plasma biomarkers and therapeutic vehicles. Yet little is known about the disease-associated changes in EVs in the central nervous system (CNS). To address this gap, we characterized the physical and proteomic changes of mouse spinal cord-derived EVs before and at 16 and 25 days after the induction of experimental autoimmune encephalomyelitis (EAE), a neuroinflammatory model of MS. Using various bioinformatic tools, we found changes in inflammatory, glial, and synaptic proteins and pathways, as well as a shift in the predicted contribution of immune and glial cell types over time. These results show that EVs provide snapshots of crucial disease processes such as CNS-compartmentalized inflammation, re/de-myelination, and synaptic pathology, and might also mediate these processes. Additionally, inflammatory plasma EV biomarkers previously identified in people with MS were also altered in EAE spinal cord EVs, suggesting commonalities of EV-related pathological processes during EAE and MS and overlap of EV proteomic changes between CNS and circulating EVs.


Asunto(s)
Encefalomielitis Autoinmune Experimental , Vesículas Extracelulares , Ratones Endogámicos C57BL , Médula Espinal , Vesículas Extracelulares/metabolismo , Animales , Médula Espinal/metabolismo , Médula Espinal/patología , Ratones , Encefalomielitis Autoinmune Experimental/metabolismo , Encefalomielitis Autoinmune Experimental/patología , Femenino , Enfermedades Neuroinflamatorias/metabolismo , Enfermedades Neuroinflamatorias/patología , Proteómica
7.
Artículo en Inglés | MEDLINE | ID: mdl-38806240

RESUMEN

Acquired demyelinating diseases of the central nervous system (CNS) comprise inflammatory conditions, including multiple sclerosis (MS) and related diseases, as well as noninflammatory conditions caused by toxic, metabolic, infectious, traumatic, and neurodegenerative insults. Here, we review the spectrum of diseases producing acquired CNS demyelination before focusing on the prototypical example of MS, exploring the pathologic mechanisms leading to myelin injury in relapsing and progressive MS and summarizing the mechanisms and modulators of remyelination. We highlight the complex interplay between the immune system, oligodendrocytes and oligodendrocyte progenitor cells (OPCs), and other CNS glia cells such as microglia and astrocytes in the pathogenesis and clinical course of MS. Finally, we review emerging therapeutic strategies that exploit our growing understanding of disease mechanisms to limit progression and promote remyelination.

8.
Neurol Neuroimmunol Neuroinflamm ; 11(4): e200257, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38754047

RESUMEN

OBJECTIVES: To assess whether the rate of change in synaptic proteins isolated from neuronally enriched extracellular vesicles (NEVs) is associated with brain and retinal atrophy in people with multiple sclerosis (MS). METHODS: People with MS were followed with serial blood draws, MRI (MRI), and optical coherence tomography (OCT) scans. NEVs were immunocaptured from plasma, and synaptopodin and synaptophysin proteins were measured using ELISA. Subject-specific rates of change in synaptic proteins, as well as brain and retinal atrophy, were determined and correlated. RESULTS: A total of 50 people with MS were included, 46 of whom had MRI and 45 had OCT serially. The rate of change in NEV synaptopodin was associated with whole brain (rho = 0.31; p = 0.04), cortical gray matter (rho = 0.34; p = 0.03), peripapillary retinal nerve fiber layer (rho = 0.37; p = 0.01), and ganglion cell/inner plexiform layer (rho = 0.41; p = 0.006) atrophy. The rate of change in NEV synaptophysin was also correlated with whole brain (rho = 0.31; p = 0.04) and cortical gray matter (rho = 0.31; p = 0.049) atrophy. DISCUSSION: NEV-derived synaptic proteins likely reflect neurodegeneration and may provide additional circulating biomarkers for disease progression in MS.


Asunto(s)
Atrofia , Encéfalo , Vesículas Extracelulares , Esclerosis Múltiple , Retina , Sinaptofisina , Humanos , Masculino , Femenino , Persona de Mediana Edad , Vesículas Extracelulares/metabolismo , Adulto , Encéfalo/patología , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Retina/patología , Retina/diagnóstico por imagen , Retina/metabolismo , Esclerosis Múltiple/patología , Esclerosis Múltiple/metabolismo , Esclerosis Múltiple/diagnóstico por imagen , Sinaptofisina/metabolismo , Tomografía de Coherencia Óptica , Imagen por Resonancia Magnética , Proteínas de Microfilamentos/metabolismo
9.
Res Sq ; 2024 Apr 19.
Artículo en Inglés | MEDLINE | ID: mdl-38699321

RESUMEN

Introduction: The cerebellum is a common lesion site in persons with multiple sclerosis (PwMS). Physiologic and anatomic studies have identified a topographic organization of the cerebellum including functionally distinct motor and cognitive areas. This study implemented a recent parcellation algorithm developed by Han et al., 2020 to a sample of PwMS and healthy controls to examine relationships among specific cerebellar regions, fall status, and common clinical measures of motor and cognitive functions. Methods: Thirty-one PwMS and 29 age and sex-matched controls underwent an MRI scan and motor and cognitive testing. The parcellation algorithm was applied to all images and divided the cerebellum into 28 regions. Mann-Whitney U tests were used to compare cerebellar volumes among PwMS and controls, and MS fallers and MS non-fallers. Relationships between cerebellar volumes and motor and cognitive function was evaluated using Spearman correlations. Results: PwMS performed significantly worse on functional measures compared to controls. We found significant differences in volumetric measures between PwMS and controls in the corpus medullare, lobules I-III, and lobule V. Volumetric differences seen between PwMS and controls were primarily driven by the MS fallers. Finally, functional performance on motor and cognitive tasks was associated with cerebellar volumes. Conclusions: Using the parcellation tool, our results showed that volumes of motor and cognitive lobules impact both motor and cognitive performance, and that functional performance and cerebellar volumes distinguishes MS fallers from non-fallers. Future studies should explore the potential of cerebellar imaging to predict falls in PwMS.

10.
Neurotherapeutics ; 21(4): e00379, 2024 May 25.
Artículo en Inglés | MEDLINE | ID: mdl-38797642

RESUMEN

Preclinical studies of pro-remyelinating therapies for multiple sclerosis tend to neglect the effect of the disease-relevant inflammatory milieu. Interferon-gamma (IFN-γ) is known to suppress oligodendrocyte progenitor cell (OPC) differentiation and induce a recently described immune OPC (iOPC) phenotype characterized by expression of major histocompatibility complex (MHC) molecules. We tested the effects of cladribine (CDB), dimethylfumarate (DMF), and interferon-beta (IFN-ß), existing anti-inflammatory therapies for MS, on the IFN-γ-induced iOPC formation and OPC differentiation block. In line with previous reports, we demonstrate that IFN-ß and DMF inhibit OPC proliferation, while CDB had no effect. None of the drugs exhibited cytotoxic effects at the physiological concentrations tested in vitro. In a differentiation assay, none of the drugs were able to promote differentiation, under inflammatory or basal conditions. To study drug effects on iOPCs, we monitored MHC expression in vitro with live cell imaging using cells isolated from MHC reporter mice. IFN-ß suppressed induction of MHC class II, and DMF led to suppression of both class I and II. CDB had no effect on MHC induction. We conclude that promoting proliferation and differentiation and suppressing iOPC induction under inflammatory conditions may require separate therapeutic strategies and must be balanced for maximal repair. Our in vitro MHC screening assay can be leveraged across cell types to test the effects of drug candidates and disease-related stimuli.

11.
J Neurochem ; 2024 May 04.
Artículo en Inglés | MEDLINE | ID: mdl-38702968

RESUMEN

Ependymal cells form a specialized brain-cerebrospinal fluid (CSF) interface and regulate local CSF microcirculation. It is becoming increasingly recognized that ependymal cells assume a reactive state in response to aging and disease, including conditions involving hypoxia, hydrocephalus, neurodegeneration, and neuroinflammation. Yet what transcriptional signatures govern these reactive states and whether this reactivity shares any similarities with classical descriptions of glial reactivity (i.e., in astrocytes) remain largely unexplored. Using single-cell transcriptomics, we interrogated this phenomenon by directly comparing the reactive ependymal cell transcriptome to the reactive astrocyte transcriptome using a well-established model of autoimmune-mediated neuroinflammation (MOG35-55 EAE). In doing so, we unveiled core glial reactivity-associated genes that defined the reactive ependymal cell and astrocyte response to MOG35-55 EAE. Interestingly, known reactive astrocyte genes from other CNS injury/disease contexts were also up-regulated by MOG35-55 EAE ependymal cells, suggesting that this state may be conserved in response to a variety of pathologies. We were also able to recapitulate features of the reactive ependymal cell state acutely using a classic neuroinflammatory cocktail (IFNγ/LPS) both in vitro and in vivo. Taken together, by comparing reactive ependymal cells and astrocytes, we identified a conserved signature underlying glial reactivity that was present in several neuroinflammatory contexts. Future work will explore the mechanisms driving ependymal reactivity and assess downstream functional consequences.

12.
13.
Mult Scler ; 30(8): 1072-1076, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38481081

RESUMEN

This study aimed to determine whether choroid plexus volume (CPV) could differentiate multiple sclerosis (MS) from its mimics. A secondary analysis of two previously enrolled studies, 50 participants with MS and 64 with alternative diagnoses were included. CPV was automatically segmented from 3T magnetic resonance imaging (MRI), followed by manual review to remove misclassified tissue. Mean normalized choroid plexus volume (nCPV) to intracranial volume demonstrated relatively high specificity for MS participants in each cohort (0.80 and 0.76) with an area under the receiver-operator characteristic curve of 0.71 (95% confidence interval (CI) = 0.55-0.87) and 0.65 (95% CI = 0.52-0.77). In this preliminary study, nCPV differentiated MS from its mimics.


Asunto(s)
Plexo Coroideo , Imagen por Resonancia Magnética , Esclerosis Múltiple , Humanos , Plexo Coroideo/diagnóstico por imagen , Plexo Coroideo/patología , Esclerosis Múltiple/diagnóstico por imagen , Esclerosis Múltiple/patología , Femenino , Adulto , Masculino , Persona de Mediana Edad , Diagnóstico Diferencial
14.
EBioMedicine ; 101: 104970, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38354532

RESUMEN

Neurofilament light chain (NfL) is a long-awaited blood biomarker that can provide clinically useful information about prognosis and therapeutic efficacy in multiple sclerosis (MS). There is now substantial evidence for this biomarker to be used alongside magnetic resonance imaging (MRI) and clinical measures of disease progression as a decision-making tool for the management of patients with MS. Serum NfL (sNfL) has certain advantages over traditional measures of MS disease progression such as MRI because it is relatively noninvasive, inexpensive, and can be repeated frequently to monitor activity and treatment efficacy. sNfL levels can be monitored regularly in patients with MS to determine change from baseline and predict subclinical disease activity, relapse risk, and the development of gadolinium-enhancing (Gd+) lesions. sNfL does not replace MRI, which provides information related to spatial localisation and lesion stage. Laboratory platforms are starting to be made available for clinical application of sNfL in several countries. Further work is needed to resolve issues around comparisons across testing platforms (absolute values) and normalisation (reference ranges) in order to guide interpretation of the results.


Asunto(s)
Esclerosis Múltiple , Humanos , Esclerosis Múltiple/diagnóstico por imagen , Esclerosis Múltiple/tratamiento farmacológico , Filamentos Intermedios , Biomarcadores , Pronóstico , Progresión de la Enfermedad , Proteínas de Neurofilamentos
15.
Neuroimage Rep ; 4(1)2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38370461

RESUMEN

Clinical magnetic resonance images (MRIs) lack a standard intensity scale due to differences in scanner hardware and the pulse sequences used to acquire the images. When MRIs are used for quantification, as in the evaluation of white matter lesions (WMLs) in multiple sclerosis, this lack of intensity standardization becomes a critical problem affecting both the staging and tracking of the disease and its treatment. This paper presents a study of harmonization on WML segmentation consistency, which is evaluated using an object detection classification scheme that incorporates manual delineations from both the original and harmonized MRIs. A cohort of ten people scanned on two different imaging platforms was studied. An expert rater, blinded to the image source, manually delineated WMLs on images from both scanners before and after harmonization. It was found that there is closer agreement in both global and per-lesion WML volume and spatial distribution after harmonization, demonstrating the importance of image harmonization prior to the creation of manual delineations. These results could lead to better truth models in both the development and evaluation of automated lesion segmentation algorithms.

16.
medRxiv ; 2024 Jan 23.
Artículo en Inglés | MEDLINE | ID: mdl-38293182

RESUMEN

Background: Bile acid metabolism is altered in multiple sclerosis (MS) and tauroursodeoxycholic acid (TUDCA) supplementation ameliorated disease in mouse models of MS. Methods: Global metabolomics was performed in an observational cohort of people with MS followed by pathway analysis to examine relationships between baseline metabolite levels and subsequent brain and retinal atrophy. A double-blind, placebo-controlled trial, was completed in people with progressive MS (PMS), randomized to receive either TUDCA (2g daily) or placebo for 16 weeks. Participants were followed with serial clinical and laboratory assessments. Primary outcomes were safety and tolerability of TUDCA, and exploratory outcomes included changes in clinical, laboratory and gut microbiome parameters. Results: In the observational cohort, higher primary bile acid levels at baseline predicted slower whole brain, brain substructure and specific retinal layer atrophy. In the clinical trial, 47 participants were included in our analyses (21 in placebo arm, 26 in TUDCA arm). Adverse events did not significantly differ between arms (p=0.77). The TUDCA arm demonstrated increased serum levels of multiple bile acids. No significant differences were noted in clinical or fluid biomarker outcomes. Central memory CD4+ and Th1/17 cells decreased, while CD4+ naïve cells increased in the TUDCA arm compared to placebo. Changes in the composition and function of gut microbiota were also noted in the TUDCA arm compared to placebo. Conclusion: Bile acid metabolism in MS is linked with brain and retinal atrophy. TUDCA supplementation in PMS is safe, tolerable and has measurable biological effects that warrant further evaluation in larger trials with a longer treatment duration.

17.
Brain ; 147(9): 2913-2933, 2024 Sep 03.
Artículo en Inglés | MEDLINE | ID: mdl-38226694

RESUMEN

Chronic active lesions (CAL) are an important manifestation of chronic inflammation in multiple sclerosis and have implications for non-relapsing biological progression. In recent years, the discovery of innovative MRI and PET-derived biomarkers has made it possible to detect CAL, and to some extent quantify them, in the brain of persons with multiple sclerosis, in vivo. Paramagnetic rim lesions on susceptibility-sensitive MRI sequences, MRI-defined slowly expanding lesions on T1-weighted and T2-weighted 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.


Asunto(s)
Consenso , Imagen por Resonancia Magnética , Esclerosis Múltiple , Humanos , Esclerosis Múltiple/diagnóstico por imagen , Esclerosis Múltiple/patología , Imagen por Resonancia Magnética/normas , Imagen por Resonancia Magnética/métodos , Neuroimagen/métodos , Neuroimagen/normas , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Tomografía de Emisión de Positrones/normas , Tomografía de Emisión de Positrones/métodos
18.
Mult Scler ; 30(1): 35-43, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-37982154

RESUMEN

BACKGROUND: Macrophage migration inhibitory factor (MIF) is a cytokine linked to multiple sclerosis (MS) progression that is thought to be inhibited by ibudilast. SPRINT-MS was a phase 2 placebo-controlled trial of ibudilast in progressive multiple sclerosis (PMS). OBJECTIVE: To determine whether baseline MIF levels predict imaging outcomes and assess the effects of ibudilast on serum and cerebrospinal fluid (CSF) MIF levels in people with PMS treated with ibudilast. METHODS: Participants in the SPRINT-MS trial were treated with either ibudilast or placebo and underwent brain magnetic resonance imaging (MRI) every 24 weeks over a duration of 96 weeks. MIF was measured in serum and CSF. RESULTS: MIF levels were compared with imaging outcomes in 223 participants from the SPRINT-MS study. In the primary progressive multiple sclerosis (PPMS) cohort, males had higher serum (p < 0.001) and CSF (p = 0.01) MIF levels, as compared with females. Higher baseline serum MIF levels in PPMS were associated with faster brain atrophy (beta = -0.113%, 95% confidence interval (CI): -0.204% to -0.021%; p = 0.016). These findings were not observed in secondary progressive multiple sclerosis (SPMS). Ibudilast did not affect either serum or CSF MIF levels. CONCLUSIONS: Serum MIF levels were associated with male sex and predicted brain atrophy in PPMS, but not SPMS. Ibudilast did not demonstrate an effect on MIF levels, as compared with placebo, although we cannot exclude a functional effect.


Asunto(s)
Enfermedades del Sistema Nervioso Central , Factores Inhibidores de la Migración de Macrófagos , Esclerosis Múltiple Crónica Progresiva , Esclerosis Múltiple , Femenino , Humanos , Masculino , Atrofia/patología , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Factores Inhibidores de la Migración de Macrófagos/líquido cefalorraquídeo , Factores Inhibidores de la Migración de Macrófagos/uso terapéutico , Esclerosis Múltiple/diagnóstico por imagen , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple Crónica Progresiva/diagnóstico por imagen , Esclerosis Múltiple Crónica Progresiva/tratamiento farmacológico , Esclerosis Múltiple Crónica Progresiva/patología
19.
Mult Scler ; 30(1): 25-34, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-38088067

RESUMEN

BACKGROUND: The central vein sign (CVS) is a proposed magnetic resonance imaging (MRI) biomarker for multiple sclerosis (MS); the optimal method for abbreviated CVS scoring is not yet established. OBJECTIVE: The aim of this study was to evaluate the performance of a simplified approach to CVS assessment in a multicenter study of patients being evaluated for suspected MS. METHODS: Adults referred for possible MS to 10 sites were recruited. A post-Gd 3D T2*-weighted MRI sequence (FLAIR*) was obtained in each subject. Trained raters at each site identified up to six CVS-positive lesions per FLAIR* scan. Diagnostic performance of CVS was evaluated for a diagnosis of MS which had been confirmed using the 2017 McDonald criteria at thresholds including three positive lesions (Select-3*) and six positive lesions (Select-6*). Inter-rater reliability assessments were performed. RESULTS: Overall, 78 participants were analyzed; 37 (47%) were diagnosed with MS, and 41 (53%) were not. The mean age of participants was 45 (range: 19-64) years, and most were female (n = 55, 71%). The area under the receiver operating characteristic curve (AUROC) for the simplified counting method was 0.83 (95% CI: 0.73-0.93). Select-3* and Select-6* had sensitivity of 81% and 65% and specificity of 68% and 98%, respectively. Inter-rater agreement was 78% for Select-3* and 83% for Select-6*. CONCLUSION: A simplified method for CVS assessment in patients referred for suspected MS demonstrated good diagnostic performance and inter-rater agreement.


Asunto(s)
Esclerosis Múltiple , Adulto , Humanos , Femenino , Adulto Joven , Persona de Mediana Edad , Masculino , Esclerosis Múltiple/diagnóstico por imagen , Esclerosis Múltiple/patología , Proyectos Piloto , Reproducibilidad de los Resultados , Venas , Imagen por Resonancia Magnética/métodos , Encéfalo/patología
20.
Artículo en Inglés | MEDLINE | ID: mdl-37990735

RESUMEN

The meninges, located between the skull and brain, are composed of three membrane layers: the pia, the arachnoid, and the dura. Reconstruction of these layers can aid in studying volume differences between patients with neurodegenerative diseases and normal aging subjects. In this work, we use convolutional neural networks (CNNs) to reconstruct surfaces representing meningeal layer boundaries from magnetic resonance (MR) images. We first use the CNNs to predict the signed distance functions (SDFs) representing these surfaces while preserving their anatomical ordering. The marching cubes algorithm is then used to generate continuous surface representations; both the subarachnoid space (SAS) and the intracranial volume (ICV) are computed from these surfaces. The proposed method is compared to a state-of-the-art deformable model-based reconstruction method, and we show that our method can reconstruct smoother and more accurate surfaces using less computation time. Finally, we conduct experiments with volumetric analysis on both subjects with multiple sclerosis and healthy controls. For healthy and MS subjects, ICVs and SAS volumes are found to be significantly correlated to sex (p<0.01) and age (p ≤ 0.03) changes, respectively.

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