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Objective: To compare the incidence of and adjusted hazard ratios for common cardiometabolic diseases, musculoskeletal disorders, and psychological morbidities among adults with and without multiple sclerosis (MS). Patients and Methods: Beneficiaries were included if they had an International Classification of Diseases, Ninth Revision, Clinical Modification diagnostic code for MS (n=9815) from a national private insurance claims database (Clinformatics Data Mart; OptumInsight). Adults without MS were also included (n=1,474,232) as a control group. Incidence estimates of common cardiometabolic diseases, musculoskeletal disorders, and psychological morbidities were compared at 5 years of continuous enrollment. Survival models were used to quantify unadjusted and adjusted hazard ratios for incident morbidities. Results: Adults with MS had a higher incidence of any common cardiometabolic disease (51.6% [2663 of 5164] vs 36.4% [328,690 of 904,227]), musculoskeletal disorder (68.8% [3411 of 4959] vs 47.5% [512,422 of 1,077,737]), and psychological morbidity (49.4% [3305 of 6691] vs 30.8% [380,893 of 1,235,388]) than adults without MS, and differences were clinically meaningful (all P

A 48-year-old woman who had been receiving long-term interferon-β for 8 years for multiple sclerosis developed drug-induced World Health Organization group I pulmonary arterial hypertension. Triple therapy for pulmonary arterial hypertension and suspension of interferon-β led to improvement from a high-risk to low-risk state and improvement in exercise hemodynamics, including vascular distensibility, and right ventricle–pulmonary artery coupling. (Level of Difficulty: Advanced.), Central Illustration

Human dihydroorotate dehydrogenase (DHODH) is a viable target for the development of therapeutics to treat cancer and immunological diseases, such as rheumatoid arthritis (RA), psoriasis and multiple sclerosis (MS). Herein, a series of acrylamide-based novel DHODH inhibitors as potential RA treatment agents were designed and synthesized. 2-Acrylamidobenzoic acid analog 11 was identified as the lead compound for structure−activity relationship (SAR) studies. The replacement of the phenyl group with naphthyl moieties improved inhibitory activity significantly to double-digit nanomolar range. Further structure optimization revealed that an acrylamide with small hydrophobic groups (Me, Cl or Br) at the 2-position was preferred. Moreover, adding a fluoro atom at the 5-position of the benzoic acid enhanced the potency. The optimization efforts led to potent compounds 42 and 53‒55 with IC50 values of 41, 44, 32, and 42 nmol/L, respectively. The most potent compound 54 also displayed favorable pharmacokinetic (PK) profiles and encouraging in vivo anti-arthritic effects in a dose-dependent manner., Graphical abstract Dihydroorotate dehydrogenase (DHODH) is an attracting target for the treatment of immunological diseases. A series of acrylamide-based novel DHODH inhibitors as potential rheumatoid arthritis (RA) treatment agents were designed and synthesized, among which 54 is the most potent one with good pharmacokinetic profiles and favorable in vivo anti-arthritic effects.Image 1

Despite a common CD4+ T-cell precursor, helper T (Th) 1 and 2 lymphocytes affect different immunologic responses, including cellular and humoral pathways, respectively. Th1 cells stimulate the activation of type 1 macrophages, IgG/immunoglobulin M production, and cytokine release (eg, interferon gamma [IFN-γ], interleukin 2) to respond to intracellular pathogens. In contrast, Th2 cells target extracellular pathogens, leading to increases in immunoglobulin E and proliferation of eosinophils, basophils, B lymphocytes, type 2 macrophages, and mast cells through the actions of interleukin 4 (IL-4), interleukin 5, interleukin 13 (IL-13), and interleukin 31.1 Th17 cells are important for host defense against extracellular bacteria and fungi, as well as injury, and are thought to be key drivers of autoimmune diseases. Th17 cells produce interleukin 17A, interleukin 17F, interleukin 22, and C-C motif chemokine ligand 20 and are characterized by neutrophil and macrophage recruitment. The Th2 cytokine, IL-4, has been shown to inhibit Th17 development.2 Dupilumab (Dupixent, Regeneron Pharmaceuticals and Sanofi Genzyme), a fully human monoclonal (IgG4) antibody, inhibits the signaling of IL-4/13 by blocking the shared receptor subunit, IL-4 receptor α. Dupilumab is an effective treatment for a number of Th2-driven conditions, including atopic dermatitis (AD), asthma, and chronic rhinosinusitis with nasal polyposis. Multiple sclerosis (MS) is an inflammatory disease of the central nervous system, which is characterized by multifocal demyelination and neuroaxonal degeneration, where the immune system is skewed toward Th1/Th17 axes.3 Interestingly, epidemiologic studies have suggested that a history of allergic diseases may confer some protection from MS.4 We report a temporal association of relapsing-remitting MS flareup and dupilumab treatment for AD. We provide a potential mechanism by which dupilumab leads to Th2 suppression with secondary Th1/17 dysregulation.

Background & Aims Inflammatory bowel disease (IBD) is a polygenic disorder characterized principally by dysregulated inflammation impacting the gastrointestinal tract. However, there also is increasing evidence for a clinical association with stress and depression. Given the role of the hypothalamus in stress responses and in the pathogenesis of depression, useful insights could be gleaned from understanding its genetic role in IBD. Methods We conducted genetic correlation analyses on publicly available genome-wide association study summary statistics for depression and IBD traits to identify genetic commonalities. We used partitioned linkage disequilibrium score regression, leveraging our ATAC sequencing and promoter-focused Capture C data, to measure enrichment of IBD single-nucleotide polymorphisms within promoter-interacting open chromatin regions of human embryonic stem cell-derived hypothalamic-like neurons (HNs). Using the same data sets, we performed variant-to-gene mapping to implicate putative IBD effector genes in HNs. To contrast these results, we similarly analyzed 3-dimensional genomic data generated in epithelium-derived colonoids from rectal biopsy specimens from donors without pathologic disease noted at the time of colonoscopy. Finally, we conducted enrichment pathway analyses on the implicated genes to identify putative IBD dysfunctional pathways. Results We found significant genetic correlations (rg) of 0.122 with an adjusted P (Padj) = 1.4 × 10-4 for IBD: rg = 0.122; Padj = 2.5 × 10-3 for ulcerative colitis and genetic correlation (rg) = 0.094; Padj = 2.5 × 10-3 for Crohn’s disease, and significant approximately 4-fold (P = .005) and approximately 7-fold (P = .03) enrichment of IBD single-nucleotide polymorphisms in HNs and colonoids, respectively. We implicated 25 associated genes in HNs, among which CREM, CNTF, and RHOA encode key regulators of stress. Seven genes also additionally were implicated in the colonoids. We observed an overall enrichment for immune and hormonal signaling pathways, and a colonoid-specific enrichment for microbiota-relevant terms. Conclusions Our results suggest that the hypothalamus warrants further study in the context of IBD pathogenesis., Graphical abstract

Objective To investigate prevalence of EMG patterns underlying hypertonia in multiple sclerosis (MS) and whether these patterns indicate different levels of spinal excitability. Methods We investigated the EMG activity recorded from 108 hypertonic muscles of 59 consecutive MS patients. To investigate spastic dystonia (SD), we looked for the presence of EMG activity in muscles in a resting position. To investigate dynamic stretch reflex (DSR) and static stretch reflex (SSR), we looked for the presence of EMG activity in response to a manually performed passive stretch of the muscle. Results DSR was evoked in 104 muscles. In 51 muscles, DSR was the sole EMG activity. This pattern corresponds to the classical notion of spasticity, and was predominant in extensors. In contrast, SSR was detected in 48 muscles – predominantly in flexors. SD was observed in 28 muscles, showing even distribution in flexor and extensor muscles. Only in the flexors, SSR was associated with a larger DSR compared to spasticity. Conclusions These findings likely depend on the central effects of both flexor and extensor spindle afferents on the homonymous spinal motor neurons. Significance Improving our capacity to assess spinal excitability in MS patients.

As the news of approval of COVID-19 vaccination emerge, neurologists across the globe ponder upon whether to use immunotherapies in patients with Multiple Sclerosis (MS). This paper highlights the mechanism of various disease modifying therapies (DMTs) as well as the recently approved Pfizer and Moderna vaccines for COVID-19 as well as guidelines as introduced by National Multiple Sclerosis Society. As their mechanisms counteract each other at the molecular level, we believe further evidence and data might lay the foundation to formulate much needed recommendations for the usage of these medications while vaccinating MS patients on DMTs.

Highlights • Purinergic signaling is involved in the pathogenesis of neuroinfectious disease. • P2 receptors have pro-inflammatory and deleterious effects in viral Neuroinfections. • ATP-P2X7 receptor signaling contributes to sepsis-associated encephalopathy. • Adenosine favors brain parasite persistence in cerebral toxoplasmosis., The incidence of infectious diseases affecting the central nervous system (CNS) has been increasing over the last several years. Among the reasons for the expansion of these diseases and the appearance of new neuropathogens are globalization, global warming, and the increased proximity between humans and wild animals due to human activities such as deforestation. Neurotropism affecting normal brain function is shared by organisms such as viruses, bacteria, fungi, and parasites. Neuroinfections caused by these agents activate immune responses, inducing neuroinflammation, excitotoxicity, and neurodegeneration. Purinergic signaling is an evolutionarily conserved signaling pathway associated with these neuropathologies. During neuroinfections, host cells release ATP as an extracellular danger signal with pro-inflammatory activities. ATP is metabolized to its derivatives by ectonucleotidases such as CD39 and CD73; ATP and its metabolites modulate neuronal and immune mechanisms through P1 and P2 purinergic receptors that are involved in pathophysiological mechanisms of neuroinfections. In this review we discuss the beneficial or deleterious effects of various components of the purinergic signaling pathway in infectious diseases that affect the CNS, including human immunodeficiency virus (HIV-1) infection, herpes simplex virus type 1 (HSV-1) infection, bacterial meningitis, sepsis, cryptococcosis, toxoplasmosis, and malaria. We also provide a description of this signaling pathway in emerging viral infections with neurological implications such as Zika and SARS-CoV-2.

Graphical abstract, Multiple sclerosis (MS) is an autoimmune disease that involves demyelination of axons in the central nervous system (CNS) and affects patients worldwide. It has been demonstrated that ligand-activated aryl hydrocarbon receptor (Ahr) ameliorates experimental autoimmune encephalomyelitis (EAE), a murine model of MS, by increasing CD4+FoxP3+ T cells. Recent evidence indicates that AT-rich interactive domain-containing protein 5a (Arid5a) is required for EAE pathogenesis by stabilizing Il6 and OX40 mRNAs. However, the differential modulation of Ahr and Arid5a in autoimmunity as a therapeutic strategy is unexplored. Herein, an in silico, in vitro and in vivo approach identified Flavipin (3,4,5-trihydroxy-6-methylphthalaldehyde) as an Ahr agonist that induces the expression of Ahr downstream genes in mouse CD4+ T cells and CD11b+ macrophages. Interestingly, Flavipin inhibited the stabilizing function of Arid5a and its counteracting effects on Regnase-1 on the 3′ untranslated region (3′UTR) of target mRNAs. Furthermore, it inhibited the stabilizing function of Arid5a on Il23a 3′UTR, a newly identified target mRNA. In EAE, Flavipin ameliorated disease severity, with reduced CD4+IL-17+ T cells, IL-6 and TNF-α and increased CD4+FoxP3+ T cells. Moreover, EAE amelioration was concomitant with reduced CD4+OX40+ and CD4+CD45+ T cells in the CNS. RNA interference showed that the modulatory effects of Flavipin on pro- and anti-inflammatory mediators in CD4+ T cells and macrophages were Ahr- and/or Arid5a-dependent. In conclusion, our findings reveal differential modulation of Ahr and Arid5a as a new therapeutic strategy for MS.

Monoacylglycerol lipase (MAGL) is a serine hydrolase that plays a crucial role catalysing the hydrolysis of monoglycerides into glycerol and fatty acids. It links the endocannabinoid and eicosanoid systems together by degradation of the abundant endocannabinoid 2-arachidaoylglycerol into arachidonic acid, the precursor of prostaglandins and other inflammatory mediators. MAGL inhibitors have been considered as important agents in many therapeutic fields, including anti-nociceptive, anxiolytic, anti-inflammatory, and even anti-cancer. Currently, ABX-1431, a first-in-class inhibitor of MAGL, is entering clinical phase 2 studies for neurological disorders and other diseases. This review summarizes the diverse (patho)physiological roles of MAGL and will provide an overview on the development of MAGL inhibitors. Although a large number of MAGL inhibitors have been reported, novel inhibitors are still required, particularly reversible ones., Graphical abstract Monoacylglycerol lipase (MAGL) plays a crucial role catalysing the hydrolysis of monoglycerides. MAGL inhibitors have been considered as important agents in many therapeutic fields, including anti-nociceptive, anti-inflammatory and anti-cancer. The diverse (patho)physiological roles of MAGL and a comprehensive overview of reported MAGL inhibitors were summarized in this review.Image 1

Highlights • A subset of Canadian physicians, orthopedic surgeons, and plastic surgeons are using perioperative botulinum toxin (BoNT). • Forty-one percent of Canadian respondents stated that they were not notified of their patient's surgical date. • Increased collaboration between specialties and the creation of national guidelines will increase the benefits of perioperative BoNT surgical outcomes., Objective To investigate the practice patterns of Canadian physicians who use perioperative botulinum toxin (BoNT) injections to improve surgical outcomes on spastic limbs. Design A cross-sectional national survey composed of an invitation email and an 18-item questionnaire was disseminated by a national physical medicine and rehabilitation (PMR) society to 138 physician members involved in spasticity management. Setting Not applicable. Participants Twenty-five percent of the participants (N=34) fully completed the survey. Interventions Not applicable. Main Outcome Measures Participants completed an online questionnaire that examined the practice patterns and surgical outcomes associated with perioperative BoNT injections. Results The majority (n=21; 84%) of Canadian physicians who inject BoNT perioperatively to improve outcomes of surgeries performed on spastic limbs are specialists in PMR practicing in academic settings. Most respondents (74%) used BoNT injections for perioperative treatment for patients with limb spasticity undergoing surgery. Of those surveyed, 65% of physicians used BoNT preoperatively, 21% used BoNT intraoperatively, and 24% used BoNT postoperatively. Of the physicians who performed BoNT injections preoperatively, 6% performed BoNT injections 7 to 12 weeks preoperatively, 32% performed BoNT injections 4 to 6 weeks preoperatively, 47% performed BoNT injections 2 to 3 weeks preoperatively, and 15% performed BoNT injections 0 to 1 week preoperatively. The majority of physicians (85%) responded that injecting BoNT perioperatively may improve a patient's surgical outcome and all of the participants (100%) stated that BoNT did not contribute to any perioperative complications or adverse effects. Qualitative responses emphasized that successful outcomes from the perioperative BoNT were linked to enhanced collaboration with surgeons and that more research is needed to determine the optimal timing of perioperative BoNT. Conclusion Canadian physicians, mostly PMR specialists, administer perioperative BoNT to improve outcomes of surgeries performed on spastic limbs. The optimal timing for perioperative BoNT was suggested to be 2 to 3 weeks before the surgery by 47% of survey respondents. All participating physicians responded that perioperative BoNT did not contribute to any known perioperative complications or adverse events. This study highlights the importance of conducting more robust research to better understand optimal timing for perioperative BoNT injection, enhancing collaboration between physicians and surgeons, and increasing awareness of perioperative BoNT when planning for surgeries on spastic limbs.

Disruption or loss of oligodendrocytes (OLs) and myelin has devastating effects on CNS function and integrity, which occur in diverse neurological disorders, including Multiple Sclerosis (MS), Alzheimer’s disease and neuropsychiatric disorders. Hence, there is a need to develop new therapies that promote oligodendrocyte regeneration and myelin repair. A promising approach is drug repurposing, but most agents have potentially contrasting biological actions depending on the cellular context and their dose-dependent effects on intracellular pathways. Here, we have used a combined systems biology and neurobiological approach to identify compounds that exert positive and negative effects on oligodendroglia, depending on concentration. Notably, next generation pharmacogenomic analysis identified the PI3K/Akt modulator LY294002 as the most highly ranked small molecule with both pro- and anti-oligodendroglial concentration-dependent effects. We validated these in silico findings using multidisciplinary approaches to reveal a profoundly bipartite effect of LY294002 on the generation of OPCs and their differentiation into myelinating oligodendrocytes in both postnatal and adult contexts. Finally, we employed transcriptional profiling and signalling pathway activity assays to determine cell-specific mechanisms of action of LY294002 on oligodendrocytes and resolve optimal in vivo conditions required to promote myelin repair. These results demonstrate the power of multidisciplinary strategies in determining the therapeutic potential of small molecules in neurodegenerative disorders., Graphical Abstract ga1

Background During the era of the Coronavirus disease 2019 (COVID-19) pandemic, various neurological syndromes were reported during or after the infection. Fortunately, efforts were made to successfully develop various vaccines with high efficacy and safety. Despite the promising results of those vaccines, they are too novel to be fully understood. Here we are shedding light on a neurological case presentation that may be attributed to one of the COVID-19 vaccines. Case presentation A 23-year-old male patient with no prior comorbidities presented with quadriparesis and numbness that were clinically and electrophysiologically consistent with Guillain-Barré Syndrome (GBS). The condition started 10 days after the first dose of the AstraZeneca vaccine. Moreover, MRI of the brain and spinal cord has shown evidence of non-specific central demyelination. Despite the radiological finding, the patient is not fulfilling the diagnosis of a known demyelination disorder and the lesions regressed on follow-up. Since no better explanation or trigger could be found, a post-vaccination immune-mediated reaction was considered. Conclusion We still cannot assume the certainty of the causality association between the vaccine and the neurological presentation. Meanwhile, we suggest vigilance for cases of GBS or myelitis following vaccination for Covid-19 and that post-vaccination surveillance programs ensure a statistically significant tool to prove or dispsrove the causality.

OBJECTIVE: The objective of this study was to measure humoral responses after SARS-CoV-2 vaccination in MS patients treated with ocrelizumab (OCR) compared to MS patients without disease modifying therapies (DMTs) in relation to timing of vaccination and B-cell count.METHODS: OCR treated patients were divided into an early and a late group (cut-off time 12 weeks between infusion and first vaccination). Patients were vaccinated with mRNA-1273 (Moderna). B-cells were measured at baseline (time of first vaccination) and SARS-CoV-2 antibodies were measured at baseline, day 28, 42, 52 and 70.RESULTS: 87 patients were included (62 OCR patients, 29 patients without DMTs). At day 70, seroconversion occurred in 39.3% of OCR patients compared to 100% of MS patients without DMTs. In OCR patients, seroconversion varied between 26% (early group) to 50% (late group) and between 27% (low B-cells) to 56% (at least 1 detectable B-cell/µL).CONCLUSIONS: Low B-cell counts prior to vaccination and shorter time between OCR infusion and vaccination may negatively influence humoral response but does not preclude seroconversion. We advise OCR treated patients to get their first vaccination as soon as possible. In case of an additional booster vaccination, timing of vaccination based on B-cell count and time after last infusion may be considered.

Background Several concerns exist on the immunogenicity of SARS-CoV-2 vaccines in multiple sclerosis (MS) subjects due to their immunomodulating disease modifying therapies (DMTs). Here we report a comparison of the humoral response to BNT162b2-mRNA coronavirus (COVID)-19 vaccine and the immunological phenotype in a cohort of 125 MS subjects undergoing different DMTs, with no history of SARS-CoV-2 infection. Methods We collected serum and blood samples at the first day of vaccine (T0) and 21 days after the second vaccine dose (T1) from 125 MS subjects, undergoing eight different DMTs. Sera were tested using the Elecsys anti-SARS-CoV-2-IgG assay for the detection of IgG antibodies to SARS-CoV-2 spike protein. The anti-spike IgG titres from MS subjects were compared with 24 age- and sex-matched healthy controls (HC). Percentage and absolute number of B and T lymphocytes were evaluated by cytofluorimetric analysis in the same study cohort. Results When compared with SARS-CoV-2 IgG levels in HC (n = 24, median 1089 (IQR 652.5–1625) U/mL), we observed an increased secretion of SARS-CoV-2 IgG in interferon-beta 1a (IFN)-treated MS subjects (n = 22, median 1916 (IQR 1024–2879) U/mL) and an impaired humoral response in MS subjects undergoing cladribine (CLAD) (n = 10, median 396.9 (IQR 37.52–790.9) U/mL), fingolimod (FTY) (n = 19, median 7.9 (IQR 4.8–147.6) U/mL) and ocrelizumab (OCRE) (n = 15, median 0.67 (IQR 0.4–5.9) U/mL) treatment. Moreover, analysis of geometric mean titre ratio (GMTR) between different DMT's groups of MS subjects revealed that, when compared with IFN-treated MS subjects, intrinsic antibody production was impaired in teriflunomide (TERI)-, natalizumab (NAT)-, CLAD-, FTY- and OCRE-, while preserved in DMF- and GA-treated MS subjects. Conclusion Humoral response to BNT162b2-mRNA-vaccine was increased in IFN-treated MS subjects while clearly blunted in those under CLAD, FTY and OCRE treatment. This suggests that the DMTs could have a key role in the protection from SARS-CoV-2 related disease and complication in MS subjects, underlying a novel aspect that should be considered in the selection of the most appropriate therapy under COVID-19 pandemic.

Proteomics studies are important for the discovery of new biomarkers as clinical tools for diagnosis and disease monitoring. However, preanalytical variations caused by differences in sample handling protocol pose challenges for assessing biomarker reliability and comparability between studies. The purpose of this study was to examine the effects of delayed centrifuging on measured protein levels in plasma and cerebrospinal fluid (CSF). Blood from healthy individuals and patients with multiple sclerosis along with CSF from patients with suspected neurological disorders were left at room temperature for different periods (blood: 1, 24, 48, 72 h; CSF: 1 and 6 h) prior to centrifuging. Ninety-one inflammation-related proteins were analyzed using a proximity extension assay, a high-sensitivity multiplex immunoassay. Additional metabolic and neurology-related markers were also investigated in CSF. In summary, many proteins, particularly in plasma, had increased levels with longer delays in processing likely due in part to intracellular leakage. Levels of caspase 8, interleukin 8, interleukin 18, sirtuin 2, and sulfotransferase 1A1 increased 2-fold to 10-fold in plasma after 24 h at room temperature. Similarly, levels of cathepsin H, ectonucleoside triphosphate diphosphohydrolase 5, and WW domain containing E3 ubiquitin protein ligase 2 differentiated in CSF with, Graphical Abstract, Highlights • Several blood and cerebrospinal fluid proteins are affected by sample handling. • Plasma protein levels increased with longer centrifugation delay from hemolysis. • Certain proteins may assess sample handling variability and predict delay time., In Brief We assessed the effects of delayed sample handling on a panel of 92 inflammation-related proteins in the blood and cerebrospinal fluid. Plasma protein levels were measured at delayed centrifugation times of 1, 24, 48, and 72 h corresponding with common postal-transit delays, and changes in relative concentration were modeled and validated using an external dataset. Several proteins were selected as markers of assessing sample handling variability for application in future studies.

Highlights • The demyelination of peripheral nerves due to Guillain-Barré syndrome can cause conduction blocks, similar to that seen in multiple sclerosis. • 4-Aminopyridine conjugates can aid in reducing conduction blocks and may improve function in patients with demyelinating peripheral neuropathy. • This study demonstrated the safety and the potential to improve the functional status in patients Guillain-Barré syndrome with chronic functional deficits., Objective To determine the safety and efficacy of orally delivered 4-aminopyridine (4-AP) in persons with Guillain-Barré Syndrome (GBS) >6 months from initial diagnosis. Design A randomized, double-blind, placebo-controlled, crossover study. Setting Tertiary care clinical outpatient program. Participants Nineteen participants enrolled (14 male, 5 female; N=19), neurologic impairment secondary to GBS and functional loss on the FIM motor score (stable for ≥12mo) and >3.0 but

Highlights • eSC and eFC outperformed SC and FC in classifying pwMS by disability level. • Increased regional eFC in the visual network was associated with disability. • Weaker eSC in the default mode and ventral attention was associated with disability. • Feature weights for the regional eFC and FC models were significantly correlated., Background Multiple Sclerosis (MS), a neurodegenerative and neuroinflammatory disease, causing lesions that disrupt the brain’s anatomical and physiological connectivity networks, resulting in cognitive, visual and/or motor disabilities. Advanced imaging techniques like diffusion and functional MRI allow measurement of the brain’s structural connectivity (SC) and functional connectivity (FC) networks, and can enable a better understanding of how their disruptions cause disability in people with MS (pwMS). However, advanced MRI techniques are used mainly for research purposes as they are expensive, time-consuming and require high-level expertise to acquire and process. As an alternative, the Network Modification (NeMo) Tool can be used to estimate SC and FC using lesion masks derived from pwMS and a reference set of controls' connectivity networks. Objective Here, we test the hypothesis that estimated SC and FC (eSC and eFC) from the NeMo Tool, based only on an individual’s lesion masks, can be used to classify pwMS into disability categories just as well as SC and FC extracted from advanced MRI directly in pwMS. We also aim to find the connections most important for differentiating between no disability vs evidence of disability groups. Materials and Methods One hundred pwMS (age:45.5 ± 11.4 years, 66% female, disease duration: 12.97 ± 8.07 years) were included in this study. Expanded Disability Status Scale (EDSS) was used to assess disability, 67 pwMS had no disability (EDSS

Background Ankylosing spondylitis (AS) is a chronic inflammatory disease with worldwide high prevalence. Although AS is strongly associated with HLA-B27 MHC-I antigen presentation, the role played by αβ T cells in AS remains elusive. Methods Utilizing TCRβ repertoire sequencing and bioinformatics tools developed in house, we analyzed overall TCR repertoire structures and antigen-recognizing CDR3 motifs in AS patients with different disease activities. Findings We found that disease progression is associated with both CD4+ and CD8+ T cell oligo-clonal expansion, which suggests that αβ T cell activation may mediate AS disease progression. By developing a bioinformatics platform to dissect antigen-specific responses, we discovered a cell population consisting of both CD4+ and CD8+ T cells expressing identical TCRs, herein termed CD4/8 T cells. CD4/8 clonotypes were highly enriched in the spondyloarthritic joint fluid of patients, and their expansion correlated with the activity of disease. Interpretation These results provide evidence on the T cell clone side to reveal the potential role of CD4/8 T cells in the etiology of AS development.

Individuals differ substantially in their response to pharmacological treatment. Personalized medicine aspires to embrace these inter-individual differences and customize therapy by taking a wealth of patient-specific data into account. Pharmacogenomic constitutes a cornerstone of personalized medicine that provides therapeutic guidance based on the genomic profile of a given patient. Pharmacogenomics already has applications in the clinics, particularly in oncology, whereas future development in this area is needed in order to establish pharmacogenomic biomarkers as useful clinical tools. In this review we present an updated overview of current and emerging pharmacogenomic biomarkers in different therapeutic areas and critically discuss their potential to transform clinical care. Furthermore, we discuss opportunities of technological, methodological and institutional advances to improve biomarker discovery. We also summarize recent progress in our understanding of epigenetic effects on drug disposition and response, including a discussion of the only few pharmacogenomic biomarkers implemented into routine care. We anticipate, in part due to exciting rapid developments in Next Generation Sequencing technologies, machine learning methods and national biobanks, that the field will make great advances in the upcoming years towards unlocking the full potential of genomic data.

Highlights • Thymosins are thymic hormone-like peptides that can mediate immune and non-immune physiological processes. • Thymosin-α1 (Tα1) displays powerful pleiotropic activities by promoting anti-inflammatory and regulatory milieu in different settings. • Thymosin-β4 (Tβ4) provides neuroprotection, immunosuppression, and neurorestoration in the central nervous system. • This review describes what is known on the effects and the potential mechanisms of action of treatment with Tβ4 or Tα1 in Multiple Sclerosis and its experimental models., Background: Multiple sclerosis (MS) afflicts more than 2.5 million individuals worldwide and this number is increasing over time. Within the past years, a great number of disease-modifying treatments have emerged; however, efficacious treatments and a cure for MS await discovery. Thymosins, soluble hormone-like peptides produced by the thymus gland, can mediate immune and non-immune physiological processes and have gained interest in recent years as therapeutics in inflammatory and autoimmune diseases. Methods: Pubmed was searched with no time constraints for articles using a combination of the keywords “thymosin/s” or “thymus factor/s” AND “multiple sclerosis”, mesh terms with no language restriction. Results: Here, we review the state-of-the-art on the effects of thymosins on MS and its experimental models. In particular, we describe what is known in this field on the roles of thymosin-α1 (Tα1) and -β4 (Tβ4) as potential anti-inflammatory as well as neuroprotective and remyelinating molecules and their mechanisms of action. Conclusion: Based on the data that Tα1 and Tβ4 act as anti-inflammatory molecules and as inducers of myelin repair and neuronal protection, respectively, a possible therapeutic application in MS for Tα1 and Tβ4 alone or combined with other approved drugs may be envisaged. This approach is reasonable in light of the current clinical usage of Tα1 and data demonstrating the safety, tolerability and efficacy of Tβ4 in clinical practice.

Highlights • We report a case of WEMINO caused by mild traumatic brain injury, presenting with typical left ocular manifestations. • CT scan of brain was noncontributory, but MRI managed to delineate the site of injury in the MLF in the left temporo-occipital white matter. • Although more common in demyelinating diseases, clinicians should be cognizant of this syndrome in mild TBI patients that have ocular exotropia., Introduction Walled-eyed monocular internuclear ophthalmoplegia (WEMINO) syndrome is a sub-variant of internuclear ophthalmoplegia (INO) and involves the same clinical findings with the addition of exotropia of the ipsilateral eye. Causes typically include multiple sclerosis (MS) and ischemia (hemorrhagic or embolic) but can be secondary to blunt trauma as seen in our presented case. Presentation of case A 27-year-old man presented with new-onset visual changes, diplopia, and strabismus following a motor vehicle collision. Physical exam showed left ocular exotropia and slight hypertropia on forward gaze with deficiency of left convergence and disconjugate eye movements on horizontal gaze with right nystagmus on rightward gaze. Imaging showed hyperintensities in the right middle cerebellar peduncle and left temporal-occipital white matter likely consistent with diffuse axonal injury but otherwise nonspecific. The patient was treated conservatively with left eyepatch and exhibited improvement of exotropia and diplopia at 1 week follow up. Discussion Common causes of WEMINO syndrome include MS and ischemia with no prior reports, to our knowledge, being secondary to the blunt trauma seen in our case. Patients with WEMINO present with the typical signs of failure of ipsilateral adductive movement during lateral along with ipsilateral exotropia. Management involves treating the underlying disorder, if possible, with conservative measures with traumatic origins. Conclusion Until now, WEMINO syndrome secondary to trauma has not been previously documented. Our patient was effectively treated with conservative measures alone.

Type 2 diabetes (T2D) has become a global epidemic. Although several drugs are available to manage T2D, problems associated with person-to-person variability in drug efficacy and potential side-effects remain unresolved. Owing to the emerging role of the gut microbiome in obesity and T2D, the interaction between gut microbes and anti-diabetic drugs and its influence on drugs' functions remains of immediate research interest. On one hand, drugs can manipulate gut microbiome composition and metabolic capacity. Conversely, the metabolic activities of the microbiome and its metabolites can also influence drug metabolism and effects. Hence, understanding this bi-directional drug-microbiome interaction and how it influences the clinical outcomes of antidiabetic drugs can pave the way to develop next-generation strategies to ameliorate diabetes. This review presents evidences demonstrating the putative interactions between anti-diabetic drugs and the gut microbiome, and discusses the potential of microbiome modulators to manipulate drug-microbiome interactions and the drug metabolism., Graphical abstract Unlabelled Image, Highlights • Gut microbes interact with medications used to treat T2D, that at least partially mediates potential benefits of these drugs. • Anti-diabetic drugs impact gut microbiome and its metabolic activity and vice-versa. • Understanding the dynamics of drug-microbiome cross-talk would offer better therapeutic outcomes for diabetes.

Background In schizophrenia, impaired psychomotor speed is a common symptom predicting worse functional outcome. Inflammation causes changes in white matter integrity, which may lead to reduced psychomotor speed. Therefore, we wanted to investigate if peripheral inflammation assessed with cytokines affected performance on psychomotor speed in patients with a spectrum of psychotic disorders. Methods The current study is a prospective cohort study, including participants from a pragmatic, randomised controlled trial comparing three atypical antipsychotics in patients with a spectrum of psychotic disorders. For the purposes of this sub-study, we analysed drug treatment groups collectively. Psychomotor speed was assessed at baseline, and at weeks 6, 12, 26 and 52 of follow-up, using the neuropsychological tests trail making test (TMT) A and B, and symbol coding. Serum concentration of the following cytokines were measured: interleukin (IL)-β, IL-2, IL-4, IL-6, IL-10, IL12 p70, IL-17a, interferon (IFN)-γ and tumor necrosis factor (TNF)-α. Blood samples were collected at baseline and after 1, 3, 6, 12, 26, 39 and 52 weeks. We analysed the effect of cytokines levels on psychomotor speed over time in linear mixed effects models. Results In our linear mixed effects models controlling for possible confounders, IFN-γ had a significant negative effect on TMT-A and symbol coding performance. None of the other tests for psychomotor speed were significantly associated with cytokines. Overall psychomotor speed performance increased significantly across the study period while cytokine levels remained stable. Conclusion Our study indicates a negative association between IFN-γ and psychomotor speed, which might be of importance when understanding the mechanisms behind psychomotor deviations in psychotic disorders., Highlights • The cytokine interferon (IFN) – γ is related to psychomotor speed in patients with psychotic disorders. • For majority of cytokines, we found no significant association with psychomotor speed. • Cytokines remained stable during the study period of 52 weeks.

Highlights • 7 T MRI improves cortical lesion detection compared to 3 T MRI. • Type II-IV intracortical lesion detection benefit most from 7 T MRI. • Progressive multiple sclerosis patients have four times more cortical lesions. • 7 T MRI has modest sensitivity towards cortical lesions compared with histopathology. • Guidelines for image acquisition and cortical lesion segmentation at 7 T are missing., Background Cortical lesions are abundant in multiple sclerosis (MS), yet difficult to visualize in vivo. Ultra-high field (UHF) MRI at 7 T and above provides technological advances suited to optimize the detection of cortical lesions in MS. Purpose To provide a narrative and quantitative systematic review of the literature on UHF MRI of cortical lesions in MS. Methods A systematic search of all literature on UHF MRI of cortical lesions in MS published before September 2020. Quantitative outcome measures included cortical lesion numbers reported using 3 T and 7 T MRI and between 7 T MRI sequences, along with sensitivity of UHF MRI towards cortical lesions verified by histopathology. Results 7 T MRI detected on average 52 ± 26% (mean ± 95% confidence interval) more cortical lesions than the best performing image contrast at 3 T, with the largest increase in type II-IV intracortical lesion detection. Across all studies, the mean cortical lesion number was 17 ± 6 per patient. In progressive MS cohorts, approximately four times more cortical lesions were reported than in CIS/early RRMS, and RRMS. Yet, there was no difference in lesion type ratio between these MS subtypes. Furthermore, superiority of one MRI sequence over another could not be established from available data. Post-mortem lesion detection with UHF MRI agreed only modestly with pathological examinations. Mean pro- and retrospective sensitivity was 33 ± 6% and 71 ± 10%, respectively, with the highest sensitivity towards type I and type IV lesions. Conclusion UHF MRI improves cortical lesion detection in MS considerably compared to 3 T MRI, particularly for type II-IV lesions. Despite modest sensitivity, 7 T MRI is still capable of visualizing all aspects of cortical lesion pathology and could potentially aid clinicians in diagnosing and monitoring MS, and progressive MS in particular. However, standardization of acquisition and segmentation protocols is needed.

Highlights • Impaired eye movements in multiple sclerosis (MS) and functional connectivity (FC) • Eye movements related to altered FC of the oculomotor brain network. • Lower (beta band) and higher (theta/delta band) FC related to abnormal eye movements. • Regional changes were more informative than whole-network measures. • Eye movement parameters also related to disability and cognitive dysfunction., Background Impaired eye movements in multiple sclerosis (MS) are common and could represent a non-invasive and accurate measure of (dys)functioning of interconnected areas within the complex brain network. The aim of this study was to test whether altered saccadic eye movements are related to changes in functional connectivity (FC) in patients with MS. Methods Cross-sectional eye movement (pro-saccades and anti-saccades) and magnetoencephalography (MEG) data from the Amsterdam MS cohort were included from 176 MS patients and 33 healthy controls. FC was calculated between all regions of the Brainnetome atlas in six conventional frequency bands. Cognitive function and disability were evaluated by previously validated measures. The relationships between saccadic parameters and both FC and clinical scores in MS patients were analysed using multivariate linear regression models. Results In MS pro- and anti-saccades were abnormal compared to healthy controls A relationship of saccadic eye movements was found with FC of the oculomotor network, which was stronger for regional than global FC. In general, abnormal eye movements were related to higher delta and theta FC but lower beta FC. Strongest associations were found for pro-saccadic latency and FC of the precuneus (beta band β = -0.23, p = .006), peak velocity and FC of the parietal eye field (theta band β = -0.25, p = .005) and gain and FC of the inferior frontal eye field (theta band β = -0.25, p = .003). Pro-saccadic latency was also strongly associated with disability scores and cognitive dysfunction. Conclusions Impaired saccadic eye movements were related to functional connectivity of the oculomotor network and clinical performance in MS. This study also showed that, in addition to global network connectivity, studying regional changes in MEG studies could yield stronger correlations.

Highlights • Thalamus atrophy is associated with cognitive impairment in multiple sclerosis. • This was confirmed by automated and manual segmentations, but effect sizes varied. • The algorithms work in a multi-center setting. • Automated techniques exhibit proportional bias with respect to thalamus size. • Differences between vendors can affect the robustness of these associations., Background and rationale Thalamus atrophy has been linked to cognitive decline in multiple sclerosis (MS) using various segmentation methods. We investigated the consistency of the association between thalamus volume and cognition in MS for two common automated segmentation approaches, as well as fully manual outlining. Methods Standardized neuropsychological assessment and 3-Tesla 3D-T1-weighted brain MRI were collected (multi-center) from 57 MS patients and 17 healthy controls. Thalamus segmentations were generated manually and using five automated methods. Agreement between the algorithms and manual outlines was assessed with Bland-Altman plots; linear regression assessed the presence of proportional bias. The effect of segmentation method on the separation of cognitively impaired (CI) and preserved (CP) patients was investigated through Generalized Estimating Equations; associations with cognitive measures were investigated using linear mixed models, for each method and vendor. Results In smaller thalami, automated methods systematically overestimated volumes compared to manual segmentations [ρ=(-0.42)-(-0.76); p-values

In this consensus statement, we provide updated recommendations on multiple sclerosis (MS) management during the COVID-19 crisis and the post-pandemic period applicable to neurology services around the world. Statements/recommendations were generated based on available literature and the experience of 13 MS expert panelists using a modified Delphi approach online. The statements/recommendations give advice regarding implementation of telemedicine; use of disease-modifying therapies and management of MS relapses during the pandemic; management of people with MS at highest risk from COVID-19; management of radiological monitoring; use of remote pharmacovigilance; impact on MS research; implications for lowest income settings, and other key issues.

Background: In view of the emerging coronavirus pandemic, the demand for knowledge about the impact of SARS-CoV-2 on people with Multiple Sclerosis (MS) continues to grow. Patients receiving disease modifying therapy (DMT) for MS have a higher background risk of infection-related health care utilization when compared to the general population. Therefore, there is a need of evidence-based recommendations to reduce the risk of infection and also managing MS patients with SARS-CoV-2. Case Description: We present three patients with history of Multiple Sclerosis (MS) on DMTs presenting with worsening MS symptoms likely pseudo exacerbation who were diagnosed with COVID-19. Discussion: An extensive review of 7 articles was performed, in addition to a brief review on DMTs use in MS patients with COVID-19. In our cases, all patients were on DMT and severe course of disease was noted in 2 cases. No fatality was observed. Conclusions: This review provides a base on the clinical characteristics, outcomes and the roles of DMTs in MS patients suffering from n-cov-2. Physicians need to be vigilant about considering COVID-19 infection related relapse in the MS patients, especially in this COVID-19 pandemic era and look for pseudo-exacerbation. As most cases are found to have mild course and full recovery on DMTs, further research is needed to formulate evidence-based guidelines. This review will particularly be helpful for the researchers and registries to collect future data on MS and COVID-19., Highlights • Our cases presented with MS pseudo-exacerbation, with confirmatory COVID-19 • In our review, most MS patients had mild course of COVID-19 • Most of them recovered and fatality was observed only in 9 patients • Use of DMTs in MS patients with moderate to severe COVID-19 is debatable • Studies are required to develop guidelines for managing MS with COVID-19

The novel Coronavirus disease of 2019 (nCOV-19) is a viral outbreak noted first in Wuhan, China. This disease is caused by Severe Acute Respiratory Syndrome (SARS) Coronavirus (CoV)-2. In the past, other members of the coronavirus family, such as SARS and Middle East Respiratory Syndrome (MERS), have made an impact in China and the Arabian peninsula respectively. Both SARS and COVID-19 share similar symptoms such as fever, cough, and difficulty in breathing that can become fatal in later stages. However, SARS and MERS infections were epidemic diseases constrained to limited regions. By March 2020 the SARS-CoV-2 had spread across the globe and on March 11th, 2020 the World Health Organization (WHO) declared COVID-19 as pandemic disease. In severe SARS-CoV-2 infection, many patients succumbed to pneumonia. Higher rates of deaths were seen in older patients who had co-morbidities such as diabetes mellitus, hypertension, cardiovascular disease (CVD), and dementia. In this review paper, we discuss the effect of SARS-CoV-2 on CNS diseases, such as Alzheimer's-like dementia, and diabetes mellitus. We also focus on the virus genome, pathophysiology, theranostics, and autophagy mechanisms. We will assess the multiorgan failure reported in advanced stages of SARS-CoV-2 infection. Our paper will provide mechanistic clues and therapeutic targets for physicians and investigators to combat COVID-19., Graphical abstract Unlabelled Image, Highlights • SARS-CoV-2 and Dementia, Multiple Sclerosis, Encephalitis, and Parkinson's disease • SARS-CoV-2 and Diabetes Mellitus Coronaviruses and Autophagy • Protease Inhibitors and Repurposed Drugs for SARS-CoV-2 USFDA approved drugs-HCQ and Remdesivir. • SARS-CoV-2 diagnostics

T cell activation starts with formation of second messengers that release Ca2+ from the endoplasmic reticulum (ER) and thereby activate store-operated Ca2+ entry (SOCE), one of the essential signals for T cell activation. Recently, the steroidal 2-methoxyestradiol was shown to inhibit nuclear translocation of the nuclear factor of activated T cells (NFAT). We therefore investigated 2-methoxyestradiol for inhibition of Ca2+ entry in T cells, screened a library of 2-methoxyestradiol analogues, and characterized the derivative 2-ethyl-3-sulfamoyloxy-17β-cyanomethylestra-1,3,5(10)-triene (STX564) as a novel, potent and specific SOCE inhibitor. STX564 inhibits Ca2+ entry via SOCE without affecting other ion channels and pumps involved in Ca2+ signaling in T cells. Downstream effects such as cytokine expression and cell proliferation were also inhibited by both 2-methoxyestradiol and STX564, which has potential as a new chemical biology tool., Highlights • 2-Ethyl-3-sulfamoyloxy-17β-cyanomethylestra-1,3,5(10)-triene is a SOCE inhibitor. • novel inhibitor antagonizes SOCE and subsequent signaling events in different T cells • no antagonist effects on IP3 receptor, KV channels or SERCA pumps

Objectives This study reports on the feasibility of the SitLess with MS trial, an intervention targeting sedentary behavior in individuals with multiple sclerosis (MS). Design Single group, pre-post intervention design. Setting Community. Participants Participants (N=41) with mild to moderate disability from MS. Intervention The intervention was 15 weeks, with a 7-week follow-up, and included 2 stages: SitLess and MoveMore. During the SitLess stage, participants were encouraged to break up prolonged sitting bouts over a 7-week period, whereas the MoveMore stage promoted increased steps per day and interrupting sitting over a 7-week period. The intervention was delivered through weekly one-on-one coaching sessions via telerehabilitation and an accompanying newsletter based on social-cognitive theory. Activity was monitored throughout the program using a Fitbit. Main Outcome Measures Process (eg, recruitment) and resource and management (eg, personnel requirements) metrics were assessed, along with efficacy outcomes (eg, effect). Progression criteria were set a priori and were related to safety, fatigue, satisfaction, and attrition. Sedentary behavior, measured using the ActivPal, was reported pre- and postintervention, as well as 7 weeks postintervention. Effect sizes (pre to post, pre to 7 weeks post) were calculated for the sedentary behavior outcomes (eg, time sitting, transitions from sitting to standing, number of long sitting bouts). Experiences with the intervention were explored through an online survey. Results Forty-one participants enrolled, 39 of whom completed the intervention. All participants but 1 were satisfied with the experience. Pre-post intervention effect sizes for change in total sedentary time, number of transitions from sit to stand, and number of long (>30 min) sedentary bouts were 0.34, 0.02, and 0.39 respectively. All a priori progression criteria were met. Conclusions The SitLess with MS program, a novel intervention that emphasized and facilitated sitting less and moving more, was feasible and resulted in small changes in sedentary behavior in individuals with MS.

Background & Aims The epidemiology of autoimmune liver disease (AILD) is challenging to study because of the diseases' rarity and because of cohort selection bias. Increased incidence farther from the Equator has been reported for multiple sclerosis, another autoimmune disease. We assessed the incidence of primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and autoimmune hepatitis (AIH) in relation to latitude. Methods We performed a retrospective cohort study using anonymized UK primary care records from January 1, 2002, to May 10, 2016. All adults without a baseline diagnosis of AILD were included and followed up until the first occurrence of an AILD diagnosis, death, or they left the database. Latitude was measured as registered general practice rounded down to whole degrees. Results The cohort included 8,590,421 records with 53.3 × 107 years of follow-up evaluation from 694 practices. There were 1314 incident cases of PBC, 396 of PSC, and 1034 of AIH. Crude incidences were as follows: PBC, 2.47 (95% CI, 2.34–2.60); PSC, 0.74 (95% CI, 0.67–0.82); and AIH, 1.94 (95% CI, 1.83–2.06) per 100,000 per year. PBC incidence correlated with female sex, smoking, and deprivation; PSC incidence correlated with male sex and non-smoking; AIH incidence correlated with female sex and deprivation. A more northerly latitude was associated strongly with incidence of PBC: 2.16 (95% CI, 1.79–2.60) to 4.86 (95% CI, 3.93–6.00) from 50°N to 57°N (P = .002) and incidence of AIH: 2.00 (95% CI, 1.65–2.43) to 3.28 (95% CI, 2.53–4.24) (P = .003), but not incidence of PSC: 0.82 (95% CI, 0.60–1.11) to 1.02 (95% CI, 0.64–1.61) (P = .473). Incidence after adjustment for age, sex, smoking, and deprivation status showed similar positive correlations for PBC and AIH with latitude, but not PSC. Incident AIH cases were younger at more northerly latitude. Conclusions We describe an association in the United Kingdom between more northerly latitude and the incidence of PBC and AIH that requires both confirmation and explanation.

Multiple sclerosis (MS) patients have been considered a higher-risk population for COVID-19 due to the high prevalence of disability and disease-modifying therapy use; however, there is little data identifying clinical characteristics of MS associated with worse COVID-19 outcomes. Therefore, we conducted a multicenter prospective cohort study looking at the outcomes of 40 MS patients with confirmed COVID-19. Severity of COVID-19 infection was based on hospital course, where a mild course was defined as the patient not requiring hospital admission, moderate severity was defined as the patient requiring hospital admission to the general floor, and most severe was defined as requiring intensive care unit admission and/or death. 19/40(47.5%) had mild courses, 15/40(37.5%) had moderate courses, and 6/40(15%) had severe courses. Patients with moderate and severe courses were significantly older than those with a mild course (57[50–63] years old and 66[58.8–69.5] years old vs 48[40–51.5] years old, P = 0.0121, P = 0.0373). There was differing prevalence of progressive MS phenotype in those with more severe courses (severe:2/6[33.3%]primary-progressing and 0/6[0%]secondary-progressing, moderate:1/14[7.14%] and 5/14[35.7%] vs mild:0/19[0%] and 1/19[5.26%], P = 0.0075, 1 unknown). Significant disability was found in 1/19(5.26%) mild course-patients, but was in 9/15(60%, P = 0.00435) of moderate course-patients and 2/6(33.3%, P = 0.200) of severe course-patients. Disease-modifying therapy prevalence did not differ among courses (mild:17/19[89.5%], moderate:12/15[80%] and severe:3/6[50%], P = 0.123). MS patients with more severe COVID-19 courses tended to be older, were more likely to suffer from progressive phenotype, and had a higher degree of disability. However, disease-modifying therapy use was not different among courses., Highlights • In a multicenter study of 40 multiple sclerosis (MS) patients, different phenotypes and level of disability were associated with COVID-19 severity. • Poorer outcomes were associated with more severe MS disability. • The use of DMT for MS was not associated with worse outcome.

Objective To examine the safety, feasibility, and response to functional electrical stimulation (FES) cycling protocols requiring differing levels of effort in people with multiple sclerosis (MS) who are nonambulatory. Design Pilot study with pre-post intervention testing. Setting Outpatient clinic setting of a long-term acute care hospital. Participants Individuals (N=10) with MS (6 men; mean age 58.6±9.86y) who use a wheelchair for community mobility. Participants’ Expanded Disability Status Scale score ranged from 6.5 to 8.5 (median 7.5). Intervention Participants performed 3 or 4 FES cycling protocols requiring different levels of volitional effort during 6-8 testing sessions. Main Outcome Measures The primary outcome was safety, measured by adverse events and increase in MS symptoms, all assessed throughout, immediately post- and 1 day postsession. FES cycling performance for each protocol was also recorded. Exploratory outcome measures collected before and after all testing sessions included functional assessment of MS, MS Impact Scale, Exercise Self Efficacy Scale, Patient Health Questionnaire-9 item, and the Zarit Caregiver Burden Scale. Results All participants (4 women, 6 men) completed all testing sessions. There were no serious adverse events or differences in vitals or symptoms between protocols. Two participants had an isolated episode of mild hypotension. Changes in pain, spasticity, and fatigue were minimal. Five participants were able to cycle for 30 minutes and completed interval training protocols requiring increasing difficulty. The remainder cycled for, Highlights • People with multiple sclerosis who are nonambulatory can safely perform functional electrical stimulation (FES) cycling using parameters requiring more effort. • FES cycling may offer an opportunity for increased exercise stimulus or neuromuscular training if individuals are adequately challenged using an appropriate cycling protocol.

Graphical abstract, Highlights • Automated segmentation of cortical and white matter lesions in multiple sclerosis. • A clinically plausible 3T MRI setting based on FLAIR and MP2RAGE sequences. • Evaluation is done on a large cohort of 90 patients. • Results show high cortical and white matter lesion segmentation accuracy. • Our method generalizes across different hospitals and scanners., The presence of cortical lesions in multiple sclerosis patients has emerged as an important biomarker of the disease. They appear in the earliest stages of the illness and have been shown to correlate with the severity of clinical symptoms. However, cortical lesions are hardly visible in conventional magnetic resonance imaging (MRI) at 3T, and thus their automated detection has been so far little explored. In this study, we propose a fully-convolutional deep learning approach, based on the 3D U-Net, for the automated segmentation of cortical and white matter lesions at 3T. For this purpose, we consider a clinically plausible MRI setting consisting of two MRI contrasts only: one conventional T2-weighted sequence (FLAIR), and one specialized T1-weighted sequence (MP2RAGE). We include 90 patients from two different centers with a total of 728 and 3856 gray and white matter lesions, respectively. We show that two reference methods developed for white matter lesion segmentation are inadequate to detect small cortical lesions, whereas our proposed framework is able to achieve a detection rate of 76% for both cortical and white matter lesions with a false positive rate of 29% in comparison to manual segmentation. Further results suggest that our framework generalizes well for both types of lesion in subjects acquired in two hospitals with different scanners.

Despite the substantial growth of telemedicine and the evidence of its advantages, the use of telemedicine in neurosurgery has been limited. Barriers have included medicolegal issues surrounding provider reimbursement, interstate licensure, and malpractice liability as well as technological challenges. Recently, the coronavirus disease 2019 (COVID-19) pandemic has limited typical evaluation of patients with neurologic issues and resulted in a surge in demand for virtual medical visits. Meanwhile, federal and state governments took action to facilitate the rapid implementation of telehealth programs, placing a temporary lift on medicolegal barriers that had previously limited its expansion. This created a unique opportunity for widespread telehealth use to meet the surge in demand for remote medical care. After initial hurdles and challenges, our experience with telemedicine in neurosurgery at Penn Medicine has been overall positive from both the provider and the patients' perspective. One of the unique challenges we face is guiding patients to appropriately set up devices in a way that enables an effective neuroexamination. However, we argue that an accurate and comprehensive neurologic examination can be conducted through a telemedicine platform, despite minor weaknesses inherent to absence of physical presence. In addition, certain neurosurgical visits such as postoperative checks, vascular pathology, and brain tumors inherently lend themselves to easier evaluation through telehealth visits. In the era of COVID-19 and beyond, telemedicine remains a promising and effective approach to continue neurologic patient care.

The 18 kDa translocator protein (TSPO), previously known as the peripheral benzodiazepine receptor, is predominately localized to the outer mitochondrial membrane in steroidogenic cells. Brain TSPO expression is relatively low under physiological conditions, but is upregulated in response to glial cell activation. As the primary index of neuroinflammation, TSPO is implicated in the pathogenesis and progression of numerous neuropsychiatric disorders and neurodegenerative diseases, including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), multiple sclerosis (MS), major depressive disorder (MDD) and obsessive compulsive disorder (OCD). In this context, numerous TSPO-targeted positron emission tomography (PET) tracers have been developed. Among them, several radioligands have advanced to clinical research studies. In this review, we will overview the recent development of TSPO PET tracers, focusing on the radioligand design, radioisotope labeling, pharmacokinetics, and PET imaging evaluation. Additionally, we will consider current limitations, as well as translational potential for future application of TSPO radiopharmaceuticals. This review aims to not only present the challenges in current TSPO PET imaging, but to also provide a new perspective on TSPO targeted PET tracer discovery efforts. Addressing these challenges will facilitate the translation of TSPO in clinical studies of neuroinflammation associated with central nervous system diseases., Graphical abstract The 18 kDa translocator protein (TSPO) expression in the central nervous system is upregulated in response to glial cell activation. There is a great potential for the future application of TSPO radioligands as diagnostic and prognostic tools, as well as for assessing therapeutic interventions for neurologic diseases.Image 1

The treatments of nervous system diseases (NSDs) have long been difficult issues for researchers because of their complexity of pathogenesis. With the advent of aging society, searching for effective treatments of NSDs has become a hot topic. Ginseng polysaccharides (GP), as the main biologically active substance in ginseng, has various biological properties in immune-regulation, anti-oxidant, anti-inflammation and etc. Considering the association between the effects of GP and the pathogenesis of neurological disorders, many related experiments have been conducted in recent years. In this paper, we reviewed previous studies about the effects and mechanisms of GP on diseases related to nervous system. We found GP play an ameliorative role on NSDs through the regulation of immune system, inflammatory response, oxidative damage and signaling pathway. Structure-activity relationship was also discussed and summarized. In addition, we provided new insights into GP as promising neuroprotective agent for its further development and utilization.

Highlights • T1ρ and RAFF4 - MRI protocols sensitive to slow motional regimes – are able to detect changes in T2w-defined normally appearing white matter of patients with multiple sclerosis. • RAFF4, T1ρ and T2ρ showed differences in hippocampus in patients with multiple sclerosis despite the absence of alterations in resting-state functional MRI metrics. • Hence, RAFF4, T1ρ and T2ρ hold promise as potential non-invasive tools for monitoring MS activity and eventually for the evaluation of therapeutic effects., Even though MRI visualization of white matter lesions is pivotal for the diagnosis and management of multiple sclerosis (MS), the issue of detecting diffuse brain tissue damage beyond the apparent T2-hyperintense lesions continues to spark considerable interest. Motivated by the notion that rotating frame MRI methods are sensitive to slow motional regimes critical for tissue characterization, here we utilized novel imaging protocols of rotating frame MRI on a clinical 3 Tesla platform, including adiabatic longitudinal, T1ρ, and transverse, T2ρ, relaxation methods, and Relaxation Along a Fictitious Field (RAFF) in the rotating frame of rank 4 (RAFF4), in 10 relapsing-remitting multiple sclerosis patients and 10 sex- and age-matched healthy controls. T1ρ, T2ρ and RAFF4 relaxograms extracted from the whole white matter exhibited a significant shift towards longer relaxation time constants in MS patients as compared to controls. T1ρ and RAFF4 detected alterations even when considering only regions of normally appearing white matter (NAWM), while other MRI metrics such as T1w/T2w ratio and diffusion tensor imaging measures failed to find group differences. In addition, RAFF4, T2ρ and, to a lesser extent, T1ρ showed differences in subcortical grey matter structures, mainly hippocampus, whereas no functional changes in this region were detected in resting-state functional MRI metrics. We conclude that rotating frame MRI techniques are exceptionally sensitive methods for the detection of subtle abnormalities not only in NAWM, but also in deep grey matter in MS, where they surpass even highly sensitive measures of functional changes, which are often suggested to precede detectable structural alterations. Such abnormalities are consistent with a wide spectrum of different, but interconnected pathological features of MS, including the loss of neuronal cells and their axons, decreased levels of myelin even in NAWM, and altered iron content.

International audience; Thermoregulation is a homeostatic mechanism that is disrupted in some neurological diseases. Patients with multiple sclerosis (MS) are susceptible to increases in body temperature, especially with more severe neurological signs. This condition can become intolerable when these patients suffer febrile infections such as coronavirus disease-2019 (COVID-19). We review the mechanisms of hyperthermia in patients with MS, and they may encounter when infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Finally, the thermoregulatory role and relevant adaptation to regular physical exercise are summarized.

Background multiple sclerosis (MS) patients are treated with immunomodulatory treatments that can influence their ability to develop a protective antibody response to the SARS-CoV-2 vaccine. Vaccine efficacy is important for treatment decision and for patients’ reassurance. The main objective is to assess antibody response to SARS-CoV-2 vaccine in MS patients treated with cladribine. Methods Serology response was tested in 97 participants, 67 MS patients and 30 healthy controls (HCs), using two independent methods, 2–3 weeks following the second dose of the BNT162b2 vaccine. Results HCs (n = 30) and MS patients treated with cladribine (n = 32) had 100% positive serology response against the SARS-CoV-2 spike protein following the second vaccine dose (mean S1/S2-IgG and RBD-IgG:284.5 ± 104.9, 13,041±9411 AU/mL and 226.3 ± 121.4, 10,554±11,405 AU/mL respectively). Comparable findings were observed for untreated MS patients, and interferon beta-1a-treated MS patients (mean S1/S2-IgG: 282.1 ± 100.1, 276.9 ± 94.31 AU/mL respectively). No correlation was found between lymphocyte counts, treatment duration, or time between cladribine dose and vaccination, and serology response or antibody titers. Conclusion and relevance Cladribine treated MS patients are able to produce antibodies to the SARS-CoV-2 mRNA vaccine. In the era of the COVID-19 pandemic, it is reassuring and important for both patients and physicians and will allow to develop consensus guidelines.

Respiratory silicosis is a preventable occupational disease that develops secondary to the aspiration of crystalline silicon dioxide (silica) into the lungs, activation of the NLRP3 inflammasome, and IL-1β production. Cathepsin Z has been associated with the development of inflammation and IL-1β production; however, the mechanism of how cathepsin Z leads to IL-1β production is unknown. Here, the requirement for cathepsin Z in silicosis was determined using wildtype mice and mice deficient in cathepsin Z. The activation of the NLRP3 inflammasome in macrophages was studied using wildtype and cathepsin Z-deficient bone marrow-derived murine dendritic cells and the human monocytic cell line THP-1. Cells were activated with silica, and IL-1β release was determined using enzyme-linked immunosorbent assay or IL-1β bioassays. The relative contribution of the active domain or integrin-binding domain of cathepsin Z was studied using recombinant cathepsin Z constructs and the α5 integrin neutralizing antibody. We report that the lysosomal cysteine protease cathepsin Z potentiates the development of inflammation associated with respiratory silicosis by augmenting NLRP3 inflammasome-derived IL-1β expression in response to silica. Secreted cathepsin Z functions non-proteolytically via the internal integrin-binding domain to impact caspase-1 activation and the production of active IL-1β through integrin α5 without affecting transcription levels of NLRP3 inflammasome components. This work reveals a regulatory pathway for the NLRP3 inflammasome that occurs in an outside-in fashion and provides a link between extracellular cathepsin Z and inflammation. Furthermore, it reveals a level of NLRP3 inflammasome regulation that has previously only been found downstream of extracellular pathogens.

Background B-cell depleting agents are FDA approved for the treatment of RRMS (ocrelizumab (OCR) and ofatumumab (OFA)) and PPMS (OCR). In the case of OCR, prior studies have raised concerns about patients’ ability to form antibodies in response to various antigens, especially SARS-CoV-2. In addition, emerging data have shown an attenuated humoral response to vaccines against SARS-CoV-2. The objective of this study is to determine whether b-cell depleters or sphingosine 1-phosphate (S1P) modulators attenuate the antibody response to various SARS-CoV-2 vaccines in patients with MS as compared with other MS disease modifying therapies (DMTs). Methods This is a case-control study looking at the odds of developing antibodies to three SARS-CoV-2 vaccines (Pfizer-BioNTech, Moderna, and Johnson & Johnson) in patients treated with b-cell depleters or S1P modulators versus other disease modifying therapies. Patients were recruited at the Comprehensive MS Center at Methodist Hospitals. Patients who did not have a prior COVID-19 infection and received one of the three vaccines were tested for antibodies against the SARS-CoV-2 spike protein (Labcorp, semi-quantitative total antibody) at least two weeks following the final dose of the vaccine. Groups (B-cell, S1P modulators, other DMT, and no DMT) were compared on antibody level. The main outcome was whether or not a humoral response was detected by antibody testing. Dichotomous antibody response was tested using logistic regression models, and the quantitative response was tested using ANCOVA adjusted for covariates (age, sex, race, MS type, disease duration, vaccine, and lymphocyte count). P-values

Background Diffusion Tensor Imaging (DTI) can evaluate microstructural tissue damage in the optic radiation (OR) of patients with clinically isolated syndrome (CIS), early relapsing-remitting multiple sclerosis and neuromyelitis optica spectrum disorders (NMOSD). Different post-processing techniques, e.g. tract-based spatial statistics (TBSS) and probabilistic tractography, exist to quantify this damage. Objective To evaluate the capacity of TBSS-based atlas region-of-interest (ROI) combination with 1) posterior thalamic radiation ROIs from the Johns Hopkins University atlas (JHU-TBSS), 2) Juelich Probabilistic ROIs (JUEL-TBSS) and tractography methods using 3) ConTrack (CON-PROB) and 4) constrained spherical deconvolution tractography (CSD-PROB) to detect OR damage in patients with a) NMOSD with prior ON (NMOSD-ON), b) CIS and early RRMS patients with ON (CIS/RRMS-ON) and c) CIS and early RRMS patients without prior ON (CIS/RRMS-NON) against healthy controls (HCs). Methods Twenty-three NMOSD-ON, 18 CIS/RRMS-ON, 21 CIS/RRMS-NON, and 26 HCs underwent 3 T MRI. DTI data analysis was carried out using JUEL-TBSS, JHU-TBSS, CON-PROB and CSD-PROB. Optical coherence tomography (OCT) and visual acuity testing was performed in the majority of patients and HCs. Results Absolute OR fractional anisotropy (FA) values differed between all methods but showed good correlation and agreement in Bland-Altman analysis. OR FA values between NMOSD and HC differed throughout the methodologies (p-values ranging from p, Highlights • We describe a fully-automated optic radiation probabilistic tractography approach (CSD-PROB) that is feasible in healthy controls and patients with neuroimmunological diseases. • We demonstrate CSD-PROB to yield superior sensitivity and specificity in differentiating NMOSD from healthy controls compared to TBSS-based optic radiation ROI methods and ConTrack-based probabilistic tractography. • CSD-PROB shows significant differences between healthy controls and patients with clinically isolated syndrome and early multiple sclerosis without prior optic neuritis. • The comparison of different subject groups by use of different DWI post-processing methods may lead to either false-positive or false-negative results, which may be of particular significance for future optic radiation DTI comparison in studies and meta-analyses.

Atrophy of the brain grey matter (GM) is an accepted and important feature of multiple sclerosis (MS). However, its accurate measurement is hampered by various technical, pathological and physiological factors. As a consequence, it is challenging to investigate the role of GM atrophy in the disease process as well as the effect of treatments that aim to reduce neurodegeneration. In this paper we discuss the most important challenges currently hampering the measurement and interpretation of GM atrophy in MS. The focus is on measurements that are obtained in individual patients rather than on group analysis methods, because of their importance in clinical trials and ultimately in clinical care. We discuss the sources and possible solutions of the current challenges, and provide recommendations to achieve reliable measurement and interpretation of brain GM atrophy in MS., Highlights • Accurate measurement of brain GM atrophy in MS is hampered by various physiological, pathological and technical factors. • Challenges to achieve accuracy in quantification and interpretation of atrophy in MS are discussed. • Recommendations on how to achieve reliable measurement and interpretation of GM atrophy in MS are suggested.

Objective To investigate the rich-club organization in clinically isolated syndrome (CIS) and multiple sclerosis (MS), and to characterize its relationships with physical disabilities and cognitive impairments. Methods We constructed high-resolution white matter (WM) structural networks in 41 CIS, 32 MS and 35 healthy controls (HCs) using diffusion MRI and deterministic tractography. Group differences in rich-club organization, global and local network metrics were investigated. The relationship between the altered network metrics, brain lesions and clinical variables including EDSS, MMSE, PASAT, disease duration were calculated. Additionally, reproducibility analysis was performed using different parcellation schemes. Results Compared with HCs, MS patients exhibited a decreased strength in all types of connections (rich-club: p, Highlights • The rich-club organization was disrupted in MS patients and preserved in CIS. • The disrupted rich-club connectivity correlated with cognitive impairment in MS. • The rich-club results are reproducible across data analysis methods.

Long term irreversible disability in multiple sclerosis (MS) is thought to be primarily driven by axonal degeneration. Axonal degeneration leads to degenerative atrophy, therefore early markers of axonal degeneration are required to predict clinical disability and treatment efficacy. Given that additional pathologies such as inflammation, demyelination and oedema are also present in MS, it is essential to develop axonal markers that are not confounded by these processes. The present study investigated a novel method for measuring axonal degeneration in MS based on high angular resolution diffusion magnetic resonance imaging. Unlike standard methods, this novel method involved advanced acquisition and modelling for improved axonal sensitivity and specificity. Recent work has developed analytical methods, two novel axonal markers, fibre density and cross-section, that can be estimated for each fibre direction in each voxel (termed a “fixel”). This technique, termed fixel-based analysis, thus simultaneously estimates axonal density and white matter atrophy from specific white matter tracts. Diffusion-weighted imaging datasets were acquired for 17 patients with a history of acute unilateral optic neuritis (35.3 ± 10.2 years, 11 females) and 14 healthy controls (32.7 ± 4.8 years, 8 females) on a 3 T scanner. Fibre density values were compared to standard diffusion tensor imaging parameters (fractional anisotropy and mean diffusivity) in lesions and normal appearing white matter. Group comparisons were performed for each fixel to assess putative differences in fibre density and fibre cross-section. Fibre density was observed to have a comparable sensitivity to fractional anisotropy for detecting white matter pathology in MS, but was not affected by crossing axonal fibres. Whole brain fixel-based analysis revealed significant reductions in fibre density and fibre cross-section in the inferior fronto-occipital fasciculus (including the optic radiations) of patients compared to controls. We interpret this result to indicate that this fixel-based approach is able to detect early loss of fibre density and cross-section in the optic radiations in MS patients with a history of optic neuritis. Fibre-specific markers of axonal degeneration should be investigated further for use in early stage therapeutic trials, or to monitor axonal injury in early stage MS., Highlights • Fibre density is reduced in lesions and normal-appearing white matter in MS • Fibre density detects white matter pathology in regions of crossing fibres • Loss of fibre density and cross-section selectively evident in visual pathways of optic neuritis patients.