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Background: Cognitive impairment (CI) is common in multiple sclerosis (MS), affecting half of persons with MS (PwMS). Cognitive reserve has been associated with delaying the onset and slowing the progression of CI in PwMS. Multilingualism has been demonstrated to be a protective factor against CI in Alzheimer's disease (AD) but has never been studied in PwMS., Objective: To explore if multilingualism is a protective factor against CI in PwMS., Methods: This is a retrospective cohort study of PwMS aged 18-59, with a confirmed diagnosis of relapsing MS, fluent in English, who completed the Minimal Assessment of Cognitive Function in MS (MACFIMS) at the London (ON) MS Clinic. Any PwMS with a history of dementia or developmental delay, daily marijuana use, a major psychiatric disorder, or less than grade 9 education was excluded. We focused on the Brief Visuospatial Memory Test (BVMTR), immediate recall (-IR) and delayed recall (-DR) as it would be the least affected by language, as well as the Symbol Digit Modalities Test (SDMT), as information processing speed is the most commonly affected domain in PwMS. One-way ANOVA was used to compare raw scores on the BVMTR and SDMT between groups (uni- vs. multillingual), while chi-square was used to compare impairment on BVMTR and SDMT between groups., Results: The cohort consisted of 678 subjects. The mean age was 39.7 (± 9.6) years with 501 (73.9 %) females (sex at birth), the mean duration of disease of 5.9 (± 6.9) years, and mean years of education was 13.9 (±2.2). The majority of subjects (563, 83 %) were unilingual and (115, 17 %) were multilingual; 102 subjects were bilingual and 13 subjects fluent in ≥ three languages. English was the first language was in most of subjects (614, 90.6 %). There was no significant difference on the BVMTR-IR scores (p = 0.189) or BVMTR-DR (p = 0.096) between groups. Similarly, there was no difference in the number of subjects impaired on the BVMTR-IR (X2 (1, N = 678) = 3.167, p = 0.057) or BVMT-DR between groups (X2 (1, N = 678) = 2.996, p = 0.083). Further, there was no significant difference on the SDMT (p = 0.506) between groups, or in number of subjects impaired on the SDMT between groups (X2 (1, N = 678) = 1.023, p = 0.312)., Conclusion: This study shows that multilingualism does not have a protective effect against CI in PwMS and does not play a role in enriching the cognitive reserve, in contrast to studies in AD. This difference may be explained by a different underlying pathological mechanism in these diseases and warrants further study., Competing Interests: Declaration of Competing Interest This study was self—funded. There was no financial support for the conduct of the research and/or preparation of the article., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Persons with Multiple Sclerosis (PwMS) have a higher rate of anxiety and depression than the general population. Depression has been associated with clinical relapses; temporal lesions were shown to predict depression severity. Anxiety is considerably understudied. The role of MS lesions in the limbic system is also understudied, partly due to difficulties identifying limbic lesions on standard 1.5 and 3 Tesla MRI., Methods: This is a retrospective study of 23 PwMS who underwent 7T MRI on the same day as completing the Hospital Anxiety and Depression Scale (HADS). MRI was performed on a Siemens 7T MRI Plus and an 8-channel transmit coil with 32 receiver channels operating in pTx mode. MP2RAGE and DIR-SPACE sequences were analyzed to determine the number of lesions within the limbic system., Results: The median number of lesions in the limbic system was 2.0 (range 0-7). When comparing the presence or absence of lesions in the limbic system, there was a significant relationship with anxiety (X 2 (1, N = 23)=4.44, p = 0.035), but not for depression., Conclusion: Although only a small sample size, this study provides preliminary evidence that lesions in the limbic system are associated with the presence of anxiety in PwMS. This relationship warrants further investigation., Competing Interests: Declaration of Competing Interest Alexandra Hillyer received one time stipend from American Academy of Neurology for this research. Ravi Menon received research support from Siemens Healthineers. Dr. Sarah A. Morrow, in the past 3 years, has served on advisory boards for Biogen Idec, Celgene/BMS, EMD Serono, Novartis, Roche, Sanofi Genzyme, Teva Neurosciences; Received Investigator Initiated Grant Funds from Biogen Idec, Novartis, Roche, Sanofi Genzyme and acted as site PI for multi-center trials funded by AbbVie, Novartis, Genzyme, Roche, Sanofi Genzyme. All other authors have no disclosures to report., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Persons with multiple sclerosis (PwMS) commonly experience cognitive fatigue (CF), defined as a decrease in cognitive performance with sustained activity, yet CF remains understudied. Further, the relationship between subjective CF and objective CF, or cognitive fatiguability, has not been fully elucidated in previous studies. Understanding the predictors of cognitive fatigue may scaffold the development of interventions that target this symptom. The objective of this prospective study was to evaluate the extent to which depression, anxiety, information processing speed, and sleep quality predict subjective and objective CF., Methods: PwMS were recruited from one academic MS clinic in London (ON) Canada. Objective CF was measured by the Paced Auditory Serial Addition Test (PASAT), where performance on the last third of the PASAT is compared to performance on the 1st third, a validated measurement of objective CF. Subjective CF was measured by the cognitive component of the Modified Fatigue Impact Scale (MFIS). Additionally, depression, anxiety, information processing speed, and sleep quality data was collected. All assessments took place on the same day. Pearson's r was calculated to examine the relationship among all continuous outcome measures while linear regression analyses were used to examine predictors of subjective and objective CF., Results: The sample consisted of 53 subjects who were mostly female (37; 69.8%) with a mean age of 44.2 years; the majority (47; 88.7%) had relapsing MS. Objective CF and subjective CF were not significantly related (r = - 0.16). Further, there was no statistically significant predictors of objective CF noted. In contrast, subjective CF demonstrated a statistically significant relationship with the Symbol Digit Modalities Test (SDMT; r = - 0.29, p = .05), Hospital Anxiety and Depression Scale (HADS), depression subscale (r = 0.61, p < .001), HADS anxiety subscale (r = 0.54, p < .001), and sleep quality (r = 0.33, p = .02). Additionally, all variables predicted subjective CF, R 2 adj  = 0.384 [F (6, 40) = 5.783, p = .0002]. In particular, anxiety significantly predicted subjective CF when controlling for depression, information speed, and sleep quality., Conclusion: This study demonstrated that subjective CF is significantly predicted by anxiety, and strongly influenced by information processing impairment and depression. Addressing underlying affective factors, such as anxiety or depression, may help alleviate perceived or subjective CF among PwMS, thus improving their function and quality of life. Further studies with a larger sample size or longitudinal follow up may help define predictors of objective CF., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Relapsing MS (RMS) is a lifelong disease without a cure, usually diagnosed between 20-40 years of age. Being newly diagnosed with RMS is a highly stressful event due to the unpredictable disease course after diagnosis. Thus, it is imperative that persons with MS have the skills and support to cope with the negative physical and emotional effects of the disease. The objective of this study was to assess whether a mindfulness-based intervention (MBI) would improve coping skills and thus lessen the negative consequences of stress due to being newly diagnosed with RMS., Methods: This was a single-blind (assessor), randomized, prospective study of a 10-week MBI vs. usual standard of care in persons newly diagnosed (within 1 year) with RMS, recruited from one tertiary care MS clinic in London (ON), Canada. The MBI was administered in group format with a trained MBI facilitator. Primary outcomes included the Brief COPE measure and the Hospital Anxiety and Depression Scale (HADS) subscales. Secondary outcomes included measures of perceived stress, cognitive function, fatigue, and quality of life. Exploratory (tertiary) outcomes included serum markers of inflammation and stress. Subjects were assessed at baseline, post intervention (or equivalent) and 6 months later. A repeated measures multivariate analysis of covariance (MANCOVA) was used, with baseline scores employed as covariates and the test scores, to compare longitudinal changes, immediately after the MBI sessions and 6 months later., Results: Twenty-five subjects were recruited (16 MBI, 9 controls) for two (Fall and Spring) MBI interventions over 1.5 years. All controls completed the study, while 4 MBI participants did not, leaving 21 subjects in the analysis. Most were women (17, 81%), with a mean age of 37.1 ± 9.4 years. Two thirds had already started a DMT at the time of consent; the median EDSS was 2.0 (0.0-4.0). The groups were well matched on baseline characteristics, with the exception of months since diagnosis (MBI 6.4 ± 6.5 vs. control 3.6 ± 2.8, p=0.023). All controls completed the study, while 4 MBI participants did not. The MBI group improved significantly on the COPE measure when compared to the control group (p=0.024) pre and post intervention; the MBI group also improved significantly on the HADS depression subscale (p=0.007). There was no significant difference over time on the HADS anxiety subscale (p=0.179). The effect size on COPE was 0.56 and 0.40 on HADS-D. On the secondary outcomes, there was a significant improvement on the Perceived Stress Scale (p=0.015). The exploratory outcomes were not significantly different. None of the outcomes were significant at the six-month follow-up., Conclusion: This pilot study demonstrates that an MBI may improve coping, depression and perceived stress in newly diagnosed (within one year) persons with RMS in the short term. Future research to confirm these results, as well as further investigate measures to extend the benefit beyond the immediate intervention., (Copyright © 2021. Published by Elsevier B.V.)

Background: Cognitive deficits, especially in attention, are common in persons with MS (PwMS) and are associated with clinically meaningful outcomes, such as work disability and lower quality of life (QOL). In this study, we aimed to determine whether Cogmed Working Memory Training (CWMT) improves attention/working memory in PwMS displaying impairment in these domains., Methods: This single blind, randomized controlled, pilot study compared the effects of CWMT, a five-week evidenced-based computer-assisted training program that is supported by weekly meetings with a coach, to standard medical care (treatment as usual). We recruited PwMS from one MS center (London (ON) Canada), aged 18-64, with an Expanded Disability Status Scale (EDSS) score of ≤ 7.0, and a visual acuity (corrected) of at least 20/70. Potential subjects had to demonstrate impaired attention on at least two of three measures (Paced Auditory Serial Addition Test [PASAT], Symbol Digit Modalities Test [SDMT], and/or DKEFS Color-Word Interference Test); these measures also served as the primary study outcomes. Subjects were randomized to either the CWMT or treatment as usual. Secondary cognitive outcomes included other measures of attention, memory, as well as a self-reported cognitive function measure. Self-reported measures of mood (depression and anxiety), pain, and QOL were also included as other secondary outcomes. Subjects received assessments at baseline, post-treatment, and 6-month follow-up, or an equivalent time period for the treatment as usual group. The two groups were compared at baseline on background measures using independent samples t-tests, Chi-Square tests, and Mann-Whitney U tests. To analyze primary and secondary outcomes, a non-parametric approach was used due the small sample size and that many of our outcomes did not meet assumptions for parametric analyses. Friedman's test was conducted followed by post hoc pairwise comparisons within each group using Wilcoxon Signed-Rank tests with Bonferroni corrected post hoc contrasts, which allowed us to examine for differences between time points., Results: Of 30 subjects, 15 were assigned to CWMT. Significant training effects were noted in 1 of 3 primary attentional outcomes (DKEFS Color-Word Interference Test), 2 of 3 secondary attentional outcomes (Letter-Number Sequencing, Digit Span), and 1 mood scale (Hospital Anxiety and Depression scale (HADS) - Depression Subscale), ps < .025. No significant changes were observed in the treatment as usual group., Conclusion: This pilot study demonstrates that cognitive training with CWMT has the potential to improve attention/working memory in PwMS, as well as a potential positive effect on mood, in PwMS. Further exploration of this intervention in PwMS with attention/working memory impairment is warranted., (Copyright © 2021. Published by Elsevier B.V.)

Background: Multiple Sclerosis (MS) is a common cause of neurological disability in young to middle-aged adults, resulting in physical, psychosocial, and cognitive impairments. Manifestation of these symptoms during crucial work-life years can greatly influence the ability of persons with (PwMS) to retain employment. It is unknown what factors are most important in leading to work disability, and if/how these different factors interact with each other and result in work disability., Objective: To determine significant predictors of vocational status among PwMS using a structural equation modeling approach., Methods: A retrospective chart review identified PwMS at an academic tertiary care hospital. The following data was collected: demographics and disease characteristics, vocational status, physical disability status (Expanded Disability Status Scale, EDSS), fine motor function (Nine Hole Peg Test, NHPT), generalized fatigue (Fatigue Severity Scale, FSS), mood and anxiety symptoms (Hospital Anxiety and Depression Scale, HADS) and cognitive function (Symbol Digit Modalities Test, SDMT). An exploratory structural equation model (SEM) was developed to examine the predictive utility of clinical and psychosocial variables on vocational status after controlling for demographic and disease characteristics. The fit of the model to the data was examined using the comparative fit index (CFI), normal fit index (NFI), root-mean-squared error of approximation (RMSEA), and standardized root mean residual (SRMR)., Results: There were 158 PwMS included in the analysis. The final model demonstrated that SDMT (β = 0.16), EDSS (β = -0.33), and HADS-D (β = -0.23) significantly predicted vocational status (ps < 0.05). It explained 37% of the variance and provided a good fit to the data (χ 2 (11) = 13.01, p > 0.05, SRMR = 0.055, RMSEA = 0.034, NFI = 0.94, CFI = 0.99., Conclusions: Physical disability, depressive symptoms, and reduced information processing affect work-related disability and vocational status among PwMS. Interventions targeting these factors should be prioritized by clinicians., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Cognitive fatigue (CF) is a common complaint in persons with MS (PwMS). Fampridine-SR improves ambulation, fatigue and endurance, due to enhancing action potential formation by blocking potassium channels in demyelinated axons. Thus, through this same mechanism, it is hypothesized that Fampridine-SR could improve CF., Objective: To determine if Fampridine-SR objectively improves CF in PwMS., Methods: Sixty PwMS of any type with CF, defined as 3 or less correct responses when comparing the last third to the first third on the Paced Auditory Serial Addition Test (PASAT), were recruited from a tertiary care MS clinic in London (ON) Canada. Subjects also had to be between 18 and 64 years of age, inclusive, not had a relapse in the last 60 days or corticosteroids in the last 30 days, EDSS 0.0-7.0, and no other diagnosis that could cause cognitive impairment. A randomized double blind crossover design was used: subjects were randomized to either placebo or Fampridine-SR for 4 weeks, then after at least a one week washout, received the opposite treatment. Subjects were assessed before and after each treatment block. The primary outcome was the PASAT CF score after treatment with Fampridine-SR compared to placebo. T-tests and chi-square were used to compare demographics between the two groups (placebo-Fampridine-SR vs. Fampridine SR-placebo). Treatment effects were assessed using factorial ANOVA, with treatment (Fampridine-SR vs. placebo) and time (before and after treatment) as within-subject variables., Results: Of the 60 subjects randomized, 48 completed the study; three were removed due to an adverse event while in the treatment arm (one due to relapse while on placebo, one due to urinary retention and one due to dizziness and headache while on Fampridine-SR). The subjects had a mean age of 46.5±10.0 years, education of 13.6±1.9 years, and were diagnosed with MS 10.6±9.6 years ago. The majority were female (46, 76.7%), had relapsing remitting MS (41, 68.3%) with median EDSS of 3.5 (range 1.0-7.0). There were no significant demographic differences between the two groups. The treatment x time interaction within the factorial ANOVA on PASAT CF scores was statistically significant, F(1, 45)=8.28, p=0.006, suggesting there is a difference between the treatments (placebo vs. Fampridine-SR), over the course of the study. An evaluation of the mean scores suggests, however, that subjects saw a greater improvement when they were given the placebo, than when they were given the active medication. Similarly, individuals showed a greater increase in their information processing speed (as measured by the PASAT) over the course of treatment when they were given the placebo, as compared with the active medication F(1,45)=4.17, p=0.047., Conclusion: Although this small pilot study does not suggest that Fampridine-SR results in a statistically significant improvement of CF in MS patients, as compared to placebo, individuals demonstrated an improvement in both information processing speed and CF, suggesting further studies are warranted., (Copyright © 2016 Elsevier B.V. All rights reserved.)