Long-Term Follow-Up before and during Riluzole Treatment in Six Patients from Two Families with Spinocerebellar Ataxia Type 7.

BACKGROUND: Currently no curative treatment exists for spinocerebellar ataxias (SCAs). Riluzole repurposing was proposed as a symptomatic treatment in different types of cerebellar ataxia. We report a long-term-follow up under riluzole treatment in SCA type 7. METHODS: Six patients received Riluzole 50 mg twice daily on a compassionate use program for a mean of 4.8 years (range 3.5-9). We measured ataxia onset and progression through the Scale for the Assessment and Rating of Ataxia (SARA), and collected extensive ophthalmological data before and after Riluzole treatment. Electrocardiogram and laboratory profile for drug safety were performed every six months. RESULTS: Riluzole treatment showed no effect on visual function in two patients with an advanced retinal damage. Improvements of visual function occurred in four patients followed by ophthalmologic stability up to 5 years after starting treatment. Two patients had a less steep deterioration of ataxia after treatment compared to pre-treatment, during the first 2,5 years of therapy. One showed soon after therapy an improvement of the SARA score, and then overall stability lasting 3,5 years, followed by ataxia worsening. One visually impaired patient without neurological impairment did not worse until the last visit after 3,5 years of follow-up. The remaining 2 patients showed an improvement of SARA scores soon after therapy, and an overall stability lasting respectively 5 and 3 years. No adverse event was registered during the observation period. DISCUSSION: This study suggests a possible beneficial action of Riluzole in SCA7 and provides a detailed description of the ophthalmologic profile of these patients.

Disentangling multiple sclerosis phenotypes through Mendelian disorders: A network approach.

BACKGROUND: The increasing knowledge about multiple sclerosis (MS) pathophysiology has reinforced the need for an improved description of disease phenotypes, connected to disease biology. Growing evidence indicates that complex diseases constitute phenotypical and genetic continuums with "simple," monogenic disorders, suggesting shared pathomechanisms. OBJECTIVES: The objective of this study was to depict a novel MS phenotypical framework leveraging shared physiopathology with Mendelian diseases and to identify phenotype-specific candidate drugs. METHODS: We performed an enrichment testing of MS-associated variants with Mendelian disorders genes. We defined a "MS-Mendelian network," further analyzed to define enriched phenotypic subnetworks and biological processes. Finally, a network-based drug screening was implemented. RESULTS: Starting from 617 MS-associated loci, we showed a significant enrichment of monogenic diseases (p < 0.001). We defined an MS-Mendelian molecular network based on 331 genes and 486 related disorders, enriched in four phenotypic classes: neurologic, immunologic, metabolic, and visual. We prioritized a total of 503 drugs, of which 27 molecules active in 3/4 phenotypical subnetworks and 140 in subnetwork pairs. CONCLUSION: The genetic architecture of MS contains the seeds of pathobiological multiplicities shared with immune, neurologic, metabolic and visual monogenic disorders. This result may inform future classifications of MS endophenotypes and support the development of new therapies in both MS and rare diseases.

Clinical and Immunological Impact of Ocrelizumab Extended Interval Dosing in Multiple Sclerosis: A Single-Center, Real-World Experience.

Ocrelizumab (OCR), an anti-CD20 monoclonal antibody, is approved for treating relapsing remitting (RR) and primary progressive (PP) multiple sclerosis (MS). The standard interval dosing (SID) regimen requires intravenous infusions every six months. Experience of extended dosing due to COVID-19 pandemic-related issues suggests that this strategy may provide comparable efficacy while reducing treatment burden and healthcare costs. This study aimed to evaluate clinical effectiveness, changes in B- and T-cell count, and immunoglobulin dynamics associated with extended interval dosing (EID) of ocrelizumab in a real-world setting. We retrospectively included RRMS or PPMS patients treated with OCR that had already received two OCR cycles and with at least 6 months of follow up after the last infusion. EID was defined as a ≥4 weeks delay compared to SID. Clinical outcomes were occurrence of relapses, MRI activity, 6-months confirmed disability progression (CDP) and their combination (No Evidence of Disease Activity, NEDA-3). We also evaluated changes in CD19+ B cell count, CD4+ and CD8+ T cell count, immunoglobulin titers, and occurrence of hypogammaglobulinemia (hypo-Ig). Frequency tests, multivariate regression models, and survival analysis were applied as appropriate. We analyzed data on 93 subjects (75.3% RRMS) for a total of 389 infusions (272 SID, 117 EID). Clinical and MRI activity, CDP, and NEDA 3 did not significantly differ between EID and SID. EID was associated with lower rates of B-cell depletion. T-cell dynamics and incidence of hypo-Ig were comparable following EID and SID. Hypo-IgG at index infusion was associated with further occurrence of hypo-IgG; male sex and hypo-IgM at index infusion were independently associated with hypo-IgM. In conclusion, OCR EID does not impact MS clinical and radiological outcomes, although it interferes with B-cell dynamics. These findings provide support for a tailored schedule of OCR in MS.

Peripheral Biomarkers in Manifest and Premanifest Huntington's Disease.

Huntington's disease (HD) is characterized by clinical motor impairment (e.g., involuntary movements, poor coordination, parkinsonism), cognitive deficits, and psychiatric symptoms. An inhered expansion of the CAG triplet in the huntingtin gene causing a pathogenic gain-of-function of the mutant huntingtin (mHTT) protein has been identified. In this review, we focus on known biomarkers (e.g., mHTT, neurofilament light chains) and on new biofluid biomarkers that can be quantified in plasma or peripheral blood mononuclear cells from mHTT carriers. Circulating biomarkers may fill current unmet needs in HD management: better stratification of patients amenable to etiologic treatment; the initiation of preventive treatment in premanifest HD; and the identification of peripheral pathogenic central nervous system cascades.

ADEM after ChAdOx1 nCoV-19 vaccine: A case report.

Acute disseminated encephalomyelitis (ADEM) is an inflammatory demyelinating disease of the central nervous system (CNS), clinically defined by an acute polyfocal neurological syndrome usually with monophasic course. ADEM often occurs after infections, but 5%-10% of cases are preceded by vaccinations. Several cases of ADEM have been described after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, whereas no case has been reported after adenovirus-vectored or mRNA COVID-19 vaccine administration. Here we describe a case of ADEM presenting 2 weeks after receiving the first dose of ChAdOx1 nCoV-19 vaccine. Patient clinical/magnetic resonance imaging (MRI) status spontaneously improved and rapidly resolved with corticosteroids. A 4-month follow-up showed complete recovery and no relapses.

Circulating U13 Small Nucleolar RNA as a Potential Biomarker in Huntington's Disease: A Pilot Study.

Plasma small RNAs have been recently explored as biomarkers in Huntington's disease (HD). We performed an exploratory study on nine HD patients, eight healthy subjects (HS), and five psychiatric patients (PP; to control for iatrogenic confounder effects) through an Affymetrix-Gene-Chip-miRNA-Array. We validated the results in an independent population of 23 HD, 15 pre-HD, 24 PP, 28 Alzheimer's disease (AD) patients (to control the disease-specificity) and 22 HS through real-time PCR. The microarray results showed higher levels of U13 small nucleolar RNA (SNORD13) in HD patients than controls (fold change 1.54, p = 0.003 HD vs. HS, and 1.44, p = 0.0026 HD vs. PP). In the validation population, a significant increase emerged with respect to both pre-HD and the control groups (p < 0.0001). SNORD13 correlated with the status of the mutant huntingtin carrier (r = 0.73; p < 0.001) and the disease duration (r = 0.59; p = 0.003). The receiver operating characteristic (ROC) curve analysis showed the high accuracy of SNORD13 in discriminating HD patients from other groups (AUC = 0.963). An interactome and pathway analysis on SNORD13 revealed enrichments for factors relevant to HD pathogenesis. We report the unprecedented finding of a potential disease-specific role of SNORD13 in HD. It seems to peripherally report a 'tipping point' in the pathogenic cascade at the neuronal level.

A Case of Double Standard: Sex Differences in Multiple Sclerosis Risk Factors.

Multiple sclerosis is a complex, multifactorial, dysimmune disease prevalent in women. Its etiopathogenesis is extremely intricate, since each risk factor behaves as a variable that is interconnected with others. In order to understand these interactions, sex must be considered as a determining element, either in a protective or pathological sense, and not as one of many variables. In particular, sex seems to highly influence immune response at chromosomal, epigenetic, and hormonal levels. Environmental and genetic risk factors cannot be considered without sex, since sex-based immunological differences deeply affect disease onset, course, and prognosis. Understanding the mechanisms underlying sex-based differences is necessary in order to develop a more effective and personalized therapeutic approach.

Gut Microbiota Composition Is Causally Linked to Multiple Sclerosis: A Mendelian Randomization Analysis.

Accumulating evidence links the microbial communities inhabiting the gut to the pathophysiological processes underlying multiple sclerosis (MS). However, most studies on the microbiome in MS are correlative in nature, thus being at risk of confounding and reverse causality. Mendelian randomization (MR) analyses allow the estimation of the causal relationship between a risk factor and an outcome of interest using genetic variants as proxies for environmental exposures. Here, we performed a two-sample MR to assess the causality between the gut microbiome and MS. We extracted genetic instruments from summary statistics from three large genome-wide association studies (GWASs) on the gut microbiome (18,340, 8959, and 7738 subjects). The exposure data were derived from the latest GWAS on MS susceptibility (47,429 patients and 68,374 controls). We pinpointed several microbial strains whose abundance is linked with enhanced MS risk (Actinobacteria class, Bifidobacteriaceae family, Lactobacillus genus) or protection (Prevotella spp., Lachnospiranaceae genus, Negativibacillus genus). The largest risk effect was seen for Ruminococcus Torques (OR, 2.89, 95% C.I. 1.67-5, p = 1.51 × 10-4), while Akkermansia municiphila emerged as strongly protective (OR, 0.43, 95% C.I. 0.32-0.57, p = 1.37 × 10-8). Our findings support a causal relationship between the gut microbiome and MS susceptibility, reinforcing the relevance of the microbiome-gut-brain axis in disease etiology, opening wider perspectives on host-environmental interactions for MS prevention.

The value of Interferon ß in multiple sclerosis and novel opportunities for its anti-viral activity: a narrative literature review.

Interferon-beta (IFN-ß) for Multiple Sclerosis (MS) is turning 30. The COVID-19 pandemic rejuvenated the interest in interferon biology in health and disease, opening translational opportunities beyond neuroinflammation. The antiviral properties of this molecule are in accord with the hypothesis of a viral etiology of MS, for which a credible culprit has been identified in the Epstein-Barr Virus. Likely, IFNs are crucial in the acute phase of SARS-CoV-2 infection, as demonstrated by inherited and acquired impairments of the interferon response that predispose to a severe COVID-19 course. Accordingly, IFN-ß exerted protection against SARS-CoV-2 in people with MS (pwMS). In this viewpoint, we summarize the evidence on IFN-ß mechanisms of action in MS with a focus on its antiviral properties, especially against EBV. We synopsize the role of IFNs in COVID-19 and the opportunities and challenges of IFN-ß usage for this condition. Finally, we leverage the lessons learned in the pandemic to suggest a role of IFN-ß in long-COVID-19 and in special MS subpopulations.

Frailty and relapse activity in multiple sclerosis: A longitudinal observation.

Recent cross-sectional investigations suggest a relationship between frailty, as measured by Frailty Index (FI), and multiple sclerosis (MS). However, if and how frailty is associated with relapse activity in MS is still unknown. To explore this issue, a one-year follow-up study involving 471 patients was conducted. A univariate regression model showed an inverse association between baseline FI score and the presence of relapse, which was also confirmed in the multivariate model. These results suggest that frailty may reflect pathophysiological mechanisms involved in MS disease activity and that the FI may be used as an enrichment criterion in clinical trials.

Drugs Used in the Treatment of Multiple Sclerosis During COVID-19 Pandemic: A Critical Viewpoint.

Since COVID-19 has emerged as a word public health problem, attention has been focused on how immune-suppressive drugs used for the treatment of autoimmune disorders influence the risk for SARS-CoV-2 infection and the development of acute respiratory distress syndrome (ARDS). Here, we discuss the disease-modifying agents approved for the treatment of multiple sclerosis (MS) within this context. Interferon (IFN)-ß1a and -1b, which display antiviral activity, could be protective in the early stage of COVID-19 infection, although SARS-CoV-2 may have developed resistance to IFNs. However, in the hyperinflammation stage, IFNs may become detrimental by facilitating macrophage invasion in the lung and other organs. Glatiramer acetate and its analogues should not interfere with the development of COVID-19 and may be considered safe. Teriflunomide, a first-line oral drug used in the treatment of relapsing-remitting MS (RRMS), may display antiviral activity by depleting cellular nucleotides necessary for viral replication. The other first-line drug, dimethyl fumarate, may afford protection against SARS-CoV-2 by activating the Nrf-2 pathway and reinforcing the cellular defenses against oxidative stress. Concern has been raised regarding the use of second-line treatments for MS during the COVID-19 pandemic. However, this concern is not always justified. For example, fingolimod might be highly beneficial during the hyperinflammatory stage of COVID-19 for a number of mechanisms, including the reinforcement of the endothelial barrier. Caution is suggested for the use of natalizumab, cladribine, alemtuzumab, and ocrelizumab, although MS disease recurrence after discontinuation of these drugs may overcome a potential risk for COVID-19 infection.

Late-Onset MS: Disease Course and Safety-Efficacy of DMTS.

Multiple sclerosis (MS), an inflammatory demyelinating and neurodegenerative disease of the central nervous system, usually begins between the ages of 20 and 49 years, though in rare cases it is diagnosed in childhood and adolescence before the age of 18 years, or at the age of 50 years and later. When the onset of the disease occurs at 50 years or older it is conventionally defined as late onset MS (LOMS). Compared to classical MS, the LOMS is characterized by progressive course, a greater delay in diagnosis and a higher prevalence of motor disability. The older the patients, the greater is the risk of comorbidities that can negatively influence the course of the disease and can limit therapeutic strategies. To date, there is no study focused on the efficacy of Disease Modifying Therapies (DMT) in older patients with MS. The only data available are retrievable from subgroup analysis from phase-3 trials of DMT efficacy. In this work, we discuss how the aging process influences the onset, the clinical course and the therapeutic approach in LOMS.

CNS inflammatory demyelinating events after COVID-19 vaccines: A case series and systematic review.

Background: Vaccinations provided the most effective tool to fight the SARS-CoV-2 pandemic. It is now well established that COVID-19 vaccines are safe for the general population; however, some cases of rare adverse events following immunization have been described, including CNS Inflammatory Demyelinating Events (CIDEs). Although observational studies are showing that these events are rare and vaccines' benefits highly outweigh the risks, collecting and characterizing post-COVID-19 vaccine CIDEs might be relevant to single out potential risk factors and suggest possible underlying mechanisms. Methods: Here we describe six CIDEs, including two acute transverse myelitis (ATM), three multiple sclerosis (MS), and one neuromyelitis optica spectrum disorder (NMOSD), occurring between 8 and 35 days from a COVID-19 vaccine. Moreover, we performed a systematic literature search of post-COVID-19 vaccines CIDEs, including ATM, ADEM, MS, and NMOSD/MOGAD, published worldwide between December 2020 and December 2021, during 1 year of the vaccination campaign. Clinical/MRI and CSF/serum characteristics were extracted from reviewed studies and pooled-analyzed. Results: Forty-nine studies were included in the systematic review, reporting a total amount of 85 CIDEs. Considering our additional six cases, 91 CIDEs were summarized, including 24 ATM, 11 ADEM, 47 MS, and nine NMOSD/MOGAD. Overall, CIDEs occurred after both mRNA (n = 46), adenoviral-vectored (n = 37), and inactivated vaccines (n = 8). Adenoviral-vectored vaccines accounted for the majority of ADEM (55%) and NMOSD/MOGAD (56%), while mRNA vaccines were more frequent in MS new diagnoses (87%) and relapses (56%). Age was heterogeneous (19-88) and the female sex was prevalent. Time from vaccine to symptoms onset was notably variable: ADEM and NMOSD/MOGAD had a longer median time of onset (12.5 and 10 days) compared to ATM and MS (6 and 7 days) and further timing differences were observed between events following different vaccine types, with ATM and MS after mRNA-vaccines occurring earlier than those following adenoviral-vectored ones. Conclusion: Both the prevalence of vaccine types for certain CIDEs and the heterogeneity in time of onset suggest that different mechanisms-with distinct dynamic/kinetic-might underly these events. While epidemiological studies have assessed the safety of COVID-19 vaccines, descriptions and pooled analyses of sporadic cases may still be valuable to gain insights into CIDE's pathophysiology.

Leukocyte Telomere Length Variability as a Potential Biomarker in Patients with PolyQ Diseases.

SCA1, SCA2, and SCA3 are the most common forms of SCAs among the polyglutamine disorders, which include Huntington's Disease (HD). We investigated the relationship between leukocyte telomere length (LTL) and the phenotype of SCA1, SCA2, and SCA3, comparing them with HD. The results showed that LTL was significantly reduced in SCA1 and SCA3 patients, while LTL was significantly longer in SCA2 patients. A significant negative relationship between LTL and age was observed in SCA1 but not in SCA2 subjects. LTL of SCA3 patients depend on both patient's age and disease duration. The number of CAG repeats did not affect LTL in the three SCAs. Since LTL is considered an indirect marker of an inflammatory response and oxidative damage, our data suggest that in SCA1 inflammation is present already at an early stage of disease similar to in HD, while in SCA3 inflammation and impaired antioxidative processes are associated with disease progression. Interestingly, in SCA2, contrary to SCA1 and SCA3, the length of leukocyte telomeres does not reduce with age. We have observed that SCAs and HD show a differing behavior in LTL for each subtype, which could constitute relevant biomarkers if confirmed in larger cohorts and longitudinal studies.

Multiple sclerosis genetic and non-genetic factors interact through the transient transcriptome.

A clinically actionable understanding of multiple sclerosis (MS) etiology goes through GWAS interpretation, prompting research on new gene regulatory models. Our previous investigations suggested heterogeneity in etiology components and stochasticity in the interaction between genetic and non-genetic factors. To find a unifying model for this evidence, we focused on the recently mapped transient transcriptome (TT), that is mostly coded by intergenic and intronic regions, with half-life of minutes. Through a colocalization analysis, here we demonstrate that genomic regions coding for the TT are significantly enriched for MS-associated GWAS variants and DNA binding sites for molecular transducers mediating putative, non-genetic, determinants of MS (vitamin D deficiency, Epstein Barr virus latent infection, B cell dysfunction), indicating TT-coding regions as MS etiopathogenetic hotspots. Future research comparing cell-specific transient and stable transcriptomes may clarify the interplay between genetic variability and non-genetic factors causing MS. To this purpose, our colocalization analysis provides a freely available data resource at www.mscoloc.com .

MAIT Cells and Microbiota in Multiple Sclerosis and Other Autoimmune Diseases.

The functions of mucosal-associated invariant T (MAIT) cells in homeostatic conditions include the interaction with the microbiota and its products, the protection of body barriers, and the mounting of a tissue-repair response to injuries or infections. Dysfunction of MAIT cells and dysbiosis occur in common chronic diseases of inflammatory, metabolic, and tumor nature. This review is aimed at analyzing the changes of MAIT cells, as well as of the microbiota, in multiple sclerosis and other autoimmune disorders. Common features of dysbiosis in these conditions are the reduced richness of microbial species and the unbalance between pro-inflammatory and immune regulatory components of the gut microbiota. The literature concerning MAIT cells in these disorders is rather complex, and sometimes not consistent. In multiple sclerosis and other autoimmune conditions, several studies have been done, or are in progress, to find correlations between intestinal permeability, dysbiosis, MAIT cell responses, and clinical biomarkers in treated and treatment-naïve patients. The final aims are to explain what activates MAIT cells in diseases not primarily infective, which interactions with the microbiota are potentially pathogenic, and their dynamics related to disease course and disease-modifying treatments.

Multiple Sclerosis and SARS-CoV-2: Has the Interplay Started?

Current knowledge on Multiple Sclerosis (MS) etiopathogenesis encompasses complex interactions between the host's genetic background and several environmental factors that result in dysimmunity against the central nervous system. An old-aged association exists between MS and viral infections, capable of triggering and sustaining neuroinflammation through direct and indirect mechanisms. The novel Coronavirus, SARS-CoV-2, has a remarkable, and still not fully understood, impact on the immune system: the occurrence and severity of both acute COVID-19 and post-infectious chronic illness (long COVID-19) largely depends on the host's response to the infection, that echoes several aspects of MS pathobiology. Furthermore, other MS-associated viruses, such as the Epstein-Barr Virus (EBV) and Human Endogenous Retroviruses (HERVs), may enhance a mechanistic interplay with the novel Coronavirus, with the potential to interfere in MS natural history. Studies on COVID-19 in people with MS have helped clinicians in adjusting therapeutic strategies during the pandemic; similar efforts are being made for SARS-CoV-2 vaccination campaigns. In this Review, we look over 18 months of SARS-CoV-2 pandemic from the perspective of MS: we dissect neuroinflammatory and demyelinating mechanisms associated with COVID-19, summarize pathophysiological crossroads between MS and SARS-CoV-2 infection, and discuss present evidence on COVID-19 and its vaccination in people with MS.