Sclerosis, Volume 3, Issue 1 (March 2025) – 8 articles

Background/Objectives: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the progressive degeneration of motor neurons. The gut microbiota, a community of microorganisms in the digestive tract, has recently been implicated in ALS pathogenesis through its influence on neuroinflammation and metabolic pathways. This review explores the potential role of digestive microbiota and its metabolites in ALS progression and investigates therapeutic approaches targeting gut microbiota. Methods: A comprehensive review of the current literature was conducted to assess the relationship between gut microbiota composition, microbial metabolites, and ALS progression in patients. We searched for published reports on microbiota composition, microbial metabolites, and ALS, emphasizing the complex interplay between dysbiosis, neuroinflammation, and systemic metabolism. Special emphasis was placed on studies exploring short-chain fatty acids (SCFAs), bacterial amyloids (curli-like factors), and neurotoxins such as β-methylamino-L-alanine (BMAA). The role of the liver–gut axis was evaluated as well. The potential changes in microbiota would sustain the rationale for therapeutic strategies such as probiotics, prebiotics, fecal microbiota transplantation (FMT), and dietary interventions. Results: ALS patients exhibit gut dysbiosis, characterized by reduced SCFA-producing bacteria and an increase in potentially pathogenic genera. Of note, different studies do not agree on common patterns of microbiota being linked to ALS, supporting the need for further, more extensive studies. Dysbiosis sometimes correlates with systemic inflammation and disrupted liver function, amplifying neuroinflammatory responses. Key microbial metabolites, including SCFAs, bacterial amyloids, and BMAA, may exacerbate motor neuron degeneration by promoting protein misfolding, oxidative stress, and neuroinflammation. Emerging therapeutic strategies, including probiotics and FMT, show potential in restoring microbial balance, although clinical data in ALS patients remain limited. Conclusions: The gut microbiota could modulate neuroinflammation and systemic metabolism in ALS. Microbiota-targeted therapies, such as probiotics and dietary interventions, represent promising avenues for mitigating disease progression. Further research is required to validate these interventions through large-scale, longitudinal studies and to develop personalized microbiota-based treatments tailored to individual ALS phenotypes. Full article

Background: The 2011 Very Early Diagnosis of Systemic Sclerosis (VEDOSS) criteria include both patients at risk of progression and those with mild non-progressive forms of SSc. Early diastolic and systolic dysfunction can indicate myocardial fibrosis in SSc patients, yet data on myocardial impairment in the VEDOSS population are limited. Objectives: This study aimed to identify subclinical echocardiographic changes and predictive markers of cardiac dysfunction in both very early and mild-longstanding forms of VEDOSS. Methods: We conducted a cross-sectional observational study involving 61 patients meeting VEDOSS criteria followed up regularly within our Scleroderma referral center. Patients were categorized as early VEDOSS (e-VEDOSS) or mild-longstanding VEDOSS (ml-VEDOSS) based on disease duration (≥10 years). We analyzed clinical and demographic data, focusing on echocardiographic parameters such as the E/A ratio and left ventricular (LV) thickness. Statistical analyses included chi-square, Fischer exact, and student’s t tests, with a significance threshold of p < 0.05. Results: ml-VEDOSS patients were older and reported a higher burden of comorbidities. Autoantibody-positive patients exhibited lower E/A ratios and increased left atrial size. Late nailfold videocapillaroscopic pattern patients exhibited increased PWED thickening and aortic valve insufficiency. Notably, patients undergoing vasodilators experienced larger right atrial volume, while patients receiving Renin-Angiotensin-Aldosterone System (RAAS) inhibitors reported reduced E/A ratio. Multivariable analysis confirmed DLCO% as the sole predictor of both diastolic and systolic impairment in VEDOSS population. Conclusions: Careful monitoring of cardiac function in VEDOSS patients is crucial as subclinical alterations may occur even in the absence of symptoms. DLCO% emerged as an important predictor of LV diastolic dysfunction. Full article

Apolipoprotein L1 (APOL1) genetic variations, notably the G1 and G2 alleles, have important roles in the pathophysiology of focal segmental glomerulosclerosis (FSGS) and other kidney problems, especially in people of African descent. This review summarizes current understanding about the genetic, molecular, and clinical features of APOL1-associated FSGS and investigates new therapeutic options. It reveals how APOL1 mutations generate kidney injury through mechanisms such as podocyte dysfunction, mitochondrial impairment, and dysregulated inflammatory networks. Recent treatment developments, such as small-molecule inhibitors like inaxaplin, antisense oligonucleotides, and novel interventions targeting lipid metabolism and inflammatory pathways, are being assessed for their capacity to address the specific issues presented by APOL1-associated nephropathy. We also address gaps in knowledge, such as the function of environmental triggers and the systemic consequences of APOL1 mutations, emphasizing the significance of targeted research. Full article

Background: Systemic sclerosis (SSc), also known as scleroderma, is a complex, chronic autoimmune disease characterized by fibrosis of the skin and internal organs, vasculopathy, and immune system dysregulation. The treatment of SSc has historically focused on symptom management and slowing down disease progression through conventional immune-suppressive agents. New therapeutic approaches have been emerging due to advances in understanding of the disease mechanisms, particularly in the areas of fibrosis, vascular involvement, and immune dysregulation. Methods: In this review of the literature, we discuss the current stage of development of B-cell-depleting immune therapies in SSc. Results: B-cell depletion therapy has become an area of growing interest in the treatment of SSc due to the role played by B cells in the pathogenesis of the disease. There is increasing evidence that B cells contribute to disease progression through multiple mechanisms. B cells in SSc are implicated in autoantibody production, cytokine production, and fibroblast activation. B cells are responsible for producing autoantibodies, such as anti-topoisomerase I (Scl-70) and anti-centromere antibodies, which are hallmarks of SSc. B cells release pro-inflammatory cytokines (such as interleukin-6 [IL-6] and transforming growth factor β [TGF-β]), which promote fibrosis and inflammation, they also contribute to the activation of fibroblasts, the cells responsible for excessive collagen production and fibrosis, a key feature of SSc. Conclusions: In light of these findings, therapies that target B cells are being investigated for their potential to modify the disease course in SSc, particularly by reducing autoantibody production, inflammation, and fibrosis. Full article

Background: Multiple sclerosis (MS) is a chronic inflammatory disease characterized by demyelination in the central nervous system (CNS). Despite the availability of interventions for disease exacerbations and symptomatic management, EM remained without a cure. Oxidative stress has been implicated in the MS demyelination mechanism. Adjuvant therapies like α-lipoic acid (ALA) have garnered interest for their potential to mitigate oxidative damage and control MS symptoms. ALA is found naturally in vegetables and red meat and can also be synthesized in mitochondria through enzymatic reactions involving octanoic acid and cysteine. However, its bioavailability from dietary sources is limited, prompting an investigation into supplemental forms. We conducted a systematic review and meta-analysis to assess the effect of ALA on disability in randomized clinical trials (RCTs) for MS. Methods: Records were searched until June 2023 (CRD42023397760). Five RCTs evaluated ALA’s effect on MS progression using the Expanded Disability Status Scale (EDSS). The quality of evidence was assessed using GRADE, and publication bias was evaluated using Egger’s and Begg’s tests. Results: Following the selection process, five studies were included involving 179 patients (87 placebo and 92 ALA). Oral administration of racemic ALA (R/S-ALA) at 600 mg twice daily reduced EDSS, indicating a potential for ALA supplementation to mitigate MS disability. The North American trials (SPMS patients) did not show heterogeneity, while Asian studies (RRMS patients) were moderated. The quality of evidence was high without publication bias. Conclusions: ALA treatment reduce EDSS scores. However, further studies are warranted to establish the role of ALA as an adjuvant in clinical practice in long-term follow-up (>2 years) RCTs. Full article

Background/Objectives: Footfall placement variability is associated with falls in older adults and neurological diseases. Thus, the study of dual-task gait impairment in middle-aged to older-aged adults with multiple sclerosis (MS) is clinically relevant, particularly in environments that mimic the obstacles experienced in daily ambulation. Methods: A total of 10 middle-aged to older-aged adults with MS (eight female, mean ± SD age = 56 ± 5 years), 12 healthy older adults (HOAs, nine female, age = 63 ± 4 years), and 10 healthy young adults (HYAs, five female, age = 22 ± 3) were asked to perform cued walking (CW) or obstacle walking (OW) tasks without or with a concurrent backward alphabet recitation task (CWT, OWT), or dual tasks. Gait performance and attentional demands were measured using hit rate, stride velocity, footfall placement bias and variance, and prefrontal cortex (PFC) oxygenated hemoglobin HbO levels. Results: A significant dual-task condition-by-cohort interaction was seen in footfall placement bias and variance as indicated by a higher footfall placement bias and variance in dual-task vs. single-task conditions seen in HOAs, in comparison to HYAs and adults with MS. Further, a significant walking condition-by-cohort interaction was seen in the HbO levels as indicated by the higher PFC HbO levels seen in OW vs. CW in adults with MS, compared to adults without MS. Conclusions: The decreased accuracy and increased attention in footfall placement to visual cues on the ground observed in adults with MS and HOAs, relative to HYAs, may provide a marker for gait impairment and fall risk in older adults with MS. Full article

Background/Objectives: Multiple sclerosis (MS) is a chronic autoimmune disease marked by inflammatory demyelination in the central nervous system, leading to debilitating spasticity. Managing spasticity in MS remains a challenge, and intrathecal baclofen (ITB) therapy has emerged as a potential targeted treatment. This systematic review investigated the efficacy of ITB pumps in managing MS-related spasticity and explored their immunomodulatory effects. Methods: This review adhered to PRISMA guidelines and was submitted for registration retrospectively with the Open Science Foundation. A comprehensive literature search was conducted in PubMed, Embase, Scopus, and Web of Science from January 2013 to August 2024. Studies were included if they examined adult MS patients receiving ITB for spasticity, reporting outcomes related to spasticity and quality of life. Risk of bias was assessed using the Joanna Briggs Institute Critical Appraisal Tools, and findings were synthesized narratively. Results: Eight studies (n = 723 participants) met inclusion criteria. ITB was associated with significant reductions in spasticity severity and improvements in quality of life, with reduced reliance on oral antispasticity medications. Immunologically, ITB has demonstrated potential in modulating inflammatory pathways, downregulating pro-inflammatory cytokines, and shifting immune responses toward an anti-inflammatory profile. Common complications included catheter-related issues and infections, with low overall complication rates. Sensitivity analyses indicated robustness in outcomes across higher-quality studies. Conclusions: ITB pumps are effective in controlling spasticity and offer additional immunological benefits for MS patients. Further research should explore ITB’s long-term immunomodulatory effects and its potential in combined therapeutic strategies. The review was not financially supported, and no conflicts of interest were declared by the authors. Full article

Background: Amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) are, in essence, neurodegenerative disorders with significant individual, social, and economic burdens worldwide. Despite having different clinical onset and evolution, the two diseases share common risk factors and underlying pathophysiological mechanisms. Environmental risk factors are particularly interesting, considering the available effective counter strategies. High-fat diets remain a significant element that negatively impacts the onset and evolution of several disorders, including ALS and MS. Focusing on changeable disease-related aspects is increasingly appealing in the context of a lack of an effective treatment. Methods: This review aims to offer an updated overview of the influence of high-fat diets in modulating the risk of onset and progression of ALS and MS, based on the search of three relevant online databases. Results: In the first part, the shared pathophysiological mechanisms of ALS and MS are shown, and significant differences between the two disorders are highlighted. Subsequently, the most relevant research on this topic conducted in animal models and humans is presented, bringing additional proof of the critical role of high-fat diets in neurodegeneration. Finally, based on current knowledge, the authors offer potential therapeutic approaches and future relevant research directions to better control nutrition in ALS and MS patients, hoping to increase survival and quality of life. Conclusions: High-fat diets negatively impact the onset and evolution of ALS and MS. Full article