Melatonin Contributes to the Seasonality of Multiple Sclerosis Relapses.

Seasonal changes in disease activity have been observed in multiple sclerosis, an autoimmune disorder that affects the CNS. These epidemiological observations suggest that environmental factors influence the disease course. Here, we report that melatonin levels, whose production is modulated by seasonal variations in night length, negatively correlate with multiple sclerosis activity in humans. Treatment with melatonin ameliorates disease in an experimental model of multiple sclerosis and directly interferes with the differentiation of human and mouse T cells. Melatonin induces the expression of the repressor transcription factor Nfil3, blocking the differentiation of pathogenic Th17 cells and boosts the generation of protective Tr1 cells via Erk1/2 and the transactivation of the IL-10 promoter by ROR-α. These results suggest that melatonin is another example of how environmental-driven cues can impact T cell differentiation and have implications for autoimmune disorders such as multiple sclerosis.

Remyelinating effect driven by transferrin-loaded extracellular vesicles.

Extracellular vesicles (EVs) are involved in diverse cellular functions, playing a significant role in cell-to-cell communication in both physiological conditions and pathological scenarios. Therefore, EVs represent a promising therapeutic strategy. Oligodendrocytes (OLs) are myelinating glial cells developed from oligodendrocyte progenitor cells (OPCs) and damaged in chronic demyelinating diseases such as multiple sclerosis (MS). Glycoprotein transferrin (Tf) plays a critical role in iron homeostasis and has pro-differentiating effects on OLs in vivo and in vitro. In the current work, we evaluated the use of EVs as transporters of Tf to the central nervous system (CNS) through the intranasal (IN) route. For the in vitro mechanistic studies, we used rat plasma EVs. Our results show that EVTf enter OPCs through clathrin-caveolae and cholesterol-rich lipid raft endocytic pathways, releasing the cargo and exerting a pro-maturation effect on OPCs. These effects were also observed in vivo using the animal model of demyelination induced by cuprizone (CPZ). In this model, IN administered Tf-loaded EVs isolated from mouse plasma reached the brain parenchyma, internalizing into OPCs, promoting their differentiation, and accelerating remyelination. Furthermore, in vivo experiments demonstrated that EVs protected the Tf cargo and significantly reduced the amount of Tf required to induce remyelination as compared to soluble Tf. Collectively, these findings unveil EVs as functional nanocarriers of Tf to induce remyelination.

Iron deficiency in astrocytes alters cellular status and impacts on oligodendrocyte differentiation.

Iron deficiency (ID) has been shown to affect central nervous system (CNS) development and induce hypomyelination. Previous work from our laboratory in a gestational ID model showed that both oligodendrocyte (OLG) and astrocyte (AST) maturation was impaired. To explore the contribution of AST iron to the myelination process, we generated an in vitro ID model by silencing divalent metal transporter 1 (DMT1) in AST (siDMT1 AST) or treating AST with Fe3+ chelator deferoxamine (DFX; DFX AST). siDMT1 AST showed no changes in proliferation but remained immature. Co-cultures of oligodendrocyte precursors cells (OPC) with siDMT1 AST and OPC cultures incubated with siDMT1 AST-conditioned media (ACM) rendered a reduction in OPC maturation. These findings correlated with a decrease in the expression of AST-secreted factors IGF-1, NRG-1, and LIF, known to promote OPC differentiation. siDMT1 AST also displayed increased mitochondrial number and reduced mitochondrial size as compared to control cells. DFX AST also remained immature and DFX AST-conditioned media also hampered OPC maturation in culture, in keeping with a decrease in the expression of AST-secreted growth factors IGF-1, NRG-1, LIF, and CNTF. DFX AST mitochondrial morphology and number showed results similar to those observed in siDMT1 AST. In sum, our results show that ID, induced through two different methods, impacts AST maturation and mitochondrial functioning, which in turn hampers OPC differentiation.

Clinical impact of gender and age at onset on disease trajectory in primary progressive multiple sclerosis patients.

BACKGROUND AND OBJECTIVES: Primary-progressive multiple sclerosis (PPMS) is characterized by gradual neurological deterioration without relapses. This study aimed to investigate the clinical impact of gender and age at disease onset on disease progression and disability accumulation in patients with this disease phenotype. METHODS: Secondary data from the RelevarEM registry, a longitudinal database in Argentina, were analyzed. The cohort comprised patients with PPMS who met inclusion criteria. Statistical analysis with multilevel Bayesian robust regression modeling was conducted to assess the associations between gender, age at onset, and Expanded Disability Status Scale (EDSS) score trajectories. RESULTS: We identified 125 patients with a confirmed diagnosis of PPMS encompassing a total of 464 observations. We found no significant differences in EDSS scores after 10 years of disease progression between genders (-0.08; credible interval (CI): -0.60, 0.42). A 20-year difference in age at onset did not show significant differences in EDSS score after 10 years of disease progression (0.281; CI: -0.251, 0.814). Finally, we also did not find any clinically relevant difference between gender EDSS score with a difference of 20 years in age at onset (-0.021; CI: -0.371, 0.319). CONCLUSION: Biological plausibility of gender and age effects does not correlate with clinical impact measured by EDSS score.

Assessing robustness and generalization of a deep neural network for brain MS lesion segmentation on real-world data.

OBJECTIVES: Evaluate the performance of a deep learning (DL)-based model for multiple sclerosis (MS) lesion segmentation and compare it to other DL and non-DL algorithms. METHODS: This ambispective, multicenter study assessed the performance of a DL-based model for MS lesion segmentation and compared it to alternative DL- and non-DL-based methods. Models were tested on internal (n = 20) and external (n = 18) datasets from Latin America, and on an external dataset from Europe (n = 49). We also examined robustness by rescanning six patients (n = 6) from our MS clinical cohort. Moreover, we studied inter-human annotator agreement and discussed our findings in light of these results. Performance and robustness were assessed using intraclass correlation coefficient (ICC), Dice coefficient (DC), and coefficient of variation (CV). RESULTS: Inter-human ICC ranged from 0.89 to 0.95, while spatial agreement among annotators showed a median DC of 0.63. Using expert manual segmentations as ground truth, our DL model achieved a median DC of 0.73 on the internal, 0.66 on the external, and 0.70 on the challenge datasets. The performance of our DL model exceeded that of the alternative algorithms on all datasets. In the robustness experiment, our DL model also achieved higher DC (ranging from 0.82 to 0.90) and lower CV (ranging from 0.7 to 7.9%) when compared to the alternative methods. CONCLUSION: Our DL-based model outperformed alternative methods for brain MS lesion segmentation. The model also proved to generalize well on unseen data and has a robust performance and low processing times both on real-world and challenge-based data. CLINICAL RELEVANCE STATEMENT: Our DL-based model demonstrated superior performance in accurately segmenting brain MS lesions compared to alternative methods, indicating its potential for clinical application with improved accuracy, robustness, and efficiency. KEY POINTS: • Automated lesion load quantification in MS patients is valuable; however, more accurate methods are still necessary. • A novel deep learning model outperformed alternative MS lesion segmentation methods on multisite datasets. • Deep learning models are particularly suitable for MS lesion segmentation in clinical scenarios.

Incidence of SARS-CoV-2 infection in patients with multiple sclerosis who received SARS-CoV-2 vaccines and are under treatment with high-efficacy therapies in Argentina.

We aimed to evaluate the incidence of SARS-CoV-2 breakthrough infection of SARS-CoV-2 vaccines in people with MS (PwMS) on high-efficacy disease-modifying therapies (HET) included in the national MS registry in Argentina (RelevarEM). METHODS: Non-interventional, retrospective cohort study that collected information directly from RelevarEM. Adult PwMS who had been treated for at least 6 months with a HET (ocrelizumab, natalizumab, alemtuzumab, cladribine) who had received at least two doses of SARS-CoV-2 vaccines available in Argentina were included. Full course of vaccination was considered after the second dose of the corresponding vaccines. Cumulative incidence of SARS-CoV-2 infection was reported for the whole cohort by Kaplan-Meier survival curves (which is expressed in percentage) as well as incidence density (which is expressed per 10.000 patients/day with 95% CI). RESULTS: Two hundred twenty-eight PwMS were included. Most frequent first and second dose received was AstraZeneca vaccine, followed by Sputnik vaccine. Most frequent HETs used in included patients were cladribine in 79 (34.8%). We found an incidence density of breakthrough COVID-19 infection of 3.5 × 10.000 patients/day (95% CI 2.3-6.7) after vaccination in Argentina. We described the incidence rate after vaccination for every HET used, it being significantly higher for ocrelizumab compared with other HETs (p = 0.005). Only five patients presented a relapse during the follow-up period with no differences regarding the pre-vaccination period. CONCLUSIONS: We found an incidence density of breakthrough COVID-19 infection of 3.5 × 10.000 patients/day (95% CI 2.3-6.7) after vaccination in Argentina.

Ofatumumab versus Teriflunomide in Multiple Sclerosis.

BACKGROUND: Ofatumumab, a subcutaneous anti-CD20 monoclonal antibody, selectively depletes B cells. Teriflunomide, an oral inhibitor of pyrimidine synthesis, reduces T-cell and B-cell activation. The relative effects of these two drugs in patients with multiple sclerosis are not known. METHODS: In two double-blind, double-dummy, phase 3 trials, we randomly assigned patients with relapsing multiple sclerosis to receive subcutaneous ofatumumab (20 mg every 4 weeks after 20-mg loading doses at days 1, 7, and 14) or oral teriflunomide (14 mg daily) for up to 30 months. The primary end point was the annualized relapse rate. Secondary end points included disability worsening confirmed at 3 months or 6 months, disability improvement confirmed at 6 months, the number of gadolinium-enhancing lesions per T1-weighted magnetic resonance imaging (MRI) scan, the annualized rate of new or enlarging lesions on T2-weighted MRI, serum neurofilament light chain levels at month 3, and change in brain volume. RESULTS: Overall, 946 patients were assigned to receive ofatumumab and 936 to receive teriflunomide; the median follow-up was 1.6 years. The annualized relapse rates in the ofatumumab and teriflunomide groups were 0.11 and 0.22, respectively, in trial 1 (difference, -0.11; 95% confidence interval [CI], -0.16 to -0.06; P<0.001) and 0.10 and 0.25 in trial 2 (difference, -0.15; 95% CI, -0.20 to -0.09; P<0.001). In the pooled trials, the percentage of patients with disability worsening confirmed at 3 months was 10.9% with ofatumumab and 15.0% with teriflunomide (hazard ratio, 0.66; P = 0.002); the percentage with disability worsening confirmed at 6 months was 8.1% and 12.0%, respectively (hazard ratio, 0.68; P = 0.01); and the percentage with disability improvement confirmed at 6 months was 11.0% and 8.1% (hazard ratio, 1.35; P = 0.09). The number of gadolinium-enhancing lesions per T1-weighted MRI scan, the annualized rate of lesions on T2-weighted MRI, and serum neurofilament light chain levels, but not the change in brain volume, were in the same direction as the primary end point. Injection-related reactions occurred in 20.2% in the ofatumumab group and in 15.0% in the teriflunomide group (placebo injections). Serious infections occurred in 2.5% and 1.8% of the patients in the respective groups. CONCLUSIONS: Among patients with multiple sclerosis, ofatumumab was associated with lower annualized relapse rates than teriflunomide. (Funded by Novartis; ASCLEPIOS I and II ClinicalTrials.gov numbers, NCT02792218 and NCT02792231.).

Association between infections, the microbiome, vaccination, and neuromyelitis optica spectrum disorder.

Neuromyelitis optica spectrum disorder (NMOSD) is a devastating antibody-mediated condition of the central nervous system. As in other autoimmune diseases, there is considerable evidence to suggest that NMOSD arises from complex interactions between genetic susceptibility and environmental factors. However, whether factors like aquaporin-4-Antibody production initiate NMOSD attacks, currently remains unclear, and requires further investigation. Infectious diseases have also been proposed as possible environmental factors associated with NMOSD onset or relapses, some of which are more common in Asia and Latin America than in Europe and North America, in parallel with the higher incidence of NMOSD in these geographic locations. In this review, we examine current evidence on specific infections and vaccines associated with NMOSD onset and/or attacks, as well as the most recent data on gut microbiome composition and SARS-CoV-2 infection in NMOSD patients.

Performance of McDonald 2017 multiple sclerosis diagnostic criteria and evaluation of genetic ancestry in patients with a first demyelinating event in Argentina.

BACKGROUND: Information on performance of multiple sclerosis (MS) diagnostic criteria is scarce for populations from Latin America, Asia, or the Caribbean. OBJECTIVE: To assess performance of revised 2017 McDonald criteria as well as evaluate genetic ancestry in a group of MS patients from Argentina experiencing a debut demyelinating event. METHODS: Demographic and clinical characteristics, cerebrospinal fluid (CSF), and magnetic resonance imaging (MRI) findings and new T2 lesions were recorded at baseline and during relapses. Diagnostic accuracy in predicting conversion to clinically defined MS (CDMS) based on initial imaging applying revised 2017 criteria was evaluated and genetic ancestry-informative markers analyzed. RESULTS: Of 201 patients experiencing their first demyelinating event (median follow-up 60 months), CDMS was confirmed in 67. We found 2017 diagnostic criteria were more sensitive (84% vs 67%) and less specific (14% vs 33%) than 2010 criteria, especially in a group of patients revised separately, presenting positive oligoclonal bands (88% vs 8%). Genetic testing performed in 128 cases showed 72% of patients were of European ancestry and 27% presented genetic admixture. CONCLUSION: 2017 McDonald criteria showed higher sensitivity and lower specificity compared with 2010 criteria, shortening both time-to-diagnosis and time-to-treatment implementation.

Long-term follow-up of patients with relapsing multiple sclerosis from the CLARITY/CLARITY Extension cohort of CLASSIC-MS: An ambispective study.

BACKGROUND: CLASSIC-MS evaluated the long-term efficacy of cladribine tablets in patients with relapsing multiple sclerosis. OBJECTIVE: Report long-term mobility and disability beyond treatment courses received in CLARITY/CLARITY Extension. METHODS: This analysis represents CLASSIC-MS patients who participated in CLARITY with/without participation in CLARITY Extension, and received ⩾1 course of cladribine tablets or placebo (N = 435). Primary objective includes evaluation of long-term mobility (no wheelchair use in the 3 months prior to first visit in CLASSIC-MS and not bedridden at any time since last parent study dose (LPSD), i.e. Expanded Disability Status Scale (EDSS) score <7). Secondary objective includes long-term disability status (no use of an ambulatory device (EDSS < 6) at any time since LPSD). RESULTS: At CLASSIC-MS baseline, mean ± standard deviation EDSS score was 3.9 ± 2.1 and the median time since LPSD was 10.9 (range = 9.3-14.9) years. Cladribine tablets-exposed population: 90.6% (N = 394), including 160 patients who received a cumulative dose of 3.5 mg/kg over 2 years. Patients not using a wheelchair and not bedridden: exposed, 90.0%; unexposed, 77.8%. Patients with no use of an ambulatory device: exposed, 81.2%; unexposed, 75.6%. CONCLUSION: With a median 10.9 years' follow-up after CLARITY/CLARITY Extension, findings suggest the sustained long-term mobility and disability benefits of cladribine tablets.

Frequency of new asymptomatic MRI lesions during attacks and follow-up of patients with NMOSD in a real-world setting.

BACKGROUND: We aimed to assess the frequency of new asymptomatic lesions on brain and spinal imaging (magnetic resonance imaging (MRI)) and their association with subsequent relapses in a large cohort of neuromyelitis optica spectrum disorder (NMOSD) patients in Argentina. METHODS: We retrospectively reviewed 675 MRI (225 performed during an attack and 450 during the relapse-free period (performed at least 3 months from the last attack)) of NMOSD patients who had at least 2 years of clinical and MRI follow-up since disease onset. Kaplan-Meier (KM) curves were used for depicting time from remission MRI to subsequent relapse. RESULTS: We included 135 NMOSD patients (64.4% were aquaporin-4-immunoglobulin G (AQP4-IgG)-positive). We found that 26 (19.26%) and 66 (48.88%) of patients experienced at least one new asymptomatic MRI lesion during both the relapse-free period and attacks, respectively. The most frequent asymptomatic MRI lesions were optic nerves followed by short-segment myelitis during the relapse-free period and attacks. KM curves did not show differences in the time taken to develop a new relapse. CONCLUSION: Our findings showed that new asymptomatic lesions are relatively frequent. However, the presence of new asymptomatic MRI lesions during the relapse-free period and at relapses was not associated with a shorter time to developing subsequent relapses.

Clinically relevant increases in serum neurofilament light chain and glial fibrillary acidic protein in patients with Susac syndrome.

BACKGROUND AND PURPOSE: Serum levels of neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) are promising neuro-axonal damage and astrocytic activation biomarkers. Susac syndrome (SS) is an increasingly recognized neurological condition and biomarkers that can help assess and monitor disease evolution are highly needed for the adequate management of these patients. sNfL and sGFAP levels were evaluated in patients with SS and their clinical relevance in the relapse and remission phase of the disease was assessed. METHODS: As part of a multicentre study that enrolled patients diagnosed with SS from six international centres, sNfL and sGFAP levels were assessed in 22 SS patients (nine during a relapse and 13 in remission) and 59 age- and sex-matched healthy controls using SimoaTM assay Neurology 2-Plex B Kit. RESULTS: Serum NfL levels were higher than those of healthy controls (p < 0.001) in SS patients and in both subgroups of patients in relapse and in remission (p < 0.001 for both), with significantly higher levels in relapse than in remission (p = 0.008). sNfL levels showed a negative correlation with time from the last relapse (r = -0.663; p = 0.001). sGFAP levels were slightly higher in the whole group of patients than in healthy controls (p = 0.046) and were more pronounced in relapse than in remission (p = 0.013). CONCLUSION: In SS patients, both sNFL and sGFAP levels increased compared with healthy controls. Both biomarkers had higher levels during clinical relapse and much lower levels in remission. sNFL was shown to be time sensitive to clinical changes and can be useful to monitor neuro-axonal damage in SS.

Susac syndrome: challenges in the diagnosis and treatment.

Susac syndrome is a disorder thought to be mediated by an autoimmune response towards endothelial cells, leading to a characteristic clinical triad of encephalopathy, visual disturbances due to branch arterial occlusions and sensorineural hearing impairment. Although it is a rare disease, three reasons make it important. First, given its variable presentation, Susac syndrome is underdiagnosed. Second, it is considered an important differential diagnosis in different neurological, psychiatric, ophthalmological and hearing disorders, and consequently is frequently misdiagnosed. Third, in many cases, Susac syndrome is diagnosed and treated late, with significant irreversible sequelae including dementia, blindness and hearing loss. Neuropathology findings derived from both Susac syndrome patient tissue and novel transgenic mouse models indicate cytotoxic CD8+ T cells adhere to microvessels, inducing endothelial cell swelling, vascular narrowing and occlusion, causing microinfarcts. Anti-endothelial cell antibodies are present in serum in 25% of Susac syndrome patients, but it is unclear whether they are aetiologically related to the disease, or an epiphenomenon. The clinical triad comprising encephalopathy, branch arterial occlusions, and sensorineural hearing impairment is considered pathognomonic, although great variability is found in presentation and natural course of disease. At first evaluation, only 13-30% of patients exhibit the full clinical triad, making diagnosis difficult. Retinal fluorescein angiography, optic coherence tomography, MRI and tonal audiometry are helpful methods for diagnosing and monitoring disease activity during treatment. By contrast, there are no reliable objective immune markers to monitor disease activity. Immunosuppression is the current treatment, with high-dose corticosteroid therapy as the mainstay, but additional therapies such as intravenous immunoglobulins, cyclophosphamide, rituximab and mycophenolate mofetil are often necessary, because the disease can be devastating, causing irreversible organ damage. Unfortunately, low rates of disease, variability in presentation and paucity of objective biomarkers make prospective controlled clinical trials for Susac syndrome treatment difficult. Current immunosuppressive treatments are therefore based on empirical evidence, mainly from retrospective case series and expert opinion. In this review, we draw attention to the need to take consider Susac syndrome in the differential diagnosis of different neurological, psychiatric, ophthalmological and hearing disorders. Furthermore, we summarize our current knowledge of this syndrome, in reference to its pathophysiology, diagnosis and management, emphasizing the need for prospective and controlled studies that allow a better therapeutic approach.

Disability outcomes in NMOSD and MOGAD patients: data from a nationwide registry in Argentina.

The objective was to evaluate time to reach an EDSS of 4, 6, and 7 in NMOSD and MOGAD patients included in the Argentinean MS and NMOSD registry (RelevarEM, NCT 03,375,177). METHODS: NMOSD patients diagnosed according to 2015 criteria and with MOGAD were identified. Patients with at least 3 years of follow-up and periodic clinical evaluations with EDSS outcomes were included. AQP4-antibody and MOG-antibody status was recorded, and patients were stratified as seropositive and seronegative for AQP4-antibody. EDSS of 4, 6, and 7 were defined as dependent variables. Log rank test was used to identify differences between groups. RESULTS: Registry data was provided for a total of 137 patients. Of these, seventy-five presented AQP4-ab-positive NMOSD, 45 AQP4-ab-negative NMOSD, and 11 MOGAD. AQP4-ab status was determined by cell-based assay (CBA) in 72% of NMOSD patients. MOG-ab status was tested by CBA in all cases. Mean time to EDSS of 4 was 53.6 ± 24.5 vs. 63.1 ± 32.2 vs. 44.7 ± 32 months in seropositive, seronegative NMOSD, and MOGAD, respectively (p = 0.76). Mean time to EDSS of 6 was 79.2 ± 44.3 vs. 75.7 ± 48.6 vs. 54.7 ± 50 months in seropositive, seronegative NMOSD, and MOGAD (p = 0.23), while mean time to EDSS of 7 was 86.8 ± 54 vs. 80.4 ± 51 vs. 58.5 ± 47 months in seropositive, seronegative NMOSD, and MOGAD (p = 0.39). CONCLUSION: No differences were observed between NMOSD (seropositive and seronegative) and MOGAD in survival curves.

Colony-stimulating factor-1 receptor inhibition attenuates microgliosis and myelin loss but exacerbates neurodegeneration in the chronic cuprizone model.

Multiple sclerosis (MS), especially in its progressive phase, involves early axonal and neuronal damage resulting from a combination of inflammatory mediators, demyelination, and loss of trophic support. During progressive disease stages, a microenvironment is created within the central nervous system (CNS) favoring the arrival and retention of inflammatory cells. Active demyelination and neurodegeneration have also been linked to microglia (MG) and astrocyte (AST)-activation in early lesions. While reactive MG can damage tissue, exacerbate deleterious effects, and contribute to neurodegeneration, it should be noted that activated MG possess neuroprotective functions as well, including debris phagocytosis and growth factor secretion. The progressive form of MS can be modeled by the prolonged administration to cuprizone (CPZ) in adult mice, as CPZ induces highly reproducible demyelination of different brain regions through oligodendrocyte (OLG) apoptosis, accompanied by MG and AST activation and axonal damage. Therefore, our goal was to evaluate the effects of a reduction in microglial activation through orally administered brain-penetrant colony-stimulating factor-1 receptor (CSF-1R) inhibitor BLZ945 (BLZ) on neurodegeneration and its correlation with demyelination, astroglial activation, and behavior in a chronic CPZ-induced demyelination model. Our results show that BLZ treatment successfully reduced the microglial population and myelin loss. However, no correlation was found between myelin preservation and neurodegeneration, as axonal degeneration was more prominent upon BLZ treatment. Concomitantly, BLZ failed to significantly offset CPZ-induced astroglial activation and behavioral alterations. These results should be taken into account when proposing the modulation of microglial activation in the design of therapies relevant for demyelinating diseases. Cover Image for this issue: https://doi.org/10.1111/jnc.15394.

GAS6 signaling tempers Th17 development in patients with multiple sclerosis and helminth infection.

Multiple sclerosis (MS) is a highly disabling neurodegenerative autoimmune condition in which an unbalanced immune response plays a critical role. Although the mechanisms remain poorly defined, helminth infections are known to modulate the severity and progression of chronic inflammatory diseases. The tyrosine kinase receptors TYRO3, AXL, and MERTK (TAM) have been described as inhibitors of the immune response in various inflammatory settings. We show here that patients with concurrent natural helminth infections and MS condition (HIMS) had an increased expression of the negative regulatory TAM receptors in antigen-presenting cells and their agonist GAS6 in circulating CD11bhigh and CD4+ T cells compared to patients with only MS. The Th17 subset was reduced in patients with HIMS with a subsequent downregulation of its pathogenic genetic program. Moreover, these CD4+ T cells promoted lower levels of the co-stimulatory molecules CD80, CD86, and CD40 on dendritic cells compared with CD4+ T cells from patients with MS, an effect that was GAS6-dependent. IL-10+ cells from patients with HIMS showed higher GAS6 expression levels than Th17 cells, and inhibition of phosphatidylserine/GAS6 binding led to an expansion of Th17 effector genes. The addition of GAS6 on activated CD4+ T cells from patients with MS restrains the Th17 gene expression signature. This cohort of patients with HIMS unravels a promising regulatory mechanism to dampen the Th17 inflammatory response in autoimmunity.

Computational basis of decision-making impairment in multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is commonly associated with decision-making, neurocognitive impairments, and mood and motivational symptoms. However, their relationship may be obscured by traditional scoring methods. OBJECTIVES: To study the computational basis underlying decision-making impairments in MS and their interaction with neurocognitive and neuropsychiatric measures. METHODS: Twenty-nine MS patients and 26 matched control subjects completed a computer version of the Iowa Gambling Task (IGT). Participants underwent neurocognitive evaluation using an expanded version of the Brief Repeatable Battery. Hierarchical Bayesian Analysis was used to estimate three established computational models to compare parameters between groups. RESULTS: Patients showed increased learning rate and reduced loss-aversion during decision-making relative to control subjects. These alterations were associated with: (1) reduced net gains in the IGT; (2) processing speed, executive functioning and memory impairments; and (3) higher levels of depression and current apathy. CONCLUSION: Decision-making deficits in MS patients could be described by the interplay between latent computational processes, neurocognitive impairments, and mood/motivational symptoms.

The frequency and characteristics of multiple sclerosis misdiagnosis in Latin America: A referral center study in Buenos Aires, Argentina.

OBJECTIVE: Most contemporary data concerning the frequency and causes of multiple sclerosis (MS) misdiagnosis are from North America and Europe with different healthcare system structure and resources than countries in Latin America. We sought to determine the frequency, and potential contributors to MS misdiagnosis in patients evaluated at an MS referral center in Argentina. METHODS: The study was a retrospective medical record review. We included patients evaluated at the MS Clinic at Fleni between April 2013 and March 2021. Diagnoses prior to consultation, final diagnoses after consultation, demographic, clinical and paraclinical data, and treatment were extracted and classified. RESULTS: Seven hundred thirty-six patients were identified. Five hundred seventy-two presented with an established diagnosis of MS and after evaluation, misdiagnosis was identified in 89 (16%). Women were at 83% greater risk of misdiagnosis (p = 0.034). The most frequent alternative diagnoses were cerebrovascular disease, radiological isolated syndrome (RIS), and headache. Seventy-four (83%) of misdiagnosed patients presented with a syndrome atypical for demyelination, 62 (70%) had an atypical brain magnetic resonance imaging (MRI), and 54 (61%) were prescribed disease-modifying therapy. CONCLUSION: Sixteen percent of patients with established MS were subsequently found to have been misdiagnosed. Women were at higher risk for misdiagnosis. Expert application of the McDonald criteria may prevent misdiagnosis and its associated morbidity and healthcare system cost.

Combination therapy of apo-transferrin and thyroid hormones enhances remyelination.

The current study presents two different approaches with a view to elucidating the interaction between thyroid hormones (TH) and apo-transferrin (aTf) and their role in myelination and remyelination. First, in vitro assays were conducted to determine the single and combined effects of aTf and triiodothyronine (T3) on oligodendroglial cell lineage proliferation and oligodendrocyte (OLG) maturation in primary cultures. Results revealed higher proliferation rates upon single aTf treatment but Control values upon T3 and aTf + T3 treatments. In addition, both aTf and T3 accelerated OLG maturation, with the greatest effects being exerted by combined aTf + T3 administration in terms of both myelin basic protein (MBP) expression and morphological complexity. Second, in vivo assays were carried out to establish single and combined effects of aTf and T3, as well as TH receptor (THR) inhibitor I-850, on remyelination following a CPZ-induced demyelination protocol. Results showed an increase in myelin deposition and the number of mature remyelinating OLG upon single treatments, but a synergic effect upon combined aTf + T3 treatment which was prevented by THR inhibition. It may be thus concluded that combined treatment yielded the most beneficial effects on OLG maturation parameters in vitro and remyelinating capacity in vivo when compared to single treatments. These findings may help explore the development of new target molecules in the treatment of demyelinating diseases.

Interleukin-35 is a critical regulator of immunity during helminth infections associated with multiple sclerosis.

Multiple sclerosis (MS) is currently thought to arise by interactions between genetic susceptibility and environmental factors. Infections in general trigger autoimmune responses causing clinical manifestations of disease. However, as a result of regulatory T (Treg)- and regulatory B (Breg)-cell induction, helminth infections tend to dampen disease activity. IL-35, the newest member of the IL-12 family, is an inhibitory cytokine composed of an EBI3ß chain subunit, and an IL-12p35 subunit. The aim of this study was to investigate the role of IL-35 during parasite infections occurring in individuals with MS. Numbers of IL-35-producing Breg cells are higher in CSF from helminth-infected than from uninfected MS subjects, a finding associated with decreased MRI disease activity. Interestingly, stimulation of CD19+ B cells with IL-35 promotes conversion of these cells to Breg cells producing both IL-35 and IL-10. Coculture of B cells from helminth-infected MS patients inhibits proliferation of Th1 and Th17 myelin peptide-specific T cells, as well as production of IFN-γ and IL-17. Following activation, CD4+ CD25+ Treg cells significantly upregulate expression of EBI3 and IL-12p35 mRNA. Furthermore, CD4+ CD25- T cells activated in the presence of IL-35 induce a population of cells with regulatory function, known as iTR35. Finally, B cells from normal individuals cultured in vitro in the presence of the helminth antigen SEA increase expression of the transcription BATF, IRF4 and IRF8, acquiring a pattern similar to that of IL-35 Breg cells. These data highlight the important immunoregulatory effects of IL-35 on both Breg and Treg cells, observed in helminth-infected MS subjects.