Aducanumab: A look two years after its approval / Aducanumab: una mirada dos años después de su aprobación

Alzheimer's disease is the leading cause of dementia worldwide and a critical public health problem. While deaths from cardiovascular diseases have decreased, those attributed to Alzheimer's disease have increased in recent years with no curative treatment to date. In this context, effective treatment development has become a global priority. Aducanumab is a human anti-amyloid ß monoclonal antibody approved by the FDA in June 2021 for the treatment of Alzheimer's disease but failed to show the expected clinical efficacy in phase III trials. This review analyzes the history of its controversial acceptance, implications, and prospects for future treatment.

La enfermedad de Alzheimer es la principal causa de demencia en todo el mundo y representa un importante problema de salud pública. Si bien las muertes por enfermedades cardiovasculares han disminuido, las atribuidas a la enfermedad de Alzheimer han aumentado en los últimos años y hasta la fecha no existe tratamiento curativo. Por este motivo, el desarrollo de un tratamiento eficaz se ha convertido en una prioridad mundial. Aducanumab es un anticuerpo monoclonal anti-amiloide ß humano aprobado para el tratamiento de la enfermedad de Alzheimer en junio de 2021 por la FDA, sin la eficacia clínica esperada en los ensayos de fase III. Esta revisión analiza la historia de su controvertida aceptación, implicaciones y perspectivas para el tratamiento futuro.

Selection of disease modifying therapies in multiple sclerosis based on patient's age and disease activity: Data from a nationwide registry.

BACKGROUND: Knowledge of the safety and efficacy of disease-modifying therapies (DMTs) in older patients with Multiple Sclerosis (pwMS) is limited due to their exclusion from clinical trials. Our purpose is to evaluate the choice of DMTs in pwMS older than 50 years old in a real-world setting. METHODS: Cross-sectional study of pwMS from the Argentine MS and NMOSD Registry. We included patients under 35 and above 50 years old prescribed DMTs. Disease activity was categorized as highly active (HA) or not highly active (NHA), and DMTs were classified as low efficacy therapies (LET) or high efficacy therapies (HET). RESULTS: 1460 patients (65% females) were enrolled. The HA group comprised 241 patients, 198 young (82.2%) and 43 older (17.8%). The NHA group included 1219 patients, 893 young (73%) and 326 older (27%). In the NHA group, older patients received LET more frequently than younger patients (66% versus 44%; p < 0.01). In the HA group, older patients received LET in 61% of cases, whereas younger patients received HET in 71% (p = 0.01). CONCLUSION: The study shows the preference of LET in older patients regardless of disease activity. However it does not demonstrate a difference in disability in older patients based on low vs high efficacy DMTs used, probably due to the design of the study. Further longitudinal studies are warranted to address this issue.

Central nervous system demyelinating diseases: glial cells at the hub of pathology.

Inflammatory demyelinating diseases (IDDs) are among the main causes of inflammatory and neurodegenerative injury of the central nervous system (CNS) in young adult patients. Of these, multiple sclerosis (MS) is the most frequent and studied, as it affects about a million people in the USA alone. The understanding of the mechanisms underlying their pathology has been advancing, although there are still no highly effective disease-modifying treatments for the progressive symptoms and disability in the late stages of disease. Among these mechanisms, the action of glial cells upon lesion and regeneration has become a prominent research topic, helped not only by the discovery of glia as targets of autoantibodies, but also by their role on CNS homeostasis and neuroinflammation. In the present article, we discuss the participation of glial cells in IDDs, as well as their association with demyelination and synaptic dysfunction throughout the course of the disease and in experimental models, with a focus on MS phenotypes. Further, we discuss the involvement of microglia and astrocytes in lesion formation and organization, remyelination, synaptic induction and pruning through different signaling pathways. We argue that evidence of the several glia-mediated mechanisms in the course of CNS demyelinating diseases supports glial cells as viable targets for therapy development.

Achieving no evidence of disease activity-3 in highly active multiple sclerosis patients treated with cladribine and monoclonal antibodies.

Background: We aimed to determine the proportion of highly active multiple sclerosis patients under high-efficacy therapies (HETs) achieve no evidence of disease activity-3 (NEDA-3) at 1 and 2 years, and to identify factors associated with failing to meet no evidence of disease activity 3 at 2 years. Methods: This retrospective cohort study based on Argentina Multiple Sclerosis patient registry (RelevarEM), includes highly active multiple sclerosis patients who received HETs. Results: In total, 254 (78.51%) achieved NEDA-3 at year 1 and 220 (68.12%) achieved NEDA-3 at year 2. Patients who achieved NEDA-3 at 2 years had a shorter duration of multiple sclerosis (p < 0.01) and a shorter time between first treatment and current treatment (p = 0.01). Early high-efficacy strategy patients reached NEDA-3 more frequently (p < 0.01). Being a naïve patient (odds ratio: 3.78, 95% confidence interval 1.50-9.86, p < 0.01) was an independent predictor to reach NEDA-3 at 2 years. No association was found between type of HETs and NEDA-3 at 2 years when adjusted for potential confounders (odds ratio: 1.73; 95% confidence interval 0.51-6.06, p 0.57). Conclusion: We found a high proportion of patients who achieved NEDA-3 at 1 and 2 years. Early high-efficacy strategy patients had a higher probability of achieving NEDA-3 at 2 years.

Disease activity after discontinuation of disease-modifying therapies in patients with multiple sclerosis in Argentina: data from the nationwide registry RelevarEM.

INTRODUCTION: The discontinuation of disease-modifying therapies (DMTs) in multiple sclerosis (MS) is commonly seen in real-world settings due to several factors. AREA COVER: The aim of this study is to describe the frequency of disease activity after discontinuation of DMTs in MS patients included in the Argentinean MS and NMOSD registry. DISCUSION: Patients with relapsing remitting MS (RRMS) and active secondary progressive MS (SPMS) were included based on the following criteria: they discontinued treatment for more than 6 months, they had been treated with a DMT for ≥2 years, and they had at least 6 months of follow-up in the registry after discontinuation. Demographic and clinical data were collected. Disease activity during follow-up was defined as the presence of a clinical relapse or a new magnetic resonance (MRI) lesion (either new lesions on T2-weighted sequence and/or contrast enhancement). Bivariate analysis was applied to identify clinical and demographic factors related to disease activity. CONCLUSION: We included 377 patients (75.5% RRMS, 22.5% SPMS) who had discontinued DMTs. The mean (SD) follow-up after discontinuation was 15.7 (7.9) months. After discontinuation, the presence of relapse was detected in 18.8% and 3.5% in RRMS and SPMS, respectively; and new MRI activity in 22% and 3.5%, respectively. We found that higher risk of relapse and MRI activity was associated with younger age (p < 0.001), shorter disease duration (p < 0.001), and RRMS phenotype (p = 0.006). Males showed higher MRI activity (p 0.011). This study provides real-world data that can guide physicians when considering discontinuation of DMTs.

TnP Peptide Suppresses Experimental Autoimmune Encephalomyelitis (EAE) in a Preclinical Mouse Model.

TnP is a family of patented synthetic peptides which is in a preclinical development stage with valuable potential therapeutic indication for multiple sclerosis (MS), an autoimmune demyelinating disease of the central nervous system (CNS). The use of a preclinical animal model, such as experimental autoimmune encephalomyelitis (EAE) has deepened our knowledge of the immunomodulatory functions of TnP as a drug. We have shown that TnP possesses a disease suppressive function in EAE, ameliorating disease severity by 40% and suppressing the accumulation of T helper (Th)1- and Th17-producing lymphocytes (by 55% and 60%, respectively) in CNS along with activated microglia/macrophages populations (by 33% and 50%, respectively), and also conferred a protective effect anticipating the remyelination process to day 66 compared to day 83 of untreated cuprizone-mice. Here we expanded our knowledge about its effects compared with current first-line disease-modifying therapies (DMT). We demonstrated that prophylactic treatment with TnP generated similar protection to betaseron (30%) or was more effective than glatiramer (44% versus 6%) or fingolimod (50% versus 19%) against the development of clinical symptoms. Although TnP controlled the leukocyte infiltration (87% versus 82%) into demyelinated areas of the spinal cord in the same way as betaseron and fingolimod, it was more effective (72% to 78% decrease) in the long-term control of neuronal degeneration compared to them. Also, when compared to glatiramer, TnP was more efficient in reversing leukocytes infiltration into the spinal cord (55% versus 24%), as well as induced a higher percentage of regulatory cells in spleen (2.9-fold versus 2.3-fold increase over vehicle-treated EAE mice) an in the spinal cord (8-fold versus 6-fold increase over vehicle-treated EAE mice). This specialized TnP profile for inducing immune tolerance and neuronal regeneration has significant therapeutic potential for the treatment of MS and other autoimmune diseases.

Interferon-Beta Injection in Multiple Sclerosis Patients Related to the Induction of Headache and Flu-Like Pain Symptoms: A Systematic Review and Meta-Analysis of Randomised Controlled Trials.

Multiple sclerosis (MS) is a chronic neurodegenerative, inflammatory, and autoimmune disease characterised by the demyelination of the central nervous system. One of the main approaches for treating MS is the use of disease-modifying therapies (DMTs). Among the DMTs are interferons (IFNs), which are cytokines responsible for controlling the activity of the immune system while exerting immunomodulatory, antiviral, and antiproliferative activities. IFN-beta (IFN-ß) is the first-choice drug used to treat relapsing-remitting MS. However, the administration of IFN-ß causes numerous painful adverse effects, resulting in lower adherence to the treatment. Therefore, this study aimed to investigate the headache and flu-like pain symptoms observed after IFNß injection in MS patients using a systematic review and meta-analysis of randomised controlled trials. A total of 2370 articles were identified through research databases. Nine articles were included (three involving IFNß-1b and six involving IFNß-1a). All studies included in the meta-analysis had a low risk of bias. The odds ratio of headache and flu-like pain symptoms increased in MS patients treated with IFN-ß. Thus, the adverse effects of headache and flu-like pain symptoms appear to be linked to IFN-ß treatment in MS. The protocol of the study was registered in the Prospective International Registry of Systematic Reviews (registration number CRD42021227593).

TnP peptide suppresses experimental autoimmune Encephalomyelitis (EAE) in a preclinical mouse model

TnP is a family of patented synthetic peptides which is in a preclinical development stage with valuable potential therapeutic indication for multiple sclerosis (MS), an autoimmune demyelinating disease of the central nervous system (CNS). The use of a preclinical animal model, such as experimental autoimmune encephalomyelitis (EAE) has deepened our knowledge of the immunomodulatory functions of TnP as a drug. We have shown that TnP possesses a disease suppressive function in EAE, ameliorating disease severity by 40% and suppressing the accumulation of T helper (Th)1- and Th17-producing lymphocytes (by 55% and 60%, respectively) in CNS along with activated microglia/macrophages populations (by 33% and 50%, respectively), and also conferred a protective effect anticipating the remyelination process to day 66 compared to day 83 of untreated cuprizone-mice. Here we expanded our knowledge about its effects compared with current first-line disease-modifying therapies (DMT). We demonstrated that prophylactic treatment with TnP generated similar protection to betaseron (30%) or was more effective than glatiramer (44% versus 6%) or fingolimod (50% versus 19%) against the development of clinical symptoms. Although TnP controlled the leukocyte infiltration (87% versus 82%) into demyelinated areas of the spinal cord in the same way as betaseron and fingolimod, it was more effective (72% to 78% decrease) in the long-term control of neuronal degeneration compared to them. Also, when compared to glatiramer, TnP was more efficient in reversing leukocytes infiltration into the spinal cord (55% versus 24%), as well as induced a higher percentage of regulatory cells in spleen (2.9-fold versus 2.3-fold increase over vehicle-treated EAE mice) an in the spinal cord (8-fold versus 6-fold increase over vehicle-treated EAE mice). This specialized TnP profile for inducing immune tolerance and neuronal regeneration has significant therapeutic potential for the treatment of MS and other autoimmune diseases.

Predictors of adherence and persistence to disease-modifying therapies in Multiple Sclerosis.

BACKGROUND AND AIMS: In multiple sclerosis (MS), non-adherence/non-persistence is related to suboptimal response to treatment, including disease relapses and the need for more expensive healthcare. The aim of this study was to identify predictors related to adherence to disease modifying therapies (DMTs) in a cohort of Argentinian MS patients. METHODS: We conducted a cross-sectional study at the National Medical Care Program from Argentina. MS patients with at least one claim for a DMT from 1 January 2017 to 1 October 2017 were identified. A telephone survey was performed to assess clinical and demographic factors. The medication possession ratio (MPR) was used to estimate adherence; MPR <80% defined non-adherence. Associations were studied using a logistic regression model. RESULTS: Our database included 648 MS patients. A total of 360 patients (60% females, mean age 55.3 years) accepted to participate. Of these, 308 (85.5%) patients were receiving DMT at the time of the survey. Some 198 (63.7%) were receiving injectable therapies. Optimal adherence was 47.7%. Adherence was associated with oral medication [odds ratio (OR) 1.83 95% confidence interval (CI) 1.13-3.00, p = 0.014]. A factor related to oral drugs was higher educational level (OR 2.86 95%CI 1.41-5.81, p = 0.004). CONCLUSION: This real-world study showed better adherence and persistence on treatment with oral therapies in MS patients in Argentina.

Barriers to access and utilization of multiple sclerosis care services in a large cohort of Latin American patients.

BACKGROUND: Multiple sclerosis (MS), is an emergent disease in Latin America (LATAM), which raises substantial socioeconomic challenges to a region where most countries remain as economies in development. OBJECTIVE: To assess barriers to access and utilization of MS care services in a regional cohort survey. METHODS: We conducted a cross-sectional study based on a self-reported survey. Patients with MS (PwMS) completed this regional survey in 12 Latin American (LATAM) countries. PwMS were also divided into those with healthcare insurance (including certain local national social security programs) and those without healthcare insurance (treated at public institutions). RESULTS: We surveyed 1469 PwMS and identified significant regional differences in relation to access to complementary tests, rehabilitation services, and prescription of disease-modifying therapies (DMTs). Between 44.4% and 73.5% of PwMS were unemployed and nearly 50% had completed higher education. PwMS receiving care from the private sector reported greater access to imaging, DMTs, and fewer problems obtaining DMTs compared to those treated at public institutions. Multivariate analysis showed that lack of private insurance (OR = 2.21, p < 0.001), longer MS duration (OR = 1.02, p = 0.001), lower level of education (OR = 0.66, p = 0.009), and unemployment (OR = 0.73, p = 0.03) were independently associated with inappropriate delivery of DMTs. CONCLUSION: These findings suggest barriers to access and utilization of MS care services across LATAM are prevalent. We identified several factors predicting unmet healthcare needs in PwMS.

Physical exercise and human adipose-derived mesenchymal stem cells ameliorate motor disturbances in a male rat model of Parkinson's disease.

Parkinson's disease (PD) is a disabling and highly costly neurodegenerative condition with worldwide prevalence. Despite advances in treatments that slow progression and minimize locomotor impairments, its clinical management is still a challenge. Previous preclinical studies, using mesenchymal stem cell (MSC) transplantation and isolated physical exercise (EX), reported beneficial results for treatment of PD. Therefore, this experimental randomized study aimed to elucidate the therapeutic potential of combined therapy using adipose-derived human MSCs (ADSCs) grafted into the striatum in conjunction with aerobic treadmill training, specifically in terms of locomotor performance in a unilateral PD rat model induced by 6-hydroxydopamine (6-OHDA). Forty-one male Wistar rats were categorized into five groups in accordance with the type of treatment to which they were subjected (Sham, 6-OHDA - injury, 6-OHDA + exercise, 6-OHDA + cells, and 6-OHDA + combined). Subsequently, dopaminergic depletion was assessed by the methylphenidate challenge and the specified therapeutic intervention was conducted in each group. The foot fault task was performed at the end of the experiment to serve as an assessment of motor skills. The results showed that despite disturbances in motor balance and coordination, locomotor dysfunction was ameliorated in all treatment categories in comparison to the injury group (sign test, p < 0.001, effect size: 0.71). The exercise alone and combined groups were the categories that exhibited the best recovery in terms of movement performance (p < 0.001). Overall, this study confirms that exercise is a powerful option to improve motor function and a promising adjuvant intervention for stem cell transplantation in the treatment of PD motor symptoms. OPEN PRACTICES: This article has been awarded Open Data. All materials and data are publicly accessible at https://figshare.com/s/18a543c101a17a1d5560. Learn more about the Open Practices badges from the Center for Open Science: https://osf.io/tvyxz/wiki.

Regular Exercise Modifies Histopathological Outcomes of Pharmacological Treatment in Experimental Autoimmune Encephalomyelitis.

Background: Although it has been suggested that healthier lifestyle may optimize effects of the immunomodulation drugs for treating multiple sclerosis (MS), the knowledge regarding this kind of interactions is limited. Objective: The aim of the present study was to investigate the effects of treadmill exercise in combination with pharmacological treatment in an animal model for MS. Methods: C57BL/6J female mice were subjected to daily treadmill exercise for 4 weeks before immunization and 6 weeks before clinical presentation of disease. Dimethyl fumarate (DMF) or glatiramer acetate (GA) were administered after the first clinical relapse. Histopathological analyses were carried out in the lumbar spinal cord at peak disease and at 1 or 14 days post-treatment (dpt). Results: Exercised-GA treated animals demonstrated decreased astrocytic response in the spinal dorsal horn with an improvement in the paw print pressure. Exercised-DMF treated animals showed an increased microglial/macrophage response on both ventral and dorsal horn that were associated with clinical improvement and synaptic motoneuron inputs density. Conclusion: The present data suggest that prior regular exercise can modify the effects of pharmacological treatment administered after the first relapse in a murine model for MS.

Stem Cell Transplantation and Physical Exercise in Parkinson's Disease, a Literature Review of Human and Animal Studies.

The absence of effective and satisfactory treatments that contribute to repairing the dopaminergic damage caused by Parkinson's Disease (PD) and the limited recovery capacity of the nervous system are troubling issues and the focus of many research and clinical domains. Recent advances in the treatment of PD through stem cell (SC) therapy have recognized their promising restorative and neuroprotective effects that are implicated in the potentiation of endogenous mechanisms of repair and contribute to functional locomotor improvement. Physical exercise (PE) has been considered an adjuvant intervention that by itself induces beneficial effects in patients and animal models with Parkinsonism. In this sense, the combination of both therapies could provide synergic or superior effects for motor recovery, in contrast with their individual use. This review aims to provide an update on recent progress and the potential effectiveness of SC transplantation and PE for the treatment of locomotor deficits in PD. It has reviewed the neuropathological pathways involved in the classical motor symptoms of this condition and the mechanisms of action described in experimental studies that are associated with locomotor enhancement through exercise, cellular transplantation, and their union in some neurodegenerative conditions.

Disease-modifying therapies in multiple sclerosis in Latin America.

The treatment of multiple sclerosis (MS) has become increasingly complex during the last 10 years, mainly because of the advent of new and more potent disease-modifying therapies (DMTs). In Latin America, the therapeutic repertoire available for MS treatment is similar to the one in the rest of the world, but the high costs of these drugs, in conjunction with the limited resources of the social security health systems, makes the treatment of MS more difficult. For neurologists in Latin America, providing personalized MS treatment has become a challenge. We present a review of the status of the DMT in Central and South America, benefits as well as limitations for providing full access to these medications in Latin America.