Background and Objectives It is unclear how multiple sclerosis (MS) affects the severity of COVID-19. The aim of this study is to compare COVID-19–related outcomes collected in an Italian cohort of patients with MS with the outcomes expected in the age- and sex-matched Italian population. Methods Hospitalization, intensive care unit (ICU) admission, and death after COVID-19 diagnosis of 1,362 patients with MS were compared with the age- and sex-matched Italian population in a retrospective observational case-cohort study with population-based control. The observed vs the expected events were compared in the whole MS cohort and in different subgroups (higher risk: Expanded Disability Status Scale [EDSS] score > 3 or at least 1 comorbidity, lower risk: EDSS score ≤ 3 and no comorbidities) by the χ² test, and the risk excess was quantified by risk ratios (RRs). Results The risk of severe events was about twice the risk in the age- and sex-matched Italian population: RR = 2.12 for hospitalization (p < 0.001), RR = 2.19 for ICU admission (p < 0.001), and RR = 2.43 for death (p < 0.001). The excess of risk was confined to the higher-risk group (n = 553). In lower-risk patients (n = 809), the rate of events was close to that of the Italian age- and sex-matched population (RR = 1.12 for hospitalization, RR = 1.52 for ICU admission, and RR = 1.19 for death). In the lower-risk group, an increased hospitalization risk was detected in patients on anti-CD20 (RR = 3.03, p = 0.005), whereas a decrease was detected in patients on interferon (0 observed vs 4 expected events, p = 0.04). Discussion Overall, the MS cohort had a risk of severe events that is twice the risk than the age- and sex-matched Italian population. This excess of risk is mainly explained by the EDSS score and comorbidities, whereas a residual increase of hospitalization risk was observed in patients on anti-CD20 therapies and a decrease in people on interferon.

Neurodegenerative diseases, particularly affecting aged people, have relevant health and social costs. Different forms of diseases, often involving serious forms of dementia, are included in this class of pathology requiring specific clinical treatments to be fronted. Thus, timely and reliable diagnosis is a critical aspect for choosing a valid medical therapy. A mild cognitive impairment (MCI) reflects a cognitive decline but not yet a state of dementia and often does not compromise daily life activities.¹ Alzheimer’s disease (AD) is a more severe neurodegenerative pathology characterized by a progressive damage of synaptic links and neuronal cells mainly in the hippocampus brain region. The occurrence of pathological aggregates of proteins including beta-amyloid fragments ($\mathrm{A}\beta$-plaques) in the interneuronal spaces of brain tissue and the increased level of tau- and hyperphosphorylated-tau proteins in the cerebrospinal fluid of AD-affected subjects indicated the relevance of beta-amyloids ($\mathrm{A}\beta$) and tau-protein in the AD development.^{2 – 4} Both substances are biomarkers of AD progression^2,4 and are a reliable sign of a neurodegenerative cerebral process also in the early-stage phase.^{5 – 7} These biomarkers can be transported into the vascular system across the blood–brain barrier (BBB).^8,9 The BBB plays an important role in the selective passage of several substances between brain and blood systems and in the maintenance and integrity of the brain. A dysfunctional BBB with impaired ability to clear $\mathrm{A}\beta$ and tau protein from the brain has been associated with the development of AD.¹⁰ Traces of these biomarkers are present in the systemic blood circulation and can rejoin the vascularization of other body districts, as the retina, lens, and lacrimal regions, affecting the composition of tears.^{11 – 13} The relevance of changes occurring in the eye as a consequence of AD has been reported by Lim et al.¹⁴ Consequently, tears are an ideal medium for investigating changes induced by neurodegenerative pathologies. They are easily accessible and can be collected using minimally invasive methods.

Clinical trials in multiple sclerosis (MS) have been including digital technology tools to overcome limitations in treatment delivery and disease monitoring. In March 2020, we conducted a systematic search on pubmed.gov and clinicaltrials.gov databases (with no restrictions) to identify all relevant published and unpublished clinical trials, in English language, including MS patients, in which digital technology was applied. We used “multiple sclerosis” and “clinical trial” as the main search words, and “app”, “digital”, “electronic”, “internet” and “mobile” as additional search words, separately. Digital technology is part of clinical trial interventions to deliver psychotherapy and motor rehabilitation, with exergames, e-training, and robot-assisted exercises. Digital technology has been used to standardise previously existing outcome measures, with automatic acquisitions, reduced inconsistencies, and improved detection of symptoms (e.g., electronic recording of motor performance). Other clinical trials have been using digital technology for monitoring symptoms that would be otherwise difficult to detect (e.g., fatigue, balance), for measuring treatment adherence and side effects, and for self-assessment purposes. Collection of outcome measures is progressively shifting from paper-based on site, to internet-based on site, and, in the future, to internet-based at home, with the detection of clinical and treatment features that would have remained otherwise invisible. Similarly, remote interventions provide new possibilities of motor and cognitive rehabilitation.

Cognitive impairment is a frequent and meaningful symptom in multiple sclerosis (MS), caused by the accrual of brain structural damage only partially counteracted by effective functional reorganization. As both these aspects can be successfully investigated through the application of advanced neuroimaging, here, we offer an up-to-date overview of the latest findings on structural, functional and metabolic correlates of cognitive impairment in adults with MS, focusing on the mechanisms sustaining damage accrual and on the identification of useful imaging markers of cognitive decline.

Physical disability impacts psychosocial wellbeing in people with multiple sclerosis. However, the role of physical activity in this context is still debated. By taking advantage of a previous survey, conducted online from 22 April to 7 May 2020, we performed a post-hoc analysis with the aim to assess the associations between disability, physical exercise, and mental health in multiple sclerosis. We retrieved the following data: (i) sociodemographic information, (ii) changes in lifestyle (including exercise), (iii) physical disability, as measured with the Patient-Determined Disease Steps scale, and (iv) anxiety feelings and depressive symptoms assessed via the items included in the Quality of Life in Neurological Disorders measurement system. Examination of the interaction plot showed that the effect of disability on depression, but not on anxious symptoms, was significant for all levels of physical exercise (low: b = 1.22, 95% C.I. 0.85, 1.58, p < 0.001; moderate: b = 0.95, 95% C.I. 0.66, 1.24, p < 0.001; and high: b = 0.68, 95% C.I. 0.24, 1.13, p = 0.003). Based on these data, we can conclude that disability significantly impacted depression during the COVID-19 pandemic, with physical activity playing a moderating role. Our results suggest that favoring exercise in multiple sclerosis (MS) would ameliorate psychological wellbeing regardless of the level of physical disability.

Background and Objectives To define the clinical and pathologic correlations of compartmentalized perivascular B cells in postmortem progressive multiple sclerosis (MS) brains. Methods Brain slices were acquired from 11 people with secondary progressive (SP) MS, 5 people with primary progressive (PP) MS, and 4 controls. Brain slices were immunostained for B lymphocytes (CD20), T lymphocytes (CD3), cytotoxic T lymphocytes (CD8), neuronal neurofilaments (NF200), myelin (SMI94), macrophages/microglia (CD68 and IBA1), astrocytes (glial fibrillary acidic protein [GFAP]), and mitochondria (voltage-dependent anion channel and cytochrome c oxidase subunit 4). Differences in CD20 immunostaining intensity between disease groups and associations between CD20 immunostaining intensity and both clinical variables and other immunostaining intensities were explored with linear mixed regression models and Cox regression models, as appropriate. Results CD20 immunostaining intensity was higher in PPMS (Coeff = 0.410; 95% confidence interval [CI] = 0.046, 0.774; p = 0.027) and SPMS (Coeff = 0.302; 95% CI = 0.020, 0.585; p = 0.036) compared with controls. CD20 immunostaining intensity was higher in cerebellar, spinal cord, and pyramidal onset (Coeff = 0.274; 95% CI = 0.039, 0.510; p = 0.022) compared with optic neuritis and sensory onset. Higher CD20 immunostaining intensity was associated with younger age at onset (hazard ratio [HR] = 1.033; 95% CI = 1.013, 1.053; p = 0.001), SP conversion (HR = 1.056; 95% CI = 1.022, 1.091; p = 0.001), wheelchair dependence (HR = 1.472; 95% CI = 1.108, 1.954; p = 0.008), and death (HR = 1.684; 95% CI = 1.238, 2.291; p = 0.001). Higher immunostaining intensity for CD20 was associated with higher immunostaining intensity for CD3 (Coeff = 0.114; 95% CI = 0.005, 0.224; p = 0.040), CD8 (Coeff = 0.275; 95% CI = 0.200, 0.350; p < 0.001), CD68 (Coeff = 0.084; 95% CI = 0.023, 0.144; p = 0.006), GFAP (Coeff = 0.002; 95% CI = 0.001, 0.004; p = 0.030), and damaged mitochondria (Coeff = 3.902; 95% CI = 0.891, 6.914; p = 0.011). Discussion Perivascular B cells were associated with worse clinical outcomes and CNS-compartmentalized inflammation. Our findings further support the concept of targeting compartmentalized B-cell inflammation in progressive MS.