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

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

Plasma membrane calcium ATPase downregulation in dopaminergic neurons alters cellular physiology and motor behaviour in Drosophila melanogaster.

The accumulation of Ca2+ and its subsequent increase in oxidative stress is proposed to be involved in selective dysfunctionality of dopaminergic neurons, the main cell type affected in Parkinson's disease. To test the in vivo impact of Ca2+ increment in dopaminergic neurons physiology, we downregulated the plasma membrane Ca2+ ATPase (PMCA), a pump that extrudes cytosolic Ca2+ , by expressing PMCARNAi in Drosophila melanogaster dopaminergic neurons. In these animals, we observed major locomotor alterations paralleled to higher cytosolic Ca2+ and increased levels of oxidative stress in mitochondria. Interestingly, although no overt degeneration of dopaminergic neurons was observed, evidences of neuronal dysfunctionality were detected such as increases in presynaptic vesicles in dopaminergic neurons and in the levels of dopamine in the brain, as well as presence of toxic effects when PMCA was downregulated in the eye. Moreover, reduced PMCA levels were found in a Drosophila model of Parkinson's disease, Parkin knock-out, expanding the functional relevance of PMCA reduction to other Parkinson's disease-related models. In all, we have generated a new model to study motor abnormalities caused by increments in Ca2+ that lead to augmented oxidative stress in a dopaminergic environment, added to a rise in synaptic vesicles and dopamine levels.

Quality of life in patients with epilepsy or psychogenic nonepileptic seizures and the contribution of psychiatric comorbidities.

Epilepsy is a common neurological disorder, and psychogenic nonepileptic seizures (PNES) is an important differential diagnosis. Psychiatric comorbidities are prevalent among people with epilepsy (PWE). Additionally, lower quality of life (QoL) in people with PNES compared with PWE was reported with higher rates of general psychiatric comorbidity. Although there are previous studies evaluating the QoL in patients with epilepsy, this study is unique and compelling because it represents a study comparing PNES and PWE on QoL, depression, and anxiety in a Spanish-speaking group of Argentine patients. The aim of this study was to analyze self-reported anxiety and depression in PWE and PNES and to establish the impact on QoL. METHODS: This is a cross-sectional study; QoL was measured using the Quality of Life in Epilepsy Inventory (QOLIE-31). To study anxiety and depression, the Hospital Anxiety and Depression Scale (HADS) was administered. Clinical and complementary data were recorded. RESULTS: Psychogenic nonepileptic seizures scored significantly higher in anxiety and depression and with lower levels of QoL compared with PWE. Anxiety and depression had a negative correlation with QoL. CONCLUSION: Nonepileptic seizures have an even greater impact on QoL than epileptic seizures, and this could be influenced by psychiatric comorbidities. These findings corroborate what other studies in English-speaking nations that have found regarding the impact of psychopathology on QoL in those with PNES and further support the importance of assessing for psychiatric comorbidities to tailor treatment.

A new focal model resembling features of cortical pathology of the progressive forms of multiple sclerosis: Influence of innate immunity.

Multiple sclerosis (MS) is an inflammatory and demyelinating disease of unknown aetiology that causes neurological disabilities in young adults. MS displays different clinical patterns, including recurrent episodes with remission periods ("relapsing-remitting MS" (RRMS)), which can progress over several years to a secondary progressive form (SPMS). However, 10% of patients display persistent progression at the onset of disease ("primary progressive MS" (PPMS)). Currently, no specific therapeutic agents are available for the progressive forms, mainly because the underlying pathogenic mechanisms are not clear and because no animal models have been specifically developed for these forms. The development of MS animal models is required to clarify the pathological mechanisms and to test novel therapeutic agents. In the present work, we overexpressed interleukin 1 beta (IL-1ß) in the cortex to develop an animal model reflecting the main pathological hallmarks of MS. The treated animals presented with neuroinflammation, demyelination, glial activation, and neurodegeneration along with cognitive symptoms and MRI images consistent with MS pathology. We also demonstrated the presence of meningeal inflammation close to cortical lesions, with characteristics similar to those described in MS patients. Systemic pro-inflammatory stimulation caused a flare-up of the cortical lesions and behavioural symptoms, including impairment of working memory and the appearance of anxiety-like symptoms. Our work demonstrated induced cortical lesions, reflecting the main histopathological hallmarks and cognitive impairments characterizing the cortical pathology described in MS patients with progressive forms of the disease.

Do immunosuppressive treatments influence immune responses against adenovirus-based COVID-19 vaccines in patients with multiple sclerosis? An Argentine multicenter study.

Introduction: There are no reports in LATAM related to longitudinal humoral and cellular response to adenovirus based COVID-19 vaccines in people with Multiple Sclerosis (pwMS) under different disease modifying therapies (DMTs) and neutralization of the Omicron and Wuhan variants of SARS-COV-2. Methods: IgG anti- SARS-COV-2 spike titer were measured in a cohort of 101 pwMS under fingolimod, dimethyl fumarate, cladribine and antiCD20, as well as 28 healthy controls (HC) were measured 6 weeks after vaccination with 2nd dose (Sputnik V or AZD1222) and 3nd dose (homologous or heterologous schedule). Neutralizing capacity was against Omicron (BA.1) and Wuhan (D614G) variants and pseudotyped particles and Cellular response were analyzed. Results: Multivariate regression analysis showed anti-cd20 (ß= -,349, 95% CI: -3655.6 - -369.01, p=0.017) and fingolimod (ß=-,399, 95% CI: -3363.8 - -250.9, p=0.023) treatments as an independent factor associated with low antibody response (r2 adjusted=0.157). After the 2nd dose we found a correlation between total and neutralizing titers against D614G (rho=0.6; p<0.001; slope 0.8, 95%CI:0.4-1.3), with no differences between DMTs. Neutralization capacity was lower for BA.1 (slope 0.3, 95%CI:0.1-0.4). After the 3rd dose, neutralization of BA.1 improved (slope: 0.9 95%CI:0.6-1.2), without differences between DMTs. A fraction of pwMS generated anti-Spike CD4+ and CD8+ T cell response. In contrast, pwMS under antiCD20 generated CD8+TNF+IL2+ response without differences with HC, even in the absence of humoral response. The 3rd dose significantly increased the neutralization against the Omicron, as observed in the immunocompetent population. Discussion: Findings regarding humoral and cellular response are consistent with previous reports.

Relevance and Impact of Social Support on Quality of Life for Persons With Multiple Sclerosis.

BACKGROUND: Social support is crucial for persons with multiple sclerosis (MS). We sought to analyze differences in perceived social support in persons with MS vs controls; to study associations between perceived social support, clinical measures, and health-related quality of life (HRQOL) variables in persons with MS; and to establish a predictive value of perceived social support for HRQOL. METHODS: We studied 151 persons with MS (mean ± SD: age, 42.01 ± 9.97 years; educational level, 14.05 ± 3.26 years) and 89 controls (mean ± SD: age, 41.46 ± 12.25 years; educational level, 14.60 ± 2.44 years) using the Medical Outcomes Study Social Support Survey (MOS-SSS), Expanded Disability Status Scale, Fatigue Severity Scale, Beck Depression Inventory, and Multiple Sclerosis International Quality of Life (MusiQoL) questionnaire. Parametric and nonparametric statistical methods were used accordingly; P < .05. RESULTS: Persons with MS exhibited lower scores on the MOS-SSS's overall support index (t238 = -1.98, P = .04) and on each functional subscale (t238 = -2.56 to -2.19, P < .05). No significant differences were found on the social support structural component (P > .05). Significant associations were observed between social support and depression and fatigue (r = -0.20 to -0.29, P < .05) and with MusiQoL dimensions (r = -0.18 to 0.48, P < .05). Multiple regression analysis showed all 4 tested models contributed to HRQOL-explained variance (41%-47%). The emotional/informational support model explained the most HRQOL variability (47%). CONCLUSIONS: Persons with MS perceived reduced social support, presenting lower functional scores than controls. Perceived social support proved to be a predictor of HRQOL. These findings should be considered during therapeutic treatment.

Barriers to access and unmet needs to neuromyelitis optica spectrum disorders care in an Argentinean cohort.

INTRODUCTION: Neuromyelitis optica spectrum disorder (NMOSD) is a rare but severe neuroimmunological condition associated with a significant financial burden. NMOSD is also associated with increased health care utilization, including neurology outpatient visits, magnetic resonance imaging (MRI) use, long-term medication, among others. We aimed to evaluate real-world patient experiences in access to care and NMOSD burden in an Argentinean cohort. METHODS: This cross-sectional study used a self-administered survey and was conducted in Argentina (2022). Patients with NMOSD were divided into three groups: private health insurance (PHI), social health insurance (SHI), and public health insurance (PHI, Ministry of Public Health). Differences in access and health care barriers were assessed. RESULTS: One hundred patients with NMOSD (74 women) with a mean age at diagnosis of 38.7 years were included. Their EDSS was 2.8 and they were followed for 5.2 years. Of them, 51%, 11%, and 13% were employed (full-time: 57.5%), currently unemployed and retired by NMOSD, respectively. 55% of them visited between 2-3 specialists before NMOSD diagnosis. Aquaporin-4-antibody and/or myelin oligodendrocyte glycoprotein-antibody testing was requested in 91% (health insurance covered this partially in 15.3% and 32.9% of the time the test was entirely paid by patient/family). Patients with NMOSD receiving private medical care reported greater access to MRI, outpatient visits, and fewer issues to obtain NMOSD medications compared to those treated at public institutions. A longer mean time to MRI and neurology visit was found in the PHI group when compared with the other two subgroups. Regression analysis showed that private insurance (OR=3.84, p=0.01) was the only independent factor associated with appropriate access to NMOSD medications in Argentina. CONCLUSION: These findings suggest that barriers to access and utilization of NMOSD care services in Argentina are common. NMOSD patients experienced problems to receive NMOSD medication properly, especially those from the public sector.

Understanding the role of the blood brain barrier and peripheral inflammation on behavior and pathology on ongoing confined cortical lesions.

BACKGROUND: Inflammation in the Central Nervous System (CNS) is associated with blood brain barrier (BBB) breakdown during the early stages of Multiple Sclerosis (MS), indicating a facilitated entry of waves of inflammatory cells from the circulation to the CNS. In the progressive forms of MS, as the lesion becomes chronic, the inflammation remains trapped within the CNS compartment forming the slow evolving lesion, characterized by low inflammation and microglia activation at the lesions edges. The chronic expression of interleukin 1ß (IL-1ß) in the cortex induces BBB breakdown, demyelination, neurodegeneration, microglial/macrophage activation and impaired cognitive performance. The latter can be improved, as long as the BBB recovers and the lesion presents low inflammation. Here, we study the effects of peripheral inflammation on cortical central lesions after the restoration of the BBB, in order to elucidate the role of the peripheral inflammation on these lesions with intact BBB, as it occurs in the progressive forms of MS. MATERIALS AND METHODS: Cortical lesions and peripheral inflammation were induced by the chronic expression of IL-1ß using an adenovector. We performed histological, immunohistochemistry on brain tissue and behavioural analyses. RESULTS: The effects of the chronic expression of IL-1ß in the cortex resolved within 56 days. However, peripheral and sustained inflammation re-opened the BBB, allowing the reappearance of the neuroinflammatory processes within the cortical lesions, increased demyelination and neurodegeneration, and an increase of the behavioral symptoms, such as cognitive impairment and anxiety-like symptoms. CONCLUSIONS: The early treatment of peripheral inflammatory processes should be considered in order to protect the brain from exacerbation of the ongoing neurodegenerative process.

Decision making process in multiple sclerosis: An Argentine pilot study.

BACKGROUND: There is scarce information regarding the decision-making process (DMP) in people with MS (PwMS) from Latin America. OBJECTIVE: To evaluate the DMP in Argentinean PwMS and to assess its relationship with patient preferences, and clinical-demographic characteristics. METHODS: PwMS from the patient organization Esclerosis Múltiple Argentina (n = 1275) were invited to participate in a self-administered web-based survey. Participants were asked to provide clinical-demographic information and to complete a questionnaire on their perceptions about the information provided by their physician, the Control Preference Scale, and the Satisfaction with the Decisions and Care Questionnaire, and were inquired on their preferred sources of information about MS. RESULTS: The survey was completed by 379 PwMS. Most were females (67%); mean age: 40.3 (SD = 11.1) years; mean disease duration: 7.9 (SD = 7.2) years. Patients' decisional control preferred role was active in 47%, shared in 27%, and passive in 26%. A moderate concordance (weighted kappa 0.55) was observed between patients' preferences and self-reported DMP. Seventy-two percent participated in the DMP according to their preferences (concordance rates: active 66%, shared 87%, passive 51%). Most (83%) declared receiving information from their neurologists, matching their preferences (94%). CONCLUSIONS: Argentinian PwMS have distinctive preferences regarding information management and decision making.

Evaluation of the times of disability progression and related factors in patients with primary progressive multiple sclerosis from Argentina.

Background PPMS (primary progressive multiple sclerosis) patients represent less than 10% of MS patients in Argentina, men and women were similarly affected and most of them had a severe functional impairment. More rapid progression has been reported in males, but this is not the case in all datasets. The main objective of our study was to determine the time to EDSS (Expanded disability Status Scale) 4, 6 and 7 in PPMS patients. We also compared the times to reach these EDSS in men and women and aimed to identify factors associated with the disability progression. Method This cohort of patients with diagnosis of PPMS (n = 253) was selected from follow-up recorded in the RelevarEM registry database. Result The median times to EDSS 4, 6 and 7 were 24 (IQR 12-48), 72 (IQR 36-96) and 96 (IQR 60-120) months, respectively. Comparison of the survival curves to EDSS 4, 6 and 7 according to gender did not show significant differences (p = 0.33, p = 0.55 and p = 0.59). There is no evidence of an association between the clinical adjustment variables (sex, age >40 years at diagnosis, EDSS > 3 at onset and multifocal MS symptoms at disease onset) and the time of arrival at the EDSS 4, 6 and 7. Conclusion Severe disability was observed six years after the onset of symptoms. No association was found between the studied factors and the time to arrival to severe disability.

Insights into the role of B cells in the cortical pathology of Multiple sclerosis: evidence from animal models and patients.

Multiple sclerosis (MS) is a chronic, immune-mediated disease of the central nervous system (CNS) that affects both white and gray matter. Although it has been traditionally considered as a T cell mediated disease, the role of B cell in MS pathology has become a topic of great research interest. Cortical lesions, key feature of the progressive forms of MS, are involved in cognitive impairment and worsening of the patients' outcome. These lesions present pathognomonic hallmarks, such as: absence of blood-brain barrier (BBB) disruption, limited inflammatory events, reactive microglia, neurodegeneration, demyelination and meningeal inflammation. B cells located in the meninges, either as part of diffuse inflammation or as part of follicle-like structures, are strongly associated with cortical damage. The function of CD20-expressing B cells in MS is further highlighted by the success of specific therapies using anti-CD20 antibodies. The possible roles of B cells in pathology go beyond their ability to produce antibodies, as they also present antigens to T cells, secrete cytokines (both pathogenic and protective) within the CNS to modulate T and myeloid cell functions, and are involved in meningeal inflammation. Here, we will review the contributions of B cells to the pathogenesis of meningeal inflammation and cortical lesions in MS patients as well as in preclinical animal models.

Changes on the health care of people with multiple sclerosis from Latin America during the COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic has resulted in uncertain access to medical treatment for people with multiple sclerosis (pwMS) all over the world. However, there is no data regarding its impact on access to health care of pwMS from Latin America. OBJECTIVES: We investigated and described changes in health care delivery for pwMS from Latin America during the COVID-19 pandemic. METHODS: PwMS from 18 patient organizations of the region completed a web-based survey hosted from May to October 2020. RESULTS: A total of 602 pwMS completed the questionnaire. Changes in disease-modifying therapies (DMTs) use: 6.7% of pwMS on continuous DMTs claimed to stopped them; 14.1% of those on infusion therapies declared to postpone their dosing; 68.8% declared delaying the initiation of a DMT. Disruptions in accessing rehabilitation services were reported by 65.7%. Changes in laboratory and MRI monitoring were reported by 30% and 33%, respectively. In a multivariable-adjusted logistic regression model, changes in laboratory monitoring were significantly associated with increased odds of postponing MRI monitoring (OR 4.09 CI95% 2.79-6.00, p < 0.001). CONCLUSIONS: The COVID-19 pandemic has disrupted all aspects of the routine care for pwMS from Latin America. Consequences are yet to be determined.

Training the brain: could it improve multiple sclerosis treatment?

Multiple sclerosis (MS) is a neurological disease characterized by neuroinflammation, demyelination and axonal degeneration along with loss of function in the central nervous system. For many years, research in MS has focused on the efficacy of pharmacological treatments. However, during the last years, many publications have been dedicated to the study of the efficacy of non-pharmacological strategies, such as physical exercise and cognitive training. Beneficial effects of the combination of both strategies on cognitive function have been described in both ageing adults and patients with neurodegenerative diseases, such as MS. The analysis of combining both physical and cognitive stimulation can be summarized by the environmental enrichment (EE) experiments, which are more suitable for animal models. EE refers to housing conditions consisting of exercise and cognitive and social stimulation. In this review, we will summarize the available studies that describe the influence of EE in both MS patients and MS animal models.

Environmental enrichment improves cognitive symptoms and pathological features in a focal model of cortical damage of multiple sclerosis.

Multiple Sclerosis (MS) is a neuroinflammatory disease affecting white and grey matter, it is characterized by demyelination, axonal degeneration along with loss of motor, sensitive and cognitive functions. MS is a heterogeneous disease that displays different clinical courses: relapsing/remitting MS (RRMS), and MS progressive forms: primary progressive (PPMS) and secondary progressive (SPMS). Cortical damage in the progressive MS forms has considerable clinical relevance due to its association with cognitive impairment and disability progression in patients. One treatment is available for the progressive forms of the disease, but none are specific for cognitive deficits. We developed an animal model that reflects most of the characteristics of the cortical damage, such as cortical neuroinflammation, demyelination, neurodegeneration and meningeal inflammation, which was associated with cognitive impairment. Cognitive rehabilitation, exercise and social support have begun to be evaluated in patients and animal models of neurodegenerative diseases. Environmental enrichment (EE) provides exercise as well as cognitive and social stimulation. EE has been demonstrated to exert positive effects on cognitive domains, such as learning and memory, and improving anxiety-like symptoms. We proposed to study the effect of EE on peripherally stimulated cortical lesion induced by the long term expression of interleukin IL-1ß (IL-1ß) in adult rats. Here, we demonstrated that EE: 1) reduces the peripheral inflammatory response to the stimulus, 2) ameliorates cognitive deficits and anxiety-like symptoms, 3) modulates neurodegeneration, demyelination and glial activation, 4) regulates neuroinflammation by reducing the expression of pro-inflammatory cytokines and enhancing the expression of anti-inflammatory ones. Our findings correlate with the fact that EE housing could be considered an effective non- pharmacological therapeutic agent that can synergistically aid in the rehabilitation of the disease.

Cortical and meningeal pathology in progressive multiple sclerosis: a new therapeutic target?

Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease that involves an intricate interaction between the central nervous system and the immune system. Nevertheless, its etiology is still unknown. MS exhibits different clinical courses: recurrent episodes with remission periods ('relapsing-remitting') that can evolve to a 'secondary progressive' form or persistent progression from the onset of the disease ('primary progressive'). The discovery of an effective treatment and cure has been hampered due to the pathological and clinical heterogeneity of the disease. Historically, MS has been considered as a disease exclusively of white matter. However, patients with progressive forms of MS present with cortical lesions associated with meningeal inflammation along with physical and cognitive disabilities. The pathogenesis of the cortical lesions has not yet been fully described. Animal models that represent both the cortical and meningeal pathologies will be critical in addressing MS pathogenesis as well as the design of specific treatments. In this review, we will address the state-of-the-art diagnostic and therapeutic alternatives and the development of strategies to discover new therapeutic approaches, especially for the progressive forms.