Background:
Stigma is prevalent among individuals with chronic diseases, such as multiple sclerosis (MS) and those with comorbid mental health disorders, but its associated factors are poorly ...understood.
Objective:
To investigate the prevalence and correlates of stigma in people living with MS.
Methods:
We analyzed data from the MS Partners Advancing Technology and Health Solutions (MS PATHS) network, which collected patient information and outcomes during routine clinic visits. We used a multinomial logistic regression model to examine the cross-sectional association between stigma and demographic, socioeconomics, and MS-related factors.
Results:
We included 11,634 participants. The mean Neuro-QoL stigma T-score was 47.2 ± 8.6, and 17.7% of participants were classified as having moderate to severe stigma using established cutoffs. Multinomial logistic regression models suggest that higher disability levels, progressive form of the disease, shorter duration of the disease, and unemployment were associated with higher stigma while being male, married, undergoing treatment with high-efficacy disease-modifying therapies (DMTs), and being from European MS centers were associated with lower stigma perception. Disability levels, measured by Patient-Determined Disease Steps (PDDS), had the strongest independent association with stigma.
Conclusion:
Stigma remains a relevant issue for people living with MS. Factors, such as physical and cognitive disability, DMT, and employment status may influence the severity of perceived stigma.
Background:
Fatigue is the most common symptom of MS and has no effective pharmacotherapy.
Objective:
To determine the tolerability, safety, and efficacy of low-dose ketamine infusion for MS-related ...fatigue.
Methods:
In this double-blind, randomized, active-placebo-controlled trial, 18 subjects with multiple sclerosis (MS) and reported fatigue received a single intravenous infusion of ketamine (0.5 mg/kg) or midazolam (0.05 mg/kg). The primary outcome was change in Daily Fatigue Severity (DFS) for 7 days following the infusion. Secondary outcomes included Fatigue Severity Scale (FSS) and Modified Fatigue Impact Scale (MFIS) measured up to day 28 post-infusion. We analyzed changes in all outcomes using mixed-effect models.
Results:
In total, 18 participants were enrolled; 67% participants received ketamine. Side effects of ketamine were transient. No change in the DFS was observed after 7 days (−0.10 point; 95% confidence interval (CI): −0.32, 0.12; p = 0.40). We observed a trend in reduced FSS scores at 1 week (−5.2 points; 95% CI: −10.4, 0.14; p = 0.06) and a clinically and statistically significant reduction in MFIS score at day 28 (−13.5 point; 95% CI: −25.0, −1.98; p = 0.04).
Conclusions:
Ketamine infusions were safe and well-tolerated. While no change in DFS after 7 days was observed, secondary analyses suggest a benefit of ketamine infusion for reduction of longer term fatigue severity in people with MS.
Background:
Results of research on radiological hallmarks of multiple sclerosis (MS) fatigue have been conflicting.
Objective:
To investigate the associations of lesion and brain compartment volumes ...with fatigue severity and persistence in people with multiple sclerosis (PwMS).
Methods:
The Multiple Sclerosis Partners Advancing Technology and Health Solutions (MS PATHS) network collects standardized data during routine care of PwMS from 10 healthcare institutions. Magnetic resonance imaging (MRI) predictors included baseline brain parenchymal (BPF) and gray matter fractions (GMF) and T2 lesion volume (T2LV). The Quality of Life in Neurological Disorders (Neuro-QOL) fatigue subscore was analyzed linearly and categorically using T-score cutpoints, with a period of elevated symptoms defined as T-score ⩾ mean + 0.5 SD over follow-up.
Results:
At baseline, of 4012 participants (average age: 45.6 ± 11.8 years; 73% female; 31% progressive MS), 2058 (51%) had no fatigue, 629 (16%) had mild fatigue, and 1325 (33%) had moderate-to-severe fatigue. One SD greater baseline BPF and GMF were associated with 0.83 (p < 0.001) and 0.38 (p = 0.02) lower values in the baseline Neuro-QOL fatigue T-score. A 1 SD lower log of total T2LV was associated with a 0.49 (p < 0.001) lower baseline fatigue T-score. Higher BPF and lower T2LV at baseline were associated with lower odds of subsequent periods of elevated fatigue.
Conclusion:
Baseline lesion burden and lower generalized whole-brain volumes were associated with MS fatigue in cross-sectional and longitudinal analyses in a large, real-world cohort of PwMS.
Background:
The circulating metabolome is altered in multiple sclerosis (MS), but its prognostic capabilities have not been extensively explored. Lipid metabolites might be of particular interest due ...to their multiple roles in the brain, as they can serve as structural components, energy sources, and bioactive molecules. Gaining a deeper understanding of the disease may be possible by examining the lipid metabolism in the periphery, which serves as the primary source of lipids for the brain.
Objective:
To determine if altered serum lipid metabolites are associated with the risk of relapse and disability in children with MS.
Methods:
We collected serum samples from 61 participants with pediatric-onset MS within 4 years of disease onset. Prospective longitudinal relapse data and cross-sectional disability measures (Expanded Disability Status Scale EDSS) were collected. Serum metabolomics was performed using untargeted liquid chromatography and mass spectrometry. Individual lipid metabolites were clustered into pre-defined pathways. The associations between clusters of metabolites and relapse rate and EDSS score were estimated utilizing negative binomial and linear regression models, respectively.
Results:
We found that serum acylcarnitines (relapse rate: normalized enrichment score NES = 2.1, q = 1.03E–04; EDSS: NES = 1.7, q = 0.02) and poly-unsaturated fatty acids (relapse rate: NES = 1.6, q = 0.047; EDSS: NES = 1.9, q = 0.005) were associated with higher relapse rates and EDSS, while serum phosphatidylethanolamines (relapse rate: NES = −2.3, q = 0.002; EDSS: NES = −2.1, q = 0.004), plasmalogens (relapse rate: NES = −2.5, q = 5.81E–04; EDSS: NES = −2.1, q = 0.004), and primary bile acid metabolites (relapse rate: NES = −2.0, q = 0.02; EDSS: NES = −1.9, q = 0.02) were associated with lower relapse rates and lower EDSS.
Conclusion:
This study supports the role of some lipid metabolites in pediatric MS relapses and disability.
Fatigue is one of the most common multiple sclerosis (MS) symptoms. Despite this, monitoring and measuring fatigue (subjective lack of energy)- and fatigability (objectively measurable and ...quantifiable performance decline)- in people with MS have remained challenging. Traditionally, administration of self-report questionnaires during in-person visits has been used to measure fatigue. However, remote measurement and monitoring of fatigue and fatigability have become feasible in the past decade. Traditional questionnaires can be administered through the web in any setting. The ubiquitous availability of smartphones allows for momentary and frequent measurement of MS fatigue in the ecological home-setting. This approach reduces the recall bias inherent in many traditional questionnaires and demonstrates the fluctuation of fatigue that cannot be captured by standard measures. Wearable devices can assess patients' fatigability and activity levels, often influenced by the severity of subjective fatigue. Remote monitoring of fatigue, fatigability, and activity in real-world situations can facilitate quantifying symptom-severity in clinical and research settings. Combining remote measures of fatigue as well as objective fatigability in a single construct, composite score, may provide a more comprehensive outcome. The more granular data obtained through remote monitoring techniques may also help with the development of interventions aimed at improving fatigue and lowering the burden of this disabling symptom.
The circulating metabolome provides unique insights into multiple sclerosis (MS) pathophysiology, but existing studies are relatively small or characterized limited metabolites. We test for ...differences in the metabolome between people with MS (PwMS; n = 637 samples) and healthy controls (HC; n = 317 samples) and assess the association between metabolomic profiles and disability in PwMS. We then assess whether metabolic differences correlate with changes in cellular gene expression using publicly available scRNA-seq data and whether identified metabolites affect human immune cell function. In PwMS, we identify striking abnormalities in aromatic amino acid (AAA) metabolites (p = 2.77E−18) that are also strongly associated with disability (p = 1.01E−4). Analysis of scRNA-seq data demonstrates altered AAA metabolism in CSF and blood-derived monocyte cell populations in PwMS. Treatment with AAA-derived metabolites in vitro alters monocytic endocytosis and pro-inflammatory cytokine production. We identify shifts in AAA metabolism resulting in the reduced production of immunomodulatory metabolites and increased production of metabotoxins in PwMS.
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•Significant alterations in the circulating metabolome are noted in multiple sclerosis•Aromatic amino acid (AAA) metabolite levels are linked to disease severity•Expression of AAA metabolism genes is altered in MS blood and CSF immune cells•AAA metabolites alter human monocyte cytokine production and endocytosis
Fitzgerald et al. identify alterations in circulating aromatic amino acid (AAA) metabolites in multiple sclerosis that are related to disease severity. They also demonstrate changes in AAA metabolism-related gene expression in blood and cerebrospinal fluid immune cells, and that treatment with AAA metabolites alters monocyte pro-inflammatory cytokine production and endocytosis.
Mast cells (MCs) have been thought to play a pathogenic role in the development of autoimmune diseases, including experimental autoimmune encephalomyelitis (EAE), an animal model of multiple ...sclerosis. However, an immunoregulatory function of these cells has recently been suggested. We investigated the role of MCs in EAE using the W(-sh) mouse strain, which is MC deficient. W(-sh) mice developed earlier and more severe clinical and pathological disease with extensive demyelination and inflammation in the CNS. The inflammatory cells were mainly composed of CD4(+) T cells, monocyte/macrophages, neutrophils, and dendritic cells. Compared with wild-type mice, MC-deficient mice exhibited an increased level of MCP-1/CCR2 and CD44 expression on CD4(+) T cells in addition to decreased production of regulatory T cells, IL-4, IL-5, IL-27, and IL-10. We also found that levels of IL-17, IFN-γ, and GM-CSF were significantly increased in peripheral lymphocytes from immunized W(-sh) mice compared with those in peripheral lymphocytes from wild-type mice. Reconstitution of W(-sh) mice downregulated susceptibility to EAE, which correlated with MC recruitment and regulatory T cell activation in the CNS. These findings indicate that responsiveness is not required in the pathogenesis of inflammatory demyelination in the CNS and that, in the absence of MCs, increased MCP-1, CCR2, IL-17, IFN-γ, CD44, and other inflammatory molecules may be responsible for increased severity of EAE.
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