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Over the past three years, humanity faced the abrupt spread of COVID-19, responsible for a worldwide health crisis. Initially, it was believed that individuals with chronic disorders, including multiple sclerosis, were more likely to be infected and suffer a worse degree of COVID-19 disease. Therefore, data with regard to COVID-19 disease outcomes in these populations may provide additional insight with regard to the management of chronic diseases during viral pandemics. The objective of this study is to evaluate COVID-19 disease course in people with multiple sclerosis (PwMS) during the COVID-19 pandemic in Greece and explore the impact of vaccination in the outcome of SARS-CoV-2 infection in this population. Anonymized data, extracted from nationwide administrative records between February 2020 and December 2021, were retrospectively analyzed in order to identify PwMS with SARS-CoV-2 infection. Demographic data, as well as data regarding COVID-19 infection and vaccination, were additionally collected. The study sample included 2351 PwMS (65.1% females, 51.2% unvaccinated at the time of infection). A total of 260 PwMS were hospitalized, while 25 PwMS died from COVID-19 disease and its complications. Older age, male sex and the presence of comorbidities were independently associated with a higher probability of hospitalization. The risk of hospitalization was decreased in PwMS receiving some disease-modifying treatments. Anti-CD20s demonstrated high odds ratios without reaching statistical significance. Regarding fatal outcome, only age reached statistical significance. Vaccination provided a significant protective effect against hospitalization but did not exhibit a statistically significant effect on mortality.

Secondary demyelinating diseases comprise a wide spectrum group of pathological conditions and may either be attributed to a disorder primarily affecting the neurons or axons, followed by demyelination, or to an underlying condition leading to secondary damage of the myelin sheath. In the elderly, primary demyelinating diseases of the central nervous system (CNS), such as multiple sclerosis, are relatively uncommon. However, secondary causes of CNS demyelination may often occur and in this case, extensive diagnostic workup is usually needed. Infectious, postinfectious, or postvaccinal demyelination may be observed, attributed to age-related alterations of the immune system in this population. Osmotic disturbances and nutritional deficiencies, more commonly observed in the elderly, may lead to conditions such as pontine/extrapontine myelinolysis, Wernicke encephalopathy, and demyelination of the posterior columns of the spinal cord. The prevalence of malignancies is higher in the elderly, sometimes leading to radiation-induced, immunotherapy-related, or paraneoplastic CNS demyelination. This review intends to aid clinical neurologists in broadening their diagnostic approach to secondary CNS demyelinating diseases in the elderly. Common clinical conditions leading to secondary demyelination and their clinical manifestations are summarized here, while the current knowledge of the underlying pathophysiological mechanisms is additionally presented.

Multiple sclerosis (MS) is a heterogeneous disease of the central nervous system that is governed by neural tissue loss and dystrophy during its progressive phase, with complex reactive pathological cellular changes. The immune-mediated mechanisms that promulgate the demyelinating lesions during relapses of acute episodes are not characteristic of chronic lesions during progressive MS. This has limited our capacity to target the disease effectively as it evolves within the central nervous system white and gray matter, thereby leaving neurologists without effective options to manage individuals as they transition to a secondary progressive phase. The current review highlights the molecular and cellular sequelae that have been identified as cooperating with and/or contributing to neurodegeneration that characterizes individuals with progressive forms of MS. We emphasize the need for appropriate monitoring via known and novel molecular and imaging biomarkers that can accurately detect and predict progression for the purposes of newly designed clinical trials that can demonstrate the efficacy of neuroprotection and potentially neurorepair. To achieve neurorepair, we focus on the modifications required in the reactive cellular and extracellular milieu in order to enable endogenous cell growth as well as transplanted cells that can integrate and/or renew the degenerative MS plaque.

Background: Besides disease-modifying therapies, various pharmacologic agents are frequently prescribed to people with multiple sclerosis (MS) for symptom treatment and for comorbid conditions. The present study aims to investigate the types and frequencies of agents prescribed to people with MS in Greece using records from the nationwide digital prescription database., Methods: Prescription records for 21,218 people (65.9% women) with MS were included in the study. The criterion for study inclusion was a minimum of 3 months of continuous prescription of an agent. Identified treatments were further examined by age group., Results: Antispasticity agents (17.5%) and fampridine (14.5%) were the most regularly prescribed symptomatic medications. Antihypertensives (21.1%) and drugs for affective disorders, including antidepressants (36.1%) and anxiolytics (16.2%), were the most frequently prescribed medications for comorbid conditions. Antidepressants were prescribed at almost equally high rates among individuals older than 40 years. Hypertension was one of the leading comorbidities among the study sample, with rates rising significantly after age 40 years and plateauing after age 60 years. Polypharmacy was observed in 22.5% of the study sample, with a higher incidence among people with MS older than 60 years (46.98%)., Conclusions: Agents prescribed for the treatment of disease symptoms and other medical conditions are expected to positively affect quality of life in people with MS. However, polypharmacy seems to be particularly high, especially in the aged population. The potential implications of polypharmacy in the disease course should further be explored., Competing Interests: The other authors declare no conflicts of interest., (© 2023 The Consortium of Multiple Sclerosis Centers.)

Introduction: Obesity has been linked to vascular dysfunction, cognitive impairment and neurodegenerative diseases. However, experimental models that recapitulate brain pathology in relation to obesity and vascular dysfunction are still lacking., Methods: In this study we performed the histological and histochemical characterization of brains from Ldlr-/-.Leiden mice, an established model for obesity and associated vascular disease. First, HFD-fed 18 week-old and 50 week-old Ldlr-/-.Leiden male mice were compared with age-matched C57BL/6J mice. We then assessed the effect of high-fat diet (HFD)-induced obesity on brain pathology in Ldlr-/-.Leiden mice and tested whether a treatment with an anti-complement component 5 antibody, a terminal complement pathway inhibitor recently shown to reduce vascular disease, can attenuate neurodegeneration and neuroinflammation. Histological analyses were complemented with Next Generation Sequencing (NGS) analyses of the hippocampus to unravel molecular pathways underlying brain histopathology., Results: We show that chow-fed Ldlr-/-.Leiden mice have more severe neurodegeneration and show an age-dependent astrogliosis that is not observed in age-matched C57BL/6J controls. This was substantiated by pathway enrichment analysis using the NGS data which showed that oxidative phosphorylation, EIF2 signaling and mitochondrial dysfunction pathways, all associated with neurodegeneration, were significantly altered in the hippocampus of Ldlr-/-.Leiden mice compared with C57BL/6J controls. Obesity-inducing HFD-feeding did not aggravate neurodegeneration and astrogliosis in Ldlr-/-.Leiden mice. However, brains from HFD-fed Ldlr-/-.Leiden mice showed reduced IBA-1 immunoreactivity and increased CD68 immunoreactivity compared with chow-fed Ldlr-/-.Leiden mice, indicating alteration of microglial immunophenotype by HFD feeding. The systemic administration of an anti-C5 treatment partially restored the HFD effect on microglial immunophenotype. In addition, NGS data of hippocampi from Ldlr-/-.Leiden mice showed that HFD feeding affected multiple molecular pathways relative to chow-fed controls: HFD notably inactivated synaptogenesis and activated neuroinflammation pathways. The anti-C5 treatment restored the HFD-induced effect on molecular pathways to a large extent., Conclusion: This study shows that the Ldlr-/-.Leiden mouse model is suitable to study brain histopathology and associated biological processes in a context of obesity and provides evidence of the potential therapeutic value of anti-complement therapy against obesity-induced neuroinflammation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Seidel, Fluiter, Kleemann, Worms, van Nieuwkoop, Caspers, Grigoriadis, Kiliaan, Baas, Michailidou and Morrison.)

Multiple sclerosis (MS) can progress with neurodegeneration as a consequence of chronic inflammatory mechanisms that drive neural cell loss and/or neuroaxonal dystrophy in the central nervous system. Immune-mediated mechanisms can accumulate myelin debris in the disease extracellular milieu during chronic-active demyelination that can limit neurorepair/plasticity and experimental evidence suggests that potentiated removal of myelin debris can promote neurorepair in models of MS. The myelin-associated inhibitory factors (MAIFs) are integral contributors to neurodegenerative processes in models of trauma and experimental MS-like disease that can be targeted to promote neurorepair. This review highlights the molecular and cellular mechanisms that drive neurodegeneration as a consequence of chronic-active inflammation and outlines plausible therapeutic approaches to antagonize the MAIFs during the evolution of neuroinflammatory lesions. Moreover, investigative lines for translation of targeted therapies against these myelin inhibitors are defined with an emphasis on the chief MAIF, Nogo-A, that may demonstrate clinical efficacy of neurorepair during progressive MS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Rashidbenam, Ozturk, Pagnin, Theotokis, Grigoriadis and Petratos.)

Background: The prognostic significance of non-disabling relapses in people with relapsing-remitting multiple sclerosis (RRMS) is unclear., Objective: To determine whether early non-disabling relapses predict disability accumulation in RRMS., Methods: We redefined mild relapses in MSBase as 'non-disabling', and moderate or severe relapses as 'disabling'. We used mixed-effects Cox models to compare 90-day confirmed disability accumulation events in people with exclusively non-disabling relapses within 2 years of RRMS diagnosis to those with no early relapses; and any early disabling relapses. Analyses were stratified by disease-modifying therapy (DMT) efficacy during follow-up., Results: People who experienced non-disabling relapses within 2 years of RRMS diagnosis accumulated more disability than those with no early relapses if they were untreated ( n  = 285 vs 4717; hazard ratio (HR) = 1.29, 95% confidence interval (CI) = 1.00-1.68) or given platform DMTs ( n  = 1074 vs 7262; HR = 1.33, 95% CI = 1.15-1.54), but not if given high-efficacy DMTs ( n  = 572 vs 3534; HR = 0.90, 95% CI = 0.71-1.13) during follow-up. Differences in disability accumulation between those with early non-disabling relapses and those with early disabling relapses were not confirmed statistically., Conclusion: This study suggests that early non-disabling relapses are associated with a higher risk of disability accumulation than no early relapses in RRMS. This risk may be mitigated by high-efficacy DMTs. Therefore, non-disabling relapses should be considered when making treatment decisions.

Neuroglial cells, and especially astrocytes, constitute the most varied group of central nervous system (CNS) cells, displaying substantial diversity and plasticity during development and in disease states. The morphological changes exhibited by astrocytes during the acute and chronic stages following CNS injury can be characterized more precisely as a dynamic continuum of astrocytic reactivity. Different subpopulations of reactive astrocytes may be ascribed to stages of degenerative progression through their direct pathogenic influence upon neurons, neuroglia, the blood-brain barrier, and infiltrating immune cells. Multiple sclerosis (MS) constitutes an autoimmune demyelinating disease of the CNS. Despite the previously held notion that reactive astrocytes purely form the structured glial scar in MS plaques, their continued multifaceted participation in neuroinflammatory outcomes and oligodendrocyte and neuronal function during chronicity, suggest that they may be an integral cell type that can govern the pathophysiology of MS. From a therapeutic-oriented perspective, astrocytes could serve as key players to limit MS progression, once the integral astrocyte-MS relationship is accurately identified. This review aims toward delineating the current knowledge, which is mainly focused on immunomodulatory therapies of the relapsing-remitting form, while shedding light on uncharted approaches of astrocyte-specific therapies that could constitute novel, innovative applications once the role of specific subgroups in disease pathogenesis is clarified.

Introduction: Fingolimod is the first approved oral therapy for relapsing-remitting multiple sclerosis (RRMS). The present study aimed to further characterize fingolimod's safety profile, and to assess the patient-reported treatment satisfaction and impact of fingolimod on the quality of life (QoL) of patients with multiple sclerosis (MS) treated in routine care in Greece., Methods: This was a multicenter, prospective, observational, 24-month study conducted in Greece by hospital-based and private practice neurologists who specialize in MS. Eligible patients had initiated fingolimod within 15 days in accordance with the locally approved label. Safety outcomes included any adverse event (AE) observed during the study period and efficacy outcomes included both objective (disability progression and 2-year annualized relapse rate) and patient-reported assessments (Treatment Satisfaction Questionnaire for Medication (TSQM) v1.4 and the EuroQol (EQ)-5-dimension (5D) 3-level instruments)., Results: A total of 489 eligible patients (age 41.2 ± 9.8 years; 63.7% female; 4.2% treatment-naive) were exposed to fingolimod for a median of 23.7 months. During the observation period, 20.5% of the participants experienced 233 AEs. Lymphopenia (8.8%), leukopenia (4.2%), hepatic enzyme increased (3.4%), and infections (3.0%) were the most common. Most patients (89.3%) did not experience disability progression; the 2-year annualized relapse rate decreased by 94.7% compared to baseline. The median EQ-visual analogue scale (VAS) was 74.5 at month 24 vs. 65.0 at enrollment (p < 0.001) and the EQ-5D index score was 0.80 vs. 0.78, respectively. Significant improvements were noted in the TSQM global satisfaction and effectiveness domain scores between 6 and 24 months post enrollment (median scores at month 24, 71.4 and 66.7, respectively) (p < 0.001). Significant increases from enrollment to the 24th month were also noted in the patients' global satisfaction and effectiveness domain scores [mean change of 7.4 ± 17.7 (p = 0.005) and mean increase of 5.4 ± 16.2) (p = 0.043), respectively]., Conclusion: In the real-world setting of Greece, fingolimod demonstrates a clinical benefit and a predictable and manageable safety profile, which contribute towards high patient-reported treatment satisfaction and improvements in the QoL of patients with MS., (© 2023. The Author(s), under exclusive licence to Springer Healthcare Ltd., part of Springer Nature.)

Introduction/aims: There is limited knowledge regarding the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines οn coronavirus disease 2019 (COVID-19) disease course in people with myasthenia gravis. In this study, we aimed to investigate whether SARS-CoV-2 vaccination influences hospitalization and mortality due to COVID-19 in this population., Methods: This is a retrospective analysis of administrative data extracted from the Greek nationwide database that holds the COVID-19 disease and vaccination registry, as well as all medical prescription records. The study period extended from the onset of the pandemic (February 2020) until the 10th of January 2022., Results: We identified 278 people with myasthenia gravis (mean age 58.1 ± 17.2, 47.5% males) who tested positive for SARS-CoV-2. Of those, 139 (50%) were not vaccinated at the time of infection. Multivariable binary logistic regression analysis showed that the probability of hospitalization increased with age (odds ratio [OR]: 1.058; 95% confidence interval [CI], 1.036-1.080; p < .001) and immunosuppressive treatment (OR: 2.872; 95% CI 1.412-5.839; p = .004), and decreased with vaccination (OR: 0.244; 95% CI 0.132-0.453; p < .001). The probability of a fatal outcome increased with age (OR: 1.085; 95% CI 1.043-1.129; p < .001) and decreased with vaccination (OR: 0.315; 95% CI 0.125-0.791; p = .014)., Discussion: SARS-CoV-2 vaccination significantly reduces hospitalization and mortality due to COVID-19 in people with myasthenia gravis. This study regarding the efficacy of these vaccines, together with previous studies regarding their safety, provide evidence to support their use in people with myasthenia gravis., (© 2023 Wiley Periodicals LLC.)

Defective neuritogenesis is a contributing pathogenic mechanism underlying a variety of neurodevelopmental disorders. Single gene mutations in activity-dependent neuroprotective protein (ADNP) are the most frequent among autism spectrum disorders (ASDs) leading to the ADNP syndrome. Previous studies showed that during neuritogenesis, Adnp localizes to the cytoplasm/neurites, and Adnp knockdown inhibits neuritogenesis in culture. Here, we hypothesized that Adnp is localized in the cytoplasm during neurite formation and that this process is mediated by 14-3-3. Indeed, applying the 14-3-3 inhibitor, difopein, blocked Adnp cytoplasmic localization. Furthermore, co-immunoprecipitations showed that Adnp bound 14-3-3 proteins and proteomic analysis identified several potential phosphorylation-dependent Adnp/14-3-3 binding sites. We further discovered that knockdown of Adnp using in utero electroporation of mouse layer 2/3 pyramidal neurons in the somatosensory cortex led to previously unreported changes in neurite formation beginning at P0. Defects were sustained throughout development, the most notable included increased basal dendrite number and axon length. Paralleling the observed morphological aberrations, ex vivo calcium imaging revealed that Adnp deficient neurons had greater and more frequent spontaneous calcium influx in female mice. GRAPHIC, a novel synaptic tracing technology substantiated this finding, revealing increased interhemispheric connectivity between female Adnp deficient layer 2/3 pyramidal neurons. We conclude that Adnp is localized to the cytoplasm by 14-3-3 proteins, where it regulates neurite formation, maturation, and functional cortical connectivity significantly building on our current understanding of Adnp function and the etiology of ADNP syndrome., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Technological advancements have facilitated the availability of reliable and thorough genetic analysis in many medical fields, including neurology. In this review, we focus on the importance of selecting the appropriate genetic test to aid in the accurate identification of disease utilizing currently employed technologies for analyzing monogenic neurological disorders. Moreover, the applicability of comprehensive analysis via NGS for various genetically heterogeneous neurological disorders is reviewed, revealing its efficiency in clarifying a frequently cloudy diagnostic picture and delivering a conclusive and solid diagnosis that is essential for the proper management of the patient. The feasibility and effectiveness of medical genetics in neurology require interdisciplinary cooperation among several medical specialties and geneticists, to select and perform the most relevant test according to each patient's medical history, using the most appropriate technological tools. The prerequisites for a comprehensive genetic analysis are discussed, highlighting the utility of appropriate gene selection, variant annotation, and classification. Moreover, genetic counseling and interdisciplinary collaboration could improve diagnostic yield further. Additionally, a sub-analysis is conducted on the 1,502,769 variation records with submitted interpretations in the Clinical Variation (ClinVar) database, with a focus on neurology-related genes, to clarify the value of suitable variant categorization. Finally, we review the current applications of genetic analysis in the diagnosis and personalized management of neurological patients and the advances in the research and scientific knowledge of hereditary neurological disorders that are evolving the utility of genetic analysis towards the individualization of the treatment strategy., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Nogo receptor 1 is the high affinity receptor for the potent myelin-associated inhibitory factors that make up part of the inflammatory extracellular milieu during experimental autoimmune encephalomyelitis. Signalling through the Nogo receptor 1 complex has been shown to be associated with axonal degeneration in an animal model of multiple sclerosis, and neuronal deletion of this receptor homologue, in a disease specific manner, is associated with preserving axons even in the context of neuroinflammation. The local delivery of Nogo receptor(1-310)-Fc, a therapeutic fusion protein, has been successfully applied as a treatment in animal models of spinal cord injury and glaucoma. As multiple sclerosis and experimental autoimmune encephalomyelitis exhibit large numbers of inflammatory cell infiltrates within the CNS lesions, we utilized transplantable haematopoietic stem cells as a cellular delivery method of the Nogo receptor(1-310)-Fc fusion protein. We identified CNS-infiltrating macrophages as the predominant immune-positive cell type that overexpressed myc-tagged Nogo receptor(1-310)-Fc fusion protein at the peak stage of experimental autoimmune encephalomyelitis. These differentiated phagocytes were predominant during the extensive demyelination and axonal damage, which are associated with the engulfment of the protein complex of Nogo receptor(1-310)-Fc binding to myelin ligands. Importantly, mice transplanted with haematopoietic stem cells transduced with the lentiviral vector carrying Nogo receptor(1-310)-Fc and recovered from the peak of neurological decline during experimental autoimmune encephalomyelitis, exhibiting axonal regeneration and eventual remyelination in the white matter tracts. There were no immunomodulatory effects of the transplanted, genetically modified haematopoietic stem cells on immune cell lineages of recipient female mice induced with experimental autoimmune encephalomyelitis. We propose that cellular delivery of Nogo receptor(1-310)-Fc fusion protein through genetically modified haematopoietic stem cells can modulate multifocal experimental autoimmune encephalomyelitis lesions and potentiate neurological recovery., Competing Interests: All other authors listed declare no competing financial and/or non-financial interests in relation to the work described., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background and Objectives: Rare diseases (RDs) are life-threatening or chronically impairing conditions that affect about 6% of the world's population. RDs are often called 'orphan' diseases, since people suffering from them attract little support from national health systems. Aim: The aim of this study is to describe the clinical characteristics of, and the available laboratory examinations for, patients who were hospitalized in a tertiary referral center and finally received a diagnosis associated with a Rare Neurological Disease (RND). Materials and Methods: Patients that were hospitalized in our clinic from 1 January 2014 to 31 March 2022 and were finally diagnosed with an RND were consecutively included. The RND classification was performed according to the ORPHAcode system. Results: A total of 342 out of 11.850 (2.9%) adult patients admitted to our department during this period received a diagnosis associated with an RND. The most common diagnosis (N = 80, 23%) involved an RND presenting with dementia, followed by a motor neuron disease spectrum disorder (N = 64, 18.7%). Family history indicative of an RND was present in only 21 patients (6.1%). Fifty-five (16%) people had previously been misdiagnosed with another neurological condition. The mean time delay between disease onset and diagnosis was 4.24 ± 0.41 years. Conclusions: Our data indicate that a broad spectrum of RNDs may reach a tertiary Neurological Center after a significant delay. Moreover, our data underline the need for a network of reference centers, both at a national and international level, expected to support research on the diagnosis and treatment of RND.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) with a profound neurodegenerative component early in the disease pathogenesis. Age is a factor with a well-described effect on the primary disease phenotype, namely, the relapsing-remitting vs. the primary progressive disease. Moreover, aging is a prominent factor contributing to the transition from relapsing-remitting MS (RRMS) to secondary progressive disease. However, sex also seems to, at least in part, dictate disease phenotype and evolution, as evidenced in humans and in animal models of the disease. Sex-specific gene expression profiles have recently elucidated an association with differential immunological signatures in the context of experimental disease. This review aims to summarize current knowledge stemming from experimental autoimmune encephalomyelitis (EAE) models regarding the effects of sex, either independently or as a factor combined with aging, on disease phenotype, with relevance to the immune system and the CNS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Boziki, Theotokis, Kesidou, Karafoulidou, Konstantinou, Michailidou, Bahar, Altintas and Grigoriadis.)

Background and Purpose: Multiple sclerosis (MS) is an unpredictable disease characterised by a highly variable disease onset and clinical course. Three main clinical phenotypes have been described. However, distinguishing between the two progressive forms of MS can be challenging for clinicians. This article examines how the diagnostic definitions of progressive MS impact clinical research, the design of clinical trials and, ultimately, treatment decisions., Methods: We carried out an extensive review of the literature highlighting differences in the definition of progressive forms of MS, and the importance of assessing the extent of the ongoing inflammatory component in MS when making treatment decisions., Results: Inconsistent results in phase III clinical studies of treatments for progressive MS, may be attributable to differences in patient characteristics (e.g., age, clinical and radiological activity at baseline) and endpoint definitions. In both primary and secondary progressive MS, patients who are younger and have more active disease will derive the greatest benefit from the available treatments., Conclusions: We recommend making treatment decisions based on the individual patient's pattern of disease progression, as well as functional, clinical and imaging parameters, rather than on their clinical phenotype. Because the definition of progressive MS differs across clinical studies, careful selection of eligibility criteria and study endpoints is needed for future studies in patients with progressive MS., (© 2022 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

One of the major mediators of neuroinflammation in PD is tumour necrosis factor alpha (TNF-α), which, similar to other cytokines, is produced by activated microglia and astrocytes. Although TNF-α can be neuroprotective in the brain, long-term neuroinflammation and TNF release can be harmful, having a neurotoxic role that leads to death of oligodendrocytes, astrocytes, and neurons and, therefore, is associated with neurodegeneration. Apart from cytokines, a wide family of molecules with homologous structures, namely chemokines, play a key role in neuro-inflammation by drawing cytotoxic T-lymphocytes and activating microglia. The objective of the current study was to examine the levels of the serum TNF-α and CCL2 (Chemokine (C-C motif) ligand 2), also known as MCP-1 (Monocyte Chemoattractant Protein-1), in PD patients compared with healthy controls. We also investigated the associations between the serum levels of these two inflammatory mediators and a number of clinical symptoms, in particular, disease severity and cognition. Such an assessment may point to their prognostic value and provide some treatment hints. PD patients with advanced stage on the Hoehn-Yahr scale showed an increase in TNF-α levels compared with PD patients with stages 1 and 2 ( p = 0.01). Additionally, the UPDRS score was significantly associated with TNF-α levels. CCL2 levels, however, showed no significant associations.

There is no consensus regarding the classification of optic neuritis, and precise diagnostic criteria are not available. This reality means that the diagnosis of disorders that have optic neuritis as the first manifestation can be challenging. Accurate diagnosis of optic neuritis at presentation can facilitate the timely treatment of individuals with multiple sclerosis, neuromyelitis optica spectrum disorder, or myelin oligodendrocyte glycoprotein antibody-associated disease. Epidemiological data show that, cumulatively, optic neuritis is most frequently caused by many conditions other than multiple sclerosis. Worldwide, the cause and management of optic neuritis varies with geographical location, treatment availability, and ethnic background. We have developed diagnostic criteria for optic neuritis and a classification of optic neuritis subgroups. Our diagnostic criteria are based on clinical features that permit a diagnosis of possible optic neuritis; further paraclinical tests, utilising brain, orbital, and retinal imaging, together with antibody and other protein biomarker data, can lead to a diagnosis of definite optic neuritis. Paraclinical tests can also be applied retrospectively on stored samples and historical brain or retinal scans, which will be useful for future validation studies. Our criteria have the potential to reduce the risk of misdiagnosis, provide information on optic neuritis disease course that can guide future treatment trial design, and enable physicians to judge the likelihood of a need for long-term pharmacological management, which might differ according to optic neuritis subgroups., Competing Interests: Declaration of interests AP received grant support for remyelination trials in multiple sclerosis to the Amsterdam University Medical Centre, Department of Neurology, MS Centre (RESTORE trial), and UCL, London RECOVER trial; received grant fees from Fight for Sight (nimodipine in optic neuritis trial); received royalties or licenses from Up-to-Date (Wolters Kluwer) for a book chapter; received speaker fees for the Heidelberg Academy; participates on advisory board for SC Zeiss OCTA Angi-Network, and the SC Novartis OCTiMS study; holds leadership roles for governing board IMSVISUAL; was chairman of ERN-EYE Neuro-ophthalmology (until Oct, 2020); is board member of National Dutch Neuro-ophthalmology Association; received equipment from OCTA from Zeiss (Plex Elite); and received medical writing support from Novartis for a manuscript (https://doi.org/10.1002/acn3.51473). CF received consulting fees from Invex Therapeutics; received speaker honoraria from University of Dunedin; and holds leadership as Director of Royal Australian and New Zealand College of Ophthalmologists. VB received personal fees as consultant for Gensight and Neurophoenix. PC obtained grants from Annexon, Biogen, Genentech; received royalties from Cambridge Press for an OCT book; received consulting fees from Disarm Therapeutics, Nervgen, Biogen, Avidea; received honoraria from NY Academy of Sciences; and received equipment from Myelin Repair Foundation, Academic CME, Neuraly, and Landos. FC received speaker honoraria from Alexion, Accure Therapeutics, and the Sumiara Foundation. RDe obtained consulting fees from Alexion. JdS received consulting fees from Biogen, Teva, BMS Celegen, Roche, Novartis, Janssen, Merck, Alexion, CSL Behring; and honoraria from Biogen, Teva, BMS Celegen, Roche, Novartis, Janssen, Merck, Alexion, and CSL Behring. JFR received consulting fees from Roche, and Sanofi. EF holds honoraria from Alexion, Genzyme, Biogen, Novartis, and Janssen. TF holds honoraria from Alexion. CFT received honoraria from Novartis; and received support for attending meetings and travel from Novartis and Teva. KF obtained grants from Ministry of Education, Science and Technology of Japan as well as the Ministry of Health, Welfare and Labor of Japan; received consulting fees from Alexion Chugai-Roche Mitsubishi Tanabe, Novartis, Biogen, Eisai, Takeda, Teijin, Viela Bio, UCB, Merck, Japan Tobacco Pharma, and Abbvie; received honoraria from Alexion, Chugai-Roche, Mitsubishi Tanabe, Novartis, Biogen, Eisai, Takeda, Asahi Kasei Medical, Teijin, and Bayer; participated on a data safety monitoring board or advisory board from Alexion, Chugai, Mitsubishi Tanabe, Novartis, Biogen, Eisai, Takeda, Asahi Kasei Medical, Teijin, UCB, and Viela Bio; and received medical writing support from Oxford PharmaGenesis and Apothecom. RG acquired personal fees for participation on data safety monitoring boards, and served on the advisory boards for Biogen, Hikma, Merck, Roche, and Sanofi as well as receiving a grant from Roche. FG received grants or contracts from Roche (NMO epidemiologic studies) and Novartis (MS epidemiologic studies); received honoraria from for lectures from Roche, Novartis, Stendhal, and Merck; received support for attending meetings from the European Charcot Foundation, and ECTRIMS; and reports leadership of FOCEM (Foro Centroamericano y del Caribe de la Esclerosis Múltiple y otras enfermedades desmielinizantes del Sistema Nervioso Central) and Academia Panameña de Medicina y Cirugía (both unpaid). MHab obtained honoraria from Biogen, Sanofi Genzyme, Merck, Bayer, Novartis, Pliva-Teva, Roche, and Zentiva; received support for attending meetings from Biogen, Sanofi Genzyme, Merck, Bayer, Novartis, Pliva-Teva, and Roche; and participated on advisory board for Biogen, Sanofi Genzyme, Merck, Bayer, Novartis, Pliva-Teva, and Roche. ZIl obtained grants or contracts from Biogen and Alexion; received honoraria from Biogen, Novartis, Roche, Merck, and Alexion; received payment for expert testimony from Roche; received support for attending meetings and travel from Biogen and Sanofi; and participated on a data safety monitoring board or advisory board from Biogen, Novartis, Merck, Sanofi, Roche, and Alexion. HJK received grants or contracts from National Research Foundation of Korea, Aprilbio, and Eisai; received consulting fees from Aprilbio, Daewoong, HanAll BioPharma, MDimune, Roche, Sanofi Genzyme, Teva-Handok, UCB, and Viela Bio; and received honoraria from Alexion, Biogen, Celltrion, Eisai, GC Pharma, Merck Serono, Novartis, Sanofi Genzyme, and Teva-Handok. RM received consulting fees from UCB, Alexion, Merck, Viela Bio, Novartis, and Roche; and participated on an advisory board for Viela Bio and Roche. FP obtained research support from Alexion; received grants or contracts from German Ministry for Research Support Recipient Charité Education and Research (BMBF), Deutsche Forschungsgemeinschaft (DFG), Einstein Foundation, Guthy Jackson Charitable Foundation, EU FP7 Framework Program, Biogen, Genzyme, Merck, Serono, Novartis, Bayer, Roche, Parexel, and Almirall; received honoraria from the Guthy Jackson Foundation, Bayer, Biogen, Merck Serono, Sanofi Genzyme, Novartis, Viela Bio, Roche, UCB, Mitsubishi Tanabe, and Celgene; received support for attending meetings from Guthy Jackson Foundation, Bayer, Biogen, Merck Serono, Sanofi Genzyme, Novartis, Alexion, Viela Bio, Roche, UCB, Mitsubishi Tanabe, and Celgene; participated on an advisory board for Celgene, Roche, UCB, Merck; and reports leadership as academic editor for Plos One, and associate editor for Neurology, Neuroimmunology, and Neuroinflammation. MBR received support for attending meeting from Novartis. BSD received consulting fees from Chiesi; received honoraria from Chiesi and Sanofi; received support for attending meetings from Bausch + Lomb; participated on an advisory board for Chiesi; and has stock options from Accure Therapeutics. DS received grants or contracts from National Institute of Neurological Disorders and Stroke (NINDS), National Institute of Mental Health (NIMH), American Academy of Neurology (AAN), National Institute of Aging (NIA), National Multiple Sclerosis Society (NMSS), and United States Department of State; and was a committee member for Multiple Sclerosis International Federation (MSIF) and American Neurological Association (ANA). AS received grants or contracts from the Turkish MS society, and Istanbul University Research Support Grants; received consulting fees from Roche, Merck Serono, Biogen, Gen Pharma of Türkiye, Sanofi Genzyme, and Novartis; received honoraria from Sanofi Genzyme, Novartis, Roche, and Teva; and received support for attending meetings from Sanofi Genzyme. VvP obtained grants or contracts from Biogen; received consulting fees from Biogen, Merck, Sanofi, BMS, Novartis, Janssen, Almirall, and Roche; received honoraria from Biogen, Merck, Sanofi, BMS, Novartis, Roche; and received support for attending meetings from Biogen, Roche, and Almirall. MPW received royalties from Springer Healthcare and Elsevier; received consulting fees from Biogen, Roche, Biologix, Novartis, BMS-Celgene, Imcyse, Merck Serono, Sanofi Aventis, IXICO, and Icometrix; received honoraria from Bayer, Biogen, Biologix, Genilac, Novartis, Medison, Merck Serono, Roche, Sanofi Aventis, and BMS-Celgene; and participated on a data safety monitoring board for VU University Medical Center. LB received consulting fees as editor for the Journal of Neuro-Ophthalmology. GTP is an Emeritus editor for Neuro-ophthalmology. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Competing Interests: The authors report no conflict of interest.

Current therapeutics targeting chronic phases of multiple sclerosis (MS) are considerably limited in reversing the neural damage resulting from repeated inflammation and demyelination insults in the multi-focal lesions. This inflammation is propagated by the activation of microglia, the endogenous immune cell aiding in the central nervous system homeostasis. Activated microglia may transition into polarized phenotypes; namely, the classically activated proinflammatory phenotype (previously categorized as M1) and the alternatively activated anti-inflammatory phenotype (previously, M2). These transitional microglial phenotypes are dynamic states, existing as a continuum. Shifting microglial polarization to an anti-inflammatory status may be a potential therapeutic strategy that can be harnessed to limit neuroinflammation and further neurodegeneration in MS. Our research has observed that the obstruction of signaling by inhibitory myelin proteins such as myelin-associated inhibitory factor, Nogo-A, with its receptor (NgR), can regulate microglial cell function and activity in pre-clinical animal studies. Our review explores the microglial role and polarization in MS pathology. Additionally, the potential therapeutics of targeting Nogo-A/NgR cellular mechanisms on microglia migration, polarization and phagocytosis for neurorepair in MS and other demyelination diseases will be discussed.

Biomarker research across the health-to-disease continuum is being increasingly applied. We applied blood-based metabolomics in order to identify patient clusters with a first demyelinating episode, and explored the prognostic potential of the method by thoroughly characterizing each cluster in terms of clinical, laboratory and MRI markers of established prognostic potential for Multiple Sclerosis (MS). Recruitment consisted of 11 patients with Clinically Isolated Syndrome (CIS), 37 patients with a first demyelinating episode in the context of Relapsing-Remitting MS (RRMS) and 11 control participants. Blood-based metabolomics and hierarchical clustering analysis (HCL) were applied. Constructed OPLS-DA models illustrated a discrimination between patients with CIS and the controls (p = 0.0014), as well as between patients with RRMS and the controls (p = 1 × 10−5). Hierarchical clustering analysis (HCL) for patients with RRMS identified three clusters. RRMS-patients-cluster-3 exhibited higher mean cell numbers in the Cerebro-spinal Fluid (CSF) compared to patients with CIS (18.17 ± 6.3 vs. 1.09 ± 0.41, p = 0.004). Mean glucose CSF/serum ratio and infratentorial lesion burden significantly differed across CIS- and HCL-derived RRMS-patient clusters (F = 14.95, p < 0.001 and F = 6.087, p = 0.002, respectively), mainly due to increased mean values for patients with RRMS-cluster-3. HCL discriminated a cluster of patients with a first demyelinating episode in the context of RRMS with increased disability, laboratory findings linked with increased pathology burden and MRI markers of poor prognosis.

RNA editing is an epitranscriptomic modification, leading to targeted changes in RNA transcripts. It is mediated by the action of ADAR (adenosine deaminases acting on double-stranded (ds) RNA and APOBEC (apolipoprotein B mRNA editing enzyme catalytic polypeptide-like) deaminases and appears to play a major role in the pathogenesis of many diseases. Here, we assessed its role in experimental autoimmune encephalomyelitis (EAE), a widely used non-clinical model of autoimmune inflammatory diseases of the central nervous system (CNS), which resembles many aspects of human multiple sclerosis (MS). We have analyzed in silico data from microglia isolated at different timepoints through disease progression to identify the global editing events and validated the selected targets in murine tissue samples. To further evaluate the functional role of RNA editing, we induced EAE in transgenic animals lacking expression of APOBEC-1. We found that RNA-editing events, mediated by the APOBEC and ADAR deaminases, are significantly reduced throughout the course of disease, possibly affecting the protein expression necessary for normal neurological function. Moreover, the severity of the EAE model was significantly higher in APOBEC-1 knock-out mice, compared to wild-type controls. Our results implicate regulatory epitranscriptomic mechanisms in EAE pathogenesis that could be extrapolated to MS and other neurodegenerative disorders (NDs) with common clinical and molecular features.

Objectives: To assess the effectiveness of Neuroaspis plp10 nutritional supplement when added to interferon (IFN)-β treatment in patients with relapsing-remitting multiple sclerosis (RRMS)., Design: A 30-month phase III multicentre, randomised, double-blind, placebo-controlled trial. Randomisation stratified by centre using a computer-generated procedure with Neuroaspis plp10 versus placebo in 1:1 ratio. The first 6 months were used as both the pre-entry and normalisation period., Setting: 3 teaching hospitals in Greece and 1 Neurology Institute in Cyprus., Participants: 61 patients with RRMS on IFN-β were randomly assigned to receive Neuroaspis plp10 (n=32) or placebo (n=29), 20 mL, orally, once daily, for 30 months., Intervention: Neuroaspis plp10, a cocktail mixture, containing specific PUFA (12 150 mg) and γ-tocopherol (760 mg) versus virgin olive oil (placebo)., Main Outcome Measure: The primary end point was the annual relapse rate (ARR) whereas the secondary ones were the rate of sustained progression of disability, as measured by the Expanded Disability Status Scale (EDSS) and the brain T2 and gadolinium-enhancing lesions, at 2 years., Results: For the intention-to-treat analyses Neuroaspis plp10 significantly reduced the ARR by 80%, (RRR, 0.20; 95% CI: 0.09 to 0.45; p=0.0001) and the risk of sustained progression of disability by 73% (HR, 0.27; 95% CI: 0.09 to 0.83; p=0.022) versus placebo, at 2 years. The number of T1 gadolinium-enhancing lesions and the number of new/enlarged T2-hyperintense lesions were significantly reduced (p=0.01 and p<0.0001, respectively). Both T1-enhancing and new/enlarging T2-hyperintense lesions were significantly reduced (p=0.05 and p<0.0001, respectively). No significant adverse events were reported., Conclusions: Neuroaspis plp10 added to IFN-β was significantly more effective than IFN-β alone in patients with RRMS., Trial Registration Number: ISRCTN06166891., Competing Interests: Competing interests: MCP, GL, IP received grand support from the Cyprus Ministry of Energy, Commerce, Industry and Tourism—Structural Funds Program (Creation of New High Technology and Innovation Enterprises). PALUPA Medical is a research company formed and registered under the Incubator program. MCP, GL and IP are stockholders of PALUPA Medical. MAR received speaker honoraria from Bayer, Biogen, Bristol Myers Squibb, Celgene, Genzyme, Merck Serono, Novartis, Roche and Teva, and receives research support from the MS Society of Canada and Fondazione Italiana Sclerosi Multipla. NG received speaker honoraria from Bayer, Biogen, Gensis Pharma, Celgene, Sanofi, Merck, Novartis, Roche and Teva, and receives research support from Biogen and TEVA. CB received travel support and/or lecture fees from Novartis, Merck, Genesis, Sanofi, Teva, Roche and Mylan. GH, ED, EN, GM, SO, PV, RM and PP declare no competing interests. No pharmaceutical companies were involved in this project. The intervention, trade marked as Neuroaspis plp10, is under a US patent application, and covered with granted patent in several other countries including Canada, Japan, China, Ukraine, Australia, Israel and New Zealand., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The mechanisms by which exercise training (ET) elicits beneficial effects on the systemic immune system and the central nervous system (CNS) in autoimmune neuroinflammation are not fully understood., Objectives: To investigate (1) the systemic effects of high-intensity continuous training (HICT) on the migratory potential of autoimmune cells; (2) the direct effects of HICT on blood-brain-barrier (BBB) properties., Methods: Healthy mice were subjected to high-intensity continuous training (HICT) by treadmill running. The proteolipid protein (PLP) transfer EAE model was utilized to examine the immunomodulatory effects of training, where PLP-reactive lymph-node cells (LNCs) from HICT and sedentary donor mice were analyzed in vitro and transferred to naïve recipients that developed EAE. To examine neuroprotection, encephalitogenic LNCs from donor mice were transferred into HICT or sedentary recipient mice and the BBB was analyzed., Results: Transfer of PLP-reactive LNCs obtained from HICT donor mice attenuated EAE severity and inflammation in recipient mice. HICT markedly inhibited very late antigen (VLA)-4 and lymphocyte function-associated antigen (LFA)-1 expression in LNCs. Transfer of encephalitogenic LNCs into HICT recipients resulted in milder EAE and attenuated CNS inflammation. HICT reduced BBB permeability and the expression of intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 in CNS blood vessels., Interpretation: HICT attenuates EAE development by both immunomodulatory and neuroprotective effects. The reduction in destructive CNS inflammation in EAE is attributed to systemic inhibition of autoreactive cell migratory potential, as well as reduction in BBB permeability, which are associated with reduced VLA-4/VCAM-1 and LFA-1/ICAM-1 interactions., (© 2022 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Carotid atherosclerosis is a major cause for stroke, with significant associated disease burden morbidity and mortality in Western societies. Diagnosis, grading and follow-up of carotid atherosclerotic disease relies on imaging, specifically ultrasound (US) as the initial modality of choice. Traditionally, the degree of carotid lumen stenosis was considered the sole risk factor to predict brain ischemia. However, modern research has shown that a variety of other imaging biomarkers, such as plaque echogenicity, surface morphology, intraplaque neovascularization and vasa vasorum contribute to the risk for rupture of carotid atheromas with subsequent cerebrovascular events. Furthermore, the majority of embolic strokes of undetermined origin are probably arteriogenic and are associated with nonstenosing atheromas. Therefore, a state-of-the-art US scan of the carotid arteries should take advantage of recent technical developments and should provide detailed information about potential thrombogenic (/) and emboligenic arterial wall features. This manuscript reviews recent advances in ultrasonographic assessment of vulnerable carotid atherosclerotic plaques and highlights the fields of future development in multiparametric arterial wall imaging, in an attempt to convey the most important take-home messages for clinicians performing carotid ultrasound.

It has been over a year since people with multiple sclerosis (pwMS) have been receiving vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). With a negligible number of cases in which vaccination led to a relapse or new onset MS, experts around the world agree that the potential consequences of COVID-19 in pwMS by far outweigh the risks of vaccination. This article reviews the currently available types of anti-SARS-CoV-2 vaccines and the immune responses they elicit in pwMS treated with different DMTs. Findings to date highlight the importance of vaccine timing in relation to DMT dosing to maximize protection, and of encouraging pwMS to get booster doses when offered., Competing Interests: MP has received honoraria, consulting fees or travelling costs from Bayer, Biogen, Sanofi-Genzyme, Teva, Merck and Almirall. CO-G has received speaker and consultation fees from Biogen Idec, Celgene, Sanofi-Genzyme, Novartis, Roche, Merck and Teva. CP has served on scientific advisory boards for Novartis, Merck, Biogen, Bristol Myers Squibb, Roche, Janssen, Alexion, has received funding for travel and speaker honoraria from Merck, Biogen, Bristol Myers Squibb, Roche, Almirall, Janssen, Alexion and Novartis, and receives research support from Merck, Biogen, Novartis, Roche and Almirall. LA has received institutional research support from Novartis, Genzyme and Merck, and compensation for lectures and consulting fees from Novartis, Sanofi Genzyme, Merck, Biogen, Roche and Janssen. MA has received speaker honoraria, consulting fees, and/or educational travel support from Biogen, Merck, Sanofi-Genzyme, Roche, Novartis, Hikma and SAJA. NG has received honoraria and travel support, consultancy and lecture fees from Biogen Idec, Biologix, Novartis, Teva, Bayer, Merck Serono, Genesis Pharma, Sanofi – Genzyme, Roche, Elpen. He has also received research grants from Biogen Idec, Novartis, Teva, Merck Serono, Genesis Pharma, Sanofi – Genzyme and Roche. MM has served on scientific advisory boards for Sanofi, Novartis and Merck. She has received honoraria for lecturing from Biogen, Merck, Novartis, Roche, Genzyme and BMS. BW has received Research and Travel Grants, Honoraria for MS-Expert Advice and Speakers Fees from: Almirall, Actelion/Janssen, Bayer, Biogen, Celgene/BMS, Merck, Novartis, Roche, Sanofi-Genzyme and Teva. AC has received speakers’/board honoraria from Actelion (Janssen/J&J), Almirall, Bayer, Biogen, Celgene (BMS), Genzyme, Merck KGaA (Darmstadt, Germany), Novartis, Roche, and Teva, all for hospital research funds. He received research support from Biogen, Genzyme, and UCB, the European Union, and the Swiss National Foundation. PV has received honoraria and consulting fees from Biogen, Sanofi-Genzyme, Novartis, Teva, Merck, Roche, Imcyse, AB Science and BMS-Celgene. He also receives research support from Novartis, Sanofi-Genzyme and Roche. TB has received honoraria and consulting fees from Almirall, Bayer, Biogen, Biologix, Bionorica, Celgene/BMS, GSK, GW/Jazz Pharma, Horizon, MedDay, Merck, Novartis, Octapharma, Roche, Sandoz, Sanofi-Genzyme, TEVA, TG Therapeutics and UCB. He has received institutional research support from Almirall, Biogen, Bayer, Celgene/BMS, Merck, Novartis, Roche, Sanofi-Genzyme and Teva, and has participated in clinical trials sponsored by Alexion, Bayer, Biogen, Celgene/BMS, Merck, Novartis, Octapharma, Roche, Sanofi-Genzyme and Teva. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest., (Copyright © 2022 Pugliatti, Hartung, Oreja-Guevara, Pozzilli, Airas, Alkhawajah, Grigoriadis, Magyari, Van Wijmeersch, Zakaria, Linker, Chan, Vermersch and Berger.)

Background: Peripheral neuropathy is among the most common complications among people with HIV with prevalence rates varying widely among studies (10-58%)., Objective: This study aims to assess the prevalence of HIV-associated peripheral neuropathy among HIV-positive people in Northern Greece monitored during the last 5-year period and investigate possible correlations with antiretroviral therapy, disease staging, and potential risk factors, as there is no prior epidemiological record in Greek patients., Methods: Four hundred twenty patients were divided into a group with peripheral neuropathy ( n = 269), and those without ( n = 151). Peripheral neuropathy was assessed with a validated Peripheral Neuropathy Screening tool. Statistical analyses were performed with SPSS, were two-tailed, and p -value was set at 0.05., Results: The incidence of peripheral neuropathy was estimated at 35.9%. Age was found to correlate with higher odds of developing HIV-peripheral neuropathy, rising by 4%/year. Females encountered 77% higher probability to develop peripheral neuropathy. Stage 3 of the disease associated with higher occurrence of peripheral neuropathy (96% as compared to stage-1 patients). Among patients with peripheral neuropathy, the duration of antiretroviral therapy was found to be longer than in those without., Conclusions: Peripheral neuropathy remains one of the most common complications regardless of the antiretroviral-therapy type, indicating the involvement of other risk factors in its occurrence, such as the stage of the disease, age and gender. Therefore, the treating physician should screen patients as early and frequently as possible upon HIV-diagnosis to prevent the progression of this debilitating condition so that prolonged life-expectancy is accompanied by a good quality of life.

The clinical course of multiple sclerosis (MS) is highly variable among patients, thus creating important challenges for the neurologist to appropriately treat and monitor patient progress. Despite some patients having apparently similar symptom severity at MS disease onset, their prognoses may differ greatly. To this end, we believe that a proactive disposition on the part of the neurologist to identify prognostic "red flags" early in the disease course can lead to much better long-term outcomes for the patient in terms of reduced disability and improved quality of life. Here, we present a prognosis tool in the form of a checklist of clinical, imaging and biomarker parameters which, based on consensus in the literature and on our own clinical experiences, we have established to be associated with poorer or improved clinical outcomes. The neurologist is encouraged to use this tool to identify the presence or absence of specific variables in individual patients at disease onset and thereby implement sufficiently effective treatment strategies that appropriately address the likely prognosis for each patient., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Van Wijmeersch, Hartung, Vermersch, Pugliatti, Pozzilli, Grigoriadis, Alkhawajah, Airas, Linker and Oreja-Guevara.)

Multiple sclerosis (MS) is a heterogeneous autoimmune disease whereby the pathological sequelae evolve from oligodendrocytes (OLs) within the central nervous system and are targeted by the immune system, which causes widespread white matter pathology and results in neuronal dysfunction and neurological impairment. The progression of this disease is facilitated by a failure in remyelination following chronic demyelination. One mediator of remyelination is thyroid hormone (TH), whose reliance on monocarboxylate transporter 8 (MCT8) was recently defined. MCT8 facilitates the entry of THs into oligodendrocyte progenitor cell (OPC) and pre-myelinating oligodendrocytes (pre-OLs). Patients with MS may exhibit downregulated MCT8 near inflammatory lesions, which emphasizes an inhibition of TH signaling and subsequent downstream targeted pathways such as phosphoinositide 3-kinase (PI3K)-Akt. However, the role of the closely related mammalian target of rapamycin (mTOR) in pre-OLs during neuroinflammation may also be central to the remyelination process and is governed by various growth promoting signals. Recent research indicates that this may be reliant on TH-dependent signaling through β1-integrins. This review identifies genomic and non-genomic signaling that is regulated through mTOR in TH-responsive pre-OLs and mature OLs in mouse models of MS. This review critiques data that implicates non-genomic Akt and mTOR signaling in response to TH-dependent integrin receptor activation in pre-OLs. We have also examined whether this can drive remyelination in the context of neuroinflammation and associated sequelae. Importantly, we outline how novel therapeutic small molecules are being designed to target integrin receptors on oligodendroglial lineage cells and whether these are viable therapeutic options for future use in clinical trials for MS., Competing Interests: SP is the founder and Chief Scientific Officer of the start-up company NeuOrphan Pty Ltd. (currently 50% shareholder) that will be commercializing the development of DITPA-like molecules in collaboration with Monash University. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Emamnejad, Dass, Mahlis, Bozkurt, Ye, Pagnin, Theotokis, Grigoriadis and Petratos.)

Existing data suggest that people with multiple sclerosis (pwMS) are at an elevated risk for experiencing olfactory impairment. We investigated if smell dysfunction can be used as an MS disease marker. This is a cross-sectional, case−control study. All data were collected prospectively from 171 participants, 115 pwMS and 56 controls (age and sex stratified and matched to the patients), who reported smell, taste, and nasal breathing, and completed the Greek-validated questionnaires for nasal obstruction (NOSE), nasal-symptoms QoL (SNOT-22), and olfaction-associated QoL (QOD). The smell was assessed with the “Sniffin’ sticks” (odor threshold (OT), discrimination (OD), identification (OI) test, and total TDI). We recorded the pwMS disease characteristics (Expanded Disability Status Scale-EDSS, the disease type and duration), cognitive function, emotional status, fatigue, and impact of MS in everyday activities. A TDI < 30.75 (hyposmia) was detected in 30.8% of the patients. The patients’ OD and TDI scores were significantly lower than the controls’ (p = 0.005, and 0.015, respectively). The hyposmia correlated with disease severity and duration. The EDSS score correlated negatively with OD (r = −0.299, p = 0.001) and TDI (r = −0.242, p = 0.01). The disease duration correlated negatively with OD (r = −0.305, p = 0.001, OI (r = −0.253, p = 0.008) and TDI (r = −0.3, p = 0.001). The information processing speed (SDMT) correlated with OD, OT, and TDI (r = 0.302, p = 0.002; r = 0.242, p = 0.016; r = 0.326, p = 0.001). The olfactory function is changing in MS in accordance with disease progression.

Introduction: Multiple sclerosis (MS) is a highly heterogeneous inflammatory disease of the central nervous system. Patient-reported outcomes (PROs) in a real-world clinical setting can provide detailed information about MS from the patient's perspective. PROs were used here to assess quality of life (QoL), treatment satisfaction, clinical efficacy, and safety outcomes in a Greek cohort of relapsing remitting MS (RRMS) patients treated with oral teriflunomide (14 mg/day)., Methods: AURELIO was a 2-year, prospective, observational study whose QoL primary endpoint was assessed with the Multiple Sclerosis Impact Scale (MSIS-29). Secondary endpoints included analyses of Patient Determined Disease Steps (PDDS), Treatment Satisfaction Questionnaire for Medication (TSQM), Expanded Disability Status Scale (EDSS), annualized relapse rate (ARR), adherence, and safety outcomes., Results: AURELIO enrolled 282 patients (62.8% female; mean age 44.8 [SD ± 11] years; EDSS 2.0 [SD ± 1.6]; 44.6% treatment-naïve), with 212 patients (75%) remaining on treatment at study end. MSIS-29 total scores remained stable, while the MSIS-29 psychological scale showed significant improvement (p = 0.0015) at 2 years vs. baseline. TSQM scores at 2 years showed significant improvements in effectiveness (+ 6.6, p = 0.0001), convenience (+ 1.9, p = 0.0256), and global satisfaction (+ 8.1, p = 0.0001) vs. baseline. Disease progression was stable as indicated by non-significant changes in PDDS and EDSS vs. baseline. The ARR was low at 0.065, with a slightly higher ARR in previously treated (0.070) vs. naïve patients (0.058). Adherence was high at > 90%. Overall, 91 patients (32.3%) in the study reported a total of 215 safety events (32 serious, of which 21 were classified as mild-moderate). No new safety signals were observed., Conclusions: These data highlight the importance of PROs to facilitate personalized treatment strategies in MS. In line with other teriflunomide studies, AURELIO showed stable QoL, efficacy and safety outcomes, and good treatment satisfaction both in treatment-naïve and previously treated patients in this Greek cohort of patients with RRMS., (© 2022. The Author(s).)

Multiple sclerosis (MS) is an inflammatory and neurodegenerative, potentially disabling disease of the central nervous system. OCT (Optical Coherence Tomography) and OCT-A (Optical Coherence Tomography with Angiography) are imaging techniques for the retina and choroid that are used in the diagnosis and monitoring of ophthalmological conditions. Their use has recently expanded the study of several autoimmune disorders, including MS. Although their application in MS remains unclear, the results seem promising. This review aimed to provide insight into the most recent OCT and OCT-A findings in MS and may function as a reference point for future research. According to the current literature, the retinal nerve fibre layer (RNFL) and ganglion cell-inner plexiform complex (GC-IPL) are significantly reduced in people with MS and are inversely correlated with disease duration. The use of OCT might help distinguish between MS and neuromyelitis optica spectrum disorders (NMOSD), as the latter presents with more pronounced thinning in both the RNFL and GC-IPL. The OCT-A findings in MS include reduced vessel density in the macula, peripapillary area, or both, and the enlargement of the foveal avascular zone (FAZ) in the setting of optic neuritis. Additionally, OCT-A might be able to detect damage in the very early stages of the disease as well as disease progression in severe cases.

The mammalian central nervous system (CNS) coordinates its communication through saltatory conduction, facilitated by myelin-forming oligodendrocytes (OLs). Despite the fact that neurogenesis from stem cell niches has caught the majority of attention in recent years, oligodendrogenesis and, more specifically, the molecular underpinnings behind OL-dependent myelinogenesis, remain largely unknown. In this comprehensive review, we determine the developmental cues and molecular drivers which regulate normal myelination both at the prenatal and postnatal periods. We have indexed the individual stages of myelinogenesis sequentially; from the initiation of oligodendrocyte precursor cells, including migration and proliferation, to first contact with the axon that enlists positive and negative regulators for myelination, until the ultimate maintenance of the axon ensheathment and myelin growth. Here, we highlight multiple developmental pathways that are key to successful myelin formation and define the molecular pathways that can potentially be targets for pharmacological interventions in a variety of neurological disorders that exhibit demyelination.

Experimental autoimmune encephalomyelitis (EAE) is a basic and reliable model used to study clinical and pathological hallmarks of multiple sclerosis (MS) in rodents. Several studies suggest neural precursor cells (NPCs) as a significant research tool while reporting that transplanted NPCs are a promising therapeutic approach to treating neurological disorders, such as MS. The main objective was to approach a preclinical, in vivo scenario of oligodendrogenesis with NPCs, targeting the main chronic demyelinated lumbosacral milieu of EAE, via the least invasive delivery method which is lumbar puncture. We utilized MOG 35-55 peptide to induce EAE in C57BL/6 mice and prior to the acute relapse, we intervened with either the traceable GFP + cellular therapy or saline solution in the intrathecal space of their lumbar spine. A BrdU injection, which enabled us to monitor endogenous proliferation, marked the endpoint 50 days post-induction (50 dpi). Neuropathology with high-throughput, triple immunofluorescent, and transmission electron microscopy (TEM) data were extracted and analyzed. The experimental treatment attenuated the chronic phase of EAE (50 dpi; score <1) following an acute, clinical relapse. Myelination and axonal integrity were rescued in the NPC-treated animals along with suppressed immune populations. The differentiation profile of the exogenous NPCs and endogenous BrdU + cells was location-dependent where GFP + -rich areas drove undifferentiated phenotypes toward the oligodendrocyte lineage. In situ oligodendrocyte enrichment was demonstrated through increased (p < 0.001) gap junction channels of Cx32 and Cx47, reliable markers for proliferative oligodendroglia syncytium. TEM morphometric analysis ultimately manifested an increased g-ratio in lumbosacral fibers of the recovered animals (p < 0.001). Herein, we suggest that a single, lumbar intrathecal administration of NPCs capacitated a viable cellular load and resulted in clinical and pathological amelioration, stimulating resident OPCs to overcome the remyelination failure in EAE demyelinating locale., (© 2021 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology.)

Background: ADNP is essential for embryonic development. As such, de novo ADNP mutations lead to an intractable autism/intellectual disability syndrome requiring investigation., Methods: Mimicking humans, CRISPR (clustered regularly interspaced short palindromic repeats)-Cas9 editing produced mice carrying heterozygous Adnp p.Tyr718∗ (Tyr), a paralog of the most common ADNP syndrome mutation. Phenotypic rescue was validated by treatment with the microtubule/autophagy-protective ADNP fragment NAPVSIPQ (NAP)., Results: RNA sequencing of spleens, representing a peripheral biomarker source, revealed Tyr-specific sex differences (e.g., cell cycle), accentuated in females (with significant effects on antigen processing and cellular senescence) and corrected by NAP. Differentially expressed, NAP-correctable transcripts, including the autophagy and microbiome resilience-linked FOXO3, were also deregulated in human patient-derived ADNP-mutated lymphoblastoid cells. There were also Tyr sex-specific microbiota signatures. Phenotypically, Tyr mice, similar to patients with ADNP syndrome, exhibited delayed development coupled with sex-dependent gait defects. Speech acquisition delays paralleled sex-specific mouse syntax abnormalities. Anatomically, dendritic spine densities/morphologies were decreased with NAP amelioration. These findings were replicated in the Adnp +/- mouse, including Foxo3 deregulation, required for dendritic spine formation. Grooming duration and nociception threshold (autistic traits) were significantly affected only in males. Early-onset tauopathy was accentuated in males (hippocampus and visual cortex), mimicking humans, and was paralleled by impaired visual evoked potentials and correction by acute NAP treatment., Conclusions: Tyr mice model ADNP syndrome pathology. The newly discovered ADNP/NAP target FOXO3 controls the autophagy initiator LC3 (microtubule-associated protein 1 light chain 3), with known ADNP binding to LC3 augmented by NAP, protecting against tauopathy. NAP amelioration attests to specificity, with potential for drug development targeting accessible biomarkers., (Copyright © 2021 Society of Biological Psychiatry. All rights reserved.)

Ocrelizumab is a B-cell-depleting monoclonal antibody approved for the treatment of relapsing-remitting multiple sclerosis (RRMS) and active primary progressive MS (aPPMS). This prospective, uncontrolled, open-label, observational study aimed to assess the efficacy of ocrelizumab in patients with aPPMS and to dissect the clinical, radiological and laboratory attributes of treatment response. In total, 22 patients with aPPMS followed for 24 months were included. The primary efficacy outcome was the proportion of patients with optimal response at 24 months, defined as patients free of relapses, free of confirmed disability accumulation (CDA) and free of T1 Gd-enhancing lesions and new/enlarging T2 lesions on the brain and cervical MRI. In total, 14 (63.6%) patients and 13 patients (59.1%) were classified as responders at 12 and 24 months, respectively. Time exhibited a significant effect on mean absolute and normalized gray matter cerebellar volume (F = 4.342, p = 0.23 and F = 4.279, p = 0.024, respectively). Responders at 24 months exhibited reduced peripheral blood ((%) of CD19+ cells) plasmablasts compared to non-responders at the 6-month point estimate (7.69 ± 4.4 vs. 22.66 ± 7.19, respectively, p = 0.043). Response to ocrelizumab was linked to lower total and gray matter cerebellar volume loss over time. Reduced plasmablast depletion was linked for the first time to sub-optimal response to ocrelizumab in aPPMS.

Objective : Cognitive screening instruments (CSIs) are essential for everyday practice. The Quick Mild Cognitive Impairment (Qmci) screen, a short instrument designed to identify mild cognitive impairment, was recently translated into Greek (Qmci-Gr). The present study compared its diagnostic value against the Montreal Cognitive Assessment (MoCA) screen and examined its optimal cutoffs. Method : We recruited consecutive patients aged ≥55 years that presented with cognitive complaints from two outpatient clinics in Greece. The Q mci -Gr and MoCA were completed by all patients. Furthermore, they were assessed independently with a comprehensive flexible neuropsychological battery to establish a diagnostic classification. Results : In the current study, we assessed a total of 145 patients, with a median age of 70 years; 44 were classified as having Subjective Memory Complaints (SMC) but normal cognition, 32 with MCI and 69 with dementia. The Qmci-Gr had a higher accuracy compared to the MoCA in discriminating MCI from dementia, area under the curve (AUC) of 0.81 versus 0.75, respectively; however, this finding was marginally significant ( p = 0.08). Its accuracy was marginally higher for distinguishing SMC from dementia, AUC of 0.94 versus 0.89 ( p = 0.03). However, Qmci-Gr presented a lower accuracy than MoCa in differentiating SMC from MCI, AUC of 0.76 versus 0.94 ( p = 0.006). Conclusions : The Qmci-Gr has comparable diagnostic accuracy to the MoCA regarding MCI and dementia groups. Further research, with larger and more diverse samples, may be necessary to ensure generalizability.

Objective: Cognitive dysfunction is common in multiple sclerosis (MS). The Brief International Cognitive Assessment for MS (BICAMS) battery of tests has been suggested as a measure for the evaluation of the cognitive status of MS patients. This study aims to validate the BICAMS battery in the Russian population of MS patients., Methods: Age- and sex-matched MS patients (n = 98) and healthy individuals (n = 86) were included in the study. Symbol Digit Modalities Test (SDMT), California Verbal Learning Test, 2nd edition (CVLT-II) and the Brief Visuospatial Memory Test - Revised (BVMT-R) were administered to all participants. The battery was readministered 1 month later to 44 MS patients to investigate the test-retest reliability., Results: MS patients exhibited a significantly lower performance in testing with BICAMS than the control group in all three neuropsychological tests. Test-retest reliability was good for SDMT and CVLT-II (r = .82 and r = .85, respectively) and adequate for BVMT-R (r = .70). Based on the proposed criterion for impairment as z score below 1.5 SD the mean of the control group, we found that 34/98 (35%) of MS patients were found impaired at least in one cognitive domain. Patients with Expanded Disability Status Scale score ≥3.5 performed significantly worse than controls (SDMT, p < .0001; CVLT-II, p = .03; BVMT-R, p = .0004), while those with ≤3.0 scores did not., Conclusion: This study demonstrates that the BICAMS battery is a valid instrument to identify cognitive impairment in MS patients and it can be recommended for routine use in the Russian Federation.

Background: Recently, the number of available disease modifying therapies for multiple sclerosis (MS) has increased. However, a proportion of patients treated with these agents continue to experience relapses and disease progression. Cladribine tablets, approved in 2017 for highly active relapsing MS, comprise a sparsely administered oral treatment which exerts its therapeutic effect through a reduction and subsequent repletion of the lymphocyte population., Purpose/study Sample: Here we describe the design of CLAD CROSS, a prospective, non-interventional, multicenter, Phase IV study in patients with a confirmed diagnosis of RRMS who switch from first-line disease modifying drugs (DMDs) to treatment with cladribine tablets in routine clinical practice. 242 adult patients will be recruited in 61 sites (6 countries) over 30 months and will be followed up for 2 years following prescription of cladribine tablets per the decision of the treating physicians., Research Design: The primary endpoint is the change in annualized relapse rate (ARR) between the 12-month pre-baseline period and over the 12-month period before end of study. Secondary endpoints are the percentage of patients with 6-month disability progression or improvement at the end of the study, measured by the Expanded Disability Status Scale, Timed 25 Foot Walk and 9-Hole Peg Test scales and quality of life, treatment satisfaction, and healthcare resource utilization, measured through the MSIS-29, TSQM 1.4, and EQ-5D-3L scales, respectively. MRI lesions will be compared in the exploratory setting between the 12-month pre-baseline period, baseline, and at years 1 and 2. Adverse events will be monitored throughout the study. Interim analyses are pre-planned when 30% and 60% of patients will complete the 12-month follow-up visit., Conclusions: CLAD CROSS will provide efficacy data on cladribine tablets, used as a follow-up treatment to first-line DMDs in the real-world setting, will further establish its safety profile and will collect information to support pharmacoeconomic studies., Competing Interests: Declaration of Conflicting Interests: SD in an employee of Merck AE, Greece. All remaining authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2022.)

Body dysmorphic disorder (BDD) is characterized by an individual's preoccupation with a perceived defect in their appearance which to others may be barely noticeable or even completely unnoticed. It confers significant disturbances of everyday functioning in affected persons. The present review study provides an overview of neuroimaging findings on BDD. Literature on three platforms, PubMed, Google Scholar and PsycArticles of APA PsycNet, was searched for studies on patients with BBD compared with healthy controls (HCs), with a focus on neuroimaging findings. Out of an initial yield of 414 articles, 23 fulfilled inclusion criteria and were reviewed. Among the most remarkable findings were functional abnormalities in visual processing, frontostriatal and limbic systems, reduced global efficiency of White Matter (WM) connectivity, reduced cortical thickness in temporal and parietal lobes, and correlations between these neuroimaging findings and clinical variables such as symptom severity and degree of insight. Structural, volumetric and functional neuroimaging findings in BDD affected persons may help shed light on the pathophysiology and neurobiological underpinnings of this condition. Future studies should further investigate the use of imaging findings as potential prognostic biomarkers of treatment efficacy and disease outcome., Competing Interests: The authors declare no conflict of interest., (© 2022 The Author(s). Published by IMR Press.)

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) characterized by inflammation and neurodegeneration. The most prominent clinical features include visual loss and sensorimotor symptoms and mainly affects those of young age. Some of the factors affecting its pathogenesis are genetic and/or environmental including viruses, smoking, obesity, and nutrition. Current research provides evidence that diet may influence MS onset, course, and quality of life of the patients. In this review, we address the role of nutrition on MS pathogenesis as well as dietary interventions that show promising beneficial results with respect to MS activity and progression. Investigation with large prospective clinical studies is required in order to thoroughly evaluate the role of diet in MS.